Hereditary Cancer Clinics Improve Adherence to NCCN Germline Testing Guidelines for Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). METHODS: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. RESULTS: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]). CONCLUSIONS: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVES: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation. METHODS: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis. RESULTS: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001). CONCLUSIONS: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Clinical Outcomes in Patients With Krukenberg Tumors From Colorectal Cancer.

INTRODUCTION: Ovarian metastases from gastrointestinal cancers such as colorectal cancer, also known as Krukenberg tumors (KTs), present unique challenges in management due to diagnostic uncertainty, decreased responsiveness to systemic therapies compared to other sites of metastasis, and associated debilitating symptomatology. Thus, we sought to characterize our institutional outcomes in metastatic colorectal cancer (mCRC) patients with KTs. METHODS: A retrospective single-institution study was performed identifying adult, female patients from 2012 to 2021 with a diagnosis of mCRC. Patient demographics and clinicopathologic characteristics were collected and analyzed. Descriptive statistics, univariate and multivariable analyses, and Kaplan-Meier survival analyses were performed. RESULTS: Of 235 mCRC patients, 45 (19.1%) had KTs, 41 (91.1%) of whom had KTs in conjunction with other metastatic sites. Other initial sites of metastasis included the liver (n = 93, 39.6%), lung (n = 28, 11.9%), and peritoneum (n = 18, 7.7%). In the KT cohort, the median age was 48 y, 53.3% were non-Hispanic White, 100% had microsatellite stable tumors, 33.3% had Kristen Rat Sarcoma Virus (KRAS) mutations, and 6.7% had V-raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations. Fifty five point six percent of KT patients underwent cytoreductive surgery (CRS), 24.4% underwent palliative debulking, and 20% underwent no surgical intervention. Reasons for not undergoing CRS were disease-related (n = 14, 70%), due to poor performance status (n = 1, 5%), or both (n = 5, 25%). Five-year overall survival was 48.2% in KT patients who underwent CRS. Poor tumor grade was an independent predictor of mortality (hazard ratio 10.69, 95% confidence interval 1.20-95.47, P = 0.03). CONCLUSIONS: Almost 90% of our patient cohort with KTs from mCRC experience additional sites of metastasis. Around half of KT patients who underwent CRS were alive at 5 y.

Attitudes of physicians and patients toward immediate and intraoperative chemotherapy treatment in colon cancer.

INTRODUCTION: We have shown in a Phase I trial that immediate adjuvant chemotherapy (IAC) during surgical resection and immediately postoperative is safe and feasible in patients with colon cancer (CC). IAC avoids delays in adjuvant treatment and has the potential to improve survival and quality of life. We aim to determine patients and providers attitudes toward this novel multidisciplinary treatment approach. METHODS: Two web-based surveys were administered to newly diagnosed CC patients, survivors, surgeons and oncologists. Surveys assessed treatment preferences and perceived barriers to IAC. Chi-square tests were conducted to compare differences between patients' and providers' responses. RESULTS: Responses were collected from 35 patients and 40 providers. Patients were more willing to: (1) proceed with IAC to finish treatment earlier thus possibly improving quality of life (p = 0.001); (2) proceed with IAC despite potential side effects (p < 0.001); and (3) proceed with a dose of intraoperative chemotherapy even if on final pathology, may not have been needed (p = 0.002). Patients were more likely to indicate no barriers to collaborative care (p = 0.001) while providers were more likely to cite that it is time consuming, thus a barrier to participation (p = 0.001), has scheduling challenges (p = 0.001), and physicians are not available to participate (p = 0.003). CONCLUSIONS: We observed a discordance between what providers and patients value in perioperative and adjuvant CC treatment. Patients are willing to accept IAC despite potential side effects and without survival benefit, highlighting the importance of understanding patient preference.

Rural-Urban Disparities in Colorectal Cancer Screening, Diagnosis, Treatment, and Survivorship Care: A Systematic Review and Meta-Analysis.

