BACKGROUND: Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). METHODS/DESIGN: This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. DISCUSSION: A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021).

BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study. METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo. RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo. CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.

BACKGROUND: Preoperative neoadjuvant chemoradiation (nCRT) has been the standard treatment for locally advanced rectal cancer. Serum biomarkers to stratify patients with respect to prognosis and response to nCRT are needed due to the diverse response to the therapy. METHODS: Thirteen paired pre- and post-nCRT sera from rectal cancer patients were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Twenty-five proteins were selected for validation by parallel reaction monitoring (PRM) in ninety-one patients. RESULTS: Totally, 310 proteins were identified and quantified in sera samples. Reactome pathway analysis showed that the immune activation-related pathways were enriched in response to nCRT. Twenty-five proteins were selected for further validation. PRM result showed that the level of PZP was higher in pathological complete response (pCR) patients than non-pCR patients. The Random Forest algorithm identified a prediction model composed of 10 protein markers, which allowed discrimination between pCR patients and non-pCR patients (area under the curve (AUC) = 0.886 on testing set). Higher HEP2 and GELS or lower S10A8 in baseline sera were associated with better prognosis. Higher APOA1 in post nCRT sera was associated with better disease-free survival (DFS). CONCLUSIONS: We identified and confirmed a 10-protein panel for nCRT response prediction and four potential biomarkers HEP2, GELS, S10A8 and APOA1 for prognosis of rectal cancer based on iTRAQ-based comparative proteomics screening and PRM-based targeted proteomic validation.

LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It's essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort (n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.

BACKGROUND: The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. METHODS: In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. RESULTS: Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached (P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. CONCLUSIONS: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02461836 . Registered 03/06/2015.

BACKGROUND: IFN-γ has been traditionally recognized as an inflammatory cytokine that involves in inflammation and autoimmune diseases. Previously we have shown that sustained IFN-γ induced malignant transformation of bovine mammary epithelial cells (BMECs) via arginine depletion. However, the molecular mechanism underlying this is still unknown. METHODS: In this study, the amino acids contents in BMECs were quantified by a targeted metabolomics method. The acquisition of differentially expressed genes was mined from RNA-seq dataset and analyzed bioinformatically. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) assay were performed to detect gene mRNA and protein expression levels. CCK-8 and would healing assays were used to detect cell proliferation and migration abilities, respectively. Cell cycle phase alternations were analyzed by flow cytometry. RESULTS: The targeted metabolomics analysis specifically discovered IFN-γ induced arginine depletion through accelerating arginine catabolism and inhibiting arginine anabolism in BMECs. Transcriptome analysis identified leucine aminopeptidase 3 (LAP3), which was regulated by p38 and ERK MAPKs, to downregulate arginine level through interfering with argininosuccinate synthetase (ASS1) as IFN-γ stimulated. Moreover, LAP3 also contributed to IFN-γ-induced malignant transformation of BMECs by upregulation of HDAC2 (histone deacetylase 2) expression and promotion of cell cycle proteins cyclin A1 and D1 expressions. Arginine supplementation did not affect LAP3 and HDAC2 expressions, but slowed down cell cycle process of malignant BMECs. In clinical samples of patients with breast cancer, LAP3 was confirmed to be upregulated, while ASS1 was downregulated compared with healthy control. CONCLUSIONS: These results demonstrated that LAP3 mediated IFN-γ-induced arginine depletion to malignant transformation of BMECs. Our findings provide a potential therapeutic target for breast cancer both in humans and dairy cows.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is prone to metastasis and likely to develop resistance to chemotherapeutic drugs. DNA repair has been reported to be involved in the progression and chemoresistance of LUSC. However, the relationship between LUSC patient prognosis and DNA damage repair genes is still unclear. METHODS: The clinical information of LUSC patients and tumour gene expression level data were downloaded from the TCGA database. Unsupervised clustering and Cox regression were performed to obtain molecular subtypes and prognosis-related significant genes based on a list including 150 DNA damage repair genes downloaded from the GSEA database. The coefficients determined by the multivariate Cox regression analysis and the expression level of prognosis-related DNA damage repair genes were employed to calculate the risk score, which divided LUSC patients into two groups: the high-risk group and the low-risk group. Immune viability, overall survival, and anticarcinogen sensitivity analyses of the two groups of LUSC patients were performed by Kaplan-Meier analysis with the log rank test, ssGSEA and the pRRophetic package in R software. A time-dependent ROC curve was applied to compare the survival prediction ability of the risk score, which was used to construct a survival prediction model by multivariate Cox regression. The prediction model was used to build a nomogram, the discriminative ability of which was confirmed by C-index assessment, and its calibration was validated by calibration curve analysis. Differentially expressed DNA damage repair genes in LUSC patient tissues were retrieved by the Wilcoxon test and validated by qRT-PCR and IHC. RESULT: LUSC patients were separated into two clusters based on molecular subtypes, of which Cluster 2 was associated with worse overall survival. A prognostic prediction model for LUSC patients was constructed and validated, and a risk score calculated based on the expression levels of ten DNA damage repair genes was employed. The clinical utility was evaluated by drug sensitivity and immune filtration analyses. Thirteen-one genes were upregulated in LUSC patient samples, and we selected the top four genes that were validated by RT-PCR and IHC. CONCLUSION: We established a novel prognostic model based on DNA damage repair gene expression that can be used to predict therapeutic efficacy in LUSC patients.

BACKGROUND: There is no clear consensus on the benefits of adjuvant chemotherapy for tumor-node-metastasis (TNM) stage T1 (T1N0M0) breast cancer (BC). Our study investigated the effects of adjuvant chemotherapy on T1N0M0 BC patients. METHODS: Seventy-five thousand one hundred thirty-nine patients diagnosed with T1N0M0 BC were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox analyses were performed to investigate the effects of adjuvant chemotherapy on T1a, T1b, and T1cN0M0 BC, including various tumor grades, and four molecular subtypes. Propensity score matching (PSM) was used to eliminate confounding factors and further compare the results between adjuvant chemotherapy and no adjuvant chemotherapy. Additionally, 545 T1N0M0 BC patients treated at the Northern Jiangsu People's Hospital were included as an independent external validation cohort. Univariate and multivariate Cox analyses were used to confirm the effects of adjuvant chemotherapy in T1a, T1b, and T1cN0M0 BC. Survival curves for the different tumor grades and molecular subtypes were plotted using the Kaplan-Meier method. RESULTS: Adjuvant chemotherapy demonstrated a statistically significant improvement in overall survival (OS) in T1b and T1c BC, but not in T1a BC. Within T1b BC, adjuvant chemotherapy was found to have effects on grade III, and hormone receptor + (HoR +)/human epidermal growth factor receptor 2 + (HER2 +), HoR-/HER2 + , and HoR-/HER2- molecular subtypes, respectively. Adjuvant chemotherapy was beneficial to OS for grade II/III and T1c BC. Identical results were obtained after PSM. We also obtained similar results with external validation cohort, except that adjuvant chemotherapy made a difference in grade II and T1b BC of the external validation dataset. CONCLUSIONS: Partial T1N0M0 BC patients with grade III T1bN0M0, patients with tumor grade II and III T1cN0M0, and excluding those with HoR + /HER2- subtype tumors, could obtain OS benefits from adjuvant chemotherapy.

BACKGROUND: Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC. METHODS: In total, 395 patients with histologically confirmed T1N0-2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors. RESULTS: The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80-36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91-11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21-7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively. CONCLUSIONS: For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis.

BACKGROUND: Cervical cancer is a preventable disease, but it is a major public health problem despite having a good prognosis when diagnosed early. Although the Pap smear has led to huge drops in rates of cervical cancer and death from the disease, it has some limitations, making new approaches necessary for early diagnosis and biomarkers discovery. MiRNAs have been considered a new class of non-invasive biomarkers and may have great clinical value for screening early-stage cervical intraepithelial neoplasia. Well-designed studies have emerged as a necessary strategy for the identification of miRNAs that could be used safely and reliably for a differential diagnosis. This review aims to provide an up-to-date perspective on the assessment of circulating miRNA expression from precursor lesions to cervical cancer, identifying circulating miRNAs or specific miRNA signatures that can be used as potential biomarkers of different stages of cervical carcinogenesis. METHODS: A systematic review was performed and searches were conducted in the PubMed, LILACS, and Scopus electronic databases. RESULTS: Most studies involved Chinese ethnic women and searched for circulating miRNAs in serum samples. Thirty three microRNAs were evaluated in the eligible studies and 17 (miR-196a, miR-16-2, miR-497, miR-1290, miR-425-5p, hsa-miR- 92a, miR-1266, miR-9, miR-192, miR-205, miR-21, miR-152, miR-15b, miR-34a, miR-218, miR-199a-5p and miR-155-5p) showed up-regulation in women with precursor lesion and cervical cancer and 16 microRNAs showed decreased expression in these same groups of women compared to healthy controls (miR-195, miR-2861, miR-145, miR-214, miR-34a, miR-200a, let-7d-3p, miR-30d-5p, miR-638, miR-203a-3p, miR-1914-5p, miR-521, miR-125b, miR-370, miR-218 and miR-100). CONCLUSION: Therefore, defining promising circulating miRNAs or specific miRNA signatures of biological fluid samples can be useful for the screening, diagnosis, prognosis and clinical monitoring of women undergoing cervical carcinogenesis, but greater standardization of studies seems to be necessary for greater consolidation of information.

BACKGROUND: The adjuvant treatment with Aromatase Inhibitor (AI) is considered standard of care for postmenopausal breast cancer (BC) women with hormone receptor-positive (HR +), however, it often causes adverse effects such as cancer-related fatigue (CRF). The high prevalence of vitamin D deficiency in postmenopausal women who start adjuvant AI supports the hypothesis that hypovitaminosis D would be one of the biological explanations for toxicity of AI. This study aimed to identify the relationship between 25-hydroxyvitamin D [25(OH)D] and CRF, and to analyze their associations and effects on depression, anxiety, functional disability, muscle/joint aches and HRQL. METHODS: This prospective study included 89 postmenopausal women diagnosed with HR + early BC in adjuvant endocrine therapy with AI. Anthropometric and body composition assessments were performed, as well as dietary assessments by application of 24-h dietary recall, at three time points, totaling 24 months of follow-up. The women completed the Cervantes Scale (CS), Hospital Anxiety and Depression Scale (HADS) and Health Assessment Questionnaire (HAQ). The CRF was determined from the Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F). The serum 25(OH)D was determined by electrochemiluminescence, with cut-off point above 75 nmol/L adopted as sufficiency. Generalized Linear Model (GLzM) and Generalized Mixed Model (GMM) analysis were used. RESULTS: At baseline, 36% (n = 32) of the women presented CRF and 39.3% (n = 35) had 25(OH)D below 75 nmol/L. None of the women reached the Estimated Average Requirements (EAR) of vitamin D. The causality between 25(OH)D and CRF was not significant. Longitudinally, lower levels of 25(OH)D had a negative effect on anxiety (p = 0.020), Menopause and Health (p = 0.033) and Vasomotor scores (p = 0.007). Also, the CRF had a negative effect on anxiety (p = 0.028); depression (p = 0.027); functional disability (p = 0.022); HRQL (p = 0.007); Menopause and Health (p = 0.042), Psychological (p = 0.008) and Couple Relations (p = 0.008) domains; and on Health (p = 0.019) and Aging (p = 0.036) subdomains. Vasomotor subdomain (β = -2.279, p = 0.045) and muscle/joint aches (β = -0.779, p = 0.013) were significant with CRF only at baseline. CONCLUSIONS: This study found negative effect of body adiposity on CRF. Still, the clinical relevance of 25(OH)D and CRF is highlighted, especially that of CRF, considering the consistent impact on several adverse effects reported by BC survivors during adjuvant endocrine therapy.

BACKGROUND: The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. METHODS: A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. RESULTS: The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT-PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).

BACKGROUND: Active surveillance (AS) is one of the treatment methods for patients with small renal masses (SRMs; < 4 cm), including renal cell carcinomas (RCCs). However, some small RCCs may exhibit aggressive neoplastic behaviors and metastasize. Little is known about imaging biomarkers capable of identifying potentially aggressive small RCCs. Contrast-enhanced computed tomography (CECT) often detects collateral vessels arising from neoplastic angiogenesis in RCCs. Therefore, this study aimed to evaluate the association between SRM differential diagnoses and prognoses, and the detection of collateral vessels using CECT. METHODS: A total of 130 consecutive patients with pathologically confirmed non-metastatic SRMs (fat-poor angiomyolipomas [fpAMLs; n = 7] and RCCs [n = 123]) were retrospectively enrolled. Between 2011 and 2019, SRM diagnoses in these patients were confirmed after biopsy or surgical resection. All RCCs were surgically resected. Regardless of diameter, a collateral vessel (CV) was defined as any blood vessel connecting the tumor from around the kidney using CECT. First, we analyzed the role of CV-detection in differentiating between fpAML and RCC. Then, we evaluated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of RCC diagnosis based on CV-detection using CECT. We also assessed the prognostic value of CV-detection using the Fisher exact test, and Kaplan-Meier method and the log-rank test. RESULTS: The sensitivity, specificity, PPV, NPV, and accuracy of CV-detection for the diagnosis of small RCCs was 48.5, 45.5, 100, 100, and 9.5% respectively. Five of 123 (4.1%) patients with RCC experienced recurrence. CV-detection using CECT was the only significant factor associated with recurrence (p = 0.0177). Recurrence-free survival (RFS) was significantly lower in patients with CV compared with in those without CV (5-year RFS 92.4% versus 100%, respectively; p = 0.005). In addition, critical review of the CT images revealed the CVs to be continuous with the venous vessels around the kidney. CONCLUSIONS: The detection of CVs using CECT is useful for differentiating between small fpAMLs and RCCs. CV-detection may also be applied as a predictive parameter for small RCCs prone to recurrence after surgical resection. Moreover, AS could be suitable for small RCCs without CVs.

BACKGROUND: Persistent high-risk (hr) human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Cervical cancer is a major public health problem in Sub-Saharan Africa including South Africa. This study investigated the prevalence of and factors associated with hr-HPV infection among women attending a tertiary hospital in Gauteng Province, South Africa. METHODS: Cervical samples were collected from 526 participants aged ≥ 18 years using a Cervex Brush® Combi and tested for hr-HPV types on the Abbott m2000 analyzer using the Abbott RealTime HR HPV assay. Samples that tested hr-HPV deoxyribonucleic acid (DNA)-positive were further tested for hr-HPV E6/E7 messenger ribonucleic acid (mRNA) using the APTIMA® HPV assay on the Panther system (Hologic, Inc.). Sociodemographic data were collected using a self-administered questionnaire. Binomial regression analysis was used to assess factors associated with hr-HPV infection. RESULTS: Overall hr-HPV DNA prevalence was 48.1% (95%CI: 43.8-52.4%). Of the hr-HPV DNA-positives, 24.5% (95%CI: 19.3-30.1) had HPV-16; 12.3% (95%CI: 8.5-16.9) had HPV-18 and 87.4% (95%CI: 82.6-91.2) had other 12 h-HPVs. Of the samples positive for hr-HPV DNA, 84.2% (95%CI: 79.1-88.5) (213/253) were positive for hr-HPV E6/E7 mRNA. Advanced age was an important factor linked to hr-HPV E6/E7 mRNA positivity. Based on multivariate binomial regression analysis, unemployment (PR: 1.50; 95%CI: 1.23-1.83) and being married (PR: 0.61; 95%CI: 0.47-0.81) were identified as statistically significant (p < 0.0001) predictive and protective factors, respectively, for hr-HPV infection. CONCLUSIONS: The prevalence of hr-HPV infection was high. Furthermore, hr-HPV DNA-positive samples had a high hr-HPV E6/E7 mRNA prevalence. The presence of hr-HPV E6/E7mRNA indicates active infection and thus a greater risk of developing the cervical disease. Therefore, HPV mRNA testing could be a better test to monitor women who are positive with Pap smear before colposcopy is performed to reduce the burden of referrals.

BACKGROUND: Inflammatory parameters and Epstein-Barr virus (EBV) DNA status have been confirmed to be associated with prognosis in nasopharyngeal carcinoma (NPC) patients. However, there are few in-depth studies on the prognosis of NPC patients with negative EBV DNA. Our study aimed to look for inflammatory biomarkers that can identify disease progression in NPC patients with negative EBV DNA. METHODS: A total of 795 NPC patients were recruited, and ultimately 325 NPC patients with negative EBV DNA were included in this study (170 in training cohort and 155 in validation cohort). Kaplan-Meier method and log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). The multivariate analysis of Cox proportional hazards regression model was used to determine the independent prognostic factors. Receiver operating characteristic (ROC) curves were used to assess prognostic value. The logistic regression was used to evaluate the relationship between EBV DNA status and inflammatory parameters. The correlation between clinical characteristics was analyzed by the chi-squared test or the Fisher's exact test. RESULTS: The optimal cutoff point for the SIRI was 1.12. The EBV DNA-negative NPC patients with high SIRI level had worse PFS and OS (all p < 0.001). In multivariate Cox proportional hazard models analysis, SIRI was an independent prognostic factor for PFS and OS (all p < 0.05), and had higher prognostic value than other indicators. Above results were found in the training cohort and confirmed in the validation cohort. In addition, EBV DNA status was not associated with any inflammatory parameters. CONCLUSIONS: The SIRI can provide more accurate risk stratification and better prognostic prediction for NPC patients with negative EBV DNA.

