Underrepresentation of Racial and Ethnic Minorities in Metastatic Colorectal Carcinoma Clinical Trials within the United States.

OBJECTIVE: To investigate if underrepresentation of racial and ethnic minorities exists in metastatic colorectal carcinoma (CRC) clinical trials. SUMMARY BACKGROUND DATA: Representation of vulnerable subpopulations is essential for generalizability of clinical trials. Limited studies to date have investigated racial and ethnic representation of patients enrolled in clinical trials for metastatic CRC. METHODS: ClinicalTrials.gov was queried for metastatic CRC clinical trials in the United States from 2000-2020. Incidence data were extracted from the SEER Database. Enrollment fraction (EF) was defined as number of trial participants divided by U.S. incidence of metastatic CRC in each race, ethnicity, and gender. Representation Quotient (RQ) was defined as the proportion of trial participants divided by proportion of U.S. metastatic CRC incidence for each subgroup. RESULTS: 8084 patients from 135 clinical trials were analyzed. 49.6% of clinical trials reported race data and 34.8% reported ethnicity data. Compared to 2000-2009, 2010-2019 had increased representation data reporting for race (61.2% vs. 38.8%) and ethnicity (64.6% vs. 35.4%). Of trials with race data, White patients represented 77.0%, Black patients 6.6%, Asian/Pacific Islander (API) patients 16.1%, American Indian/Alaska Native (AIAN) patients 0.2%, and Hispanic patients 6.8%. Black patients (median RQ 0.54), API patients (median RQ 0.19), AIAN patients (median RQ 0.00), and Hispanic patients (median RQ 0.26) were underrepresented. Black patients had a higher degree of underrepresentation in clinical trials with serum creatinine inclusion criteria (RQ 0.40 vs. 0.86, P=0.034). CONCLUSIONS: Strategies are needed to increase minority enrollment in clinical trials for metastatic CRC. Identification of systemic barriers is integral in public policy advocacy to increase representation.

Predicting Survival in Mucinous Adenocarcinoma of the Appendix: Demographics, Disease Presentation, and Treatment Methodology.

BACKGROUND: Mucinous adenocarcinoma of the appendix (MACA) follows a complex disease course with variable survival. Large-scale predictive modeling may determine subtle yet important prognostic factors otherwise unseen in smaller cohort analyses. METHODS: Patients with MACA were identified from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database (2005-2019). Primary, secondary, and tertiary outcomes were disease-specific survival (DSS), overall survival (OS), and average annual percent change (AAPC) in incidence. RESULTS: Among 4,258 included patients, MACA was most frequently diagnosed at 50 to 69 years (52.0%), with female preponderance (55.9%). MACA incidence AAPC was 3.8 (95% confidence interval [CI] 1.9-5.9). For patients with exclusive, first-diagnosis MACA included in survival analysis (3,222 patients), median DSS and OS were 118 and 88 months, respectively. In DSS-based multivariable analysis, worse prognosis was associated with non-Hispanic Black background (HR 1.36, 95% CI 1.02-1.82; p = 0.036), high grade (grade 3 HR 3.10, 95% CI 2.44-3.92; p < 0.001), lymphatic spread (HR 2.73, 95% CI 2.26-3.30; p < 0.001), and distant metastasis (HR 5.84, 95% CI 3.86-8.83; p < 0.001). In subcohort analysis of patients with rationale for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC, 2,387 patients), CRS-HIPEC was associated with survival benefit compared with surgery alone but only for moderate-grade tumors (median DSS/OS 138/138 vs. 116/87 months; p < 0.001). CONCLUSIONS: Mucinous adenocarcinoma of the appendix incidence is increasing in the United States. Survival rates are affected by both demographics and classical risk factors, and CRS-HIPEC-associated survival benefit predominantly occurs in moderate-grade tumors. Further exploration of biologic and clinicopathologic features may enhance risk stratification for this disease.

Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.

INTRODUCTION: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood. METHODS: Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG. RESULTS: Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology. CONCLUSION: The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process. TRIAL REGISTRATION NUMBER: NCT03030404.

Germline CDH1 Variants and Lifetime Cancer Risk.

Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Cytoreduction and HIPEC for Gastric Carcinomatosis: Multi-institutional Analysis of Two Phase II Clinical Trials.