BACKGROUND: Rural residents have a higher prevalence of colorectal cancer (CRC) mortality compared to urban individuals. Policies have been aimed at improving access to CRC screening to reduce these outcomes. However, little attention has been paid to other determinants of CRC-related outcomes, such as stage at diagnosis, treatment, or survivorship care. The main objective of this analysis was to evaluate literature describing differences in CRC screening, stage at diagnosis, treatment, and survivorship care between rural and urban individuals. MATERIALS AND METHODS: We conducted a systematic review of electronic databases using a combination of MeSH and free-text search terms related to CRC screening, stage at diagnosis, treatment, survivorship care, and rurality. We identified 921 studies, of which 39 were included. We assessed methodological quality using the ROBINS-E tool and summarized findings descriptively. A meta-analysis was performed of studies evaluating CRC screening using a random-effects model. RESULTS: Seventeen studies reported disparities between urban and rural populations in CRC screening, 12 on treatment disparities, and 8 on staging disparities. We found that rural individuals were significantly less likely to report any type of screening at any time period (pooled odds ratio = 0.81, 95% CI, 0.76-0.86). Results were inconclusive for disparities in staging at diagnosis and treatment. One study reported a lower likelihood of use of CRC survivorship care for rural individuals compared to urban individuals. CONCLUSION: There remains an urgent need to evaluate and address CRC disparities in rural areas. Investigators should focus future work on assessing the quality of staging at diagnosis, treatment, and survivorship care in rural areas.

A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil in Metastatic Colorectal Adenocarcinoma.

INTRODUCTION: This study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: Single institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed. RESULTS: Fifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%. CONCLUSION: The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC. CLINICALTRIALS: GOV: NCT04868773.

Disparities in Receipt of National Comprehensive Cancer Network Guideline-Adherent Care and Outcomes among Women with Triple-Negative Breast Cancer by Race/Ethnicity, Socioeconomic Status, and Insurance Type.

BACKGROUND: The National Comprehensive Cancer Network guidelines were designed to improve patient outcomes. Here, we examine factors that may contribute to outcomes and guideline adherence in patients with triple-negative breast cancer. METHODS: This was a retrospective cohort study of women with triple-negative breast cancer using the California Cancer Registry. Adherent treatment was defined as the receipt of a combination of surgery, lymph node assessment, adjuvant radiation, and/or chemotherapy. A multivariable logistic regression was used to determine the effects of independent variables on adherence to the NCCN guidelines. Disease-specific survival was calculated using Cox regression analysis. RESULTS: A total of 16,858 women were analyzed. Black and Hispanic patients were less likely to receive guideline-adherent care (OR 0.82, 95%CI 0.73-0.92 and OR 0.87, 95%CI 0.79-0.95, respectively) compared to White patients. Hazard ratios adjusted for adherent care showed that Black patients had increased disease-specific mortality (HR 1.28, 95%CI 1.16-1.42, p < 0.0001) compared to White patients. CONCLUSIONS: A significant majority of breast cancer patients in California continue to receive non-guideline-adherent care. Non-Hispanic Black patients and patients from lower SES quintile groups were less likely to receive guideline-adherent care. Patients with non-adherent care had worse disease-specific survival compared to recipients of NCCN guideline-adherent care.

NCI Rectal-Anal Task Force consensus recommendations for design of clinical trials in rectal cancer.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients.

After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

Clinical implications of conflicting variant interpretations in the cancer genetics clinic.

PURPOSE: The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants. METHODS: Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict. RESULTS: Fifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were used for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification. CONCLUSION: Our findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.

Population-Based Analysis of National Comprehensive Cancer Network (NCCN) Guideline Adherence for Patients with Anal Squamous Cell Carcinoma in California.

