The Impact of Race on Pancreatic Cancer Treatment and Survival in the Nationwide Veterans Affairs Healthcare System.

OBJECTIVES: Among patients with pancreatic cancer, studies show racial disparities at multiple steps of the cancer care pathway. Access to healthcare is a frequently cited cause of these disparities. It remains unclear if racial disparities exist in an integrated, equal access public system such as the Veterans Affairs healthcare system. METHODS: We identified all patients diagnosed with pancreatic adenocarcinoma in the national Veterans Affairs Central Cancer Registry from January 2010 to December 2018. We examined the independent association between race and 3 endpoints: stage at diagnosis, receipt of treatment, and survival while adjusting for sociodemographic factors and medical comorbidities. RESULTS: We identified 8529 patients with pancreatic adenocarcinoma, of whom 79.5% were White and 20.5% were Black. Black patients were 19% more likely to have late-stage disease and 25% less likely to undergo surgical resection. Black patients had 13% higher mortality risk compared with White patients after adjusting for sociodemographic characteristics and medical comorbidities. This difference in mortality was no longer statistically significant after additionally adjusting for cancer stage and receipt of potentially curative treatment. CONCLUSIONS: Equal access to healthcare might have reduced but failed to eliminate disparities. Dedicated efforts are needed to understand reasons underlying these disparities in an attempt to close these persistent gaps.

Disparities in Surgical Treatment of Resectable Pancreatic Adenocarcinoma at Minority Serving Hospitals.

INTRODUCTION: Minority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. METHODS: Patients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. RESULTS: Of the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). CONCLUSIONS: Patients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Reporting of Circumferential Resection Margin in Rectal Cancer Surgery.

Importance: Circumferential resection margin (CRM) in rectal cancer surgery is a major prognostic indicator associated with local recurrence and overall survival. Facility rates of CRM positivity have recently been established as a new quality measure by the Commission on Cancer (CoC); however, the completeness of CRM status reporting is not well characterized. Objective: To describe the changes in CRM reporting and factors associated with low rates of reporting. Design, Setting, and Participants: A retrospective cohort study was conducted using data from the National Cancer Database between January 2010 and December 2019. Data were analyzed between October 1, 2021, and February 1, 2022. Data from the National Cancer Database included patients diagnosed with nonmetastatic rectal adenocarcinoma receiving surgical treatment at CoC-accredited facilities throughout the US. Exposures: Patient, tumor, and facility-level factors. Facilities were divided by surgical volume, safety-net status, and CoC facility type. Main Outcomes and Measures: Circumferential resection margin missingness rates. Results: A total of 110 571 patients (59.3% men) with rectal adenocarcinoma who underwent curative-intent surgery at 1307 CoC-accredited hospitals were included for analysis. Reporting of CRM improved over the study period, with a mean (SE) missing 12.0% (0.32%) decreased from 16.3% (0.36%). Academic facilities had a higher missingness than other facility types (14.3% vs 10.5%-12.7%; P < .001). Mean (SE) rates of missingness were similar between hospitals of varying volume (lowest quartile: 12.2% [0.93%] vs highest quartile: 12.4% [0.53%]; P = .96). Cases in which fewer than 12 lymph nodes were removed had higher rates of missingness (18.1% vs 11.4%; P < .001). Increased odds of CRM missingness were noted with T category (odds ratio [OR], 1.50; 95% CI, 1.35-1.65) and N category (OR, 2.00; 95% CI, 1.82-2.20). Black race was associated with missingness (OR, 1.13; 95% CI, 1.06-1.14). Conclusion and Relevance: Although CRM positivity reporting has improved over the last decade, the findings of this study suggest there is substantial room for improvement as it becomes a quality standard. Missingness appears to be associated with poor performance on other quality metrics and facility type. This measure appears to be ideal for targeted institution-level feedback to improve quality of care nationally.

Prognostic value of pre-therapeutic FDG-PET radiomic analysis in gastro-esophageal junction cancer.

