BACKGROUND: A plethora of prognostic biomarkers for esophageal squamous cell carcinoma (ESCC) that have hitherto been reported are challenged with low reproducibility due to high molecular heterogeneity of ESCC. The purpose of this study was to identify the optimal biomarkers for ESCC using machine learning algorithms. METHODS: Biomarkers related to clinical survival, recurrence or therapeutic response of patients with ESCC were determined through literature database searching. Forty-eight biomarkers linked to recurrence or prognosis of ESCC were used to construct a molecular interaction network based on NetBox and then to identify the functional modules. Publicably available mRNA transcriptome data of ESCC downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets included GSE53625 and TCGA-ESCC. Five machine learning algorithms, including logical regression (LR), support vector machine (SVM), artificial neural network (ANN), random forest (RF) and XGBoost, were used to develop classifiers for prognostic classification for feature selection. The area under ROC curve (AUC) was used to evaluate the performance of the prognostic classifiers. The importances of identified molecules were ranked by their occurrence frequencies in the prognostic classifiers. Kaplan-Meier survival analysis and log-rank test were performed to determine the statistical significance of overall survival. RESULTS: A total of 48 clinically proven molecules associated with ESCC progression were used to construct a molecular interaction network with 3 functional modules comprising 17 component molecules. The 131,071 prognostic classifiers using these 17 molecules were built for each machine learning algorithm. Using the occurrence frequencies in the prognostic classifiers with AUCs greater than the mean value of all 131,071 AUCs to rank importances of these 17 molecules, stratifin encoded by SFN was identified as the optimal prognostic biomarker for ESCC, whose performance was further validated in another 2 independent cohorts. CONCLUSION: The occurrence frequencies across various feature selection approaches reflect the degree of clinical importance and stratifin is an optimal prognostic biomarker for ESCC.

BACKGROUND: The tumor microenvironment (TME) has significantly correlation with tumor occurrence and prognosis. Our study aimed to identify the prognostic immune-related genes (IRGs)in the tumor microenvironment of colorectal cancer (CRC). METHODS: Transcriptome and clinical data of CRC cases were downloaded from TCGA and GEO databases. Stromal score, immune score, and tumor purity were calculated by the ESTIMATE algorithm. Based on the scores, we divided CRC patients from the TCGA database into low and high groups, and the differentially expressed genes (DEGs) were identified. Immune-related genes (IRGs) were selected by venn plots. To explore underlying pathways, protein-protein interaction (PPI) networks and functional enrichment analysis were used. After utilizing LASSO Cox regression analysis, we finally established a multi-IRGs signature for predicting the prognosis of CRC patients. A nomogram consists of the thirteen-IRGs signature and clinical parameters was developed to predict the overall survival (OS). We investigated the association between prognostic validated IRGs and immune infiltrates by TIMER database. RESULTS: Gene expression profiles and clinical information of 1635 CRC patients were collected from the TCGA and GEO databases. Higher stromal score, immune score and lower tumor purity were observed positive correlation with tumor stage and poor OS. Based on stromal score, immune score and tumor purity, 1517 DEGs, 1296 DEGs, and 1892 DEGs were identified respectively. The 948 IRGs were screened by venn plots. A thirteen-IRGs signature was constructed for predicting survival of CRC patients. Nomogram with a C-index of 0.769 (95%CI, 0.717-0.821) was developed to predict survival of CRC patients by integrating clinical parameters and thirteen-IRGs signature. The AUC for 1-, 3-, and 5-year OS were 0.789, 0.783 and 0.790, respectively. Results from TIMER database revealed that CD1B, GPX3 and IDO1 were significantly related with immune infiltrates. CONCLUSIONS: In this study, we established a novel thirteen immune-related genes signature that may serve as a validated prognostic predictor for CRC patients, thus will be conducive to individualized treatment decisions.

Erratum in BMC Cancer. 2021 Sep 15;21(1):1023.

BACKGROUND: 5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells. METHODS: MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines. RESULTS: Treatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax. CONCLUSION: Mitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.

BACKGROUND: Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. METHODS: Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. RESULTS: We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 +  (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. CONCLUSION: TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.

BACKGROUND: D-limonene and its derivatives have demonstrated potential chemopreventive and anticancer activity in preclinical and clinical studies. The aim of this scoping review was to assess and critically appraise current literature on the effect of these bioactive citrus peel compounds on breast cancer in human trials and to identify knowledge gaps for exploration in future studies. METHODS: This study followed a scoping review framework. Peer-reviewed journal articles were included if they reported the effect of d-limonene or its derivatives on breast cancer in human subjects. Articles were retrieved from academic databases - PubMed, EMBASE, CINAHL, Web of Science, and Cochrane reviews - and iteratively through review of bibliographies of relevant manuscripts. Titles and abstracts were appraised against the aforementioned inclusion criteria in a first round of screening. Through consensus meetings and full article review by authors, a final set of studies were selected. Results were reported according to the PRISMA extension for scoping reviews. RESULTS: Our search strategy yielded 367 records. Following screening and adjudication, five articles reporting on phase 1(n = 2), phase 2 (n = 2) and both trial phases (n = 1) were included as the final dataset for this review. Trials evaluating the effect of d-limonene (n = 2) showed it was well tolerated in subjects. One study (n = 43 participants) showed d-limonene concentrated in breast tissue (mean 41.3 μg/g tissue) and reduction in tumor cyclin D1 expression, which is associated with tumor proliferation arrest. This study did not show meaningful change in serum biomarkers associated with breast cancer, except for a statistically significant increase in insulin-like growth factor-1 (IGF-I) levels. While elevation of IGF-I is associated with increased cancer risk, the clinical implication of this study remains uncertain given its short duration. Trials with perillyl alcohol (n = 3) showed low tolerance and no effect on breast cancer. CONCLUSION: This review demonstrated a dearth of clinical studies exploring the effect of d-limonene and its derivatives on breast cancer. Limited literature suggests d-limonene is safe and tolerable in human subjects compared to its derivative, perillyl alcohol. Our review demonstrates the need for additional well-powered placebo-controlled trials that assess d-limonene's efficacy on breast cancer compared to other therapies.

BACKGROUND: Radical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream. METHODS: The number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined. RESULTS: The results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form. CONCLUSION: Collectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.

BACKGROUND: Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. METHODS: The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/- durvalumab +/- oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. DISCUSSION: combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. TRIAL REGISTRATION: trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.

BACKGROUND: Colorectal cancer (CRC) is a major public health issue due to high morbidity and mortality. Different screening programs were implemented to reduce its burden. OBJECTIVES: To estimate the prevalence of CRC screening uptake using fecal immunochemical test (FIT) or guaiac fecal occult blood testing (gFOBT) in Emirati nationals. Other objectives were to measure the incidence of CRC in the screened population, to measure the outcomes of follow-up screening colonoscopy after positive FIT/gFOBT and to identify the causes of not performing follow-up screening colonoscopy after positive FIT/gFOBT. METHODOLOGY: Adult Emirati nationals aged 40-75 years who visited Ambulatory healthcare services clinics, Abu Dhabi in 2015-2016 were included in the study. The electronic medical records of the eligible individuals were reviewed retrospectively. The prevalence of CRC screening was measured among the eligible population using the FIT/gFOBT. The IBM SPSS Statistics program, version 21.0.0, was used for analysis. RESULT: 45,147 unique individuals were eligible for screening, and only 23.5% were screened using FIT/gFOBT. Of the screened individuals, 13.5% had positive FIT/ gFOBT, and 30.5% of those underwent follow-up screening colonoscopy. CRC was diagnosed in 11 individuals. Colonic polyp were found in 30.5% of individuals who had undergone a follow-up colonoscopy. Collectively 933 individuals did not undergo follow-up screening colonoscopy after having a positive FIT/gFOBT, and about 36.3% had collected the result and referred to a gastroenterologist but did not attend the appointment. CONCLUSION: CRC screening uptake using FIT/gFOBT is low among the adult Emirati nationals.

BACKGROUND: This study aimed to assess the utility of deep learning analysis using pretreatment FDG-PET images to predict local treatment outcome in oropharyngeal squamous cell carcinoma (OPSCC) patients. METHODS: One hundred fifty-four OPSCC patients who received pretreatment FDG-PET were included and divided into training (n = 102) and test (n = 52) sets. The diagnosis of local failure and local progression-free survival (PFS) rates were obtained from patient medical records. In deep learning analyses, axial and coronal images were assessed by three different architectures (AlexNet, GoogLeNET, and ResNet). In the training set, FDG-PET images were analyzed after the data augmentation process for the diagnostic model creation. A multivariate clinical model was also created using a binomial logistic regression model from a patient's clinical characteristics. The test data set was subsequently analyzed for confirmation of diagnostic accuracy. Assessment of local PFS rates was also performed. RESULTS: Training sessions were successfully performed with an accuracy of 74-89%. ROC curve analyses revealed an AUC of 0.61-0.85 by the deep learning model in the test set, whereas it was 0.62 by T-stage, 0.59 by clinical stage, and 0.74 by a multivariate clinical model. The highest AUC (0.85) was obtained with deep learning analysis of ResNet architecture. Cox proportional hazards regression analysis revealed deep learning-based classification by a multivariate clinical model (P < .05), and ResNet (P < .001) was a significant predictor of the treatment outcome. In the Kaplan-Meier analysis, the deep learning-based classification divided the patient's local PFS rate better than the T-stage, clinical stage, and a multivariate clinical model. CONCLUSIONS: Deep learning-based diagnostic model with FDG-PET images indicated its possibility to predict local treatment outcomes in OPSCCs.

BACKGROUND: Research recommends the development and evaluation of interventions to support women with breast cancer in returning to, or managing, work. Despite this, there has historically been a paucity of rehabilitation interventions to support women with breast cancer to maintain or return to their work role. The aim of this systematic review was to examine key characteristics of rehabilitation interventions, and their effectiveness on work outcomes for women with breast cancer, compared to usual care. METHODS: A systematic review was conducted of controlled studies of rehabilitation interventions with work outcomes for women with breast cancer. Six databases were systematically searched: EMBASE, Web of Science, MEDLINE (OVID), CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL). Results are presented either as pooled odds ratio (OR) or pooled effect size (hedges g) between groups, with 95% confidence intervals (CI). Narrative synthesis was conducted on intervention outcomes not suitable for meta-analysis. RESULTS: Five thousand, five hundred and thirty-five studies were identified. Nine out of 28 abstracts met inclusion criteria. Heterogeneity of interventions and outcomes precluded meta-analysis for most outcomes. Of the interventions included in meta-analysis, no significant differences compared to usual care were found for sick leave (2 studies (12 months); OR 1.11 (95% CI: 0.66 to 1.87), number of sick days taken (2 studies (six months); difference in effect: - 0.08, (95% CI: - 0.48 to 0.38) or working hours (2 studies (12 months); 0.19, (95% CI: - 0.20 to 0.64). Only one study, with a multidisciplinary intervention, showed a significant difference for work outcomes when compared to usual care. Work-specific content featured in three interventions only, none of which provided conclusive evidence for improvement in work outcomes. Enhanced physical and psychological sequalae, and quality of life was observed in some studies. CONCLUSION: There remains a lack of effective and methodologically rigorous rehabilitation intervention studies for breast cancer survivors. The development and evaluation of effective rehabilitation interventions to support return to work is warranted.

BACKGROUND: In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. METHODS: We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. RESULTS: PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. CONCLUSIONS: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12-18 months as median survival, and 5-10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary. METHODS: Immunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy. RESULTS: From the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)]. CONCLUSIONS: ERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.

BACKGROUND: Because lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed. METHOD: This study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated. RESULTS: The overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner. CONCLUSION: Lenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm.

BACKGROUND: Colon cancer is largely implicated in elderly patients (age ≥ 60 years). The prognosis of patients diagnosed with the M1b stage is vastly poor. Marital and insurance status has been considered important prognostic factors in various cancer types. However, how these factors influence elderly patients with stage M1b colon cancer remains to be explored. This study aims to uncover the role of marital and insurance status in the survival of elderly patients with stage M1b colon cancer. METHODS: We retrieved data for patients diagnosed with stage M1b colon cancer between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis of the clinicopathological features, overall survival (OS), and cancer-specific survival (CSS) was based on the marital and insurance status, respectively. RESULTS: In sum, 5709 stage M1b colon cancer patients with complete information from SEER were enrolled for analysis. The OS and CSS of the Non-married group were poorer compared to that of the Married group. The OS and CSS of the Uninsured group were poorer than both of the Insured group and Medicaid group. However, OS was comparable between Uninsured group and Medicaid groups. The findings allude that marital and insurance status potentially impact the long-term survival of elderly patients with M1b colon cancer. The subgroup survival analyses revealed the lowest risk for death among the Insured Married group based on the comparison of the OS and CSS across all other groups. Moreover, Univariate and multivariate analyses revealed race, marital status, surgery, and chemotherapy as independent predictors for OS, whereas insurance status, surgery,and chemotherapy were independent predictors for CSS in elderly patients with M1b colon cancer. CONCLUSION: The marital and insurance status greatly impact the survival of elderly patients with M1b colon cancer. Therefore, it is imperative to provide more support to this vulnerable patient group who are lonely and uninsured, particularly in the psychological and health insurance aspect.

BACKGROUND: Although many intratumoral biomarkers have been reported to predict clear cell renal cell carcinoma (ccRCC) patient prognosis, combining intratumoral and clinical indicators could predict ccRCC prognosis more accurately than any of these markers alone. This study mainly examined the prognostic value of HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1) expression in ccRCC patients in combination with established clinical indicators. METHODS: The expression level of HECW1 was screened out by data-independent acquisition mass spectrometry (DIA-MS) and analyzed in ccRCC patients from the The Cancer Genome Atlas (TCGA) database and our cohort. A total of 300 ccRCC patients were stochastically divided into a training cohort and a validation cohort, and real-time PCR, immunohistochemistry (IHC) and statistical analyses were employed to examine the prognostic value of HECW1 in ccRCC patients. RESULTS: The expression level of HECW1 usually decreased in human ccRCC specimens relative to control specimens in TCGA (p < 0.001). DIA-MS, Real-time PCR, and IHC analyses also showed that the majority of ccRCCs harbored decreased HECW1 expression compared with that in normal adjacent tissues (p < 0.001). Additionally, HECW1 expression was reduced in ccRCC cell lines compared with the normal renal cell line HK-2 (p < 0.001). Moreover, lower HECW1 expression was found in ccRCC patients with a higher tumor node metastasis (TNM) stage, bone metastasis, or first-line targeted drug resistance (p < 0.001). Low HECW1 expression indicated higher TNM stage, SSIGN (Stage, Size, Grade, and Necrosis) score and WHO/ISUP grade and poor prognosis in ccRCC patients (p < 0.05). Even after multivariable adjustment, HECW1, TNM stage, and SSIGN score served as independent risk factors. The c-index analysis showed that integrating intratumoral HECW1 expression into TNM stage or SSIGN score resulted in a higher c-index value than these indicators alone for predicting ccRCC patient prognosis. CONCLUSION: HECW1 is a novel prognostic biomarker and therapeutic target in ccRCC, and integrating intratumoral HECW1 expression with established clinical indicators yields higher accuracy in assessing the postoperative prognosis of ccRCC patients.