PURPOSE: We analyzed adherence to the National Comprehensive Cancer Network treatment guidelines for anal squamous cell carcinoma in California and the associated impacts on survival. METHODS: This was a retrospective study of patients in the California Cancer Registry aged 18 to 79 years with recent diagnoses of anal squamous cell carcinoma. Predefined criteria were used to determine adherence. Adjusted odds ratios and 95% confidence intervals were estimated for those receiving adherent care. Disease-specific survival (DSS) and overall survival (OS) were examined with a Cox proportional hazards model. RESULTS: 4740 patients were analyzed. Female sex was positively associated with adherent care. Medicaid status and low socioeconomic status were negatively associated with adherent care. Non-adherent care was associated with worse OS (Adjusted HR 1.87, 95% CI = 1.66, 2.12, p < 0.0001). DSS was worse in patients receiving non-adherent care (Adjusted HR 1.96, 95% CI = 1.56, 2.46, p < 0.0001). Female sex was associated with improved DSS and OS. Black race, Medicare/Medicaid, and low socioeconomic status were associated with worse OS. CONCLUSIONS: Male patients, those with Medicaid insurance, or those with low socioeconomic status are less likely to receive adherent care. Adherent care was associated with improved DSS and OS in anal carcinoma patients.

Differential Effects of Race, Socioeconomic Status, and Insurance on Disease-Specific Survival in Rectal Cancer.

BACKGROUND: National Comprehensive Cancer Network guideline adherence improves cancer outcomes. In rectal cancer, guideline adherence is distributed differently by race/ethnicity, socioeconomic status, and insurance. OBJECTIVE: This study aimed to determine the independent effects of race/ethnicity, socioeconomic status, and insurance status on rectal cancer survival after accounting for differences in guideline adherence. DESIGN: This was a retrospective study. SETTINGS: The study was conducted using the California Cancer Registry. PATIENTS: This study included patients aged 18 to 79 years diagnosed with rectal adenocarcinoma between January 1, 2004, and December 31, 2017, with follow-up through November 30, 2018. Investigators determined whether patients received guideline-adherent care. MAIN OUTCOME MEASURES: ORs and 95% CIs were used for logistic regression to analyze patients receiving guideline-adherent care. Disease-specific survival analysis was calculated using Cox regression models. RESULTS: A total of 30,118 patients were examined. Factors associated with higher odds of guideline adherence included Asian and Hispanic race/ethnicity, managed care insurance, and high socioeconomic status. Asians (HR, 0.80; 95% CI, 0.72-0.88; p < 0.001) and Hispanics (HR, 0.91; 95% CI, 0.83-0.99; p = 0.0279) had better disease-specific survival in the nonadherent group. Race/ethnicity were not factors associated with disease-specific survival in the guideline adherent group. Medicaid disease-specific survival was worse in both the nonadherent group (HR, 1.56; 95% CI, 1.40-1.73; p < 0.0001) and the guideline-adherent group (HR, 1.18; 95% CI, 1.08-1.30; p = 0.0005). Disease-specific survival of the lowest socioeconomic status was worse in both the nonadherent group (HR, 1.42; 95% CI, 1.27-1.59) and the guideline-adherent group (HR, 1.20; 95% CI, 1.08-1.34). LIMITATIONS: Limitations included unmeasured confounders and the retrospective nature of the review. CONCLUSIONS: Race, socioeconomic status, and insurance are associated with guideline adherence in rectal cancer. Race/ethnicity was not associated with differences in disease-specific survival in the guideline-adherent group. Medicaid and lowest socioeconomic status had worse disease-specific survival in both the guideline nonadherent group and the guideline-adherent group. See Video Abstract at http://links.lww.com/DCR/B954 . EFECTOS DIFERENCIALES DE LA RAZA, EL NIVEL SOCIOECONMICO COBERTURA SOBRE LA SUPERVIVENCIA ESPECFICA DE LA ENFERMEDAD EN EL CNCER DE RECTO: ANTECEDENTES: El cumplimiento de las guías de la National Comprehensive Cancer Network mejora los resultados del cáncer. En el cáncer de recto, el cumplimiento de las guías se distribuye de manera diferente según la raza/origen étnico, nivel socioeconómico y el cobertura médica.OBJETIVO: Determinar los efectos independientes de la raza/origen étnico, el nivel socioeconómico y el estado de cobertura médica en la supervivencia del cáncer de recto después de tener en cuenta las diferencias en el cumplimiento de las guías.DISEÑO: Este fue un estudio retrospectivo.ENTORNO CLINICO: El estudio se realizó utilizando el Registro de Cáncer de California.PACIENTES: Pacientes de 18 a 79 años diagnosticados con adenocarcinoma rectal entre el 1 de enero de 2004 y el 31 de diciembre de 2017 con seguimiento hasta el 30 de noviembre de 2018. Los investigadores determinaron si los pacientes recibieron atención siguiendo las guías.PRINCIPALES MEDIDAS DE RESULTADO: Se utilizaron razones de probabilidad e intervalos de confianza del 95 % para la regresión logística para analizar a los pacientes que recibían atención con adherencia a las guías. El análisis de supervivencia específico de la enfermedad se calculó utilizando modelos de regresión de Cox.RESULTADOS: Se analizaron un total de 30.118 pacientes. Los factores asociados con mayores probabilidades de cumplimiento de las guías incluyeron raza/etnicidad asiática e hispana, seguro de atención administrada y nivel socioeconómico alto. Los asiáticos e hispanos tuvieron una mejor supervivencia específica de la enfermedad en el grupo no adherente HR 0,80 (95 % CI 0,72 - 0,88, p < 0,001) y HR 0,91 (95 % CI 0,83 - 0,99, p = 0,0279). La raza o el origen étnico no fueron factores asociados con la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. La supervivencia específica de la enfermedad de Medicaid fue peor tanto en el grupo no adherente HR 1,56 (IC del 95 % 1,40 - 1,73, p < 0,0001) como en el grupo adherente a las guías HR 1,18 (IC del 95 % 1,08 - 1,30, p = 0,0005). La supervivencia específica de la enfermedad del nivel socioeconómico más bajo fue peor tanto en el grupo no adherente HR 1,42 (IC del 95 %: 1,27 a 1,59) como en el grupo adherente a las guías HR 1,20 (IC del 95 %: 1,08 a 1,34).LIMITACIONES: Las limitaciones incluyeron factores de confusión no medidos y la naturaleza retrospectiva de la revisión.CONCLUSIONES: La raza, el nivel socioeconómico y cobertura médica están asociados con la adherencia a las guías en el cáncer de recto. La raza/etnicidad no se asoció con diferencias en la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. Medicaid y el nivel socioeconómico más bajo tuvieron peor supervivencia específica de la enfermedad tanto en el grupo que no cumplió con las guías como en los grupos que cumplieron. Consulte Video Resumen en http://links.lww.com/DCR/B954 . (Traducción- Dr. Francisco M. Abarca-Rendon).