BACKGROUND: Liver cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC). However, some HCC cases can also originate from non-cirrhotic livers. The aim of this study was to identify key circular RNAs (circRNAs) associated with the tumorigenesis of non-cirrhotic liver disease. METHODS: The differently expressed circRNAs between non-cirrhotic and cirrhotic HCCs were assessed with use of high-throughput circRNAs sequencing and validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Potential biological functions of these dysregulated circRNAs were predicted with use of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA-miRNA-mRNA regulation network was constructed as achieved with use of miRanda software and visualized using Cytoscape software. Biological functions of the four most prominent dysregulated circRNAs identified were confirmed by in vitro experiments. Moreover, possible translations of these dysregulated circRNAs were also predicted. RESULTS: A total of 393 dysregulated circRNAs were identified between non-cirrhotic and cirrhotic HCC, including 213 that were significantly up-regulated and 180 significantly down-regulated circRNAs. Expression levels of the six most prominent dysregulated circRNAs were further validated using qRT-PCR. Many tumor related miRNAs were involved in the circRNA-miRNA-mRNA networks, including miR-182-5p, miR-561-3p, miR-125a-5p, miR-145, miR-23b-3p and miR-30e-3p, and downstream mRNAs of dysregulated circRNAs were significantly related with biological processes involved in the progression of tumors, including proliferation, migration, differentiation, and focal adhesion. Results from the in vitro experiments demonstrated that the most prominent dysregulated circRNAs exerted notable effects upon the proliferation and migration of HCC cells. Finally, we also identified 19 dysregulated circRNAs having potential for the coding of functional peptides. CONCLUSION: The results of this present study indicate that circRNAs may play important roles in tumorigenesis of non-cirrhotic HCC. Such findings provide some novel insights and pave the way for the development of future studies directed at investigating the initiation and treatment of HCC.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC. METHODS: The present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC). RESULTS: The expression of insulin-like growth factor 1 receptor (IGF-1R) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan-Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA. CONCLUSION: IGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development.

BACKGROUND: The pandemic disrupted society and health services through lockdowns and resource reallocation to care for COVID-19 patients. Reductions in numbers of cancer patients having surgery, being diagnosed pathologically or via 2-week wait, and screening programs pauses have been described. The effect on emergency presentation, which represents an acute episode with poor outcomes, has not been investigated. This study explored the pandemic's impact on emergency hospital admissions for cancer patients in a UK region. METHODS: Hospital discharge data for cancer patients in Northern Ireland, which included route to admission, were analysed for the pandemic era in 2020 compared to averages for March to December 2017-2019, focusing on volume and route of emergency admissions by demography and tumour site. FINDINGS: Compared with the pre-pandemic era, the number of cancer emergency admissions fell by 12·3% in 2020. Emergency admissions for cancer were significantly reduced when COVID-19 levels were highest (- 18·5% in April and - 16.8% in October). Females (- 15·8%), urban residents (- 13·2%), and age groups 0 to 49 and 65-74 years old (- 17%) experienced the largest decreases as did those with haematological (- 14·7%), brain and CNS (- 27·9%), and lung cancers(- 14·3%). Significant reductions in referrals from outpatient departments (- 51%) and primary care (- 43%) (p < 0·001) were counterbalanced by admissions from other routes including confirmed or suspected COVID-19 infection (increase 83·6%). INTERPRETATION: Reductions in emergency admissions, and pathologically diagnosed cancers, as reported by the Northern Ireland Cancer Registry (NICR), indicate undiagnosed patients in the community which has implications for future workloads and survival. Data suggest undiagnosed cases may be higher for haematological, brain and CNS, and lung cancers and among females. Efforts should be made to encourage people with symptoms to present for diagnosis or reassurance. FUNDING: The NICR is funded by the Public Health Agency of Northern Ireland. This work was supported by Macmillan Cancer Support and uses data collected by health services as part of their care and support functions.

BACKGROUND AND AIMS: High-sensitivity C-reactive protein (hs-CRP) levels and metabolic syndrome (MetS) are known to be associated with an increased incidence of different cancers. We aimed to evaluate the effect of MetS combined with high hs-CRP levels on the risk of primary liver cancer (PLC). METHODS: Participants were recruited from the Kailuan cohort study and were classified into four groups according to the presence or absence of MetS and inflammation (hs-CRP ≥ 3 or < 3 mg/L). The associations of MetS and inflammation with the risk of PLC were assessed using Cox proportional hazards models. RESULTS: This study included 92,770 participants. The mean age was 51.4 years old. Over a median follow-up of 13.02 years, 395 participants were diagnosed as PLC. Compared to the control participants without inflammation (hs-CRP < 3 mg/L) and MetS (n = 69,413), participants with high hs-CRP levels combined with MetS (n = 2,269) had a higher risk of PLC [hazard ratios (HR) 2.91; 95% confidence interval (CI), 1.77-4.81], and participants with high hs-CRP levels and without MetS (n = 14,576) had the same trend (HR, 1.36; 95%CI, 1.05-1.75). However, participants with low hs-CRP levels and MetS (n = 6,512) had no significant association with an elevated risk of PLC (HR, 1.18; 95%CI, 0.76-1.82). After excluding participants who had cancer during the first year of follow-up, sensitivity analysis showed the same trend. In addition, co-occurrence of MetS and high hs-CRP levels had significant interactive effects on the risk of PLC between the sexes (P < 0.001) and the patients with HBV infection (P = 0.012). CONCLUSIONS: Participants with co-occurrence of MetS and high hs-CRP levels have an elevated risk of PLC. TRIAL REGISTRATION: Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050.

BACKGROUND: Breast cancer is an umbrella term referring to a group of biologically and molecularly heterogeneous diseases originating from the breast. Globally, incidences of breast cancer has been increasing dramatically over the past decades. Analyses of multiple clinical "big data" can aid us in clarifying the means of preventing the disease. In addition, predisposing risk factors will be the most important issues if we can confirm their relevance. This study aims to provide an overview of the predisposing factors that contribute to a higher possibility of developing breast cancer and emphasize the signs that we ought to pay more attention to. METHODS: This is a matched nested case-control study. The cohort focused on identifying the eligible risk factors in breast cancer development by data screening (2000-2013) from the Taiwan National Health Insurance Research Database (NHIRD) under approved protocol. A total of 486,069 females were enrolled from a nationwide sampled database, and 3281 females was elligible as breast cancer cohort, 478,574 females who had never diagnosed with breast cancer from 2000 to 2013 were eligible as non-breast cancer controls, and matched to breast cancer cases according to age using a 1:6 ratio. RESULTS: We analyzed 3281 breast cancer cases and 19,686 non-breast cancer controls after an age-matched procedure. The significant predisposing factors associated with breast cancer development including obesity, hyperlipidemia, thyroid cancer and liver cancer. As for patients under the age of 55, gastric cancer does seem to have an impact on the development of breast cancer; compared with their counterparts over the age of 55, endometrial cancer appears to exhibit an evocative effect. CONCLUSIONS: In this nationwide matched nested case-control study, we identified obesity, hyperlipidemia, previous cancers of the thyroid, stomach and liver as risk factors associated with breast cancer. However, the retrospective nature and limited case numbers of certain cancers still difficult to provide robust evidence. Further prospective studies are necessitated to corroborate this finding in order to nip the disease in the bud. TRIAL REGISTRATION: The studies involving human participants were reviewed and approved by the China Medical University Hospital [CMUH104-REC2-115(AR-4)].

BACKGROUND: Trials investigating neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1 (HSV-1), is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neoadjuvant setting. METHODS: This single center, single arm, phase II study aims to show an improved major pathologic complete response (pCR) rate, either pCR or near-pCR, up to 45% in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combination treatment with intralesional T-VEC and systemic nivolumab (anti-PD-1 antibody). Patients will receive four courses of T-VEC up to 4 mL (first dose as seroconversion dose) and three doses of nivolumab (240 mg flatdose) every 2 weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate. Secondary endpoints are safety, the rate of delay of surgery and event-free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed. DISCUSSION: Intralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the first trial investigating the efficacy and safety of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity. TRIAL REGISTRATION: This trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT- number: 2019-001911-22 ) and the Central Committee on Research Involving Human Subjects (NL71866.000.19) on 4th June 2020. Secondary identifying number: NCT04330430 .

Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.

In human colorectal cancer (CRC), TP53 is one of the most important driver genes. Immunohistochemistry (IHC) has been used most often to assess the variational status of TP53. Recently, next-generation sequencing (NGS) of the TP53 gene has increased. However, to our knowledge, a comparison between TP53 status evaluated by IHC and NGS has not been studied. Therefore, the primary aim of this study was to compare the clinical effect of TP53 status evaluated by IHC and NGS in patients with CRC. The secondary aim was to investigate the correlation between expression of p53 by IHC and variational status of TP53 by NGS. We performed immunohistochemical staining of p53 and sequencing of TP53 by NGS in 204 human samples of CRC. We then analyzed the correlation between variational status of TP53 and p53 expression, along with their prognostic impact in CRC patients. There was significant correlation between p53 expression and TP53 variation, TP53 variation and higher N stage, and positive p53 expression and higher N stage. Positive IHC expression of p53 was significantly associated with overall survival (OS) of CRC patients by univariate analysis and was revealed as an independent prognostic factor by multivariate analysis. Additionally, the nonsense/frameshift p53 expression pattern showed a significantly better prognosis than the wild type and missense p53 expression patterns. However, the variational status of TP53 was not significant in OS of CRC patients. These results suggest that IHC expression of p53 protein correlates with variation status of TP53 and expression of p53 protein rather than variation status of TP53 has more significant impact on the OS of CRC patients.

BACKGROUND: This analysis presents the outcomes of the operations of the National Cancer Network (NCN) pilot project in Lower Silesian Voivodeship, Poland, for lung cancer for the period of 2019-2021. The results concerning measures of the quality of medical processes were analysed. METHODS: Twenty-one measures used to gauge the quality of oncological care for lung cancer were assessed. Data collection and processing for the purpose of calculating the measures were carried out as part of the NCN pilot project based on the Regulation of the Ministry of Health enacted on 13 December 2018. The measures were calculated at the Voivodeship Coordination Center, and the data were derived from the centres included in the network in the area of the analysed voivodeship. RESULTS: A total of 3,638 patients diagnosed with lung cancer were enrolled in the NCN pilot program during the analysed period. For 3 measures, out of 21, target values were obtained. For 2 measures, the values differed significantly from the assumed target value. CONCLUSION: In our opinion, the NCN pilot study, as a test of the network's functioning, meets the assumed goal. The NCN assessment is based on, inter alia, analysis of the outcomes of oncological quality of care measures for lung cancer, and facilitates monitoring of the quality of medical services provided and the identification of areas for improvement. In addition, the pilot program, which will last until the end of 2022, will allow for further in-depth analysis regarding the network's limitations before implementing the system on a national scale in Poland. This will be the subject of further investigation.

BACKGROUND: Primary thyroid lymphoma (PTL) and papillary thyroid carcinoma (PTC) are both thyroid malignancies, but their therapeutic methods and prognosis are different. This study aims to explore their sonographic and computed tomography(CT)features, and to improve the early diagnosis rate. METHODS: The clinical and imaging data of 50 patients with non-diffuse PTL and 100 patients with PTC confirmed by pathology were retrospectively analysed. RESULTS: Of the 150 patients, from the perspective of clinical data, between non-diffuse PTL and PTC patients existed significant difference in age, maximum diameter of nodule, asymmetric enlargement and Hashimoto's thyroiditis (P < 0.001), but not in gender ratio, echo texture, cystic change and anteroposterior-to-transverse ratio (P > 0.05). With respect to sonographic feature, non-diffuse PTL patients had a higher proportion than PTC patients in markedly hypoechoic, internal linear echogenic strands, posterior echo enhancement, rich vascularity, lack of calcification and homogeneous enhancement, with statistically significant difference (P < 0.05), while PTC patients had a higher proportion than non-diffuse PTL patients in irregular border, circumscribed margin, capsular invasion and significant enhancement, with statistically significant difference (P < 0.001). With respect to CT feature, non-diffuse PTL patients were significantly different from PTC patients in the non-contrast CT value mean, venous phase CT value mean, enhanced intensity and homogeneity of nodules (P < 0.05). Multivariate logistic regression analysis showed that age (OR = 1.226, 95%CI:1.056 ~ 1.423, P = 0.007), posterior echo enhancement (OR = 51.152, 95%CI: 2.934 ~ 891.738, P = 0.007), lack of calcification (OR = 0.013, 95%CI: 0.000 ~ 0.400, P = 0.013) and homogeneous enhancement (OR = 0.020, 95%CI: 0.001 ~ 0.507, P = 0.018) were independent risk factors. CONCLUSIONS: Sonographic and CT features of the presence of posterior echo enhancement, lack of calcification and homogeneous enhancement were valuable to distinguishing non-diffuse PTL from PTC.

BACKGROUND: Melanoma is a malignant tumor characterized by high proliferation and aggressive metastasis. To address the molecular mechanisms of the proto-oncogene, Rous sarcoma oncogene (Src), which is highly activated and promotes cell proliferation, migration, adhesion, and metastasis in melanoma. Plectin, a cytoskeletal protein, has recently been identified as a Src-binding protein that regulates Src activity in osteoclasts. Plectin is a candidate biomarker of certain tumors because of its high expression and the target of anti-tumor reagents such as ruthenium pyridinecarbothioamide. The molecular mechanisms by which plectin affects melanoma is still unclear. In this study, we examined the role of plectin in melanoma tumor formation. METHODS: We used CRISPR/Cas9 gene editing to knock-out plectin in B16 mouse melanoma cells. Protein levels of plectin and Src activity were examined by western blotting analysis. In vivo tumor formation was assessed by subcutaneous injection of B16 cells into nude mice and histological analysis performed after 2 weeks by Hematoxylin-Eosin (H&E) staining. Cell proliferation was evaluated by direct cell count, cell counting kit-8 assays, cyclin D1 mRNA expression and Ki-67 immunostaining. Cell aggregation and adhesion were examined by spheroid formation, dispase-based dissociation assay and cell adhesion assays. RESULTS: In in vivo tumor formation assays, depletion of plectin resulted in low-density tumors with large intercellular spaces. In vitro experiments revealed that plectin-deficient B16 cells exhibit reduced cell proliferation and reduced cell-to-cell adhesion. Since Src activity is reduced in plectin-deficient melanomas, we examined the relationship between plectin and Src signaling. Src overexpression in plectin knockout B16 cells rescued cell proliferation and improved cell-to-cell adhesion and cell to extracellular matrix adhesion. CONCLUSION: These results suggest that plectin plays critical roles in tumor formation by promoting cell proliferation and cell-to-cell adhesion through Src signaling activity in melanoma cells.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a frequent issue that arises after mastectomy surgery in women and compromises physical and mental function. Previously published studies have shown positive effects with the use of Low-level laser therapy in another term Photo-biomodulation therapy (PBM). This research investigated the efficacy of clinical use of LLLT (PBM) in the treatment of metastatic breast cancer-related lymphedema. METHODS: PubMed, PEDro, Medline, and the Cochrane Library were searched for LLLT clinical trials published before October 2021. The methodological quality of randomized trials and the effectiveness of Laser Therapy for BCRL were evaluated. The primary objectives were arm circumference or arm volume, whereas the secondary goals were to assess shoulder mobility and pain severity. RESULTS: Eight clinical trials were analyzed in total. Typically, the included RCTs had good research quality. At four weeks, there was a considerable reduction in arm circumference/volume, and this continued with long-term follow-up. However, no statistically significant change in shoulder mobility or pain severity was seen between the laser and placebo groups at 0-, 1-, 2-, and 3-month short-term follow-up. CONCLUSIONS: The findings of this comprehensive study demonstrated that LLLT (PBM) was successful in diminishing arm circumference and volume than improving shoulder mobility and pain. Data indicates that laser therapy (PBM) may be a beneficial treatment option for females with PML. Because of the scarcity of evidence, there is a strong need for well-conducted and longer-duration trials in this field. TRIAL REGISTRATION: Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42022315076 .

BACKGROUND: Mantle cell lymphoma (MCL) has remained incurable in most patients. The expression of PD-L1 as a prognostic and predictive marker has not been fully evaluated in MCL. The current study aimed to determine PD-1/PD-L1 expression in MCL specimens and its significance as an immune check point inhibitor. METHODS: This retrospective study was conducted on the formalin-fixed paraffin-embedded blocks of 79 confirmed MCL patients based on immunohistochemistry (IHC). The IHC method was used to stain patient samples for PD1 and PDL1. Positive PD-1/PD-L1 expression was defined as moderate to strong or memberanous or memberanous/cytoplasmic staining in at least 5% of tumor and/or 20% of associated immune cells. Tumor aggressiveness was determined based on Ki67 and variant. RESULTS: The mean age of the patients was 60.08 ± 10.78 years old. Majority of the patients were male. The prevalence of aggressive tumor was 25%. Positive PD1 and PDL1 expression were identified in 12 (15.0%) and 3 (3.8%) of tumor cells, respectively. PD1 and PDL1 were positive in zero (0%) and 7 (8.9%) of background cells, respectively. There was no significant difference in terms of study parameters between positive and negative groups for both PD1 and PDL1 proteins. PD1 tumor cell percentage was negatively correlated with age (r = -0.254, p = 0.046). CONCLUSION: Our results suggest that neither PD-1 nor its ligands represent relevant targets for MCL treatment. Age may impact the efficiency of immune checkpoint inhibitors and could be related to the increased incidence of MCL with age.