BACKGROUND: The prognostic roles of three lymph node classifications, number of positive lymph nodes (NPLN), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) in lung adenocarcinoma are unclear. We aim to find the classification with the strongest predictive power and combine it with the American Joint Committee on Cancer (AJCC) 8th TNM stage to establish an optimal prognostic nomogram. METHODS: 25,005 patients with T1-4N0-2M0 lung adenocarcinoma after surgery between 2004 to 2016 from the Surveillance, Epidemiology, and End Results database were included. The study cohort was divided into training cohort (13,551 patients) and external validation cohort (11,454 patients) according to different geographic region. Univariate and multivariate Cox regression analyses were performed on the training cohort to evaluate the predictive performance of NPLN (Model 1), LODDS (Model 2), LNR (Model 3) or LODDS+LNR (Model 4) respectively for cancer-specific survival and overall survival. Likelihood-ratio χ2 test, Akaike Information Criterion, Harrell concordance index, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to evaluate the predictive performance of the models. Nomograms were established according to the optimal models. They're put into internal validation using bootstrapping technique and external validation using calibration curves. Nomograms were compared with AJCC 8th TNM stage using decision curve analysis. RESULTS: NPLN, LODDS and LNR were independent prognostic factors for cancer-specific survival and overall survival. LODDS+LNR (Model 4) demonstrated the highest Likelihood-ratio χ2 test, highest Harrell concordance index, and lowest Akaike Information Criterion, and IDI and NRI values suggested Model 4 had better prediction accuracy than other models. Internal and external validations showed that the nomograms combining TNM stage with LODDS+LNR were convincingly precise. Decision curve analysis suggested the nomograms performed better than AJCC 8th TNM stage in clinical practicability. CONCLUSIONS: We constructed online nomograms for cancer-specific survival and overall survival of lung adenocarcinoma patients after surgery, which may facilitate doctors to provide highly individualized therapy.

BACKGROUND: There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. METHODS: EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. RESULTS: 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). CONCLUSIONS: Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

BACKGROUND: Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of protoporphyrin-IX within the tumor cells. Recent studies showed that a novel anti-cancer drug, Alectinib, an orally available, highly selective, potent second-generation inhibitor of anaplastic lymphoma tyrosinkinase binds to ferrochelatase. Therefore, we were interested to see whether Alectinib treatment might lead to an accumulation of protoporphyrin IX. METHODS: Tumor cells of different origin were cultured, treated with LED-light and Alectinib. Results were gained by flow cytometry, immunohistochemistry and western blotting. Apoptosis was determined by flow cytometric analysis of Annexin V-FITC stained cells. In addition, cells were counterstained with propidium iodide to distinguish early apoptotic cells and late apoptotic/necrotic cells. RESULTS: Here, we report that photodynamic treatment of tumor cell lines of different origin in combination with Alectinib increased protoporphyrin-IX specific fluorescence and concomitantly cell death. CONCLUSIONS: The usage of Alectinib could be another step for enhancing the effectiveness of photodynamic therapy. Further experiments will show whether photodynamic therapy in combination with Alectinib could be a new strategy for the treatment of e.g. peritoneal disseminated carcinomas.

BACKGROUND: Tumor mutation burden is an emerging biomarker for immunotherapy. Although several clinical trials for immunotherapy in lymphoma have been carried out, the mutation burden of various lymphomas is not well known yet. Thus, the objective of this study was to compare tumor mutation burden of various non-Hodgkin lymphomas using panel based massively parallel sequencing. METHODS: We conducted 405 gene panel based massively parallel sequencing of 300 non-Hodgkin lymphomas and investigate the number of SNV/Indel in each lymphoma. RESULTS: The number of SNV/Indel was higher in mature B-cell lymphoma than in mature T- and NK-cell lymphoma. (P < 0.001) The number of SNV/Indel in primary mediastinal large B-cell lymphoma and primary diffuse large B-cell lymphoma of the central nervous system was the highest, which was significantly higher than that in diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS).(P = 0.030 and P = 0.008, respectively) The SNV/Indel number in EBV-positive DLBCL NOS was significantly lower than that in DLBCL NOS. (P = 0.048) Peripheral T-cell lymphoma, NOS showed no significant difference in the number of SNV/Indel from extranodal NK/T-cell lymphoma, nasal type (P = 0.942) or angioimmunoblastic T-cell lymphoma (P = 0.739). The number of SNV/Indel in anaplastic large cell lymphoma, ALK-positive was significantly lower than that in anaplastic large cell lymphoma, ALK-negative (P = 0.049). It was the lowest among all the lymphomas considered. CONCLUSION: Various lymphomas have different mutation burdens. Thus, tumor mutation burden can be used as a promising biomarker for immunotherapy in lymphomas.

BACKGROUND: Ovarian cancer is the leading cause of death among gynecological malignancies. Immunotherapy has demonstrated potential effects in ovarian cancer. However, few studies on immune-related prognostic signatures in ovarian cancer have been reported. This study aimed to identify hub genes associated with immune infiltrates to provide insight into the immune regulatory mechanisms in ovarian cancer. METHODS: Raw data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and University of California, Santa Cruz (UCSC) Xena websites. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Kaplan-Meier analysis and differential expression analysis were applied to explore the real hub genes. RESULTS: Through ssGSEA and WGCNA, 7 hub genes (LY9, CD5, CXCL9, IL2RG, SLAMF1, SLAMF6, and SLAMF7) were identified. Finally, LY9 and SLAMF1 were recognized as the real hub genes in immune infiltrates of ovarian cancer. LY9 and SLAMF1 are classified as SLAM family receptors involved in the activation of hematopoietic cells and the pathogenesis of multiple malignancies. Furthermore, 12 lncRNAs and 43 miRNAs significantly related to the 2 hub genes were applied to construct a lncRNA-miRNA-mRNA ceRNA network. The lncRNA-miRNA-mRNA ceRNA network shows upstream regulatory sites of the 2 hub genes. CONCLUSIONS: These findings improve our understanding of the regulatory mechanism of and reveal potential immune checkpoints for immunotherapy for ovarian cancer.

BACKGROUND: Optic nerve astrocytomas (ONAs) are neurological neoplasms in the central nervous system (CNS), and they have the highest incidence rate among all the tumor types in the visual pathway. In this study, we conducted a Surveillance, Epidemiology, and End Results (SEER) -based research to explore the demographic, survival, and prognostic factors of patients diagnosed with ONAs. METHODS: Utilizing the SEER database, we retrospectively evaluated data of patients diagnosed with ONAs of all ages from 1984 to 2016. We used the Student's t distribution to test variables of patients and various characteristics, and Kaplan-Meier curve to illustrate overall survival (OS) with 95.0% confidence intervals (CIs). We also performed univariate and multivariate analyses to evaluate various variables' validity on overall survival. RESULTS: A total of 1004 cases were analyzed, and revealed that age (P<0.001, hazard ratio (HR) = 8.830, 95% CI: 4.088-19.073), tumor grade (P<0.001, HR = 1.927, 95% CI: 1.516-2.450), diagnostic confirmation (P<0.001, HR = 2.444, 95% CI: 1.632-3.660), and histology type (P = 0.046, HR = 1.563, 95% CI: 1.008-2.424) of the tumor were associated with decreased survival. CONCLUSIONS: From this large, comparative study of ONAs, we found that younger age may be considered as a protective indicator, while high-grade astrocytic tumors have a worse prognosis. We also found that diagnostic confirmation and tumor grade were independent prognostic factors in this patient population.

BACKGROUND: Breast cancer in men accounts for fewer than 1 % of all breast cancer cases diagnosed in men and women. Genes which predispose to male breast cancer include BRCA1 and BRCA2. The role of other genes is less clear. In Poland, 20 founder mutations in BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL are responsible for the majority of hereditary breast cancer cases in women, but the utility this genes panel has not been tested in men. METHODS: We estimated the prevalence of 20 alleles in six genes (BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL) in 165 Polish male breast cancer patients. We compared the frequency of selected variants in male breast cancer cases and controls. RESULTS: One of the 20 mutations was seen in 22 of 165 cases (13.3%). Only one BRCA1 mutation and two BRCA2 mutations were found. We observed statistically significant associations for PALB2 and CHEK2 truncating mutations. A PALB2 mutation was detected in four cases (OR = 11.66; p < 0.001). A CHEK2 truncating mutation was detected in five cases (OR = 2.93;p = 0.02). CONCLUSION: In conclusion, we recommend that a molecular test for BRCA1, BRCA2, PALB2 and CHEK2 recurrent mutations should be offered to male breast cancer patients in Poland.

BACKGROUND: This study compared the long-term efficacy of different durations of adjuvant chemotherapy for patients with gastric cancer after radical gastrectomy with D2 lymphadenectomy. METHODS: We retrospectively identified 428 patients with stage II-III gastric cancer who underwent D2 gastrectomy between 2009 and 2016. Patients were divided into four groups according to the duration of adjuvant chemotherapy, including 0 week (no adjuvant, group A), 20 to 24 weeks (completed 7-8 cycles every 3 weeks or 10-12 cycles every 2 weeks, group B), and 12 to18 weeks (completed 4-6 cycles every 3 weeks or 6-9 cycles every 2 weeks, group C), and less than 12 weeks (received up to 3 cycles every 3 weeks or 5 cycles every 2 weeks, group D). The chemotherapy regimens included XELOX, SOX, and FOLFOX. 5-year overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: The 5-year OS rates for groups A, B, C, and D were 52.3, 73.7, 72.0, and 53.3%, respectively, and the 5-year DFS rates were 50.0, 68.0, 65.4, and 50.0%, respectively. OS and DFS were higher in group B than in groups A and D. Similarly, patients in group C were more likely to have higher OS and DFS than those in groups A and D. Meanwhile, there were no significant differences in OS and DFS between groups B and C. The multivariate analysis confirmed with high statistical significance the efficacy of complete courses of adjuvant chemotherapy, and, among them, the similar impact of 4-6/6-9 and 7-8/10-12 cycles, resulting in similar HRs vs Group A (0.52 and 0.42, respectively). CONCLUSIONS: To reduce toxicity and maintain efficacy, XELOX or SOX chemotherapy regimens administered for 4-6 cycles every 3 weeks or FOLFOX regimen for 6-9 cycles every 2 weeks might be a favorable option for patients with stage II-III gastric cancer after D2 gastrectomy. Prospective multicenter clinical trials with adequate sample sizes are necessary to verify these findings.

BACKGROUND: The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a+ DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a+ DCs in laryngeal cancer remains to be unequivocally established. METHODS: We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a+ DCs, S100+ DCs and CD8+ cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters. RESULTS: Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8+ CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a+ DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013). CONCLUSIONS: Our results demonstrated that the infiltration of CD1a+ DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis is effective against many cancer types. However, due in part to unresponsiveness or acquired resistance, not all patients experience a durable response to ICIs. HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor that directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. We hypothesized that HBI-8000 functions as an epigenetic immunomodulator to reprogram the tumor microenvironment from immunologically cold (nonresponsive) to hot (responsive). METHOD: Mice bearing syngeneic tumors (MC38 and CT26 murine colon carcinoma and A20 B-cell lymphoma were treated daily with HBI-8000 (orally), alone or in combination with PD-1, PD-1 L, or CTLA-4 antibodies. MC38 tumors were also analyzed in nanoString gene expression analysis. RESULTS: HBI-8000 augmented the activity of ICI antibodies targeting either PD-1, PD-L1 or CTLA-4, and significantly increased tumor regression (p < 0.05) in the above models. Gene expression analysis of the treated MC38 tumors revealed significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell and antigen-presenting cell functions, and modulation of MHC class I and II molecules. CONCLUSIONS: These findings suggest that HBI-8000 mediates epigenetic modifications in the tumor microenvironment, leading to improved efficacy of ICIs, and provide strong rationale for combination therapies with ICIs and HBI-8000 in the clinical setting. PRECIS: As an HDACi, HBI-8000 plays an important role in priming the immune system in the tumor microenvironment. The current preclinical data further justifies testing combination of HBI-8000 and ICIs in the clinic.

BACKGROUND: We have proposed a modified, completely intrafascial radical cysprostatectomy (RC) to treat bladder cancer patients with the aim of preserving the patients' post-surgical urinary control and erectile function. This study aimed to evaluate the oncological and functional outcomes of this innovation relatively to that with the conventional technique. METHODS: A retrospective, single-center, blinded, and controlled study was conducted using the medical data of patients since the past 5 years from the hospital database. A total of 44 patients were included, including 20 who received complete intrafascial cysprostatectomy and 24 who received conventional interfascial surgeries. The patients' continent and sexual information of 1-year follow-up after the surgery were extracted. The oncological and functional outcomes of the 2 groups were compared and analyzed. RESULTS: The demographics parameters of the 2 groups showed no significant difference. The results of follow-up of the oncological outcomes did not reveal any significant difference between the completely intrafascial group and the conventional interfascial group in terms of the positive surgical margins, local recurrences, and distant metastasis. Patients following neobladder diversion in the intrafascial group showed a faster recovery of the urinary control, with a 76.9% (10/13) daytime continent rate at 3-month, as well as 46.2% (6/13) and 58.3% (7/12) nighttime continent rates at 3-month and 6-month, respectively. Regarding the sexual functions, our results revealed significant advantages in favor of completely intrafascial technique on the post-surgical International Index of Erectile Function (IIEF)-5 score at 3-, 9-, and 12-month follow-up relative to that with the conventional interfascial process. Thus, the IIEF score of patients in the intrafascial group was 11.4 ± 3.5 at 3-month, 14.1 ± 3.6 at 9-month, and 15.2 ± 3.8 at 12-month follow-up after the cystectomy, which was significantly greater than that of the patients in the control group. CONCLUSIONS: Our novel data illustrated that the modified completely intrafascial technique could result in a better sexual function and faster continence recovery for patients following RC, without any compromise in the cancer control. Thus, this technique could be considered as an alternative extirpative technique for bladder cancer treatment in a clinical setting.

INTRODUCTION: The study aimed to assess resilience and its associated factors in head and neck cancer patients, post-treatment in a low middle income country (LMIC) such as Pakistan. METHODS: An analytical cross-sectional study was conducted from November 2019 to May 2020 among head and neck cancer patients aged at least 18 years at the largest private tertiary care hospital, in Karachi, Pakistan. Information regarding their resilience scores was collected through Wagnild and Young's Resilience scale that comprises of 14 items (RS-14). Moreover, depression and anxiety were also assessed via Hospital Anxiety and Depression Scale (HADS) and social support was assessed by Enriched Social Support Instrument (ESSI). RESULTS: The data was analyzed by linear regression modeling. Unadjusted and adjusted beta coefficients with 95% CI were reported. A total of 250 head and neck cancer patients were recruited, 79% of them were males. Mean age of the patients was 51.59 years with 93% having high social support and only 8% having severe depression and 3% having severe anxiety. After adjusting for the covariates in multivariable analysis resilience was associated with severe depression (- 17[- 20.98,-12.93]) or borderline depression (- 4[- 8.41,-0.39]), severe anxiety (- 11 [- 17.88,-4.18]), low social support (- 6[- 9.62,-1.71]), having family members of > 6 in the household (- 2[- 4.31,-0.29), smokeless tobacco users post- treatment (10[5.79, 14.45]), and those who underwent tracheotomy (- 4[- 7.67,-0.21]). There was a significant interaction between education and role in the family (decision maker). CONCLUSION: In Pakistan, a South Asian LMIC, collectivist culture prevails, family ties are greatly promoted thus resilience and social support is highly prevalent in head and neck cancer patients resulting in lower prevalence of depression and anxiety. Our study highlights that higher resilience is prevalent among small families less than six members, as the welfare of the individual is prioritized over multiple needs of the family. Formal Education and role in household/decision making power are effect modifiers in our study, demonstrating its protective effect on the mental health of head and neck cancer patients. High resilience scores were reported among current smokeless tobacco users as compared to quitters post treatment. Resilience-building interventions should be formulated to aid head and neck cancer patients to cope with the disease and its sequel.