Assessment of Attitudes Toward Initiation of Immediate Adjuvant Chemotherapy for Colon Cancer.

INTRODUCTION: Early initiation of chemotherapy after surgery for colon cancer has survival benefits. Immediate adjuvant chemotherapy (IAC) involves giving chemotherapy during surgical resection and immediately postoperatively. This novel approach has been shown to be safe, eliminating delays in adjuvant treatment that could increase the risk of micro-metastatic spread. The aim of this study was to assess the willingness of the general public to accept IAC. MATERIALS AND METHODS: Between March and April 2021, 800 telephone interviews were conducted with a sample of adult New York State residents. The Survey Research Institute of Cornell University conducted all surveys. Kruskal-Wallis, chi-squared, and Fisher's tests were conducted using R 4.0.2. RESULTS: Three scenarios were presented: (1) receiving IAC resulting in improved survival and quality of life, (2) finishing chemotherapy earlier without survival impact, and (3) finishing chemotherapy earlier but with possible side effects. Respondents with higher education were more likely to accept (1) & (2), males were more likely to accept (2) & (3), higher income respondents were more likely to accept (1) & (3), and those with more work hours were more likely to accept (2). Lastly, 16% responded they would be very or extremely likely, and 52% respondents would be somewhat likely or likely to accept intraoperative chemotherapy, even if it may not be necessary. CONCLUSIONS: Respondents were likely to accept IAC if offered. Given the known risk of delayed adjuvant chemotherapy (AC) in colon cancer, further research is warranted to determine the survival and quality of life (QOL) benefits of IAC.

