ObjectivesThe aim of this study was to evaluate the use of cathepsin-activated intraoperative near-infrared (NIR) imaging to detect insulinomas in dogs, a spontaneous large animal model for human disease.Materials and methodsA prospective, pilot clinical trial was performed on dogs with naturally occurring insulinomas undergoing exploratory laparotomy. Each dog underwent routine preoperative diagnostic assessment, and a cathepsin-activated fluorophore (VGT-309) was administered intravenously 1-2 days preoperatively. All intraoperative findings with visible light and NIR imaging were recorded and mean NIR fluorescence intensity of tumors and grossly normal pancreas were quantified. Excision of any identified primary tumor and suspected metastatic lesions was performed. All excised tissues underwent histologic evaluation and immunohistochemistry (IHC) for cathepsin B expression. Descriptive statistics were calculated, and differential fluorescence intensity and cathepsin B expression between the pancreatic mass and adjacent grossly normal pancreatic tissue were assessed for statistical significance via paired t tests with p < 0.05 used for significance.ResultsSix dogs were enrolled. No adverse events occurred secondary to administration of the imaging agent. In situ, insulinomas had significantly greater mean fluorescence intensities than the surrounding pancreas, and the median tumor to background ratio was 1.906 (range 1.286-2.556). One dog had an occult pancreatic mass that was identified intraoperatively with NIR guidance. Background fluorescence of liver and lymph nodes was observed in all cases, and one dog was diagnosed with nodal and hepatic metastasis. Histologic tumor margins correlated with margins of NIR fluorescence. Cathepsin B expression was determined to be significantly greater in the pancreatic tumor compared to adjacent non-neoplastic pancreas via IHC, and there was no overlap in the range of median IHC-positive proportion values for these tissues. However, there was overlap in the range of IHC-positive proportion values for neoplastic pancreatic samples and lymph node and liver tissues.Clinical significanceThe findings of this pilot study support further investigation of cathepsin-activated NIR imaging to enhance intraoperative canine insulinoma localization and margin evaluation. Future studies are needed to further characterize and optimize the utility of targeted NIR imaging, particularly to identify metastatic lesions, for canine insulinoma, which may serve as an effective translational model for humans with pancreatic neuroendocrine tumors.

Introduction Robotic surgery has been increasingly used for the treatment of small bowel neuroendocrine tumors and offers potential advantages in visualization of nodal disease and mesenteric dissection compared to laparoscopy; however, oncologic outcomes of robotic surgery have not yet been characterized. We sought to compare lymph node harvest of robotic surgery versus laparoscopy and associated long-term survival for small bowel neuroendocrine tumors using a large national cohort. Methods The National Cancer Database was queried for patients who underwent robotic surgery/laparoscopy for stage I-III small bowel neuroendocrine tumors from 2015 to 2022. Kaplan-Meier and multivariable Cox proportional hazards analyses were used to assess overall survival. Multivariable logistic regression was used to identify factors associated with adequate lymph node harvest (defined as ≥9 nodes resected). Results Of 5,432 eligible patients, 1,066 (19.6%) underwent robotic surgery. After propensity-matching, robotic surgery was associated with greater lymph node harvest versus laparoscopy (median 17 vs 14 nodes, P < .001) and improvement in select short-term perioperative outcomes. On Cox proportional hazards analysis, the threshold lymph node harvest of ≥9 nodes was associated with the greatest 5-year mortality reduction (adjusted hazard ratio: 0.696, P = .002). On multivariable logistic regression, undergoing robotic surgery was associated with increased likelihood of achieving lymph node harvest of ≥9, even when controlling for tumor characteristics/location (adjusted odds ratio: 2.09, P < .001). Conclusion Robotic surgery was associated with greater lymph node harvest in patients with stage I-III small bowel neuroendocrine tumors compared to laparoscopy. Patients with ≥9 nodes harvested exhibited improved overall survival , and robotic surgery was significantly associated with achievement of this threshold. Robotic surgery may offer technical and oncologic advantages over laparoscopy in appropriately selected patients with resectable small bowel neuroendocrine tumors.