BACKGROUND: Identifying ineffective practices that have been used in oncology is important in reducing wasted resources and harm. We sought to examine the prevalence of practices that are being used but have been shown in RCTs to be ineffective (medical reversals) in published oncology studies. METHODS: We cross-sectionally analyzed studies published in three high-impact oncology medical journals (2009-2018). We abstracted data relating to the frequency and characterization of medical reversals. RESULTS: Of the 64 oncology reversals, medications (44%) represented the most common intervention type (39% were targeted). Fourteen (22%) were funded by pharmaceutical/industry only and 56% were funded by an organization other than pharmaceutical/industry. The median number of years that the practice had been in use prior to the reversal study was 9 years (range 1-50 years). CONCLUSION: Here we show that oncology reversals most often involve the administration of medications, have been practiced for years, and are often identified through studies funded by non-industry organizations.

BACKGROUND: Adherence to colorectal cancer screening in the United States is suboptimal, particularly in medically underserved populations due to significant barriers to care. Unique accessible, low-cost, and non-invasive screening tests for this population could greatly benefit current rates. In this article, we assess patient preference and the impact of offering a blood-based test on screening rates in a cost-free health fair setting from April 2017 to April 2019. METHODS: Participants who met colorectal cancer screening eligibility criteria set forth by the United States Preventive Services Task Force were recommended to attend the colon cancer screening station. Those participants who elected to attend were offered various, accepted screening methods, and if they declined, were offered alternative blood-based testing. Screening rates, test outcomes, and the rate of follow up completion of colonoscopy were measured and compared with historic screening outcomes. RESULTS: Of 1401 participants who were recommended to attend, 640 (45.7%) participants were evaluated at the colon cancer screening station, of whom 460 were eligible for testing. Amongst these, none selected colonoscopy, 30 (6.5%) selected fecal immunochemical testing, and 430 (93.5%) selected blood-based testing. Only 2 participants returned the fecal immunochemical tests. In the blood test cohort, 88 were positive and 20 received a follow up colonoscopy. CONCLUSIONS: Based on this assessment, blood-based testing is an effective method to increase screening rates in medically underserved populations, though efforts to further improve access to follow up colonoscopy are necessary.

BACKGROUND: To develop nomograms for the prediction of the 1-, 3-, and 5-year overall survival (OS) and breast cancer-specific survival (BCSS) for patients with lymph node positive, luminal A breast cancer. METHODS: Thirty-nine thousand fifty-one patients from The Surveillance, Epidemiology, and End Results (SEER) database were included in our study and were set into a training group (n = 19,526) and a validation group (n = 19,525). Univariate analysis and Cox proportional hazards analysis were used to select variables and set up nomogram models on the basis of the training group. Kaplan-Meier curves and the log-rank test were adopted in the survival analysis and curves plotting. C-index, calibration plots and ROC curves were used to performed internal and external validation on the training group and validation group. RESULTS: Following independent factors were included in our nomograms: Age, marital status, grade, ethnic group, T stage, positive lymph nodes numbers, Metastasis, surgery, radiotherapy, chemotherapy. In both the training group and testing group, the calibration plots show that the actual and nomogram-predicted survival probabilities are consistent greatly. The C-index values of the nomograms in the training and validation cohorts were 0.782 and 0.806 for OS and 0.783 and 0.804 for BCSS, respectively. The ROC curves show that our nomograms have good discrimination. CONCLUSIONS: The nomograms may assist clinicians predict the 1-, 3-, and 5-year OS and BCSS of patients with lymph node positive, luminal A breast cancer.

BACKGROUND: Patients with breast cancer who overexpress the human epidermal growth factor receptor 2 (HER2) and subsequently develop brain metastasis (BM) typically experience poor quality of life and low survival. We conducted a comprehensive literature review to identify prognostic factors for BM and predictors of survival after developing BM, and the effects of therapies with different mechanisms of action among patients with HER2+ breast cancer (BC). METHODS: A prespecified search strategy was used to identify research studies investigating BM in patients with HER2+ BC published in English during January 1, 2009-to June 25, 2021. Articles were screened using a two-phase process, and data from selected articles were extracted. RESULTS: We identified 25 published articles including 4097 patients with HER2+ BC and BM. Prognostic factors associated with shorter time to BM diagnosis after initial BC diagnosis included younger age, hormone receptor negative status, larger tumor size or higher tumor grade, and lack of treatment with anti-HER2 therapy. Factors predictive of longer survival after BM included having fewer brain lesions (< 3 or a single lesion) and receipt of any treatment after BM, including radiosurgery, neurosurgery and/or systemic therapy. Patients receiving combination trastuzumab and lapatinib therapy or trastuzumab and pertuzumab therapy had the longest median survival compared with other therapies assessed in this review. CONCLUSIONS: More research is needed to better understand risk factors for BM and survival after BM in the context of HER2+ BC, as well as the assessment of new anti-HER2 therapy regimens that may provide additional therapeutic options for BM in these patients.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) therapy has resulted in significant survival benefits in patients with non-small-cell lung cancer (NSCLC) without increasing toxicity. However, the utilisation of immunotherapy for small-cell lung cancer (SCLC) remains unclear, with a scarcity of systematic comparisons of therapeutic effects and safety of immunotherapy in these two major lung cancer subtypes. Herein, we aimed to provide a comprehensive landscape of immunotherapy and systematically review its specific efficacy and safety in advanced lung cancer, accounting for histological types. METHODS: We identified studies assessing immunotherapy for lung cancer with predefined endpoints, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAE), from PubMed, Embase, Medline, and Cochrane library. A random-effects or fixed-effect model was adopted according to different settings. RESULTS: Overall, 38 trials with 20,173 patients with lung cancer were included in this study. ICI therapy resulted in a significantly prolonged survival in both patients with NSCLC and SCLC when compared with chemotherapy (hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.70-0.79] and [HR = 0.82; 95% CI, 0.75-0.90], respectively). The magnitude of disease control and survival benefits appeared superior with ICI plus standard of care (SOC) when compared with SOC alone. OS and PFS advantages were observed only when immunotherapy was employed as the first-line treatment in patients with SCLC. CONCLUSION: ICI therapy is a promising therapeutic option in patients with NSCLC and SCLC. ICI plus SOC can be recommended as the optimal first-line treatment for patients with SCLC, and double-target ICIs combined with SOC are recommended in patients with NSCLC as both the first and subsequent lines of treatment. Additionally, non-first-line immunotherapy is not recommended in patients with SCLC.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in the world owing to limitations in its prognosis. The current prognosis approaches include radiological examination and detection of serum biomarkers, however, both have limited efficiency and are ineffective in early prognosis. Due to such limitations, we propose to use RNA-Seq data for evaluating putative higher accuracy biomarkers at the transcript level that could help in early prognosis. METHODS: To identify such potential transcript biomarkers, RNA-Seq data for healthy liver and various HCC cell models were subjected to five different machine learning algorithms: random forest, K-nearest neighbor, Naïve Bayes, support vector machine, and neural networks. Various metrics, namely sensitivity, specificity, MCC, informedness, and AUC-ROC (except for support vector machine) were evaluated. The algorithms that produced the highest values for all metrics were chosen to extract the top features that were subjected to recursive feature elimination. Through recursive feature elimination, the least number of features were obtained to differentiate between the healthy and HCC cell models. RESULTS: From the metrics used, it is demonstrated that the efficiency of the known protein biomarkers for HCC is comparatively lower than complete transcriptomics data. Among the different machine learning algorithms, random forest and support vector machine demonstrated the best performance. Using recursive feature elimination on top features of random forest and support vector machine three transcripts were selected that had an accuracy of 0.97 and kappa of 0.93. Of the three transcripts, two were protein coding (PARP2-202 and SPON2-203) and one was a non-coding transcript (CYREN-211). Lastly, we demonstrated that these three selected transcripts outperformed randomly taken three transcripts (15,000 combinations), hence were not chance findings, and could then be an interesting candidate for new HCC biomarker development. CONCLUSION: Using RNA-Seq data combined with machine learning approaches can aid in finding novel transcript biomarkers. The three biomarkers identified: PARP2-202, SPON2-203, and CYREN-211, presented the highest accuracy among all other transcripts in differentiating the healthy and HCC cell models. The machine learning pipeline developed in this study can be used for any RNA-Seq dataset to find novel transcript biomarkers. Code: www.github.com/rajinder4489/ML_biomarkers.

BACKGROUND: Receiving a cancer diagnosis may trigger immediate fatal non-cancer health outcomes in addition to dying of cancer itself. We aim to investigate the full pattern of non-cancer deaths in patients within a year of a cancer diagnosis. METHODS: Patients diagnosed with cancer between 1990 and 2016 were identified from the SEER program. Standardized mortality ratios (SMRs) were calculated to characterize the relative risks of non-cancer deaths compared with the general population. RESULTS: Among 7,366,229 patients, 241,575 non-cancer deaths (15.9%) were recorded in the first year following a cancer diagnosis. The relative risk of non-cancer deaths was 2.34-fold (95% confidence interval (CI): 2.33-2.35) that of the general population. The majority of non-cancer deaths were caused by cardiovascular diseases (21.8%), followed by infectious diseases (7.2%). Significant elevations in mortality risks were observed for nearly all non-cancer causes, particularly in infectious diseases (SMR: 5.08; 95% CI: 5.03-5.13). Patients with liver cancer (SMR: 12.29; 95% CI: 12.06-12.53) were at the highest risk of early non-cancer deaths. The risks of non-cancer deaths were highest within the first month after diagnosis, and decreased rapidly thereafter. CONCLUSIONS: Risks of non-cancer deaths vary by the types of causes and anatomic sites of cancer. Our data underscore the importance of close observation and early multidisciplinary care for noncancer conditions in patients who have recently received a cancer diagnosis.

OBJECTIVE: The main aim of this study was to ascertain the effectiveness of ultrasound-guided fine needle aspiration cytology (US-FNAC) in the diagnosis of para-aortic lymph node (PALN) metastasis in uterine cervical cancer and to establish its potential impact on clinical therapeutic decision making. METHODS: We retrospectively reviewed clinical data from 92 patients diagnosed with cervical cancer with PALN enlargement between 2010 and 2018. Cytological results obtained with US-FNAC were classified by the same experienced cellular pathologists. Diagnostic indicators were determined on the basis of biopsy, imaging and clinical follow-up results. Univariate and multivariate analyses were used to assess the differences of influencing factors. The effect of US-FNAC on clinical decision making was evaluated. RESULTS: Cytological results of US-FNAC were categorized as malignancy (n = 62; 67.4%), suspicious malignancy (n = 11; 12.0%), undetermined (n = 5; 5.4%), benign (n = 10; 10.9%), and inadequate (n = 4; 4.3%). Satisfactory biopsy samples were obtained from 95.7% of PALNs sampled (88/92). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of FNAC in distinguishing benign from malignant cases were 90.1% (95% CI: 0.809-0.953), 100% (95% CI: 0.561-1), 100% (95% CI: 0.938-1), 46.7% (95% CI: 0.223-0.726) and 90.9% (95% CI: 0.848-0.970), respectively. Univariate analysis indicated significant differences in experience of puncture physicians (radiologists) between the correct and wrong diagnosis groups (P < 0.05), which was further confirmed as an independent predictor of diagnostic accuracy in multivariate analysis (p = 0.031, OR = 0.077, 95% CI: 0.354-0.919). All patients tolerated the US-FNAC procedure well and only nine presented slight abdominal discomfort. The therapeutic strategies for 74 patients (80.4%) were influenced by US-FNAC findings. CONCLUSIONS: US-FNAC was a relatively safe and effective technique for examination of enlarged para-aortic lymph nodes and may therefore serve as a routine diagnostic tool to guide clinical decision making for management of cervical cancer.

BACKGROUND: The advanced hepatocellular carcinoma (HCC), such as the recurrent tumor after liver transplantation (LT), is an obstacle of HCC treatment. The aim of this study was to discover the underlying mechanism of HCC progression caused by non-coding RNAs (ncRNAs). METHODS: To this end, we investigated the selected patient cohort of matching primary and recurrent HCC after receiving LT. The recurrent tumors after LT were regarded as clinical models of the advanced HCC. Microarrays were used to profile lncRNA and mRNA expression in HCC recurrent and primary tissue samples. The mRNA profile characteristics were analyzed by bioinformatics. Two cell lines, HepG2 and QGY-7703, were used as HCC cell models. The protein-coding potential, length, and subcellular location of the interested lncRNAs were examined by bioinformatics, Northern blot, fluorescent in situ hybridization (FISH), and quantitative RT-PCR (qRT-PCR) assays. HCC cell proliferation was detected by CCK-8, doubling time and proliferation marker gene quantitation assays. DNA replication during the cell cycle was measured by EdU/PI staining and flow cytometry analyses. Promoter activity was measured using a luciferase reporter assay. Interactions between DNA, RNA, and protein were examined by immunoprecipitation and pull-down assays. The miRNA-target regulation was validated by a fluorescent reporter assay. RESULTS: Both lncRNA and mRNA profiles exhibited characteristic alterations in the recurrent tumor cells compared with the primary HCC. The mRNA profile in the HCC recurrent tissues, which served as model of advanced HCC, showed an aberrant cell cycle regulation. Two lncRNAs, the highly expressed lncRNA in recurrent HCC (HERH)-1 and HERH-4, were upregulated in the advanced HCC cells. HERH-1/4 enhanced proliferation and promoted DNA replication and G1-S transition during the cell cycle in HCC cells. HERH-1 interacted with the transcription factor CREB1. CREB1 enhanced cyclin A2 (CCNA2) transcription, depending on HERH-1-CREB1 interaction. HERH-4 acted as an miR-29b/c sponge to facilitate CCNA2 protein translation through a competing endogenous RNA (ceRNA) pathway. CONCLUSIONS: The oncogenic lncRNA HERH-1/4 promoted CCNA2 expression at the transcriptional and post-transcriptional levels and accelerated cell cycle progression in HCC cells. The HERH-1-CREB1-CCNA2 and HERH-4-miR-29b/c-CCNA2 axes served as molecular stimuli for HCC advance.

BACKGROUND: Alternative splicing (AS), one of the main post-transcriptional biological regulation mechanisms, plays a key role in the progression of glioblastoma (GBM). Systematic AS profiling in GBM is limited and urgently needed. METHODS: TCGA SpliceSeq data and the corresponding clinical data were downloaded from the TCGA data portal. Survival-related AS events were identified through Kaplan-Meier survival analysis and univariate Cox analysis. Then, splicing correlation network was constructed based on these AS events and associated splicing factors. LASSO regression followed by multivariate Cox analysis was performed to validate independent AS biomarkers and to construct a risk prediction model. Enrichment analysis was subsequently conducted to explore potential signaling pathways of these AS events. RESULTS: A total of 132 TCGA GBM samples and 45,610 AS events were included in our study, among which 416 survival-related AS events were identified. An AS correlation network, including 54 AS events and 94 splicing factors, was constructed, and further functional enrichment was performed. Moreover, the novel risk prediction model we constructed displayed moderate performance (the area under the curves were > 0.7) at both one, two and three years. CONCLUSIONS: Survival-related AS events may be vital factors of both biological function and prognosis. Our findings in this study can deepen the understanding of the complicated mechanisms of AS in GBM and provide novel insights for further study. Moreover, our risk prediction model is ready for preliminary clinical applications. Further verification is required.

