Neoadjuvant Chemotherapy for Intrahepatic, Perihilar, and Distal Cholangiocarcinoma:a National Population-Based Comparative Cohort Study

IntroductionData supporting the utilization of neoadjuvant chemotherapy (NAC) in patients receiving resection for cholangiocarcinoma (CCA) remains uncertain. We aimed to determine whether NAC followed by resection improves long-term survival in intrahepatic (iCCA), perihilar (hCCA), and distal (dCCA) cholangiocarcinoma, analyzed separately.MethodsPatients undergoing surgery for iCCA, hCCA, and dCCA, receiving either none, NAC, or adjuvant chemotherapy (AC) from 2010 to 2016 were identified from the National Cancer Database (NCDB). Cox regression was performed to account for selection bias and to assess the impact of surgery alone (SA) versus either NAC or AC on overall survival (OS).ResultsThere were 9411 patients undergoing surgery for iCCA (n = 3772, 39.5%), hCCA (n = 1879, 20%), and dCCA (n = 3760, 40%). Of these, 10.6% (n = 399), 6.5% (n = 123), and 7.2% (n = 271) with iCCA, hCCA, and dCCA received NAC, respectively. On adjusted analyses, patients receiving NAC followed by surgery had significantly improved OS, compared to SA for iCCA (HR 0.75, CI95% 0.64-0.88, p < 0.001), hCCA (HR 0.72, CI95% 0.54-0.97, p = 0.033), and for dCCA (HR 0.65, CI95% 0.53-0.78, p < 0.001). However, sensitivity analyses demonstrated no differences in OS between NACs, followed by surgery or AC after surgery in iCCA (HR 1.19, CI95% 0.99-1.45, p = 0.068), hCCA (HR 0.83 CI95% 0.59-1.19, p = 0.311), and dCCA (HR 1.13 CI95% 0.91-1.41, p = 0.264).ConclusionsThis study associated NAC with increased OS for all CCA subtypes, even in patients with margin-negative and node-negative disease; however, no differences were found between NAC and AC. Our results highlight that a careful and interdisciplinary evaluation should be sought to consider NAC in CCA and warrant the need of larger studies to provide robust recommendation

Discovery of SMAD4 promoters, transcription factor binding sites and deletions in juvenile polyposis patients

Inactivation of SMAD4 has been linked to several cancers and germline mutations cause juvenile polyposis (JP). We set out to identify the promoter(s) of SMAD4, evaluate their activity in cell lines and define possible transcription factor binding sites (TFBS). 5′-rapid amplification of cDNA ends (5′-RACE) and computational analyses were used to identify candidate promoters and corresponding TFBS and the activity of each was assessed by luciferase vectors in different cell lines. TFBS were disrupted by site-directed mutagenesis (SDM) to evaluate the effect on promoter activity. Four promoters were identified, two of which had significant activity in several cell lines, while two others had minimal activity. In silico analysis revealed multiple potentially important TFBS for each promoter. One promoter was deleted in the germline of two JP patients and SDM of several sites led to significant reduction in promoter activity. No mutations were found by sequencing this promoter in 65 JP probands. The predicted TFBS profiles for each of the four promoters shared few transcription factors in common, but were conserved across several species. The elucidation of these promoters and identification of TFBS has important implications for future studies in sporadic tumors from multiple sites, and in JP patients

Adjuvant Chemotherapy Associated with Survival Benefit Following Neoadjuvant Chemotherapy and Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Population-Based Cohort Study.

BACKGROUND Data supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection. METHODS Patients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of < 6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression analysis were performed to account for selection bias and analyze the impact of AC on overall survival. RESULTS Of 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p < 0.001), which remained after multivariable adjustment (HR 0.81, 95% confidence interval [CI] 0.75-0.88; p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (hazard ratio [HR] 0.80, 95% CI 0.72-0.90; p < 0.001), N1 (HR 0.76, 95% CI 0.67-0.86; p < 0.001), R0 margin status (HR 0.82, 95% CI 0.75-0.89; p < 0.001), R1 margin status (HR 0.77, 95% CI 0.64-0.93; p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74-0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73-0.88; p < 0.001). Stratified analysis by nodal, margin, and NART status demonstrated consistent results. CONCLUSION AC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC

Assessment of Textbook Oncologic Outcomes Following Proctectomy for Rectal Cancer.