INTRODUCTION: There are no approved locoregional therapies for peritoneal carcinomatosis from gastric adenocarcinoma (GA). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) represents a potential treatment for advanced GA with isolated peritoneal metastasis. PATIENTS AND METHODS: Two separate single-institution phase II, single-arm studies evaluating CRS-HIPEC using cisplatin with mitomycin C (NIH: NCT03092518, MDACC: NCT02891447) in patients with GA and confirmed peritoneal metastasis were analyzed. The primary endpoint of each trial was overall survival (OS). Clinical, pathologic, and treatment variables were analyzed for association with outcomes. RESULTS: Over 4 years, 41 patients with peritoneal carcinomatosis from GA underwent CRS-HIPEC. All patients had synchronous peritoneal metastasis and received systemic chemotherapy as front-line therapy. A total of 23 patients also received laparoscopic HIPEC prior to open CRS-HIPEC. The majority (63%, n = 26) were male, and median PCI score at CRS-HIPEC was 2. Median OS was 24.9 months from diagnosis and 14.4 months from CRS-HIPEC. Three-year OS was 25% from diagnosis and 22% from CRS-HIPEC. Median RFS was 7.4 months. The rate of 30-day Clavien-Dindo grade ≥ 3 complications was 32%; specifically, the rate of anastomotic leak was 22%. Multivariable analysis identified the number of pathologically positive lymph nodes as an independent predictor of postoperative OS. CONCLUSIONS: In patients with gastric adenocarcinoma and isolated peritoneal metastasis treated with CRS-HIPEC, 3-year OS was 22% from CRS-HIPEC, and complications were common. The number of pathologic lymph node metastases was inversely correlated with overall survival. Further investigation of CRS-HIPEC for GA should include patient selection based on response to systemic chemotherapy or incorporate novel intraperitoneal treatment strategies.

Age Determines Adjuvant Chemotherapy Use in Resected Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in resected stage II colon cancer remains controversial. Treatment recommendations rely largely on the presence of certain high-risk features for recurrence. OBJECTIVE: We sought to define patient and clinicopathologic differences between early-onset and late-onset colorectal cancer and determine whether these differences impact treatment. We hypothesized that high-risk features in stage II colorectal cancer differed between age groups and would most strongly influence administration of adjuvant chemotherapy. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a Commission on Cancer designated hospital as well as the National Cancer Institute Intramural Research Program. PATIENTS: Patients with resected stage II colon cancer were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. Patients were stratified into young (≤45), middle-aged (50-75), and older (>75) age groups. MAIN OUTCOME MEASURES: Incidence of high-risk clinicopathologic features and receipt of adjuvant chemotherapy were measured. RESULTS: A total of 14,966 patients met inclusion criteria. Young patients were found to have had at least one high-risk feature ( n = 489, 44%) slightly more often than both middle-aged ( n = 3734, 40%) and older patients ( n = 1890, 42%). A total of 332 (7%) older patients received adjuvant chemotherapy compared to 627 (56%) young patients and 2854 (30%) middle-aged patients. Age group was independently associated with receipt of adjuvant chemotherapy when controlling for relevant clinicopathologic factors. LIMITATIONS: This was a retrospective study without granular detail on treatment decisions. CONCLUSIONS: Young patients are frequently prescribed adjuvant chemotherapy for both high- and low-risk tumors despite questionable benefit in the latter. Older patients rarely receive adjuvant therapy. Both medical and surgical oncologists should be aware of disparities in cancer treatment and remain conscientious about making treatment decisions solely based on age. See Video Abstract at http://links.lww.com/DCR/B846 . LA EDAD DETERMINA EL USO DE QUIMIOTERAPIA ADYUVANTE EN EL CNCER DE COLON RESECADO EN ESTADIO II: ANTECEDENTES:El papel de la quimioterapia adyuvante en el cáncer de colon resecado en estadio II sigue siendo controversial . Las recobmendaciones para el tratamiento dependen en gran medida de la presencia de ciertas características de alto riesgo de recurrencia.OBJETIVO:Buscamos definir las diferencias clínico-patológicas del paciente entre el CCR de inicio temprano y tardío; y determinar si estas diferencias afectan el tratamiento. Hipotetizamos que las características de alto riesgo del cáncer colorrectal en estadio II difieren entre los grupos de edad y que influyen fuertemente en la administración de quimioterapia adyuvante.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital designado por la Comisión sobre el Cáncer, así como el Programa de Investigación Intramural del Instituto Nacional del Cáncer.PACIENTES:Se identificaron los pacientes con cáncer de colon resecado en estadio II en la Base de datos nacional del cáncer y se registraron las características clínico-patológicas. Los pacientes se estratificaron en grupos de edad jóvenes (≤45), de mediana edad (50-75) y mayores (> 75).PRINCIPALES MEDIDAS DE RESULTADO:Se estudiaron la incidencia de las características clínico-patológicas de alto riesgo y la recepción de quimioterapia adyuvante.RESULTADOS:Un total de 14.966 pacientes cumplieron con los criterios de inclusión. Se encontró que los pacientes jóvenes tenían al menos una característica de alto riesgo (n = 489, 44%) un poco más frecuente que los pacientes de mediana edad (n = 3734, 40%) y los pacientes mayores (n = 1890, 42%). Un total de 332 (7%) de los pacientes mayores recibieron quimioterapia adyuvante en comparación con 627 (56%) de los pacientes jóvenes y 2854 (30%) de los pacientes de mediana edad. El grupo de edad se asoció de forma independiente con la recepción de quimioterapia adyuvante al controlar los factores clínico-patológicos relevantes.LIMITACIONES:Este fue un estudio retrospectivo sin detalles granulares sobre las decisiones de tratamiento.CONCLUSIONES:A los pacientes jóvenes se les prescribe con frecuencia quimioterapia adyuvante para tumores de alto y bajo riesgo, a pesar de los cuestionables beneficios en estos últimos. Los pacientes de edad avanzada rara vez reciben terapia adyuvante. Tanto los oncólogos clínicos como los quirúrgicos deben ser conscientes de las disparidades en el tratamiento del cáncer y ser conscientes de tomar decisiones de tratamiento basadas únicamente en la edad. Consulte Video Resumen en http://links.lww.com/DCR/B846 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Adjuvant chemotherapy is associated with improved overall survival in select patients with Stage II colon cancer: A National Cancer Database analysis.