BACKGROUND: Although immune-checkpoint inhibitors (ICI) are overall promissory for cancer treatment, they entail, in some cases, an undesired side-effect called hyperprogressive-cancer disease (HPD) associated with acceleration of tumor growth and shortened survival. METHODS: To understand the mechanisms of HPD we assayed the ICI therapy on two murine tumors widely different regarding immunogenicity and, subsequently, on models of local recurrences and metastases of these tumors. To potentiate the immune response (IR), we combined ICI with meta-tyrosine-that counteracts immune-suppressive signals-and a selective inhibitor of p38 pathway that proved to counteract the phenomenon of tumor-immunostimulation. RESULTS: ICI were therapeutically effective against both tumor models (proportionally to their immunogenicity) but only when they faced incipient tumors. In contrast, ICI produced acceleration of large and residual tumors. The combined treatment strongly inhibited the growth of large tumors and it managed to cure 80% of mice with local recurrences and 60% of mice bearing residual metastases. CONCLUSIONS: Tumor enhancement was paradoxically correlated to a weak increase of the antitumor IR suggesting that a weak IR - different from a strong tumor-inhibitory one-may produce stimulation of tumor growth, mimicking the HPD observed in some clinical settings.

BACKGROUND: While cancer outcomes have improved over time, in Northern Ireland they continue to lag behind those of many other developed economies. The role of comorbid conditions has been suggested as a potential contributory factor in this but issues of data comparability across jurisdictions has inhibited efforts to explore relationships. We use data from a single jurisdiction of the UK using data from - the Northern Ireland Cancer Registry (NICR), to examine the association between mortality (all-cause and cancer specific) and pre-existing cardiovascular diseases among patients with cancer. MATERIALS AND METHODS: All patients diagnosed with cancer (excluding non-melanoma skin cancer) between 2011 and 2014 were identified from Registry records. Those with a pre-existing diagnosis of cardiovascular diseases were identified by record linkage with patient hospital discharge data using ICD10 codes. Survival following diagnosis was examined using descriptive statistics and Cox proportional hazards regression analyses. Analyses examined all-cause mortality and cancer specific mortality for lung, colorectal, breast and prostate cancer. As well as cardiovascular diseases, regression models controlled for age, gender (where appropriate), deprivation (as quintiles), stage at diagnosis and other comorbidities. RESULTS: Almost 35,000 incident cancer cases were diagnosed during the study period of which approximately 23% had a prior heart condition. The pan-cancer hazard ratio for death in the presence of pre-existing cardiovascular diseases was 1.28 (95% CI: 1.18-1.40). All-cause and cancer specific mortality was higher for patients with cardiovascular diseases across lung, female breast, prostate and colorectal cancer groups after controlling for age, gender (where appropriate), deprivation (as quintiles), stage at diagnosis and other comorbidities. CONCLUSION: Pre-existing morbidity may restrict the treatment of cancer for many patients. In this cohort, cancer patients with pre-existing cardiovascular diseases had poorer outcomes than those without cardiovascular diseases. A high prevalence of cardiovascular diseases may contribute to poorer cancer outcomes at a national level.

BACKGROUND: Whether hypokalemia can affect the short-term outcomes of CRC patients after radical surgery remains unclear. The purpose of this study was to investigate the impact of preoperative hypokalemia on the short-term outcomes for colorectal cancer (CRC) patients who underwent radical CRC surgery using propensity score matching (PSM). METHODS: We retrospectively enrolled consecutive CRC patients from Jan 2011 to Dec 2021 in a single-center hospital. Hypokalemia was defined as a serum potassium concentration < 3.5 mmol/L. The short-term outcomes were compared between the hypokalemia group and the normal blood potassium group. In addition, univariate and multivariate logistic regression analyses were conducted to identify independent risk factors for overall complications. RESULTS: A total of 6183 CRC patients who underwent radical surgery were included in this study, of whom 390 (6.3%) patients were diagnosed with hypokalemia before surgery. After 1:1 ratio PSM, there were 390 patients in the hypokalemia group and in the normal potassium group. No significant difference was found between the two groups after PSM in terms of baseline information (p > 0.05). Regarding short-term outcomes, the hypokalemia group had a longer hospital stay (p = 0.028), a higher proportion of overall complications (p = 0.048) and a higher incidence of postoperative pneumonia (p = 0.008) after PSM. Moreover, hypokalemia (p = 0.036, OR = 1.291, 95% CI = 1.017-1.639) was an independent risk factor for overall complications. CONCLUSION: Preoperative hypokalemia could increase complications after CRC surgery and prolong the hospital stay. Moreover, preoperative hypokalemia was an independent risk factor for overall complications.

Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate different aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess GBM invasiveness based on detecting tumor-specific anti-luciferase staining in brain slices, we found that U251-RedFLuc cells are more invasive than U87-luc2 cells. Lastly, we determined expression levels of ABC transporters in both models. Our findings indicate that U87-luc2 and U251-RedFLuc GBM models recapitulate different aspects of GBM heterogeneity that need to be considered in preclinical research.

BACKGROUND: The Notch signaling mutation is associated with enhanced anti-tumor immune response in colorectal cancer (CRC). In this study, we aim to investigate the underlying mechanism and the predictive potential of Notch signaling mutation for responding to immunotherapy in CRC. METHODS: We analyzed the immune response associated genes in CRC with Notch signaling mutation concomitant with or without microsatellite instability (MSI) using TCGA dataset and investigated the mutation profiles of the Notch signaling pathway using cBioPortal. The Notch signaling scores and immune cell infiltration scores in different groups were calculated. We applied the Kaplan-Meier method for survival analysis in CRC patients who underwent immunotherapy, and the log-rank test to determine the statistically significant differences in survival. Notch1-knock-down cell line was constructed to detect the pathway and gene variations. RESULTS: We found that Notch signaling pathway mutation was associated with activated immune response, especially in those with MSI. Such association is useful for predicting a prolonged overall survival of CRC patients who underwent immune checkpoint inhibitor treatment. The mutation resulted in the functional loss of Notch signaling and may modulate the tumor immune microenvironment by increasing the expression of chemokines that are important for recruiting immune cells. CONCLUSIONS: The Notch signaling mutation can modulate the chemotaxis of immune cells by upregulating the chemokine levels of the tumor immune microenvironment, and CRC patients with Notch signaling pathway mutation have better overall survival after immune checkpoint inhibitor treatment.

BACKGROUND: Colposcopy is a tool for triaging screen positive women regardless of method used for cervical cancer screening. The objective of this study was to evaluate the diagnostic performance of colposcopy in the diagnosis of histologic cervical intraepithelial neoplasia 2+ (CIN 2+) at Jigme Dorji Wangchuck National Referral Hospital (JDWNRH), Thimphu, Bhutan. METHODS: This cross-sectional study was conducted from March 2021 to August 2021 among 299 women who availed colposcopy services at the colposcopy clinic of JDWNRH, Bhutan. Women included in this study were either screen positive (Pap smear) or were suspected to have invasive cancer; they underwent colposcopy and a cervical biopsy irrespective of colposcopy impression. This histopathologic assessment was considered as the gold standard test for the diagnosis of cervical intraepithelial neoplasia (CIN) or invasive cancer. RESULTS: The mean age of the study participants was 43 years (ranges, 25-76 years). The sensitivity, specificity and accuracy of senior colposcopists to diagnose histologic CIN 2+ were 80.0% (95% CI 59.30, 93.17), 71.07% (95% CI 62.13, 78.95), and 72.60% (95% CI 64.61, 79.65), and for junior colposcopists were 59.46% (95% CI 42.10, 75.25), 76.72% (95% CI 67.97, 84.04), and 72.55% (95% CI 64.76, 79.45) respectively. The overall sensitivity, specificity, and accuracy of colposcopy to diagnose histologic CIN 2+ were 66.67% (95% CI 53.66, 78.05), 73.73% (95% CI 67.63, 79.23), and 72.24% (95% CI 66.79, 77.24) respectively. CONCLUSIONS: In this study, the senior and junior colposcopists had a comparable colposcopic accuracy to diagnose histologic CIN 2+, whereas senior had a higher sensitivity but a lower specificity than junior colposcopists.

OBJECTIVE: Osteosarcoma is the most common primary bone cancer that affects mostly children and young adults. Despite the advances in osteosarcoma treatment, the long-term survival rate of metastatic patients has not significantly improved in the past few decades, thus demonstrating the need for novel therapeutic targets or methods to improve metastatic osteosarcoma treatment. In this study we aimed to elucidate the role of miR-659-3p and SRPK1 in osteosarcoma. METHODS: We evaluated miR-659-3p and SRPK1 function in osteosarcoma cell proliferation, migration, and cell cycle progression in vitro by using gain- and loss-of-function strategies. The effect of miR-659-3p in tumor progression and metastasis was determined by in vivo mouse model. RESULTS: We revealed that expression of miR-659-3p was significantly downregulated in osteosarcoma compared with normal bone cells and was inversely correlated with serine-arginine protein kinase 1 (SRPK1) expression. We proved that miR-659-3p targets 3' UTR of SRPK1 and negatively regulates SRPK1 expression in osteosarcoma cells via luciferase assay. In vitro studies revealed that gain of miR-659-3p function inhibited osteosarcoma cells growth, migration, and invasion by down-regulating SRPK1 expression. Inversely, inhibiting miR-659-3p in osteosarcoma cells promoted cell growth, migration, and invasion. Cell cycle profile analysis revealed that miR-659-3p inhibited osteosarcoma cells' G1/G0 phase exit by down-regulating SRPK1 expression. By using an in vivo mouse model, we demonstrated that miR-659-3p inhibits osteosarcoma tumor progression and lung metastasis by inhibiting SRPK1 expression and potentially downstream cell proliferation, and epithelial-to-mesenchymal transition genes. CONCLUSIONS: This study demonstrated that miR-659-3p is a potential therapeutic method and SRPK1 is a potential therapeutic target for osteosarcoma treatment.

BACKGROUND: Hepatectomy is currently the most effective modality for the treatment of intrahepatic cholangiocarcinoma (ICC). The status of the lymph nodes directly affects the choice of surgical method and the formulation of postoperative treatment plans. Therefore, a preoperative judgment of lymph node status is of great significance for patients diagnosed with this condition. Previous prediction models mostly adopted logistic regression modeling, and few relevant studies applied random forests in the prediction of ICC lymph node metastasis (LNM). METHODS: A total of 149 ICC patients who met clinical conditions were enrolled in the training group. Taking into account preoperative clinical data and imaging features, 21 indicators were included for analysis and modeling. Logistic regression was used to filter variables through multivariate analysis, and random forest regression was used to rank the importance of these variables through the use of algorithms. The model's prediction accuracy was assessed by the concordance index (C-index) and calibration curve and validated with external data. RESULT: Multivariate analysis shows that Carcinoembryonic antigen (CEA), Carbohydrate antigen19-9 (CA19-9), and lymphadenopathy on imaging are independent risk factors for lymph node metastasis. The random forest algorithm identifies the top four risk factors as CEA, CA19-9, and lymphadenopathy on imaging and Aspartate Transaminase (AST). The predictive power of random forest is significantly better than the nomogram established by logistic regression in both the validation group and the training group (Area Under Curve reached 0.758 in the validation group). CONCLUSIONS: We constructed a random forest model for predicting lymph node metastasis that, compared with the traditional nomogram, has higher prediction accuracy and simultaneously plays an auxiliary role in imaging examinations.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has poor prognosis mainly due to lacking of effective diagnostic biomarkers. Aberrant expression of secreted phosphoprotein 1 (SPP1) protein has been observed in several cancers. The purpose of this study is to assess the feasibility of serum autoantibody to SPP1 in detection of ESCC. METHODS: The SPP1 protein levels in 108 ESCC tissues and 72 adjacent normal tissues were analyzed by immunohistochemistry. Discovery group containing 62 serum samples from ESCC patients and 62 serum samples from normal controls (NC) were used to detect the levels of anti-SPP1 autoantibody by enzyme-linked immunosorbent assay (ELISA). Validation group containing another 100 ESCC and 100 NC serum samples were tested to confirm the levels of autoantibody to SPP1. Western blotting was performed to further confirm the results of ELISA. RESULTS: SPP1 protein was significantly overexpressed in ESCC tissues compared to adjacent normal tissues. ELISA results showed that serum autoantibody to SPP1 was significantly increased in ESCC compared to NC in both discovery and validation groups. Autoantibody to SPP1 could discriminate patients with ESCC from NC with the area under curve (AUC) values of 0.653 and 0.739 in discovery and validation group, respectively. The results of ELISA and the occurrence of immunoreactivity to SPP1 in ESCC sera were confirmed by western blotting. CONCLUSION: Our study indicated the potential significance of anti-SPP1 autoantibody as a novel biomarker for detection of ESCC.

BACKGROUND: Long non-coding RNAs (lncRNAs) play a functional role in the progression of prostate cancer (PCa). However, the molecular mechanism, expression, or function of the lncRNA XIST in PCa is not well understood. Therefore, the major goal of this study was to investigate the involvement of XIST in PCa. METHODS: We used the The Cancer Genome Atlas (TCGA) database to conduct a pan-cancer bioinformatics analysis of XIST and identified that it may play an important role in prostate cancer. This finding was verified using clinical samples and in vitro assays. Finally, we constructed an XIST ceRNA network for prostate cancer. RESULTS: Our in vitro and in vivo results showed that the XIST gene expression level was higher in PCa derived cells and tissues compared to that in normal cells and tissues. XIST gene expression level was positively correlated with the invasion and proliferation of tumour cells. Furthermore, the downregulation of XIST inhibited the growth of subcutaneous 22Rv1 xenografts in nude mice. In addition, we constructed a XIST ceRNA network. Consistent with previous studies, we found that the role of XIST is mediated through via sponges, such as miRNA -96-5p, miRNA -153-3p, and miRNA-182-5p. CONCLUSION: High expression level of XIST can lead to enhanced carcinogenicity in PCa. Therefore, XIST has the potential to be used as a prognostic marker and may become a new research focus for the treatment of PCa.

BACKGROUND: Automated breast ultrasound (ABUS) is a useful choice in breast disease diagnosis. The axillary lymph node (ALN) status is crucial for predicting the clinical classification and deciding on the treatment of early-stage breast cancer (EBC) and could be the primary indicator of locoregional recurrence. We aimed to establish a prediction model using ABUS features of primary breast cancer to predict ALN status. METHODS: A total of 469 lesions were divided into the axillary lymph node metastasis (ALNM) group and the no ALNM (NALNM) group. Univariate analysis and multivariate analysis were used to analyze the difference of clinical factors and ABUS features between the two groups, and a predictive model of ALNM was established. Pathological results were as the gold standard. RESULTS: Ki-67, maximum diameter (MD), posterior feature shadowing or enhancement and hyperechoic halo were significant risk factors for ALNM in multivariate logistic regression analysis (P < 0.05). The four risk factors were used to build the predictive model, and it achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.791 (95% CI: 0.751, 0.831). The accuracy, sensitivity and specificity of the prediction model were 72.5%, 69.1% and 75.26%. The positive predictive value (PPV) and negative predictive value (NPV) were 66.08% and 79.93%, respectively. Distance to skin, MD, margin, shape, internal echo pattern, orientation, posterior features, and hyperechoic halo showed significant differences between stage I and stage II (P < 0.001). CONCLUSION: ABUS features and Ki-67 can meaningfully predict ALNM in EBC and the prediction model may facilitate a more effective therapeutic schedule.

INTRODUCTION: Neuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear. MATERIALS AND METHODS: The clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT-PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored. RESULTS: NED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression. CONCLUSION: lnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression.

BACKGROUND: The gap in treatment and health outcomes after diagnosis of pancreatic cancer is a major public health concern. We aimed to investigate the differences in the health outcomes and treatment of pancreatic cancer patients in healthcare vulnerable and non-vulnerable areas. METHODS: This retrospective cohort study evaluated data from the Korea National Health Insurance Corporation-National Sample Cohort from 2002 to 2019. The position value for relative comparison index was used to define healthcare vulnerable areas. Cox proportional hazard regression was used to estimate the risk of mortality in pancreatic cancer patients according to healthcare vulnerable areas, and multiple logistic regression was used to estimate the difference in treatment. RESULTS: Among 1,975 patients, 279 (14.1%) and 1,696 (85.9%) lived in the healthcare vulnerable and non-vulnerable areas, respectively. Compared with the non-vulnerable area, pancreatic cancer patients in the vulnerable area had a higher risk of death at 3 months (hazard ratio [HR]: 1.33, 95% confidence interval [CI] = 1.06-1.67) and 6 months (HR: 1.23, 95% CI = 1.03-1.48). In addition, patients with pancreatic cancer in the vulnerable area were less likely to receive treatment than patients in the non-vulnerable area (odds ratio [OR]: 0.70, 95% CI = 0.52-0.94). This trend was further emphasized for chemotherapy (OR: 0.68, 95% CI = 0.48-0.95). CONCLUSION: Patients with pancreatic cancer belonging to medically disadvantaged areas receive less treatment and have a higher risk of death. This may be a result of the late diagnosis of pancreatic cancer among these patients.