BACKGROUND Outcomes of rectal adenocarcinoma vary considerably. Composite "textbook oncologic outcome" (TOO) is a single metric that estimates optimal clinical performance for cancer surgery. METHODS Patients with stage II/III rectal adenocarcinoma who underwent single-agent neoadjuvant chemoradiation and proctectomy within 5-12 weeks were identified in the National Cancer Database (NCDB). TOO was defined as achievement of negative distal and circumferential resection margin (CRM), retrieval of ≥ 12 nodes, no 90-day mortality, and length of stay (LOS) < 75th percentile of corresponding year's range. Multivariable logistic regression was used to identify predictors of TOO. RESULTS Among 318,225 patients, 8869 met selection criteria. Median age was 62 years (IQR 54-71), and 5550 (62.6%) were males. Low anterior resection was the most common procedure (LAR, 6,037 (68.1%) and 3084 (34.8%) were treated at a high-volume center (≥ 20 rectal resections/year). TOO was achieved in 3967 patients (44.7%). Several components of TOO were achieved commonly, including negative CRM (87.4%), no 90-day mortality (98.0%), no readmission (93.0%), and no prolonged hospitalization (78.8%). Logistic regression identified increasing age, non-private insurance, low-volume centers, open approach, Black race, Charlson score ≥ 3, and abdominoperineal resection (APR) as predictors of failure to achieve TOO. Over time, TOOs were attained more commonly which correlated with increased minimally invasive surgery (MIS) adoption. TOO achievement was associated with improved survival. CONCLUSIONS Rectal adenocarcinoma patients achieve TOO uncommonly. Treatment at high-volume centers and MIS approach were among modifiable factors associated with TOO in this study

Palliative gastrectomy for metastatic gastric adenocarcinoma: A national population-based cohort study.

BACKGROUND The impact of palliative gastrectomy for metastatic gastric adenocarcinoma, especially by site of metastasis remains unclear. METHODS The National Cancer Database, 2010-2015, was used to identify patients with clinical metastatic (cM1) gastric adenocarcinoma (n = 19,411) at diagnosis. The main variable was index management for cM1 gastric adenocarcinoma (ie, no treatment, palliative chemotherapy, or palliative gastrectomy). Cox multivariable analyses were used to account for treatment selection bias and reported as hazard ratio (HR) and 95% confidence interval. RESULTS Of 19,411 patients, 10,893 (56%) received palliative chemotherapy, and only 1,101 (6%) received palliative gastrectomy only. The median survival was 6.1 months, and 5-year survival was 4% in the entire cohort. Patients receiving palliative gastrectomy had a significantly longer survival than patients without any treatment or palliative chemotherapy (median: 12.8 vs 1.8 vs 9.5 months, P < .001), which remained after multivariable adjustment (HR: 0.76, 95% confidence interval: 0.71-0.81, P < .001) compared with palliative chemotherapy. Stratified analyses by clinical nodal stage (cN) demonstrated survival benefit with palliative gastrectomy: cN0 (HR: 0.71, 95% confidence interval: 0.62-0.82), cN1 (HR: 0.68, 95% confidence interval: 0.59-0.79), cN2 (HR: 0.86, 95% confidence interval: 0.70-0.94), and cN3 (HR: 0.82, 95% confidence interval: 0.70-0.92) over palliative chemotherapy. Stratified analyses by metastasis site demonstrated that palliative gastrectomy remained superior compared with palliative chemotherapy for metastatic disease limited to liver, bone, and peritoneum, but equivalent to lung metastasis and inferior to brain metastasis. CONCLUSION Palliative gastrectomy appears to have a modest survival benefit over palliative chemotherapy alone. Differences in outcomes by site of metastasis warrant further research to understand tumor biology and identify specific subgroups which may benefit from palliative gastrectomy

Adjuvant radiotherapy improves long-term survival after resection for gallbladder cancer A population-based cohort study.

BACKGROUND Data supporting routine use of adjuvant radiotherapy (RT) compared to without RT (noRT) for gallbladder cancer (GBC) is unclear. This study aimed to determine whether RT improves long-term survival following resection for GBC. METHODS Patients receiving resection for GBC followed by RT from 2004 to 2016 were identified from the National Cancer Database (NCDB). Patients with survival <6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of RT on overall survival. RESULTS Of 7514 (77%) noRT and 2261 (23%) RT, 2067 noRT and 2067 RT patients remained after PSM. After matching, RT was associated with improved survival (median: 26.2 vs 21.5 months, p < 0.001), which remained after multivariable adjustment (HR: 0.82, CI: 0.76-0.89, p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (HR: 0.84, CI: 0.77-0.93), N1 (HR: 0.77, CI: 0.68-0.88), N2/N3 (HR: 0.56, CI: 0.35-0.91), margin status: R0 (HR: 0.85, CI: 0.78-0.93), R1 (HR: 0.78, CI: 0.68-0.88) and use of adjuvant chemotherapy (AC) (HR: 0.67, CI: 0.57-0.79). Benefit with RT were also seen in patients with T2 - T4 disease and in patients undergoing simple and extended cholecystectomy. CONCLUSION RT following resection was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings may suggest addition of RT into multimodality therapy for GBC