BACKGROUND: The impact of smokeless tobacco (SLT) use on the risk of oral cavity cancer (OCC) has been confirmed; however, the sex-based difference in this association remains inconclusive. Therefore, this study aimed to estimate the association between SLT use and OCC risk in women and compared it to that in men. METHODS: PubMed, Embase, and Cochrane Library databases were systematically searched for eligible studies from their inception up to August 2020. Studies reporting the effect estimates of SLT use on OCC risk in men and women, were eligible for inclusion. The relative risk ratio (RRR) was applied to calculate the sex-based difference in the relationship between SLT use and OCC risk, and pooled analysis was conducted using a random-effects model with inverse variance weighting. RESULTS: Nineteen studies reporting a total of 6593 OCC cases were included in the final meta-analysis. The pooled relative risk (RR) suggested that SLT use was associated with an increased risk of OCC in both men (RR, 2.94; 95% confidence interval [CI], 2.05-4.20; P < 0.001) and women (RR, 6.39; 95%CI, 3.16-12.93; P < 0.001). Moreover, the SLT-use-related risk of OCC was higher in women than that in men (RRR,1.79; 95%C, 1.21-2.64; P = 0.003). The risk of OCC related to SLT use in women was still significantly higher than that in men (RRR, 1.75; 95%CI, 1.15-2.66; P = 0.008) after excluding indirect comparison results. Finally, a subgroup analysis suggested significant sex-based differences only in individuals who received chewed smokeless products, regardless of the control definition. Pooled analysis of studies with high design quality confirmed the notably higher risk of OCC in women than in men. CONCLUSIONS: This study found that SLT use was associated with a higher risk of OCC in women than in men. Further large-scale prospective cohort studies should be conducted to verify sex-based differences in the association between use of specific smokeless products and OCC risk.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. Given the limited treatment options, prognostic assessment of ACC is increasingly crucial. In this study, we aim to assess the correlation between preoperative serum albumin and prognosis in patients with ACC after primary resection. METHODS: We retrospectively collected and reviewed medical information about 71 ACC patients who underwent primary resection. Survival analysis was performed by Kaplan-Meier analysis with log-rank test or Breslow test. Receiver operating characteristic (ROC) curve and Jordan index was generated to explore optimal cut-off value of albumin. Univariate and multivariate analysis was conducted using Cox's hazards model. Statistical significance was defined as P < 0.05. RESULTS: Among included patients, 33 patients (46.5%) relapsed at the end of follow-up, while 39 patients (54.9%) died. The median overall survival (OS) of included patients was 17 (range 1-104) months, and median recurrence-free survival (RFS) was 10 (range 0-104) months. In univariate analysis, the albumin was significantly associated with OS (HR:0.491, 95% CI: 0.260-0.930, P = 0.029) and RFS (HR: 0.383, 95% CI: 0.192-0.766, P = 0.007). In multivariate analysis, serum albumin as an independent prognostic factor of OS was confirmed (HR: 0.351, 95% CI: 0.126-0.982, P = 0.046). CONCLUSIONS: Preoperative albumin might be a significant prognostic factor for ACC patients after primary resection. This result may be useful for risk stratification and management of this rare malignancy.

BACKGROUND: It is very necessary to implement gastric cancer screening in China to reduce the mortality of gastric cancer, but there are no national screening guidelines and programs. Understanding of individual preferences is conducive to formulating more acceptable screening strategies, and discrete choice experiments can quantify individual preferences. In addition, the first-degree relatives of gastric cancer patients are at high risk for gastric cancer. Compared with those without a family history of gastric cancer, the risk of gastric cancer in first-degree relatives of gastric cancer patients is increased by 60%. Therefore, a discrete choice experiment was carried out to quantitatively analyse the preferences of first-degree relatives of gastric cancer patients for gastric cancer screening to serve as a reference for the development of gastric cancer screening strategies. METHODS: A questionnaire was designed based on a discrete choice experiment, and 342 first-degree relatives of gastric cancer patients were investigated. In STATA 15.0 software, the data were statistically analysed using a mixed logit model. RESULTS: The five attributes included in our study had a significant influence on the preferences of first-degree relatives of gastric cancer patients for gastric cancer screening (P < 0.05). Participants most preferred the sensitivity of the screening program to be 95% (coefficient = 1.424, P < 0.01) with a willingness to pay 2501.902 Yuan (95% CI, 738.074-4265.729). In addition, the participants' sex and screening experiences affected their preferences. An increase in sensitivity 35 to 95% had the greatest impact on the participants' willingness to choose a gastric cancer screening program. CONCLUSION: The formulation of gastric cancer screening strategies should be rooted in people's preferences. The influence of sex differences and screening experiences on the preferences of people undergoing screening should be considered, and screening strategies should be formulated according to local conditions to help them play a greater role.

BACKGROUNDS: Cervical cancer (CC) incidence remains unacceptably high in Côte d'Ivoire. In an effort to prevent this malignant condition, a national CC screening program has been scaled up in the country. This study aimed at assessing CC screening uptake and its associated factors in Abidjan in 2018. METHODS: A cross-sectional survey was conducted from July to September 2018 in the main healthcare facilities of three randomly selected out of the eight health districts of Abidjan. During the study period, a standardized questionnaire was administrated by research assistants to all women aged 25 to 55 years old, attending the three participating facilities. Demographics, knowledge on CC, personal history of CC screening and reasons for not attending CC screening were collected. A logistic regression model was computed to document factors associated with reported CC screening uptake. RESULTS: A total of 1158 women with a median age of 32 years (IQR [27-36]), including 364 (31.4%) with no formal education were included. Of those participants, 786 (67.9%) had ever heard about CC. CC screening uptake at least once was reported by 7.5% [95% CI: 6.0-9.0] participants. In multivariable analysis, being ≥45 years (aOR: 6.2 [2.3-17.2]), having a university level (aOR: 2.8 [1.2-6.6]) (versus non formal education) and access to mass campaign information (aOR: 18.2 [8.5-39.1]) were associated with a reported CC screening uptake. The main reported barriers to CC screening were unawareness towards CC screening (75.5%), negligence (20.5%), fear of CC detection (3.9%) and fear of additional costs (3.3%). CONCLUSION: CC screening uptake remains low despite current initiatives to support awareness and prevention in Abidjan. Awareness campaigns need to be massively increased with the adjunction of tailored messages based on the level of women's education to enhance the CC screening coverage and reach the WHO goal of CC elimination by 2030.

BACKGROUND: The improved prognosis of classic Hodgkin lymphoma (cHL) has been accompanied by elevated risks of non-cancer-specific death (non-CSD). The aim of this study was to verify the occurrence of non-CSD and its effect on rates of overall survival among adult patients with cHL. METHODS: To ensure sufficient follow-up time, we analyzed retrospective data from patients aged ≥20 years with cHL that was diagnosed between 1983 and 2005 in the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was applied to analyze the non-CSD occurrence in relation to all factors. Using Fine-Gray's method, we calculated the cumulative incidences of CSD and non-CSD. Stacked cumulative incidence plots and ratio of non-CSD to all causes of death were applied to evaluate the effect of non-CSD on rates of overall survival. Finally, we analyzed long-term mortality through Cox proportional hazard regression analysis and competing risk regression analysis to emphasize a more appropriate model of survival for patients with cHL. RESULTS: Among the 18,518 patients included, there were 3768 cases of CSD (20.3%) and 3217 of non-CSD (17.4%). Older age, earlier period, male sex, unmarried status, mixed cellularity (MC) and lymphocyte-depletion (LD) histological subtype, and patients received radiotherapy (RT) only were associated with more non-CSD according to binary logistic analysis. The cumulative incidence of non-CSD exceeded CSD after approximately 280 months follow-up. The most common causes of non-CSDs were cardiovascular disease, subsequent primary neoplasms, infectious diseases, accidents, and suicide. In a Cox proportional hazards model, patients who were black, unmarried, at an advanced stage or underwent chemotherapy (CT) alone were at greater risk of mortality than were white patients, who were married, at an early stage, and underwent combined modality; these populations were also found to be at greater risk for CSD in a competing risk model, but the risk of non-CSD did not differ significantly according to race and marital status, patients with early-stage disease and who underwent RT only were found to be at higher risk of non-CSD instead. CONCLUSIONS: Lymphoma was the cause of death in most patients who died, but non-CSD was not unusual. Patients with cHL should be monitored closely for signs of cardiovascular disease and malignant tumors. Rates of overall survival of patients were diminished by non-CSD, and a competing risk model was more suitable for establishing the prognosis than was the Cox proportional hazards model.

BACKGROUND: Abnormal activation of the coagulation system has been reported in patients with malignancies, but its prognostic significance in biliary tract cancer (BTC) remains unclear. This study aims to analyze and compare the prognostic value of coagulation indices in patients with BTC. METHODS: The medical records of 450 patients with BTC who underwent surgical resection at our hospital between 2003 and 2017 were retrospectively analyzed. Time-dependent receiver operating characteristic curves were plotted to compare the predictive accuracy of coagulation indices. A predictive nomogram for overall survival (OS) was established based on the Cox regression analysis and validated in both the training and validation cohorts. A novel stratification model was created according to the total points of the nomogram. RESULTS: Fibrinogen and international normalized ratio (INR) had the best predictive accuracy among the coagulation indices considered and were also the independent prognostic factors for OS. The nomogram and the novel stratification model had satisfactory performance and outperformed TNM staging. CONCLUSIONS: The study demonstrated that coagulation indices are valuable in predicting OS in BTC, with fibrinogen and INR having the best predictive ability. The nomogram and the novel stratification model could be applied to predict survival for patients with BTC.

BACKGROUND: Colorectal cancer (CRC) is the most diagnosed cancer among males and third among females in Saudi Arabia, with up to two-third diagnosed at advanced stage. The objective of our study was to estimate CRC survival and determine prognostic factors. METHODS: Ministry of National Guard- Health Affairs (MNG-HA) registry data was utilized to identify patients diagnosed with CRC between 2009 and 2017. Cases were followed until December 30th, 2017 to assess their one-, three-, and five-year CRC-specific survivals. Kaplan-Meier method and Cox proportional hazard models were used to assess survival from CRC. RESULTS: A total of 1012 CRC patients were diagnosed during 2009-2017. Nearly, one-fourth of the patients presented with rectal tumor, 42.89% with left colon and 33.41% of the cases were diagnosed at distant metastasis stage. The overall one-, three-, and five-year survival were 83, 65 and 52.0%, respectively. The five-year survival was 79.85% for localized stage, 63.25% for regional stage and 20.31% for distant metastasis. Multivariate analyses showed that age, diagnosis period, stage, nationality, basis of diagnosis, morphology and location of tumor were associated with survival. CONCLUSIONS: Findings reveal poor survival compared to Surveillance, Epidemiology, and End Results (SEER) population. Diagnoses at late stage and no surgical and/or perioperative chemotherapy were associated with increased risk of death. Population-based screening in this population should be considered.

BACKGROUND: The gasdermin E gene (GSDME, also known as DFNA5) is mutated in familial aging-related hearing loss. Recent studies have also revealed that the expression of DFNA5 is suppressed in many cancer types; however, little is known about the function of DFNA5 in head and neck squamous cell carcinoma (HNSCC). Accordingly, the aim of the present study was to evaluate the expression of DFNA5 and explore its prognostic value in HNSCC. RESULT: We used a set of bioinformatics tools, including Oncomine, TIMER, TISIDB, cBioPortal, and GEPIA, to analyze the expression of DFNA5 in patients with HNSCC from public databases. Kaplan-Meier plotter was used to evaluate the potential prognostic significance of DFNA5. DFNA5 mRNA levels were significantly higher in HNSCC tissues than in normal tissues, and high DFNA5 expression was correlated with worse survival. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that DFNA5 expression has a strong positive correlation with cell adhesion and the integrin signaling pathway, whereas its expression was negatively correlated with the levels of infiltrating B cells (cor = - 0.223, P = 8.57e-07) and CD8 T cells (cor = - 0.223, P = 2.99e-07). CONCLUSION: This study demonstrates that DFNA5 expression has prognostic value for HNSCC patients. Moreover, these results suggest that regulation of lymphocyte infiltration is the mechanism underlying the function of DFNA5 in HNSCC.

BACKGROUND: Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB. METHODS: BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines. RESULTS: High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. CONCLUSION: T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

BACKGROUND: Cytology and HPV genotype screening play an important role in cervical cancer detection. Whether multiple HPV genotyping can predict cytological lesions remains to be further studied. METHODS: Two thousand two hundred twenty-four females were analyzed for cytology and HPV genotypes test. The possibility of predicting cytological lesions by HPV genotypes test was evaluated by multivariate logistic regression and area under the receiver operator characteristic curve (AUC). RESULT: Abnormal cytological results were found in 479 participants. A total of 688 patients were detected with HPV infection, 619 with HR-HPV infection and 112 with LR-HRV infection. HPV-52 was found to be the most common type among these patients, and a relatively higher risk of cervical lesions was found in HPV positive females. HPV-16, 31, 33 and 58 were found to have significantly higher infection rates in patients with HSIL and higher lesions. The prediction model was developed based on age and HPV-specific genotypes, with the AUC of 0.73 for cytological abnormalities and 0.82 for HSIL and higher lesions. CONCLUSION: HPV-16, 31, 33 and 58 infection are significant risk factors for cervical lesions. Combined HPV genotypes test can effectively predict cytological abnormalities.

BACKGROUND: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. METHODS: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. RESULTS: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). CONCLUSIONS: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. TRIAL REGISTRATION: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920.

BACKGROUND: In patients with average risk of bleeding, second-look endoscopy does not reportedly reduce bleeding after gastric endoscopic submucosal dissection. However, effectiveness of second-look endoscopy for patients with a high risk of bleeding, such as those who are taking antithrombotic agents, is unclear. Hence, this study aims to clarify the effectiveness of second-look endoscopy for patients with antithrombotic therapy. METHODS: We studied 142 consecutive patients with 173 gastric epithelial neoplasms who were routinely taking antithrombotic agents and were treated by endoscopic submucosal dissection at Tonan Hospital between November 2013 and December 2019. They were classified into two groups: those with second-look endoscopy (SLE group, 69 patients with 85 lesions) and those without second-look endoscopy (non-SLE group, 73 patients with 88 lesions). The incidence of post-endoscopic submucosal dissection bleeding was compared between the SLE and non-SLE groups. RESULTS: There were no statistical differences in the rate of patients undergoing single antiplatelet therapy, single anticoagulant therapy, and multiple therapy between the SLE and non-SLE groups (SLE group vs. non-SLE group; 32 [46.4%], 16 [23.2%], and 21 [30.4%] patients vs. 37 [50.7%], 20 [27.4%], and 16 [21.9%] patients, respectively; p = 0.50). Post-endoscopic submucosal dissection bleeding incidence was 21.7% (15/69) and 21.9% (16/73) in the SLE and non-SLE groups, respectively, and did not significantly differ between the two groups (p = 0.98). CONCLUSIONS: For patients taking antithrombotic agents, the incidence of post-endoscopic submucosal dissection bleeding was not reduced by second-look endoscopy.

