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Meningiomas are the most common type of primary brain tumor; they have a low risk for extracranial metastases, which are primarily associated with increased tumor grade. Hepatic metastases from cranial meningiomas are extremely rare, with only a paucity of cases reported in the literature and no standardized approach to management. Herein, we report a case of an incidentally discovered giant (>20 cm) metastatic meningioma to the liver treated with surgical resection 10 years following resection of a low-grade cranial meningioma. This report also highlights the use of (68Ga) DOTATATE PET/CT as the diagnostic imaging modality of choice when evaluating for meningioma metastases. To our knowledge, this report describes the largest hepatic metastasis from a cranial meningioma to undergo surgical resection in the literature.

Improved post-operative outcomes have been demonstrated in gastrointestinal procedures where a narcotic sparing strategy has been utilized. Data for pancreaticoduodenectomy (PD) patients is limited. This study reviews an institutional database for outcomes based on initial analgesic strategy.1004 consecutive patients who underwent PD at Emory University between 2010 and 2017, were included in the analysis. Patients were divided into groups based on primary analgesic strategy employed: epidural alone (EPI), patient controlled opiate analgesia (PCA), dual (dual-PCA/EPI) and other (non-PCA/EPI). Postoperative outcomes for each group were analyzed utilizing univariate and multivariate linear regression.448 (44.6%) patients were treated with EPI, 300 (29.9%) were given a PCA, 78 (7.8%) had dual-PCA/EPI and 178 (17.7%) had non-PCA/EPI analgesia. On univariate analysis, increased BMI (p = 0.030), PCA use (p 0.001), venous thromboembolism (VTE) (p 0.001), post-operative pancreatic fistula (POPF) (p 0.001) and Ileus/delayed gastric emptying (DGE) (p 0.001) were all correlated with increased LOS. On multivariate linear regression, VTE (b-coefficient 9.07, p = 0.004) POPF (8.846, p = 0.001), Ileus/DGE (4.464, p = 0.004) and PCA use (1.75, p = 0.003) were associated with significantly increased LOS.A primary narcotic sparing strategy is associated with a significantly reduced LOS and lower rates of Ileus/DGE. Mean opiate usage was significantly lower in the EPI and non-EPI/PCA groups.

Supplemental Figures S1-S7

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts >= 1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts >= 1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients.Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics.A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS.Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.

Early identification of complications after distal pancreatectomy splenectomy (DPS) poses challenges, as white blood cell count (WBC) is confounded by physiologic leukocytosis. We examined WBC patterns associated with complications after DPS.Clinicopathologic data were collected for patients who underwent DPS in our system from 2009 to 2016. We examined WBC, temperature, platelet count (PC), and ratios of these variables as potential early indicators of patients at risk of infections or major complications (MCs).348 patients met study inclusion, of whom 206 (59%) were women and the median patient age was 59 ± 15 years. Infectious and MC rates were 11% and 16%, respectively, with1% 30-day mortality. Postoperative WBC peaks were higher in patients with infections and MCs compared with no complication (23 vs. 17, p 0.0001). WBC peak timing occurred postoperative day (POD) 2-3 for uncomplicated cases while peaks occurred POD9 for patients with infections and MCs.These data define patterns of leukocytosis following DPS. Although differences in infection markers were identified for patients with and without complications, no obvious thresholds were identified. Clinical suspicion for complications after DPS remains our best tool for early identification.

Minimally invasive approaches to major liver resection have been limited by presumed difficulty of the operation. While some concerns arise from mastering the techniques, factors such as tumor size and liver parenchymal features have anecdotally been described as surrogates for operative difficulty. These factors have not been systematically studied for minimally invasive right hepatectomy (MIRH). Seventy-five patients who underwent MIRH during 2007–2016 by the senior author were evaluated; these were compared to control group of open right hepatectomy. Demographics, operative, and post-operative variables were collected. Operative times and estimated blood loss, two objective parameters of operative difficulty were correlated to volume of hepatic resection, parenchymal transection diameter and liver parenchymal features using regression analysis. Thirty-eight (50.6%) resections were performed for malignant indications. Average tumor size was 5.7 cm (±3.6), mean operative time was 196 min (±74), and mean EBL was 220 mL (±170). Average transection diameter was 10.1 cm (±1.7). There was no correlation between operative difficulty with parenchymal transection diameter or presence of steatosis. Blood loss was higher with increased right hepatic lobe volume and body mass index. This analysis of a very defined anatomical resection suggests that the often quoted radiographic and pathologic features indicative of a challenging procedure were not significant in determining operative difficulty.