The main aim of this study was to evaluate the prognostic value of radiomic approach in pre-therapeutic 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET/CT) in a large cohort of patients with gastro-esophageal junction cancer (GEJC). This was a retrospective monocenter study including 97 consecutive patients with GEJC who underwent a pre-therapeutic FDG-PET and were followed up for 3 years. Standard first-order radiomic PET indices including SUVmax, SUVmean, SUVpeak, MTV and TLG and 32 textural features (TFs) were calculated using LIFEx software on PET imaging. Prognostic significance of these parameters was assessed in univariate and multivariate analysis. Relapse-free survival (RFS) and overall survival (OS) were respectively chosen as primary and secondary endpoints. An internal validation cohort was used by randomly drawing one-third of included patients. The main characteristics of this cohort were: median age of 65 years [41-88], sex ratio H/F = 83/14, 81.5% of patients with a histopathology of adenocarcinoma and 43.3% with a stage IV disease. The median follow-up was 28.5 months [4.2-108.5]. Seventy-seven (79.4%) patients had locoregional or distant progression or recurrence and 71 (73.2%) died. In univariate analysis, SUVmean, Histogram-Entropy and 2 TFs (GLCM-Homogeneity and GLCM-Energy) were significantly correlated with RFS and OS, as well as 2 others TFs (GLRLM-LRE and GLRLM-GLNU) with OS only. In multivariate analysis, Histogram-Entropy remained an independent prognostic factor of both RFS and OS whereas SUVmean was an independent prognostic factor of OS only. These results were partially confirmed in our internal validation cohort of 33 patients. Our results suggest that radiomic approach reveals independent prognostic factors for survival in patients with GEJC.

Surgeon proficiency gain and survival after gastrectomy for gastric adenocarcinoma: A population-based cohort study.

OBJECTIVE: Quality of surgery is essential for survival in gastric adenocarcinoma, but studies examining surgeons' proficiency gain of gastrectomies are scarce. This study aimed to reveal potential proficiency gain curves for surgeons operating patients with gastric cancer. METHODS: Population-based cohort study of patients who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006 and 2015 with follow-up throughout 2020. Data were retrieved from national registries and medical records. Risk prediction models were used to calculate outcome probabilities, and risk-adjusted cumulative sum curves were plotted to assess differences (change points) between observed and expected outcomes. The main outcome was long-term (>3-5 years) all-cause mortality after surgery. Secondary outcomes were all-cause mortality within 30 days, 31-90 days, 91 days to 1 year and>1-3 years of surgery, resection margin status, and lymph node yield. RESULTS: The study included 261 surgeons and 1636 patients. The>3- to 5-year mortality was improved after 20 cases, and decreased from 12.4% before to 8.6% after this change point (p = 0.027). Change points were suggested, but not statistically significant, after 22 cases for 30-day mortality, 28 cases for 31- to 90-day mortality, 9 cases for 91-day to 1-year mortality, and 10 cases for>1- to 3-year all-cause mortality. There were statistically significant improvements in tumour-free resection margins after 28 cases (p < 0.005) and greater lymph node yield after 13 cases (p < 0.001). CONCLUSIONS: This study reveals proficiency gain curves regarding long-term survival, resection margin status, and lymph node yield in gastrectomy for gastric adenocarcinoma, and that at least 20 gastrectomies should be conducted with experienced support before doing these operations independently.

Patients with esophageal adenocarcinoma showed better prognosis than those with adenocarcinoma of the gastroesophageal junction.

OBJECTIVES: We followed The Cancer Genome Atlas (TCGA) grouping criteria and conducted a clinicopathological cohort study in a unique patient population to gain insight into the pathobiology of esophageal adenocarcinoma (EAC) and adenocarcinoma of the gastroesophageal junction (AGEJ). METHODS: We studied and statistically compared the clinicopathological and prognostic features of both cancers in 303 consecutive patients treated at the Veterans Affairs Boston Healthcare System over a 20-year period using uniform criteria and standardized routines. RESULTS: Over 99% of patients were white men with a mean age of 69.1 years and an average body mass index (BMI) of 28.0 kg/m2 . No significant differences were detected in age, gender, ethnicity, BMI, and history of tobacco abuse between the two groups. Compared to AGEJ patients, a significantly higher proportion of EAC patients had gastroesophageal reflux disease, long-segment Barrett's esophagus, common adenocarcinoma type, smaller tumor size, better differentiation, more stages I or II but fewer stages III or IV diseases, scarcer lymph node invasion, fewer distant metastases, and better overall, disease-free, and relapse-free survival. The 5-year overall survival rate was significantly higher in EAC patients than in AGEJ patients (41.3% vs 17.2%, P < 0.001). This improved survival among EAC patients remained significant after censoring all cases detected during endoscopic surveillance, suggesting different pathogenesis mechanisms between EAC and AGEJ. CONCLUSIONS: EAC patients showed significantly better outcomes than AGEJ patients. Our results require validation in other patient populations.