BACKGROUND: Saskatchewan has one of the highest incidence of prostate cancer (PCa) in Canada. This study assesses if geographic factors in Saskatchewan, including location of where patients live and physician density are affecting the PCa incidence. First, the objective of this study is to estimate the PCa standardized incidence ratio (SIRs) in Saskatchewan stratified by PCa risk-level. Second, this study identifies clusters of higher than and lower than expected PCa SIRs in Saskatchewan. Lastly, this study identifies the association (if any) between family physician density and estimated PCa SIRs in Saskatchewan. METHODS: First, using Global Moran's I, Local Moran's I, and the Kuldorff's Spatial Scan Statistic, the study identifies clusters of PCa stratified by risk-levels. Then this study estimates the SIRs of PCa and its association with family physician density in Saskatchewan using the Besag, York, and Mollie (BYM) Bayesian method. RESULTS: Higher than expected clusters of crude estimated SIR for metastatic PCa were identified in north-east Saskatchewan and lower than expected clusters were identified in south-east Saskatchewan. Areas in north-west Saskatchewan have lower than expected crude estimated SIRs for both intermediate-risk and low-risk PCa. Family physician density was negatively associated with SIRs of metastatic PCa (IRR: 0.935 [CrI: 0.880 to 0.998]) and SIRs of high-risk PCa (IRR: 0.927 [CrI: 0.880 to 0.975]). CONCLUSIONS: This study identifies the geographical disparities in risk-stratified PCa incidence in Saskatchewan. The study identifies areas with a lower family physician density have a higher-than-expected incidences of metastatic and high-risk PCa. Hence policies to increase the number of physicians should ensure an equitable geographic distribution of primary care physicians to support early detection of diseases, including PCa.

BACKGROUND: The prognostic nutritional index (PNI) reflects immunonutritional status. We evaluated the effects of postoperative PNI and perioperative changes in the PNI on overall survival (OS) in glioblastoma (GBM) patients. METHODS: Demographic, laboratory, and clinical data were retrospectively collected from 335 GBM patients. Preoperative and postoperative PNIs were calculated from serum albumin concentration and lymphocyte count, which were measured within 3 weeks before surgery and 1 month after surgery. Patients were classified into high (n = 206) or low (n = 129) postoperative PNI groups according to the postoperative PNI cutoff value and further classified into four groups according to the cutoff values of the preoperative and postoperative PNIs, as follows: Group HH (both high PNIs, n = 92), Group HL (high preoperative and low postoperative PNI, n = 70), Group LH (low preoperative and high postoperative PNI, n = 37), and Group LL (both low PNIs, n = 136). RESULTS: The median OS was significantly longer in the high postoperative PNI (PNI ≥ 50.2) group than the low postoperative PNI (PNI < 50.2) group (24.0 vs. 15.0 months, p <  0.001). In multivariate analysis, high postoperative PNI was a significant predictor of OS. OS was significantly longer in Group HH than in Group LL and seemed longer in Group HH than in Group HL and in Group LH than in Group LL. OS was not different between Groups HH and LH or between Groups HL and LL. CONCLUSIONS: High postoperative PNI was associated with improved OS and perioperative changes in PNI may provide additional important information for prognostic prediction in GBM patients.

BACKGROUND: The effective treatment and prognosis prediction of bladder cancer (BLCA) remains a medical problem. Ferroptosis is an iron-dependent form of programmed cell death. Ferroptosis is closely related to tumour occurrence and progression, but the prognostic value of ferroptosis-related genes (FRGs) in BLCA remains to be further clarified. In this study, we identified an FRG signature with potential prognostic value for patients with BLCA. METHODS: The corresponding clinical data and mRNA expression profiles of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to extract FRGs related to survival time, and a Cox regression model was used to construct a multigene signature. Both principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were performed for functional annotation. RESULTS: Clinical traits were combined with FRGs, and 15 prognosis-related FRGs were identified by Cox regression. High expression of CISD1, GCLM, CRYAB, SLC7A11, TFRC, ACACA, ZEB1, SQLE, FADS2, ABCC1, G6PD and PGD was related to poor survival in BLCA patients. Multivariate Cox regression was used to construct a prognostic model with 7 FRGs that divided patients into two risk groups. Compared with that in the low-risk group, the overall survival (OS) of patients in the high-risk group was significantly lower (P < 0.001). In multivariate regression analysis, the risk score was shown to be an independent predictor of OS (HR = 1.772, P < 0.01). Receiver operating characteristic (ROC) curve analysis verified the predictive ability of the model. In addition, the two risk groups displayed different immune statuses in ssGSEA and different distributed patterns in PCA. CONCLUSION: Our research suggests that a new gene model related to ferroptosis can be applied for the prognosis prediction of BLCA. Targeting FRGs may be a treatment option for BLCA.

BACKGROUND: Genomic profiles of specific gene sets have been established to guide personalized treatment and prognosis for patients with breast cancer (BC). However, epigenomic information has not yet been applied in a clinical setting. ST14 encodes matriptase, a proteinase that is widely expressed in BC with reported prognostic value. METHODS: In this present study, we evaluated the effect of ST14 DNA methylation (DNAm) on overall survival (OS) of patients with BC as a representative example to promote the use of the epigenome in clinical decisions. We analyzed publicly available genomic and epigenomic data from 1361 BC patients. Methylation was characterized by the β-value from CpG probes based on sequencing with the Illumina Human 450 K platform. RESULTS: A high mean DNAm (β > 0.6779) across 34 CpG probes for ST14, as the gene-associated methylation (GAM) pattern, was associated with a longer OS after adjusting age, stage, histology and molecular features in Cox model (p value < 0.001). A high GAM status was also associated with a higher XBP1 expression level and higher proportion of hormone-positive BC (p value < 0.001). Pathway analysis revealed that altered GAM was related to matrisome-associated pathway. CONCLUSIONS: Here we show the potential role of ST14 DNAm in BC prognosis and warrant further study.

BACKGROUND: Proton beam therapy (PBT) is a new-emerging cancer treatment in China but its treatment costs are high and not yet covered by Chinese public medical insurance. The advanced form of PBT, intensity-modulated proton radiation therapy (IMPT), has been confirmed to reduce normal tissue complication probability (NTCP) as compared to conventional intensity-modulated photon-radiation therapy (IMRT) in patients with oropharyngeal cancer (OPC). Herein, we evaluated the cost-effectiveness and applicability of IMPT versus IMRT for OPC patients in China, aiming at guiding the proper use of PBT. METHODS: A 7-state Markov model was designed for analysis. Base-case evaluation was performed on a 56-year-old (median age of OPC in China) patient under the assumption that IMPT could provide a 25% NTCP-reduction in long-term symptomatic dysphagia and xerostomia. Model robustness was examined using probabilistic sensitivity analysis, cohort analysis, and tornado diagram. One-way sensitivity analyses were conducted to identify the cost-effective scenarios. IMPT was considered as cost-effective if the incremental cost-effectiveness ratio (ICER) was below the societal willingness-to-pay (WTP) threshold. RESULTS: Compared with IMRT, IMPT provided an extra 0.205 quality-adjusted life-year (QALY) at an additional cost of 34,926.6 US dollars ($), and had an ICER of $170,082.4/ QALY for the base case. At the current WTP of China ($33,558 / QALY) and a current IMPT treatment costs of $50,000, IMPT should provide a minimum NTCP-reduction of 47.5, 50.8, 55.6, 63.3 and 77.2% to be considered cost-effective for patient age levels of 10, 20, 30, 40 and 50-year-old, respectively. For patients at the median age level, reducing the current IMPT costs ($50,000) to a $30,000 level would make the minimum NTCP-reduction threshold for "cost-effective" decrease from 91.4 to 44.6%, at the current WTP of China (from 69.0 to 33.5%, at a WTP of $50,000 / QALY; and from 39.7 to 19.1%, at a WTP of $100,000 / QALY). CONCLUSIONS: Cost-effective scenarios of PBT exist in Chinese OPC patients at the current WTP of China. Considering a potential upcoming increase in PBT use in China, such cost-effective scenarios may further expand if a decrease of proton treatment costs occurs or an increase of WTP level.

BACKGROUND: Radiation therapy (RT) plays a key role in curative-intent treatment for locally advanced lung cancer. Radiation induced pulmonary toxicity can be significant for some patients and becomes a limiting factor for radiation dose, suitability for treatment, as well as post treatment quality of life and suitability for the newly introduced adjuvant immunotherapy. Modern RT techniques aim to minimise the radiation dose to the lungs, without accounting for regional distribution of lung function. Many lung cancer patients have significant regional differences in pulmonary function due to smoking and chronic lung co-morbidity. Even though reduction of dose to functional lung has shown to be feasible, the method of preferential functional lung avoidance has not been investigated in a randomised clinical trial. METHODS: In this study, single photon emission computed tomography (SPECT/CT) imaging technique is used for functional lung definition, in conjunction with advanced radiation dose delivery method in randomised, double-blind trial. The study aims to assess the impact of functional lung avoidance technique on pulmonary toxicity and quality of life in patients receiving chemo-RT for lung cancer. Eligibility criteria are biopsy verified lung cancer, scheduled to receive (chemo)-RT with curative intent. Every patient will undergo a pre-treatment perfusion SPECT/CT to identify functional lung. At radiation dose planning, two plans will be produced for all patients on trial. Standard reference plan, without the use of SPECT imaging data, and functional avoidance plan, will be optimised to reduce the dose to functional lung within the predefined constraints. Both plans will be clinically approved. Patients will then be randomised in a 2:1 ratio to be treated according to either the functional avoidance or the standard plan. This study aims to accrue a total of 200 patients within 3 years. The primary endpoint is symptomatic radiation-induced lung toxicity, measured serially 1-12 months after RT. Secondary endpoints include: a quality of life and patient reported lung symptoms assessment, overall survival, progression-free survival, and loco-regional disease control. DISCUSSION: ASPECT trial will investigate functional avoidance method of radiation delivery in clinical practice, and will establish toxicity outcomes for patients with lung cancer undergoing curative chemo-RT. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04676828 . Registered 1 December 2020.

BACKGROUND: It is known that one of the reasons for the increased incidence of hematological malignancies is caused by the growth of multiple myeloma (MM). Worldwide, approximately 159,985 new cases of MM are diagnosed representing 0.9% of all cancer diagnoses and 106,105 patients will die from MM accounting for 1.1% of all cancer deaths per year. Despite significant advances in the MM treatment the mortality rates are still high. The presented study is the first accurate epidemiological study of ММ in Armenia for the period of 2006-2018. METHODS: The initial data for this retrospective cohort survey were derived from ambulance cards, hospitalization journals, and clinical data from the Registry of Blood Diseases at the Yeolyan Hematology Center. RESULTS: Data analysis showed that during 2006-2018 the average annual incidence for the MM was 1.2 per 100,000 population. A significant increase was observed in 2018 compared to 2006, 1.9 vs. 0.7 per 100,000 population. Interestingly, there were no sex differences in the overall MM incidence during the study period. According to the received data, during the period of the 2006-2009 and 2014-2018 the 1-year survival rate for both sexes decreased dramatically from 83 to 64.1% at age group 60 years and below and from 78.5 to 68.1% in group 60 years and over. The 1-year overall survival (OS) for both sexes decreased by 18.9% for patients (≤60 age group) and 10.4% (> 60 age group) in the period of 2006-2009 to the period of 2014-2018. CONCLUSIONS: The incidence rates for the MM increased during the analyzed period. Our study showed that males and females in the age group 60 years and below had better 5-year overall survival compared to elder ones and females have better survival.

BACKGROUND: Microparticles (MPs) are extracellular vesicles that are associated with cancer development and progression. Advanced non-small cell lung cancer (NSCLC) still shows disease progression after multiple lines of treatment. Therefore, the objective of this study was to explore the correlation between circulating MPs and disease progression in advanced NSCLC, and to find a new method for concise and rapid determination of disease progression. METHODS: Patients with advanced NSCLC admitted to hospital between October 2019 and October 2020 were included and divided into objective remission (OR) and progressive disease (PD) groups. The morphology of MPs was observed using transmission electron microscopy. The circulating total MPs, neutrophil MPs (NMPs), and platelet MPs (PMPs) before and after treatment were detected by flow cytometry, and a predictive model for disease progression in advanced NSCLC was developed. RESULTS: Eighty-six patients were included; 60 in the OR group and 26 in the PD group. There was no significant difference in total MPs, NMPs, or PMPs at baseline between the two groups. After treatment, total MPs, NMPs, and PMPs were significantly higher in the PD than those in the OR group. Multivariate regression analysis showed that post-treatment NMPs≥160 events/μL(OR,3.748;95%CI,1.147-12.253,p = 0.029), PMPs≥80 events/μL(OR,10.968;95%CI,2.973-40.462,p < 0.0001) and neutrophil/lymphocyte ratio (NLR) ≥3.3 (OR,4.929;95%CI,1.483-16.375,p = 0.009) were independently associated with progression of advanced NSCLC. Post-treatment NMPs and PMPs combined with NLR were used to build a predictive model for progression of advanced NSCLC. The area under the curve was 0.825 (95%CI,0.715-0.934, p < 0.0001), optimal cut-off value was 16, sensitivity was 80.8%, and specificity was 88.3%. CONCLUSION: NMPs and PMPs are associated with progression of advanced NSCLC. The predictive model for progression of advanced NSCLC, established combining NMPs, PMPs, and NLR, can screen out 80.8% of patients with PD. This is helpful for real-time accurate, concise and rapid assessment of disease progression and timely adjustment of drug therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800020223 . Registered 20 December 2018, http://www.chictr.org.cn/index.aspx .

BACKGROUND: Lung adenocarcinoma (LUAD) is a major subtype of lung cancer and closely associated with poor prognosis. N6-methyladenosine (m6A), one of the most predominant modifications in mRNAs, is found to participate in tumorigenesis. However, the potential function of m6A RNA methylation in the tumor immune microenvironment is still murky. METHODS: The gene expression profile cohort and its corresponding clinical data of LUAD patients were downloaded from TCGA database and GEO database. Based on the expression of 21 m6A regulators, we identified two distinct subgroups by consensus clustering. The single-sample gene-set enrichment analysis (ssGSEA) algorithm was conducted to quantify the relative abundance of the fraction of 28 immune cell types. The prognostic model was constructed by Lasso Cox regression. Survival analysis and receiver operating characteristic (ROC) curves were used to evaluate the prognostic model. RESULT: Consensus classification separated the patients into two clusters (clusters 1 and 2). Those patients in cluster 1 showed a better prognosis and were related to higher immune scores and more immune cell infiltration. Subsequently, 457 differentially expressed genes (DEGs) between the two clusters were identified, and then a seven-gene prognostic model was constricted. The survival analysis showed poor prognosis in patients with high-risk score. The ROC curve confirmed the predictive accuracy of this prognostic risk signature. Besides, further analysis indicated that there were significant differences between the high-risk and low-risk groups in stages, status, clustering subtypes, and immunoscore. Low-risk group was related to higher immune score, more immune cell infiltration, and lower clinical stages. Moreover, multivariate analysis revealed that this prognostic model might be a powerful prognostic predictor for LUAD. Ultimately, the efficacy of this prognostic model was successfully validated in several external cohorts (GSE30219, GSE50081 and GSE72094). CONCLUSION: Our study provides a robust signature for predicting patients' prognosis, which might be helpful for therapeutic strategies discovery of LUAD.

