BACKGROUND: Patients with cancer often endure substantial symptoms and treatment toxicities leading to high healthcare utilization, including hospitalizations and emergency department visits, throughout the continuum of their illness. Innovative oncology care models are needed to improve patient outcomes and reduce their healthcare utilization. Using a novel hospital at home care platform, we developed a Supportive Oncology Care at Home intervention to address the needs of patients with cancer. METHODS: We are conducting three trials to delineate the role of Supportive Oncology Care at Home for patients with cancer. The Supportive Oncology Care at Home intervention includes: (1) a hospital at home care model for symptom assessment and management; (2) remote monitoring of daily patient-reported symptoms, vital signs, and body weight; and (3) structured communication with the oncology team. Our first study is a randomized controlled trial to test the efficacy of Supportive Oncology Care at Home versus standard oncology care for improving healthcare utilization, cancer treatment interruptions, and patient-reported outcomes in patients with cancer receiving definitive treatment of their cancer. Participants include adult patients with gastrointestinal and head and neck cancer, as well as lymphoma, receiving definitive treatment (e.g., treatment with curative intent). The second study is a single-arm trial assessing the feasibility and acceptability of the Supportive Oncology Care at Home intervention for hospitalized patients with advanced cancer. Eligible participants include adult patients with incurable cancer who are admitted with an unplanned hospitalization. The third study is a single-arm trial assessing the feasibility and acceptability of the Supportive Oncology Care at Home intervention to enhance the end-of-life care for patients with advanced hematologic malignancies. Eligible participants include adult patients with relapsed or refractory hematologic malignancy receiving palliative therapy or supportive care alone. DISCUSSION: These studies are approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board and are being conducted in accordance with the Consolidated Standards of Reporting Trials statement for non-pharmacological trials. This work has the potential to transform the paradigm of care for patients with cancer by providing them with the necessary support at home to improve their health outcomes and care delivery. TRIAL REGISTRATIONS: NCT04544046, NCT04637035, NCT04690205.

BACKGROUND: Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers of tumour invasion. Invadopodia formation has been observed in-vitro and in-vivo in numerous metastatic cell lines derived from multiple tumour types. However, prostate cancer cell lines have not been routinely reported to generate invadopodia and the few instances have always required external stimulation. METHODS: In this study, the invasive potential of primary prostate adenocarcinoma cell lines, which have never been fully characterised before, was investigated both in-vitro invadopodia assays and in-vivo zebrafish dissemination assay. Subsequently, circulating tumour cells from prostate cancer patients were isolated and tested in the invadopodia assay. RESULTS: Retention of E-cadherin and N-cadherin expression indicated a transitional state of EMT progression, consistent with the idea of partial EMT that has been frequently observed in aggressive prostate cancer. All cell lines tested were capable of spontaneous invadopodia formation and possess a significant degradative ability in-vitro under basal conditions. These cell lines were invasive in-vivo and produced visible metastasis in the zebrafish dissemination assay. Importantly we have proceeded to demonstrate that circulating tumour cells isolated from prostate cancer patients exhibit invadopodia-like structures and degrade matrix with visible puncta. This work supports a role for invadopodia activity as one of the mechanisms of dissemination employed by prostate cancer cells. CONCLUSION: The combination of studies presented here provide clear evidence that invadopodia activity can play a role in prostate cancer progression.

PURPOSE: The phase 3 ATTRACTION-2 study demonstrated that nivolumab monotherapy improved survival compared to placebo in patients with pretreated advanced gastric cancer (AGC). However, the efficacy of nivolumab seems to be limited to a subset of patients. MATERIALS AND METHODS: The predictive values of blood neutrophil-lymphocyte ratio (NLR), serum Na, PD-L1 expression, MSI status, tumor EBV infection, and tumor mutation burden (TMB) were investigated in patients with AGC refractory to ≥2 lines of chemotherapy enrolled from Asan Medical Center in ATTRACTION-2 study. RESULTS: All 45 patients were analyzed; nivolumab (n = 28) and placebo (n = 17) groups. The objective response rate, median progression-free survival (PFS), and overall survival (OS) were 16.7%, 1.6 months, and 8.1 months in nivolumab group and 0%, 1.6 months and 6.5 months in placebo group. When comparing nivolumab with the placebo group, tumor PD-L1 expression, blood NLR, and serum Na were significant predictive factors of PFS and OS. A multivariate analysis revealed that PD-L1 ( +) and low NLR (≤ 2.9, median) were associated with better PFS. In the nivolumab group, PD-L1 ( +), low NLR, and normal Na (≥ 135 mmol/L) were associated with higher response and disease control rates, while tumor EBV infection and TMB were not. CONCLUSION: Tumor PD-L1 expression, blood NLR, and serum Na could be predictive biomarkers for the efficacy of nivolumab in previously treated cases of AGC.

BACKGROUND: Little is known about whether age at initial diagnosis influences the prognosis of recurrent metastatic breast cancer (rMBC). Here, we analyzed the association between age at initial diagnosis and rMBC mortality in China. METHODS: A total of 1636 women diagnosed with rMBC between 1989 and 2020 at West China Hospital, Sichuan University were included in this study. The age at initial diagnosis was categorized as young (≤ 40 years), middle-aged (41-64 years) and elderly (≥ 65 years). Post-metastasis mortality was the primary outcome and its associated factors were analyzed by Cox proportional hazards models. RESULTS: During a median follow-up of 5.2 years after initial diagnosis of breast cancer, 620 deaths were identified. Compared with middle-aged patients, elderly patients had a 70% increased risk of post-metastasis mortality (95%CI, 1.24-2.33) after adjusting for demographics, tumor characteristics and treatment modes. Similarly, elderly patients were associated with a 75% increased risk of post-metastasis mortality (95%CI, 1.19-2.59) compared with young patients. Subgroup analyses also showed similar trends. CONCLUSION: Our findings suggest that in breast cancer, elderly patients at initial diagnosis face a higher risk of post-metastasis mortality.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child-Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child-Pugh B cirrhosis at Week 8. METHODS: This was a retrospective analysis of adult patients with previously treated advanced HCC. Child-Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo. RESULTS: Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child-Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child-Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18-0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25-0.76), and best response was stable disease in 57% versus 23% of patients. CONCLUSIONS: These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child-Pugh B liver function. CLINICAL TRIAL REGISTRATION: NCT01908426.

BACKGROUND: The accuracy of CT and tumour markers in screening lung cancer needs to be improved. Computer-aided diagnosis has been reported to effectively improve the diagnostic accuracy of imaging data, and recent studies have shown that circulating genetically abnormal cell (CAC) has the potential to become a novel marker of lung cancer. The purpose of this research is explore new ways of lung cancer screening. METHODS: From May 2020 to April 2021, patients with pulmonary nodules who had received CAC examination within one week before surgery or biopsy at First Affiliated Hospital of Zhengzhou University were enrolled. CAC counts, CT scan images, serum tumour marker (CEA, CYFRA21-1, NSE) levels and demographic characteristics of the patients were collected for analysis. CT were uploaded to the Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) to assess the malignancy probability of nodules. We compared diagnosis based on PNAIDS, CAC, Mayo Clinic Model, tumour markers alone and their combination. The combination models were built through logistic regression, and was compared through the area under (AUC) the ROC curve. RESULTS: A total of 93 of 111 patients were included. The AUC of PNAIDS was 0.696, which increased to 0.847 when combined with CAC. The sensitivity (SE), specificity (SP), and positive (PPV) and negative (NPV) predictive values of the combined model were 61.0%, 94.1%, 94.7% and 58.2%, respectively. In addition, we evaluated the diagnostic value of CAC, which showed an AUC of 0.779, an SE of 76.3%, an SP of 64.7%, a PPV of 78.9%, and an NPV of 61.1%, higher than those of any single serum tumour marker and Mayo Clinic Model. The combination of PNAIDS and CAC exhibited significantly higher AUC values than the PNAIDS (P = 0.009) or the CAC (P = 0.047) indicator alone. However, including additional tumour markers did not significantly alter the performance of CAC and PNAIDS. CONCLUSIONS: CAC had a higher diagnostic value than traditional tumour markers in early-stage lung cancer and a supportive value for PNAIDS in the diagnosis of cancer based on lung nodules. The results of this study offer a new mode of screening for early-stage lung cancer using lung nodules.

BACKGROUND: Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS). METHODS: A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS. RESULTS: Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193). CONCLUSIONS: To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy. HIGHLIGHTS: • We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third-most deadly cancer worldwide. More breakthroughs are needed in the clinical practice for liver cancer are needed, and new treatment strategies are required. This study aims to determine the significant differences in genes associated with LIHC and further analyze its prognostic value further. METHODS: Here, we used the TCGA-LIHC database and the profiles of GSE25097 from GEO to explore the differentially co-expressed genes in HCC tissues compared with paratumor (or healthy) tissues. Then, we utilized WGCNA to screen differentially co-expressed genes. Finally, we explored the function of FYN in HCC cells and xenograft tumor models. RESULTS: We identified ten hub genes in the protein-protein interaction (PPI) network, but only three (COLEC10, TGFBR3, and FYN) appeared closely related to the prognosis. The expression of FYN was positively correlated with the prognosis of HCC patients. The xenograft model showed that overexpression of FYN could significantly inhibit malignant tumor behaviors and promote tumor cell apoptosis. CONCLUSION: Thus, FYN may be central to the development of LIHC and maybe a novel biomarker for clinical diagnosis and treatment.

BACKGROUND: A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. METHODS: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. DISCUSSION: The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04934982 , Registered on 22 June 2021).

BACKGROUND: The combined application of immune cells and specific biomarkers related to the tumor immune microenvironment has a better predictive value for the prognosis of HCC. The purpose of this study is to construct a new prognostic model based on immune-related genes that regulate cross-talk between immune and tumor cells to assess the prognosis and explore possible mechanisms. METHOD: The immune cell abundance ratio of 424 cases in the TCGA-LIHC database is obtained through the CIBERSORT algorithm. The differential gene analysis and cox regression analysis is used to screen IRGs. In addition, the function of IRGs was preliminarily explored through the co-culture of M2 macrophages and HCC cell lines. The clinical validation, nomogram establishment and performing tumor microenvironment score were validated. RESULTS: We identified 4 immune cells and 9 hub genes related to the prognosis. Further, we identified S100A9, CD79B, TNFRSF11B as an IRGs signature, which is verified in the ICGC and GSE76427 database. Importantly, IRGs signature is closely related to the prognosis, tumor microenvironment score, clinical characteristics and immunotherapy, and nomogram combined with clinical characteristics is more conducive to clinical promotion. In addition, after co-culture with M2 macrophages, the migration capacity and cell pseudopod of MHCC97H increased significantly. And CD79B and TNFRSF11B were significantly down-regulated in MHCC97H, Huh7 and LM3, while S100A9 was up-regulated. CONCLUSION: We constructed an IRGs signature and discussed possible mechanisms. The nomogram established based on IRGs can accurately predict the prognosis of HCC patients. These findings may provide a suitable therapeutic target for HCC.

BACKGROUND: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis. METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods. RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results. CONCLUSION: EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.

BACKGROUND: The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered 'low-risk' do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters. METHODS: Classification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees). RESULTS: In patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 - 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57-15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 - 8.72); p = 0.001). CONCLUSION: KCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients.

BACKGROUND: In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. METHODS: Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. RESULTS: In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). CONCLUSIONS: Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.

BACKGROUND: Circular RNAs (circRNAs) modulate gene expression in various malignancies. However, their roles in the occurrence of bladder cancer (BC) and their underlying mechanisms of action are currently unclear. METHODS: We measured levels of the circRNA phenylalanyl-tRNA synthetase subunit alpha (circFARSA) and target microRNAs (miRNAs/miRs) in BC tissues and cell lines using quantitative polymerase chain reactions. The functions of circFARSA in tumor formation were examined in mice with BC xenografts in vivo and in BC cells via determination of their proliferation, activity, apoptosis, metastasis, and invasion in vitro using cell counting kit-8 assays, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, flow cytometry, western blotting, Transwell assays, and cell wound healing assays. Interactions between miR-330 and circFARSA were predicted and confirmed by bioinformatic processing and dual-luciferase reporter gene assays, respectively. Expression profiles of miR-330 targets in BC cells were assessed via western blotting. RESULTS: circFARSA expression was markedly upregulated in BC tissues and cell lines compared with that in normal bladder samples. Silencing circFARSA expression decreased BC cell proliferation, invasion, and migration but induced their apoptosis in vitro. Downregulating circFARSA expression slowed tumor growth in vivo and directly sponged miR-330 and inhibited its function in BC cells in vitro. Inhibiting miR-330 expression abolished the regulatory effects of circFARSA silencing on the tumor phenotypes of BC cells. CONCLUSIONS: circFARSA expression is upregulated and exerts oncogenic functions in BC by sponging miR-330.

BACKGROUND: Studies investigating breast cancer polygenic risk score (PRS) in Chinese women are scarce. The objectives of this study were to develop and validate PRSs that could be used to stratify risk for overall and subtype-specific breast cancer in Chinese women, and to evaluate the performance of a newly proposed Artificial Neural Network (ANN) based approach for PRS construction. METHODS: The PRSs were constructed using the dataset from a genome-wide association study (GWAS) and validated in an independent case-control study. Three approaches, including repeated logistic regression (RLR), logistic ridge regression (LRR) and ANN based approach, were used to build the PRSs for overall and subtype-specific breast cancer based on 24 selected single nucleotide polymorphisms (SNPs). Predictive performance and calibration of the PRSs were evaluated unadjusted and adjusted for Gail-2 model 5-year risk or classical breast cancer risk factors. RESULTS: The primary PRSANN and PRSLRR both showed modest predictive ability for overall breast cancer (odds ratio per interquartile range increase of the PRS in controls [IQ-OR] 1.76 vs 1.58; area under the receiver operator characteristic curve [AUC] 0.601 vs 0.598) and remained to be predictive after adjustment. Although estrogen receptor negative (ER-) breast cancer was poorly predicted by the primary PRSs, the ER- PRSs trained solely on ER- breast cancer cases saw a substantial improvement in predictions of ER- breast cancer. CONCLUSIONS: The 24 SNPs based PRSs can provide additional risk information to help breast cancer risk stratification in the general population of China. The newly proposed ANN approach for PRS construction has potential to replace the traditional approaches, but more studies are needed to validate and investigate its performance.

BACKGROUND: High-grade and recurrent meningiomas are often treatment resistant and pose a therapeutic challenge after surgical and radiation therapy (RT) failure. Temozolomide (TMZ) is a DNA alkylating agent that appears to have a radiosensitizing effect when used in combination with RT and may be worthwhile in meningioma treatment. Thus, we investigated the potential efficacy of concomitant RT plus TMZ compared to historical controls of just RT used in the treatment of high-grade and recurrent meningiomas. METHODS: We performed a retrospective analysis of patients with meningioma treated at the University of Colorado with TMZ chemoradiation. Progression free survival (PFS) and overall survival (OS) were calculated from the start of chemoradiation to local recurrence or death, respectively. RESULTS: Eleven patients (12 tumors) were treated with chemoradiation with a median follow-up of 41.5 months. There were two WHO grade 1, eight grade 2 and two grade 3 meningiomas. Three patients died during the follow-up period-one being disease related (11.1%). Two patients had meningioma recurrence-at 2.3 months (WHO grade 3), and 5.4 years (WHO grade 2). Three-year OS and PFS for grade 2 meningiomas were each 88%. Historical controls demonstrate a 3-year median OS and PFS of 83% and 75.8%, respectively. CONCLUSIONS: Treatment options are limited for meningiomas after local failure. In this study, TMZ chemoradiation demonstrated no significant difference in PFS and OS in the treatment of grade 2 meningiomas compared to historic controls. Further study is warranted to find novel methods for the treatment of malignant and recurrent meningiomas.

BACKGROUND: Toxicity during chemoradiotherapy (CRT) in cervical cancer patients might limit the chances of receiving an optimal treatment and to be cured. Few studies have shown relationships between acute side effects and patient's age. Here, the association between age and acute side effects such as nausea/vomiting, diarrhea and weight loss during CRT was analysed in cervical cancer patients. METHODS: This study included 93 patients with primary cervical cancer stage IBI to IVA who received CRT from 2013 to 2019. The frequency of symptoms/toxicity grade was analysed by using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Patients ≥ 52 years had a significantly higher frequency of nausea/vomiting and increased grade ≥ 3 toxicity during CRT compared to younger patients (p < 0.001, p = 0.001). Toxicity grade ≥ 3 of nausea/vomiting was associated with increased frequency of weight loss (p = 0.001), reduced ADL (p = 0.001) and dose modifications of both radiotherapy (RT) (p = 0.020) and chemotherapy (CT) (p = 0.030) compared to toxicity grade 2. The frequency of diarrhea (p = 0.015) and weight loss (p = 0.020) was higher in older patients compared to younger. CONCLUSIONS: Older patients have an increased risk of acute side effects as nausea/vomiting, diarrhea and weight loss. Age could be useful in predicting acute side effects in primary cervical cancer patients with CRT.

BACKGROUND: The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. Here, we aimed to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations. METHODS: We followed 3 patients with resectable disease and 4 patients with unresectable disease, including 4 patients with ≥ 3 serial follow-up samples, of whom 2 were rare long survivors (> 5 years). We performed whole exome sequencing of tumour gDNA and plasma ctDNA (n = 20) collected over a ~ 2-year period from diagnosis through treatment to death or final follow-up. Plasma from 3 chronic pancreatitis cases was used as a comparison for analysis of ctDNA mutations. RESULTS: We detected > 55% concordance between somatic mutations in tumour tissues and matched serial plasma. Mutations in ctDNA were detected within known PDAC driver genes (KRAS, TP53, SMAD4, CDKN2A), in addition to patient-specific variants within alternative cancer drivers (NRAS, HRAS, MTOR, ERBB2, EGFR, PBRM1), with a trend towards higher overall mutation loads in advanced disease. ctDNA alterations with potential for therapeutic actionability were identified in all 7 patients, including DNA damage response (DDR) variants co-occurring with hypermutation signatures predictive of response to platinum chemotherapy. Longitudinal tracking in 4 patients with follow-up > 2 years demonstrated that ctDNA mutant allele fractions and clonal trends were consistent with CA19-9 measurements and/or clinically reported disease burden. The estimated prevalence of 'stem clones' was highest in an unresectable patient where changes in ctDNA dynamics preceded CA19-9 levels. Longitudinal evolutionary trajectories revealed ongoing subclonal evolution following chemotherapy. CONCLUSION: These results provide proof-of-concept for the use of exome sequencing of serial plasma to characterise patient-specific ctDNA profiles, and demonstrate the sensitivity of ctDNA in monitoring disease burden in PDAC even in unresectable cases without matched tumour genotyping. They reveal the value of tracking clonal evolution in serial ctDNA to monitor treatment response, establishing the potential of applied precision medicine to guide stratified care by identifying and evaluating actionable opportunities for intervention aimed at optimising patient outcomes for an otherwise intractable disease.