Aortic aneurysms occur concomitantly with malignancy in approximately 1.0-17.0% of patients. There is little published information regarding the effects of subsequent oncological therapies on aortic aneurysm growth. The aim of this study was to determine the effects of chemoradiation therapies on the natural progression of small abdominal aortic aneurysm (AAA), thoracic aortic aneurysm, and thoracoabdominal aortic aneurysm.Patients with aortic aneurysms with and without malignancy between 2005 and 2017 were identified within institutional databases using Current Procedural Terminology and International Classification of Disease codes. Inclusion criteria included complete chemotherapy documentation, a minimum of 3 multiplanar axial/coronal imaging or ultrasonography before, during, and after receiving therapy or 2 studies for patients without malignancy. Propensity matching, Cox and linear regression, and Kaplan-Meier survival analyses were performed.A total of 159 (172 aneurysms) patients with malignancy and 127 (149 aneurysms) patients without malignancy were included. Average patient demographics were 74.4 ± 9.8-years-old, Caucasian (66.8%), male (70.3%), with hypertension (71.1%), current smoking (24.5%), coronary atherosclerotic disease (26.2%), and AAA (71.0%). The most common malignancy was lung cancer (48.4%) with most chemotherapy regimens including a platinum-based alkylating agent and concurrent antimetabolite (56.0%). The overall median follow-up time was 28.2 (range 3.1-174.4) months. Aortic aneurysms in patients without malignancy grew to larger sizes (4.43 ± 0.96 vs. 4.14 ± 1.00, P = 0.008) with similar median growth rates (0.12 vs. 0.12 cm/year, P = 0.090), had more atypical morphologic features (14.1% vs. 0.6%, P 0.001), more frequently underwent repair (22.1% vs. 8.7%, P = 0.001), and more frequently required emergency repair for rupture (5.4% vs. 0.0%, P = 0.087). Cox regression identified initial aortic size ≥4.0 cm (hazard ratio [HR] 3.028), AAA (HR 2.146), chronic aortic findings (3.589), and the use of topoisomerase inhibitors (HR 2.694). Linear regression demonstrated increased growth rates predicted by antimetabolite chemotherapy (β 0.170), initial aortic size (β 0.086), and abdominal aortic location (β 0.139, all P 0.002).Small aortic aneurysms with concomitant malignancies are discovered at smaller initial sizes, grow at similar rates, require fewer interventions, and have fewer ruptures and acute dissections than patients without malignancy. Antimetabolite therapies modestly accelerate aneurysmal growth, and patients receiving topoisomerase inhibitors may require earlier repair. Patients with concomitant disease can be confidently treated according to standard institutional aneurysm surveillance protocols. Overall, we recommend treatment of the malignancy before small aortic aneurysm repair as these aneurysms behave similarly to those in patients without malignancy.

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

The cause of most pancreatic and periampullary cancers (PAC) is unknown. Recently, anatomic variations such as pancreatobiliary maljunction have been recognized as risk factors, similar to Barrett-related gastro-esophageal cancers.Pre-operative MRI from 860 pancreatic/biliary resections, including 322 PACs, were evaluated for low-union (cystic duct joining the common hepatic duct inside of the pancreas or within 5 mm of the pancreatic border) RESULTS: Low-union, seen10% of the population, was present in 44% of PACs (73% distal bile duct/cholangiocarcinoma, 42% pancreatic head, and 34% ampullary). It was significantly lower(11%) in conditions without connection to the ductal system (thus not exposed to the ductal/biliary tract contents), namely mucinous cystic neoplasms and intrahepatic cholangiocarcinomas(p0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p0.0001).This study establishes an association between low-union and PACs, and points to an anatomy-induced chemical/bilious carcinogenesis. This may explain why most pancreas cancers are in the head. It is possible that the same chemical milieu, caused by conditions other than low-union/insertion, may also play a role in the remaining half of PACs. This opens various treatment opportunities including milieu modifications (chemoprevention), focused screening of at-risk patients, and early detection with possible corrective actions.

Existing research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system.From 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan-Meier survival curves and multivariate cox proportional regression analysis.Of 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p 0.001) and increasing age (p = 0.001) were associated with reduced survival.In contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC.

Background The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. Methods In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. Results MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. Conclusions In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

Background Postoperative returns to acute care represent fragmented care, are costly, and often evolve into readmission. Reduction of postoperative readmissions and emergency department visits represents an opportunity to improve quality of care and decrease resource use. The aim of this study was to assess the impact of 2 failure modes and effects analysis-guided quality improvement interventions on return to acute care within 30 days postoperatively. Methods An American College of Surgeons NSQIP database analysis of adult patients treated by a single hepatopancreatobiliary surgeon at a quaternary academic center was performed. Two failure modes and effects analysis-guided quality improvement interventions were assessed in a staged fashion, including a post-discharge phone call follow-up, and a preoperative clinic visit to discuss plans of care. The primary end point of interest was return to acute care (readmission or emergency department use) within 30 days from postoperative discharge. Results During the 4-year study period, 684 patients underwent a hepatopancreatobiliary operation. After the implementation of the failure modes and effects analysis interventions, the baseline 30-day readmission rate was reduced by 48% post intervention (13.5% vs 6.9%; p = 0.011). This impact was sustained, with a readmission rate below the lowest baseline in 5 of 6 postintervention quarters. Short-stay readmissions were reduced by > 76% after the interventions (28.5% vs 6.6%). Post-discharge emergency department visits were also reduced by nearly 40% after initiation of both failure modes and effects analysis-guided quality improvement interventions (11.3% vs 6.9%; p = 0.125), which showed similar sustained response. Conclusions The results from this study can be used to help identify, develop, and test interventions to optimize emergency department use and readmission to reduce healthcare costs and improve patient quality of life.

Background The amount of IV fluids sufficient to prevent post-operative acute kidney injury (AKI) during pancreaticoduodenectomy (PD) is unknown. We assessed the restrictive IOIVF use in PD on the rate of post-operative AKI, delayed gastric emptying and ileus, and pancreatic fistulas (POPF). Methods Patients who underwent PD between 2012 and 2017 were reviewed. Univariate and multivariate analyses looked for association between pre- and intra-operative factors on AKI, ileus and POPF. Results Of 395 included patients, 97, 172, and 126 patients received less than 1000 mL (ultra-restrictive), 1000 mL to less than 2000 mL (restrictive), and 2000 mL and greater (nonrestrictive) normalized total IOIVF respectively. Of these 23 (24.2%), 34(20.4%), and 21(17.4%) developed AKI respectively, most of them mild. There was no difference in odds of developing AKI, ileus, or pancreatic fistula among fluid groups. While there was no difference in Clavien-Dindo III-IV complications, the incidence of Clavien-Dindo type I-II complications was lower in the restricted fluid groups. Discussion Restricted fluids did not lead to higher AKI rates but were associated with fewer low-grade complications.

