Extent of Resection and Long-Term Outcomes for Appendiceal Adenocarcinoma: a SEER Database Analysis of Mucinous and non-Mucinous Histologies.

BACKGROUND: Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. PATIENTS AND METHODS: Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000-2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan-Meier estimates and examined using Cox proportional hazards modeling. RESULTS: Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81-1.22]. CONCLUSIONS: Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required.

Pancreatectomy for intraductal papillary mucinous neoplasm: has anything changed in North America?

BACKGROUND: Multiple guidelines on the management of intraductal papillary mucinous neoplasm (IPMN) have been published over the past decade. However, practice data are lacking. This study aims to determine whether pancreatectomy procedures, IPMN pathology, or outcomes have changed. METHODS: ACS-NSQIP Procedure Targeted Pancreatectomy database was queried for patients with IPMN from 2014 to 2019. Cases were stratified by pathology, tumor stage/cyst size and procedure. Pancreatectomies for IPMN by year, 30-day morbidity, and clinically relevant postoperative pancreatic fistula (CR-POPF) were quantified. Mann-Kendall trend tests were performed to assess surgical trends and associated outcomes over time. RESULTS: 3912 patients underwent pancreatectomy for IPMN. 21% demonstrated malignancy and 79% were benign. Morbidity and mortality occurred in 29.7% and 1.5% of cases, respectively. Over time, no change was observed in use of pancreatectomy for IPMN (10%) or in benign/malignant pathology, or cyst size. Robotic approach increased from 9.1% to 16.5% with decreases in laparoscopic (19.5%-15.0%) and open interventions (71.5%-68.1%, p = 0.016). No change was observed over time in morbidity or mortality; however, rates of CR-POPF decreased (18.8%-13.8%, p < 0.001). CONCLUSIONS: Practice patterns in treatment of IPMN have not changed significantly in North America. More patients are undergoing robotic pancreatectomy, and postoperative pancreatic fistula rates are improving.

Chronologic Age, Independent of Frailty, is the Strongest Predictor of Failure-to-Rescue After Surgery for Gastrointestinal Malignancies.

BACKGROUND: Prior studies of older cancer patients undergoing large operations have reported similar rates of complications to the general population but higher rates of mortality, suggesting higher rates of failure-to-rescue (FTR) with advanced age. Whether age is a marker for frailty, or an independent predictor of FTR, is not clear. METHODS: The ACS-NSQIP database was queried from 2015-19 for patients undergoing surgery for gastrointestinal (GI) malignancy. Patients were divided into age-stratified cohorts: C1 (18-55), C2 (56-65), C3 (66-75), C4 (76-89). Adjusted odds ratios (aOR) were computed to assess the relationship of the FTR rate and age, while controlling for potential confounders. A second analysis was specified with all covariates converted to Z-scores, which generated scaled adjusted odds ratios (saOR) to determine the strongest predictor of FTR. RESULTS: Multivariable analysis suggests that age is an independent predictor of FTR: C2:C1 aOR = 1.87 (p < 0.001); C3:C1 aOR = 3.33 (p < 0.001); C4:C1 aOR = 5.71 (p < 0.001). The scaled analysis demonstrated that age is the strongest predictor of FTR (saOR = 1.92, p < 0.001); a one standard deviation increase in age was associated with a 92% increased odds of FTR. The saOR for frailty (1.18, p < 0.001) and for number of comorbidities (1.10, p = 0.005) also were statistically significant. CONCLUSIONS: Chronologic age was independently associated with increased FTR after surgery for GI malignancy and was the strongest predictor of FTR. These results suggest that chronologic age must be carefully considered when evaluating the fitness of a patient for GI cancer surgery.

Robotic pancreatoduodenectomy: trends in technique and training challenges.