BACKGROUND: Radiation therapy is among the most effective and commonly used therapeutic modalities of cancer treatments in current clinical practice. The fundamental paradigm that has guided radiotherapeutic regimens are 'one-size-fits-all', which are not in line with the dogma of precision medicine. While there were efforts to build radioresponse signatures using OMICS data, their ability to accurately predict in patients is still limited. METHODS: We proposed to integrate two large-scale radiogenomics datasets consisting of 511 with 23 tissues and 60 cancer cell lines with 9 tissues to build and validate radiation response biomarkers. We used intrinsic radiation sensitivity, i.e., surviving fraction of cells (SF2) as the radiation response indicator. Gene set enrichment analysis was used to examine the biological determinants driving SF2. Using SF2 as a continuous variable, we used five different approaches, univariate, rank gene ensemble, rank gene multivariate, mRMR and elasticNet to build genomic predictors of radiation response through a cross-validation framework. RESULTS: Through the pathway analysis, we found 159 pathways to be statistically significant, out of which 54 and 105 were positively and negatively enriched with SF2. More importantly, we found cell cycle and repair pathways to be enriched with SF2, which are inline with the fundamental aspects of radiation biology. With regards to the radiation response gene signature, we found that all multivariate models outperformed the univariate model with a ranking based approach performing well compared to other models, indicating complex biological processes underpinning radiation response. CONCLUSION: To summarize, we found biological processes underpinning SF2 and systematically compared different machine learning approaches to develop and validate predictors of radiation response. With more patient data available in the future, the clinical value of these biomarkers can be assessed that would allow for personalization of radiotherapy.

PURPOSE: To identify subgroups of female breast cancer patients with distinct self-reported employment interference (EI) profiles and determine which demographic, clinical, and symptom characteristics, and quality of life outcomes were associated with subgroup membership. METHODS: Women with breast cancer (n = 385) were assessed for changes in EI over ten times, from prior to, through 12 months after breast cancer surgery. Latent profile analysis (LPA) was used to identify subgroups of patients with distinct EI profiles. RESULTS: Three distinct EI profiles (i.e., None - 26.2% (n = 101), Low - 42.6% (n = 164), High - 31.2% (n = 120)) were identified. Compared to the None and Low groups, patients in the High group were more likely to be younger. Higher proportions in the High group were non-White, pre-menopausal prior to surgery, had more advanced stage disease, had received an axillary lymph node dissection, had received neoadjuvant chemotherapy, had received adjuvant chemotherapy, and had a re-excision or mastectomy on the affected breast within 6 months after surgery. In addition, these patients had lower quality of life scores. Compared to the None group, the High group had higher levels of trait and state anxiety, depressive symptoms, fatigue and sleep disturbance and lower levels of cognitive function. CONCLUSIONS: This study provides new knowledge regarding EI profiles among women in the year following breast cancer surgery. The non-modifiable risk factors (e.g., younger age, being non-White, having more advanced stage disease) can inform current screening procedures. The potentially modifiable risk factors can be used to develop interventions to improve employment outcomes of breast cancer patients.

BACKGROUND: Up to now, limited researches focused on the association between transcription factor 7-like 2 gene (TF7L2) gene single nucleotide polymorphisms (SNPs) and breast cancer (BC) risk. The aim of this study was to evaluate the associations between TF7L2 and BC risk in Chinese Han population. METHODS: Logistic regression model was used to test the correlation between polymorphisms and BC risk. Strength of association was evaluated by odds ratio (OR) and 95% confidence interval (CI). Generalized multifactor dimensionality reduction (GMDR) was applied to analyze the SNP-SNP and gene-environment interaction. RESULTS: Logistic regression analysis indicated that the BC risk was obviously higher in carriers of rs1225404 polymorphism C allele than that in TT genotype carriers (TC or CC versus TT), adjusted OR (95%CI) =1.40 (1.09-1.72). Additionally, we also discovered that people with rs7903146- T allele had an obviously higher risk of BC than people with CC allele (CT or TT versus CC), adjusted OR (95%CI) =1.44 (1.09-1.82). GMDR model was used to research the effect of interaction among 4 SNPs and environmental factors on BC risk. We discovered an important two-locus model (p = 0.0100) including rs1225404 and abdominal obesity, suggesting a potential gene-environment correlation between rs1225404 and abdominal obesity. In general, the cross-validation consistency of two-locus model was 10 of 10, and the testing accuracy was 0.632. Compared with subjects with normal waist circumference (WC) value and rs1225404 TT genotype, abdominal obese subjects with rs1225404 TC or CC genotype had the highest BC risk. After covariate adjustment, OR (95%CI) was 2.23 (1.62-2.89). Haplotype analysis indicated that haplotype containing rs1225404-T and rs7903146-C alleles were associated with higher BC risk. CONCLUSIONS: C allele of rs1225404 and T allele of rs7903146, interaction between rs1225404 and abdominal obesity, rs1225404-T and rs7903146-C haplotype were all related to increased BC risk.

BACKGROUND: Considering the clinical and genetic characteristics, acute lymphoblastic leukemia (ALL) is a rather heterogeneous hematological neoplasm for which current standard diagnostics require various analyses encompassing morphology, immunophenotyping, cytogenetics, and molecular analysis of gene fusions and mutations. Hence, it would be desirable to rely on a technique and an analytical workflow that allows the simultaneous analysis and identification of all the genetic alterations in a single approach. Moreover, based on the results with standard methods, a significant amount of patients have no established abnormalities and hence, cannot further be stratified. METHODS: We performed WTS and WGS in 279 acute lymphoblastic leukemia (ALL) patients (B-cell: n = 211; T-cell: n = 68) to assess the accuracy of WTS, to detect relevant genetic markers, and to classify ALL patients. RESULTS: DNA and RNA-based genotyping was used to ensure correct WTS-WGS pairing. Gene expression analysis reliably assigned samples to the B Cell Precursor (BCP)-ALL or the T-ALL group. Subclassification of BCP-ALL samples was done progressively, assessing first the presence of chromosomal rearrangements by the means of fusion detection. Compared to the standard methods, 97% of the recurrent risk-stratifying fusions could be identified by WTS, assigning 76 samples to their respective entities. Additionally, read-through fusions (indicative of CDKN2A and RB1 gene deletions) were recurrently detected in the cohort along with 57 putative novel fusions, with yet untouched diagnostic potentials. Next, copy number variations were inferred from WTS data to identify relevant ploidy groups, classifying an additional of 31 samples. Lastly, gene expression profiling detected a BCR-ABL1-like signature in 27% of the remaining samples. CONCLUSION: As a single assay, WTS allowed a precise genetic classification for the majority of BCP-ALL patients, and is superior to conventional methods in the cases which lack entity defining genetic abnormalities.

BACKGROUND: Neuroligin1 (NLGN1) is a main component of excitatory glutamatergic synapses complex and is important for synapse assembly and function. The clinical value of NLGN1 in colorectal cancer (CRC) is not clear. METHODS: We obtained the expression data of 1143 CRC patients from 3 independent Gene Expression Omnibus (GEO) datasets (GSE32323, GSE24551, GSE39582) and The Cancer Genome Atlas (TCGA) to make the comparison of the NLGN1 expression level between CRC tissues and matched noncancerous tissues, and to evaluate its value in predicting survival of CRC patients. At the protein level, these results were further confirmed by immunohistochemical staining of 52 CRC samples in our own centre. Finally, the function of NLGN1 was explored by gene set enrichment analysis (GSEA). RESULTS: Increased mRNA and protein levels of NLGN1 expression were associated with worse overall survival or recurrence-free survival in CRC patients from 2 GEO datasets, the TCGA database, and our cohort. In addition, multivariate regression analysis showed that NLGN1 was an independent poor prognostic factor of survival in patients with CRC in TCGA database (OR = 2.524, P = 0.010). Functional analysis revealed that NLGN1 was correlated with function involving the Hedgehog signaling pathway, mismatch repair process, and some material metabolism processes. CONCLUSIONS: This study is the first to implicate and verify NLGN1 as a new poor prognostic marker for CRC.

The human microbiome is defined as the microorganisms that reside in or on the human body, such as bacteria, viruses, fungi, and protozoa, and their genomes. The human microbiome participates in the modulation of human metabolism by influencing several intricate pathways. The association between specific bacteria or viruses and the efficacy of cancer treatments and the occurrence of treatment-related toxicity in cancer patients has been reported. However, the understanding of the interaction between the host microbiome and the cancer treatment response is limited, and the microbiome potentially plays a greater role in the treatment of cancer than reported to date. Here, we provide a thorough review of the potential role of the gut and locally resident bacterial microbiota in modulating responses to different cancer therapeutics to demonstrate the association between the gut or locally resident bacterial microbiota and cancer therapy. Probable mechanisms, such as metabolism, the immune response and the translocation of microbiome constituents, are discussed to promote future research into the association between the microbiome and other types of cancer. We conclude that the interaction between the host immune system and the microbiome may be the basis of the role of the microbiome in cancer therapies. Future research on the association between host immunity and the microbiome may improve the efficacy of several cancer treatments and provide insights into the cause of treatment-related side effects.

BACKGROUND: Cervical cancer incidence is influenced by screening and risk factors in the population. The main risk factor for cervical cancer is sexually transmitted human papillomavirus (HPV), which is sexually transmitted and thus associated with sexual behavior. Smoking, parity and hormonal contraceptive use may also be associated with cervical cancer risk. We compared incidence, screening coverage and risk behaviors for cervical cancer between health regions in Norway. METHODS: We obtained data on incidence of cervical cancer among Norwegian women during 1992-2016 and data on screening coverage from the Cancer Registry of Norway. We obtained data on sexual behavior and smoking from a population-based survey of 16,575 Norwegian women who were 18-45 years old in 2005. RESULTS: Cervical cancer incidence was higher in the northern and southeastern region than in the middle and western region (range in incidence per 100,000 person-years during 1992-2016; north: 10.5 to 14.6; southeast: 9.3 to 12.9; mid: 6.8 to 9.5; west: 8.4 to 10.0). The incidence decreased modestly in the north (average annual percentage change (95% confidence interval) - 1.0 (- 1.2 to - 0.7)) and southeast (- 0.7 (- 1.0 to - 0.3)), but did not change significantly in the mid (- 0.3 (- 1.0 to 0.4)) and west (- 0.3 (- 0.6 to 0.0)). Compared to the national average, women in the north had earlier sexual debut, more partners and higher prevalence of ever having had a sexually transmitted infection (STI), while the opposite was observed among women in the west. Women in the middle and southeastern regions tended to be similar to the national average for sexual behaviors. Although less pronounced, the prevalence of smoking showed regional patterns similar to that observed for sexual behaviors, while ever-use of hormonal contraceptives and cervical screening coverage was similar between regions. CONCLUSIONS: There were regional differences in cervical cancer incidence during the era of nationally organized cervical screening in Norway. To some extent, these differences corresponded to regional differences in risk behavior for cervical cancer in the Norwegian female population.

BACKGROUND: Tumor microenvironment (e.g., cancer-associated fibroblast) plays a key role in cancer tumorigenesis and metastasis. However, the detailed mechanism of whether hypoxia promotes CRC progression via tumor microenvironment remains unclear. METHODS: In this study, circEIF3K exosome was examined by NanoSight Tracking Analysis and RT-qPCR. We used cell colony formation assay, transwell assay and tube formation assay to determine proliferation, invasion and metastasis of HCT116 or SW620 cells. Xenograft tumor assay was employed to show in vivo tumor growth of HCT116 cells. RESULTS: We found that hypoxia could induce secretion of circEIF3K exosome. Conditioned medium (CM) and exosome from circEIF3K knockdown CAF significantly attenuated proliferation, invasion and tube formation of HCT116 or SW620 cells, which could be reverted by miR-214 under hypoxia treatment. Besides, we observed that circEIF3K knockdown evidently impaired tumor growth in mice. TCGA dataset analysis showed that low expression of circEIF3K was observed in normal tissues and associated with prolonged survival time. Finally, PD-L1 was confirmed as important target for miR-214 in CRC. CONCLUSION: In conclusion, our study reveals that a novel axis circEIF3K/miR-214/PD-L1 mediates hypoxia-induced CRC progression via CAF, providing the rationale for developing new targeted therapeutics to treat CRC.

BACKGROUND: Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. METHODS AND DESIGN: MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. DISCUSSION: MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019.

BACKGROUND: Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. METHODS/DESIGN: MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. DISCUSSION: MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018.

BACKGROUND: To assess the effects of Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection on the tumor microenvironment, we examined the relationship between viral infection status, macrophage migration inhibitory factor (MIF), and tumor-associated macrophages in nasopharyngeal carcinoma (NPC). METHODS: A tissue microarray containing 150 cores from 90 patients with NPC and six with chronic inflammation was used. EBV and HPV status were detected using in situ hybridization with commercial EBER1 and HPV16/18 probes. Immunofluorescence double staining of MIF, pan-macrophage marker CD68, M1 macrophage marker CD11c, and M2 macrophage marker CD163 were analyzed using the same tissue microarray. The levels of these markers between NPC and inflammation cases and between tumor nests and stroma were compared. Correlations among these markers were analyzed. RESULTS: We found EBER1(+) cases in 90% of NPC patients, including 10% EBV/HPV co-infection. M1 macrophages mainly infiltrated the tumor nest, while M2 macrophages infiltrated the tumor stroma. We found a significant positive correlation between EBER1 levels and MIF levels in tumor nests and a significant positive correlation between HPV16/18 and CD11c(+) cell levels in NPC tissues. CONCLUSIONS: It is suggested that MIF is associated with EBV, and M1 macrophage infiltration is affected by HPV status in NPC.

BACKGROUND: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. METHODS: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50-74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. DISCUSSION: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01538550 .