Weekday of gastrectomy and long-term survival in gastric adenocarcinoma.

BACKGROUND: Cancer surgery conducted late during the working week might decrease long-term survival for some tumours. Studies on how weekday of gastrectomy influences long-term survival following gastric cancer are few and show conflicting results, which prompted the present investigation. METHODS: This population-based cohort study included almost all patients who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006 and 2015, with follow-up throughout 2020. Associations between weekday of gastrectomy and 5-year all-cause mortality (main outcome) and 5-year disease-specific mortality (secondary outcome) were analysed using multivariable Cox regression. The hazard ratios (HR) with 95% confidence intervals (CI) were adjusted for age, sex, education, comorbidity, pathological tumour stage, tumour sub-location, neoadjuvant therapy, annual surgeon volume of gastrectomy, and calendar year. RESULTS: Among 1678 patients, surgery on Thursday-Friday was not associated with any statistically significantly increased risk of 5-year all-cause mortality (HR 1.05, 95% CI 0.91-1.22) or 5-year disease-specific mortality (HR 1.04, 95% CI 0.89-1.23) compared to Monday-Wednesday. No associations were found when each weekday was analysed separately, with point estimates close to 1.00 (range 0.98-1.00) Monday-Thursday, but increased for Friday (HR 1.22, 95% CI 0.89-1.68) when fewer patients underwent surgery (4% of all). Stratified analyses by age, comorbidity, tumour stage, neoadjuvant therapy, surgeon volume, and tumour sub-location did not reveal any associations between weekday of surgery on Thursday-Friday compared with Monday-Wednesday and risk of 5-year all-cause mortality. CONCLUSIONS: Weekday of gastrectomy might not influence the 5-year survival in patients with gastric adenocarcinoma.

Integrated bioinformatics analysis of microarray data from the GEO database to identify the candidate genes linked to poor prognosis in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality and remains a crucial factor endangering human health. OBJECTIVE: This study aimed to elucidate the potential treatment target and prognostic biomarker in patients with LUAD through a comprehensive bioinformatics analysis. METHODS: The three public microarray datasets of GSE118370, GSE116959, and GSE43767 were obtained from the GEO data resource. The DEGs were explored between LUAD and non-malignant samples using GEO2R online tool in GEO data resource. GO along with KEGG analysis of DEGs were examined using WebGestalt tool. The STRING web resource was employed to develop the PPI network of DEGs, whereas Cytoscape software was employed to perform module analysis. Finally, the mRNA, protein expression along with survival analysis of hub genes were explored via GEPIA, HPA along with Kaplan-Meier plotter web resource, respectively. RESULTS: Only 82 upregulated and 105 downregulated DEGs were found among the three datasets. Further, GO analysis illustrated that 187 DEGs were primary enriched in extracellular structure organization, tube development along with cell adhesion. The KEGG enrichments showed that these DEGs were primary linked to leukocyte transendothelial migration, vascular smooth muscle contraction along with ECM-receptor interaction. Among the 187 DEGs, the 10 hub genes (P4HB, SPP1, CP, GOLM1, COL1A1, MMP9, COL10A1, APOA1, COL4A6, and TIMP1) were identified. The mRNA along with protein levels of hub genes in LUAD tissues were further verified by Oncomine, UCSC Xena, GEPIA and HPA databases. Additionally, overall survival curves illustrated that LUAD patients with the higher levels of P4HB, SPP1, COL1A1, and MMP9 were dramatically linked to shorter overall survival. CONCLUSIONS: The current study identified DEGs candidate genes (P4HB, SPP1, COL1A1, and MMP9) and pathways in LUAD using bioinformatics analysis, which could enhance our understanding of pathogenesis along with underlying molecular events in LUAD, and these hub genes and pathways may help provide candidate treatment targets for LUAD.

A novel nomogram based on log odds of positive lymph nodes to predict survival for non-metastatic gallbladder adenocarcinoma after surgery.