BACKGROUND: Transthoracic single-port assisted laparoscopic five-step maneuver inferior mediastinal lymphadenectomy for Siewert type II adenocarcinoma of esophagogastric junction (AEG) has superiority in lower mediastinal lymph nodes dissection and digestive tract reconstruction. However, the right pleura was probably ruptured in this surgical technique. The aim of this study was to explore whether the infracardiac bursa (ICB) exposed could protect right pleura. METHODS: We retrospectively collected and evaluated the clinical and pathological data of patients who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymphadenectomy for Siewert II AEG at Guangdong Provincial Hospital of Chinese Medicine between May 2017 and February 2022. RESULTS: A total of 49 patients were eligible, including 31 patients in ICB exposed group (group A) and 18 patients in ICB unexposed group (group B). There were no statistically significant differences in baseline characteristics between the two groups. 4 patients (12.9%) had right pleura rupture in group A, while 14 patients (77.8%) in group B, and the difference was statistically significant (p < 0.001). Compared with group B, the extubation time of endotracheal intubation (10.0 (6.0 ~ 12.0) vs. 13.0 (8.0 ~ 15.0) min, p = 0.003) and thoracic drainage tube stay (6.0 (5.0 ~ 7.0) vs. 8.0 (6.0 ~ 10.5) days, p = 0.041) were significantly shorted in the group A. The drainage volume of thorax (351.61 ± 125.00 vs. 418.61 ± 207.86 mL, p = 0.146) was non-significant less and the rate of complications (3.2% vs. 11.1%, p = 0.074) was non-significant lower in group A compared with group B. The postoperative hospital stay (9.0 (8.0,13.0) vs. 9.0 (8.0,12.0) days, p = 0.983) were similar in two groups. No serious adverse event occurred in any patient. CONCLUSIONS: The ICB exposed could protect the right pleura and may promote postoperative recovery, which may be used as an anatomical marker in inferior mediastinal lymphadenectomy.

BACKGROUND: This study developed a gene signature associated with a malignant and common tumor of the urinary system, the Bladder Urothelial Carcinoma (BLCA). METHODS: The Cancer Genome Atlas (TCGA) database was searched to obtain 414 BLCA samples and the expression spectra of 19 normal samples. Single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to determine the enrichment levels in the BLCA samples of the 29 immune genes. Unsupervised hierarchical clustering, gene set enrichment analysis (GSEA), single-factor Cox analysis, least absolute shrinkage and selection operator (LASSO) regression models, and GEO queues were used to determine the BLCA immune gene subtype, analyze the biological pathway differences between immune gene subtypes, determine the characteristic genes of BLCA associated with prognosis, identify the BLCA-related genes, and verify the gene signature, respectively. RESULTS: We identified two immune gene subtypes (immunity_L and immunity_H). The latter was significantly related to receptors, JAK STAT signaling pathways, leukocyte interleukin 6 generation, and cell membrane signal receptor complexes. Four characteristic genes (RBP1, OAS1, LRP1, and AGER) were identified and constituted the gene signature. Significant survival advantages, higher mutation frequency, and superior immunotherapy were observed in the low-risk group patients. The gene signature had good predictive ability. The results of the validation group were consistent with TCGA queue results. CONCLUSIONS: We constructed a 4-gene signature that helps monitor BLCA occurrence and prognosis, providing an important basis for developing personalized BLCA immunotherapy.

AIM: To translate and validate the Chinese version of the MDASI-THY among thyroid cancer patients. BACKGROUND: The M.D. Anderson Symptom Inventory-Thyroid Cancer module (MDASI-THY) is one of well-validated instruments for thyroid-specific symptom assessment. To date, the instrument has not been used in China. METHODS: After standard forward- and back-translation procedures, two instruments, the Chinese version of MDASI-THY and the European Organization for Research and Treatment of Cancer QLQ C30, were answered by 309 thyroid patients. The content, convergent discriminant validity and reliability of the MDASI-THY were evaluated. RESULTS: The scale of content validity index (S-CVI) and the item of content validity index (I-CVI) of the instrument were over 0.80. There were significant relationships between MDASI-THY and EORTC QLQ-C30 (r range, 0.139 ~ 0.766, -0.759 ~ -0.461, p < 0.001). Symptoms were severer for patients underwent surgical treatment (Z = -9.999, p < 0.001). The Cronbach's alpha was 0.966 (between 0.954 and 0.827 for subscales). Most symptom items had moderate to high interitem correlations (r range, 0.297 ~ 0.773). CONCLUSIONS: The Chinese version of MDASI-THY demonstrated favorable validity and reliability. It can be used in development of symptom management program in thyroid cancer patients in China. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers can apply this instrument to assess Chinese thyroid cancer patients to increase the understanding of their symptom experience, resulting in a better symptom management.

PURPOSE: This study aimed to explore the efficiency and safety of the new generation antibody-drug conjugate Trastuzumab deruxtecan (DS-8201a) in treating HER2-positive solid cancers. METHOD: By searching PubMed, Medline and Ovid for all clinical trials related to the safety and efficacy of DS-8201a. Event rates were calculated for all adverse events (AEs) to evaluate the safety of DS-8201a. Objective response rate (ORR) and progression-free survival (PFS) were summarized to assess the potency of DS-8201a. RESULT: The AEs with event rates greater than 30% regardless of grades were nausea, decreased appetite, vomiting, fatigue, anemia, decreased neutrophil count, alopecia and diarrhea. In the grade 3 or more, decreased neutrophil count, anemia and decreased white blood cell count were the only three AEs with event rates greater than 10% (20.3, 15.0 and 10.3%). The median PFS of patients with breast cancer, gastric cancer and other HER2-positive solid cancers were 9.0-22.1, 3.0-8.3 and 4.1-11.9 months. The median ORR was 37-79.9% in patients with breast and gastric cancer and 28.3-55% in patients with other HER2-positive cancers. CONCLUSION: DS-8201a plays an active role in treating HER2-positive cancers, especially breast and gastric cancer, which have HER2 amplification. The most common AEs of DS-8201a were related to gastrointestinal and hematological system. Decreased white blood cell count and appetite were the AEs occurred with high grades.

BACKGROUND: The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection. METHODS: AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models. RESULTS: A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p = 0.002) and serious operation injury condition (HR = 1.539, p = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong's Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs. CONCLUSIONS: Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival.

BACKGROUND: Lymph node metastasis (LNM) is a critical event during the colorectal cancer (CRC) development and is indicative of poor prognosis. Identification of molecular markers of LNM may facilitate better therapeutic decision-making. METHODS: Six pairs of CRC tissues and corresponding adjacent tissues [3 pairs diagnosed as pT1N0M0 (M_Low group) and 3 pairs diagnosed as pT4N2M0 (M_High group)] collected from CRC patients who underwent surgical resection were used. MicroRNA sequencing was performed to screen differential microRNAs involved in CRC LNM. The selected microRNAs were validated in CRC tissues and cell lines using qRT-PCR. The functions of candidate hsa-miR-1248 were evaluated by CCK-8, colony formation, and Transwell assay. The binding of hsa-miR-1248 with its target PSMD10 was confirmed by luciferase activity assay, and the expression of PSMD10 in tissues was detected by droplet digital polymerase chain reaction. RESULTS: Ninety-five miRNAs were downregulated in carcinoma tissues (M_Low and M_high groups) compared with the normal group. Their expression in M_High group was significantly lower compared with M_Low group. The top 3 were hsa-miR-635, hsa-miR-1248, and hsa-miR-668-3p. After validation in tissues/cell lines, only hsa- hsa-miR-1248 was decreased in high metastatic tissues or SW620 cells compared to low metastatic tissues or SW480 cells. Hsa-miR-1248 was found to inhibit CRC cell viability, proliferation, invasion, and migration. The tumor suppressor effect of has-miR-1248 in CRC cells was attenuated or enhanced by up-regulating or down-regulating PSMD10, respectively. CONCLUSION: Hsa-miR-1248 may act as a tumor suppressor gene in CRC by targeting and inhibiting PSMD10, which provides a clue for CRC treatment.

OBJECTIVES: There are increasing numbers of studies of pleural tags (PTs). The purpose of this case series was to classify the PTs in patients with peripheral pulmonary adenocarcinoma based on radiologic-pathologic comparison and to study the prognosis. METHODS: The clinical, imaging, pathological and prognostic data of 161 patients with peripheral pulmonary adenocarcinoma in three hospitals were analyzed retrospectively. We classified PTs using computed tomography (CT) for pathologic comparison. RESULTS: According to the relationship between tumors and pleural on CT images, PTs were classified into four types: type 1, one or more linear pleural tag; type 2, one or more linear pleural tag with soft tissue component at the pleural end; type 3, one soft tissue cord-like pleural tag; type 4, directly abutting the visceral pleura, pulling or pushing the visceral pleura. In these PTs, the incidence of visceral pleural invasion (VPI) was high in type 2 (46.88%) and type 3 (56.41%) of PTs. Our prognostic analysis showed that micropapillary or solid histological subtype (HR = 5.766, 95% CI: 1.435-23.159, P = 0.014) and type 3 of PTs (HR = 11.058, 95% CI: 1.349-90.623, P = 0.025) were two independent risk factors for tumor progression. CONCLUSIONS: PT is a risk factor for poor prognosis in patients with peripheral pulmonary adenocarcinoma, the presence of which on CT images can remind us to provide patients with a more reasonable treatment.

BACKGROUND: While many studies investigated changes in working status in cancer survivors, most studies have been performed in survivors of breast cancer and few studies evaluated factors associated with changes in the working status of cancer survivors comprehensively. We aimed to evaluate the changes in the working status of cancer survivors after diagnosis and socio-demographic, clinical, work-related and psychological factors associated with it. METHODS: We conducted a cross-sectional survey of adult patients with cancer who were working at the time of diagnosis. A trained interviewer inquired about participants' current working status, including leave of absence, discontinuing, continuing, and changing work. Sociodemographic, clinical, work-related and psychological factors were measured. Multinomial logistic regression was used to identify factors associated with changes in the working status. RESULTS: Among the 730 patients, 29%, 18% and 6% were currently on a discontinued working, leave of absence and had changed jobs, respectively. Patients who discontinued working after cancer diagnosis were more likely to be female, have ≥ $3,000 of monthly family income, not be the principal wage earners for their families and be blue-collar workers. In clinical characteristics, advanced-stage cancer and experienced cancer recurrence was associated with leave of absence and discontinued working. In work-related and psychological factors, stress due to insufficient job control (relative risk ratio [RRR] = 2.26), interpersonal conflict (RRR = 1.86), job insecurity (RRR = 2.63), organizational system (RRR = 3.49), and lack of reward (RRR = 11.76), and less meaning to work were more likely to discontinue working after a cancer diagnosis. CONCLUSION: Occupational health care professionals and other stakeholders need to openly communicate with patients with cancer about potential barriers during the return-to-work trajectory.

BACKGROUND: The incidence and mortality rate of rectal cancer are still high, the metastasis of rectal cancer are main causes of death. The control of the distant metastasis is one of the main concerns in the treatment of locally advanced rectal cancer, but there are few studies on predicting synchronous distant metastasis (SDM) of rectal cancer. METHOD: The data of patients with rectal adenocarcinoma confirmed by endoscopic biopsy or postoperative pathology from September 2015 to May 2020 in hospital A (center 1) and hospital B (center 2) were analyzed retrospectively, including age, sex, carcinoembryonic antigen, carbohydrate antigen 19-9, tumor location, tumor length, image staging and characteristics. The average age of the 169 patients consisting of 105 males and 64 females in study is 61.2 years. All patients underwent rectal routine rectal MRI, DKI and IVIM examinations on a 3.0-T scanner. Two radiologists sketched regions of interest (ROIs) on b = 1000 s/mm2 DKI and IVIM images to obtain quantitative parameters with FireVoxel manually. We evaluated the difference of histogram analysis, clinical and image data between SDM group and non-SDM group, and evaluated the efficacy of each index in predicting SDM of rectal cancer. RESULTS: The 90th percentile of f values in the SDM group is lower than that in the non-SDM group (29.4 ± 8.4% vs. 35 ± 17.8%, P = 0.005). CA19-9 in the SDM group is higher than that in the non-SDM group (P = 0.003). Low and high rectal cancer are more likely to develop SDM than middle rectal cancer (P = 0.05 and P = 0.047). The combination of these three indexes has a greater area under the curve (AUC) than any one index (0.801 vs. 0.685 (f (90th percentile)) and 0.627 (CA19-9), P = 0.0075 and 0.0058, respectively), and its specificity and sensitivity are 80.0% and 71.6%, respectively. When this combination is incorporated into the predictive nomogram model, the c-index is 0.801 (95% confidence interval (CI): 0.730-0.871). CONCLUSIONS: IVIM quantitative parameters combine with CA19-9 and tumor location can better predict the risk of SDM of rectal cancer.

BACKGROUND: Selective activation of Delta-like 1 (DLL1)-Notch signaling is a new approach to activate CD8+ T cell and suppress tumor growth, while the efficacy remains modest. Lentinan (LNT) is a clinically used immunomodulation agent. Thus, we hypothesized that LNT could improve the efficacy of DLL1. METHODS: The effects of LNT combined with DLL1 on tumor growth were evaluated by growth curve and tumor weight in EO771 breast and LAP0297 lung tumor models. The impacts on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR. Neutrophil depletion was used to investigate the mechanism of the combination therapy on tumor growth. The data sets were compared using unpaired student's t-test or ordinary one-way ANOVA. RESULTS:  LNT treatments additively improved the antitumor effects of DLL1 in EO771 breast tumor growth. Remarkably, LNT treatments synergistically enhanced the suppression of DLL1 on LAP0297 lung tumor growth, resulting in tumor regression. Mechanically, the combination of LNT and DLL1 interventions not only promoted the accumulation and activation of CD8+ T cells, but also increased intratumoral CD45+CD11b+Ly6G+ neutrophils. Reduced neutrophils by anti-Gr1 antibody administrations reversed the improved antitumor effects by LNT treatments in LAP0297 lung tumor. These results suggest that LNT treatments improve the inhibition of DLL1 on tumor growth via neutrophils. CONCLUSIONS: Our findings indicates that LNT and DLL1 may induce synergistical antitumor immunity via simultaneous modulating lymphoid and myeloid cell populations regardless of the type of tumor, providing a potential new strategy to potentiate cancer immunotherapy.

BACKGROUND: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). METHODS: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. RESULTS: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. CONCLUSION: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. TRIAL REGISTRATION: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.

BACKGROUND: Extralevator abdominoperineal excision (ELAPE) has been recommended for treating low rectal cancer due to its potential advantages in improving surgical safety and oncologic outcomes as compared to conventional abdominoperineal excision (APE). In ELAPE, however, whether the benefits of intraoperative position change to a prone jackknife position outweighs the associated risks remains controversial. This study is to introduce a modified position change in laparoscopic ELAPE and evaluate its feasibility, safety and the long-term therapeutic outcomes. METHODS: Medical records of 56 consecutive patients with low rectal cancer underwent laparoscopic ELAPE from November 2013 to September 2016 were retrospectively studied. In the operation, a perineal dissection in prone jackknife position was firstly performed and the laparoscopic procedure was then conducted in supine position. Patient characteristics, intraoperative and postoperative outcomes, pathologic and 5-year oncologic outcomes were analyzed. RESULTS: The mean operation time was 213.5 ± 29.4 min and the mean intraoperative blood loss was 152.7 ± 125.2 ml. All the tumors were totally resected, without intraoperative perforation, conversion to open surgery, postoperative 30-day death, and perioperative complications. All the patients achieved pelvic peritoneum reconstruction without the usage of biological mesh. During the follow-up period, perineal hernia was observed in 1 patient, impaired sexual function in 1 patient, and parastomal hernias in 3 patients. The local recurrence rate was 1.9% and distant metastasis was noted in 12 patients. The 5-year overall survival rate was 76.4% and the 5-year disease-free survival rate was 70.9%. CONCLUSIONS: Laparoscopic ELAPE with modified position change is a simplified, safe and feasible procedure with favorable outcomes. The pelvic peritoneum can be directly closed by the laparoscopic approach without the application of biological mesh.

BACKGROUND: Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). METHODS: This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3-) to nitrite (NO2-) with nitrate reductase, followed by quantitation of NO2- based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. RESULTS: After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively). CONCLUSION: Decreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

BACKGROUND: The modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed. METHODS: The CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included. DISCUSSION: This will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690 .

OBJECTIVE: The aim of this study was to establish and validate a clinical prediction model for assessing the risk of metastasis and patient survival in Ewing's sarcoma (ES). METHODS: Patients diagnosed with ES from the Surveillance, Epidemiology and End Results (SEER) database for the period 2010-2016 were extracted, and the data after exclusion of vacant terms was used as the training set (n=767). Prediction models predicting patients' overall survival (OS) at 1 and 3 years were created by cox regression analysis and visualized using Nomogram and web calculator. Multicenter data from four medical institutions were used as the validation set (n=51), and the model consistency was verified using calibration plots, and receiver operating characteristic (ROC) verified the predictive ability of the model. Finally, a clinical decision curve was used to demonstrate the clinical utility of the model. RESULTS: The results of multivariate cox regression showed that age, , bone metastasis, tumor size, and chemotherapy were independent prognostic factors of ES patients. Internal and external validation results: calibration plots showed that the model had a good agreement for patient survival at 1 and 3 years; ROC showed that it possessed a good predictive ability and clinical decision curve proved that it possessed good clinical utility. CONCLUSIONS: The tool built in this paper to predict 1- and 3-year survival in ES patients ( https://drwenleli0910.shinyapps.io/EwingApp/ ) has a good identification and predictive power.

BACKGROUND: The histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in colorectal cancer liver metastasis (CRLM). This study evaluates the relationship between the HGP and primary colorectal cancer (CRC) histopathology. METHODS: A total of 183 treatment-naive patients with resected CRC and CRLM were included. Thirteen CRC histopathology markers were determined and compared between the desmoplastic and non-desmoplastic HGP; tumour sidedness, pT&pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn's-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. Logistic regression analysis was performed using both CRC and CRLM characteristics. RESULTS: Unfavourable CRC histopathology was more frequent in non-desmoplastic CRLM for all markers evaluated, and significantly so for a lower TIL density, absent Crohn's-like lymphoid reaction, and a "non-mature" stroma (all p < 0.03). The cumulative prevalence of unfavourable CRC histopathology was significantly higher in patients with non-desmoplastic compared to desmoplastic CRLM, with a median (IQR) of 4 (3-6) vs 2 (1-3.5) unfavourable characteristics observed, respectively (p < 0.001). Multivariable regression with 9 CRC histopathology markers and 2 CRLM characteristics achieved good discriminatory performance (AUC = 0.83). CONCLUSIONS: The results of this study associates primary CRC histopathology with the HGP of corresponding liver metastases.