BACKGROUND AND OBJECTIVES: Guidelines for Stage II colon cancer recommend adjuvant chemotherapy (AC) only for tumors with high-risk features, but long-term outcomes data are mixed. We aimed to determine if AC was associated with a survival benefit in this population. METHODS: Patients were identified from the National Cancer Database and included if they met the following criteria: diagnosis of Stage II colon cancer, surgery, survival data, and complete data on six high-risk features. The cohort of 57 335 patients was stratified by receipt of AC. Subgroup analysis was performed on patients under the age of 65 years with no comorbidities. Overall survival (OS) was the primary endpoint. RESULTS: An increasing number of high-risk features was associated with significantly decreased median OS. AC was associated with significantly increased OS for patients with 0, 1, 2, and ≥3 high-risk features. On subgroup analysis, receipt of AC was associated with a reduced risk of death (hazard ratio: 0.66; confidence interval: 0.59-0.74). For patients in the subgroup who had a T4 tumor, AC was associated with increased OS (92.7 vs. 83.6 months). CONCLUSIONS: AC should be considered for all younger, healthy patients with Stage II colon cancer and may be associated with a survival benefit for patients with T4 disease.

Desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma: a case report of two rare diseases.

BACKGROUND: Desmoid-type fibromatosis (DTF) is a rare benign lesion that usually arises from the abdominal wall or extremities and rarely from the mesentery or intrabdominal organs. Malignant peritoneal mesothelioma is also a rare, yet aggressive disease. To our knowledge, this is the first case report of desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma. CASE PRESENTATION: An early 30-year-old female was referred to our center for large intra-abdominal mass concerning for recurrent malignant peritoneal mesothelioma after previous cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy. Further investigation revealed a large mesenteric mass, which was resected en bloc with the cecum and terminal ileum. Pathologic findings confirmed a surprising diagnosis of desmoid-type fibromatosis. CONCLUSIONS: No adjuvant therapy was offered to this patient due to negative tumor margins; however, close follow-up will be provided for recurrence of both malignant peritoneal mesothelioma and desmoid-type fibromatosis, which can be differentiated in the future via biopsy in this patient.