BACKGROUND: T-cell immunoglobulin mucin-1 (TIM-1) has been reported to be associated with the biological behavior of several malignant tumors; however, it is not clear whether it has a role in cervical cancer (CC). METHODS: TIM-1 expression in cervical epithelial tumor tissues and cells was detected by immunohistochemistry or real-time quantitative-PCR and western blotting. CC cells from cell lines expressing low levels of TIM-1 were infected with lentiviral vectors encoding TIM-1. Changes in the malignant behavior of CC cells were assessed by CCK-8, wound healing, Transwell migration and invasion assays, and flow cytometry in vitro; while a xenograft tumor model was established to analyze the effects of TIM-1 on tumor growth in vivo. Changes in the levels of proteins related to the cell cycle, apoptosis, and Epithelial-mesenchymal transition (EMT) were determined by western blotting. RESULTS: TIM-1 expression was higher in CC tissues, than in high grade squamous intraepithelial lesion, low grade squamous intraepithelial lesion, or normal cervical tissues, and was also expressed in three CC cell lines. In HeLa and SiHa cells overexpressing TIM-1, proliferation, invasion, and migration increased, while whereas apoptosis was inhibited. Furthermore, TIM-1 downregulated the expression of p53, BAX, and E-cadherin, and increased cyclin D1, Bcl-2, Snail1, N-cadherin, vimentin, MMP-2, and VEGF. PI3K, p-AKT, and mTOR protein levels also increased, while total AKT protein levels remained unchanged. CONCLUSIONS: Our study indicated that TIM-1 overexpression promoted cell migration and invasion, and inhibited cell apoptosis in CC through modulation of the PI3K/AKT/p53 and PI3K/AKT/mTOR signaling pathways, and may be a candidate diagnostic biomarker of this disease.

PURPOSE: This study aimed to evaluate the utility of inflammation-based prognostic scores (IBPS) and systemic immune-inflammation index (SII) in the treatment of oral cancer patients. METHODS: For the 183 patients enrolled in this study, IBPS and SII were calculated from peripheral blood samples obtained before and after treatment and at the time of relapse. We examined overall survival (OS) and disease-free survival (DFS) using previously reported cut-off values for IBPS. Cut-off values of neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) were analyzed as NLR 1.79, PLR 114.97, LMR 5, and PNI 52.44. The cut-off value for SII was set at 569. OS and DFS were analyzed by Kaplan-Meier methods using the cutoff of each IBPS and SII. Univariate analysis and multivariate analysis using Cox proportional hazards were performed for OS and DFS. RESULTS: Kaplan-Meier methods showed the high-PNI group showed good prognosis including OS and DFS, while the high-SII group displayed poor DFS. Univariate analysis showed that pre-treatment high PNI and low SII were significantly associated with better prognosis. Multivariate analysis identified pre-treatment PNI as independently associated with OS. For DFS, univariate analysis using Cox proportional hazards modeling showed that pre-treatment high NLR and high SII were significantly associated with worse prognosis, while high PNI was significantly associated with better prognosis. Multivariate analysis identified pre-treatment PNI and SII as independently associated with DFS. Parameters of PNI and SII components were compared between pre-treatment, post-treatment and at relapse in the high- and low-PNI groups. PNI was predominantly decreased in both high- and low-PNI groups at post-treatment and at relapse compared to pre-treatment. This trend was also observed for albumin. CONCLUSIONS: Higher pre-treatment PNI was associated with better OS, while lower pre-treatment PNI and higher treatment SII were associated with poorer DFS in oral cancer patients. Our data indicated that PNI and SII might offer useful biomarkers for gauging prognosis and the efficacy of conventional therapies.

Erratum in BMC Cancer. 2022 Apr 28;22(1):467.

OBJECTIVE: N6-methyladenosine (m6A) mRNA modification triggers malignant behaviors of tumor cells and thereby drives malignant progression in gastric cancer (GC). However, data regarding the prognostic values of m6A RNA methylation-related long non-coding RNAs (lncRNAs) in GC are very limited in the literature. We aimed to investigate the prognostic potential of m6A-related lncRNAs in predicting prognosis and monitoring immunotherapy efficacy in GC patients. METHODS: Transcriptome and clinical data were obtained from GC biopsies from Cancer Genome Atlas (TCGA). M6A-related lncRNAs associated with GC were identified by constructing a co-expression network, and the gene pairs differentially expressed in GC were selected using univariate analysis. We constructed a risk model based on prognosis-related lncRNA pairs selected using the LASSO algorithm and quantified the best cutoff by comparing the area under the curve (AUC) for risk stratification. A risk model with the optimal discrimination between high- and low-risk GC patients was established. Its feasibility for overall survival prediction and discrimination of clinicopathological features, tumor-infiltrating immune cells, and biomarkers of immune checkpoint inhibitors between high- and low-risk groups were assessed. RESULTS: Finally, we identified 11 m6A-related lncRNA pairs associated with GC prognosis based on transcriptome analysis of 375 GC specimens and 32 normal tissues. A risk model was constructed with an AUC of 0.8790. We stratified GC patients into high- and low-risk groups at a cutoff of 1.442. As expected, patients in the low-risk group had longer overall survival versus the high-risk group. Infiltration of cancer-associated fibroblasts, endothelial cells, macrophages, particularly M2 macrophages, and monocytes was more severe in high-risk patients than low-risk individuals, who exhibited high CD4+ Th1 cell infiltration in GC. Altered expressions of immune-related genes were observed in both groups. PD-1 and LAG3 expressions were found higher in low-risk patients than high-risk patients. Immunotherapy, either single or combined use of PD-1 or CTLA4 inhibitors, had better efficacy in low-risk patients than high-risk patients. CONCLUSION: The new risk model based on a 11-m6A-related lncRNA signature can serve as an independent predictor for GC prognosis prediction and may aid in the development of personalized immunotherapy strategies for patients.

BACKGROUND: In clinical practice, the effect of durvalumab and radiation pneumonitis (RP) on survival after intensity-modulated radiotherapy (IMRT) is not fully understood. The purpose of this retrospective study was to investigate factors related to distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) after IMRT for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: All patients who were treated with conventional fractionated IMRT for LA-NSCLC between April 2016 and March 2021 were eligible. Time-to-event data were assessed by using the Kaplan-Meier estimator, and the Cox proportional hazards model was used for prognostic factor analyses. Factors that emerged after the start of IMRT, such as durvalumab administration or the development of RP, were analysed as time-dependent covariates. RESULTS: A total of 68 consecutive patients treated with conventional fractionated IMRT for LA-NSCLC were analysed. Sixty-six patients completed radiotherapy, 50 patients received concurrent chemotherapy, and 36 patients received adjuvant durvalumab. During the median follow-up period of 14.3 months, 23 patients died, and tumour progression occurred in 37 patients, including 28 patients with distant metastases. The 1-year DMFS rate, PFS rate and OS rate were 59.9%, 48.7% and 84.2%, respectively. Grade 2 RP occurred in 16 patients, grade 3 in 6 patients and grade 5 in 1 patient. The 1-year cumulative incidences of grade 2 or higher RP and grade 3 or higher RP were 33.8% and 10.3%, respectively. The results of multivariate analyses showed that durvalumab had a significantly lower hazard ratio (HR) for DMFS, PFS and OS (HR 0.31, p < 0.01; HR 0.33, p < 0.01 and HR 0.32, p = 0.02), respectively. Grade 2 or higher RP showed significance for DMFS and a nonsignificant trend for OS (HR 2.28, p = 0.04 and HR 2.12, p = 0.13), respectively, whereas a higher percentage of lung volume receiving 20 Gy or higher was significant for PFS (HR 2.25, p = 0.01). CONCLUSIONS: In clinical practice, durvalumab administration following IMRT with concomitant chemotherapy showed a significant survival benefit. Reducing the risk of grade 2 or higher RP would also be beneficial.

OBJECTIVE: Cervical microbial community in the cervical intraepithelial neoplasia and cervical cancer patients was analysed to study its composition, diversity and signalling pathways by high-throughput 16S rDNA sequencing,and the candidate genes associated with occurrence and progression of cervical intraepithelial neoplasia were screened out and the model was established to predict the evolution of cervical intraepithelial neoplasia malignant transformation from the cervical microbial genes aspect. METHODS: Cervical tissues of normal, cervical intraepithelial neoplasia and cervical cancer patients without receiving any treatment were collected. The correlation between candidate genes and cervical intraepithelial neoplasia progression was initially determined by analyzing the microbial flora. Real-time fluorescence quantitative PCR was used to detect the expression of candidate genes in different cervical tissues, ROC curve and logistic regression was used to analyse and predict the risk factors related to the occurrence and progression of cervical intraepithelial neoplasia. Finally, the early warning model of cervical intraepithelial neoplasia occurrence and progression is established. RESULTS: Cervical tissues from normal, cervical intraepithelial neoplasia and cervical cancer patients were collected for microbial community high-throughput 16S rDNA sequencing. The analysis revealed five different pathways related to cervical intraepithelial neoplasia. 10 candidate genes were selected by further bioinformatics analysis and preliminary screening. Real time PCR, ROC curve and Logistic regression analysis showed that human papillomavirus infection, TCT severity, ABCG2, TDG, PCNA were independent risk factors for cervical intraepithelial neoplasia. We used these indicators to establish a random forest model. Seven models were built through different combinations. The model 4 (ABCG2 + PCNA + TDG) was the best early warning model for the occurrence and progression of CIN. CONCLUSIONS: A total of 5 differential pathways and 10 candidate genes related to occurrence and progression of cervical intraepithelial neoplasia were found in cervical microbial community. This study firstly identified the genes from cervical microbial community that play an important role in the occurrence and progression of cervical intraepithelial neoplasia. At the same time, the early warning model including ABCG2 + PCNA+TDG genes provided a new idea and target for clinical prediction and blocking the evolution of cervical intraepithelial neoplasia malignant transformation from the aspect of cervical microbiological related genes.

Radio-chemotherapy with 5-flu orouracil (5-FU) is the standard of care treatment for patients with colorectal cancer, but it is only effective for a third of them. Despite our understanding of the mechanism of action of 5-FU, drug resistance remains a significant limitation to the clinical use of 5-FU, as both intrinsic and acquired chemoresistance represents the major obstacles for the success of 5-FU-based chemotherapy. In order to identify the mechanism of acquired resistance, 5-FU chemoresistance was induced in CRC cell lines by passaging cells with increasing concentrations of 5-FU. To study global molecular changes, quantitative proteomics and transcriptomics analyses were performed on these cell lines, comparing the resistant cells as well as the effect of chemo and radiotherapy. Interestingly, a very high proportion of downregulated genes were annotated as transcription factors coding for Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter were downregulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. To confirm the observations of the proteomic and transcriptomic approaches, the abundance of 20 different KZFPs and control mRNAs was validated by RT-qPCR. In fact, several KZFPs were no longer detectable using qPCR in cell lines resistant to 5-FU, and the KZFPs that were downregulated only in one or two cell lines showed similar pattern of expression as measured by the omics approaches. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights a possible new mechanism involved in the cellular adaptation to 5-FU and therefore identifies potential new therapeutic targets to overcome this resistance.

BACKGROUND: Prognostic indicators, treatments, and survival estimates vary by cancer type. Therefore, disease-specific models are needed to estimate patient survival. Our primary aim was to develop models to estimate survival duration after treatment for skeletal-related events (SREs) (symptomatic bone metastasis, including impending or actual pathologic fractures) in men with metastatic bone disease due to prostate cancer. Such disease-specific models could be added to the PATHFx clinical-decision support tool, which is available worldwide, free of charge. Our secondary aim was to determine disease-specific factors that should be included in an international cancer registry. METHODS: We analyzed records of 438 men with metastatic prostate cancer who sustained SREs that required treatment with radiotherapy or surgery from 1989-2017. We developed and validated 6 models for 1-, 2-, 3-, 4-, 5-, and 10-year survival after treatment. Model performance was evaluated using calibration analysis, Brier scores, area under the receiver operator characteristic curve (AUC), and decision curve analysis to determine the models' clinical utility. We characterized the magnitude and direction of model features. RESULTS: The models exhibited acceptable calibration, accuracy (Brier scores < 0.20), and classification ability (AUCs > 0.73). Decision curve analysis determined that all 6 models were suitable for clinical use. The order of feature importance was distinct for each model. In all models, 3 factors were positively associated with survival duration: younger age at metastasis diagnosis, proximal prostate-specific antigen (PSA) < 10 ng/mL, and slow-rising alkaline phosphatase velocity (APV). CONCLUSIONS: We developed models that estimate survival duration in patients with metastatic bone disease due to prostate cancer. These models require external validation but should meanwhile be included in the PATHFx tool. PSA and APV data should be recorded in an international cancer registry.

BACKGROUND: The Lauren classification of gastric tumors strongly correlates with prognosis. The purpose of this study was to explore the specific molecular mechanism of Lauren classification of gastric cancer and provide a possible theoretical basis for the treatment of gastric cancer. METHODS: We standardized the gene expression data of five Gene Expression Omnibus gastric cancer databases and constructed a Weighted Co-expression Network Analysis (WGCNA) model based on clinicopathological information. The overall survival (OS) and disease-free survival (DFS) curves were extracted from the Cancer Genome Atlas (TCGA) and GSE62254 databases. Western blotting was used to measure protein expression in cells and tissues. Scratch and transwell experiments were used to test the migration ability of tumor cells. Immunohistochemistry was used to measure tissue protein expression in clinical tissue samples to correlate to survival data. RESULTS: The WGCNA model demonstrated that blue cyan was highly correlated with the Lauren classification of the tumor (r = 0.24, P = 7 × 1016). A protein-protein interaction network was used to visualize the genes in the blue cyan module. The OS and PFS TCGA analysis revealed that LMOD1 was a gene of interest. The proportion of diffuse gastric cancer patients with high expression of LMOD1 was significantly higher than that of intestinal type patients. LMOD1 promoted the migration of gastric cancer cells by regulating the FAK-Akt/mTOR pathway in vitro. Additionally, a Gene Set Enrichment Analysis using the TCGA and GSE62254 databases, and western blot data, showed that LMOD1 could promote an epithelial-mesenchymal transition (EMT), thus potentially affecting the occurrence of peritoneal metastasis of gastric cancer. Immunohistochemistry showed that LMOD1 was highly expressed in cancer tissues, and the prognosis of patients with high LMOD1 expression was poor. CONCLUSION: LMOD1 is an oncogene associated with diffuse gastric cancer and can affect the occurrence and development of EMT by regulating the FAK-Akt/mTOR pathway. LMOD1 can therefore promote peritoneal metastasis of gastric cancer cells and can be used as a novel therapeutic target for gastric cancer.

BACKGROUND: Social media platforms are increasingly being used by stakeholders to generate, access, and share health-related information and experiences. Lung cancer is the most common cancer, impacting > 2 million patients globally. This observational study utilized a social listening approach to analyze social media trends and gain insights into stakeholder perceptions of lung cancer. METHODS: This social media study retrospectively collated data from open access blogs, forums, and social networking sites. Social media posts were collected between June 2019-May 2020 from 14 European countries. Using social media aggregator tools, posts comprising lung cancer and non-small cell lung cancer-specific terms were extracted. Manual and automated relevancy algorithms filtered the extracted information to provide the relevant dataset. This contextualized dataset was further mined to generate the final data for analysis. RESULTS: Of 1360 conversations analyzed, 42% were generated by patients/caregivers and 14% by healthcare professionals (HCPs). A majority of patients were 51-70 years old (approximately 50%) and 91% (n = 500/550) had late-stage cancer. Treatment (35%) and disease awareness (30%) were among the most discussed topic of the patient journey. Although the overall treatment sentiment was neutral, chemotherapy was the treatment type with the highest associated negative sentiment (28%); fewer negative sentiments were associated with immunotherapy (9%) and targeted therapy (2%), due to perceptions of longer survival outcomes and fewer side effects. In conversations that discussed clinical endpoints, "survivability" and "overall survival" (47 and 30%, respectively; n = 539) were most frequently mentioned by stakeholders. HCPs mostly used technical terms, whereas patients and caregivers used colloquial terms such as "getting rid of cancer". Emotional wellness was identified to have a huge impact on quality of life in lung cancer. Delay or treatment cancellations due to COVID-19, lack of effective treatments and funding, and lack of empathy by physicians emerged as the key unmet needs among patients/caregivers. CONCLUSIONS: Social listening proved to be an effective tool to explore stakeholders' perceptions and their key unmet needs, typically not available in published literature or databases, and provides HCPs with valuable insights into the distress, doubts, and needs of lung cancer patients and caregivers.

BACKGROUND: Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer deaths globally, with late diagnosis, low survival rate, and poor prognosis. This case-control study aimed to evaluate the expression of cystatin B (CSTB) and deleted in malignant brain tumor 1 (DMBT1) in the saliva of GC patients with healthy individuals to construct diagnostic algorithms using statistical analysis and machine learning methods. METHODS: Demographic data, clinical characteristics, and food intake habits of the case and control group were gathered through a standard checklist. Unstimulated whole saliva samples were taken from 31 healthy individuals and 31 GC patients. Through ELISA test and statistical analysis, the expression of salivary CSTB and DMBT1 proteins was evaluated. To construct diagnostic algorithms, we used the machine learning method. RESULTS: The mean salivary expression of CSTB in GC patients was significantly lower (115.55 ± 7.06, p = 0.001), and the mean salivary expression of DMBT1 in GC patients was significantly higher (171.88 ± 39.67, p = 0.002) than the control. Multiple linear regression analysis demonstrated that GC was significantly correlated with high levels of DMBT1 after controlling the effects of age of participants (R2 = 0.20, p < 0.001). Considering salivary CSTB greater than 119.06 ng/mL as an optimal cut-off value, the sensitivity and specificity of CSTB in the diagnosis of GC were 83.87 and 70.97%, respectively. The area under the ROC curve was calculated as 0.728. The optimal cut-off value of DMBT1 for differentiating GC patients from controls was greater than 146.33 ng/mL (sensitivity = 80.65% and specificity = 64.52%). The area under the ROC curve was up to 0.741. As a result of the machine learning method, the area under the receiver-operating characteristic curve for the diagnostic ability of CSTB, DMBT1, demographic data, clinical characteristics, and food intake habits was 0.95. The machine learning model's sensitivity, specificity, and accuracy were 100, 70.8, and 80.5%, respectively. CONCLUSION: Salivary levels of DMBT1 and CSTB may be accurate in diagnosing GCs. Machine learning analyses using salivary biomarkers, demographic, clinical, and nutrition habits data simultaneously could provide affordability models with acceptable accuracy for differentiation of GC by a cost-effective and non-invasive method.