BACKGROUND: Controversy exists regarding the relationship of the outcome of patients with colorectal cancer (CRC) with the time from symptom onset to diagnosis. The aim of this study is to investigate this association, with the assumption that this relationship was nonlinear and with adjustment for multiple confounders, such as tumor grade, symptoms, or admission to an emergency department. METHODS: This multicenter study with prospective follow-up was performed in five regions of Spain from 2010 to 2012. Symptomatic cases of incident CRC from a previous study were examined. At the time of diagnosis, each patient was interviewed, and the associated hospital and clinical records were reviewed. During follow-up, the clinical records were reviewed again to assess survival. Cox survival analysis with a restricted cubic spline was used to model overall and CRC-specific survival, with adjustment for variables related to the patient, health service, and tumor. RESULTS: A total of 795 patients had symptomatic CRC and 769 of them had complete data on diagnostic delay and survival. Univariate analysis indicated a lower HR for death in patients who had diagnostic intervals less than 4.2 months. However, after adjustment for variables related to the patient, tumor, and utilized health service, there was no relationship of the diagnostic delay with survival of patients with colon and rectal cancer, colon cancer alone, or rectal cancer alone. Cubic spline analysis indicated an inverse association of the diagnostic delay with 5-year survival. However, this association was not statistically significant. CONCLUSIONS: Our results indicated that the duration of diagnostic delay had no significant effect on the outcome of patients with CRC. We suggest that the most important determinant of the duration of diagnostic delay is the biological profile of the tumor. However, it remains the responsibility of community health centers and authorities to minimize diagnostic delays in patients with CRC and to implement initiatives that improve early diagnosis and provide better outcomes.

BACKGROUND: HuR/ELAVL1 (embryonic lethal abnormal vision 1) was a downstream target of miR-29b in some cancer cells. HuR protein exerts important prognostic effects of involving in the pathogenesis and development of acute myeloid leukemia (AML). This study aims to investigate the role of miR-29b-3p in biological behaviors of AML cells by targeting HuR and the involvement of the NF-κB and JAK/STAT signaling pathways. METHODS: The expressions of HuR and miR-29b-3p in AML cells were determined using RT-qPCR and Western blot, and the association between them was analyzed using the Spearman method. Next, the target relationship between HuR and miR-29b-3p was predicted by biological information databases and verified by the dual-luciferase reporter gene assay. MTS, methyl cellulose, flow cytometry and transwell assay were employed to detect the cell proliferation, clone formation, cell cycle and apoptosis, invasion and migration respectively, the effect of miR-29b-3p targeted HuR on the biological behaviors of AML cells was explored after over- /down-expression of miR-29b-3p and rescue experiment. Then, immunofluorescence assay and western blot were employed to detect location expression and phosphorylation levels of NF-κB and JAK/STAT signaling pathways related molecules respectively. RESULTS: HuR was negatively correlated with miR-29b-3p, and was the downstream target of miR-29b-3p in AML cells. When miR-29b-3p was overexpressed in AML cells, HuR was down-regulated, accompanied by cell viability decreased, cell cycle arrest, apoptosis increased, invasion and migration weakened. Moreover, the opposite result appeared after miR-29b-3p was down-regulated. The rescue experiment showed that miR-29b-3p inhibitor could reverse the biological effect of HuR down-regulation in AML cells. Molecular pathway results showed that miR-29b-3p could inhibit p65 expression in nucleus and phosphorylation levels of p65, IκBα, STAT1, STAT3 and STAT5. CONCLUSION: miR-29b-3p can inhibit malignant biological behaviors of AML cells via the inactivation of the NF-κB and JAK/STAT signaling pathways by targeting HuR. miR-29b-3p and its target HuR can be used as a new potential molecular for AML treatment.

BACKGROUND: Less than 20 % of patients with resectable oesophageal adenocarcinoma obtain a pathological response following neoadjuvant chemotherapy. Studies using oesophageal cancer cell lines have shown that drug sensitive tumour cells undergo apoptosis in response to drug treatment, whereas resistant cells induce autophagy and can recover following withdrawal of drug. In this study, we evaluated markers of apoptosis (active/cleaved caspase-3) and autophagy (LC3B) to establish whether these markers are useful prognostic indicators following neoadjuvant therapy. METHODS: Oesophageal adenocarcinoma tumour tissue from the Northern Ireland Biobank at Queens University Belfast was examined retrospectively. Tumours from 144 patients treated with platinum-based neoadjuvant chemotherapy followed by surgical resection were assembled into tissue microarrays prior to immunohistochemical analysis. Kaplan-Meier survival curves and log-rank tests were used to assess the impact of cleaved caspase-3 and LC3B expression on survival. Cox regression was used to examine association with clinical risk factors. RESULTS: High levels of cleaved caspase-3 were found in 14.6 % of patients and this correlated with a significantly better overall survival (p = 0.03). 38.9 % of patients had high cytoplasmic LC3B expression, which correlated with poor overall survival (p = 0.041). In addition, a distinct globular pattern of LC3B expression was identified in 40.3 % of patients and was also predictive of overall survival (p < 0.001). LC3B globular structures are also associated with tumour recurrence (p = 0.014). When these markers were assessed in combination, it was found that patients who showed low/negative cleaved caspase-3 staining and high/positive staining for both patterns of LC3B had the worst overall survival (p < 0.001). Multi-variate analysis also indicated that this marker combination was an independent predictor of poor prognosis (p = 0.008; HR = 0.046, 95% CI = (0.005-0.443). CONCLUSIONS: The expression of cleaved caspase-3 and specific LC3B staining patterns are associated with overall survival following neoadjuvant treatment. The combination of these markers is an independent indicator of outcome in neoadjuvant chemotherapy treated oesophageal adenocarcinoma.

BACKGROUND: Acute, catastrophic bleeding in patients with head and neck cancer (HNC) is challenging and also a burden for their families and frontline physicians. This study analyzed the risk factors for rebleeding and long-term outcomes in these patients with HNC. METHODS: Patients who presented to the emergency department (ED) with HNC bleeding were enrolled in this study (N = 231). Variables of patients with or without rebleeding were compared, and associated factors were investigated using Cox's proportional hazard model. RESULTS: Of the 231 patients enrolled, 112 (48.5%) experienced a recurrent bleeding event. The cumulative rebleeding incidence rate was 23% at 30 days, 49% at 180 days, and 56% at 1 year. Multivariate Cox regression analyses demonstrated that overweight-to-obesity (HR = 0.52, 95% CI 0.28-0.98, p = 0.043), laryngeal cancer (hazard ratio [HR] = 2.13, 95% confidence interval [CI] 1.07-4.23, p = 0.031), chemoradiation (HR = 1.49, 95% CI 1.001-2.94, p = 0.049), and second primary cancer (HR = 1.75, 95% CI 1.13-2.70, p = 0.012) are significant independent predictors of rebleeding, and the prognostic factors for overall survival included underweight (HR = 1.89, 95% CI 1.22-2.93, p = 0.004), heart rate > 110 beats/min (HR = 1.58, 95% CI 1.04-2.39, p = 0.032), chemoradiation (HR = 2.31, 95% CI 1.18-4.52, p = 0.015), and local recurrence (HR = 1.74, 95% CI 1.14-2.67, p = 0.011). CONCLUSIONS: Overweight-to-obesity is a protective factor, while laryngeal cancer, chemoradiation and a second primary cancer are risk factors for rebleeding in patients with HNC. Our results may assist physicians in risk stratification of patients with HNC bleeding.

BACKGROUND: Glioblastoma (GB) is the most common and most aggressive malignant brain tumor. In understanding its resistance to conventional treatments, iron metabolism and related pathways may represent a novel avenue. As for many cancer cells, GB cell growth is dependent on iron, which is tightly involved in red-ox reactions related to radiotherapy effectiveness. From new observations indicating an impact of RX radiations on the expression of ceruloplasmin (CP), an important regulator of iron metabolism, the aim of the present work was to study the functional effects of constitutive expression of CP within GB lines in response to beam radiation depending on the oxygen status (21% O2 versus 3% O2). METHODS AND RESULTS: After analysis of radiation responses (Hoechst staining, LDH release, Caspase 3 activation) in U251-MG and U87-MG human GB cell lines, described as radiosensitive and radioresistant respectively, the expression of 9 iron partners (TFR1, DMT1, FTH1, FTL, MFRN1, MFRN2, FXN, FPN1, CP) were tested by RTqPCR and western blots at 3 and 8 days following 4 Gy irradiation. Among those, only CP was significantly downregulated, both at transcript and protein levels in the two lines, with however, a weaker effect in the U87-MG, observable at 3% O2. To investigate specific role of CP in GB radioresistance, U251-MG and U87-MG cells were modified genetically to obtain CP depleted and overexpressing cells, respectively. Manipulation of CP expression in GB lines demonstrated impact both on cell survival and on activation of DNA repair/damage machinery (γH2AX); specifically high levels of CP led to increased production of reactive oxygen species, as shown by elevated levels of superoxide anion, SOD1 synthesis and cellular Fe2 + . CONCLUSIONS: Taken together, these in vitro results indicate for the first time that CP plays a positive role in the efficiency of radiotherapy on GB cells.

OBJECTIVE: To investigate the prevalence and spectrum of BRCA1 and BRCA2 mutations in Chinese Hakka patients with breast and ovarian cancer. METHODS: A total of 1,664 breast or ovarian cancer patients were enrolled for genetic testing at our hospital. Germline mutations of the BRCA gene were analysed by next-generation sequencing, including the coding regions and exon intron boundary regions. RESULTS: The 1,664 patients included 1,415 (85.04%) breast cancer patients and 245 (14.72%) ovarian cancer patients, while four (0.24%) patients had both the breast and ovarian cancers. A total of 151 variants, including 71 BRCA1 variants and 80 BRCA2 variants, were detected in the 234 (14.06%) patients. The 151 variants included 58 pathogenic variants, 8 likely pathogenic variants, and 85 variants of unknown significance (VUS). A total of 56.25% (18/32) and 65.38% (17/26) of pathogenic variants (likely pathogenic variants are not included) were distributed in exon 14 of BRCA1 and exon 11 of BRCA2, respectively. The most common pathogenic variants among this Hakka population are c.2635G > T (p.Glu879*) (n = 7) in the BRCA1 gene and c.5164_5165del (p.Ser1722Tyrfs*4) (n = 7) in the BRCA2 gene among the Hakka population. A hotspot mutation in the Chinese population, the BRCA1 c.5470_5477del variant was not found in this Hakka population. The prevalence and spectrum of variants in the BRCA genes in the Hakka patients are different from that in other ethnic groups. CONCLUSIONS: The most common pathogenic variant in this population is c.2635G > T in the BRCA1 gene, and c.5164_5165delAG in the BRCA2 gene in this population. The prevalence and spectrum of variants in the BRCA1 and BRCA2 genes in the Hakka patients from southern China are different from those in other ethnic groups.

BACKGROUND: Tumour mutation burden (TMB), defined as the number of somatic mutations per megabase within the sequenced region in the tumour sample, has been used as a biomarker for predicting response to immune therapy. Several studies have been conducted to assess the utility of TMB for various cancer types; however, methods to measure TMB have not been adequately evaluated. In this study, we identified two sources of bias in current methods to calculate TMB. METHODS: We used simulated data to quantify the two sources of bias and their effect on TMB calculation, we down-sampled sequencing reads from exome sequencing datasets from TCGA to evaluate the consistency in TMB estimation across different sequencing depths. We analyzed data from ten cancer cohorts to investigate the relationship between inferred TMB and sequencing depth. RESULTS: We found that TMB, estimated by counting the number of somatic mutations above a threshold frequency (typically 0.05), is not robust to sequencing depth. Furthermore, we show that, because only mutations with an observed frequency greater than the threshold are considered, the observed mutant allele frequency provides a biased estimate of the true frequency. This can result in substantial over-estimation of the TMB, when the cancer sample includes a large number of somatic mutations at low frequencies, and exacerbates the lack of robustness of TMB to variation in sequencing depth and tumour purity. CONCLUSION: Our results demonstrate that care needs to be taken in the estimation of TMB to ensure that results are unbiased and consistent across studies and we suggest that accurate and robust estimation of TMB could be achieved using statistical models that estimate the full mutant allele frequency spectrum.

BACKGROUND: Older patients with cancer have poorer prognosis compared to younger patients. Moreover, prognosis is related to how cancer is identified, and where in the healthcare system patients present, i.e. routes to diagnosis (RtD). We investigated whether RtD varied by patients' age. METHODS: This population-based national cohort study used Danish registry data. Patients were categorized into age groups and eight mutually exclusive RtD. We employed multinomial logistic regressions adjusted for sex, region, diagnosis year, cohabitation, education, income, immigration status and comorbidities. Screened and non-screened patients were analysed separately. RESULTS: The study included 137,876 patients. Both younger and older patients with cancer were less likely to get diagnosed after a cancer patient pathways referral from primary care physician compared to middle-aged patients. Older patients were more likely to get diagnosed via unplanned admission, death certificate only, and outpatient admission compared to younger patients. The patterns were similar across comorbidity levels. CONCLUSIONS: RtD varied by age groups, and middle-aged patients were the most likely to get diagnosed after cancer patient pathways with referral from primary care. Emphasis should be put on raising clinicians' awareness of cancer being the underlying cause of symptoms in both younger patients and in older patients.

BACKGROUND: Accumulating evidence has revealed that the gut microbiota influences the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. As a part of the human microbiome, Helicobacter pylori (H. pylori) was reported to be associated with reduced effectiveness of anti-PD1 immunotherapy in patients with non-small-cell lung cancer (NSCLC). Gastric cancer is more closely related to H. pylori, so we conducted a retrospective analysis to verify whether the association of H. pylori and effectiveness is applicable to advanced gastric cancer (AGC) patients. MATERIAL AND METHODS: AGC patients who had evidence of H. pylori and received anti-PD-1 antibodies were enrolled in the study. The differences in the disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) between the H. pylori-positive group and the negative group were compared. RESULTS: A total of 77 patients were included in this study; 34 patients were H. pylori positive, and the prevalence of H. pylori infection was 44.2%. Compared with the H. pylori-negative group, patients in the H. pylori-positive group had a higher risk of nonclinical response to anti-PD-1 antibody, with an OR of 2.91 (95% CI: 1.13-7.50). Patients in the H. pylori-negative group had a longer OS and PFS than those in the positive group, with an estimated median OS of 17.5 months vs. 6.2 months (HR = 2.85, 95% CI: 1.70-4.78; P = 0.021) and a median PFS of 8.4 months vs. 2.7 months (HR = 3.11, 95% CI: 1.96-5.07, P = 0.008). Multivariate analysis indicated that H. pylori infection was independently associated with PFS (HR = 1.90, 95% CI: 1.10-3.30; P = 0.022). CONCLUSION: Our study unveils for the first time that H. pylori infection is associated with the outcome of immunotherapy for AGC patients. Multicenter, large sample and prospective clinical studies are needed to verify the association.

BACKGROUND: Previous study has shown that chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 4 (CMTM4) can bind and maintain programmed cell death ligand 1 (PD-L1) expression to promote tumor progression by alleviating the suppression of tumor-specific T cell activity, suggesting its potential role in tumor immunotherapy. However, the role of CMTM4 in tumor immunity has not been well clarified, especially in hepatocellular carcinoma (HCC). METHODS: The protein expression of CMTM4/PD-L1/CD4/CD8 was detected by immunohistochemistry (IHC) detection in 90 cases of HCC tissues. The mRNA expression profiles and related prognosis data were obtained from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC). Two immune therapy cohorts were from Imvigor210 and GSE176307. RESULTS: Though the single protein expression of CMTM4, PD-L1, CD4 or CD8 in HCC tissues by IHC detection didn't show a significant relationship with the prognosis of HCC patients, we found that high co-expression of CMTM4/PD-L1/CD4 showed a good prognosis of HCC patients. Further Timer 2.0 analysis identified that HCC patients with high expression of CMTM4/PD-L1 and high infiltration of CD4+ T cells had a better overall survival than those with low infiltration of CD4+ T cells. Moreover, a series of bioinformatics analyses revealed that CMTM4-related genes posed important effects on prognosis and immunity in HCC patients, and CMTM4 had a positive correlation with infiltration of CD4+ and CD8+ T cells in HCC. At last, we used two immunotherapy cohorts to verify that the combination of CMTM4 with PD-L1 could improve the prognosis of tumor patients underwent immunotherapy. CONCLUSIONS: CMTM4 and PD-L1 co-expression with T cell infiltration shows prognostic significance in HCC, suggesting combined effect from multiple proteins should be considered in HCC treatment.

BACKGROUND: Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital volume and hospital level were associated with the chance of metastatic surgery. METHODS: This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009-2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted. RESULTS: A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68-2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78-0.88)). CONCLUSIONS: Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals.