Preinvasive tumor-forming gallbladder neoplasms that are composed of small, non-mucinous tubules with complex architecture remain a poorly characterized group. Here, we evaluated the clinicopathological characteristics of this entity. Twenty-eight examples were analyzed. Tumors were invariably pedunculated polyps with thin stalks, often presented as loosely attached intraluminal nodules, with cauliflower architecture (akin to cholesterol polyps) comprised of compact, back-to-back acinar-like, small tubular units with minimal/no cytoplasm showing variable complexity, creating a picture distinct from the other tubular type dysplasia in the gallbladder. Their limited stroma showed distinctive amorphous amyloid-like hyalinization (39%). While some had round nuclei with single prominent nucleoli, others exhibited slightly more elongated nuclei with washed out chromatin reminiscent of papillary thyroid carcinoma. Squamoid/meningothelial-like morules (71%) and subtle neuroendocrine cell clusters (39%) were frequent. The level of cytoarchitectural atypia qualified as high-grade dysplasia (HGD) in all cases, but none were invasive. The background mucosa showed no dysplasia, but cholesterolosis. The majority (n = 8/12) showed diffuse MUC6 expression and lacked MUC5AC expression. Based on these observations, 635 gallbladder carcinomas were re-analyzed for residual/adjacent lesions with entity-defining characteristics disclosed here, and none could be identified. Preinvasive tubular non-mucinous neoplasm of the gallbladder, which we propose to classify as intracholecystic tubular non-mucinous neoplasm, is a clinicopathologically discrete entity, which tends to occur in uninjured gallbladders and in association with cholesterol polyps. By being tubular, non-mucinous and MUC6-positive, it is akin to intraductal tubulopapillary neoplasms of pancreatobiliary tract, but it is also different in many other aspects. Although their cytoarchitectural complexity warrants an HGD/carcinoma classification, they do not show invasion and their distinct characteristics warrant their separate classification.

BACKGROUND. Pancreatoduodenectomy (PD) for duodenal adenoma (DA) resection may be associated with excessive surgical risk for patients with potentially benign lesions, given the absence of pancreatic duct obstruction. We examined factors associated with final malignant pathology and evaluated the postoperative course of patients with DA versus pancreatic ductal adenocarcinoma (PDAC). METHODS. We retrospectively analyzed patients with DA who underwent PD from 2008 to 2018 and assessed the accuracy rate of preoperative biopsy and factors associated with final malignant pathology. Complications for DA patients were compared with those of matched PDAC patients. RESULTS. Forty-five consecutive patients who underwent PD for DA were identified, and the preoperative biopsy false negative rate was 29. Factors associated with final malignant pathology included age over 70 years, preoperative biliary obstruction, and common bile duct diameter > 8 mm (p < 0.05). Compared with patients with PDAC (n = 302), DA patients experienced more major complications (31% vs. 15%, p < 0.01), more grade C postoperative pancreatic fistulas (9% vs. 1%, p < 0.01), and greater mortality (7% vs. 2%, p < 0.05). Propensity score matched patients with DA had more major complications following PD (32% vs. 12%, p < 0.05). CONCLUSIONS. Preoperative biopsy of duodenal adenomas is associated with a high false-negative rate for malignancy, and PD for DA is associated with higher complication rates than PD for PDAC. These results aid discussion among patients and surgeons who are considering observation versus PD for DA, especially in younger patients without biliary obstruction, who are less likely to harbor malignancy.

Background Limited literature is available on the postoperative development of impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) following Distal Pancreatectomy (DP). We aimed to study the post-surgical clinical evolution of IGT/DM and its association with preoperative glycemic profiles of patients undergoing DP. Methods Pre- and postoperative glycemic laboratories were measured in patients undergoing DP by the senior author from 2007–2017. Multivariate risk factor analysis was performed to determine risk factors for new-onset IGT/DM after DP. Kaplan–Meier curves were constructed for development of NODM postoperatively. Results Of 216 included patients, n = 63, n = 68 and n = 85 were preoperatively diagnosed with no-diabetes (No-DM), pre-diabetes (Pre-DM), and diabetes (DM), respectively. At 2-year follow-up, n = 37, n = 80 and n = 99 were classified as No-DM, Pre-DM or DM, respectively. Pre-diabetics had a higher risk of developing postoperative dysglycemia (RR 2.230, 95% CI 1.732–2.870, p = 0.001). Preoperative OGTT>130, HbA1c >6.0, and chronic pancreatitis were risk factors for postoperative DM. Conclusion 40% of patients undergoing DP were unaware of their dysglycemic status (pre-DM or DM) pre-operatively. At 2-year follow-up, 36% non-diabetic and 57% pre-diabetic patients had developed NODM. Appropriate pre-operative diabetic assessment is warranted for all patients undergoing pancreatic resections.