BACKGROUND: More complex cases are being performed robotically. This study aims to characterize trends in robotic pancreatoduodenectomy (RPD) over time and assess opportunities for advanced trainees. METHODS: Using the ACS-NSQIP database from 2014 to 2019, PD cases were characterized by operative approach (open-OPN, laparoscopic-LAP, robotic-ROB). Proficiency and postoperative outcomes were described by approach over time. RESULTS: 24,268 PDs were identified, with the ROB approach increasing from 2.8% to 7.5%. Unplanned conversion increased over time for LAP (27.7-39.0%, p = 0.003) but was unchanged for ROB cases (14.8-14.7%, p = 0.257). Morbidity increased for OPN PD (35.5-36.8%, p = 0.041) and decreased for ROB PD (38.7-30.3%, p = 0.010). Mean LOS was lower in ROB than LAP/OPN (9.5 vs. 10.9 vs. 10.9 days, p < 0.00001). Approximately, 100 AHPBA, SSO, and ASTS fellows are being trained each year in North America; however, only about 5 RPDs are available per trainee per year which is far below that recommended to achieve proficiency. CONCLUSION: Over a 6-year period, a significant increase was observed in the use of RPD without a concomitant increase in conversion rates. RPD was associated with decreased morbidity and length of stay. Despite this shift, the number of cases being performed is not adequate for all fellows to achieve proficiency before graduation.

Intrahepatic cholangiocarcinoma: how do hepatectomy outcomes compare to liver metastases and hepatocellular carcinoma?

BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and hepatectomy is the only cure. Perioperative outcomes following hepatectomy for colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC) are better described than for ICC. The aim was to compare post-hepatectomy outcomes for ICC to CRLM and HCC. METHODS: The 2014-2020 ACS NSQIP hepatectomy PUF was utilized. Patients with ICC, CRLM, and HCC were identified and others excluded. Demographic, disease, and procedural characteristics were collected. Univariable and multivariable analyses (Chi-Square for categorical variables; Kruskal-Wallis for continuous variables) were performed for mortality, serious morbidity, bile leak, post-hepatectomy liver failure (PHLF), and 30-day readmission. RESULTS: 17,789 patients underwent hepatectomy including 2377 for ICC, 10,195 for CRLM, and 5217 for HCC. Patients undergoing hepatectomy for ICC vs. HCC vs. CRLM were noted to have higher 30-day mortality (4.8% vs. 2.5% vs. 1.0%, respectively p < 0.05). ICC was associated with higher overall and serious morbidity, bile leak, severe PHLF, and readmission. Multivariable analyses confirmed higher odds ratios for mortality and morbidity (p < 0.05) in patients with ICC. CONCLUSION: Hepatectomy for ICC is associated with worse short-term outcomes than for CRLM or HCC. Surgeons should be aware of these risks during surgical planning.

Radical antegrade modular pancreatosplenectomy (RAMPS): does adrenalectomy alter outcomes?

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) has oncologic superiority compared to a standard distal pancreatectomy (DP). For tumors invading into the adrenal gland, a posterior RAMPS takes the left adrenal gland en bloc with the pancreas specimen. The aim of this analysis is to determine whether addition of adrenalectomy alters the outcomes of DP. METHODS: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Procedure-Targeted Pancreatectomy database was accessed from 2014 to 2019. Patients with pancreatic ductal adenocarcinoma (PDAC) undergoing posterior RAMPS were compared to patients having a standard DP. 30-day outcomes were analyzed using multivariable regression. RESULTS: 3467 PDAC patients underwent DP; 159 (4.6%) also had an adrenalectomy. Posterior RAMPS patients had higher T stage (T3-4 77% vs. 58%, p < 0.01). On multivariable analysis, posterior RAMPS patients had worse perioperative outcomes including more transfusions (OR 2.78, p < 0.01), serious morbidity (OR 1.45, p = 0.04), prolonged hospital stay (OR 1.36, p < 0.05), and less optimal pancreatic surgery (OR 0.61, p < 0.01). CONCLUSION: Radical antegrade modular pancreatosplenectomy with adrenalectomy (posterior RAMPS) is associated with worse perioperative outcomes compared to a standard distal pancreatectomy. Improved oncologic outcomes must be weighed against higher perioperative morbidity when selecting patients for this more extensive surgical resection.

Conjoined right hepatic artery from branches of the common hepatic and gastroduodenal arteries: a rare anatomic variant.

PURPOSE: To describe a previously unreported anatomical variant of the hepatic arterial supply: a conjoined right hepatic artery, formed by branches of the common hepatic artery and gastroduodenal artery. METHOD: A 54-year-old female with oligometastatic colorectal cancer with metastases to the liver presented for planning stage arteriography in preparation for Y90 radioembolization. RESULTS: Arteriography of the common hepatic artery demonstrated bifurcation into a right hepatic artery and gastroduodenal artery. The gastroduodenal artery gave rise to a proximal branch, from which the left hepatic artery originated and then continued to anastomose in the hilum of the liver to the right hepatic artery originating from the common hepatic artery. It was initially identified on visceral artery arteriography and then retrospectively recognized on pre-procedural CT scan. CONCLUSION: Anatomical variants of the hepatic arterial supply are important to recognize during planning stage arteriography in preparation for Y90 radioembolization. Knowledge of these variants is also important for pre-operative planning.