A human vascularized microtumor model of patient-derived colorectal cancer recapitulates clinical disease.

Accurately modeling tumor biology and testing novel therapies on patient-derived cells is critically important to developing therapeutic regimens personalized to a patient's specific disease. The vascularized microtumor (VMT), or "tumor-on-a-chip," is a physiologic preclinical cancer model that incorporates key features of the native human tumor microenvironment within a transparent microfluidic platform, allowing rapid drug screening in vitro. Herein we optimize methods for generating patient-derived VMT (pVMT) using fresh colorectal cancer (CRC) biopsies and surgical resections to test drug sensitivities at the individual patient level. In response to standard chemotherapy and TGF-ßR1 inhibition, we observe heterogeneous responses between pVMT derived from 6 patient biopsies, with the pVMT recapitulating tumor growth, histological features, metabolic heterogeneity, and drug responses of actual CRC tumors. Our results suggest that a translational infrastructure providing rapid information from patient-derived tumor cells in the pVMT, as established in this study, will support efforts to improve patient outcomes.

BRCA-Mutated Pancreatic Cancer: From Discovery to Novel Treatment Paradigms.

The discovery of BRCA1 and BRCA2 in the 1990s revolutionized the way we research and treat breast, ovarian, and pancreatic cancers. In the case of pancreatic cancers, germline mutations occur in about 10-20% of patients, with mutations in BRCA1 and BRCA2 being the most common. BRCA genes are critical in DNA repair pathways, particularly in homologous recombination, which has a serious impact on genomic stability and can contribute to cancerous cell proliferation. However, BRCA1 also plays a fundamental role in cell cycle checkpoint control, ubiquitination, control of gene expression, and chromatin remodeling, while BRCA2 also plays a role in transcription and immune system response. Therefore, mutations in these genes lead to multiple defects in cells that may be utilized when treating cancer. BRCA mutations seem to confer a prognostic benefit with an improved overall survival due to differing underlying biology. These mutations also appear to be a predictive marker, with patients showing increased sensitivity to certain treatments, such as platinum chemotherapy and PARP inhibitors. Olaparib is currently indicated for maintenance therapy in metastatic PDAC after induction with platinum-based chemotherapy. Resistance has been found to these therapies, and with a 10.8% five-year OS, novel therapies are desperately needed.

Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body's own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.

Immediate Adjuvant Chemotherapy in Non-Metastatic Colon Cancer: Phase I Trial Evaluating a Novel Treatment Protocol.

BACKGROUND: The optimal timing of adjuvant chemotherapy (AC) in non-metastatic colon cancer is poorly defined. Delays in AC result in decreased survival. Effective cytotoxic treatments should be considered during the perioperative phase of care. The immediate adjuvant chemotherapy (IAC) concept intends to capitalize on the therapeutic benefits that can be achieved in the perioperative period. We aim to demonstrate that IAC is safe and tolerable. PATIENT AND METHODS: Microsatellite stable invasive adenocarcinomas were treated with intravenous Leucovorin 20 mg/m2 and single dose of 5-Flurouracil 400mg/m2 at the time of surgery. High-risk stage II and stage III received the first dose of standard AC at 14 days after surgery. Serial measurements of blood-based biomarkers were measured. Quality of life (QOL) was measured using EORTC QLQ-C30. RESULTS: Of the 20 patients recruited, 40% had final pathology of stage III, 40% stage II and 20% stage I. All patients received intra-operative chemotherapy with no associated morbidity. Median length of stay was 2 days (range of 2-4). There was no intraoperative morbidity with 5% (N = 1) grade 3 complication. AC was administered to 65% of patients. The median time to AC was 14 days (range 14-36). Overall quality of life and health scores were similar before surgery and at 30-day postoperatively (P < .05). CONCLUSIONS: A protocol based on IAC starting at the time of surgical resection was found to be safe and feasible with no adverse effects on surgical morbidity or quality of life. Further prospective studies are needed to explore the oncologic benefit of this novel systemic treatment approach.