Bile cultures (BC) have routinely been used to guide empiric antibiotic therapy for developing postoperative infections. The ability of BCs to predict sensitivity and resistance patterns (SRP) of site of infection cultures (SOIC) remains controversial. The aim was to assess the concordance of pathogens and SRPs between paired BC/SOICs.Medical records of consecutive patients undergoing pancreaticoduodenectomy were reviewed between 2014 and 2018. BC/SOIC pathogens and SRPs were compared on a patient-by-patient basis and concordance (K) was assessed.Common patient characteristics of 522 included patients were 65-years-old, Caucasian (75.5%), male (54.2%), malignant indication (79.3%), and preoperative biliary stent (59.0%). Overall, 275 (89.6%) BCs matured identifiable isolates with 152 (55.2%) demonstrating polymicrobial growth. Ninety-two (17.6%) SOICs were obtained: 48 and 44 occurred in patients with and without intraoperative BCs. Stents were associated with bacteriobilia (85.7%, K = 0.947, p 0.001; OR 22.727, p 0.001), but not postoperative infections (15.2%; K = 0.302, p 0.001; OR 1.428, p = 0.122). Forty-eight patients demonstrated paired BC/SOICs to evaluate. Pathogenic concordance of this group was 31.1% (K = 0.605, p 0.001) while SRP concordance of matched pathogens was 46.7% (K = 0.167, p = 0.008).Bile cultures demonstrate poor concordance with the susceptibility/resistance patterns of postoperative infections following pancreaticoduodenectomy and may lead to inappropriate antibiotic therapies.

Better prognostication/stratification of pancreatic neuroendocrine tumors (PanNETs) is needed. In this detailed morpheomic study of 163 resected PanNETs, 11 unusual variants, some of which were not previously recognized, and others scarcely documented in the literature, were identified, and their pathologic characteristics were further analyzed. By behavior and clinicopathologic associations, these variants could be grouped into three prognostically different categories. I. More aggressive (20%). Included in this group were the variants that in average showed higher grade and stage and adverse outcome including oncocytic, plasmacytoid, lipid-rich and previously unrecognized hepatoid variants, which often had a more diffuse/broad-band growth pattern, with some also displaying discohesiveness. They were characterized by abundant cytoplasm and often had prominent nucleoli (as seen in metabolically active cells), thus the provisional name "metabolic cell phenotype." Because of their diversion from classical neuroendocrine cytomorphology, these variants created challenges on original diagnostic workup, particularly hepatoid examples, which revealed Arginase 1/Hep Par-1 expression in 50%. II. Less aggressive (10%). These cases either showed signs of maturation, including nested growth, paraganglioid pattern (which was previously unrecognized), and organoid PanNETs such as "ductulo-insular" growth, or showed symplastic/degenerative changes, and despite their paradoxically disconcerting histology, were more benevolent in behavior. III. Undetermined. There were other variants including mammary tubulolobular-like, pseudoglandular, peliotic, and sclerotic PanNETs, which although diagnostically challenging, their biologic significance could not be determined because of rarity or heterogeneous characteristics. Prognostic associations: Features that were significantly different in the more aggressive group than the less aggressive group were median size (5.0 vs 1.6 cm, p < 0.001), percentage of pT3+T4 cases (72% vs 12%, p < 0.001), Ki67 index (5.3% vs 2.3%, p = 0.001), % G2 and G3 cases (77% vs 27%, p < 0.001), and rate of lymph node and distant metastasis (96% vs 27%, p < 0.001). In stepwise logistic regression model using the 3 established prognosticators of T stage, size, and grade along with morphology, only aggressive-morphology (metabolic cell phenotype) was found to be associated with metastatic behavior with an odds ratio of 5.9 with 95% confidence interval (C.I.) 1.688 to 22.945 and p value 0.007. In conclusion, PanNETs display various morphologic patterns that are not only challenging and important diagnostically but appear to have biologic significance. Tumors with more diffuse growth of cells with nucleoli and abundant cytoplasm and/or discohesion (oncocytic, hepatoid, lipid-rich, plasmacytoid PanNETs), provisionally termed "metabolic cell phenotype," show aggressive characteristics and are an independent determinant of adverse outcome and thus may require closer post-surgical follow-up, whereas variants with more degenerative or mature features (ductuloinsular, pleomorphic, paraganglioma-like) appear to be more benevolent despite their more atypical and worrisome morphology.

Surgical resection remains the only potentially curative therapy for pancreatic ductal adenocarcinoma (PDAC). There is paucity of literature about morbidity and mortality in older patients with PDAC undergoing pancreaticoduodenectomy. This retrospective analysis evaluates the in-hospital 30-day mortality of this population utilizing the Nationwide Inpatient Sample (NIS) database.All US patients hospitalized for pancreaticoduodenectomy (Whipple procedure) were included. Data was obtained from the NIS provided by the Agency for Healthcare Research and Quality. Pancreaticoduodenectomy diagnoses were identified using Clinical Classifications Software codes based on ICD-9 between 2007 and 2010. Univariable and multivariable analyses were performed using the logistic model, weighted chi-square test, and generalized linear model.A total of 6149 patient discharges for pancreaticoduodenectomy were identified. Mean age was 64.9 years (SD ± 12.3); 21% of patients were ≥ 76 years of age. Majority were White (N = 5257, 77.9%) with a male:female ratio of 1. Patients aged 76 and older (OR: 1.76; 1.36-2.28; p .001), Hispanics (OR: 1.40; 0.92-2.13; p = .12), and high comorbidity score (OR: 5.70; 3.44-9.46; p .001) were found to be associated with a higher risk of 30-day in-hospital mortality. In the multivariable analysis, advanced age (76) remained a significant predictor of longer in-hospital length of stay (OR: 1.09; 1.04-1.14; p .001) and 30-day in-hospital mortality (OR 1.46; 1.07-2.00; p = .016). The 30-day in-hospital mortality rate for all patients across all years was 3.24%, for patients76 years 4.11% and for patients76 years 2.77%. Patients who underwent surgery at teaching hospitals (OR: 0.61; 0.42-0.88; p = .008) had a lower risk of 30-day in-hospital mortality compared to non-teaching hospitals.In-hospital 30 day mortality was higher in selected older patients with PDAC undergoing pancreaticoduodenectomy. Mortality was lower at high volume and teaching centers. Further stringent selection criteria are needed to decrease mortality in the older population.