Replaced right and common hepatic arteries with lienogastric trunk: a rare variant of celiaco-mesenteric anatomy.

We report a rare variant in mesenteric arterial anatomy: replacement of the right hepatic and common hepatic arteries to the SMA in a patient treated for hepatocellular carcinoma. The potential clinical implications of this unusual variation of celiaco-mesenteric anatomy will be discussed.

Outcomes Following Major Oncologic Operations for Non-AIDS-Defining Cancers in the HIV Population: A Matched Comparison to the General Population.

INTRODUCTION: Human immunodeficiency virus (HIV) patients are living longer due to the availability of antiretroviral therapies, and non-AIDS-defining cancers are becoming more prevalent in this patient population. A paucity of data remains on post-operative outcomes following resection of non-AIDS-defining cancers in the HIV population. METHODS: The National Inpatient Sample was utilized to identify patients who underwent surgical resection for malignancy from 2005 to 2015 (HIV, N = 52,742; non-HIV, N = 11,885,184). Complications were categorized by international classification of disease (ICD)-9 diagnosis codes. Cohorts were matched on insurance, household income, zip code and urban/rural setting. Logistic regression assessed whether HIV was an independent predictor of post-operative complications. RESULTS: Descriptive statistics found HIV patients to have an increased rate of complications following select oncologic surgical resections. Univariate and multivariate logistic regression found HIV to only be an independent predictor of complications following pulmonary lobectomy (p = 0.011; OR 2.93, 95% CI 1.29-6.73). Length of stay was statistically longer following colectomy (2.61 days, 95% CI 1.98-3.44) in those with HIV. CONCLUSIONS: Our findings are hypothesis generating and highlight the potential safety of major cancer surgery in the HIV population. However, care providers need be cognizant of the potential increased risk of post-operative complications following pulmonary lobectomy and the potential for increased length of stay. These findings are an initial insight into quality of care and outcomes metrics on HIV patients undergoing major cancer operations.

The importance of surgical margins in primary malignancies of the liver.

Resection is an important treatment modality for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Anatomic resection is generally preferred for HCC. When anatomic resection is not feasible, prospective data have demonstrated an improved outcome among HCC patients who have a resection with wide versus narrow surgical margins. Similarly, among patients with ICC, R1 resection has been associated with worse outcomes. In addition, margin width may also impact risk of recurrence and survival. As such, provided adequate functional liver remnant remains, anatomic resection with wide margins is recommended for HCC and ICC.

Operative trends for pancreatic and hepatic malignancies during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic disrupted routine health care, including many elective and non-cancer operations in the United States. Most hepato-pancreato-biliary malignancy patients require outpatient imaging, tissue sampling, and staging, and many undergo neoadjuvant therapy before operative intervention. The aims of this study were to evaluate the effect of the COVID-19 pandemic on hepato-pancreato-biliary oncologic operations and to determine whether trends in neoadjuvant therapy were altered by the pandemic. METHODS: Adult patients in the United States undergoing oncologic operations for pancreatic, primary and secondary hepatic malignancies, with or without neoadjuvant therapy, were extracted from the Vizient Clinical Data Base. Control chart analysis was used to plot trends over time and to determine whether changes were statistically significant. Wilcoxon rank-sum tests also compared monthly operative volume from pre-pandemic (12 month) and pandemic (28 months) periods. RESULTS: A total of 36,553 patients were identified over 40 months. Mean monthly pancreatic oncologic operations were unaffected by the pandemic (P = .257). Operations for pancreatic oncologic operations with prior neoadjuvant therapy increased throughout the pandemic (P = .002). Oncologic operations for primary and secondary hepatic malignancies were significantly reduced for 4 and 2 months, respectively, at the beginning of the pandemic but returned to their pre-pandemic baseline within 4 months (P = .169 and P = .598). CONCLUSION: Pancreatic operation volumes for cancer did not change, but pancreatic operations after neoadjuvant therapy continued to increase during the pandemic. Operations for hepatic malignancy were transiently disrupted but quickly normalized. These observations suggest that surgery for hepato-pancreato-biliary malignancies was prioritized during the pandemic.

Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer has increased markedly over the past decade. Although established for older adults, there are limited data on socioeconomic and racial disparities in screening, treatment, and outcomes in this distinct group. METHODS: Adults with primary colorectal cancer diagnosed at age <50 were identified from the Surveillance, Epidemiology, and End Results database. The exposure of interest was neighborhood socioeconomic status based on the Yost Index, a census-tract level composite score of neighborhood economic health. Univariate analysis was performed with χ2 analyses. Logistic regression models were created to evaluate the association of neighborhood socioeconomic status (Yost Index quintile) with metastasis at presentation and surgical intervention. Kaplan-Meier and Cox proportional hazards models were created. RESULTS: In total, 45,660 early-onset colorectal cancer patients were identified; 16.8% (7,679) were in the lowest quintile of neighborhood socioeconomic status. Patients with the lowest neighborhood socioeconomic status were 1.13 times (95% confidence interval 1.06-1.21) more likely to present with metastases and had lower survival (hazard ratio 1.45, 95% confidence interval 1.37-1.53) compared to those with the highest neighborhood socioeconomic status. Non-Hispanic Black patients were more likely to present with metastatic disease (odds ratio 1.11, 95% confidence interval 1.05-1.19), less likely to undergo surgery for localized or regional disease (odds ratio 0.48, 95% confidence interval 0.43-0.53), and had lower survival (hazard ratio 1.21, 95% confidence interval 1.15-1.27) than non-Hispanic White patients. CONCLUSION: Socioeconomic and racial disparities in early-onset colorectal cancer span diagnosis, treatment, and survival. As the disease burden of early-age onset colorectal cancer increases, interventions to boost early diagnosis and access to surgery are necessary to improve survival among minorities and patients with low neighborhood socioeconomic status.

Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

BACKGROUND: Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS: The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS: The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS: In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Racial disparities in rates of invasiveness of resected intraductal papillary mucinous neoplasms in the United States.

BACKGROUND: Racial and ethnic disparities have been observed in the multidisciplinary management of pancreatic ductal adenocarcinoma. Intraductal papillary mucinous neoplasm is the most common identifiable precursor to pancreatic ductal adenocarcinoma, where early surgical intervention before the development of an invasive intraductal papillary mucinous neoplasm improves survival. The association of race/ethnicity with the risk of identifying invasive intraductal papillary mucinous neoplasms during resection has not been previously defined. METHODS: The American College of Surgeons National Quality Improvement Program targeted pancreatectomy database (2014-2021) was queried for patients with race/ethnicity data who underwent resection of an intraductal papillary mucinous neoplasm. Backward Wald logistic regression modeling (P ≤ 0.05 for entry; P > .10 for removal) was used to identify independent predictors of invasion. RESULTS: A total of 4,505 cases of resected intraductal papillary mucinous neoplasms were identified, with 923 (20.5%) demonstrating invasive intraductal papillary mucinous neoplasms. The cohort of individuals other than non-Hispanic Whites were significantly more likely to have invasive intraductal papillary mucinous neoplasms (White, 19.9%; Black, 24.2%; Asian, 23.7%; Hispanic, 22.6%; P = .026). Such disparity could not be explained by greater comorbidity, as non-White patients were significantly younger (age <65 years: 41.7% vs 33.2%, P < .001) and had better physical status (American Society of Anesthesiologists score ≤2: 28.8% vs 25.2%, P = .053). After controlling for clinicodemographic variables, being an individual of race/ethnicity other than White was independently associated with higher odds of invasive intraductal papillary mucinous neoplasms (odds ratio, 1.280; 95% confidence interval, 1.046-1.566; P = .017). No differences in postoperative morbidity were observed. CONCLUSION: In a national cohort of patients with resected intraductal papillary mucinous neoplasms, individuals who identified as being of race/ethnicity other than White were significantly more likely to have invasive intraductal papillary mucinous neoplasms during surgical resection.

Hepatic pseudotumor associated with Strongyloides infection: A case report.