BACKGROUND:The benefit of adjuvant chemotherapy (AC) for ampullary adenocarcinoma is unclear. The Hidden Genome model classifies prognostic subtypes with greater accuracy than standard histologic classification (intestinal [INT] vs pancreatobiliary [PB]), but its predictive capacity to guide the use of AC remains unstudied. METHODS:We applied the Hidden Genome model to an international cohort of 183 patients with resected ampullary adenocarcinoma who underwent genomic sequencing. The model quantified the predicted cell of origin (colorectal vs pancreas/distal bile duct) in all specimens. Overall survival (OS) was compared using Kaplan-Meier estimates, stratified by AC use versus surgery alone (SA). RESULTS:Most patients (n=128; 69.9%) received AC, which was not associated with a significant improvement in OS (median, 50.9 months [95% CI, 36.5-76.9] vs 53.8 months [95% CI, 32.4-119.0]; P=.816). Histologic subtype was neither associated with prognosis (P=.241) nor predictive of chemotherapy efficacy for INT-subtype (P=.379) or PB-subtype (P=.544) tumors. When stratified by genomic subtype, the colorectal group had a favorable prognosis regardless of AC use (median OS, 74.4 months [95% CI, 33.8-97.8] for AC vs 98.7 months [95% CI, 32.4-140.9] for SA; P=.889). Among patients with pancreas/distal bile duct tumors, those who received AC had longer survival compared with those who underwent SA (78.2 months [9.8-not reached] vs 22.7 months [2.3-not reached], respectively; hazard ratio, 0.17 [95% CI, 0.04-0.80]; P=.024). CONCLUSIONS:AC regimens were not associated with improved survival in histologically defined INT- or PB-subtype ampullary adenocarcinoma. However, genomic classification better stratified risk groups and identified patients more likely to benefit from AC.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

INTRODUCTION:Minimally invasive surgery (MIS) has been increasingly used for the treatment of small bowel neuroendocrine tumors (SBNETs). Although some studies have found comparable oncologic outcomes for appropriately selected patients undergoing an MIS approach, comprehensive perioperative outcomes remain insufficiently characterized in this patient population. We sought to evaluate short-term postoperative outcomes of MIS vs open resection of SBNETs in a large national cohort. METHODS:The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent open or laparoscopic/robotic resection of SBNETs from 2012 to 2022. Postoperative outcomes were compared using univariable and multivariable analyses before and after 1:1 propensity-score matching. RESULTS:Of 2096 eligible patients, 848 (40%) underwent MIS resections. On multivariable logistic regression of the overall cohort, the MIS approach was associated with a significantly lower likelihood of experiencing a postoperative complication (adjusted odds ratio, 0.46; P <.001). After propensity-score matching, the MIS approach was associated with a significantly shorter length of stay (4 vs 6 days; P <.001) and fewer skin/soft tissue infections (2.1% vs 6.8%; P <.001), urinary tract infections (0.5% vs 2.4%; P =.004), occurrences of sepsis (0.2% vs 1.2%; P =.038), and blood transfusions (2.4% vs 4.8%; P =.019). CONCLUSION:MIS approaches for SBNET resection are associated with improved short-term perioperative outcomes and, when deemed appropriate based on oncologic considerations, should be part of a surgical oncologist's armamentarium.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