The prognosis of non-metastatic gallbladder adenocarcinoma (NM-GBA) patients is affected by the status of metastatic lymph nodes. The purpose of this study was to explore the prognostic value of the log odds of positive lymph nodes (LODDS) and develop a novel nomogram to predict the overall survival in NM-GBA patients. A total of 1035 patients confirmed to have NM-GBA were selected from the Surveillance, Epidemiology, and End Results (SEER) database and further divided into training and validation cohorts. The discrimination and calibration of the nomogram were evaluated using the concordance index (C-index), the area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The net benefits and clinical utility of the nomogram were quantified and compared with those of the 8th edition American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system using decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). The risk stratifications of the nomogram and the TNM-staging system were compared. LODDS showed the highest accuracy in predicting OS for NM-GBA. The C-index (0.730 for the training cohort and 0.746 for the validation cohort) and the time-dependent AUC (> 0.7) indicated the satisfactory discriminative ability of the nomogram. The calibration plots showed a high degree of consistency. The DCA, NRI, and IDI indicated that the nomogram performed significantly better than the TNM-staging (P < 0.05). A novel LODDS-included nomogram was developed and validated to assist clinicians in evaluating the prognosis of NM-GBA patients.

External beam radiation therapy treatment factors prognostic of biochemical failure free survival: A multi-institutional retrospective study for prostate cancer.

BACKGROUND AND PURPOSE: The goal of this work is to identify specific treatment planning and delivery features that are prognostic of biochemical failure-free survival (BFFS) for prostate cancer patients treated with external beam radiotherapy (EBRT). MATERIALS AND METHODS: This study reviewed patients diagnosed with localized prostate adenocarcinoma between 2005 and 2016, and treated with EBRT on a Varian linear accelerator at one of the four cancer centers in Alberta, Canada. BFFS was calculated using the Kaplan-Meier estimator. Patient demographics, tumor characteristics, and EBRT treatment planning and delivery factors, were collected for each patient. The patient cohort was split into a training dataset with patients from two centers and a validation dataset with patients from another two centers. A random survival forest was used to identify features associated with BFFS. RESULTS: This study included 2827 patients with a median follow-up of 6.4 years. The BFFS for this cohort collectively was 84.9% at 5 years and 69.3% at 10 years. 2519 patients from two centers were used for model training and 308 patients from two different centers were used for model validation. The prognostic features were Gleason score, prostate-specific antigen (PSA) at diagnosis, clinical T stage, CTV D99, pelvic irradiation, IGRT frequency, and PTV V98. Variables including bladder volume, dose calculation algorithm, PTV D99, age at diagnosis, hip prosthesis, number of malignancies, fiducial marker usage, PTV volume, RT modality, PTV HI, rectal volume, hormone treatment, PTV D1cc, equivalent PTV margin, IGRT type, and EQD2_1.5 were unlikely to be prognostic. A random survival forest using only the seven prognostic variables was built. The Harrell's concordance index for the model was 0.65 for the whole training dataset, 0.62 for out-of-bag samples of the training dataset, and 0.62 for the validation dataset. CONCLUSION: EBRT features prognostic of BFFS were identified and a random survival forest was developed for predicting prostate cancer patients' BFFS after EBRT.

Extended Delay to Treatment for Stage III-IV Non-Small-Cell Lung Cancer and Survival: Balancing Risks During the COVID-19 Pandemic.

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, patients may encounter lung cancer care delays. Here, we sought to examine the impact of extended treatment delay for stage III-IV non-small-cell lung cancer on patient survival. MATERIALS AND METHODS: Using National Lung Screening Trial (NLST) and National Cancer Data Base (NCDB) data, Cox regression analysis with penalized smoothing splines was performed to examine the association between treatment delay and all-cause mortality for stage III-IV lung adenocarcinoma and squamous cell carcinoma. In the NCDB, propensity score-matched analysis was used to compare cumulative survival in patients who received "early" versus "delayed" treatment (ie, 0-30 vs. 90-120 days following diagnosis). RESULTS: Cox regression analysis of the NLST (n = 392) and NCDB (n = 275,198) cohorts showed a decrease in hazard ratio the longer treatment was delayed. In propensity score-matched analysis, no significant differences in survival were found between early and delayed treatment for patients with stage IIIA, IIIB (T3-4,N2,M0), IIIC, and IV (M1B-C) adenocarcinoma and patients with IIIA, IIIB, IIIC, and IV squamous cell carcinoma (all log-rank P > .05). For patients with stage IIIB (T1-2,N3,M0) and stage IV (M1A) adenocarcinoma, delayed treatment was associated with improved survival (log-rank P = .03, P = .02). The findings were consistent in sensitivity analysis accounting for wait time bias. CONCLUSION: In this national analysis, for patients with stage III-IV adenocarcinoma and squamous cell carcinoma, an extended treatment delay by 3 to 4 months was not associated with significantly decreased overall survival compared to prompt treatment. These findings can be used to guide decision-making during the ongoing COVID-19 pandemic.