Preoperative Risk Score for Predicting Incomplete Cytoreduction: A 12-Institution Study from the US HIPEC Collaborative.

BACKGROUND: For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3. METHODS: All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort). RESULTS: Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained. CONCLUSION: The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.

Lymphovascular Invasion Predicts Lymph Node Involvement in Small Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Pancreatic neuroendocrine tumors (p-NETS) are increasing in incidence, and prognostic factors continue to evolve. The benefit of lymphadenectomy for p-NETS ≤2 cm remains unclear. We sought to determine the significance of lymphovascular invasion (LVI) for small p-NETS. METHODS: The National Cancer Database was queried for patients with p-NETS ≤2 cm and with ≥1 evaluated lymph node (LN), years 2004-2015. Demographic, clinical, and treatment characteristics were analyzed. Multivariate logistic regression was performed to identify predictors of LN positivity. RESULTS: Among 2,499 patients identified, tumor location was delineated as the head (26%), body (18%), tail (38%), or unspecified (18%); 74% were well-differentiated versus 10% moderate, 2% poor, and 14% unknown. LVI occurred in 11%. A median of 9 LNs were evaluated; overall positivity was 18%. Mean survival was significantly longer in node-negative patients (115 vs. 95 months, log-rank p < 0.0001). LVI was the strongest predictor of node involvement (OR 10.4, p < 0.0001) when controlling for tumor size, grade, and location. Subset analysis of patients with known LVI status, grade, location, and mitoses found that LVI was more likely in the setting of moderate-to-high tumor grade, 1-2 cm size, pancreatic head location, and high mitotic rate. Among patients with ≥2 of these 4 factors, 25% were node-positive. CONCLUSIONS: Presence of LVI was the strongest predictor of node positivity. LVI on endoscopic biopsy should prompt resection and regional LN dissection to fully stage patients with small p-NETS. Patients with other high-risk factors should also be considered for resection and regional lymphadenectomy.

The Association of Tumor Laterality and Survival After Cytoreduction for Colorectal Carcinomatosis.

BACKGROUND: Primary tumor location has emerged as an important surrogate for tumor biology in metastatic colorectal cancer treated with systemic chemotherapy. It is unclear if primary tumor location is associated with survival after cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy (HIPEC) for colorectal carcinomatosis. METHODS: Study of a contemporary cohort merged data from the California Cancer Registry, 2004-2012, and the Office of Statewide Health Planning and Development inpatient database. For patients undergoing CRS/HIPEC, clinicopathologic variables, treatment characteristics, and survival were compared by right versus left colon primary site. Survival was analyzed by Cox proportional hazards. RESULTS: Of 272 patients identified, 128 (47.1%) had right-sided tumors. Left- and right-sided cohorts had similar patient, tumor, and treatment factors. Patients with left-sided primary tumors had significantly prolonged overall survival (mean 34 versus 15.5 mo, P = 0.0010). Factors independently associated with decreased overall survival included age >80 (HR 7.0, P < 0.0001), advanced T4 stage (HR 3.6, P = 0.0031), and positive lymph nodes (HR 2.2, P = 0.0004). Metachronous peritoneal involvement (HR 0.38, P < 0.0001) and left-sided primary tumors (HR 0.72, P = 0.041) were independently associated with improved overall survival. CONCLUSIONS: This study identifies location of primary tumor as an important determinant of long-term survival after CRS/HIPEC. Patients with left-sided tumors have a more favorable prognosis.

Prognostic impact of tumor location in resected gallbladder cancer: A national cohort analysis.