BACKGROUND:Mirizzi syndrome (MS) is a rare cause of biliary obstruction. Historically, malignancy was reported in a subset of MS cases, but previous studies predated modern imaging and routine endoscopic retrograde cholangiopancreatography. This study aimed to determine the prevalence of malignancy in contemporary patients with MS and assess whether modern imaging reliably distinguishes benign from malignant cases. METHODS:Adult patients (≥18 years) with gallbladder pathology (International Classification of Diseases code K83.1 or 576.2) at a tertiary referral center (2012-2022) were reviewed. Two independent reviewers confirmed preoperative MS diagnoses. Clinical, radiological, and surgical factors were compared between patients with a final diagnosis of MS and malignancy using Fisher's exact and Wilcoxon rank-sum tests. RESULTS:Among 7406 patients with gallbladder pathology, 37 (0.5%) had a preoperative MS diagnosis. In 5 cases (13.5%), malignancy was found on final pathology. Patients with malignancy were older (69 vs 60 years; P =.04) and less likely to present with pain (40% vs 96%; P <.01). Time from presentation to surgery was longer in malignant cases (53 vs 18 days; P =.04). Despite a trend toward more imaging (2 vs 3; P =.10), no discrete mass was detected preoperatively. There was no difference in frequency of open (80% malignancy vs 59% MS; P =.61), laparoscopic (20% malignancy vs 41% MS; P =.61), or subtotal cholecystectomy (20% malignancy vs 28% MS; P =.99) during the index operation. CONCLUSION:Malignancy is common in patients undergoing surgery for MS. Contemporary diagnostic approaches have a poor sensitivity for detecting malignancy preoperatively. A high index of suspicion should be maintained, particularly in older patients without pain. Early hepatopancreaticobiliary surgeon involvement in this patient population may optimize surgical outcomes.

Introduction Primary aldosteronism affects 20% of patients with resistant hypertension and may be due to unilateral or bilateral causes. Patients with a unilateral source of aldosterone secretion are potentially curable with adrenalectomy. Adrenal vein sampling (AVS) is the definitive test for subtype differentiation but may not be accessible outside tertiary centers. The goal of this study was to determine whether clinical characteristics can predict a unilateral source of aldosterone on AVS. Methods Patients with a biochemical diagnosis of primary aldosteronism who underwent AVS between 1998 and 2019 were identified from a prospectively maintained database. Unilateral aldosterone secretion was defined as lateralization index ≥4. Univariate and multivariate logistic regression were used to assess the correlation between clinical characteristics and unilateral aldosterone secretion. A risk score was developed to predict a unilateral source of aldosterone. Results Of 461 patients, 61% were male and 39% female. The mean age was 54 ± 11 y, and median duration of hypertension was 10 (interquartile range: 5-20) y. A total of 324 patients had unilateral aldosterone secretion. On multivariate logistic regression analysis, non-Black race, lower body mass index, shorter duration of hypertension, and nonincidental diagnoses were significantly associated with a unilateral source of aldosterone. Neither age nor an adrenal adenoma on imaging was predictive of a unilateral aldosterone source. The clinical risk score had an 86% positive predictive value for a unilateral source of aldosterone. Conclusions Clinical characteristics imperfectly predict subtype differentiation. However, high clinical risk scores have a strong positive predictive value for a unilateral source of aldosterone.

Pancreatic resection not infrequently requires portal vein (PV) repair or replacement. PV reconstruction often requires bypass grafting or patch venoplasty, and these grafts and patches require time to thaw or harvest. Mesenteric ischemia and congestion with associated bowel edema may result from prolonged venous occlusion during thawing, harvesting, and reconstructing. Temporary shunting of the mesenteric venous circulation may mitigate these adverse effects. Twenty-one patients were shunted using Argyle shunts during PV reconstruction from 2010 to 2020. Reconstructions in this series consisted of aortic homograft interposition grafts (52%), bovine pericardial patches (38%), internal jugular vein interposition grafts (5%), and internal jugular patches (5%). No intraoperative complications resulted from shunt placement; technical success of PV reconstruction was 100%. Temporary venous shunting during PV reconstruction is safe, technically straightforward, and may serve to decrease the duration of venous mesenteric occlusion.

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location—perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.