BACKGROUND: Poor cancer prognosis has been observed in patients with pre-existing psychiatric disorders. Therefore, we need better knowledge about the diagnosis of cancer in this patient group. The aim of the study was to describe the routes to cancer diagnosis in patients with pre-existing psychiatric disorders and to analyse how cancer type modified the routes. METHODS: A register-based cohort study was conducted by including patients diagnosed with incident cancer in 2014-2018 (n = 155,851). Information on pre-existing psychiatric disorders was obtained from register data on hospital contacts and prescription medication. Multinomial regression models with marginal means expressed as probabilities were used to assess the association between pre-existing psychiatric disorders and routes to diagnosis. RESULTS: Compared to patients with no psychiatric disorders, the population with a psychiatric disorder had an 8.0% lower probability of being diagnosed through cancer patient pathways initiated in primary care and a 7.6% higher probability of being diagnosed through unplanned admissions. Patients with pre-existing psychiatric disorders diagnosed with rectal, colon, pancreatic, liver or lung cancer and patients with schizophrenia and organic disorders were less often diagnosed through cancer patient pathways initiated in primary care. CONCLUSION: Patients with pre-existing psychiatric disorders were less likely to be diagnosed through Cancer Patient Pathways from primary care. To some extent, this was more pronounced among patients with cancer types that often present with vague or unspecific symptoms and among patients with severe psychiatric disorders. Targeting the routes by which patients with psychiatric disorders are diagnosed, may be one way to improve the prognosis among this group of patients.

BACKGROUND: Scalable, multiple behavior change interventions are needed to address poor diet, inactivity, and excess adiposity among the rising number of cancer survivors. Efficacy-tested diet (RENEW) and exercise (BEAT Cancer) programs were adapted for web delivery among middle-aged and older cancer survivors for the AMPLIFI study, a National Cancer Institute-funded, multi-site, program project. METHODS: Throughout the continental U.S., survivors of several obesity-related cancers are being recruited for three interconnected randomized controlled trials (RCTs). Projects 1 and 2 test 6-month diet or exercise interventions versus a wait-list control condition. Upon completion of the 6-month study period, the intervention participants receive the next behavior change sequence (i.e., diet receives exercise, exercise receives diet) and the wait-list control arm initiates a 12-month combined diet and exercise intervention. Project 3 tests the efficacy of the sequential versus simultaneous interventions. Assessments occur at baseline and semi-annually for up to 2-years and include: body mass index, health behaviors (diet quality, accelerometry-assessed physical activity/sleep), waist circumference, D3 creatine-assessed muscle mass, physical performance, potential mediators/moderators of treatment efficacy, biomarkers of inflammation and metabolic regulation, health care utilization, cost, and overall health. Four shared resources support AMPLIFI RCTs: 1) Administrative; 2) Adaptation, Dissemination and Implementation; 3) Recruitment and Retention; and 4) Assessment and Analysis. DISCUSSION: Representing a new generation of RCTs, AMPLIFI will exclusively use remote technologies to recruit, intervene and assess the efficacy of the newly-adapted, web-based diet and exercise interventions and determine whether sequential or combined delivery works best for at-risk (older, rural, racial minority) cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04000880 . Registered 27 June 2019.

BACKGROUND: We aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients. METHODS: The PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in 'R' package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS. RESULTS: Among the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in 'R' package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan-Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS. CONCLUSIONS: Neutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

BACKGROUND: Laryngeal cancer represents a common malignancy that originates from the larynx, with unfavorable prognosis. Herein, this study systematically analyzed the immune signatures of laryngeal cancer and to evaluate their roles on tumor progression. METHODS: Differentially expressed immune-related genes (IRGs) were screened between laryngeal cancer and normal tissues from TCGA dataset. Then, two prognosis-related IRGs AQP9 and ZAP70 were analyzed by a series of survival analysis. Based on them, molecular subtypes were constructed by unsupervised cluster analysis. Differences in survival outcomes, HLA expression and immune cell infiltrations were assessed between subtypes. Expression of AQP9 and ZAP70 was validated in laryngeal cancer tissues and cells by RT-qPCR and immunohistochemistry. After silencing and overexpressing AQP9 and ZAP70, CCK-8, EdU, wound healing and transwell assays were performed in TU212 and LCC cells. RESULTS: Totally, 315 IRGs were abnormally expressed in laryngeal cancer. Among them, AQP9 and ZAP70 were distinctly correlated to patients' prognosis. Two subtypes were developed with distinct survival outcomes, HLA expression and immune microenvironment. Low expression of AQP9 and ZAP70 was confirmed in laryngeal cancer. AQP9 and ZAP70 up-regulation distinctly suppressed proliferation, migration, and invasion of laryngeal cancer cells. The opposite results were investigated when their knockdown. CONCLUSIONS: Our findings revealed the roles of AQP9 and ZAP70 in progression of laryngeal cancer, and suggested that AQP9 and ZAP70 could potentially act as candidate immunotherapeutic targets for laryngeal cancer.

BACKGROUND: Research in treatment of non-small cell lung cancer (NSCLC) has shown promising results with stereotactic ablative radiotherapy (SABR) of oligometastatic disease, wherein distant disease may be limited to one or a few distant organs by host factors. Traditionally, PET/CT has been used in detecting metastatic disease and avoiding futile surgical intervention, however, sensitivity and specificity is limited to only 81 and 79%, respectively. Mediastinal staging still identifies occult nodal disease in up to 20% of NSCLC patients initially thought to be operative candidates. Endobronchial ultrasound and transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive tool for the staging and diagnosis of thoracic malignancy. When EBUS is combined with endoscopic ultrasound using the same bronchoscope (EUS-B), the diagnostic sensitivity and negative predictive value increase to 84 and 97%, respectively. Endoscopic staging in patients with advanced disease has never been studied, but may inform treatment if a curative SABR approach is being taken. METHODS: This is a multi-centre, prospective, cohort study with two-stage design. In the first stage, 10 patients with oligometastatic NSCLC (lung tumour ± hilar/mediastinal lymphadenopathy) with up to 5 synchronous metastases will be enrolled An additional 19 patients will be enrolled in the second stage if rate of treatment change is greater than 10% in the first stage. Patients will be subject to EBUS or combined modality EBUS/EUS-B to assess bilateral lymph node stations using a N3 to N2 to N1 progression. Primary endpoint is defined as the rate of change to treatment plan including change from SABR to conventional dose radiation, change in mediastinal radiation field, and change from curative to palliative intent treatment. DISCUSSION: If a curative approach with SABR for oligometastatic disease is being explored, invasive mediastinal staging may guide treatment and prognosis. This study will provide insight into the use of endoscopic mediastinal staging in determining changes in treatment plan of NSCLC. Results will inform the design of future phase II trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT04852588. Date of registration: April 19, 2021. PROTOCOL VERSION: 1.1 on December 9, 2021.

OBJECTIVE: Glioma was the most common type of intracranial malignant tumor. Even after standard treatment, the recurrence and malignant progression of lower-grade gliomas (LGGs) were almost inevitable. The overall survival (OS) of patients with LGG varied widely, making it critical for prognostic prediction. Small G Protein Signaling Modulator 1 (SGSM1) has hardly been studied in gliomas. Therefore, we aimed to investigate the prognostic role of SGSM1 and its relationship with immune infiltration in LGGs. METHODS: We obtained RNA sequencing data from The Cancer Genome Atlas (TCGA) to analyze SGSM1 expression. Functional enrichment analyses, immune infiltration analyses, immune checkpoint analyses, and clinicopathology analyses were performed. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. And nomogram model has been developed. Kaplan-Meier survival analysis and log-rank test were used to estimate the relationship between OS and SGSM1 expression. The survival analyses and Cox regression were validated in datasets from the Chinese Glioma Genome Atlas (CGGA). RESULTS: SGSM1 was significantly down-regulated in LGGs. Functional enrichment analyses revealed SGSM1 was correlated with immune response. Most immune cells and immune checkpoints were negatively correlated with SGSM1 expression. The Kaplan-Meier analyses showed that low SGSM1 expression was associated with a poor outcome in LGG and its subtypes. The Cox regression showed SGSM1 was an independent prognostic factor in patients with LGG (HR = 0.494, 95%CI = 0.311-0.784, P = 0.003). CONCLUSION: SGSM1 was considered to be a new prognostic biomarker for patients with LGG. And our study provided a potential therapeutic target for LGG treatment.

BACKGROUND: The prognosis of patients with lung cancer who demonstrate pleural plaques intraoperatively, which may be associated with exposure to asbestos, is unclear. Here, we compared the clinicopathological characteristics and prognosis of these patients to those of patients without pleural plaques. METHODS: We included patients who underwent curative-intent resection for non-small cell lung cancer. We retrospectively investigated the relationship of intrathoracic findings of pleural plaques with clinicopathological features and prognosis. RESULTS: Pleural plaques were found in 121/701 patients (17.3%) during surgery. The incidence of squamous cell carcinoma (P < 0.001) and the pathological stage (P = 0.021) were higher in patients with pleural plaques. Overall survival was significantly worse in patients with pleural plaques (5-year rate; 64.5% vs. 79.3%; P < 0.001), and the same finding was noted in clinical stage I patients (5-year rate; 64.8% vs. 83.4%; P < 0.001). In multivariable analysis, the presence of pleural plaques was a significant predictor of overall survival in patients with clinical stage I (hazard ratio, 1.643; P = 0.036). In the analysis among patients with emphysema more severe than Goddard score 5 points or interstitial pneumonia, overall survival was significantly worse in those with pleural plaques than in those without pleural plaques (5-year rate; 66.3% vs. 49.5%; P < 0.001). CONCLUSIONS: Patients with non-small cell lung cancer who underwent resection and demonstrated pleural plaques intraoperatively had a significantly worse prognosis. It is important to recognize the presence of pleural plaques intraoperatively, and our findings will be useful in determining the treatment and follow-up strategy for such patients with lung cancer and pleural plaques on intrathoracic examination.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an often fatal malignancy with an extremely low survival rate. Liver metastasis, which causes high mortality, is the most common recurring metastasis for PDAC. However, the mechanisms underlying this liver metastasis and associated candidate biomarkers are unknown. METHODS: We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein-protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER). RESULTS: In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes. CONCLUSIONS: Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.

BACKGROUND: At Silkeborg Regional Hospital, Denmark, the number of stage IA lung cancer increased after implementation of increased use of CT investigations and a corresponding reduction in chest X-ray. The aim of the present study was to understand the changes in referral pathways, patient characteristics and imaging procedures behind the observed increase in early-stage lung cancer. METHODS: The referral and imaging pathways for all patients diagnosed with lung cancer in 2013-2018 were described based on manually curated information from the electronic health care systems and staging information from the Danish Lung Cancer Registry. We compared the clinical characteristics of patients diagnosed in 2013-2015 and in 2016-2018 after implementation of a change in the use of low dose CT scan (LDCT). For patients diagnosed in 2016-2018, stage IA lung cancer were compared to higher stages using univariable logistic regression analysis. RESULTS: Five hundred and forty-seven patients were diagnosed with lung cancer in 2013-2018. Stage IA constituted 13.8% (34/247) in 2013-2015, and 28.3% (85/300) in 2016-2018. Stage IA patients in 2016-2018 were characterised by more comorbidity, fewer packyears and tended to be older than patients with higher stages. In 2016-2018, the largest proportion of stage IA patients (55%) came from within-hospital referrals. The majority of these lung cancers were detected due to imaging procedures with other indications than suspicion of lung cancer. The proportion of stage IA increased from 12% (12/99) to 36% (47/129) (p < 0.001) for hospital referrals and from 17% (22/129) to 23% (38/165) for GP referrals (p = 0.21). The imaging procedures contributing to the increase in stage IA was contrast enhanced CT (22%¸11/51), LDCT (35%; 18/51) and X-ray followed by LDCT (25%; 13/51). CONCLUSION: The increased access to LDCT for patients referred from general practice and the increased hospital requested CT activity resulted in an increase in the number of stage IA lung cancers. Incidental findings on imaging performed for diagnostic purposes unrelated to suspicion of lung cancer contributed a large proportion of the increase.

BACKGROUND: The advantages of prophylactic central lymph node dissection (CLND) for clinically node-negative patients remained a great deal of controversies. Our research was aimed to analyze the relationship between cervical central lymph node metastasis (CLNM) and BRAFV600E mutation, ultrasonic and clinicopathologic characterizes in papillary thyroid carcinoma (PTC). METHODS AND MATERIALS: In current study, a total of 112 consecutive PTC patients who experienced thyroidectomy plus cervical central neck dissection were included in our research. All PTC were pre-operatively analyzed by ultrasonic features, including tumor size, multifocality or not, tumor location, internal components, echogenicity, microcalcification, margins, orientation, taller than wide shape, and internal vascularity. The presence of clinicopathologic factors, including age, sex, T stage, Hashimoto's thyroiditis, and BRAFV600E mutation was then investigated. Univariate and multivariate analysis were conducted to check into the relationship between predictive factors and cervical CLNM in PTC patients, and then a predictive model was also established. RESULTS: Pathologically, 58.0% (65/112) of the PTC patients harbored cervical CLNM. Univariate and multivariate analysis were conducted to identify age < 55 years, tumor size > 10 mm, microcalcification, non-concomitant Hashimoto's thyroiditis and BRAFV600E mutation were predictive factors for cervical CLNM in PTC. The risk score for cervical CLNM in PTC patients was calculated: risk score = 1.284 × (if age < 55 years) + 1.241 × (if tumor size > 10 mm) + 1.143 × (if microcalcification) - 2.097 × (if concomitant Hashimoto's thyroiditis) + 1.628 × (if BRAFV600E mutation). CONCLUSION: Age < 55 years old, PTC > 10 mm, microcalcification, non-concomitant Hashimoto's thyroiditis and BRAFV600E mutation are predictive factors for cervical CLNM. BRAFV600E mutation by pre-operative US-FNA technology synergized with clinicopathologic and ultrasonic features is expected to guide the appropriate surgical management for PTC patients.

BACKGROUND: Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. METHODS: This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6-8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. DISCUSSION: To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www. CLINICALTRIALS: gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1 .

BACKGROUND: Incidence of cervical cancer has been reduced by organized screening while for vaginal and vulvar cancers no systematic screening has been implemented. All these cancers are associated with human papilloma virus (HPV) infection. We wanted to analyze incidence trends and relative survival in these cancers with specific questions about the possible covariation of incidence, survival changes coinciding with incidence changes and the role of treatment in survival. We used nationwide cancer registry data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to address these questions. METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1960 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. RESULTS: In each country the incidence of cervical cancer declined subsequent to rolling out of screening activities. The attained plateau incidence was lowest at 4/100,000 in FI and highest at 10/100,000 in DK and NO. The incidence of vaginal and vulvar cancer remained relatively constant at about 2/100,000. Relative 1-year survival in cervical cancer improved in all countries from low 80%s to high 80%s in the 50-year period, and 5-year survival improved also but at 20% units lower level. Survival gains were found only in patients diagnosed before age 60 years. Survival in vaginal and vulvar cancer followed the same patterns but at a few % units lower level. CONCLUSION: Cervical cancer screening appeared to have reached its limits in the Nordic countries by year 2000. Novel treatments, such as immunotherapy, would be needed to improve survival until HPV vaccination will reach population coverage and boost the global fight against these cancers.

BACKGROUND: Integrin αvβ3 has been proposed as crucial determinant for tumor sustained progression and a molecular marker for the estimation of tumor angiogenesis. Our study suggested that integrin αvβ3 could efficiently promote lung cancer cell proliferation and stem-like phenotypes in a tribbles homolog 3 (TRIB3) dependent manner. RESULT: Integrin αvβ3 could mediate the activation of FAK/AKT pro-survival signaling pathway. Meanwhile, activated TRIB3 interacted with AKT to upregulated FOXO1 and SOX2 expression, resulting in sustained tumor progression in lung cancer. Our further analysis revealed that TRIB3 was significantly upregulated in lung tumor tissues and correlated with the poor outcome in clinical patients, indicating the potential role of TRIB3 in diagnostic and prognostic estimation for patients with lung cancer. CONCLUSION: Our study showed here for the first time that integrin αvβ3 promote lung cancer development by activating the FAK/AKT/SOX2 axis in a TRIB3 dependent signaling pathway, and interrupting TRIB3/AKT interaction significantly improved the outcome of chemotherapy in tumor-bearing mice, representing a promising therapeutic strategy in lung cancer.

BACKGROUND: Syphilis is an infectious disease that is at least discussed to be premalignant. This potential, combined with its general pathological impact, raises the question if syphilis increases mortality in oral cancer patients. The aim of the study was to assess if the five-year survival rates among patients suffering from oral squamous cell carcinoma (OSCC) with (cohort I) and without association with syphilis (cohort II) differ. METHODS: Retrospective clinical data of patients diagnosed with OSCC (International Classification of Diseases [ICD]-10 codes C01-06) within the past 20 years from the access date September 25, 2021 were retrieved from the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) to gain initial cohort 0. Subjects also diagnosed with syphilis (ICD-10 codes A51-53) were assigned to cohort I. Cohort II was comprised of the remaining individuals of cohort 0 by creating a group with the same number of patients as cohort I, and by matching for age and gender. Subsequently, Kaplan-Meier analysis and Cox proportional hazards regression were performed, and risk, odds and hazard ratios were calculated. RESULTS: Of a total of 73,736 patients in cohort 0, 199 individuals were each assigned to cohort I and II. During the five-year period after tumor diagnosis, 39 and 30 patients in cohort I and II died. The five-year survival probabilities did not significantly differ between the cohorts (I vs. II = 74.19% vs. 75.01%; p = 0.52; Log-Rank test), nor the risk of dying (I vs. II = 19.6% vs. 15.08%; risk difference = 4.52%; p = 0.23). The calculated risk, odds and hazard ratios were 1.3 (95% confidence interval [CI] = 0.84; 2.00), 1.37 (95% CI = 0.81; 2.31) and 1.17 (95% CI = 0.73; 1.88), respectively. CONCLUSIONS: The obtained results indicate that the survival rate of individuals with OSCC might not be negatively influenced if syphilis is present/associated. However, the results need to be interpreted cautiously due to limitations related to the retrospective approach, especially as data on the tumor staging were not accessible. TRIAL REGISTRATION: Due to the retrospective nature of the study, no registration was necessary.