BACKGROUND AND OBJECTIVES: Tumor location (peritoneal vs hepatic) has been incorporated in the 8th edition of the American Joint Committee on Cancer Staging system for gallbladder cancer. However, larger studies are needed to confirm the prognostic impact of tumor location. METHODS: Patients with pathologically-confirmed gallbladder cancer with information on primary tumor location were included from the National Cancer Database (2009-2012). We compared patients with hepatic-side tumors to those on the peritoneal side. Survival data were plotted using the Kaplan-Meier method. Prognostic factors were modeled with a multivariate Cox Proportional Hazards Model. Primary outcome was overall survival (OS). RESULTS: A total of 1251 patients were included. In comparison to patients with peritoneal-sided tumors, patients with hepatic-sided tumors were more likely to: be of higher pT stage (pT3: 49% vs 24%; P < .001); node positive (31% vs 24%; P = .016); undergo liver resection (53% vs 25%; P < .001); or have positive margins (29% vs 16%; P < .001). However, on multivariate analysis, there was no difference in OS between the groups (HR, 0.97; 95% CI, 0.79-1.18; P = .753). Liver resection was associated with improved survival regardless of tumor location in pT2 tumors (peritoneal: HR, 0.57; P = .034; hepatic: HR, 0.67; P < .001). CONCLUSIONS: This study failed to demonstrate the independent prognostic value of primary tumor location in patients with gallbladder cancer.

Prognostic impact of lymphovascular invasion in pT1-T3 gallbladder adenocarcinoma.

BACKGROUND: Most gallbladder cancers are diagnosed after cholecystectomy for presumed benign disease, and nodal staging to inform subsequent treatment is therefore often lacking. We evaluated the association of lymphovascular invasion (LVI) with regional lymph node involvement in gallbladder adenocarcinoma and its impact on survival. METHODS: The National Cancer Database was queried to identify patients with resected gallbladder adenocarcinoma and with available staging and LVI status. Patients with pT4 and M1 disease were excluded. Univariable and multivariable regression identified factors associated with positive lymph nodes. Cox proportional hazards model was used to evaluate overall survival (OS). RESULTS: Of 1649 patients with available LVI status, 1142 (69.7%) had at least one positive lymph node and 765 (46.4%) had LVI. On multivariable regression, presence of LVI was the strongest predictor of positive lymph nodes (odds ratio, 3.69; P < .001). The positive predictive value of LVI for positive lymph nodes in pT2 and pT3 tumors was 80.1% and 90.5%, respectively. LVI was independently associated with decreased OS (hazard ratio, 1.21; P = .001), as were node-positive disease and increasing T stage. CONCLUSION: In patients with gallbladder adenocarcinoma, LVI is independently associated with regional lymph node metastases and abbreviated OS. LVI status may help risk-stratify patients following initial cholecystectomy and inform subsequent treatment.

Institutional variation in recovery after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: An opportunity for enhanced recovery pathways.

BACKGROUND: Variations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers. METHODS: Data from the US HIPEC Collaborative represents a retrospective multi-institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed-effects linear (continuous outcomes) or logistic (binary outcomes) regression models. RESULTS: A total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8-70.9) and readmissions (overall 20.6%, range: 8.9-33.3) varied by institution (P < .001). Institution-level variation in perioperative practice patterns existed among measured ERAS pathway process/outcomes (P < .001). The percentages of variation with each process/outcome measure attributable solely to institutional practices ranged from 0.6% to 66.6%. CONCLUSIONS: Significant variation exists in the perioperative care of patients undergoing CRS/HIPEC at major US academic institutions. These findings provide a strong rationale for the investigation of best practices in CRS/HIPEC patients.

Health-related quality of life and oncologic outcomes after surgery in older adults with colorectal cancer.

PURPOSE: Data regarding changes in functional status and health-related quality of life (HRQOL) before and after surgery are lacking. We identified colorectal cancer patients from the SEER-Medicare Health Outcomes Survey (MHOS) linked database to evaluate the association between HRQOL and survival. METHODS: HRQOL survey data captured physical/mental health, activities of daily living (ADLs), and medical comorbidities. Patients who underwent surgery with HRQOL surveys prior to cancer diagnosis and ≥ 1 year after diagnosis were selected. Patient, disease, and HRQOL measures were analyzed in regard to overall survival (OS), disease-specific survival (DSS), and non-DSS. RESULTS: Of 590 patients included, 55% were female, 75% were Caucasian, and 83% had colonic primary. Disease extent was localized for 52%, regional for 41%, and distant for 7%. Median OS was 83 months. Decreased OS was independently associated with age ≥ 75 (HR 1.7, p < 0.0001), male sex (HR 1.4, p = 0.011), advanced disease (regional-HR 2.0, p < 0.0001; distant-HR 7.0, p < 0.0001), and decreased mental HRQOL (HR 1.4, p = 0.005). Decreased DSS was independently associated with advanced disease (regional-HR 4.1, p < 0.0001; distant-HR 16.5, p < 0.0001) and rectal primary (HR 1.6, p = 0.047). Decreased non-DSS was independently associated with age ≥ 75 (HR 2.2, p < 0.0001), male sex (HR 1.4, p = 0.03), decreased mental HRQOL (HR 1.4, p = 0.02), and increased comorbidities (HR 1.4, p = 0.04). CONCLUSIONS: The potential overall survival benefit of oncologic surgery is diminished by declines in physical and mental health. Early identification of older surgical patients at risk for functional and HRQOL declines may improve survival following colorectal cancer surgery.