BACKGROUND: The aim of this work was to screen and validate biomarkers of ovarian cancer-initiating cells to detect the mechanisms of recurrence of epithelial ovarian cancer (EOC). METHODS: Stably labelled the amino acid in side population (SP) cells of epithelial ovarian cancer which were rich in cancer-initiating cells and non-SP cells with isotope in culture and differentially expressed cellular membrane proteins in SP cells were identified through proteomics technology. The new candidate biomarker was screened and validated through RT-PCR and western blot. Both in cell lines and primary EOC, cancer-initiating biofunctions of CDC50A positive cells were validated. Moreover, the characteristics of mesenchymal transition (EMT) was also detected and the correlation between the biomarker and clinical prognosis was observed. RESULTS: Through proteomics technology, candidate protein CDC50A was screened, and its significantly differential expression in SP cells was validated. CDC50A-positive cells from cell lines and primary ovarian cancer tissues were validated to show characteristics of cancer-initiating cells both in vitro and in vivo, including sphere-forming, self-renewal, differentiation, tumor metastasis and tumorigenicity in mice. The relationship between CDC50A-positive cells from primary tissues and tumour metastasis was confirmed based on their mesenchymal transition characteristics. Among 16 high-grade ovarian serous cancer patients, a high ratio of CDC50A-positive cells in primary tumours was correlated with a shorter platinum-free interval (p = 0.031, HR 0.260, 95% CI 0.77 ~ 0.885). CONCLUSION: CDC50A could be used to screen ovarian cancer-initiating cells and might be a new target to resolve tumour development in EOC patients.

BACKGROUND: There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings. METHODS: This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model. RESULTS: A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients). CONCLUSIONS: The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.

BACKGROUND: New-generation silicon-photomultiplier (SiPM)-based PET/CT systems exhibit an improved lesion detectability and image quality due to a higher detector sensitivity. Consequently, the acquisition time can be reduced while maintaining diagnostic quality. The aim of this study was to determine the lowest 18F-FDG PET acquisition time without loss of diagnostic information and to optimise image reconstruction parameters (image reconstruction algorithm, number of iterations, voxel size, Gaussian filter) by phantom imaging. Moreover, patient data are evaluated to confirm the phantom results. METHODS: Three phantoms were used: a soft-tissue tumour phantom, a bone-lung tumour phantom, and a resolution phantom. Phantom conditions (lesion sizes from 6.5 mm to 28.8 mm in diameter, lesion activity concentration of 15 kBq/mL, and signal-to-background ratio of 5:1) were derived from patient data. PET data were acquired on an SiPM-based Biograph Vision PET/CT system for 10 min in list-mode format and resampled into time frames from 30 to 300 s in 30-s increments to simulate different acquisition times. Different image reconstructions with varying iterations, voxel sizes, and Gaussian filters were probed. Contrast-to-noise-ratio (CNR), maximum, and peak signal were evaluated using the 10-min acquisition time image as reference. A threshold CNR value ≥ 5 and a maximum (peak) deviation of ± 20% were considered acceptable. 20 patient data sets were evaluated regarding lesion quantification as well as agreement and correlation between reduced and full acquisition time standard uptake values (assessed by Pearson correlation coefficient, intraclass correlation coefficient, Bland-Altman analyses, and Krippendorff's alpha). RESULTS: An acquisition time of 60 s per bed position yielded acceptable detectability and quantification results for clinically relevant phantom lesions ≥ 9.7 mm in diameter using OSEM-TOF or OSEM-TOF+PSF image reconstruction, a 4-mm Gaussian filter, and a 1.65 × 1.65 x 2.00-mm3 or 3.30 × 3.30 x 3.00-mm3 voxel size. Correlation and agreement of patient lesion quantification between full and reduced acquisition times were excellent. CONCLUSION: A threefold reduction in acquisition time is possible. Patients might benefit from more comfortable examinations or reduced radiation exposure, if instead of the acquisition time the applied activity is reduced.

BACKGROUND: Increasing number of individuals will have first-degree relatives (FDRs) diagnosed with colorectal cancer (CRC), as a second primary malignancy (CRCa-2) after a non-CRC cancer. We aimed to estimate whether and to what extent a family history of CRCa-2 is associated with an increased CRC risk. METHODS: In this Swedish nationwide cohort study, rate ratio (RR) and cumulative incidence of CRC were estimated among 172,531 individuals with a family history of CRC as a first primary malignancy (CRCa-1) and 17,830 with a family history of CRCa-2, respectively, using individuals without cancer family history as the reference group. RESULTS: A cumulative incidence of CRC by age 80 was 6.3 and 5.6% for individuals with a parental and a sibling family history of CRCa-2, respectively. RRs of CRC for one FDR diagnosed with CRCa-1 and CRCa-2 were respectively 1.72 (95% CI, 1.65-1.79) and 1.50 (1.32-1.70); the latter RR was lower than the former (P = 0.0356), but no difference was observed after adjusting age of diagnosis of CRC in FDR and family relationship (P = 0.6898). Increased RRs were found to be associated with a CRCa-2 diagnosis in FDR that occured after cancers in upper aerodigestive tract, breast, prostate, kidney and nervous system. CONCLUSIONS: Individuals who have relatives with CRCa-2 have an increased risk of CRC, but the magnitude is lower than those having relatives with CRCa-1, which is related to different ages of diagnosis of CRC in FDR and family relationships.

BACKGROUND: Hexokinase 2 (HK2) is an enzyme that catalyses the conversion of glucose to glucose-6-phosphate, which has been found to be associated with malignant tumour growth. However, the potential immunological and clinical significance of HK2, especially in terms of prognostic prediction for patients with glioma, has not been fully elucidated. METHODS: To investigate the expression, immunological and clinical significance of HK2 in patients with glioma, several databases, including ONCOMINE, TIMER2.0, GEPIA, CGGA, UCSC, LinkedOmics, Metascape, STRING, GSCA, and TISIDB, as well as biochemical, cellular, and pathological analyses, were used in this study. In addition, we performed univariate, multivariate Cox regression and nomogram analyses of the hub genes positively and negatively correlated with HK2 to explore the potential regulatory mechanism in the initiation and development of glioma. RESULTS: Our results demonstrated that HK2 was highly expressed in most malignant cancers. HK2 expression was significantly higher in lower grade glioma (LGG) and glioblastoma (GBM) than in adjacent normal tissue. In addition, HK2 expression was significantly correlated with clinical parameters, histological manifestations, and prognosis in glioma patients. Specifically, the data from The Cancer Genome Atlas downloaded from UCSC Xena database analysis showed that high expression of HK2 was strongly associated with poor prognosis in glioma patients. The LinkedOmics database indicated that HK2-related genes were mainly enriched in immune-related cells. In LGG and GBM tissues, HK2 expression is usually correlated with recognized immune checkpoints and the abundance of multiple immune infiltrates. Similarly, the Metascape database revealed that HK2-related genes were mainly enriched and annotated in immune-related pathways and immune cells. Further investigations also confirmed that the inhibition of HK2 expression remarkably suppressed metastasis and vasculogenic mimicry (VM) formation in glioma cells through regulating the gene expression of inflammatory and immune modulators. CONCLUSION: HK2 expression was closely associated with the malignant properties of glioma through activating multiple immune-related signalling pathways to regulate immune responses and the infiltration of immune cells. Thus, HK2 and its hub genes may be a potential target for the treatment of glioma.

BACKGROUND: Quality of life (QoL) has become an important measure for evaluating cancer patients' treatment and prognosis. Breast cancer patients are at an increased risk of experiencing poor QoL during active treatment of cancer. This study aimed to assess QoL and it's influencing factors among breast cancer patients using the newly updated breast cancer specific tool of the European Organisation for Research and Treatment of Cancer EORTC Breast Cancer Specific Quality of Life Questionnaire QLQ-BR45. METHODS: An institutional based crossectional study was conducted with 248 breast cancer patients at Tikur Anbessa Specialized Hospital (TASH). Descriptive statistics, one-way analysis of variance (ANOVA), and linear regression were used to describe and analyze the data. RESULTS: The participant's Global health status/QoL mean score was 65.6. Among the functional scales, future perspective scored the lowest (57.1, SD ± 37.3). The highest mean score on the symptom scales/items were financial difficulties (50, SD ± 38.6), followed by appetite loss (37.4, SD ± 36.4) and fatigue (34.3, SD ± 27.1) while the lowest symptom score was diarrhoea (6.4 ± 18.4). EORTC QLQ-BR45, future perspective (mean = 57.1, SD ± 37.3) and upset by hair loss (41.8, SD ± 34.6) were the most affected functioning and symptoms scales respectively. An increased stage of tumor was associated with more pain (P = 0.041), appetite loss (P = 0.042), and arm symptoms (P = 0.003). Patients who had no comorbidity had better physical (P < 0.001), cognitive (P = 0.013), and social (P = 0.009) function. CONCLUSION: These specific functional scales and symptoms should be assessed individually to address unmet needs. Clinicians could design psychosocial interventions to improve these function and to reduce symptoms.

BACKGROUND: Allogeneic stem cell transplantation (allo-SCT) is a potentially lifesaving treatment for high-risk hematological malignancy, but survivors experience markedly elevated rates of cardiovascular disease and associated functional impairment. Mounting evidence suggests regular exercise, combined with a reduction in sedentary time through replacement with light exercise may be a useful therapeutic strategy for the prevention of cardiovascular comorbidities. However, this type of intervention has yet to be evaluated in patients undergoing allo-SCT. The ALLO-Active study will evaluate the efficacy of a ~ 4 month multi-faceted exercise intervention, commenced upon admission for allo-SCT, to preserve peak oxygen uptake (VO2peak) and peak cardiac output, compared with usual care. The study will also evaluate the effect of the intervention on functional independence, quality of life, and symptoms of fatigue. METHODS: Sixty adults with hematological malignancy scheduled for allo-SCT will be randomly assigned to usual care (n = 30) or the exercise and sedentary behaviour intervention (n = 30). Participants assigned to the intervention will complete a thrice weekly aerobic and progressive resistance training program and concomitantly aim to reduce daily sedentary time by 30 min with short, frequent, light-intensity exercise bouts. Participants will undergo testing prior to, immediately after inpatient discharge, and 12 weeks after discharge. To address aim 1, VO2peak and peak cardiac output (multiple primary outcomes, p < 0.025) will be assessed via cardiopulmonary exercise testing and exercise cardiac magnetic resonance imaging, respectively. Secondary outcomes include functional independence (defined as VO2peak ≥ 18.mL.kg-1.min-1), quality of life, and fatigue (assessed via validated questionnaire). Exploratory outcomes will include indices of resting cardiac, vascular, and skeletal muscle structure and function, cardiovascular biomarkers, anxiety and depression, transplant outcomes (e.g., engraftment, graft-versus-host disease), and habitual physical activity, sedentary time, and sleep. DISCUSSION: Multi-faceted exercise programs are a promising approach for ameliorating the cardiovascular consequences of allo-SCT. If this intervention proves to be effective, it will contribute to the development of evidence-based exercise guidelines for patients undergoing allo-SCT and assist with optimising the balance between acute cancer management and long-term health. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ID: 12619000741189 . Registered 17 May 2019.

OBJECTIVE: To evaluate the diagnostic performance of combined multiparametric 18F-fluorodeoxyglucose positron emission tomography (18FDG PET) with clinical characteristics in differentiating thymic epithelial tumors (TETs) from thymic lymphomas. PATIENTS AND METHODS: A total of 173 patients with 80 TETs and 93 thymic lymphomas who underwent 18F-FDG PET/CT before treatment were enrolled in this retrospective study. All patients were confirmed by pathology, and baseline characteristics and clinical data were also collected. The semi-parameters of 18F-FDG PET/CT, including lesion size, SUVmax (maximum standard uptake value), SUVmean (mean standard uptake value), TLG (total lesion glycolysis), MTV (metabolic tumor volume) and SUVR (tumor-to-normal liver standard uptake value ratio) were evaluated. The differential diagnostic efficacy was evaluated using the receiver operating characteristic (ROC) curve. Integrated discriminatory improvement (IDI) and net reclassification improvement (NRI), and Delong test were used to evaluate the improvement in diagnostic efficacy. The clinical efficacy was evaluated by decision curve analysis (DCA). RESULTS: Age, clinical symptoms, and metabolic parameters differed significantly between patients with TETs and thymic lymphomas. The ROC curve analysis of SUVR showed the highest differentiating diagnostic value (sensitivity = 0.763; specificity = 0.888; area under the curve [AUC] = 0.881). The combined diagnostics model of age, clinical symptoms and SUVR resulted in the highest AUC of 0.964 (sensitivity = 0.882, specificity = 0.963). Compared with SUVR, the diagnostic efficiency of the model was improved significantly. The DCA also confirmed the clinical efficacy of the model. CONCLUSIONS: The multiparameter diagnosis model based on 18F-FDG PET and clinical characteristics had excellent value in the differential diagnosis of TETs and thymic lymphomas.

BACKGROUND: Pancreatic cancer (PC) is a highly malignant tumor featured with high intra-tumoral heterogeneity and poor prognosis. Cell-in-cell (CIC) structures have been reported in multiple cancers, and their presence is associated with disease progression. Nonetheless, the prognostic values and biological functions of CIC-related genes in PC remain poorly understood. METHODS: The sequencing data, as well as corresponding clinicopathological information of PC were collected from public databases. Random forest screening, least absolute shrinkage, and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to construct a prognostic model. The effectiveness and robustness of the model were evaluated using receiver operating characteristic (ROC) curves, survival analysis and establishing the nomogram model. Functional enrichment analyses were conducted to annotate the biological functions. The immune infiltration levels were evaluated by ESTIMATE and CIBERSORT algorithms. The expression of KRT7 (Keratin 7) was validated by quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) staining. The CIC formation, cell clusters, cell proliferation, migration and invasion assays were applied to investigate the effects of silencing the expression of KRT7. RESULTS: A prognostic model based on four CIC-related genes was constructed to stratify the patients into the low- and high-risk subgroups. The high-risk group had a poorer prognosis, higher tumor mutation burden and lower immune cell infiltration than the low-risk group. Functional enrichment analyses showed that numerous terms and pathways associated with invasion and metastasis were enriched in the high-risk group. KRT7, as the most paramount risk gene in the prognostic model, was significantly associated with a worse prognosis of PC in TCGA dataset and our own cohort. High expression of KRT7 might be responsible for the immunosuppression in the PC microenvironment. KRT7 knockdown was significantly suppressed the abilities of CIC formation, cell cluster, cell proliferation, migration, and invasion in PC cell lines. CONCLUSIONS: Our prognostic model based on four CIC-related genes has a significant potential in predicting the prognosis and immune microenvironment of PC, which indicates that targeting CIC processes could be a therapeutic option with great interests. Further studies are needed to reveal the underlying molecular mechanisms and biological implications of CIC phenomenon and related genes in PC progression.

BACKGROUND: The presence of mixed-lineage leukaemia rearrangement (MLL-r) in paediatric patients with acute myeloid leukaemia (AML) is a poor prognostic predictor. Whether allogeneic haematopoietic stem cell transplantation (allo-HSCT) is beneficial in such cases remains unclear. METHODS: We evaluated the outcomes and prognostic factors of allo-HSCT in 44 paediatric patients with MLL-r AML in the first complete remission (CR1) between 2014 and 2019 at our institution. RESULTS: For all the 44 patients, the 3-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.5%, 64.1%, and 29.1%, respectively. Among them, 37 (84.1%) patients received haploidentical (haplo)-HSCT, and the 3-year OS, EFS, and CIR were 73.0%, 65.6%, and 26.4%, respectively. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) post-transplantation was 27.3%, and that of grade III-IV aGVHD was 15.9%. The overall 3-year cumulative incidence of chronic graft-versus-host disease (cGVHD) post-transplantation was 40.8%, and that of extensive cGVHD was 16.7%. Minimal residual disease (MRD)-positive (MRD +) status pre-HSCT was significantly associated with lower survival and higher risk of relapse. The 3-year OS, EFS, and CIR differed significantly between patients with MRD + pre-HSCT (n = 15; 48.5%, 34.3% and 59%) and those with MRD-pre-HSCT (n = 29; 89.7%, 81.4% and 11.7%). Pre-HSCT MRD + status was an independent risk factor in multivariate analysis. CONCLUSIONS: Allo-HSCT (especially haplo-HSCT) can be a viable strategy in these patients, and pre-HSCT MRD status significantly affected the outcomes.