Surgical Management of Gynecologic Cancers.

This article addresses the role of surgery in the management of gynecologic cancers with liver metastases. The authors review the short-term and long-term outcomes of aggressive resection through retrospective and randomized studies. Although the data supporting aggressive resection of liver metastasis are largely retrospective and case based, the randomized control data to address neoadjuvant versus chemotherapy have been widely criticized. Residual disease remains an important predictor for survival in ovarian cancer. If a patient cannot achieve near optimal cytoreduction, radical cytoreductive procedures, such as hepatic resection, should be considered for palliation only.

Changing Disparity of Gastric Cancer Incidence by Histological Types in US Race-Specific Populations.

BACKGROUND: The incidence pattern of gastric cancer by histological types across major race/ethnic groups is unknown. METHODS: Age-standardized rates from 1992-2016 by race/ethnicity were calculated using data from Surveillance, Epidemiology, and End Results Program (SEER). Annual percent changes (APCs) in rates and corresponding 95% confidence intervals (CIs) were calculated and pairwise comparison of rates between race/ethnic groups was performed using the Joinpoint Regression Program. Calendar periods of incidence rates of gastric cardia and non-cardia cancer by histological types across race/ethnicity groups were shown by figures. RESULTS: The White population has the highest incidence of gastric cardia adenocarcinoma and the incidence is keeping constant from 1992 through 2016 except the decreasing in the Asian population (AAPC = -1.4, 95%CI (-2.1, -0.8)). Although the incidence of non-cardia adenocarcinoma is decreasing in each group, the descending trend in the Asian population is the quickest (AAPC = -3.8, 95%CI (-4.0, -3.5)). Gastric carcinoids were observed to have statistically significant increasing trends in all race/ethnicity groups, especially in Hispanic women from 0.4 per 100,000 to 1.6 per 100,000 persons. The incidence of gastrointestinal stromal tumors (GISTs) is rising, with Non-Hispanic blacks having the highest incidence. CONCLUSION: This study demonstrated disparities in the incidence of gastric cancer by histological types among different race/ethnic groups. Further investigations are warranted to understand the changing incidence patterns by race/ethnicity.

Increased incidence of early onset colorectal adenocarcinoma is accompanied by an increased incidence of rectal neuroendocrine tumors.

Recent studies have reported an increasing incidence of early onset colorectal cancer (CRC). Few studies compared the changing incidence of CRC by the major histological type, adenocarcinoma and neuroendocrine tumors (NETs). Using data from the Surveillance, Epidemiology, and End Results Program (SEER), we identified CRC from 1992 to 2015 with site and histological codes. Standardized incidence rates of CRC by anatomical locations (proximal, distal and rectal colon) and histological types (adenocarcinoma, NETs and others) were calculated over calendar years. Annual percent changes (APC) and joint-point regression were further computed. A significant increase of cancers in the distal colon and rectum was observed in young populations (20-44 and 45-54 years) but not in the proximal colon. Further analyses found that the highest rise of rectal NETs was in the 45-54 years which contributed 53.47% to the total increase of rectal cancer. The APCs for NETs in the rectum were 2.9 (95% CI: -0.1, 6.0) and 6.1 (95% CI: 3.8-8.4) for 20-44 years or 45-54 years respectively. The increase of NETs in the rectum was still significant in the older than 55 years (APC=3.7, 95% CI: 2.8-4.7), although the total CRC in this group was decreasing. Incidence of NETs in the distal colon is not apparently changing. The increase of CRC incidence among young populations (age < 55) is mainly due to the increased incidence in the rectum and distal colon. Moreover, the increase of early onset cancer in the rectum could be ascribed to increased incidence of adenocarcinoma and NETs.