AIM: To independently assess the impact of mandatory testing using an extended DPYD variant panel (ToxNav®) and consequent dose adjustment of Capecitabine/5-FU on recorded quantitative toxicity, symptoms of depression, and hospital costs. METHODS: We used propensity score matching (PSM) to match 466 patients tested with ToxNav® with 1556 patients from a historical cohort, and performed regression analysis to estimate the impact of ToxNav®on toxicity, depression, and hospital costs. RESULTS: ToxNav® appeared to reduce the likelihood of experiencing moderate (OR: 0.59; 95%CI: 0.45-0.77) and severe anaemia (OR: 0.55; 95%CI: 0.33-0.90), and experience of pain for more than 4 days a week (OR: 0.50; 95%CI: 0.30-0.83), while it increased the likelihood of mild neutropenia (OR: 1.73; 95%CI: 1.27-2.35). It also reduced the cost of chemotherapy by 12% (95%CI: 3-31) or £9765, the cost of non-elective hospitalisation by 23% (95%CI: 8-36) or £2331, and the cost of critical care by 21% (95%CI: 2-36) or £1219 per patient. For the DPYD variant associated with critical risk of toxicity (rs3918290), the improved non-elective hospital costs were > £20,000, whereas variants associated with hand-foot syndrome toxicity had no detectable cost improvement. CONCLUSION: Upfront testing of DPYD variants appears to reduce the toxicity burden of Capecitabine and 5-FU in cancer patients and can lead to substantial hospital cost savings, only if the dose management of the drugs in response to variants detected is standardised and regulated.

OBJECTIVE: The study conducted a multicenter study in China to explore the learning curve of contrast enhanced ultrasound (CEUS) for sentinel lymph nodes (SLNs), the feasibility of using this technique for the localization of SLNs and lymphatic channels (LCs) and its diagnostic performance for lymph node metastasis. METHOD: Nine hundred two patients with early invasive breast cancer from six tertiary class hospitals in China were enrolled between December 2016 and December 2019. Each patient received general ultrasound scanning and SLN-CEUS before surgery. The locations and sizes of LCs and SLNs were marked on the body surface based on observations from SLN-CEUS. These body surface markers were then compared with intraoperative blue staining in terms of their locations. The first 40 patients from each center were included in determining the learning curve of SLN-CEUS across sites. The remaining patients were used to investigate the diagnostic efficacy of this technique in comparison with intraoperative blue staining and pathology respectively. RESULT: The ultrasound doctor can master SLN-CEUS after 25 cases, and the mean operating time is 22.5 min. The sensitivity, specificity, negative predictive value, and positive predictive value of SLN-CEUS in diagnosing lymph node metastases were 86.47, 89.81, 74.90, and 94.97% respectively. CONCLUSION: Ultrasound doctors can master SLN-CEUS with a suitable learning curve. SLN-CEUS is a feasible and useful approach to locate SLNs and LCs before surgery and it is helpful for diagnosing LN metastases.

BACKGROUND: Glioma is one of the main causes of cancer-related mortality worldwide and is associated with high heterogeneity. However, the key players determining the fate of glioma remain obscure. In the present study, we shed light on tumor metabolism and aimed to investigate the role of tryptophan hydroxylase 1 (TPH-1) in the advancement of glioma. METHOD: Herein, the levels of TPH-1 expression in glioma tissues were evaluated using The Cancer Genome Atlas (TCGA) database. Further, the proliferative characteristics and migration ability of TPH-1 overexpressing LN229/T98G cells were evaluated. Additionally, we performed a cytotoxicity analysis using temozolomide (TMZ) in these cells. We also examined the tumor growth and survival time in a mouse model of glioma treated with chemotherapeutic agents and a TPH-1 inhibitor. RESULTS: The results of both clinical and experimental data showed that excess TPH-1 expression resulted in sustained glioma progression and a dismal overall survival in these patients. Mechanistically, TPH-1 increased the production of serotonin in glioma cells. The elevated serotonin levels then augmented the NF-κB signaling pathway through the upregulation of the L1-cell adhesion molecule (L1CAM), thereby contributing to cellular proliferation, invasive migration, and drug resistance. In vivo experiments demonstrated potent antitumor effects, which benefited further from the synergistic combination of TMZ and LX-1031. CONCLUSION: Taken together, these data suggested that TPH-1 facilitated cellular proliferation, migration, and chemoresistance in glioma through the serotonin/L1CAM/NF-κB pathway. By demonstrating the link of amino acid metabolic enzymes with tumor development, our findings may provide a potentially viable target for therapeutic manipulation aimed at eradicating glioma.

BACKGROUND: Abnormal expression of long non-coding RNAs (lncRNAs) has been shown to be associated with the pathogenesis of cancers, including colorectal cancer (CRC). It has been reported that LINC00022 is highly expressed in some typs of cancer and its overexpression indicates poor prognosis. The function of LINC00022 in CRC progression remains unclear and is mainly investigated in the present study. METHODS: LINC00022 expression in CRC tissues was analyzed by using the TNMplot software. LINC00022 expression in CRC cells was measured by quantitative real-time PCR. The effects of LINC00022 on the malignant behaviors of CRC cells were detected by a series of in vitro and in vivo experiments. Dual-luciferase assays were used to verify the targeting relationship between LINC00022 and miR-375-3p and between miR-375-3p and Forkhead box F1 (FOXF1), followed by the rescue experiment. RESULTS: LINC00022 was highly expressed in CRC tissues compared with paired para-carcinoma tissues (n = 41). CRC cells with LINC00022 knockdown exhibited decreased cell proliferation, migration, and invasion abilities but increased apoptosis accompanied by decreased protein levels of c-Myc, cyclin D1, cleaved caspase 3, cleaved poly(ADP-ribose) polymerase, matrix metalloproteinase (MMP) 2, and MMP9. Additionally, LINC00022 downregulation in CRC cells suppressed the tube formation of human umbilical vein endothelial cells (HUVECs) as evidenced by decreased vascular endothelial growth factor A levels in LINC00022-silenced cells. The inhibitory effect of LINC00022 knockdown on tumor growth was also observed in an in vivo model. Conversely, LINC00022 overexpression showed that opposite effect. We further demonsrtaed that LINC00022 could upregulate FOXF1 expression through sponging miR-375-3p. Moreover, miR-375-3p knockdown reversed the effects of LINC00022 down-regulation. CONCLUSIONS: LINC00022 may up-regulate FOXF1 expression via competitively binding miR-375-3p, thereby promoting the development of CRC.

BACKGROUND: Whether an oxaliplatin- or cisplatin-based regimen is more optimal for treating elderly patients with advanced gastric cancer, in terms of survival and adverse events remains unclear. METHODS: In this retrospective cohort study, we used stacked claim data of residents in two Japanese prefectures collected between 2012 and 2017 and between 2014 and 2019, respectively. We included patients with advanced gastric cancer who received oxaliplatin-based and cisplatin-based regimens. Propensity score overlap weighting analysis was conducted to compare overall survival and granulocyte colony-stimulating factor use during chemotherapy between the oxaliplatin- and cisplatin-based treatment groups. RESULTS: A total of 242 patients were included in the study. After propensity score weighting, Kaplan-Meier analysis showed no significant differences in overall survival between the two groups (hazard ratio: 1.13; 95% confidence interval, 0.60-2.11; p =  0.70). However, the proportion of patients receiving granulocyte colony-stimulating factor was significantly lower in the oxaliplatin group than in the cisplatin group (2.3% vs.22.7%, p = 0.01). CONCLUSIONS: Survival did not differ significantly between elderly patients with advanced gastric cancer treated with oxaliplatin-based versus cisplatin-based regimens; however, the oxaliplatin-based regimen was associated with less granulocyte colony-stimulating factor use.

BACKGROUND: Although survival based outcomes of lung cancer patients have been well developed, institutional transition of cancer care, that is, when patients transfer from primary visiting hospitals to other hospitals, and mortality have not yet been explored using a large-scale representative population-based sample. METHODS: Data from the Korean National Elderly Sampled Cohort survey were used to identify patients with lung cancer who were diagnosed during 2005-2013 and followed up with for at least 1 year after diagnosis (3738 patients with lung cancer aged over 60 years). First, the authors examined the distribution of the study population by mortality, and Kaplan-Meier survival curves/log-rank test were used to compare mortality based on institutional transition of cancer care. Survival analysis using the Cox proportional hazard model was conducted after controlling for all other variables. RESULTS: Results showed that 1-year mortality was higher in patients who underwent institutional transition of cancer care during 30 days after diagnosis (44.2% vs. 39.7%, p = .027); however, this was not associated with 5-year mortality. The Cox proportional hazard model showed that patients who underwent institutional transition of cancer care during 30 days after diagnosis exhibited statistically significant associations with high mortality for 1 year and 5 years (1-year mortality, Hazard ratio [HR]: 1.279, p = .001; 5-year mortality, HR: 1.158, p = .002). CONCLUSION: This study found that institutional transition of cancer care was associated with higher mortality among elderly patients with lung cancer. Future consideration should also be given to the limitation of patients' choice when opting for institutional transition of care since there are currently no control mechanisms in this regard. Results of this study merit health policymakers' attention.

BACKGROUND: Nonclustered mouse protocadherin genes (Pcdh) encode proteins with a typical single ectodomain and a cytoplasmic domain with conserved motifs completely different from those of classic cadherins. Alternative splice isoforms differ in the size of these cytoplasmic domains. In view of the compelling evidence for gene silencing of protocadherins in human tumors, we started investigations on Pcdh functions in mouse cancer models. METHODS: For Pcdh10, we generated two mouse lines: one with floxed exon 1, leading to complete Pcdh10 ablation upon Cre action, and one with floxed exons 2 and 3, leading to ablation of only the long isoforms of Pcdh10. In a mouse medulloblastoma model, we used GFAP-Cre action to locally ablate Pcdh10 in combination with Trp53 and Rb1 ablation. From auricular tumors, that also arose, we obtained tumor-derived cell lines, which were analyzed for malignancy in vitro and in vivo. By lentiviral transduction, we re-expressed Pcdh10 cDNAs. RNA-Seq analyses were performed on these cell families. RESULTS: Surprisingly, not only medulloblastomas were generated in our model but also tumors of tagged auricles (pinnae). For both tumor types, ablation of either all or only long isoforms of Pcdh10 aggravated the disease. We argued that the perichondrial stem cell compartment is at the origin of the pinnal tumors. Immunohistochemical analysis of these tumors revealed different subtypes. We obtained several pinnal-tumor derived (PTD) cell lines and analyzed these for anchorage-independent growth, invasion into collagen matrices, tumorigenicity in athymic mice. Re-expression of either the short or a long isoform of Pcdh10 in two PTD lines counteracted malignancy in all assays. RNA-Seq analyses of these two PTD lines and their respective Pcdh10-rescued cell lines allowed to identify many interesting differentially expressed genes, which were largely different in the two cell families. CONCLUSIONS: A new mouse model was generated allowing for the first time to examine the remarkable tumor suppression activity of protocadherin-10 in vivo. Despite lacking several conserved motifs, the short isoform of Pcdh10 was fully active as tumor suppressor. Our model contributes to scrutinizing the complex molecular mechanisms of tumor initiation and progression upon PCDH10 silencing in many human cancers.

BACKGROUND: Currently the five-year survival of childhood cancer is up to 80% due to improved treatment modalities. However, the majority of childhood cancer survivors develop late effects including infertility. Survivors describe infertility as an important and life-altering late effect. Fertility preservation options are becoming available to pre- and postpubertal patients diagnosed with childhood cancer and fertility care is now an important aspect in cancer treatment. The use of fertility preservation options depends on the quality of counseling on this important and delicate issue. The aim of this manuscript is to present a questionnaire to determine the impact of fertility counseling in patients suffering from childhood cancer, to improve fertility care and evaluate what patients and their parents or guardians consider good fertility care. METHODS: Within the framework of the EU-Horizon 2020 TREL project, a fertility care evaluation questionnaire used in the Netherlands was made applicable for international multi-center use. The questionnaire to be used at least also in Lithuania, incorporates patients' views on fertility care to further improve the quality of fertility care and counseling. Results evaluate fertility care and will be used to improve current fertility care in a national specialized pediatric oncology center in the Netherlands and a pediatric oncology center in Lithuania. CONCLUSION: An oncofertility-care-evaluation questionnaire has been developed for pediatric oncology patients and their families specifically. Results of this questionnaire may contribute to enhancement of fertility care in pediatric oncology in wider settings and thus improve quality of life of childhood cancer patients and survivors.

BACKGROUND: The receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) is overexpressed and an important therapeutic target in Head and Neck cancer (HNC). Cetuximab is currently the only EGFR-targeting agent approved by the FDA for treatment of HNC; however, intrinsic and acquired resistance to cetuximab is a major problem in the clinic. Our lab previously reported that AXL leads to cetuximab resistance via activation of HER3. In this study, we investigate the connection between AXL, HER3, and neuregulin1 (NRG1) gene expression with a focus on understanding how their interdependent signaling promotes resistance to cetuximab in HNC. METHODS: Plasmid or siRNA transfections and cell-based assays were conducted to test cetuximab sensitivity. Quantitative PCR and immunoblot analysis were used to analyze gene and protein expression levels. Seven HNC patient-derived xenografts (PDXs) were evaluated for protein expression levels. RESULTS: We found that HER3 expression was necessary but not sufficient for cetuximab resistance without AXL expression. Our results demonstrated that addition of the HER3 ligand NRG1 to cetuximab-sensitive HNC cells leads to cetuximab resistance. Further, AXL-overexpressing cells regulate NRG1 at the level of transcription, thereby promoting cetuximab resistance. Immunoblot analysis revealed that NRG1 expression was relatively high in cetuximab-resistant HNC PDXs compared to cetuximab-sensitive HNC PDXs. Finally, genetic inhibition of NRG1 resensitized AXL-overexpressing cells to cetuximab. CONCLUSIONS: The results of this study indicate that AXL may signal through HER3 via NRG1 to promote cetuximab resistance and that targeting of NRG1 could have significant clinical implications for HNC therapeutic approaches.

BACKGROUND: The aim of the present study was to assess the prevalence of deficient mismatch repair (MMR) in Chinese ovarian clear cell carcinoma (CCC) patients and its association with clinicopathologic features. METHODS: Immunohistochemistry with four antibodies against MLH1, PMS2, MSH2 and MSH6 was performed on whole section slides, and the results were correlated with clinicopathologic variables. RESULTS: A total of 108 cases were included in the present study with a median age of 52 years at first diagnosis. Early-stage disease and platinum-sensitive recurrence accounted for 62.3 and 69.6%, respectively, of the total cases. Overall, the estimated 5-year overall survival was 70.3 and 20.7% in patients with early- and late-stage tumors, respectively. Deficient MMR was identified in 5.6% (6/108) of the cohort and included MSH2/MSH6 (n = 4) and MLH1/PMS2 (n = 2). The average age of the six patients with deficient MMR was 45.6 years, and the rate of MMR-deficient tumors in women ≤50 years was relatively higher than that in women over 50 years (10.0% vs. 2.9%; P = 0.266). Half of the patients with deficient MMR were diagnosed with synchronous (endometrial or colorectal) and metachronous (endometrial) cancer, which was significantly more than their intact counterparts (P = 0.002). All six patients with deficient MMR had early-stage tumors, and the majority (83.3%) were platinum sensitive. The median progression-free survival was slightly higher in patients with defective MMR expression than in their intact counterparts (30 months vs. 27 months), but significance was not achieved (P = 0.471). CONCLUSIONS: Young ovarian CCC patients with concurrent diagnosis of endometrial and colorectal cancer are more likely to have MMR-deficient tumors, thereby warranting additional studies to determine whether patients harboring MMR abnormalities have a favorable prognosis.

BACKGROUND: Standard groin treatment in recurrent vulvar cancer consists of uni- or bilateral inguinofemoral lymphadenectomy (IFL), whereas in the primary setting women with selected unifocal tumours will undergo a sentinel lymph node (SLN) procedure. The SLN procedure results in fewer short and long-term sequelae compared to IFL, but some concerns must first be considered. Lymph drainage of the vulvar region can be affected by a previous surgery, which might reduce the number of detectable SLN nodes (feasibility) but increase the chance of encountering aberrant lymph drainage patterns such as bilateral SLNs in lateral tumours or SLNs at unexpected locations. Therefore, the SLN procedure potentially carries a higher risk of groin recurrence if a tumour positive node is not retrieved, but may also improve outcomes for women with aberrant drainage patterns. Since the relative benefits and drawbacks of the SLN procedure are still unclear we will investigate the safety of the SLN procedure in women with a first recurrent vulvar cancer. In a simultaneously started registration study we prospectively gather information on women with a first recurrence of vulvar cancer ineligible for the SLN procedure. METHOD: In this prospective multicentre observational study all women with a first recurrence of vulvar cancer will be asked to consent to the collection of information on their diagnostics, treatment and outcome, and to complete quality of life and lymph oedema questionnaires. Women with unifocal tumours smaller than 4 cm and unsuspicious groin nodes will be offered the SLN procedure, with follow-up every 3 months together with imaging at 6 and 12 months when the SLN is tumour negative. The primary outcome is groin recurrence within 2 years of initial surgery. A total of 150 women with negative SLNs will be required to demonstrate safety, a stopping rule will apply and an extensive statistical analysis has been designed. DISCUSSION: Should the SLN procedure prove feasible and safe in recurrent vulvar cancer, it will be available for implementation in clinics worldwide. The inclusion of women ineligible for the SLN procedure in the current prospective study will help to bridge knowledge gaps and define future research questions. TRIAL REGISTRATION: Medical Ethical Committee approval number NL70149.078.19 (trial protocol version 2.0, date March 2nd, 2020). Affiliation: Erasmus Medical Centre. Dutch trial register NL8467 . Date of registration 19.03.2020.

BACKGROUND: Baculoviral IAP repeat containing 5 (BIRC5) is overexpressed and plays as a key regulator in the progression of various human carcinomas. The inflammatory tumor microenvironment (ITM) is closely associated with the development of cancers. However, the role of BIRC5 in penile cancer (PC) and the ITM-induced abnormal progression of PC is still obscure. METHODS: In this study, serum and tissues of patients with PC were recruited to evaluate the expression profile of BIRC5. We used PC cell lines (Penl1 and Penl2) and constructed a PC xenograft mice model to explore the effects of the silencing of BIRC5 on proliferation, migration, invasion and tumor growth, as well as survival of mice. Besides, interferon (IFN)-γ was utilized to mimic the ITM of PC cells. RESULTS: Our results showed that BIRC5 was dramatically upregulated in the serum and tissues of PC patients, as well as PC cell lines. Knockdown of BIRC5 inhibited the proliferation, migration and invasion of PC cells. Meanwhile, it suppressed PC xenograft tumor growth and improved mice survival. Moreover, IFN-γ significantly aggravated PC progression both in vivo and in vitro while the silencing of BIRC5 reversed these unfavorable effects. CONCLUSIONS: Taken together, our data revealed that BIRC5 silencing inhibited aggravation of PC cell processes and tumor development induced by ITM. This suggested that BIRC5 may function as a diagnosis and therapy target of PC in the future.