For patients with periampullary adenocarcinoma (PAC), pancreatoduodenectomy (PD) provides the best survival. Surgery on a subset of patients is aborted during PD. We analyzed these patients.Patients who underwent laparotomy for planned PD for PAC were identified (2006-2019). From operative notes, we identified the subset with intraoperative decision to abort. Patient, treatment, and outcome data were analyzed. The subset with pancreatic ductal adenocarcinoma (PDAC) was analyzed for survival.Only 6.7% (n = 55/819) of cases were aborted. Majority 78% (n = 43) had pathologically-confirmed diagnoses at time of surgery, and 18.2% (n = 10) received preoperative chemotherapy. Reasons for aborted PD included: distant metastases (65.5%, n = 36) and local invasion (34.5%, n = 19). Of patients with metastatic disease, 75% (n = 27) had liver metastases. Eighty-nine percent (n = 49) of patients underwent at least one palliative bypass procedure and 81.8% (n = 45) had both gastric and biliary bypass. Patients with computed tomography (CT) scans before surgery more commonly had missed metastatic disease (79.2% CT compared to 54.8% magnetic resonance imaging [MRI], χMajority of pancreatoduodenectomies for periampullary adenocarcinoma are done to completion. Liver metastases is the most common reason for aborting. Preoperative MRI may help identify hepatic metastases.

Morbidity after pancreaticoduodenectomy (PD) has been reported to be about 30-53%. These complications can double hospital costs. We sought to explore the financial implications of complications after PD in a large institutional database.A retrospective analysis of patients undergoing PD from 2010-2017 was performed. Costs for index hospitalization were divided into categories: operating room, postoperative ward, radiology and interventional radiology. Complications were categorized according to the Clavien-Dindo classification. Univariable and mutivariable analysis were performed.Median cost of index admission for 997 patients who underwent PD was $23,704 (range $10,988-$528,531). Patients with major complications incurred significantly greater median costs compared to those without ($40,005 vs $21,306, p 0.001). Patients with postoperative pancreatic fistula (POPF) grade A, B and C had progressively increasing costs ($32,164, $50,264 and $102,013, p 0.001). On multivariable analysis ileus/delayed gastric emptying, respiratory failure, clinically significant POPF, thromboembolic complications, reoperation, duration of surgery240 minutes and male sex were associated with significantly increased costs.Complications after PD significantly increase hospital costs. This study identifies the major contributors towards increased cost post-PD. Initiatives that focus on prevention of complications could reduce associated costs and ease financial burden on patients and healthcare organizations.

Insulinomas are rare endocrine malignancies of the pancreas that require surgical resection but can be difficult to localize preoperatively. We sought to review and improve the accuracy of preoperative localization techniques at our institution. We retrospectively reviewed all insulinomas that underwent resection at our institution between 1998 and 2016. Localization techniques include selective arterial calcium stimulation (CaStim), CT, MRI, angiography, and somatostatin receptor scintigraphy. Thirty-eight patients had pathologically proven insulinomas on surgical resection. Localization accuracies of CaStim, CT, and MRI were 89 per cent (31/35), 67 per cent (22/33), and 46 per cent (11/24), respectively. When compared with CTalone and CaStim alone, the combination of these two modalities resulted in 100 per cent preoperative localization (30/30), whereas the use of CaStim alone resulted in 80 per cent (4/5) localization and the use of CT alone resulted in 66 per cent (2/3) localization. Four of our patients had both negative CT and MRI. Among these patients, CaStim was 100 per cent localizing and the only positive modality for these patients. These data confirm that CaStim is accurate in preoperatively identifying single and multiple insulinomas; and when combined with CT, this accuracy is increased to 100 per cent. Based on these data, we propose that a dual imaging approach is a superior means of preoperative localization.

Serous cystadenoma (SCA) is a relatively rare benign pancreatic neoplasm. It has a very distinctive gross and microscopic appearance including pure and mixed microcystic and macrocystic patterns as well as rare solid architectural pattern. In this article, we present a rare case of SCA with a complex florid papillary architecture. A 40-year-old man was diagnosed with a 3.5 cm SCA of the uncinate process of the pancreas based on abdominal computed tomography scan. The tumor was monitored radiographically until recent magnetic resonance imaging showed a new 1.0-cm eccentric mural nodule within the tumor with multiple arterial enhancing septations and features suspicious for a neuroendocrine tumor. A pylorus-preserving Whipple procedure was subsequently performed and the mass was resected. Gross examination confirmed the radiological findings of a well-demarcated, 3.5 cm multicystic pancreatic lesion with a 1.0 cm circumscribed, tan solid nodule at its periphery. Microscopic evaluation revealed a predominantly microcystic pattern classical of SCA with occasional macrocysts. The 1.0 cm discrete nodule was also a SCA, but showed unusually exuberant complex papillary growth. To our knowledge, this is the first reported case describing this morphologic variant. Recognition of this rare and unusual pattern is important to avoid misdiagnosis, especially on small biopsy specimens.