INTRODUCTION: Globally breast cancer is the leading cause of cancer with an estimated 2.3 million new cases and 685,000 deaths in 2020. Late presentation is the hallmark of breast cancer in Ghana for which ignorance and fear are the major reasons fuelled largely by myths and misconceptions. Breast cancer awareness and education needs to start early to bring about a change in knowledge, attitude and practices. However, Breast cancer awareness activities in Ghana have usually targeted adult women. This study assessed the impact of breast cancer education among adolescent high school girls in Ghana. METHODOLOGY: A pre- post-test quasi experimental study was conducted at two senior high schools. A self-administered pre-educational questionnaire was followed by an educational intervention consisting of a drama, PowerPoint lecture, question and answer session and distribution of breast cancer information leaflets. After 3 months the same questionnaire was administered as a post-education test to assess the impact of the educational intervention. The total score for each domain was categorised into adequate knowledge > 50% and inadequate knowledge < 50%. RESULTS: The number of participants in the pre-test and post-test were 1043 and 1274; the median ages [IQR] were 16.0 [15.0-17.0] for both the pre and post-test students. General knowledge on breast cancer at pre-education (29.1%) improved to 72.5% (p < 0.001). Knowledge on signs and symptoms improved from 33.1 to 55% (p < 0.001); knowledge on risk factors improved from 55.3 to 79.2% (p < 0.001), and knowledge on breast self-examination and screening improved from 9.8 to 22.2% (p < 0.001). The overall performance of the students improved from 17.2 to 59.4% (p < 0.001). CONCLUSION: There is inadequate knowledge about breast cancer and self-examination among senior high school girls in Ghana. Our breast cancer educational intervention was effective in improving general knowledge of breast cancer, risk factors, signs and symptoms and breast self-examination. The overall knowledge base improved from 17.2 to 59.4% 3 months post intervention, accompanied by an increase in the reported practice of breast self-examination and a greater belief that breast cancer is curable. This study has demonstrated the need for a school breast cancer educational program and that breast cancer education in high schools is effective.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare histological subtype of soft-tissue sarcoma, which remains refractory to conventional cytotoxic chemotherapy. We aimed to characterize ASPS and investigate whether the oncological outcome has improved over the past decade. METHODS: One hundred and twenty patients with newly diagnosed ASPS from 2006 to 2017, identified from the Bone and Soft-Tissue Tumor Registry in Japan, were analyzed retrospectively. RESULTS: The study cohort comprised 34 (28%) patients with localized ASPS and 86 (72%) with metastatic disease at presentation. The 5-year disease-specific survival (DSS) was 68% for all patients and 86% and 62% for localized and metastatic disease, respectively (p = 0.019). Metastasis at presentation was the only adverse prognostic factor for DSS (hazard ratio [HR]: 7.65; p = 0.048). Patients who were > 25 years (80%; p = 0.023), had deep-seated tumors (75%; p = 0.002), and tumors > 5 cm (5-10 cm, 81%; > 10 cm, 81%; p < 0.001) were more likely to have metastases at presentation. In patients with localized ASPS, adjuvant chemotherapy or radiotherapy did not affect survival, and 13 patients (45%) developed distant metastases in the lung (n = 12, 92%) and brain (n = 2, 15%). In patients with metastatic ASPS (lung, n = 85 [99%]; bone, n = 12 [14%]; and brain n = 9 [11%]), surgery for the primary or metastatic site did not affect survival. Prolonged survival was seen in patients who received pazopanib treatment (p = 0.045), but not in those who received doxorubicin-based cytotoxic chemotherapy. Overall, improved DSS for metastatic ASPS has been observed since 2012 (5-year DSS, from 58 to 65%) when pazopanib was approved for advanced diseases, although without a statistically significant difference (p = 0.117). CONCLUSION: The national study confirmed a unique feature of ASPS with frequent metastasis to the lung and brain but an indolent clinical course. An overall trend toward prolonged survival after the introduction of targeted therapy encourages continuous efforts to develop novel therapeutic options for this therapeutically resistant soft-tissue sarcoma.

BACKGROUND: Worldwide 85% of cervical cancer (CC) related deaths occur in low- and middle-income countries. Sub-Saharan Africa is burdend by an overlapping high incidence of CC as well as HIV infection, a risk factor for HPV associated disease progression. Recent upscaling of CC screening activities increased the number of CC diagnoses in a previous unscreened population. The aim of the 2H study was to follow up on women with CC in the context of available health care services in Tanzania in relation to their HIV infection status. METHODS: This longitudinal observational cohort study included women with histological confirmed CC from Mbeya, Tanzania, between 2013-2019. All women were referred for CC staging and cancer-directed therapies (CDT), including surgery and/or radio-chemotherapy, or palliative care. Annual follow-up focused on successful linkage to CDT, interventions and survival. We assessed factors on compliance, used Kaplan-Meier-Survivor functions to evaluate survival time and poisson regression models to calculate incidence rate ratios on mortality (IRR) two years after diagnosis. RESULTS: Overall, 270 women with CC (123 HIV infected) were included. Staging information, available in 185 cases, showed 84.9% presented with advanced stage disease (FIGO ≥ IIB), no difference was seen in respect to HIV status. HIV-infected women were 12 years younger at the time of cancer diagnosis (median age 44.8 versus 56.4 years, p < 0.001). Median follow up period was 11.9 months (range 0.2-67.2). Survival information, available in 231 cases, demonstrated for women diagnosed in early-stage disease a median survival time of 38.3 months, in advanced-stage 16.0 months and late-stage disease 6.5 months after diagnosis. Of all women, 42% received CDT or palliative support. HIV co-infection and education were associated with higher health care compliance. CDT was significantly associated with lower 2-year mortality rates (IRR 0.62, p = 0.004). HIV coinfection did not impact mortality rates after diagnosis. CONCLUSION: High numbers of advanced and late staged CC were diagnosed, compliance to CDT was low. A beneficial impact of CDT on CC mortality could be demonstrated for local health care services. This study indicates challenges for successful linkage and supports an effective scale up of cancer care and treatment facilities.

BACKGROUND: Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells. METHODS: Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS). RESULTS: TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03-0.52), p = 0.005 for TTR and 0.25 (0.09-0.74), p = 0.01 for DFS. CONCLUSION: The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment.

BACKGROUND: Pyroptosis is a programmed cell death mediated by the gasdermin superfamily, accompanied by inflammatory and immune responses. Exogenously activated pyroptosis is still not well characterized in the tumor microenvironment. Furthermore, whether pyroptosis-related genes (PRGs) in lower-grade glioma (LGG) may be used as a biomarker remains unknown. METHODS: The RNA-Sequencing and clinical data of LGG patients were downloaded from publicly available databases. Bioinformatics approaches were used to analyze the relationship between PRGs and LGG patients' prognosis, clinicopathological features, and immune status. The NMF algorithm was used to differentiate phenotypes, the LASSO regression model was used to construct prognostic signature, and GSEA was used to analyze biological functions and pathways. The expression of the signature genes was verified using qRT-PCR. In addition, the L1000FWD and CMap tools were utilized to screen potential therapeutic drugs or small molecule compounds and validate their effects in glioma cell lines using CCK-8 and colony formation assays. RESULTS: Based on PRGs, we defined two phenotypes with different prognoses. Stepwise regression analysis was carried out to identify the 3 signature genes to construct a pyroptosis-related signature. After that, samples from the training and test cohorts were incorporated into the signature and divided by the median RiskScore value (namely, Risk-H and Risk-L). The signature shows excellent predictive LGG prognostic power in the training and validation cohorts. The prognostic signature accurately stratifies patients according to prognostic differences and has predictive value for immune cell infiltration and immune checkpoint expression. Finally, the inhibitory effect of the small molecule inhibitor fedratinib on the viability and proliferation of various glioma cells was verified using cell biology-related experiments. CONCLUSION: This study developed and validated a novel pyroptosis-related signature, which may assist instruct clinicians to predict the prognosis and immunological status of LGG patients more precisely. Fedratinib was found to be a small molecule inhibitor that significantly inhibits glioma cell viability and proliferation, which provides a new therapeutic strategy for gliomas.

BACKGROUND: This study aimed to develop and externally validate contrast-enhanced (CE) T1-weighted MRI-based radiomics for the identification of epidermal growth factor receptor (EGFR) mutation, exon-19 deletion and exon-21 L858R mutation from MR imaging of spinal bone metastasis from primary lung adenocarcinoma. METHODS: A total of 159 patients from our hospital between January 2017 and September 2021 formed a primary set, and 24 patients from another center between January 2017 and October 2021 formed an independent validation set. Radiomics features were extracted from the CET1 MRI using the Pyradiomics method. The least absolute shrinkage and selection operator (LASSO) regression was applied for selecting the most predictive features. Radiomics signatures (RSs) were developed based on the primary training set to predict EGFR mutations and differentiate between exon-19 deletion and exon-21 L858R. The RSs were validated on the internal and external validation sets using the Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Eight, three, and five most predictive features were selected to build RS-EGFR, RS-19, and RS-21 for predicting EGFR mutation, exon-19 deletion and exon-21 L858R, respectively. The RSs generated favorable prediction efficacies for the primary (AUCs, RS-EGFR vs. RS-19 vs. RS-21, 0.851 vs. 0.816 vs. 0.814) and external validation (AUCs, RS-EGFR vs. RS-19 vs. RS-21, 0.807 vs. 0.742 vs. 0.792) sets. CONCLUSIONS: Radiomics features from the CE MRI could be used to detect the EGFR mutation, increasing the certainty of identifying exon-19 deletion and exon-21 L858R mutations based on spinal metastasis MR imaging.

BACKGROUND: Histocompatibility minor 13 (HM13) is a signal sequence stubbed intramembrane cleavage catalytic protein that is essential for cell signaling, intracellular communication, and cancer. However, the expression of HM13 and its prognostic value, association with tumor-infiltrating immune cells (TIICs) in the microenvironment, and potential to predict immunotherapeutic response in HCC are unknown. METHODS: The HM13 expression, clinicopathology analysis, and its influence on survival were analyzed in multiple public databases and further verified in collected HCC and normal tissues by qRT-PCR and immunohistochemistry staining assay (IHC). Furthermore, the lentivirus vector encoding HM13-shRNA to manipulate HM13 expression was selected to investigate whether HM13 could influence the malignant growth and metastasis potential of HCC cells. Finally, significant impacts of HM13 on the HCC tumor microenvironment (TME) and reaction to immune checkpoint inhibitors were analyzed. RESULTS: Upregulated HM13 was substantially correlated with poor prognosis in patients with HCC, and could facilitate the proliferation and migratory potential of HCC cells. Additionally, patients with high HM13 expression might be more sensitive to immunotherapy. CONCLUSIONS: HM13 might be a prognostic biomarker and potential molecular therapeutic target for HCC.

BACKGROUND: Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy. METHODS: We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation. RESULTS: Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues. CONCLUSION: Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.

BACKGROUND: Obesity is a high-risk factor for development and poor prognosis of triple-negative breast cancer (TNBC), which was considered as a high malignant and poor clinical outcome breast cancer subtype. TNBC proliferation and migration regulated by obesity is complex. Here, we studied effects of cytokines secreted from adipose tissue on development of TNBC. METHODS: Forty postmenopausal cases by Yuebei People's Hospital of Shaoguan with stage I/IIA TNBC were enrolled. Cytokine concentrations were examined using ELISA analysis. Proliferation and migration of TNBC cell lines were performed using CCK8 assays and Transwell tests. The Log-rank (Mantel-Cox) test, two-tailed Mann-Whitney U test and two-tailed unpaired t test were performed using GraphPad Prism 8.4.2. RESULTS: Survival analysis indicated that obese patients with TNBC had worse disease free survival (DFS) as compared with normal weight group (Hazard Ratio 4.393, 95% confidence interval (CI) of ratio 1.071-18.02, p < 0.05). Obese patients with TNBC had severe insulin resistance and high plasma triglycerides. However, plasma adiponectin concentration was decreased and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentration was increased in obese TNBC patients as compared with the nonobese group. The similar results were found in the cytokine secretion from adipose tissues and insulin-resistant adipocytes. The secretion of adipose tissue from obese TNBC patients could promote proliferation and migration of TNBC cell lines, including MDA-MB-157, MDA-MB-231, MDA-MB-453 and HCC38 cells. These TNBC cell lines co-incubated with insulin-resistant 3T3-L1 adipocytes or supplementing these cytokines medium also exhibited increase of proliferative and migratory capacity. CONCLUSION: TNBC patients with obesity had worse prognosis compared with the normal weight groups. Alteration of cytokines secreted from adipose tissues mediated proliferation and migration of TNBC, leading to tumor progression in TNBC patients with obesity.

BACKGROUND: While individuals with normal gastrointestinal (GI) mucosa on endoscopy have a lower risk of colorectal cancer, risks of other cancers remain unexplored. METHODS: Through Sweden's 28 pathology departments, we identified 415,092 individuals with a first GI biopsy with histologically normal mucosa during 1965-2016 and no prior cancer. These individuals were compared to 1,939,215 matched reference individuals from the general population. Follow-up began 6 months after biopsy, and incident cancer data were retrieved from the Swedish Cancer Register. Flexible parametric model was applied to estimate cumulative incidences and hazard ratios (HRs) for cancers. We also used full siblings (n = 441,534) as a secondary comparison group. RESULTS: During a median follow-up of 10.9 years, 40,935 individuals with normal mucosa (incidence rate: 82.74 per 10,000 person-years) and 177,350 reference individuals (incidence rate: 75.26) developed cancer. Restricting the data to individuals where follow-up revealed no cancer in the first 6 months, we still observed an increased risk of any cancer in those with a histologically normal mucosa (average HR = 1.07; 95%CI = 1.06-1.09). Although the HR for any and specific cancers decreased shortly after biopsy, we observed a long-term excess risk of any cancer, with an HR of 1.08 (95%CI = 1.05-1.12) and a cumulative incidence difference of 0.93% (95%CI = 0.61%-1.25%) at 30 years after biopsy. An elevated risk of gastric cancer, lung cancer, and hematological malignancy (including lymphoproliferative malignancy) was also observed at 20 or 30 years since biopsy. Sibling analyses confirmed the above findings. CONCLUSION: Individuals with a histologically normal mucosa at biopsy and where follow-up revealed no cancer in the first 6 months, may still be at increased risk of cancer, although excess risks are small.

INTRODUCTION: EBV infection in nasopharyngeal cancer ensued in latent infection mode. In this latent infection various EBV oncoproteins such as EBNA1 and LMP1 was expressed. EBV oncoproteins could theoretically recruit immune cells, which might help to control cancer. Therefore, this study was aimed to elucidate the association with EBV oncoproteins (EBNA1 and LMP1), immune markers (CD4, CD8, and FOXP3) from nasopharyngeal cancer microenvironment with tumor progression. METHOD: Nasopharyngeal biopsy was obtained from patients suspected to have nasopharyngeal cancer. Those samples with microscopically confirmed nasopharyngeal cancer were tested for EBNA1, LMP1, CD4, CD8, and FOXP3 concentration with ELISA, then verified with IHC. Each patient tumor volume was assessed for primary nasopharyngeal tumor volume (GTVp) and neck nodal metastases tumor volume (GTVn). Correlation test with Spearman correlation and scatterplot were carried out. RESULT: Total 23 samples with nasopharyngeal cancer were analyzed. There was moderate correlation (ρ = 0.45; p value = 0.032) between LMP1 and GTVp. There was strong correlation (ρ = 0.81; p value < 0.001) between CD8 and GTVp. There was also moderate correlation (ρ = 0.6; p value = 0.002) between FOXP3 and GTVp. The CD8 concentration has moderate correlation with both EBNA1 (ρ = 0.46; p value = 0.026) and LMP1 (ρ = 0.47; p value = 0.023). While FOXP3 has moderate correlation with only LMP1 (ρ = 0.58; p value = 0.004). No correlation was found between all the markers tested here with GTVn. DISCUSSION: We found larger primary nasopharyngeal tumor was associated with higher CD8 marker. This was thought due to the presence of abundance CD8 T cells in the nasopharynx, but those abundance CD8 T cells were suspected to be dysfunctional. The nasopharyngeal cancer was also known to upregulate chemokines that could recruit T regulatory FOXP3 cells. Furthermore, T regulatory FOXP3 cells differentiation was induced through several pathways which was triggered by EBNA1. The correlation found in this study could guide further study to understand nasopharyngeal carcinogenesis and the relationship with our immune system.

Glioblastoma (GBM) is the most common primary intracranial tumor in the central nervous system, and resistance to temozolomide is an important reason for the failure of GBM treatment. We screened out that Solute Carrier Family 2 Member 10 (SLC2A10) is significantly highly expressed in GBM with a poor prognosis, which is also enriched in the NF-E2 p45-related factor 2 (NRF2) signalling pathway. The NRF2 signalling pathway is an important defence mechanism against ferroptosis. SLC2A10 related LINC02381 is highly expressed in GBM, which is localized in the cytoplasm/exosomes, and LINC02381 encoded micropeptides are localized in the exosomes. The micropeptide encoded by LINC02381 may be a potential treatment strategy for GBM, but the underlying mechanism of its function is not precise yet. We put forward the hypothesis: "The micropeptide encoded by LINC02381 regulates ferroptosis through the glucose transporter SLC2A10 in GBM." This study innovatively used machine learning for micropeptide to provide personalized diagnosis and treatment plans for precise treatment of GBM, thereby promoting the development of translational medicine. The study aimed to help find new disease diagnoses and prognostic biomarkers and provide a new strategy for experimental scientists to design the downstream validation experiments.

BACKGROUND: Glutathione Peroxidase 4 (GPX4) is a key protein that inhibits ferroptosis. However, its biological regulation and mechanism in endometrial cancer (EC) have not been reported in detail. METHODS: The expression of GPX4 in EC tissues was determined by TCGA databases, qRT-PCR, Western blot, and immunohistochemistry (IHC). The effects of GPX4 on EC cell proliferation, migration, apoptosis, and tumorigenesis were studied in vivo and in vitro. In addition, ETS Transcription Factor ELK1 (ELK1) was identified by bioinformatics methods, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP). Pearson correlation analysis was used to evaluate the association between ELK1 and GPX4 expression. RESULTS: The expression of GPX4 was significantly up-regulated in EC tissues and cell lines. Silencing GPX4 significantly inhibited the proliferation, migration ability, induced apoptosis, and arrested the cell cycle of Ishikawa and KLE cells. Knockdown of GPX4 accumulated intracellular ferrous iron and ROS, disrupted MMP, and increased MDA levels. The xenograft tumor model also showed that GPX4 knockdown markedly reduced tumor growth in mice. Mechanically, ELK1 could bind to the promoter of GPX4 to promote its transcription. In addition, the expression of ELK1 in EC was positively correlated with GPX4. Rescue experiments confirmed that GPX4 knockdown could reverse the strengthens of cell proliferation and migration ability and the lower level of Fe2+ and MDA caused by upregulating ELK1. CONCLUSION: The results of the present study suggest that ELK1 / GPX4 axis plays an important role in the progress of EC by promoting the malignant biological behavior and inducing ferroptosis of EC cells, which provides evidence for investigating the potential therapeutic strategies of endometrial cancer.