The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates From GLOBOCAN 2020.

BACKGROUND & AIMS: The aim of this study was to provide an overview of the burden of esophageal cancer in 185 countries in 2020 and projections for the year 2040. METHODS: Estimates of esophageal cancer cases and deaths were extracted from the GLOBOCAN database for 2020. Age-standardized incidence and mortality rates were calculated overall, by sex, histologic subtype (adenocarcinoma [AC] and squamous cell carcinoma [SCC]), country, and level of human development for 185 countries. The predicted burden of incidence and mortality in 2040 was calculated based on global demographic projections. RESULTS: Globally, there were an estimated 604,100 new cases of, and 544,100 deaths from, esophageal cancer in 2020, corresponding to age-standardized incidence and mortality rates of 6.3 and 5.6 per 100,000, respectively. Most cases were SCCs (85% [512,500 cases]) and 14% (85,700 cases) were ACs. Incidence and mortality rates were 2- to 3-fold higher in male (9.3 and 8.2, respectively) compared with female (3.6 and 3.2, respectively) individuals. Global variations in incidence and mortality were observed across countries and world regions; the highest rates occurred in Eastern Asia and Southern and Eastern Africa and the lowest occurred in Western Africa and Central America regions. If rates remain stable, 957,000 new cases (141,300 AC cases and 806,000 SCC cases) and 880,000 deaths from esophageal cancer are expected in 2040. CONCLUSIONS: These updated estimates of the global burden of esophageal cancer represent an important baseline for setting priorities in policy making and developing and accelerating cancer control initiatives to reduce the current and projected burden. Although primary prevention remains key, screening and early detection represent important components of esophageal cancer control in high-risk populations.

Development and validation of a nomogram for prognosis of sinonasal adenocarcinoma (a nomogram for sinonasal adenocarcinoma).

BACKGROUND: The incidence of sinonasal adenocarcinoma is low, and there are few studies on survival and prognosis. Therefore, we aim to develop and validate a prognostic model for predicting the overall survival of sinonasal adenocarcinoma and provide guidance for clinical management. METHODS: Patients who were diagnosed as sinonasal adenocarcinoma through Surveillance, Epidemiology, and End Results database between 1975 and 2015 were randomly divided into a training group and validation group. Univariate, multivariate survival analysis was performed to screen independent survival factors. A nomogram was established to predict the overall survival rate of sinonasal adenocarcinoma. Receiver operating characteristic curve and calibration plot were performed to verify the discrimination and accuracy of the model. A decision curve analysis was performed to verify the clinical applicability of the model. RESULTS: A total of 423 patients with sinonasal adenocarcinoma were randomly divided into training group (n = 299) and verification group (n = 124). We established and verified the Nomo map including age, marriage, grade, surgery and tumour size. The c-index of Surveillance, Epidemiology, and End Results stage, T stage and this model are 0.635, 0.626 and 0.803, respectively. The survival rate of the high-risk group scored by this model was lower than that of the low-risk group (P < 0.001). Decision curve analysis shows that the model has advantages in predicting survival rates. CONCLUSION: Our model is considered to be a useful tool for predicting the overall survival of sinonasal adenocarcinoma, with good discrimination and clinical applicability. We hope that this model will help rhinologists to make clinical decisions and manage patients diagnosed with sinonasal adenocarcinoma.

Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

Establishment of prognostic models for adenocarcinoma of oesophagogastric junction patients with neoadjuvant chemoradiotherapy: a real-world study.