BACKGROUND The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). METHODS A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. RESULTS A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts ≥1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts ≥1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

Minimally invasive approaches to major liver resection have been limited by presumed difficulty of the operation. While some concerns arise from mastering the techniques, factors such as tumor size and liver parenchymal features have anecdotally been described as surrogates for operative difficulty. These factors have not been systematically studied for minimally invasive right hepatectomy (MIRH).Seventy-five patients who underwent MIRH during 2007-2016 by the senior author were evaluated; these were compared to control group of open right hepatectomy. Demographics, operative, and post-operative variables were collected. Operative times and estimated blood loss, two objective parameters of operative difficulty were correlated to volume of hepatic resection, parenchymal transection diameter and liver parenchymal features using regression analysis.Thirty-eight (50.6%) resections were performed for malignant indications. Average tumor size was 5.7 cm (±3.6), mean operative time was 196 min (±74), and mean EBL was 220 mL (±170). Average transection diameter was 10.1 cm (±1.7). There was no correlation between operative difficulty with parenchymal transection diameter or presence of steatosis. Blood loss was higher with increased right hepatic lobe volume and body mass index.This analysis of a very defined anatomical resection suggests that the often quoted radiographic and pathologic features indicative of a challenging procedure were not significant in determining operative difficulty.

Background Both pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) have yet to widely benefit from T cell-targeted immunotherapy and have universally poor prognoses. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in preclinical models of PDAC.1 Mechanistically, Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade. Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic and colorectal cancers. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy. Methods During the phase II portion, PDAC or mCRC patients (n=16 each) were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies were obtained at baseline and at week two on treatment. A comprehensive panel of immunologic correlatives studies is being conducted to examine treatment-induced alterations in the tumor microenvironment and peripheral blood. Results As of August 23rd, 2020, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 15 patients (n=7 PDAC and n=8 mCRC). These specimens underwent single cell mass cytometry (CyTOF) analysis to assess immunophenotypic markers of T and myeloid cells. Using this approach, we have generated a comprehensive view of the immune landscape at baseline and following treatment. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. In addition to these correlative studies, using immortalized and primary CAF from PDAC patients, we have shown XL888 dampens production of IL-6 and other cytokines in vitro. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore also being assessed. Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients. Trial Registration This clinical trial is underway and registered with the ID NCT03095781. Ethics Approval The study was approved by Emory University’s Ethics Board, approval IRB00087397. Reference Zhang Y, Ware MB, Zaidi M, Ruggieri AN, Olson B, Komar H, Farren MR, Nagaraju GP, Zhang C, Chen Z, Sarmiento J, Ahmed R, Maithel SK, El-Rayes BF, Lesinski GB. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. Molecular Cancer Therapeutics 2020.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

Optimal diagnostic and surgical approaches for patients with bile duct injuries (BDI) remain debated. This study reviews results from a standardized approach to management of high-grade BDIs at a North American center. Patients undergoing surgical repair for BDIs over a 15-year period were included. Post-operative outcomes and biliary patency rates were calculated using imaging, laboratory values, and patient interviews. A total of 107 consecutive patients underwent repair for BDIs. Bismuth grade I/II injuries were identified in 46 patients (41%), grade III/IV in 41 (38%), grade V in 11 patients (10%), and 9 (10%) were unclassified. BDI anatomy was commonly identified using magnetic resonance imaging (MRI) (75%). Concomitant arterial injuries were identified in 30 (28 with formal angiography). Fifteen had early repairs (within 4 days) and remainder interval repairs (median: 65 days). Hepp-Couinaud repair was method of choice (83%). Estimated primary biliary patency was 100% at 30 days and 87% at 5 years. With appropriate referral to a specialist, surgical reconstruction of BDIs can have excellent outcomes, even with accompanying arterial injuries. Based on our experience, MR as first imaging modality and supplemental angiography served as the optimal diagnostic strategy. Delayed repair, using Hepp-Couinaud technique, with selective liver resection results in high long-term patency rates.

Background The use of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has increased in recent years. Limited data exists on the impact of NAC on biliary microbiome. Methods Patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2014 and 2017 were reviewed. Patients were stratified into two groups based on their NAC status for comparison. Results Of 168 patients included, 63 (37.5%) received NAC. Patients who received NAC exhibited significantly increased growth of Gram-negative anaerobic bacteria (p = 0.043). Patients in the non-NAC group were more likely to grow pathogens resistant to ampicillin-sulbactam (47% vs 21%, p = 0.007), cefazolin (49% vs 28%, p = 0.040), cefoxitin (42% vs 11%, p = 0.009) and cefuroxime (26% vs 4%, p = 0.019). NAC status did not impact infectious postoperative outcomes, including SSIs. Conclusion Patients who did not receive NAC were more likely to grow pathogens resistant to cephalosporins. Perioperative antibiotic prophylaxis should be tailored to cover Gram-negative organisms and enterococci.

Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (

Literature is varied regarding risk factors associated with diabetes development after major pancreatic resection. The aim was to develop and validate a scoring index that preoperatively predicts the development of diabetes after pancreaticoduodenectomy and distal pancreatectomy.In this prospective study, perioperative fasting and postprandial (OGTT, oral glucose tolerance test) plasma glucose, glycated hemoglobin A1c (HbA1c), insulin, and c-peptide were measured in select consecutive patients undergoing pancreaticoduodenectomy and distal pancreatectomy by the senior author, from 2007 to 2018. American Diabetes Association definitions were used for glycemic classifications. Statistical analyses included multivariate generalized estimated equation for factor identification and variable weighting; area under the receiver operating curve (ROC) c-statistic for predictive ability, and survival analysis risk score grouping.Of 1,083 included patients with preoperative normoglycemia (253; 23.4%), prediabetes (362; 33.4%), and diabetes (468; 43.2%), the overall postoperative incidence of each diabetic class at 120 months was 152 (14.0%), 466 (43.0%), and 465 (42.9%), respectively. The development and validation groups included 1,023 and 60 patients, respectively. Five factors were identified predicting diabetes development, with a total possible score of 8. The C-statistics for development and validation groups were 0.727 (CI 0.696 to 0.759, p 0.001) and 0.823 (CI 0.718 to 0.928, p0.001), respectively. At a cut point of 3 (sensitivity 0.691, specificity 0.644) the Post-pancreatectomy Diabetes Index (PDI) independently predicted diabetes in development (odds ratio [OR] 4.298, relative risk [RR] 2.486, CI 1.238 to 5.704, p0.001) and validation (OR 6.970, RR 2.768, CI 2.182 to 22.261, p0.001) groups. The PDI similarly predicted pre-diabetes in development (OR 1.961, RR 1.325, CI 1.202 to 2.564, p0.001) and validation (OR 4.255, RR 1.798, CI 1.247 to 14.492, p = 0.021) groups.The Post-pancreatectomy Diabetes Index predicts the development of diabetes and pre-diabetes in patients undergoing major pancreatectomy using routine endocrine laboratories and pre-surgical clinical data.

PD-1 targeted therapy has dramatically changed advanced cancer treatment. However many questions remain, including specificity of T cells activated by PD-1 therapy and how peripheral blood analysis correlates to effects at tumor sites. In this study, we utilized TCR sequencing to dissect the composition of peripheral blood CD8 T cells activated upon therapy, comparing it with tumor-infiltrating lymphocytes. We report on a nonagenarian melanoma patient who showed a prominent increase in peripheral blood Ki-67+ CD8 T cells following brain stereotactic radiation and anti-PD-1 immunotherapy. Proliferating CD8 T cells exhibited an effector-like phenotype with expression of CD38, HLA-DR and Granzyme B, as well as expression of the positive costimulatory molecules CD28 and CD27. TCR sequencing of peripheral blood CD8 T cells revealed a highly oligoclonal repertoire at baseline with one clonotype accounting for 30%. However, the majority of dominant clones - including a previously identified cytomegalovirus-reactive clone - did not expand following treatment. In contrast, expanding clones were present at low frequencies in the peripheral blood but were enriched in a previously resected liver metastasis. The patient has so far remained recurrence-free for 36 months, and several CD8 T cell clones that expanded after treatment were maintained at elevated levels for at least 8 months. Our data show that even in a nonagenarian individual with oligoclonal expansion of CD8 T cells, we can identify activation of tumor-infiltrating CD8 T cell clones in peripheral blood following anti-PD-1-based immunotherapies.

With the proliferation of bariatric surgery, there is a need to learn “the new anatomy” in these patients and the possible scenarios surgeons could face when foregut surgery is indicated. In particular, some cases of bile duct injuries after laparoscopic cholecystectomy (and any biliary reconstruction) could occur in this population; thus a whole armamentarium of techniques are needed accordingly to manage this problem. Although it is important to know the bariatric technique used previously in each patient beforehand, this chapter presents the current surgical techniques that are critical to know in this setting.

Background: The role of laparoscopy for major hepatectomies remains a matter of development to be further assessed. The purpose of this study is to compare the short-and long-term outcomes between laparoscopic and open major hepatectomies meta-analyzing individual patient data from published comparative studies. Methods: All retrospective studies comparing between laparoscopic and open major hepatectomies published until March 2017 were identified independently by 2 reviewers by searching in PubMed and Cochrane Central Register of Controlled Trials. Individual patient data were sought from all selected studies. Postoperative outcomes, including intraoperative blood loss, operative time, hospital stay, postoperative complications, mortality rates, and long-term survival were analyzed. Results: A total of 917 patients were divided into the laparoscopic (427) and open (490) groups from 8 selected studies. The hospital stay was significantly shorter, and the total morbidity was lower in the laparoscopic group. When classified by severity, the incidence of postoperative minor complications was lower; however, that of major complications was not significantly different. The operative time was longer in the laparoscopic group; however, intraoperative blood loss, perioperative mortality, and blood transfusions were comparable between the 2 groups. The overall survival in the patients with colorectal liver metastases and hepatocellular carcinoma was not significantly different between the 2 groups. Conclusion: Laparoscopic major hepatectomies offer some perioperative advantages, including fewer complications and shorter hospital stay, without increasing the blood loss volume and mortality. Whether these results can anticipate the outcomes in future randomized controlled trials has not been determined. (C) 2018 Elsevier Inc. All rights reserved.

Background Management of pancreatic cancer (PC) in elderly patients is unknown; clinical trials exclude patients with comorbidities and those of extreme age. This study evaluated treatment patterns and survival outcomes in elderly PC patients using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data. Materials and Methods Histology codes 8140, 8500, 8010, 8560, 8490, 8000, 8260, 8255, 8261, 8263, 8020, 8050, 8141, 8144, 8210, 8211, or 8262 in Medicare Parts A and B were identified. Data regarding demographic, characteristics, treatments, and vital status between 1998 and 2009 were collected from the SEER. Determinants of treatment receipt and overall survival were examined using logistic regression and Cox proportional hazards models, respectively. Results A total of 5,975 patients met inclusion. The majority of patients were non-Hispanic whites (85%) and female (55%). Most cases presented with locoregional stage disease (74%); 41% received only chemotherapy, 30% chemotherapy and surgery, 10% surgery alone, 3% radiation, and 16% no cancer-directed therapy. Patients with more advanced cancer, older age, and those residing in areas of poverty were more likely to receive no treatment. Among patients 66–74 years of age with locoregional disease, surgery alone (hazard ratio [HR] = 0.54; 95% confidence interval [CI]: 0.39–0.74) and surgery in combination with chemotherapy (HR = 0.69; 95% CI: 0.53–0.91) showed survival benefit as compared with the no treatment group. Among patients ≥75 years of age with locoregional disease, surgery alone (HR = 2.04; 95% CI: 0.87–4.8) or in combination with chemotherapy (HR = 1.59; 95% CI: 0.87–2.91) was not associated with better survival. Conclusion Treatment modality and survival differs by age and stage. Low socioeconomic status appears to be a major barrier to the receipt of PC therapy among Medicare patients. Implications for Practice Elderly patients with cancer are under-represented on clinical trials and usually have comorbid illnesses. The management of elderly patients with pancreatic cancer is unknown, with many retrospective experiences but low sample sizes. Using Surveillance, Epidemiology, and End Results-Medicare linked data to analyze treatment patterns and survival of elderly patients with pancreatic cancer on a larger population scale, this study highlights treatment patterns and their effect on survival and proposes possible obstacles to access of care in elderly patients with pancreatic cancer other than Medicare coverage.