INTRODUCTION: Pre-treatment risk and prognostic groups are the cornerstone for deciding management in non-metastatic prostate cancer. All however, were developed in the pre-MRI era. Here we compared categorisation of cancers using either only clinical parameters or with MRI enhanced information in men referred for suspected prostate cancer from an unscreened population. PATIENT AND METHODS: Data from men referred from primary care to our diagnostic service and with both clinical (digital rectal examination [DRE] and systematic biopsies) and MRI enhanced attributes (MRI stage and combined systematic/targeted biopsies) were used for this study. Clinical vs MRI data were contrasted for clinico-pathological and risk group re-distribution using the European Association of Urology (EAU), American Urological Association (AUA) and UK National Institute for Health Care Excellence (NICE) Cambridge Prognostic Group (CPG) models. Differences were retrofitted to a population cohort with long-term prostate cancer mortality (PCM) outcomes to simulate impact on model performance. We further contrasted individualised overall survival (OS) predictions using the Predict Prostate algorithm. RESULTS: Data from 370 men were included (median age 66y). Pre-biopsy MRI stage reassignments occurred in 7.8% (versus DRE). Image-guided biopsies increased Grade Group 2 and ≥ Grade Group 3 assignments in 2.7% and 2.9% respectively. The main change in risk groups was more high-risk cancers (6.2% increase in the EAU and AUA system, 4.3% increase in CPG4 and 1.9% CPG5). When extrapolated to a historical population-based cohort (n = 10,139) the redistribution resulted in generally lower concordance indices for PCM. The 5-tier NICE-CPG system outperformed the 4-tier AUA and 3-tier EAU models (C Index 0.70 versus 0.65 and 0.64). Using an individualised prognostic model, changes in predicted OS were small (median difference 1% and 2% at 10- and 15-years' respectively). Similarly, estimated treatment survival benefit changes were minimal (1% at both 10- and 15-years' time frame). CONCLUSION: MRI guided diagnostics does change pre-treatment risk groups assignments but the overall prognostic impact appears modest in men referred from unscreened populations. Particularly, when using more granular tiers or individualised prognostic models. Existing risk and prognostic models can continue to be used to counsel men about treatment option until long term survival outcomes are available.

Pancreatic cancer (PC) is a highly lethal and aggressive disease with its incidence and mortality quite discouraging. A robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Since the critical role of immune microenvironment in the progression of PC, a prognostic signature based on seven immune-related genes was established, which was validated in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set and GSE71729 set. Furthermore, S100A14 (S100 Calcium Binding Protein A14) was identified as the gene occupying the most paramount position in risk signature. According to the GSEA, CIBERSORT and ESTIMATE algorithm, S100A14 was mainly associated with lower proportion of CD8 + T cells and higher proportion of M0 macrophages in PC tissue. Meanwhile, analysis of single-cell dataset CRA001160 revealed a significant negative correlation between S100A14 expression in PC cells and CD8 + T cell infiltration, which was further confirmed by tissue microenvironment landscape imaging and machine learning-based analysis in our own PUMCH cohort. Additionally, analysis of a pan-pancreatic cancer cell line illustrated that S100A14 might inhibit CD8 + T cell activation via the upregulation of PD-L1 expression in PC cells, which was also verified by the immunohistochemical results of PUMCH cohort. Finally, tumor mutation burden analysis and immunophenoscore algorithm revealed that patients with high S100A14 expression had a higher probability of responding to immunotherapy. In conclusion, our study established an efficient immune-related prediction model and identified the potential role of S100A14 in regulating the immune microenvironment and serving as a biomarker for immunotherapy efficacy prediction.

BACKGROUND: Distinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo-keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse. METHODS: A total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan-Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS. RESULTS: A significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718. CONCLUSIONS: In conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

Author information: (1)International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France. (2)Centre for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico. (3)Servicio de Patología, Hospital de Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, México. (4)Group Infection and Cancer, School of Medicine, University of Antioquia, Medellín, Colombia. (5)Grupo Proyecto UNI-Barranquilla, Universidad del Norte, Barranquilla, Colombia. (6)Hemato Oncologos, Cali, Colombia. (7)Agencia Costarricense de Investigaciones Biomédicas (ACIB)-Fundación INCIENSA, San Jose, Costa Rica. (8)Instituto de Nutrición y de Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile. (9)National Institute of Cancer, Santiago, Chile. (10)Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, USA. (11)Hubert Department of Global Health, Emory University, Atlanta, Georgia, USA. (12)International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France. rinaldis@iarc.fr. (#)Contributed equally

BACKGROUND: The determination of HER2 expression status contributes significantly to HER2-targeted therapy in breast carcinoma. However, an economical, efficient, and non-invasive assessment of HER2 is lacking. We aimed to develop a clinicoradiomic nomogram based on radiomics scores extracted from multiparametric MRI (mpMRI, including ADC-map, T2W1, DCE-T1WI) and clinical risk factors to assess HER2 status. METHODS: We retrospectively collected 214 patients with pathologically confirmed invasive ductal carcinoma between January 2018 to March 2021 from Fudan University Shanghai Cancer Center, and randomly divided this cohort into training set (n = 128, 42 HER2-positive and 86 HER2-negative cases) and validation set (n = 86, 28 HER2-positive and 58 HER2-negative cases) at a ratio of 6:4. The original and transformed pretherapy mpMRI images were treated by semi-automated segmentation and manual modification on the DeepWise scientific research platform v1.6 ( http://keyan.deepwise.com/ ), then radiomics feature extraction was implemented with PyRadiomics library. Recursive feature elimination (RFE) based on logistic regression (LR) and LASSO regression were adpoted to identify optimal features before modeling. LR, Linear Discriminant Analysis (LDA), support vector machine (SVM), random forest (RF), naive Bayesian (NB) and XGBoost (XGB) algorithms were used to construct the radiomics signatures. Independent clinical predictors were identified through univariate logistic analysis (age, tumor location, ki-67 index, histological grade, and lymph node metastasis). Then, the radiomics signature with the best diagnostic performance (Rad score) was further combined with significant clinical risk factors to develop a clinicoradiomic model (nomogram) using multivariate logistic regression. The discriminative power of the constructed models were evaluated by AUC, DeLong test, calibration curve, and decision curve analysis (DCA). RESULTS: 70 (32.71%) of the enrolled 214 cases were HER2-positive, while 144 (67.29%) were HER2-negative. Eleven best radiomics features were retained to develop 6 radiomcis classifiers in which RF classifier showed the highest AUC of 0.887 (95%CI: 0.827-0.947) in the training set and acheived the AUC of 0.840 (95%CI: 0.758-0.922) in the validation set. A nomogram that incorporated the Rad score with two selected clinical factors (Ki-67 index and histological grade) was constructed and yielded better discrimination compared with Rad score (p = 0.374, Delong test), with an AUC of 0.945 (95%CI: 0.904-0.987) in the training set and 0.868 (95%CI: 0.789-0.948; p = 0.123) in the validation set. Moreover, calibration with the p-value of 0.732 using Hosmer-Lemeshow test demonstrated good agreement, and the DCA verified the benefits of the nomogram. CONCLUSION: Post largescale validation, the clinicoradiomic nomogram may have the potential to be used as a non-invasive tool for determination of HER2 expression status in clinical HER2-targeted therapy prediction.

BACKGROUND: EphrinA (EFNA) are Eph receptor ligands that regulate various disease processes. Nonetheless, the expression characteristics of EFNAs in pan-cancer, their relationship with tumor immune microenvironment, and prognostic value landscape remain unknown. METHODS: A comprehensive landscape of EFNAs was created using various statistical data extracted from 33 cancers. Subsequently, we identified differential expression, genetic variations, potential function enrichment, tumor immune-related analysis, and drug sensitivity. Further, we investigated the clinical features and diagnostic prognostic value of EFNAs. RT-qPCR, western blot and immunohistochemistry (IHC) were used to validate the expression level and significant clinical value of EFNA5 in lung adenocarcinoma cell lines and tissues. RESULTS: EFNAs were highly mutated in various cancers. Genomic and epigenetic alterations of EFNAs were observed in various tumors, where an oncogenic mutation in specific cancer types potentially affected EFNA expression. Moreover, tumor-derived EFNAs were significantly related to the tumor immune microenvironment, suggesting that they are promising therapeutic targets. The majority of EFNA family genes were significantly linked to patient prognosis. Eventually, EFNA5 was an independent prognostic factor in lung adenocarcinoma. CONCLUSION: In summary, EFNAs are crucial in tumor immune regulation, and EFNA5 is a prognostic marker in lung adenocarcinoma. Our findings provide new insights into EFNAs from a bioinformatics standpoint and highlight the significance of EFNAs in cancer diagnosis and treatment.

BACKGROUND: Evidences have indicated that miR-26a-5p regulates the malignant properties of various tumor cells. However, the influences of miR-26a-5p on proliferation, apoptosis and invasion are still vague in the cervical cancer (CC) cells. METHODS: The miRNA microarray and real-time quantitative PCR (RT-qPCR) analysis were utilized to detect the expression of miR-26a-5p in the patients with CC. Kaplan-Meier plotter was performed to evaluate the overall survival (OS) of the patients with CC. The CCK-8, flow cytometry, transwell and wound healing analyses were respectively used to analyze proliferation, migration and invasion in the CC cells. RT-qPCR, western blot and IHC analysis were executed to measure the expression of hydroxysteroid dehydrogenase like-2 (HSDL2) in the patients with CC. Bioinformatics and luciferase reporter assay were carried out to verify the relationship of miR-26a-5p and HSDL2. RESULTS: The expression of miR-26a-5p was downregulated and low expression of miR-26a-5p indicated a poor OS in patients with CC. Overexpression of miR-26a-5p significantly inhibited proliferation, migration and invasion, accelerated apoptosis in the Hela and C33A cells. The expression of HSDL2 was upregulated, and negatively correlated with miR-26a-5p in the patients with CC. HSDL2 was directly targeted by miR-26a-5p and rescue experiments displayed that HSDL2 partially abolished proliferation, apoptosis, migration, and invasion induced by miR-26a-5p in CC cells. CONCLUSIONS: MiR-26a-5p alleviated progression of CC by suppressing proliferation, migration and invasion, promoting apoptosis through downregulating HSDL2.

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data-driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions.We report the application of a bioinformatics-based approach probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing clinical data available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival.Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents.In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.

Lycorine (Lyc) is a natural alkaloid derived from medicinal plants of the Amaryllidaceae family. Lyc has been reported to inhibit the recurrence and metastasis of different kinds of tumors. However, Lyc's effect on angiogenesis and its specific mechanism are still not clear. This study was designed to test the antiangiogenesis effect of Lyc and to explore the possible mechanisms. We performed cell experiments to confirm Lyc's inhibitory effect on angiogenesis and employed sunitinib as a positive control. Moreover, the synergistic effect of Lyc and sunitinib was also explored. Next, we conducted bioinformatics analyses to predict the potential targets of Lyc and verified them by western blotting and immunofluorescence. Molecular docking, kinase activity assays, Biacore assays and cellular thermal shift assays (CETSAs) were applied to elucidate the mechanism by which Lyc inhibited target activity. Lyc inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Employing bioinformatics, we found that Lyc's target was PDGFRα and that Lyc attenuated PDGFRα phosphorylation. We also found that Lyc inhibited PDGFRα activation by docking to it to restrain its activity. Additionally, Lyc significantly inhibited PDGF-AA-induced angiogenesis. This study provides new insights into the molecular functions of Lyc and indicates its potential as a therapeutic agent for tumor angiogenesis.

OBJECTIVE: We studied the prognosis and clinicopathological background of lung adenocarcinoma predominance among patients who underwent lobectomy using data from the Japanese Joint Committee of Lung Cancer Registry. METHODS: Two thousand eight hundred sixty-three cases were extracted. Recurrence free survival (RFS) rates, overall survival (OS) rates and clinicopathological factors and epidermal growth factor receptor (EGFR) mutation status were examined. RESULTS: Median follow-up period was 65.5 months. Adenocarcinoma predominance was sub-grouped according to OS and RFS rate. In pathological stage I, 5-year RFS and OS rates were respectively 92.2% and 95.8% in group A (adenocarcinoma-in-situ + minimally invasive adenocarcinoma), 89.3% and 92.1% in group B (lepidic), 79.2% and 89.7% in group C (papillary + acinar + variants) and 69.0% and 79.0% in group D (solid + micropapillary). In pathological stage II + IIIA, they were, 43.6% and 72.4% in B, 39.5% and 66.9% in C and 31.0% and 53.7% in D. Group D showed significant worst outcome both in stage I and II + IIIA. Up stage rate from clinical stage I to pathological stage II + IIIA was 0.0%, 3.7%, 15.9% and 33.3%. The frequency of lymph-vessel, vascular, pleura invasion and positive EGFR mutation were 0.0%, 0.0%, 0.0% and 57.1% in group A, 15.6%, 10.0%, 12.1% and 55.1% in B, 36.6%, 31.8%, 29.7% and 44.9% in C, 50.2%, 57.8%, 38.9% and 21.3% in D. In group D, lymph-vessel, vascular and pleura invasion were most, EGFR mutation was least frequent not only in pathological stage I but also stage II + IIIA. In multivariate analysis, age, pathological stage, vascular invasion, and group D were independent factors affected RFS and OS. CONCLUSION: Limited to lobectomy cases, solid + micropapillary was independent prognostic factor both in early and locally advanced stage. Its malignant degree was related to the frequency of pathological invasive factors and EGFR mutation status.

BACKGROUND: Inflammatory indices and tumor-infiltrating lymphocytes (TILs) have prognostic value in many cancer types. This study aimed to assess the prognostic value of inflammatory indices and evaluate their correlation with survival and presence of TILs in patients with colorectal liver metastasis (CRLM). METHODS: Medical records of 117 patients who underwent hepatectomy for CRLM were retrospectively reviewed. We calculated inflammatory indices comprising the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, C-reactive protein/albumin ratio (CAR), and Glasgow prognostic score (GPS). Furthermore, we evaluated the relationship between these ratios and the GPS and survival rates and immunohistochemical results of tumor-infiltrating CD3+, CD8+, and Foxp3+ lymphocytes. RESULTS: The patients with low CAR values and low GPS had significantly better overall survival as per the log-rank test (p = 0.025 and p = 0.012, respectively). According to the multivariate analysis using the Cox proportional hazard model, the CAR (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.99; p = 0.048) and GPS (HR, 0.40; 95% CI, 0.19-0.83; p = 0.013) were independent prognostic factors. Additionally, Foxp3+ lymphocytes were more common in samples from the patients with a low CAR (p = 0.041). Moreover, the number of CD3+ TILs was significantly higher in the patients with a low GPS (p = 0.015). CONCLUSIONS: The CAR and GPS are simple, inexpensive, and objective markers associated with predicting survival in patients with CRLM. Moreover, they can predict the presence of Foxp3+ and CD3+ lymphocytes in the invasive margin of a tumor. TRIAL REGISTRATION: Retrospectively registered. https://www.kurume-u.ac.jp/uploaded/attachment/14282.pdf .

BACKGROUND: Most recent laboratory studies have suggested a promising role of vitamin D and its analogs as novel chemotherapeutic agents for cancer treatment. However, epidemiological evidence, especially regarding the effects of vitamin D on gastric cancer is still inconsistent. OBJECTIVES: Our research aimed to evaluate the associations between vitamin D intake and the risk of developing gastric cancer through a case-control study in North Vietnam. METHODS: We accessed databases of the previous completed case-control studies to derive 1182 incident gastric cancer cases and 2995 hospital controls selected from hospitals in Hanoi from 2003 to 2019. Vitamin D intake was computed by multiplying the food frequency intake with nutrient content based on the Viet Nam Food Composition Tables. Data were collected through face-to-face interviews by trained interviewers using the validated semi-quantitative food frequency and demographic lifestyle questionnaires. The odds ratio and 95% confidence interval (OR and 95%CI) were estimated using unconditional logistic regression analysis. RESULTS: We observed a continual decline in gastric cancer risk according to the level-up of vitamin D intake in both genders, men, and women [Fifth vs. bottom quintile, OR, 95%CI: 0.68 (0.53, 0.86), OR, 95%CI: 0.72 (0.53, 0.97), OR, 95%CI: 0.58 (0.38, 0.89), respectively. Per increment quintile, the statistically significant decreased risk was seen by 7% in men and 13% in women. The significant inverse association between vitamin D intake remained in the subgroups of ever and never tobacco smoking; negative and positive H. pylori infection. CONCLUSION: The findings suggested that sufficient vitamin D intake was associated with a lower risk of Gastric Cancer in the Vietnamese population.

BACKGROUND: Despite benefits of endocrine therapy (ET) for patients with hormone-receptor (HR)-positive breast cancer, many patients do not initiate or discontinue ET against recommendations. METHODS: We identified variables associated with ET initiation and continuation, analyzing pooled data from two longitudinal studies at a National Cancer Institute comprehensive cancer center in St. Louis, Missouri. The sample included 533 women with newly diagnosed, non-metastatic, HR-positive breast cancer who completed interviews at enrollment and 6, 12, and 24 months after definitive surgical treatment. Logistic regression models estimated the adjusted odds ratio and 95% confidence interval (aOR [95% CI]) for each of self-reported ET initiation by the 12-month interview and continuation for ≥12 months by the 24-month interview in association with self-reported diabetes, elevated depressed mood, menopausal-symptom severity and obesity, adjusting for race, age, insurance status, chemotherapy, and radiation therapy. RESULTS: Overall, 81.4% (434/533) of patients initiated ET, and 86.5% (371/429) continued ET ≥12 months. Patients with diabetes had lower odds of initiating ET (0.50 [0.27-0.91]). Patients reporting greater menopausal-symptom severity had lower odds of continuing ET (0.72 [0.53-0.99]). CONCLUSION: Efforts to increase ET initiation among patients with diabetes and better manage severe menopausal symptoms among ET users might promote ET continuation. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov : #NCT00929084.