BACKGROUND: Although several novel resistant breast cancer cell lines have been established, only a few resistant breast cancer cell lines overexpress breast cancer resistance proteins (BCRP). The aim of this study was to establish new resistant breast cancer cell lines overexpressing BCRP using SN38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of irinotecan and was to discover genes and mechanisms associated with multidrug resistance. METHODS: SN38-resistant T47D breast cancer cell sublines were selected from the wild-type T47D cells by gradually increasing SN38 concentration. The sensitivity of the cells to anti-cancer drugs was assessed by 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Expression profiles of the resistance-related transporters were examined using RT-qPCR, and western blot analysis. Intracellular fluorescent dye accumulation in the resistant cells was determined using flow cytometry. RESULTS: The SN38-resistant T47D breast cancer cell sublines T47D/SN120 and T47D/SN150 were established after long-term exposure (more than 16 months) of wild-type T47D cells to 120 nM and 150 nM SN38, respectively. T47D/SN120 and T47D/SN150 cells were more resistant to SN38 (14.5 and 59.1 times, respectively), irinotecan (1.5 and 3.7 times, respectively), and topotecan (4.9 and 12 times, respectively), than the wild-type parental cells. Both T47D/SN120 and T47D/SN150 sublines were cross-resistant to various anti-cancer drugs. These resistant sublines overexpressed mRNAs of MRP1, MRP2, MRP3, MRP4, and BCRP. The DNA methylase inhibitor 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A increased the expression levels of BCRP, MRP1, MRP2, MRP3, and MRP4 transcripts in T47D/WT cells. Fluorescent dye accumulation was found to be lower in T47D/SN120 and T47D/SN150 cells, compared to that in T47D/WT cells. However, treatment with known chemosensitizers increased the intracellular fluorescent dye accumulation and sensitivity of anti-tumor agents. CONCLUSION: T47D/SN120 and T47D/SN150 cells overexpressed MRP1, MRP2, MRP3, MRP4, and BCRP, which might be due to the suppression of epigenetic gene silencing via DNA hypermethylation and histone deacetylation. Although these resistant cells present a higher resistance to various anti-cancer drugs than their parental wild-type cells, multidrug resistance was overcome by treatment with chemosensitizers. These SN38 resistant T47D breast cancer cell sublines expressing resistance proteins can be useful for the development of new chemosensitizers.

INTRODUCTION: Colorectal cancer(CRC) patients are among the incurable groups who need comprehensive palliative care covering all aspects including physical, mental, social, and spiritual. The purpose of this study is to develop, implement, and evaluate a holistic palliative care program for CRC patients in order to improve quality of life of CRC patients. METHODS: This study is an exploratory mixed methods study which will be conducted using a sequential qualitative-quantitative design (QUAL quan) consists of four sequential steps using the approach proposed by Ewles & Sminett to develop the program. In the first phase, a qualitative study (semi-structured interview) will be conducted to discover the needs of CRC patients from the perspective of patients, family members and care providers. In the second phase, the literature review will be performed with the aim of confirming and completing the discovering new needs. In the third phase, in order to prioritize the identified needs and prepare a initial draft of the palliative care program will be done a panel of experts. In the fourth phase, the part of the developed program according to the opinions of the panel of experts, will be implemented as quasi-experimental intervention and the effect of intervention on quality of life will be evaluated. DISCUSSION: This results of this study are expected to meet the needs of CRC patients and their families through providing a holistic care and improve their quality of life in the socio-cultural context of Iran. This program can be useful in providing care, education, policy making and for future research.

BACKGROUND: Graft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present "Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD" - Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients. METHODS: IRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion. DISCUSSION: To our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment. TRIAL REGISTRATION: ClinicalTrials.gov : NCT05111834 . Registered 8 November 2021 - Retrospectively registered.

BACKGROUND: Radical surgery is the mainstream treatment for patients presenting with advanced primary or recurrent gastrointestinal cancers; however, the rate of postoperative complications is exceptionally high. The current evidence suggests that improving patients' fitness during the preoperative period may enhance postoperative recovery. Thus, the primary aim of this study is to establish the effectiveness of prehabilitation with a progressive, individualised, preoperative exercise and education program compared to usual care alone in reducing the proportion of patients with postoperative in-hospital complications. The secondary aims are to investigate the effectiveness of the preoperative intervention on reducing the length of intensive care unit and hospital stay, improving quality of life and morbidity, and reducing costs. METHODS: This is a multi-centre, assessor-blinded, pragmatic, comparative, randomised controlled trial. A total of 172 patients undergoing pelvic exenteration, cytoreductive surgery, oesophagectomy, hepatectomy, gastrectomy or pancreatectomy will be recruited. Participants will be randomly allocated to prehabilitation with a preoperative exercise and education program (intervention group), delivered over 4 to 8 weeks before surgery by community physiotherapists/exercise physiologists, or usual care alone (control group). The intervention will comprise 12 to 24 individualised, progressive exercise sessions (including aerobic/anaerobic, resistance, and respiratory exercises), recommendations of home exercises (16 to 32 sessions), and daily incidental physical activity advice. Outcome measures will be collected at baseline, the week prior to surgery, during the hospital stay, and on the day of discharge from hospital, and 1 month and 1 months postoperatively. The primary outcome will be the development of in-hospital complications. Secondary outcomes include the length of intensive care unit and hospital stay, quality of life, postoperative morbidity and costs. DISCUSSION: The successful completion of this trial will provide robust and high-quality evidence on the efficacy of a preoperative community- and home-based exercise and education intervention on important postoperative outcomes of patients undergoing major gastrointestinal cancer surgery. TRIAL REGISTRATION: This trial was registered prospectively with the Australian New Zealand Clinical Trials Registry ( ACTRN12621000617864 ) on 24th May 2021.

BACKGROUND: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. MATERIAL AND METHODS: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010-2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. RESULTS: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68-1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63-3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48-4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. CONCLUSION: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions.

BACKGROUND: Oral mucositis (OM) is known to be the most common and challenging side effect of conditioning chemotherapy in haematopoietic cell transplant (HCT). This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. There are few clinical trials in the literature that indicate any kind of treatment or prevention methods are effective. Therefore, the aim of this study is to perform a systematic review of literature and examine the effectiveness of oral cryotherapy (OC) in management of chemotherapy-induced OM in patients with haematological malignancies undergoing a HCT. METHODS: A systematic literature search was conducted, using the electronic databases PubMed, Embase, MEDLINE and Scopus. A total of 322 papers were identified and 9 papers were analysed based on defined inclusion and exclusion criteria. The quality of the chosen primary studies was appraised using the COCHRANE risk of bias assessment tool. RESULTS: Nine randomized controlled trials, analysing 658 participants; control group (n = 289, age mean ± SD; 41.15 ± 21) and treatment group (n = 369, age mean ± SD; 39.15 ± 20), were included in this systematic review. Seven studies had significantly addressed the effectiveness of OC (p value < 0.05), in reducing the incidence of developing severe OM in the adult population undergoing HCT, especially when the conditioning regimen protocols included high dose of alkylating agent such as melphalan. CONCLUSION: This review supports the use of OC for prevention of OM in patients undergoing HCT, with high-dose of melphalan conditioning protocols. It is recommended that more studies be conducted to compare efficacy and duration of OC with other chemotherapeutic agents with relatively short plasma half-lives. The heterogeneity of the trials demonstrated the need to regulate the validated assessment tools and similar interventions that would enable comparisons and analyses of treatment effects based on well-designed RCTs.

BACKGROUND: Patients with oesophageal and gastric cancer have a low likelihood of being cured and suffer from a broad spectrum of symptoms and problems that negatively affect their quality-of-life (QOL). Although the majority (67-75%) of patients at the time of diagnosis suffer from an incurable disease, research has primarily focused on the pre- and postoperative phase among patients treated with curative intent, with little attention to symptoms and problems in the diagnostic phase, especially in those who cannot be offered a cure. METHODS: In this cross-sectional study 158 patients newly diagnosed with oesophageal and gastric cancer visiting the surgical outpatient department for a preplanned care visit were included consecutively during 2018-2020. The validated instruments QLQ-C30 and QLQ-OG25, developed by the European Organization for Research and Treatment of Cancer (EORTC), and selected items from the Integrated Patient Outcome Scale (IPOS) were used to assess QOL, symptoms and problems. Differences between patients with a curative and a palliative treatment strategy were analysed using t-test and Mann-Whitney U test. The QLQ-C30 and QLQ-OG25 scores were compared to published reference data on the general Swedish population. RESULTS: Among all, the QOL was markedly lower, compared with general Swedish population (mean ± SD, 55.9 ± 24.7 vs 76.4 ± 22.8, p < 0.001). Compared to general population, the patients had significant impairment in all QOL aspects, particularly for role and emotional functioning and for symptoms such as eating-related problems, fatigue, insomnia and dyspnea. Majority of patients also reported severe anxiety among family and friends. Among patients with oesophageal cancer those with a palliative treatment strategy, compared with curative strategy, reported significantly lower QOL (mean ± SD, 50.8 ± 28.6 vs 62.0 ± 22.9 p = 0.030), physical (65.5 ± 22.6 vs 83.9 ± 16.5, p < 0.001) and role functioning (55.7 ± 36.6 vs 73.9 ± 33.3, p = 0.012), and a higher burden of several symptoms and problems. No significant differences between treatment groups were shown among patients with gastric cancer. CONCLUSIONS: Patients newly diagnosed with oesophageal and gastric cancer, and especially those with incurable oesophageal cancer, have a severely affected QOL and several burdensome symptoms and problems. To better address patients' needs, it seems important to integrate a palliative approach into oesophageal and gastric cancer care.

BACKGROUND: Regulatory T cells (Tregs) play an important role in the antitumor immune response in epithelial ovarian cancer (EOC). To understand the immune-inhibitory networks of EOC, we addressed the association between Tregs and immune checkpoint expression on T cells in the tumor microenvironment of EOC. METHODS: A total of 41 patients with stage IIIC and IV EOC were included in the analysis. We harvested cells from malignant ascites and investigated them using multi-color flow cytometry. We categorized the Tregs into 3 groups: effector-type Tregs, naïve Tregs and non-Tregs, based on the expression patterns of CD45RA and Foxp3 in CD4+ T cells. Furthermore, the relationships between the expression of various immune checkpoint molecules, such as PD-1, on CD8+ T cells and each of the Treg subtypes was also evaluated. RESULTS: The median frequency of naïve Tregs, effector-type Tregs and non-Tregs were 0.2% (0-0.8), 2.0% (0-11.4) and 1.5% (0.1-6.3) in CD4+ T cells of malignant ascites from EOC patients, respectively. A high frequency of effector-type Tregs was associated with high-grade serous carcinoma compared with the other histotypes. Patients with higher proportions of effector-type Tregs showed a trend towards increased progression-free survival. We also demonstrated a correlation between a higher proportion of effector-type Tregs and increased PD-1 expression on CD8+ T cells. In addition, C-C chemokine receptor 4 expression was also observed in effector-type Tregs. CONCLUSION: These data suggest that multiple immune-inhibitory networks exist in malignant ascites from EOC patients, suggesting an approach towards combinational immunotherapies for advanced EOC patients.

BACKGROUND: Cancer metastasis is the main cause of mortality in cancer patients. However, the drugs targeting metastasis processes are still lacking, which is partially due to the short of effective in vitro model for cell invasion studies. The traditional 2-D culture method cannot reveal the interaction between cells and the surrounding extracellular matrix during invasion process, while the animal models usually are too complex to explain mechanisms in detail. Therefore, a precise and efficient 3-D in vitro model is highly desirable for cell invasion studies and drug screening tests. METHODS: Precise micro-fabrication techniques are developed and integrated with soft hydrogels for constructing of 3-D lung-cancer micro-environment, mimicking the pulmonary gland or alveoli as in vivo. RESULTS: A 3-D in vitro model for cancer cell culture and metastasis studies is developed with advanced micro-fabrication technique, combining microfluidic system with soft hydrogel. The constructed microfluidic platform can provide nutrition and bio-chemical factors in a continuous transportation mode and has the potential to form stable chemical gradient for cancer invasion research. Hundreds of micro-chamber arrays are constructed within the collagen gel, ensuring that all surrounding substrates for tumor cells are composed of natural collagen hydrogel, like the in vivo micro-environment. The 3-D in vitro model can also provide a fully transparent platform for the visual observation of the cell morphology, proliferation, invasion, cell-assembly, and even the protein expression by immune-fluorescent tests if needed. The lung-cancer cells A549 and normal lung epithelial cells (HPAEpiCs) have been seeded into the 3-D system. It is found out that cells can normally proliferate in the microwells for a long period. Moreover, although the cancer cells A549 and alveolar epithelial cells HPAEpiCs have the similar morphology on 2-D solid substrate, in the 3-D system the cancer cells A549 distributed sparsely as single round cells on the extracellular matrix (ECM) when they attached to the substrate, while the normal lung epithelial cells can form cell aggregates, like the structure of normal tissue. Importantly, cancer cells cultured in the 3-D in vitro model can exhibit the interaction between cells and extracellular matrix. As shown in the confocal microscope images, the A549 cells present round and isolated morphology without much invasion into ECM, while starting from around Day 5, cells changed their shape to be spindle-like, as in mesenchymal morphology, and then started to destroy the surrounding ECM and invade out of the micro-chambers. CONCLUSIONS: A 3-D in vitro model is constructed for cancer cell invasion studies, combining the microfluidic system and micro-chamber structures within hydrogel. To show the invasion process of lung cancer cells, the cell morphology, proliferation, and invasion process are all analyzed. The results confirmed that the micro-environment in the 3-D model is vital for revealing the lung cancer cell invasion as in vivo.

BACKGROUND: While mechanisms contributing to the progression and metastasis of colorectal cancer (CRC) are well studied, cancer stage-specific mechanisms have been less comprehensively explored. This is the focus of this manuscript. METHODS: Using previously published data for CRC (Gene Expression Omnibus ID GSE21510), we identified differentially expressed genes (DEGs) across four stages of the disease. We then generated unweighted and weighted correlation networks for each of the stages. Communities within these networks were detected using the Louvain algorithm and topologically and functionally compared across stages using the normalized mutual information (NMI) metric and pathway enrichment analysis, respectively. We also used Short Time-series Expression Miner (STEM) algorithm to detect potential biomarkers having a role in CRC. RESULTS: Sixteen Thousand Sixty Two DEGs were identified between various stages (p-value ≤ 0.05). Comparing communities of different stages revealed that neighboring stages were more similar to each other than non-neighboring stages, at both topological and functional levels. A functional analysis of 24 cancer-related pathways indicated that several signaling pathways were enriched across all stages. However, the stage-unique networks were distinctly enriched only for a subset of these 24 pathways (e.g., MAPK signaling pathway in stages I-III and Notch signaling pathway in stages III and IV). We identified potential biomarkers, including HOXB8 and WNT2 with increasing, and MTUS1 and SFRP2 with decreasing trends from stages I to IV. Extracting subnetworks of 10 cancer-relevant genes and their interacting first neighbors (162 genes in total) revealed that the connectivity patterns for these genes were different across stages. For example, BRAF and CDK4, members of the Ser/Thr kinase, up-regulated in cancer, displayed changing connectivity patterns from stages I to IV. CONCLUSIONS: Here, we report molecular and modular networks for various stages of CRC, providing a pseudo-temporal view of the mechanistic changes associated with the disease. Our analysis highlighted similarities at both functional and topological levels, across stages. We further identified stage-specific mechanisms and biomarkers potentially contributing to the progression of CRC.

BACKGROUND: Timely diagnosis and management of iron deficiency anemia (IDA) in colorectal cancer (CRC) patients improves overall quality of life and survival. This study assessed the proportion of CRC patients who were formally diagnosed with IDA and factors that predict a formal diagnosis of IDA and receiving iron therapy. METHODS: We retrieved electronic medical records (EMRs) of CRC patients from a large comprehensive cancer center in the Northeastern part of the United States (n = 499). We abstracted sociodemographic characteristics, relevant laboratory results, IDA diagnosis, and iron supplementation from the EMRs. We assessed relationships between participant characteristics, a diagnosis of IDA and receiving iron therapy through adjusted logistic regressions. RESULTS: IDA was formally diagnosed in 26 (5.2%) individuals judged by EMR documentation. Only 153 (30.7%) participants had iron laboratory results available. Among the 153 patients with iron panel data available, 113 (73.9%) had iron deficiency. Seventy-six had absolute iron deficiency as shown by ferritin levels below 100 ng/mL and iron saturation less than 20% and 37 had functional iron deficiency as shown by ferritin levels between 100 and 500 ng/mL and iron saturation less than 20%. 12% of all patients had documentation of iron therapy receipt. A formal diagnosis of IDA was not associated with any of the covariates. CONCLUSIONS: Iron deficiency anemia is under-diagnosed among CRC patients and most likely under-documented in clinical notes. Rates of iron repletion are low, suggesting that many patients with IDA are untreated. Future research should explore provider-level and other strategies for improving assessment and diagnosis of IDA among CRC patients.

BACKGROUND: Adult T-cell Leukemia/Lymphoma (ATLL) is a cancer disease that is developed due to the infection by human T-cell leukemia virus type 1. It can be classified into four main subtypes including, acute, chronic, smoldering, and lymphoma. Despite the clinical manifestations, there are no reliable diagnostic biomarkers for the classification of these subtypes. METHODS: Herein, we employed a machine learning approach, namely, Support Vector Machine-Recursive Feature Elimination with Cross-Validation (SVM-RFECV) to classify the different ATLL subtypes from Asymptomatic Carriers (ACs). The expression values of multiple mRNAs and miRNAs were used as the features. Afterward, the reliable miRNA-mRNA interactions for each subtype were identified through exploring the experimentally validated-target genes of miRNAs. RESULTS: The results revealed that miR-21 and its interactions with DAAM1 and E2F2 in acute, SMAD7 in chronic, MYEF2 and PARP1 in smoldering subtypes could significantly classify the diverse subtypes. CONCLUSIONS: Considering the high accuracy of the constructed model, the identified mRNAs and miRNA are proposed as the potential therapeutic targets and the prognostic biomarkers for various ATLL subtypes.