BackgroundPancreatic ductal adenocarcinoma (PDAC) has yet to widely benefit from T cell-targeted immunotherapy and displays universally poor prognosis. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in murine models of PDAC (Zhang Y. et al., Mol Cancer Ther, 2020). Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade in preclinical systems.MethodsBased on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic cancer. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy of checkpoint blockade in a tumor type that is otherwise refractory to this approach. During the phase II portion patients were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies and blood samples were obtained at baseline and at week two on treatment and CyTOF was used to assess changes in circulating and tumor infiltrating immune populations. Further, CyTOF profiling of circulating immune cells was performed to assess impacts of XL888 on over thirty phenotypically defined immune populations (figure 1).ResultsAs of June 2021, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 8 patients and paired peripheral blood mononuclear cell samples have been analyzed in 24 patients. Our CyTOF analysis illustrated a surprising increase in myeloid cell populations within the tumor following treatment. Analysis of circulating immune cells illustrated a decrease in natural killer cells and Th17 populations following treatment while naïve B cells were increased. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore being assessed as a potential mechanism to explain this observation.Abstract 403 Figure 1Clinical trial and correlative analysis schema. Patients were randomized to receive either pembrolizumab alone or in combination with the HSP90 inhibitor XL888 for a two week cycle prior to crossover to the combination arm. Plasma, peripheral blood mononuclear cells (PBMC), and biopsies were assayed to evaluate immunomodulatory effects of the therapies.ConclusionsClinical data from this trial indicates that this combination is safe in patients. As clinical data matures, changes in soluble and cellular biomarkers will be correlated with response to elucidate mechanisms of response or resistance to this combination therapy.Trial RegistrationThis clinical trial is underway and registered with the ID NCT03095781Ethics ApprovalThe study was approved by Emory University’s Ethics Board, approval IRB00087397.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Background: Patients with prior Roux-en-Y gastric bypass (RYGB) operations for weight loss present reconstruction challenges during a pancreaticoduodenectomy (PD). With over 60,000 RYGB performed annually, the increasing odds of encountering such patients during a PD make it imperative to understand the RYGB anatomy and anticipate reconstruction options. This article describes the possible reconstruction options and their rationale. Methods: We reviewed our PD reconstruction options, compared them to what have been described in the literature, and derived a consensus from internal conferences comprising bariatric and hepatopancreatobiliary surgeons to describe known reconstruction options. Results: In general, reconstruction options can include one of three options: (1) remnant gastrectomy, (2) preservation of gastric remnant, or (3) reversal of gastric bypass. Conclusion: This article describes individualized reconstruction options for RYGB patients undergoing PD. The reconstruction options can ...

The Ki-67 index is an established prognostic marker for recurrence after resection of pancreatic neuroendocrine tumors (PanNETs) that groups tumors into three categories: low grade ( 3%), intermediate grade (3-20%), and high grade ( 20%). Given that the majority of resected PanNETs have a Ki-67 less than 3%, this study aimed to stratify this group further to predict disease recurrence more accurately.The Ki-67 index was pathologically re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray blocks made in triplicate. All patients who underwent curative-intent resection of non-metastatic PanNETs at a single institution from 2000 to 2013 were included in the study. The primary outcome was recurrence-free survival (RFS).Of 113 patients with well-differentiated PanNETs resected, 83 had tissue available for pathologic re-review. The Ki-67 index was lower than 3% for 72 tumors (87%) and between 3 and 20% for 11 tumors (13%). Considering only Ki-67 less than 3%, the tumors were further stratified by Ki-67 into three groups: group A ( 1%, n = 43), group B (1-1.99%, n = 23), and group C (2-2.99%, n = 6). Compared with group A, groups B and C more frequently had advanced T stage (T3: 44% and 67% vs 12%; p = 0.003) and lymphovascular invasion (50% and 83% vs 23%; p = 0.007). Groups B and C had similar 1- and 3-year RFS, both less than group A. After combining groups B and C, a Ki-67 of 1-2.99% was associated with decreased RFS compared with group A ( 1%). This persisted in the multivariable analysis (hazard ratio [HR] 8.6; 95% confidence interval [CI] 1.0-70.7; p = 0.045), with control used for tumor size, margin-positivity, lymph node involvement, and advanced T stage.PanNETs with a Ki-67 of 1-2.99% exhibit distinct biologic behavior and earlier disease recurrence than those with a Ki-67 lower than 1%. This new stratification scheme, if externally validated, should be incorporated into future grading systems to guide both surveillance protocols and treatment strategies.