BACKGROUND: The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. METHODS: The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. RESULTS: TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. CONCLUSIONS: The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

BACKGROUND: As major regulators of DNA replication in eukaryotes, minichromosome maintenance (MCM) proteins play an important role in the initiation and extension of DNA replication. MCMs and their related genes may be new markers of cell proliferation activity, which is of great significance for the diagnosis and prognosis of cervical cancer. METHODS: To explore the role of MCMs and their related genes in cervical cancer, various bioinformatics methods were performed. First, the ONCOMINE and UALCAN databases were used to analyze the mRNA expression of different MCMs. The Human Protein Atlas database was used to analyze the protein expression of MCMs in normal and tumor tissues. The potential clinical value of MCMs was evaluated using the UALCAN, Kaplan-Meier plotter and cBioPortal databases. Then, the related genes and key coexpressed genes of MCMs were screened using GEPIA2 and cBioPortal analysis. For these genes, we used Metascape and the DAVID database to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, construct the related molecular interaction network, and obtain the key subnetworks and related hub genes. The Kaplan-Meier plotter database was used for survival analysis of cervical cancer patients to evaluate and predict the potential clinical value of the hub genes. Moreover, multiple gene comparisons of the expression of MCMs and related genes in different cancer types also showed the clinical significance of these potential targets. RESULTS: The mRNA and protein expression of MCMs increased in tumor tissue. Overexpression of MCM2/3/4/5/6/7/8/10 was found to be significantly associated with clinical cancer stage. Higher mRNA expression levels of MCM3/5/6/7/8 were found to be significantly associated with longer overall survival, and higher mRNA expression of MCM2/3/4/5/6/7/8 was associated with favorable OS. In addition, a high mutation rate of MCMs (71%) was observed. MCM2, MCM4, MCM8, MCM3 and MCM7 were the five genes with the most genetic alterations. In addition, the coexpressed genes and related genes of MCMs were successfully screened for enrichment analysis. These genes were significantly enriched in important pathways, such as the DNA replication, cell cycle, mismatch repair, spliceosome, and Fanconi anemia pathways. A protein-protein interaction network was successfully constructed, and a total of 13 hub genes (CDC45, ORC1, RPA1, CDT1, TARDBP, RBMX, SRSF3, SRSF1, RFC5, RFC2, MSH6, DTL, and MSH2) from 4 key subnetworks were obtained. These genes and MCM2/3/4/5/6/7/8 might have potential clinical value for the survival and prognosis of cervical cancer patients. CONCLUSIONS: These findings promoted the understanding of the MCM protein family and clinically related molecular targets for cervical epithelial neoplasia and cervical cancer. Our results were helpful to evaluate the potential clinical value of MCMs and related genes in patients with cervical cancer.

BACKGROUND: This study aimed to evaluate the possible role of human papillomavirus (HPV) and Epstein-Barr virus (EBV) coinfection as an etiological factor for prostate cancer (PCa) development. METHODS: This case-control study was conducted on 67 patients with PCa and 40 control subjects. The expression levels of cellular and viral factors involved in inflammation, tumor progression, and metastasis were quantified, using the enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) assay. RESULTS: The EBV/HPV coinfection was reported in 14.9% of patients in the case group and 7.5% of the control subjects. The high-risk types of HPV, that is, HPV 16 and HPV 18, were responsible for 50 and 30% of HPV/EBV-coinfected PCa cases (n = 10), respectively. No significant relationship was observed between PCa and HPV/EBV coinfection (OR = 2.9, 95% CI: 0.18-45.2, P = 0.31). However, the highest percentage of HPV genome integration was found in the HPV/EBV-coinfected PCa group (8/10; 80%). Also, the mean expression levels of inflammatory factors (IL-17, IL-6, TNF-α, NF-κB, VEGF, ROS, and RNS), anti-apoptotic mediators (Bcl-2 and survivin), and anti-anoikis factors (Twist and N-cadherin) were significantly higher in the HPV/EBV-coinfected PCa group, compared to the non-coinfected PCa cases. Nevertheless, the tumor-suppressor proteins (p53 and pRb) and E-cadherin (inhibitor of anoikis resistance) showed significant downregulations in the HPV/EBV-coinfected PCa group, compared to the non-coinfected PCa cases. CONCLUSION: The HPV/EBV coinfection may be an etiological factor for PCa through modulation of cellular behaviors.

BACKGROUND: Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma globally, and patients with relapsed or refractory DLBCL typically experience poor long-term outcomes. METHODS: Differentially expressed genes associated with DLBCL were identified using two GEO datasets in an effort to detect novel diagnostic or prognostic biomarkers of this cancer type, after which receiver operating characteristic curve analyses were conducted. Genes associated with DLBCL patient prognosis were additionally identified via WCGNA analyses of the TCGA database. The expression of PLA2G7 in DLBCL patient clinical samples was further assessed, and the functional role of this gene in DLBCL was assessed through in vitro and bioinformatics analyses. RESULTS: DLBCL-related DEGs were found to be most closely associated with immune responses, cell proliferation, and angiogenesis. WCGNA analyses revealed that PLA2G7 exhibited prognostic value in DLBCL patients, and the upregulation of this gene in DLBCL patient samples was subsequently validated. PLA2G7 was also found to be closely linked to tumor microenvironmental composition such that DLBCL patients expressing higher levels of this gene exhibited high local monocyte and gamma delta T cell levels. In vitro experiments also revealed that knocking down PLA2G7 expression was sufficient to impair the migration and proliferation of DLBCL cells while promoting their apoptotic death. Furthmore, the specific inhibitor of PLA2G7, darapladib, could noticeably restrained the DLBCL cell viability and induced apoptosis. CONCLUSIONS: PLA2G7 may represent an important diagnostic, prognostic, or therapeutic biomarker in patients with DLBCL.

BACKGROUND: Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, has shown survival benefit in clinical trials of various malignant tumors. Nivolumab-induced pneumonitis is major immune-related adverse event (irAE) that is occasionally serious and life-threatening. The aim of this study was to examine the association between pre-existing interstitial lung disease (ILD) on chest computed tomography (CT) and nivolumab-induced pneumonitis among different types of solid tumors. METHODS: We retrospectively collected the clinical data of 311 patients who were diagnosed with non-small cell lung cancer (NSCLC), head and neck cancer (HNC), or gastric cancer (GC), and treated with nivolumab monotherapy. Patients who underwent chest CT immediately before starting nivolumab without previous thoracic radiotherapy or other immune checkpoint inhibitors were eligible. We collected baseline patient characteristics and assessed pre-existing ILD on baseline chest CT. RESULTS: Finally, 188 patients were included in the analysis: 96 patients with NSCLC, 43 patients with HNC, and 49 patients with GC. NSCLC patients had a significantly higher rate of pre-existing ILD compared with HNC/GC patients (P = 0.047). Nivolumab-induced pneumonitis occurred in 11.7% (22 of 188), including 14.6% (14 of 96) of NSCLC, and 8.7% (8 of 92) of HNC/GC. Univariate and multivariate logistic regression analyses revealed that pre-existing ILD (odds ratio, 5.92; 95% confidence interval (CI), 2.07-18.54, P = 0.0008) and male sex (odds ratio, 5.58; 95% CI, 1.01-104.40, P = 0.049) significantly increased the risk of nivolumab-induced pneumonitis. CONCLUSION: Our results indicated that pre-existing ILD and male sex are risk factors for nivolumab-induced pneumonitis in solid tumors.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied. METHODS: We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes. RESULTS: We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib. CONCLUSIONS: Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

BACKGROUND: The aim of this study was to analyze the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) LEP-R c.668A>G (p.Gln223Arg, rs1137101) of leptin receptor gene and to assess the influence this DNA marker has on endometrial cancer (EC) with respect to total body fat content. METHODS: The study comprised 120 patients treated for endometrial cancer and 90 controls treated for uterine fibroids. In total, 210 patients were included in this research. DNA was isolated from archival post-operative specimens. Polymerase Chain Reaction - Restriction Fragment Length Polymorphism was employed to analyze the SNP. RESULTS: In this paper we have demonstrated that heterozygous genotype AG of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) is statistically less frequent in women with endometrial cancer (EC) than in controls: 33 versus 57%, respectively. Similarly, this heterozygous genotype is statistically significantly less frequent in obese (BMI > 30) women with EC than in lean controls (BMI < 25): 30 versus 63%, respectively. CONCLUSIONS: AG polymorphic variant of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) in LEP-R may be considered a protective factor in the development of endometrial cancer.

OBJECTIVE: Tongue and mouth floor squamous cell carcinoma (T/MF SCC) exhibits a high rate of local recurrence and cervical lymph node metastasis. The effect of the tumor microenvironment on T/MF SCC remains unclear. MATERIALS AND METHODS: Transcriptome and somatic mutation data of patients with T/MF SCC were obtained from HNSC projects of the Cancer Genome Atlas. Immune infiltration quantification in early- (clinical stage I-II) and advanced-stage (clinical stage III-IV) T/MF SCC was performed using single sample Gene Set Enrichment Analysis and MCPcounter. Differentially expressed gene data were filtered, and their function was assessed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Kaplan-Meier survival curve analysis and Cox regression model were conducted to evaluate the survival of patients with the CCL22 signature. Maftools was used to present the overview of somatic mutations. RESULTS: In T/MF SCC, T helper (Th)2 cell counts were significantly increased in patients with early-stage disease compared to those with advanced-stage disease. Expression of the Th2 cell-related chemokine, CCL22, was downregulated in patients with advanced-stage T/MF SCC. Univariate and multivariate Cox analyses revealed that CCL22 was a good prognostic factor in T/MF SCC. A nomogram based on the expression of CCL22 was constructed to serve as a prognostic indicator for T/MF SCC. NOTCH1 mutations were found at a higher rate in patients with advanced-stage T/MF SCC than in those with early-stage T/MF SCC, resulting in the inhibition of the activation of the NOTCH1-Th2 cell differentiation pathway. The expression levels of CCL22, GATA-3, and IL4 were higher in patients with early-stage T/MF SCC than in those with advanced-stage T/MF SCC. CONCLUSION: In T/MF SCC, high expression of CCL22 may promote the recruitment of Th2 cells and help predict a better survival. Mutations in NOTCH1 inhibit the differentiation of Th2 cells, facilitating tumor progression through a decrease in Th2 cell recruitment and differentiation.

Erratum in BMC Cancer. 2021 Sep 15;21(1):1024.

BACKGROUND: Autophagy inhibits tumorigenesis by limiting inflammation. LncRNAs regulate gene expression at various levels as RNAs; thus, both autophagy and lncRNAs are closely related to the occurrence and development of tumours. METHODS: A total of 232 autophagy-related genes were used to construct a coexpression network to extract autophagy-related lncRNAs. A prognostic signature was constructed by multivariate regression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was applied to analyse enrichment in cancer-related pathways. Immune infiltration analysis was used to analyse the relationship between the prognostic signature and the tumour microenvironment. RESULTS: Nine autophagy-related lncRNAs were used to construct a prognostic model for non-small-cell lung cancer. The median risk score was used to discriminate the high- and low-risk groups, and the low-risk group was found to have better survival. Because KEGG pathway analysis showed that the prognostic signature was enriched in some immune pathways, further analysis of immune infiltration was conducted, and it was found that the prognostic signature did play a unique role in the immune microenvironment. Additionally, the prognostic signature was associated with clinical factors. CONCLUSION: We constructed a prognostic model of autophagy-related lncRNAs that can predict the prognosis of non-small-cell lung cancer.

BACKGROUND: Breast cancer (BC) is a complex disease with high heterogeneity, which often leads to great differences in treatment results. Current common molecular typing method is PAM50, which shows positive results for precision medicine; however, room for improvement still remains because of the different prognoses of subtypes. Therefore, in this article, we used lncRNAs, which are more tissue-specific and developmental stage-specific than other RNAs, as typing markers and combined single-cell expression profiles to retype BC, to provide a new method for BC classification and explore new precise therapeutic strategies based on this method. METHODS: Based on lncRNA expression profiles of 317 single cells from 11 BC patients, SC3 was used to retype BC, and differential expression analysis and enrichment analysis were performed to identify biological characteristics of new subtypes. The results were validated for survival analysis using data from TCGA. Then, the downstream regulatory genes of lncRNA markers of each subtype were searched by expression correlation analysis, and these genes were used as targets to screen therapeutic drugs, thus proposing new precision treatment strategies according to the different subtype compositions of patients. RESULTS: Seven lncRNA subtypes and their specific biological characteristics are obtained. Then, 57 targets and 210 drugs of 7 subtypes were acquired. New precision medicine strategies were proposed according to the different compositions of patient subtypes. CONCLUSIONS: For patients with different subtype compositions, we propose a strategy to select different drugs for different patients, which means using drugs targeting multi subtype or combinations of drugs targeting a single subtype to simultaneously kill different cancer cells by personalized treatment, thus reducing the possibility of drug resistance and even recurrence.

BACKGROUND: Lung cancer is the most common oncological cause of death in the Western world. Early diagnosis is critical for successful treatment. However, no effective screening methods exist. A promising approach could be the use of volatile organic compounds as diagnostic biomarkers. To date there are several studies, in which dogs were trained to discriminate cancer samples from controls. In this study we evaluated the abilities of specifically trained dogs to distinguish samples derived from lung cancer patients of various tumor stages from matched healthy controls. METHODS: This single center, double-blind clinical trial was approved by the local ethics committee, project no FF20/2016. The dog was conditioned with urine and breath samples of 36 cancer patients and 150 controls; afterwards, further 246 patients were included: 41 lung cancer patients comprising all stages and 205 healthy controls. From each patient two breath and urine samples were collected and shock frozen. Only samples from new subjects were presented to the dog during study phase randomized, double-blinded. This resulted in a specific conditioned reaction pointing to the cancer sample. RESULTS: Using a combination of urine and breath samples, the dog correctly predicted 40 out of 41 cancer samples, corresponding to an overall detection rate of cancer samples of 97.6% (95% CI [87.1, 99.9%]). Using urine samples only the dog achieved a detection rate of 87.8% (95% CI [73.8, 95.9%]). With breath samples, the dog correctly identified cancer in 32 of 41 samples, resulting in a detection rate of 78% (95% CI [62.4, 89.4%]). CONCLUSIONS: It is known from current literature that breath and urine samples carry VOCs pointing to cancer growth. We conclude that olfactory detection of lung cancer by specifically trained dogs is highly suggestive to be a simple and non-invasive tool to detect lung cancer. To translate this approach into practice further target compounds need to be identified.

BACKGROUND: Acute Limb Ischemia (ALI) carries a high morbidity and mortality rate that is compounded in the cancer patient. Though it is a relatively uncommon event, it is of extremely high adverse impact and carries poor awareness among clinicians. METHODS: Retrospective review of electronic medical records was performed of cancer patients presenting with acute limb ischemia (ALI) to the tertiary cancer center's urgent care center or as inpatient between January 1, 2014 and January 1, 2020. RESULTS: Out of the 29 cancer patients with ALI, 12 (41%) died within 3 month and 9 (31%) patients died within 1 months of ALI diagnosis. 65% had long term adverse outcome after ALI - 31% with death in 1 month, 2 (7%) with an amputation, 5 (17%) with lifestyle-limiting claudication, and 3 (10%) with subsequent wound ulceration or gangrene. Patients not eligible for standard of care (12 patients, 41%) (RR 2.33 95% CI [1.27-4.27], p <  0.01) and heparin administration ≥6 h from presentation (19 patients, 65%) (RR 2.81 [1.07-7.38], p = 0.04) were at increased risk of adverse outcome. Atypical/confounded presentation of ALI (13 patients, 45%) (RR 1.84 95% CI [1.03-3.29], p = 0.04), pulse exam not documented (12 patients, 41.4%) (RR 1.95 [95% CI [1.14-3.32], p = 0.01), and patients with services other than a vascular specialist initially consulted (8 patients, 27.6%) (RR 1.91 95% CI [1.27-2.87], p <  0.01) were significant risk factors for heparin administered ≥6 h from presentation. CONCLUSIONS: ALI is devastating in cancer patients, with a high number presenting with atypical/confounded signs and symptoms which delays treatment. Heparin administered ≥6 h from presentation is associated with adverse outcome.