Introduction: Despite superior outcomes with liver transplantation, cirrhotic patients with HCC may turn to other forms of definitive treatment. To understand perioperative outcomes, we examined perioperative mortality and major morbidity after hepatectomy for HCC among cirrhotic and non-cirrhotic patients. Method: ology: The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was queried for liver resection for HCC. Multivariable logistic regression was performed to determine the association between liver texture and risk of major non-infectious morbidity, post-hepatectomy liver failure (PHLF) and 30-day mortality. Results: From 2014 to 2018, 2203 patients underwent hepatectomy: 58.6 % cirrhotic, 12.8 % fatty and 28.6 % normal texture. Overall 30 day-mortality was 2.1 % (n = 46), although higher among fatty liver (2.8 %) and cirrhotic (2.6 %; p = 0.025) patients. The incidence of PHLF was 6.9 %, with hepatectomy type, cirrhosis, and platelet count as major risk factors. Age, resection type, and platelet count were associated with major complications. Trisegmentectomy and right hepatectomy (OR = 3.60, OR = 3.46, respectively) conferred a greater risk of major noninfectious morbidity compared to partial hepatectomy. Among cirrhotics alone, hepatectomy type, platelet count, preoperative sepsis and ASA class were associated with major morbidity. Discussion: Hepatic parenchymal disease/texture and function, presence of portal hypertension, and the extent of the liver resection are critical determinants of perioperative risk among HCC patients.

Importance Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use. Objective To test external validity of the prognostic value of the hidden genome classifier of AA. Design, Setting, and Participants This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020. Exposures The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin. Main Outcome and Measures Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models. Results Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability. Conclusions and Relevance The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

Background: Major vascular involvement is often considered a contraindication to resection of malignant tumors, but in highly selected patients, it can be performed safely, with results that are highly dependent upon the tumor biology. Resection of both the aorta and inferior vena cava (IVC) is a rare undertaking, requiring both favorable tumor biology and a patient fit for a substan-tial surgical insult; nevertheless, it provides the possibility of a cure. Methods: Patients requiring resection and reconstruction of both the aorta and IVC from 2009 through 2019 at 2 university medical centers were included. Patient characteristics, operative technique, and outcomes were retrospectively collected.Results: We identified 9 patients, all with infrarenal reconstruction or repair of the aorta and IVC. All cases were performed with systemic heparinization and required simultaneous aortic and caval cross-clamping for tumor resection. No temporary venous or arterial bypass was used. Since arterial reperfusion with the IVC clamped was poorly tolerated in 1 patient, venous reconstruction was typically completed first. Primary repair was performed in 1 patient, while 8 required replacements. In 2 patients, aortic homograft was used for replacement of both the aor-toiliac and iliocaval segments in contaminated surgical fields. In the remaining 6, Dacron was used for arterial replacement; either Dacron (n = 2) or polytetrafluoroethylene (n = 4) were used for venous replacement. Patients were discharged after a median stay of 8 days (range: 5-16). At median follow-up of 17 months (range 3-79 months), 2 patients with paraganglioma and 1 patient with Leydig cell carcinoma had cancer recurrences. Venous reconstructions occluded in 3 patients (38%), although symptoms were minimal. One patient presented acutely with a thrombosed iliac artery limb and bilateral common iliac artery anastomotic stenoses, treated successfully with thrombolysis and stenting.Conclusions: Patients with tumor involving both the aorta and IVC can be successfully treated with resection and reconstruction. En bloc tumor resection, restoration of venous return before arterial reconstruction, and most importantly, careful patient selection, all contribute to positive outcomes in this otherwise incurable population.

Supplemental Figure 3: The CD4pos Th1 immune response in the peripheral blood pre-vaccination and post-vaccination by tumor staging (DCIS vs. IBC), quantified by (A) response repertoire and (B) cumulative response

Supplemental Table 1: Overall immune response detected in the peripheral blood by route of vaccine administration and ER status