BACKGROUND: The relationship between pyroptosis and cancer is complex. It is controversial that whether pyroptosis represses or promotes tumor development. This study aimed to explore prognostic molecular characteristics to predict the prognosis of breast cancer (BRCA) based on a comprehensive analysis of pyroptosis-related gene expression data. METHODS: RNA-sequcing data of BRCA were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Ominibus (GEO) datasets. First, pyroptosis-related differentially expressed genes (DEGs) between normal and tumor tissues were identified from the TCGA database. Based on the DEGs, 1053 BRCA patients were divided into two clusters. Second, DEGs between the two clusters were used to construct a signature by a least absolute shrinkage and selection operator (LASSO) Cox regression model, and the GEO cohort was used to validate the signature. Various statistical methods were applied to assess this gene signature. Finally, Single-sample gene set enrichment analysis (ssGSEA) was employed to compare the enrichment scores of 16 types of immune cells and 13 immune-related pathways between the low- and high-risk groups. We calculated the tumor mutational burden (TMB) of TCGA cohort and evaluated the correlations between the TMB and riskscores of the TCGA cohort. We also compared the TMB between the low- and high-risk groups. RESULTS: A total of 39 pyroptosis-related DEGs were identified from the TCGA-breast cancer dataset. A prognostic signature comprising 16 genes in the two clusters of DEGs was developed to divide patients into high-risk and low-risk groups, and its prognostic performance was excellent in two independent patient cohorts. The high-risk group generally had lower levels of immune cell infiltration and lower activity of immune pathway activity than did the low-risk group, and different risk groups revealed different proportions of immune subtypes. The TMB is higher in high-risk group compared with low-risk group. OS of low-TMB group is better than that of high-TMB group. CONCLUSION: A 16-gene signature comprising pyroptosis-related genes was constructed to assess the prognosis of breast cancer patients and its prognostic performance was excellent in two independent patient cohorts. The signature was found closely associated with the tumor immune microenvironment and the potential correlation could provide some clues for further studies. The signature was also correlated with TMB and the mechanisms are still warranted.

BACKGROUND: Diabetes is an established risk factor for endometrial cancer development but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. We aimed to conduct the first systematic review and meta-analysis to compare survival outcomes in endometrial cancer patients with and without pre-existing diabetes. METHODS: We conducted a systematic search of MEDLINE, EMBASE and Web of Science databases up to February 2022 for observational studies that investigated the association between pre-existing diabetes and cancer-specific survival in endometrial cancer patients. Secondary outcomes included overall survival and progression or recurrence-free survival. Quality assessment of included studies was undertaken using the Newcastle-Ottawa Scale and a random-effects model was used to produce pooled hazard ratios (HRs) and 95% confidence intervals (CIs). (PROSPERO 2020 CRD42020196088). RESULTS: In total, 31 studies were identified comprising 55,475 endometrial cancer patients. Pooled results suggested a worse cancer-specific survival in patients with compared to patients without diabetes (n = 17 studies, HR 1.15, 95% CI 1.00-1.32, I2 = 62%). Similar results were observed for progression or recurrence-free survival (n = 6 studies, HR 1.23, 95% CI 1.02-1.47, I2 = 0%) and for overall survival (n = 24 studies, HR 1.42, 95% CI 1.31-1.54, I2 = 46%). CONCLUSION: In this systematic review and meta-analysis, we show that diabetes is associated with a worse cancer-specific and overall survival in endometrial cancer patients.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments. METHODS: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR). RESULTS: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47). CONCLUSION: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

BACKGROUND: To evaluate the effect of regorafenib on soluble MHC class I polypeptide-related sequence A (MICA) (sMICA) level in vitro. In addition, we clinically examined whether its plasma levels were associated with regorafenib activity in terms of progression-free survival (PFS) in patients with CRC. METHODS: Human CRC cell line HCT116 and HT29 cells were treated with regorafenib and its pharmacologically active metabolites, M2 or M5 at the same concentrations as those in sera of patients. We also examined the sMICA levels and the area under the plasma concentration-time curve of regorafenib, M2 and M5. RESULTS: Regorafenib, M2, and M5 significantly suppressed shedding of MICA in human CRC cells without toxicity. This resulted in the reduced production of sMICA. In the clinical examination, patients with CRC who showed long median PFS (3.7 months) had significantly lower sMICA levels than those with shorter median PFS (1.2 months) (p = 0.045). CONCLUSIONS: MICA is an attractive agent for manipulating the immunological control of CRC and baseline sMICA levels could be a predictive biomarker for the efficacy of regorafenib treatment.

BACKGROUND: Circulating long non-coding RNAs (lncRNAs) have been demonstrated to serve as diagnostic or prognosis biomarkers for various disease. We aimed to elucidate the diagnostic efficacy of serum lncRNA SCARNA10 for the hepatocellular carcinoma (HCC). METHODS: In this study, a total of 182 patients with HCC, 105 patients with benign liver disease (BLD), and 149 healthy controls (HC) were enrolled. According to different classifications, the levels of serum SCARNA10 were assessed by quantitative real-time polymerase chain reaction (qPCR). The correlations between serum SCARNA10 and clinicopathological characteristics were further analyzed. The receiver operating characteristic (ROC) curve and area under curve (AUC) were utilized to estimate the diagnostic capacity of serum SCARNA10 and its combination with AFP for HCC. RESULTS: The results demonstrated that the levels of serum SCARNA10 were significantly higher in HCC patients than in patients with BLD and healthy controls, and significantly increased in HCC patients with hepatitis B or C infection, or with liver cirrhosis. Furthermore, positive correlations were noted between serum SCARNA10 level and some clinicopathological characteristics, including tumor size, differentiation degrees, tumor stage, vascular invasion, tumor metastasis and complications. ROC analysis revealed that SCARNA10 had a significantly predictive value for HCC (Sensitivity = 0.70, Specificity = 0.77, and AUC = 0.82), the combination of SCARNA10 and AFP gained the higher sensitivity (AUCSCARNA10 + AFP = 0.92 vs AUCAFP = 0.83, p <  0.01). SCARNA10 retained significant diagnosis capabilities for AFP-negative HCC patients. CONCLUSIONS: In summary, lncRNA SCARNA10 may serve as a novel and non-invasive biomarker with relatively high sensitivity and specificity for HCC diagnosis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are used in treating cardiovascular diseases. Previous studies indicated that ACEIs/ARBs may benefit cancer patients by inhibiting tumor angiogenesis and proliferation. The effect of ACEIs/ARBs on cancer survival in esophageal and gastric cancer is still unclear. This study is to investigate the association between ACEIs/ARBs usage and esophageal and gastric cancer prognosis. METHODS: This retrospective cohort study identified esophageal and gastric cancer patients during 2008-2016 from the Taiwan Cancer Registry, and obtained medication usage and follow-up information from the National Health Insurance Research Database and Death Registry. Analysis groups were defined as ACEIs/ARBs user or non-user based on the usage of ACEIs/ARBs within the 6 months after cancer diagnosis. The stabilized inverse probability of treatment weighting using propensity scores was applied to balance covariates between study groups. We also used Kaplan-Meier estimates and Cox regression to compare survival outcome and estimate hazard ratios (HRs). RESULTS: We identified 14,463 and 21,483 newly-diagnosed esophageal and gastric cancer patients during 2008-2016. ACEIs/ARBs users were associated with lower risk of cancer-specific mortality, although only significantly in gastric cancer (gastric: adjusted HR = 0.87, 95% CI = 0.78-0.97; esophageal: adjusted HR =0.88, 95% CI = 0.76-1.02). A better survival outcome was observed among patients who received higher cumulative defined daily dose of ACEIs/ARBs. CONCLUSIONS: We found that using ACEIs/ARBs after cancer diagnosis were associated with lower risk of mortality. Our results add to the knowledge of the benefit of ACEIs/ARBs against mortality in individuals with esophageal/gastric cancer patients with hypertension.

BACKGROUND: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients. METHODS: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate. DISCUSSION: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

BACKGROUND: Lymph node (LN) status is a key prognostic factor in the decision-making process of different cancer entities, including prostate cancer (PCa). Sectioning and haematoxylin and eosin (H&E) staining technique remain the gold standard for the evaluation of LN metastases despite some limitations, especially low sensitivity in detecting an accurate tumour burden within the LN, as well as a subjective and time-consuming result. One-step nucleic acid amplification (OSNA) quantifies mRNA copies of cytokeratin 19 (CK19) in a fast, objective, automated, and reproducible way, raising a general interest to explore its utility for lymphatic metastasis identification in different malignancies. METHODS: To present the latest evidence related to the detection of LN metastases in several tumours by using OSNA compared with the conventional H&E method, a systematic review of articles published since March 2021 was conducted using PubMed, Cochrane Library, and Web of Science databases. References from primary papers and review articles were checked to obtain further potential studies. Our procedure for evaluating records identified during the literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. With the aim to design and justify future clinical routine use of OSNA in PCa, novel PCa evidence has been included in this review for the first time. RESULTS: Twenty five studies were included. LN from six different groups of tumours: breast, gastrointestinal, gynecological, lung, head and neck and prostate cancers has been assessed. OSNA was compared with post-operative formalin-fixed paraffin-embedded tissue sections with H&E staining as the reference standard. Contingency tables were created, and concordance rate, sensitivity, specificity and predictive values were reported. Seventeen studies analysed the discordant cases using different techniques. CONCLUSION: OSNA method has a high diagnostic accuracy for the detection of LN metastases in several CK19 expressing tumours. Available evidence might encourage future investigations about its usage in PCa patients to improve LN staging and prognosis.

BACKGROUND: Colorectal cancer (CRC) incidence in Finland has risen steadily. Given development in cancer treatments in recent decades, disease-specific data on the long-term prognosis of patients may be obsolete. Thus, this study aimed to report 5-year disease-specific survival (DSS) and relative survival based on tumour spread and site among CRC patients diagnosed between 1991 and 2015 in Finland. MATERIAL AND METHODS: We conducted a population-based registry study among 59 465 CRC patients identified from the Finnish Cancer Registry. RESULTS: The 5-year DSS for all CRC patients was 56.7% [95% confidence interval (CI) 56.3-57.1%] for 1991 through 2015. Tumour site-specific survival has improved for the period 2006-2015 versus 1991-2005 for right-sided colon cancer from 54.8% (95% CI 53.8-55.8%) to 59.9% (95% CI 58.7-61.1%), for left-sided colon cancer from 54.1% (95% CI 52.9-55.3%) to 61.0% (95% CI 59.8-62.2%) and for rectal cancer from 53.6% (95% CI 52.2-55.0%) to 62.3% (95% CI 61.3-63.3%). The 5-year relative survival for the period 2006 through 2015 was 93.6% for localised disease (stage I); 84.2% for locally advanced tumour invading adjacent structures (stage II); 68.2% for regional disease with regional lymph node metastases (stage III); and 14.0% for metastatic disease (stage IV). CONCLUSIONS: This study confirms that survival for CRC has improved in recent decades in Finland, mirroring observations from other Western countries. However, the classification of tumour spread within the Finnish Cancer Registry differs slightly from the TNM classification, thereby limiting the generalisability of these results.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

Comment in Int J Surg. 2022 Oct;106:106940.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic roles of these cells in different stage groups are unclear. METHODS: Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3+ TILs, CD8+ TILs, CD68+ TAMs, and CD163+ TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3+ and CD8+ cells. The "TIL score" was defined as the sum of semiquantitative scores of CD3+ E-TILs, CD3+ S-TILs, CD8+ E-TILs, and CD8+ S-TILs. For TAMs, the area of CD68+ and CD163+ cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses. RESULTS: By Cox univariate analyses, semiquantitatively low CD3+ E-TILs, low CD8+ E-TILs, and low "TIL score" were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3+ E-TILs and low CD8+ E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P < 0.0001, and P = 0.0015) and low "TIL score" (P = 0.020) were significantly correlated with worse prognosis in stage IIIC/IVB patients. By Cox multivariate analyses, semiquantitatively low CD3+ E-TILs and low CD8+ E-TILs, low "TIL score", and quantitatively low CD3+ E-TILs and low CD8+ E-TILs were independent worse prognostic factors in stage IIIC/IVB (P = 0.0011, 0.0053, 0.012, < 0.0001, and < 0.0001, respectively). CD68+ or CD163+ TAMs were not correlated with prognosis in any patients. CONCLUSIONS: Both semiquantitatively and quantitatively low E-TILs, are correlated with worse prognosis in both early and advanced stage patients with EECs. In particular, CD3+ E-TILs and CD8+ E-TILs are potentially useful prognostic markers in patients with EEC regardless of the stage.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. MATERIALS AND METHODS: The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. RESULTS: Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. CONCLUSIONS: Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.

BACKGROUND: Quality of life (QoL) is an important patient-reported outcome that has been studied extensively as an endpoint. There is a growing interest in factors that may influence QoL, such as personality. This descriptive systematic review examined the relationship between personality and QoL in women with non-metastatic breast cancer.  METHODS: On November 24th, 2020, with a update on March 7th, 2022, PubMed, PsycINFO, CINAHL, Web of Science and Embase were systematically searched for studies that assessed the direct relationship between personality traits and QoL among adult women diagnosed with non-metastatic breast cancer. The National Institutes of Health Study Quality Assessment Tool was used to assess the quality and risk of bias of the included studies. Three reviewers independently extracted data regarding objectives, population, setting, design, method, outcome measurements and key results. The results are descriptively reported. RESULTS: Twelve studies (6 cohort studies and 6 cross-sectional studies) were included. Three studies were rated as poor, one study was rated as good, and the remaining studies were rated as moderate. There was a small to moderate effect of personality on QoL as correlation coefficients ranged from 0.10 to 0.77, and the explained variance ranged from 4 to 43%. The (strength of the) relationship depended on the personality trait and QoL domain that was measured and was most apparent for the personality traits 'optimism' and 'trait anxiety' on psychosocial QoL domains. The results for the personality traits (unmitigated) agency, agreeableness, conscientiousness, novelty seeking, and self-efficacy indicated a smaller but statistically significant correlation between these personality traits and QoL. CONCLUSIONS: The results confirm that personality affects QoL in women with non-metastatic breast cancer and thus provides evidence that personality traits are indeed important influential factors of QoL. It is therefore strongly recommended for all future QoL research to measure personality traits and use these variables as predictive factors, as they are needed to accurately interpret QoL. Information regarding personality traits provide physicians and patients with an interpretation of low or deterioration of QoL, which could guide physicians to improve their patients' health outcomes and subsequently QoL using psycho-oncological support or treatment.

BACKGROUND: The purpose of this study was to investigate and validate multiparametric magnetic resonance imaging (MRI)-based machine learning classifiers for early identification of poor responders after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). METHODS: Patients with LARC who underwent nCRT were included in this retrospective study (207 patients). After preprocessing of multiparametric MRI, radiomics features were extracted and four feature selection methods were used to select robust features. The selected features were used to build five machine learning classifiers, and 20 (four feature selection methods × five machine learning classifiers) predictive models for the screening of poor responders were constructed. The predictive models were evaluated according to the area under the curve (AUC), F1 score, accuracy, sensitivity, and specificity. RESULTS: Eighty percent of all predictive models constructed achieved an AUC of more than 0.70. A predictive model using a support vector machine classifier with the minimum redundancy maximum relevance (mRMR) selection method followed by the least absolute shrinkage and selection operator (LASSO) selection method showed superior prediction performance, with an AUC of 0.923, an F1 score of 88.14%, and accuracy of 91.03%. The predictive performance of the constructed models was not improved by ComBat compensation. CONCLUSIONS: In rectal cancer patients who underwent neoadjuvant chemoradiotherapy, machine learning classifiers with radiomics features extracted from multiparametric MRI were able to accurately discriminate poor responders from good responders. The techniques should provide additional information to guide patient-tailored treatment.

BACKGROUND: Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. PATIENTS AND METHODS: Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. RESULTS: OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3β, we verified GSK3β was over-activated in OLA1-KO cell lines. CONCLUSION: OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3β.

BACKGROUND: Liver cancer is a major global health concern due to the steady increases in its incidence and mortality. Transcription factors, yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) have emerged as critical regulators in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), the two major types of primary liver cancer. However, our study as well as other previous reports have shown that activation of YAP and TAZ (YAP/TAZ) in adult murine livers is insufficient for the development of liver cancer, suggesting a requirement for an additional oncogenic collaborator for liver carcinogenesis in adulthood. Therefore, we sought to identify the oncogenic partners of YAP/TAZ that promote hepatocarcinogenesis in adults. METHODS: Data analysis of the transcriptome of patients with liver cancer was performed using the national center for biotechnology information (NCBI) gene expression omnibus (GEO) database and the cancer genome atlas (TCGA). The cancer therapeutics response portal (CTRP) was used to investigate the correlation between sensitivity to chemicals and the copy number of TAZ in human cancer cell lines. Transposons encoding constitutively activated forms of TAZ (TAZS89A), BRAF (BRAFV600E), and PIK3CA (PI3KE545K) were used for hydrodynamic tail vein injection. Mice were monitored at least twice per week and sacrificed when moribund. Tumor-bearing livers were formalin fixed for hematoxylin-eosin staining and immunohistochemistry. RESULTS: Through database analyses, we identified EGFR/HER2 signaling to be essential in human cancers with high TAZ activity. Furthermore, immunohistochemical analyses showed that human HCC and CC tissues with high YAP/TAZ activities exhibited concomitant activation of EGFR/HER2 signaling pathways. To demonstrate that EGFR/HER2 signaling promotes YAP/TAZ-mediated hepatocarcinogenesis, TAZS89A was simultaneously expressed in murine adult livers with BRAFV600E or PI3KE545K, activated forms of effector molecules downstream of EGFR/HER2 signaling pathways. Expression of TAZS89A plus BRAFV600E induced HCC, whereas TAZS89A and PI3KE545K led to the development of CC-like cancer. CONCLUSIONS: Our study demonstrates that TAZ collaborates with EGFR/HER2 signaling pathways to induce both HCC and CC.

BACKGROUND: The architectural transcriptional regulator high-mobility group AT-hook 2 (HMGA2) is an oncofetal protein which has been reported to be ectopically expressed in a variety of cancers. A high expression of HMGA2 in human renal cell carcinoma (RCC) is related with tumor invasiveness and poor prognosis. Recent in vitro studies have shown that HMGA2 knockdown was able to decrease cell proliferation and migration, and regulate the gene expression related to epithelial-mesenchymal transition (EMT). METHODS: To understand the HMGA2's effect in vivo, HMGA2 expression was knocked down in ACHN cells using small hairpin RNA (shRNA), then the HMGA2-deficient ACHN cells were xenografted into the BALB/c nude mice. Tumor growth was monitored and the expression of EMT-related genes was analyzed. RESULTS: HMGA2 expression was confirmed to be knocked down in the cultured and xenografted ACHN cells. The xenograft tumor of HMGA2-deficient cells demonstrated a retarded growth pattern compared with the control. The expression of E-cadherin was increased, whereas N-cadherin and Snail were decreased in the HMGA2-deficient xenograft tumors. CONCLUSIONS: In conclusion, to the best of our knowledge, for the first time, we have successfully developed an in vivo experiment using HMGA2-silencing ACHN cells to be grown as xenografts in nude mice. Our findings show that HMGA2 deficiency was sufficient to suppress the xenograft tumor growth in vivo, which support our hypothesis that HMGA2-induced renal carcinogenesis occurs at least in part through the regulation of tumor associated EMT genes.