BACKGROUND: To assess the efficacies and potential predictors of a corticosteroid switch in metastatic castration-resistant prostate cancer (mCRPC) patients with biochemical progression on abiraterone acetate plus prednisone (A + P). METHODS: Patients with mCRPC treated between April 2016 and August 2020, who experienced biochemical progression on A + P and then switched to A plus dexamethasone (D), were retrospectively identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were PSA response, overall survival (OS), and safety. RESULTS: One hundred and thirty consecutive cases were enrolled. The median PFS and OS on A + D were 5.0 and 18.7 months, respectively. The best PSA decline of ≥50% (PSA50) and ≥ 30% (PSA30) were observed in 29.2 and 46.2% patients, respectively. Lower PSA at corticosteroid switch (≤ 20 ng/mL; median PFS, HR 0.63, p = 0.019; median OS, HR 0.38, p = 0.001) and longer mCRPC-free survival (≥ 18 months; median PFS, HR 0.61, p = 0.013; median OS, HR 0.51, p = 0.015) were identified as independent prognostic predictors associated with longer PFS and OS. A risk stratification tool was developed to select candidates for corticosteroid switch based on the independent prognostic predictors of PFS and OS. CONCLUSIONS: A corticosteroid switch from prednisone to dexamethasone is effective for mCRPC which progressed on A + P treatment. Patients with lower PSA at corticosteroid switch and/or longer mCRPC-free survival may gain more benefits by the corticosteroid switch.

BACKGROUND: Intracranial hemangiopericytoma is a rare disease and surgery is the mainstay treatment. Although postoperative adjuvant radiotherapy is often used, there are no reports comparing different radiotherapy techniques. The purpose of this study is to analyze the impact of post-operative radiotherapy and different radiotherapy technique on the results in patients with intracranial hemangiopericytoma (HPC). METHODS: We retrospectively reviewed 66 intracranial HPC patients treated between 1999 and 2019 including 29 with surgery followed by radiotherapy (11 with intensity-modulated radiotherapy (IMRT) and 18 with stereotactic radiosurgery (SRS)) and 37 with surgery alone. Chi-square test was used to compare the clinical characteristic between the groups. The Kaplan-Meier method was used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox proportional hazards models were used to examine prognostic factors of survival. We also underwent a matched-pair analysis by using the propensity score method. RESULTS: The crude local control rates were 58.6% in the surgery plus post-operative radiotherapy group (PORT) and 67.6% in the surgery alone group (p = 0.453). In the subgroup analysis of the PORT patients, local controls were 72.7% in the IMRT group and 50% in the SRS group (p = 0.228). The median OS in the PORT and surgery groups were 122 months and 98 months, respectively (p = 0.169). The median RFS was 96 months in the PORT group and 72 months in the surgery alone group (p = 0.714). Regarding radiotherapy technique, the median OS and RFS of the SRS group were not significantly different from those in the IMRT group (p = 0.256, 0.960). The median RFS were 112 and 72 months for pathology grade II and III patients, respectively (p = 0.001). Propensity score matching did not change the observed results. CONCLUSION: In this retrospective analysis, PORT did not improve the local control rates nor the survivals. The local control rates after IMRT and SRS were similar even though the IMRT technique had a much higher biological dose compared with the SRS technique.

BACKGROUND: Gastric cancer (GC) has an unwelcoming prognosis when diagnosed at an advanced stage. The purpose of this study was to examine the expression of myosin heavy chain 11 (MYH11) in GC and mechanisms related. METHODS: The MYH11 expression in GC was investigated via the SangerBox platform. MYH11 expression in GC tissues and cell lines was examined by immunohistochemistry, RT-qPCR, and western blot. The relationship between MYH11 expression and patients' prognosis was analyzed. The effects of MYH11 on the biological behaviors of GC cells were investigated by gain-of-function experiments. Bioinformatics analysis was used to find genes with relevance to MYH11 expression in GC. The relationship was verified by luciferase and ChIP-qPCR assays, followed by rescue assay validation. The causes of MYH11 downregulation in GC were verified by quantitative methylation-specific PCR. Finally, the effect of MYH11 on tumor growth was examined. RESULTS: MYH11 was downregulated in GC and predicted poor prognoses. MYH11 reverted the malignant phenotype of GC cells. MYH11 repressed the TNFRSF14 expression by binding to the TNFRSF14 promoter. TNFRSF14 reversed the inhibitory effect of MYH11 on the malignant phenotype of GC cells. The methylation of the MYH11 promoter was elevated in GC, which was correlated with the elevated DNMT3B in GC. Overexpression of DNMT3B repressed transcription of MYH11 by promoting its methylation. Also, MYH11 upregulation inhibited tumor growth. CONCLUSION: DNMT3B inhibits MYH11 expression by promoting its DNA methylation, thereby attenuating the repressive effect of MYH11 on the transcriptional of TNFRSF14 and promoting the progression of GC.

BACKGROUND: Intake time of diet has recently been demonstrated to be associated with the internal clock and circadian pattern. However, whether and how the intake time of minerals would influence the natural course of cancer was largely unknown. METHODS: This study aimed to assess the association of mineral intake at different periods with cancer and all-cause mortality. A total of 27,455 participants aged 18-85 years old in the National Health and Nutrition Examination Survey were recruited. The main exposures were the mineral intakes in the morning, afternoon and evening, which were categorized into quintiles, respectively. The main outcomes were mortality of cancer and all causes. RESULTS: During the 178,182 person-years of follow-up, 2680 deaths, including 601 deaths due to cancer, were documented. After adjusting for potential confounders, compared to the participants who were in the lowest quintile(quintile-1) of mineral intakes at dinner, the participants in the highest quintile intake(quintile-5) of dietary potassium, calcium and magnesium had lower mortality risks of cancer (HRpotassium = 0.72, 95% CI:0.55-0.94, P for trend = 0.023; HRcalcium = 0.74, 95% CI:0.57-0.98, P for trend = 0.05; HRmagnesium = 0.75, 95% CI:0.56-0.99, P for trend = 0.037) and all-cause (HRpotassium = 0.83, 95% CI:0.73-0.94, P for trend = 0.012; HRcalcium = 0.87, 95% CI:0.76-0.99, P for trend = 0.025; HRmagnesium = 0.85, 95% CI:0.74-0.97, P for trend = 0.011; HRcopper = 0.80, 95%CI: 0.68-0.94, P for trend = 0.012). Further, equivalently replacing 10% of dietary potassium, calcium and magnesium consumed in the morning with those in the evening were associated with lower mortality risk of cancer (HRpotassium = 0.94, 95%CI:0.91-0.97; HRcalcium = 0.95, 95%CI:0.92-0.98; HRmagnesium = 0.95, 95%CI: 0.92-0.98). CONCLUSIONS: This study demonstrated that the optimal intake time of potassium, calcium and magnesium for reducing the risk of cancer and all-cause mortality was in the evening.

BACKGROUND: Although spread through air spaces (STAS) is a robust biomarker in surgically resected lung cancer, its application to biopsies is challenging. Moreover, limited resection is not an effective treatment for STAS-positive lung adenocarcinoma. This study aimed to identify histologic features from preoperative percutaneous transthoracic needle biopsies (PTNBs) to predict STAS status in the subsequently resected specimens, and thus help in selecting the surgical extent. METHODS: Between January 2014 and December 2015, 111 PTNB specimens and subsequent resection specimens from consecutive lung adenocarcinoma patients were retrospectively examined. Histopathologic features of PTNB specimens and presence of STAS in subsequent resection specimens were evaluated and correlations between them were analyzed statistically. RESULTS: The study participants had a mean age of 59 years (range, 35-81) and included 50 men and 61 women. Thirty-six patients were positive for STAS whereas 75 were negative. The micropapillary/solid histologic subtypes of lung adenocarcinoma (26 of 39; 66.7%; P <  0.001), necrotic/tumor debris (31 of 42; 73.8%; P <  0.001), intratumoral budding (ITB) (20 of 33; 60.6%; P <  0.001), desmoplasia (35 of 41; 85.4%; P <  0.001), and grade 3 nuclei (12 of 14; 85.7%; P <  0.001) were more common in STAS-positive tumors. Micropapillary/solid histologic subtype (OR, 1.35; 95% CI: 1.06, 1.67), ITB (OR, 1.64; 95% CI: 1.09, 2.83), desmoplasia (OR, 1.83; 95% CI: 1.36, 3.12), and N stage (N1 stage: OR, 1.37; 95% CI: 1.19, 1.87) (N2 stage: OR, 1.29; 95% CI: 1.07, 1.73) were independent predictors of STAS. CONCLUSIONS: Micropapillary/solid histologic subtype, ITB, and desmoplasia in preoperative PTNB specimens were independently associated with STAS in the subsequent resection specimens. Therefore, these can predict STAS and may help to optimize therapeutic planning.

BACKGROUND: Total mesorectal excision (TME) and lateral lymph node dissection (LLND) without radiotherapy (RT) are standard treatment for lower cT3/4 rectal cancers in Eastern countries. In comparative studies, both TME + LLND and RT + TME yield good local control. Although Japanese guidelines recommend LLND for locally advanced rectal cancers below the peritoneal reflection, LLND dissection of clinically negative lateral pelvic lymph nodes (LPLN) is controversial, and laparoscopic TME + LLND is technically challenging and time-consuming. New optical instruments for laparoscopy allow easy perioperative sentinel lymph node (SLN) identification using ICG. The SLN concept may facilitate accurate diagnosis of LPLN involvement, and thus reduce LLND in laparoscopic rectal cancer surgery. Here we investigated lateral pelvic SLN navigation surgery for SLN detection during laparoscopic rectal cancer surgery. METHODS: This study included 21 patients with clinical StageII/III lower rectal cancer without LPLN enlargement, who underwent curative laparoscopic surgery. All patients underwent TME, followed by lateral SLN identification and biopsy using ICG, and then laparoscopic LLND. ICG fluorescence imaging was conducted using the laparoscopic near-infrared camera system. RESULTS: Lateral SLNs were successfully identified in 16 (76.2%) of the 21 patients. Among the 15 patients without SLN tumor metastasis, the dissected lateral non-SLNs were all negative. CONCLUSIONS: A lack of metastasis in the lateral pelvic SLN seems to reflect a lack of metastases to all lateral LNs. Our present results suggest that this laparoscopic ICG-guided SLN strategy may be a low-risk and time-saving method to prevent laparoscopic LLND in cases with negative lateral pelvic lymph nodes.

BACKGROUND: To compare the value of interim 18F-FLT-PET and 18F-FDG-PET for predicting treatment outcomes in patients with metastatic breast cancer after salvage therapy. METHODS: Patients with metastatic breast cancer received PET/CT using 18F-FLT and 18F-FDG at baseline, after the 1st and 2nd cycle of systemic chemotherapy. The clinical response was classified according to Response Evaluation Criteria in Solid Tumors 1.1 based on contrast-enhanced CT after 3 months of systemic chemotherapy. The metabolic response on PET was assessed according to European Organization for Research and Treatment of Cancer criteria or PET Response Criteria in Solid Tumors (PERCIST) and was correlated to the clinical response, overall survival (OS), and progression-free survival (PFS). RESULTS: Twenty-five patients entered final analysis. On 18F-FDG-PET, clinical responders after 2 chemotherapy cycles (post-2c) had a significantly greater reduction of maximal standardized uptake value (SUV) and the peak SUV corrected for lean body mass (SULpeak) of the tumor than non-responders (P = 0.030 and 0.003). Metabolic response determined by PERCIST on post-2c 18F-FDG-PET showed a high area under the receiver operating characteristics curve of 0.801 in predicting clinical response (P = 0.011). Patients who were metabolic responders by PERCIST on post-2c 18F-FDG-PET had a significantly longer PFS (53.8% vs. 16.7%, P = 0.014) and OS (100% vs. 47.6%, P = 0.046) than non-responders. Survival differences between responders and non-responders in the interim 18F-FLT-PET were not significant. CONCLUSIONS: 18F-FLT-PET failed to show an advantage over 18F-FDG-PET in predicting the treatment response and survival in patients with metastatic breast cancer. Assessment of treatment outcome by interim 18F-FDG-PET may aid treatment. TRIAL REGISTRATION: The study was retrospectively registered on 02/06/2020 on Clinicaltrials.gov (identifier NCT04411966 ).

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare, low- to intermediate-grade sarcoma, which represents a diagnostic imaging challenge. This study aimed to analyze the clinical and ultrasound features of primary and recurrent DFSP to improve the diagnosis. METHODS: Clinical, imaging, and pathological data from a total of 58 patients (23 patients with primary DFSP and 35 patients with recurrent DFSP) were retrospectively reviewed. RESULTS: There was no statistically significant difference in age, sex, tumor size, or echogenicity between the two groups. Most of the primary DFSP lesions involved the overlying dermis and hypodermis, while most of the recurrent DFSP lesions were fixated to more deeply seated structures at the original surgical incision. Red nodules on the skin were found more frequently in the primary group. There were statistically significant differences in the type of lesion and ultrasound tumor morphology (p < 0.050). The lesions in the primary group showed more tentacle-like projections or a "claw" sign, while the lesions in the recurrent group were more commonly oval, lobulated, and irregularly shaped. Hypervascularity was common in both groups. CONCLUSIONS: For primary DFSP, a slow-growing, red nodule on the skin involving the overlying dermis and hypodermis, more frequently a hypoechoic mass with tentacle-like projections or a "claw" sign, was observed. For recurrent DFSP, palpable subcutaneous nodules or subcutaneous masses at the original surgical incision and oval, lobulated, and irregularly shaped lesions were more commonly observed. This may be useful for improving diagnostic accuracy.

BACKGROUND: Screening is defined as the identification of unrecognized disease in an apparently healthy population. Symptomatic individuals are recommended to contact a physician instead of participating in screening. However, in colorectal cancer (CRC) screening this approach may be problematic as abdominal symptoms are nonspecific. This study aimed at identifying the prevalence of self-reported abdominal symptoms among screening-eligible men and women aged 50-74 years. METHODS: This cross-sectional survey study included 11,537 individuals aged 50-74 years invited for CRC screening from 9 to 23 September 2019. Descriptive statistics of responders experiencing alarm symptoms of CRC, Low Anterior Resection Syndrome Score (LARS) and the Patient Assessment of Constipation-Symptoms (PAC-SYM) were derived. The association between abdominal symptoms and demographic and socioeconomic variables were estimated by prevalence ratio (PR) using a Poisson regression model with robust variance. RESULTS: A total of 5488 respondents were included. The respondents were more likely women, of older age, Danish, cohabiting and had higher education and income level compared to non-respondents. Abdominal pain more than once a week was experienced by 12.0% of the respondents. Of these, 70.8% had been experiencing this symptom for >1 month. Fresh blood in the stool was experienced by 0.7% and of these 82.1% for >1 month. About one third of those experiencing alarm symptoms more than once a week for >1 month had not consulted a doctor. A total of 64.1% of the respondents had no LARS, 21.7% had minor LARS and 14.2% had major LARS. The median PAC-SYM score was 0.33 (Interquartile range (IQR): 0.17;0.75), the median abdominal score was 0.50 (IQR: 0.00;1.00), median rectal score 0.00 (IQR:0.00;0.33) and median stool score 0.40 (IQR: 0.00;0.80). Men and those aged 65-74 reported less symptoms than women and those aged 50-64 years, respectively. CONCLUSIONS: This study illustrated that abdominal symptoms were frequent among screening-eligible men and women. This should be taken into account when implementing and improving CRC screening strategies. A concerning high number of the respondents experiencing alarm symptoms had not consulted a doctor. This calls for attention to abdominal symptoms in general and how those with abdominal symptoms should participate in CRC screening.