BACKGROUND: Multimodal therapies based on surgical resection have been recommended for the treatment of adenocarcinoma of the oesophagogastric junction (AEG). We aimed to evaluate prognostic factors in AEG patients receiving neoadjuvant chemoradiotherapy and to build predictive models. METHODS: T3 - T4N + M0 AEG patients with resectable Siewert type II/III tumours were enrolled in this study. All patients underwent neoadjuvant chemoradiation, followed by radical surgery or systemic therapy according to clinical response. Survival analysis was performed using the Kaplan-Meier method; multivariate analysis using the Cox proportional hazards method was also conducted. The Harrell concordance index (C-index) was used to test the prognostic value of models involving prognostic factors, and consistency between actual and predicted survival rates was evaluated by calibration curves. RESULTS: From February 2009 to February 2018, 79 patients were treated with neoadjuvant chemoradiotherapy; 60 patients of them underwent radical surgery. The R0 resection rate was 98.3%, and 46.7% of patients achieved a major pathologic response (MPR), namely, a residual tumour issue less than 10%. The 5-year overall survival (OS) rate was 63%, and the 5-year progression-free survival (PFS) rate was 48%. The incidence of grade 3 complications was 21.5%, and no grade 4 complications were reported. According to the results of univariate and multivariate analyses, we included the neutrophil-lymphocyte ratio (NLR), prognostic nutrition index (PNI), eosinophilic granulocyte (EOS) and postoperative pathologic stage in nomogram analysis to establish prediction models for OS and PFS; the C-index of each model was 0.814 and 0.722, respectively. Both the C-index and calibration curves generated to validate consistency between the actual and predicted survival indicated that the models were well calibrated and of good predictive value. CONCLUSIONS: AEG patients achieved favourable downstaging and pathologic response after neoadjuvant chemoradiation, with acceptable adverse effects. Inflammation-based and nutrition-related factors and postoperative pathologic stage had a significant influence on OS and PFS, and the predictive value was verified through prognostic models.

Bayesian Approach to Understand the Association Between Treatment Down-staging and Survival for Patients With Pancreatic Adenocarcinoma.

OBJECTIVE: To evaluate the association between staging concordance, treatment sequencing, and response to neoadjuvant therapy (NAT) on the survival of patients with pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: NAT is increasingly utilized in the management of patients with PDAC, but it is unclear whether its benefit is contingent on tumor down-staging. METHODS: This was a cohort study of stage I-III PDAC patients in the National Cancer Database (2006-2015) treated with upfront resection or NAT followed by surgery. We determined staging concordance using patients' clinical and pathological staging data. For NAT patients, we used Bayesian analysis to ascertain staging concordance accounting for down-staging. RESULTS: Among 16,597 patients treated at 979 hospitals, 13,982 had an upfront resection and 2,615 NAT followed by surgery. Overall survival (OS) at 5-years ranged from 26.0% (95% CI 24.9%-27.1%) among cT1-2N0 patients to 18.6% (17.9%-19.2%) among cT1-3N+ ones. Patients with cT3-4 or cN+ tumors had improved OS after NAT compared to upfront surgery (all p< 0.001), while there was no difference among patients with cT1-2N0 (P = 0.16) disease. Relative to accurately staged cT1-2-3N+ or cT4 patients treated with upfront surgery, NAT was associated with a lower risk of death [HR 0.46 (0.37-0.57) for N+; HR 0.56 (0.40-0.77) for T4 disease], even among those without tumor down-staging [HR 0.81 (0.73-0.90) for N+; HR 0.48 (0.39-0.60) for T4]. CONCLUSIONS: NAT is associated with improved survival for PDAC, particularly for patients with more advanced disease and regardless of down-staging. Consideration should be given to recommending NAT for all PDAC patients.

Somatic mutations in collagens are associated with a distinct tumor environment and overall survival in gastric cancer.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

The prognostic significance of apical lymph node metastasis in patients with high-risk stage III colon cancer.

The effect of apical lymph node (APN) metastasis on the prognosis of colon cancer is unknown. The present study investigated the impact of APN metastasis on the prognosis of the patients with high-risk stage III colon cancer. This retrospective multi-institutional study included patients with pathological high-risk stage III colon cancer who underwent surgery between April 2009 and December 2014. Clinicopathological factors were examined by univariate and multivariate analyses to clarify independent risk factors for overall survival (OS) and relapse-free survival (RFS). A total of 185 patients were collected. The 5-year OS rates of patients with and without APN metastasis were 35.0% and 72.1%, respectively (p = 0.0014). The 5-year RFS rates of patients with and without APN metastasis was 16.2% and 57.2%, respectively (p = 0.0002). The rate of distant metastasis in patients with APN metastasis was significantly higher than that in patients without APN metastasis (68.8% vs. 36.7%, p = 0.012). The univariate analysis revealed that the differentiation, lymph node ratio, and APN metastasis were significantly associated with 5-year OS, and the preoperative CEA and CA19-9 levels and APN metastasis were significantly associated with 5-year RFS. The multivariate analysis showed that APN metastasis was an independent risk factor for 5-year OS and RFS. APN metastasis may be independently associated with the prognosis of patients with high-risk Stage III colon cancer.