BACKGROUND: This study was to determine the prevalence and clinical significance of clonal hematopoiesis (CH)-related variants, and somatic and germline mutations in cancer patients and healthy individuals. METHODS: We performed next-generation sequencing of 275 cancer-related genes be-tween plasma and white blood cells in 92 cancer patients and 47 controls without cancer. Blood samples were recruited from May 2017 to July 2021, and blood cancer patients were excluded. For all statistical analysis in this study, p < 0.05 was considered statistically significant. RESULTS: Overall, 38.04% of patients and 46.81% of controls harbored at least one CH-related mutation in plasma cell-free DNA. Based on our results, older cancer patients exhibited a CH phenomenon more frequently than younger patients (p = 0.0024). A total of 39 somatic pathogenic (P)/likely pathogenic (LP) mutations were identified in 17 genes in 21 of 92 patients. We found that the presence of P/LP variants in cancer-related gene predicted shorter overall survival (OS) (p = 0.001). Multivariate analysis adjusted for CH-related mutations, germline mutations, and tumor stage, also indicated that somatic mutations correlated significantly with OS (p = 0.022). Moreover, the frequency of a germline P/LP variant was that of seven of 92 individuals in the cancer group and one of 42 individuals in the control group. CONCLUSIONS: We characterized the CH-related variants, and somatic and germline mutations in cancer patients and healthy individuals, and the results have important clinical significance.

BACKGROUND: Stomach cancer is one the most common neoplasms with high mortality. However, fear of cancer recurrence (FCR) in stomach cancer survivors has been scarcely evaluated. Thus, the aim of this study was to evaluate FCR and factors related to FCR in Korean stomach cancer survivors. METHODS: A total of 363 stomach cancer survivors who had completed primary treatment and had no metastasis or recurrence were recruited between September 2014 and March 2017 regardless of time lapse after the initial diagnosis. FCR was assessed using the Korean version of the FCR Inventory (FCRI). Participants were divided into two groups; clinical FCRI group (score of severity subscale of FCRI ≥ 13) and non-clinical FCRI group (the scores < 13). Socio-demographic factors, cancer stage, treatment, psychological factors, health-related quality of life (HRQoL), and health promotion and disease prevention behaviors were obtained using a self-administered questionnaire supplemented with face-to-face interview to fill out incomplete information. Factors associated with FCR were evaluated using linear regression analysis and multiple logistic regression analysis after adjusting for age, sex, cancer stage, time since cancer diagnosis, family cancer diagnosis, and comorbidities. RESULTS: Average (standard deviation) time interval between cancer diagnosis and study participation was 7.3 (3.2) years. The distribution of socio-demographic and cancer-related factors did not differ according to the level of FCR. The higher FCRI level was associated with lower levels of social support (β: -0.190, p < 0.001), lower emotional function (β: -0.356, p < 0.001), more severe fatigue (β: 0.333, p < 0.001), more sleep problems (β: 0.299, p = 0.002), higher anxiety (β: 0.443, p < 0.001), and higher depression (β: 0.207, p < 0.001). However, clinical level of FCR was not associated with health promotion and disease prevention behaviors. CONCLUSIONS: FCR in stomach cancer survivors was associated with social, psychological, and HRQoL factors rather than demographic, socioeconomic, or cancer-related factors. This finding suggests that careful attention to FCR is necessary to provide more comprehensive survivorship care for stomach cancer survivors.

BACKGROUND: Salvage external beam radiotherapy (sEBRT) for patients with a biochemical recurrence (BCR) after radical prostatectomy provides a 5-year biochemical progression-free survival up to 60%. Multiple studies have shown that dose escalation to the primary prostate tumour improves treatment outcome. However, data is lacking on the role of dose escalation in the recurrent salvage setting. The main objective of the PERYTON-trial is to investigate whether treatment outcome of sEBRT for patients with a BCR after prostatectomy can be improved by increasing the biological effective radiation dose using hypofractionation. Moreover, patients will be staged using the PSMA PET/CT scan, which is superior to conventional imaging modalities in detecting oligometastases. METHODS: The PERYTON-study is a prospective multicentre open phase III randomised controlled trial. We aim to include 538 participants (269 participants per treatment arm) with a BCR after prostatectomy, a PSA-value of < 1.0 ng/mL and a recent negative PSMA PET/CT scan. Participants will be randomised in a 1:1 ratio between the conventional fractionated treatment arm (35 × 2 Gy) and the experimental hypofractionated treatment arm (20 × 3 Gy). The primary endpoint is the 5-year progression-free survival after treatment. The secondary endpoints include toxicity, quality of life and disease specific survival. DISCUSSION: Firstly, the high rate of BCR after sEBRT may be due to the presence of oligometastases, for which local sEBRT is inappropriate. With the use of the PSMA PET/CT before sEBRT, patients with oligometastases will be excluded from intensive local treatment to avoid unnecessary toxicity. Secondly, the currently applied radiation dose for sEBRT may be too low to achieve adequate local control, which may offer opportunity to enhance treatment outcome of sEBRT by increasing the biologically effective radiotherapy dose to the prostate bed. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (Identifier: NCT04642027 ). Registered on 24 November 2020 - Retrospectively registered. The study protocol was approved by the accredited Medical Ethical Committee (METc) of all participating hospitals (date METc review: 23-06-2020, METc registration number: 202000239). Written informed consent will be obtained from all participants.

BACKGROUND: Immune-check point inhibitors (ICPIs) for treatment of cancer patients sometimes induce potentially life-threatening immune-related adverse events (irAEs), which predict ICPIs treatment efficacy. Prediction of irAEs would be useful for management of irAEs and prediction of ICPIs efficacy. This study aimed to determine predictors of irAEs in patients with recurrent or unresectable advanced gastric cancer (RUGC) treated with nivolumab. METHODS: Seventy-eight RUGC patients treated with nivolumab at nine institutions between January 2017 and April 2020 were included in this study. The usefulness of specific blood test results as predictors of irAEs was evaluated. RESULTS: We observed irAEs in 15 (19.2%) patients. The disease control rate was significantly higher in the patients with irAEs than in those without (86.7% vs. 42.9%; P < 0.001). The median progression-free survival was significantly longer for patients with irAEs than for patients without (4.9 vs. 2.6 months; P = 0.018). The median survival time was longer for patients with irAEs than for those without (9.4 vs. 5.8 months; P = 0.041). The receiver operating characteristic (ROC) curves for irAEs indicated that the area under the curve (AUC) of carbohydrate antigen 19-9 (CA19-9) was highest (0.692; P = 0.022), followed by that for the platelet count × serum C-reactive protein (P-CRP) value (0.680; P = 0.032). The AUC for the CA19-9 + P-CRP combination was 0.782, which was more useful than that for either component and significantly associated with overall survival of nivolumab-treated RUGC patients. CONCLUSIONS: The CA19-9 + P-CRP combination was predictive of irAEs and prognosis in RUGC patients.

BACKGROUND: Globally cervical cancer incidence rate has been declining continuously. However, an unfavorable trend has been observed in China during the past decades, and the underlying reasons remain unclear. We hereby explore the recent trends of cervical cancer incidence, as well as the underlying determinants using data from Guangzhou, one of biggest cities in China. METHODS: City-wide cancer registration data were obtained from the Guangzhou Center for Disease Prevention and Control from 2004 to 2018. We used the Joinpoint regression models to estimate the average annual percentage change (AAPC) of age-standardized and age-specific incidence rates by regions and by histological subtype. Age-period-cohort models were applied to analyze the period and birth cohort effects on the time trends. RESULTS: The age-standardized rates (ASRs) of cervical cancer incidence increased at an annual rate of 2.1% [95% confidence interval (CI): 1.0%-3.2%] during 2004-2018. The largest increase in ASRs was found for rural regions, with AAPC of 6.6% [95% CI: 3.7%-9.5%], followed by the suburbs (2.2% [95% CI: 1.0%-3.4%]), while there was no statistically significant increase in urban regions. The ASRs of adenocarcinoma increased faster than those of the squamous cell carcinoma (AAPC = 6.53% [95% CI: 5.0%-8.1%] versus 1.79% [95% CI: 0.8%-2.8%]). A downward trend in urban regions was found in the 20-49 age group, whereas an upward trend was found in the 50 + age group, especially in rural regions. An inverted V-shape was found for cohort effects, with the peak varied by regions, i.e., peaked in the 1966 and 1971 birth cohort in the urban and suburb regions, respectively. Period effects kept increasing during the study period. CONCLUSIONS: We systematically examine the disparities in the increases of cervical cancer incidence rates using city-wide data from Guangzhou. Extensive efforts are warranted to address the large urban-rural disparities in cervical cancer prevention. The combined strategies of vaccination, screening, and health education should be reinforced and locally customized.

BACKGROUND: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. METHODS: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. DISCUSSION: This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

BACKGROUND: Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need. METHODS: The study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5-10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival. DISCUSSION: Sn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT04616547.

BACKGROUND: Genomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity. METHODS: CAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle. RESULTS: Autophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52-84% inhibition). CONCLUSIONS: While the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.

Erratum in BMC Cancer. 2022 May 2;22(1):485.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapies represent a major advance in treating a variety of advanced-stage malignancies. Nevertheless, only a subset of patients benefit, even when selected based on approved biomarkers such as PD-L1 and tumor mutational burden. New biomarkers are needed to maximize the therapeutic ratio of these therapies. METHODS: In this retrospective cohort, we assessed a 27-gene RT-qPCR immuno-oncology (IO) gene expression assay of the tumor immune microenvironment and determined its association with the efficacy of ICI therapy in 67 advanced-stage NSCLC patients. The 27-gene IO test score (IO score), programmed cell death ligand 1 immunohistochemistry tumor proportion score (PD-L1 TPS), and tumor mutational burden (TMB) were analyzed as continuous variables for response and as binary variables for one-year progression free survival. The threshold for the IO score was prospectively set based upon a previously described training cohort. Prognostic implications of the IO score were evaluated in a separate cohort of 104 advanced-stage NSCLC patients from The Cancer Genome Atlas (TCGA) who received non-ICI therapy. RESULTS: The IO score was significantly different between responders or non-responders (p = 0.007) and associated with progression-free survival (p = 0.001). Bivariate analysis established that the IO score was independent of PD-L1 TPS and TMB in identifying patients benefiting from ICI therapy. In a separate cohort of late-stage NSCLC patients from TCGA, the IO score was not prognostic of outcome from non-ICI-treated patients. CONCLUSIONS: This study is the first application of this 27-gene IO RT-qPCR assay in a clinical cohort with outcome data. IO scores were significantly associated with response to ICI therapy and prolonged progression-free survival. Together, these data suggest the IO score should be further studied to define its role in informing clinical decision-making for ICI treatment in NSCLC.

BACKGROUND: To investigate the mechanism by which apolipoprotein A1 (APOA1) enhances the resistance of cervical squamous carcinoma to platinum-based chemotherapy. METHODS: Two cervical squamous carcinoma cell lines (SiHa and Caski) overexpressing APOA1 were constructed, treated with carboplatin, and compared to normal control cells. RESULTS: In both SiHa and Caski cell lines, the clone-forming ability of CBP-treated cells was lower than that of untreated cells, and the change in the number of clones of overexpressing cells was lower than that of normal control cells (p < 0.05), indicating that APOA1 overexpression enhanced chemoresistance. A screen for APOA1 downstream proteins affecting platinum-based chemoresistance using Tandem Mass Tag revealed 64 differentially expressed proteins in SiHa cells, which were subjected to Gene Ontology (annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, subcellular localization, structural domain annotation and enrichment, clustering, and interaction network analyses. Sixty-four differentially expressed proteins matching cancer-relavent association terms were screened and parallel response monitoring identified 29 proteins as possibly involved in the mechanism of platinum-based chemoresistance. CONCLUSIONS: Our analysis suggested that the mechanism may involve numerous regulatory pathways, including promoting tumor growth via the p38 MAPK signaling pathway through STAT1, promoting tumor progression via the PI3K signaling pathway through CD81 and C3, and promoting resistance to platinum-based chemotherapy resistance through TOP2A. The present study aimed to preliminarily explore the function and mechanism of APOA1 in platinum-based chemoresistance in cervical cancer, and the detailed mechanism needs to be further studied.

BACKGROUND: Although uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics. METHODS: Transgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed. RESULTS: Cells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A. CONCLUSIONS: As the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM.

Erratum in BMC Cancer. 2022 Apr 22;22(1):439.

BACKGROUND: Routine measurement of tumor markers is not recommended in daily clinical practice for patients with cancer of unknown primary (CUP). We evaluated the diagnostic value of tumor markers in identifying favorable or unfavorable subsets in patients with CUP. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with CUP between October 2010 and July 2015 at the National Cancer Center Hospital. The tumor markers of the patients were examined, including squamous cell carcinoma antigen, cytokeratin fraction, carcinoembryonic antigen, sialyl Lewis X, neuron-specific enolase, pro-gastrin-releasing peptide, α-fetoprotein, protein induced by vitamin K absence or antagonist II, prostate-specific antigen, soluble interleukin-2 receptor, carbohydrate antigen 19-9, cancer antigen 125, cancer antigen 15-3, NCC-ST-439 (ST439), elastase-1, human chorionic gonadotropin, and sialyl-Tn (STN). RESULTS: Among 199 patients with suspected CUP, 90 were diagnosed with confirmed CUP (12 in the favorable subset and 78 in the unfavorable subset). No tumor markers showed 100% sensitivity for unfavorable subsets. ST439 (p = 0.03) and STN (p = 0.049) showed 100% specificity for unfavorable subsets. CONCLUSIONS: For patients with suspected CUP who show elevated ST439 or STN levels, the treatment strategy should be based on the premise that the patient is likely to be placed in the unfavorable subset.

Erratum in BMC Cancer. 2022 Apr 19;22(1):422.

BACKGROUND: In this study, we performed a molecular evaluation of primary pancreatic adenocarcinoma (PAAD) based on the comprehensive analysis of energy metabolism-related gene (EMRG) expression profiles. METHODS: Molecular subtypes were identified by nonnegative matrix clustering of 565 EMRGs. An overall survival (OS) predictive gene signature was developed and internally and externally validated based on three online PAAD datasets. Hub genes were identified in molecular subtypes by weighted gene correlation network analysis (WGCNA) coexpression algorithm analysis and considered as prognostic genes. LASSO cox regression was conducted to establish a robust prognostic gene model, a four-gene signature, which performed better in survival prediction than four previously reported models. In addition, a novel nomogram constructed by combining clinical features and the 4-gene signature showed high-confidence clinical utility. According to gene set enrichment analysis (GSEA), gene sets related to the high-risk group participate in the neuroactive ligand receptor interaction pathway. CONCLUSIONS: In summary, EMRG-based molecular subtypes and prognostic gene models may provide a novel research direction for patient stratification and trials of targeted therapies.

BACKGROUND: Extranodal extension (ENE) is a poor prognostic factor for oral squamous cell carcinoma (OSCC). Identifying ENE by clinical and/or radiological examination is difficult, thereby leading to unnecessary neck dissections. Currently, no definitive predictors are available for ENE. Thus, we aimed to determine the histological predictors of ENE by routine histopathological examination using biopsy and surgically resected specimens. METHODS: This retrospective study included 186 surgically resected OSCC and 83 matched biopsy specimens. Clinical features associated with the tumor microenvironment, including desmoplastic reaction (DR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs), were evaluated using hematoxylin and eosin-stained primary OSCC and neck dissection specimens. These histological features were divided into two groups: DR-immature (DR-I) and DR-mature (DR-M); TB-high (TB-H) and TB-low (TB-L); and TILs-low (TILs-L) and TILs-high (TILs-H). Clinical depth of invasion (cDOI) and pathological DOI (pDOI) were adapted for biopsies and resections, respectively; DOI was evaluated as DOI > 10 mm and DOI ≤ 10 mm. The clinicopathological relationships between these histopathological features and ENE and the independent risk factors for ENE were analyzed. The histological predictors of ENE were evaluated. RESULTS: The histological status of DR, TILs, and TB present in biopsy and resection specimens showed high accuracy with that of ENE. DR-I, TILs-L, and TB-H were significantly associated with lymph node metastasis, cDOI, and pDOI. Bivariate and multivariate analyses revealed that TB-H and pDOI > 10 mm in resections were independent factors for the presence of ENE (ENE +). The combination of TB-H/pDOI > 10 mm in resection specimens showed high specificity (91%) and accuracy (83%) regarding ENE + . Although there proved to be no independent factors in biopsies, DR-I and TILs-L were significantly associated with ENE + (p < 0.001). The combination of DR-I/TILs-L/cDOI > 10 mm in biopsies exhibited high sensitivity and specificity with ENE + (70% and 77%, respectively, p < 0.001). These histological predictors could detect even minor ENE (< 2 mm). CONCLUSIONS: The tumor microenvironment status in primary OSCC was significantly associated with that of ENE, and TB-H was an independent risk factor for ENE. The histological status of DR-I/TILs-L/cDOI > 10 mm in biopsy specimens and TB-H/pDOI > 10 mm in resection specimens is a useful predictor of ENE.

BACKGROUND: R-CHOP with or without radiotherapy is the standard treatment for limited-stage diffuse large B-cell lymphoma (DLBCL). To prevent overtreatment, we assessed whether four cycles of CHOP plus six applications of rituximab was adequate with negative interim PET/CT and the role of consolidation radiotherapy specifically for patients with Waldeyer's ring DLBCL. One hundred and twenty-nine patients with limited-stage DLBCL were enrolled in this open-label, nonrandomized, single-arm, phase 2 clinical trial (NCT01804127). METHODS: All patients were initially treated with 4 cycles of R-CHOP and underwent interim PET/CT. Patients with negative PET/CT (Deauville scores 1-2) received 2 additional cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, extranodal primary or bulky disease). Otherwise, patients received another 2 cycles of R-CHOP. Patients with partial response on interim PET/CT received another 4 cycles of R-CHOP. No radiotherapy was conducted in Waldeyer's ring DLBCL patients with negative PET/CT. The primary endpoint was 3-year progression-free survival (PFS). Overall survival (OS) in this study was compared with those from a historical study (NCT 00854568159). RESULTS: One hundred fifteen interim PET/CT scans (89.1%) were negative after 4 cycles of R-CHOP. An elevated lactate dehydrogenase level was significantly associated with positive interim PET/CT (P < 0.05). A trend of inferior outcome was observed in patients with positive interim PET/CT in terms of 3-year PFS (78.6% vs. 91.9%, P = 0.24) and 3-year OS (85.7% vs. 95.6%, P = 0.16). There were no PFS or OS differences found between patients treated with 4R-CHOP+2R and those treated with 6R-CHOP from a historical control study. Patients with Waldeyer's ring DLBCL and negative interim PET/CT achieved a 3-year PFS of 87.2% and a 3-year OS of 89.7%. CONCLUSIONS: Our results suggested that for interim PET/CT-negative patients without risk factors, the extra 2 cycles of CHOP might be omitted, and radiotherapy might also be omitted in patients with Waldeyer's ring DLBCL without compromising the efficacy. These results need to be confirmed in a randomized study. TRIAL REGISTRATION: clinicaltrials.gov ,  NCT01804127 . Date of first registration: 05/03/2013.