BACKGROUND: Strongyloides sterocoralis is a parasitic infection caused by a roundworm that is transmitted through soil contaminated with larvae. It can infrequently cause hepatic abscesses in immunocompromised patients and is rarely reported to form hepatic lesions in immunocompetent hosts. CASE SUMMARY: We present a case study of a 45-year-old female who presented with right upper quadrant abdominal pain and constitutional symptoms for several weeks. Cross-sectional imaging identified several malignant-appearing liver masses. Further investigation, including serological testing and histopathologic examination, revealed the presence of serum Strongyloides antibodies and hepatic granulomas with extensive necrosis. Following treatment with ivermectin for 2 wk, there was complete resolution of the liver lesions and associated symptoms. CONCLUSION: This case highlights the importance of considering parasitic infections, such as Strongyloides, in the differential diagnosis of hepatic masses. Early recognition and appropriate treatment can lead to a favorable outcome and prevent unnecessary invasive procedures. Increased awareness among clinicians is crucial to ensure the timely diagnosis and management of such cases.

COVID-19 Effect on Surgery for Gastrointestinal Malignancies: Have Operative Volumes Recovered?

BACKGROUND: COVID-19 disrupted elective operations, cancer screening, and routine medical care while simultaneously overwhelming hospital staff and supplies. Operations for gastrointestinal (GI) malignancies rely on endoscopic screening, staging, and neoadjuvant therapy (NAT), each of which was disrupted by the pandemic. The aim was to evaluate the effect of the COVID-19 pandemic on the US national rates of gastrointestinal oncologic operations. METHODS: The Vizient Clinical Data Base® was queried for oncologic operations for esophageal, gastric, and colorectal malignancies with and without NAT from March 2019 to March 2022. Control chart analysis examined operative volume over time while Wilcoxon rank sum tests were used to compare mean monthly volume before and during the pandemic. RESULTS: A total of 95,912 patients were identified over 36 months; 5.8% esophageal, 6.3% gastric, 77.5% colonic, and 10.4% rectal operations. Esophageal operative volume decreased for 9 months during the pandemic and was significantly lower during than before the pandemic (p=0.002). Gastric operations decreased for 10 months early in the pandemic, but rebounded so that after 2 years volumes were unchanged (p=0.49). Colonic operations experienced a sharp decrease for 4 months at the beginning of the pandemic, but volumes quickly increased and overall were unchanged (p=0.29). Rectal operations decreased for 13 months and were significantly lower during than before the pandemic (p=0.018). Oncologic operations for patients receiving NAT varied. CONCLUSION: COVID-19 significantly disrupted the volume of gastrointestinal oncologic operations in the USA. Esophageal and rectal oncologic operations experienced prolonged and significant reductions while gastric and colonic oncologic operations transiently decreased but rebounded during the pandemic.

Association between SMAD4 Mutations and GATA6 Expression in Paired Pancreatic Ductal Adenocarcinoma Tumor Specimens: Data from Two Independent Molecularly-Characterized Cohorts.

Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). SMAD4 alterations and low GATA6 expression/modified "Moffitt" basal-like phenotype have each been associated with inferior survival uniquely for patients receiving 5-FU-based therapies. SMAD4 may directly regulate the expression of GATA6 in PDAC, pointing to a common predictive biomarker. To evaluate the relationship between SMAD4 mutations and GATA6 expression in human PDAC tumors, patients with paired SMAD4 mutation and GATA6 mRNA expression data in the TCGA and CPTAC were identified. In 321 patients (TCGA: n = 180; CPTAC: n = 141), the rate of SMAD4 alterations was 26.8%. The rate of SMAD4 alteration did not vary per tertile of normalized GATA6 expression (TCGA: p = 0.928; CPTAC: p = 0.828). In the TCGA, SMAD4 alterations and the basal-like phenotype were each associated with worse survival (log rank p = 0.077 and p = 0.080, respectively), but their combined presence did not identify a subset with uniquely inferior survival (p = 0.943). In the CPTAC, the basal-like phenotype was associated with significantly worse survival (p < 0.001), but the prognostic value was not influenced by the combined presence of SMAD4 alterations (p = 0.960). SMAD4 alterations were not associated with poor clinico-pathological features such as poor tumor grade, advanced tumor stage, positive lymphovascular invasion (LVI), or positive perineural invasion (PNI), compared with SMAD4-wildtype. Given that SMAD4 mutations were not associated with GATA6 expression or Moffitt subtype in two independent molecularly characterized PDAC cohorts, distinct biomarker-defined clinical trials are necessary.