Lymphovascular Invasion Is Associated with Lymph Node Involvement in Small Appendiceal Neuroendocrine Tumors.

BACKGROUND: Appendiceal neuroendocrine tumors (NETs) are incidentally found in up to 1% of appendectomy specimens. The association of lymphovascular invasion (LVI) with risk of regional lymph node involvement is unclear. METHODS: From the National Cancer Database, 2004-2015, this study identified patients who had tumors 2 cm or smaller with one or more lymph nodes (LNs) pathologically evaluated. The histology was defined as typical, goblet cell, or composite NETs. Patient demographics, tumor characteristics, and treatment variables were analyzed. RESULTS: The histologies for the 1767 identified patients were typical (n = 921, 52.1%), goblet cell (n = 556, 31.5%), and composite (n = 290, 16.4%). The tumor grades were low (70.4%), moderate (18.6%), and high (11%). The overall LN positivity was 17%. Of 1052 tumors evaluated, 215 (20.4%) had LVI. Overall survival decreased with node involvement (mean 84 vs. 124 months; p < 0.0001, log-rank). In the multivariate logistic regression analysis, LVI was independently associated with node involvement [odds ratio (OR) 5.0; p < 0.0001] after adjustment for patient age and tumor histologic subtype, size, and grade. In the subset analysis of typical NETs, tumor size of 1-2 cm (ref. < 1 cm; OR 5.5; p < 0.001) and presence of LVI (ref. absence of LVI; OR 4.8; p < 0.0001) were the only factors independently associated with LN involvement. CONCLUSIONS: Node involvement is associated with worse overall survival in appendiceal NETs. The presence of LVI was strongly associated with lymph node involvement. An appendectomy specimen showing LVI should prompt strong consideration of colectomy with regional lymphadenectomy even for small, typical appendiceal NETs.

Intraoperative bile spillage is associated with worse survival in gallbladder adenocarcinoma.

BACKGROUND: Gallbladder adenocarcinoma is often incidentally identified following cholecystectomy. We hypothesized that intraoperative bile spillage would be a negative prognostic factor. METHODS: A retrospective review of patients treated at a cancer center with histologically confirmed gallbladder adenocarcinoma, 2009-2017, was performed. Patient, disease, and treatment factors were analyzed in terms of progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-six patients were identified. Tumor stage was T1 (n = 8, 12%), T2 (n = 23, 35%), T3 (n = 35, 53%). Node stage was N0 (n = 22, 33%), N1+ (n = 26, 39%), Nx (n = 18, 27%). Operations included cholecystectomy alone (n = 27, 36%), cholecystectomy and partial hepatectomy (n = 30, 45%), or hepaticojejunostomy (n = 9, 14%). Median PFS was 7 months (interquartile range [IQR], 2-19); median OS was 16 months (IQR, 10-31). Subset multivariate proportional hazards regression of 41 patients who underwent initial cholecystectomy showed decreased PFS was associated with intraoperative spillage (n = 12, 29%; hazard ratio [HR], 5.5; P = .0014); decreased OS was associated with drain placement (n = 21, 51%; HR, 8.1; P = .006). CONCLUSIONS: Intraoperative bile spillage and surgical drain placement at initial cholecystectomy are negatively associated with PFS and OS in gallbladder adenocarcinoma. Explicit documentation of spillage and drain placement rationale is critical, possibly indicating locally advanced disease and prompting stronger consideration of systemic therapy before definitive resection.

Role of immune microenvironment in gastrointestinal stromal tumours.

AIMS: The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS AND RESULTS: Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. CONCLUSIONS: PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.