BACKGROUND: Cancer of Unknown Primary (CUP) is a metastatic cancer for which the primary lesion remains unidentifiable during life and little is also known about the modifiable risk factors that contribute to its development. This study investigates whether vegetables and fruits are associated with CUP risk. METHODS: We used data from the prospective Netherlands Cohort Study on Diet and Cancer which includes 120,852 participants aged between 55 and 69 years in 1986. All participants completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. As a result, 867 incident CUP cases and 4005 subcohort members were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios were calculated using proportional hazards models. RESULTS: We observed no associations between total vegetable and fruit consumption (combined or as separate groups) and CUP risk. However, there appeared to be an inverse association between the consumption of raw leafy vegetables and CUP. With respect to individual vegetable and fruit items, we found neither vegetable nor fruit items to be associated with CUP risk. CONCLUSIONS: Overall, vegetable and fruit intake were not associated with CUP incidence within this cohort.

BACKGROUND: Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. METHODS: Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. RESULTS: Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. CONCLUSIONS: Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. METHODS: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. RESULTS: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. CONCLUSION: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.

BACKGROUND: Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC). METHODS: Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20). RESULTS: ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11-1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06-3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25-3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers. CONCLUSIONS: Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum.

BACKGROUND: B4GALT5 is postulated to be an important protein in sugar metabolism that catalyzes the synthesis of lactosylceramide (LacCer). However, its role in hepatocellular carcinoma (HCC) remains unknown. METHOD: We characterized the expression of B4GALT5 in HCC tissue compared to normal tissue, and explored its function of B4GALT5 in HCC by enrichment analysis based on its co-expressed gene set. Next, we checked whether B4GALT5 expression is correlated to immune infiltration level and clinical prognosis in hepatocellular carcinoma. Finally, we verified the expression of B4GALT5 using clinical samples evaluated by RT-PCR, and conducted in vitro experiments with B4GALT5-knockdown HCC cells to investigate the function of B4GALT5 in the HCC cell proliferation, migration and invasion. RESULTS: We found B4GALT5 mRNA and protein expression levels were significantly high in HCC tissue compared to normal tissue. The enrichment analysis of the gene sets that co-expressed with B4GALT5 showed specificity in HCC-related pathways and functions. Also, the expression pattern of B4GALT5 was significantly related to the immune infiltration level, especially CD4+ T cell and macrophage cells. B4GALT5 higher mRNA expression was associated with poor overall survival (OS) in HCC patients. Furthermore, In vitro experiments showed that depletion of B4GALT5 significantly inhibited HCC cell proliferation, migration and invasion. This study revealed the function and its mediated pathways of B4GALT5 in HCC, indicating that B4GALT5 may serve as a prognostic biomarker of HCC.

Cancer-therapy related cardiotoxicity (CTRCT) is a significant and frequent complication of monoclonal antibody directed therapy, especially Trastuzumab, for human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers. Reliable, clinically available molecular predictive markers of CTRCT have not yet been developed. Identifying specific genetic variants and their molecular markers, which make the host susceptible to this complication is key to personalised risk stratification. A systematic review was conducted until April 2021, using the Medline, Embase databases and Google Scholar, to identify studies genetic and RNA-related markers associated with CTRCT in HER2 positive breast cancer patients. So far, researchers have mainly focused on HER2 related polymorphisms, revealing codons 655 and 1170 variants as the most likely SNPs associated with cardiotoxicity, despite some contradictory results. More recently, new potential genetic markers unrelated to the HER2 gene, and linked to known cardiomyopathy genes or to genes regulating cardiomyocytes apoptosis and metabolism, have been detected. Moreover, microRNAs are gaining increasing recognition as additional potential molecular markers in the cardio-oncology field, supported by encouraging preliminary data about their relationship with cardiotoxicity in breast cancers. In this review, we sought to synthesize evidence for genetic variants and RNA-related molecular markers associated with cardiotoxicity in HER2-positive breast cancer.

BACKGROUND: Saline hydration with addition of mannitol have commonly been the strategy to avoid cisplatin induced acute kidney injury (AKI). While the initial reports demonstrated that mannitol diuresis decreased cisplatin induced renal injury, others have shown renal injury to be worsened. OBJECTIVE: To compare the risk of AKI in cancer patients receiving high dose cisplatin with and without addition of mannitol. METHOD: This was an ambispective cohort study based on consecutive sampling at Cipto Mangunkusumo General Hospital (CMGH) and Mochtar Riady Comprehensive Cancer Centre (MRCCC) Siloam Hospitals. The data was obtained from September 2017 to February 2018. The choice of mannitol administration based on attending physician clinical judgement. The primary outcome was increase of serum creatinine more than 0.3 mg/dL or 1.5 times from baseline. Analysis was done by using univariate, bivariate and multivariate logistic regression to obtain crude risk ratio and adjusted risk ratio of cisplatin induced AKI probability caused by mannitol addition on top of usual saline hydration protocol. RESULT: Data from 110 patients (57.3% male) with a median age of 44.5 years (range 19 to 60 years) were collected; 63 received saline with the addition of mannitol and 47 received saline only. Incidence of AKI were higher in mannitol vs saline only group. Bivariate analysis showed higher probability of post chemotherapy AKI in mannitol group, however it was statistically insignificant (RR 2.168; 95% CI 0.839-5.6; p = 0.094). On multivariate analysis the age adjusted RR was 2.852 (95% CI 0.68-11.96; p = 0.152). CONCLUSION: The addition of mannitol to hydration did not reduce the risk of cisplatin induced AKI as compared with saline hydration only. It was also found that risk for acute kidney injury were higher in population ≥ 40 years old.

BACKGROUND: A more extensive surgical resection of glioma contributes to improved overall survival (OS) and progression-free survival (PFS). However, some patients miss the chance of surgical resection when the tumor involves critical structures. PURPOSE: The present study aimed to assess the feasibility of neoadjuvant 125I brachytherapy followed by total gross resection for initially inoperable glioma. METHODS: Six patients diagnosed with inoperable glioma due to invasion of eloquent areas, bihemispheric diffusion, or large tumor volume received 125I brachytherapy. Surgical resection was performed when the tumor shrank, allowing a safe resection, assessed by the neurosurgeons. Patients were followed up after surgery. RESULTS: Shrinkage of the tumor after adjuvant 125I brachytherapy enabled a total gross resection of all six patients. Four patients were still alive at the last follow-up, with the longest survival time of more than 50 months, two of which returned to everyday life with a KPS of 100. Another two patients had neurological injuries with KPSs of 80 and 50, respectively. One patient with grade II glioma died 34 months, and another with grade IV glioma died 40 months after the combined therapy. CONCLUSIONS: In the present study, the results demonstrated that 125I brachytherapy enabled a complete resection of patients with initially unresectable gliomas. 125I brachytherapy may offer a proper neoadjuvant therapy method for glioma.

BACKGROUND: For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. METHODS: Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4-1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0-18.0 × 105/kg). RESULTS: hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12-18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. CONCLUSIONS: Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. TRIAL REGISTRATION: Chinese Clinical Trial Registry/WHO International Clinical Trial Registry ( ChiCTR1900024456 , URL: www.chictr.org.cn ); registered on July 12, 2019.

OBJECTIVE: To present a systematic review of the literature and a meta-analysis evaluating the oncological safety of autologous fat grafting (AFG). SUMMARY BACKGROUND DATA: AFG for breast reconstruction presents difficulties during follow-up radiological exams, and the oncological potential of grafted fat is uncertain. Previous studies confirmed that the fatty tissue could be transferred under a good condition suitable would not interfere with mammographic follow-up, although the issue of oncological safety remains. METHODS: We reviewed the literature published until 01/18/2021. The outcomes were overall survival (OS), disease-free survival (DFS), and local recurrence (LR). We included studies that evaluated women with breast cancer who undergone surgery followed by reconstruction with AFG. We synthesized data using the inverse variance method on the log-HR (log of the hazard ratio) scale for time-to-event outcomes using RevMan. We assessed heterogeneity using the Chi2 and I2 statistics. RESULTS: Fifteen studies evaluating 8541 participants were included. The hazard ratios (HR) could be extracted from four studies, and there was no difference in OS between the AFG group and control (HR 0.9, 95% CI 0.53 to 1.54, p = 0.71, I2 = 58%, moderate certainty evidence), and publication bias was not detected. The HR for DFS could be extracted from six studies, and there was no difference between the AFG group and control (HR 1.01, 95% CI 0.73 to 1.38, p = 0.96, I2 = 0%, moderate certainty evidence). The HR for LR could be extracted from ten studies, and there was no difference between the AFG group and control (HR 0.86, 95% CI 0.66 to 1.12, p = 0.43, I2 = 1%, moderate certainty evidence). CONCLUSION: According to the current evidence, AFG is a safe technique of breast reconstruction for patients that have undergone BC surgery and did not affect OS, DFS, or LR.

BACKGROUND: Adjuvant chemotherapy for stage II colorectal cancer (CRC) is considered appropriate for patients with risk factors for recurrence, rather than for all patients uniformly. However, the risk factors for recurrence remain controversial, and there is limited information, especially for elderly patients. The Geriatric Nutritional Risk Index (GNRI) is widely used as a simple nutritional screening tool in the elderly and is associated with cancer prognosis and recurrence. This study aimed to investigate the risk factors for recurrence in the elderly with stage II CRC, focusing on the GNRI. METHODS: We enrolled 348 elderly patients (≥ 75 years) with stage II CRC who underwent curative resection at the Department of Surgery, Tottori University and our 10 affiliated institutions. The patients were divided into GNRIhigh (≥ 93.465) and GNRIlow (< 93.465) groups. RESULTS: The GNRIlow group showed a significantly worse overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) (P < 0.001, P < 0.001, and P < 0.001, respectively). In a multivariate analysis, GNRIlow (hazard ratio [HR]: 2.244, P < 0.001), pathologic T4 stage (HR: 1.658, P = 0.014), and moderate to severe lymphatic or venous invasion (HR: 1.460, P = 0.033) were independent factors affecting RFS. By using these three factors to score the risk of recurrence from 0 to 3 points, the prognosis was significantly stratified in terms of OS, CSS, and RFS (P < 0.001, P < 0.001, and P < 0.001, respectively). The recurrence rate for each score was as follows: 0 points, 9.8%; 1 point, 22.0%; 2 points, 37.3%; and 3 points, 61.9%. CONCLUSIONS: GNRIlow, pathologic T4 stage, and moderate to severe lymphatic or venous invasion are high-risk factors for recurrence in the elderly with stage II CRC. The scoring system using these three factors appropriately predicted their recurrence and outcome.

BACKGROUND: Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT1) and ACAT1-mediated cholesterol esterified with fatty acids (CE) contribute to cancer progression in various cancers. Our findings of increased CE and ACAT1 levels in epithelial ovarian cancer (EOC) cell lines prompted us to investigate whether such an increase occurs in primary clinical samples obtained from human subjects diagnosed with EOC. We evaluated the diagnostic/prognostic potential of ACAT1 and CE in EOC by: 1) assessing ACAT1 and CE levels in plasma, peritoneal fluid, and ovarian/tumor tissues; 2) assessing diagnostic performance by Receiver Operating Characteristic (ROC) analysis; and 3) comparing expression of ACAT1 and CE with that of tumor proliferation marker, Ki67. METHODS: ACAT1 protein levels in plasma, peritoneal fluid and tissue were measured via enzyme-linked immunosorbent assay. Tissue expression of ACAT1 and Ki67 proteins were confirmed by immunohistochemistry and mRNA transcript levels were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). CE levels were assessed in plasma, peritoneal fluid (colorimetric assay) and in tissue (thin layer chromatography). RESULTS: Preoperative levels of ACAT1 and CE on the day of surgery were significantly higher in tissue and peritoneal fluid from EOC patients vs. the non-malignant group, which included subjects with benign tumors and normal ovaries; however, no significant differences were observed in plasma. In tissue and peritoneal fluid, positive correlations were observed between CE and ACAT1 levels, as well as between ACAT1/CE and Ki67. CONCLUSIONS: ACAT1 and CE accumulation may be linked to the aggressive potential of EOC; therefore, these mediators may be useful biomarkers for EOC prognosis and target-specific treatments.

BACKGROUND: Accumulating evidence suggests that LINC00511 acts as an oncogenic long non-coding RNA (lncRNA) in various cancers, including lung adenocarcinoma (LUAD). Hence, we attempted to elucidate the potential role of LINC00511 in LUAD. METHODS: LINC00511, miR-195-5p, and GCNT3 expression in LUAD was detected by qRT-PCR. Changes in the proliferation, migration, and invasion of LUAD cells after abnormal regulation of LINC00511, miR-195-5p, or GCNT3 were detected by CCK-8, BrdU, wound healing, and transwell assays. Bax and Bcl-2 protein expression was measured by western blotting. Additionally, we identified the targeting effects of LINC00511, miR-195-5p, and GCNT3 using luciferase and RNA immunoprecipitation (RIP) assays. RESULTS: LINC00511 and GCNT3 were found to be upregulated in LUAD, while miR-195-5p was downregulated. Silencing LINC00511 or GCNT3 decreased the proliferation, migration, invasion, and Bcl-2 protein content in LUAD cells and increased the expression of Bax. Interference with miR-195-5p promoted malignant proliferation of cancer cells. miR-195-5p expression was affected by LINC00511and targeted GCNT3. CONCLUSION: Silencing LINC00511 promotes GCNT3 expression by inhibiting miR-195-5p and ultimately stimulates the malignant progression of LUAD.

BACKGROUND: Colposcopy alone can result in misidentification of high-grade squamous intraepithelial or worse lesions (HSIL +), especially for women with Type 3 transformation zone (TZ) lesions, where colposcopic assessment is particularly imprecise. This study aimed to improve HSIL + case identification by supplementing referral screening results to colposcopic findings. METHODS: This is an observational multicenter study of 2,417 women, referred to colposcopy after receiving cervical cancer screening results. Logistic regression analysis was conducted under uni- and multivariate models to identify factors which could be used to improve HSIL + case identification. Histological diagnosis was established as the gold standard and is used to assess accuracy, sensitivity, and specificity, as well as to incrementally improve colposcopy. RESULTS: Multivariate analysis highlighted age, TZ types, referral screening, and colposcopists' skills as independent factors. Across this sample population, diagnostic accuracies for detecting HSIL + increased from 72.9% (95%CI 71.1-74.7%) for colposcopy alone to 82.1% (95%CI 80.6-83.6%) after supplementing colposcopy with screening results. A significant increase in colposcopic accuracy was observed across all subgroups. Although, the highest increase was observed in women with a TZ3 lesion, and for those diagnosed by junior colposcopists. CONCLUSION: It appears possible to supplement colposcopic examinations with screening results to improve HSIL + detection, especially for women with TZ3 lesions. It may also be possible to improve junior colposcopists' diagnoses although, further psychological research is necessary. We need to understand how levels of uncertainty influence diagnostic decisions and what the concept of "experience" actually is and what it means for colposcopic practice.

BACKGROUND: We aimed to investigate response and prognostic factors in patients with human epidermal growth factor receptor 2 (HER2) positive metastatic colorectal cancer (mCRC) and compare the curative effect on patients who received different therapy regimens (including chemotherapy and chemotherapy combined with targeted drugs). METHODS: We retrospectively analyzed all HER2 positive mCRC patients treated at Peking University Cancer Hospital between September 2011 and February 2021. We divided 63 HER2 positive mCRC into group A and group B according to the use of trastuzumab or not. Besides, we assigned four subgroups according to the first-line therapies of KRAS/NRAS/BRAF WT patients. The Kaplan-Meier estimator was used to calculate PFS and OS. Univariable analysis and Cox proportional hazards models were used to analyze the association between clinicopathological features and survival outcomes. RESULTS: Among 63 patients, 54 (85.7%) were KRAS/NRAS/BRAF wild-type (WT). Univariate analysis showed that the male sex, primary lesions in the right colon, simultaneous metastasis, and unresectable primary lesions were significant risk factors for poor survival of HER2 positive mCRC (P < 0.05). Using Cox proportional hazards models, we found that the two factors of gender and resection of primary lesions were independent prognostic factors (P < 0.05). The median PFS and median OS of HER2-positive patients with mCRC who received first-line treatment were 8.4 months [95% confidence interval (CI): 5.0-11.7] and 48.2 months (95% CI: 23.5-72.8), respectively. The log-rank test revealed a significant difference in median OS survival between group A and group B (χ2 = 5.852, P = 0.016), and the two groups were divided according to the use or absence of trastuzumab treatment. In KRAS/NRAS/BRAF WT patients, there was a significant difference in median PFS and median OS between the fourth group patients (chemotherapy plus trastuzumab) and each of the other three groups (P < 0.05). CONCLUSIONS: The two factors of gender and resection for primary lesion may be independent prognostic factors of advanced HER2 positive colorectal cancer patients. For patients with HER2-positive mCRC, patients in the chemotherapy combined with trastuzumab group have better efficacy than those without trastuzumab.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common histological type of thyroid malignancy that tends to metastasize to cervical lymph nodes. In the present study, we aimed to investigate which clinicopathologic and ultrasound features of PTC are associated with clinical lymph node metastasis (LNM) and numbers of pathological LNM. METHODS: From January 2016 to December 2018, we identified a cohort of patients with PTC who underwent cervical ultrasonography and were diagnosed through operation and pathology. Clinical N1(cN1) and > 5 pathologic N1(pN1) were considered in the postoperative stratification to have an intermediate risk according to the 2015 ATA guidelines. Clinicopathological and ultrasound features in PTC patients were performed in accordance with the independent risk factors of cN1 and > 5pN1 respectively by using the univariate and multivariate analyses. RESULTS: We collected 748 PTC patients in the final inclusion criteria. There were 688 cN0 cases and 60 cN1 cases. From the analyses, primary tumor size > 2 cm, capsule contact, extrathyroidal extensions (ETE) and central LNM remained independent risk factors for cN1 in PTC patients. In the 748 PTC patients, 707 cases had ≤ 5 pN1, and 41 cases had > 5 pN1. Multifocality, primary tumor size > 2 cm, capsule contact and ETE are significant independent risk factors for > 5 pN1. CONCLUSIONS: We concluded that multifocality, primary tumor size > 2 cm, capsule contact, ETE and central LNM were independent risk factors for the intermediate risk stratification in patients with PTC. Ultrasonography is a good technique for the preoperative lymph node staging of PTC and is helpful for detecting LNM.