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Implementation of fast-track perioperative care pathways for gastric cancer patients in the U.S. has been challenging due to low disease incidence and limited safety and efficacy data. Our institution recently implemented such a pathway for gastric cancer patients undergoing gastrectomy, and we sought to study its effects.We analyzed data from consecutive patients who underwent gastrectomy for gastric adenocarcinoma from January 2014 to August 2020. Patients who had surgery for recurrence, urgent surgery for obstruction, bleeding, or perforation, or an intrathoracic anastomosis were excluded. The primary predictor was whether the patient had surgery before or after implementation of a perioperative fast-track gastrectomy pathway in July 2018, and the primary outcome was length of stay.One hundred sixty patients were identified, 109 pre-pathway implementation and 51 post-pathway implementation. Following pathway implementation, length of stay was significantly shorter (median 6 days versus 9 days, p0.001), and there was no significant difference in 30-day complication rates (29% pre versus 24% post, P = 0.56) or readmission rates (18% pre versus 16% post, P = 0.85). Using linear segmented regression analysis adjusting for age, body mass index, tumor stage (early versus late), type of surgery (distal/subtotal versus total gastrectomy), and approach (open versus minimally invasive), pathway implementation was found to be associated with a 31% decreased length of stay (effect size 0.69, 95% confidence interval 0.49 - 0.98, P = 0.04).Fast-track gastrectomy care pathways are safe and feasible for U.S. gastric cancer patients undergoing gastrectomy and are associated with decreased length of stay.

Background Several studies have identified disparities in pancreatic cancer treatment associated with gender, race, and ethnicity. There are limited data examining disparities in short-term adverse outcomes after pancreatic resection for cancer. The aim of this study is to evaluate associations of gender, race, and ethnicity with morbidity and mortality after pancreatic resection for malignancy. Methods The American College of Surgeons National Surgical Quality Improvement database was retrospectively reviewed. The χ2 test and Student's t-test were used for univariable analysis and hierarchical logistic regression for multivariable analysis. Results Morbidity and major morbidity after pancreaticoduodenectomy are associated with male gender, Asian race, and Hispanic ethnicity, whereas 30-day mortality is associated with the male gender. Morbidity and major morbidity after distal pancreatectomy are associated with the male gender. Morbidity after pancreaticoduodenectomy is independently associated with male gender, Asian race, and Hispanic ethnicity; major morbidity is independently associated with male gender and Asian race, and mortality is independently associated with Hispanic ethnicity. Conclusions Gender, race, and ethnicity are independently associated with morbidity after pancreaticoduodenectomy for cancer; gender and race are independently associated with major morbidity; and ethnicity is independently associated with mortality. Further studies are warranted to determine the basis of these associations.

Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series.This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test.Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006).Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic.Significance:FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)–treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. Significance: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired. This article is highlighted in the In This Issue feature, p. 1861

The postoperative mortality rate of pancreaticoduodenectomy is decreasing over time. It is unknown whether this is related to reduction in incidence of major morbidity or failure to rescue. We aimed to make this determination.ACS-NSQIP was retrospectively reviewed from 2006 to 2016. Comparisons were assessed with Spearman's rank-order correlation test, chi-square test with linear-by-linear association, and multivariable hierarchical logistic regression.Mortality decreased significantly from 2.9% to 1.5% (p 0.001). This decrease was independent of preoperative variables on multivariable analysis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.55-5.21, p 0.001). In contrast, no change in incidence of major morbidity was seen on univariable (26.8% to 25.9%, p = 1.00) or multivariable analysis (OR 1.22, 95% CI 1.03-1.45, p = 0.060). Failure to rescue was observed to decrease on univariable (9.8% to 4.1%, p 0.001) and multivariable analysis (OR 3.65, 95% CI 2.07-6.76, p 0.001).There has been a sizeable reduction in the mortality rate after pancreaticoduodenectomy from 2006 to 2016. This predominantly results from a reduction in failure to rescue rate rather than a decrease in incidence of major morbidity.

Background Neoadjuvant treatment (NT) has become standard in the management of borderline resectable pancreatic cancer (BR-PDAC), improving prognosis. The primary mechanism for this improvement remains unclear. Methods Clinicopathological data of patients with BR-PDAC who underwent resection between January 2008 and December 2018 at a single institution were retrospectively reviewed. Univariable and multivariate analyses were used to compare survival between patients who received NT vs. those who underwent upfront resection (UR). Results A total of 138 patients were included, 64 underwent UR and 74 NT. Neoadjuvant treatment resulted in higher margin-negative (R0) resection rate (68.9%) than UR (43.8%, P = .005). Neoadjuvant treatment was associated with improved overall survival (OS, P = .009) and progression-free survival (PFS, P = .027). R0 resection was also associated with improved OS ( P < .001) and PFS ( P < .001). On multivariable analysis, when adjusting for clinically relevant variables without considering R status, NT was an independent predictor for improved OS ( P = .046) and PFS ( P = .040). When additionally accounting for margin status, R0 was an independent predictor for improved OS ( P < .001) and PFS ( P < .001), while NT was not. Subgroup analysis, stratified by margin status, revealed that NT was not an independent predictor for OS or PFS for either subgroup. Discussion Neoadjuvant treatment is associated with improved OS and PFS in patients with BR-PDAC; however, this effect is outweighed by margin status. These results suggest that the primary benefit of NT was dependent on facilitating R0 resection. Upfront resection might remain a valid treatment option if R0 resection could be accurately predicted.

Background The prognostic significance of the platelet (PLR) and neutrophil (NLR) to lymphocyte ratios for patients with resectable colorectal cancer liver metastases (CLM) was evaluated. Methods Clinicopathologic data from patients who underwent hepatectomy for CLM at two tertiary care hospitals between 1995 and 2017 were collected. Blood counts were evaluated for prognostic significance. Results 151 patients met inclusion criteria. The median age was 58 years, 44% were female, and 58% had synchronous metastases. Median number of liver metastases was 2, and 59% of patients underwent lobectomy or extended lobectomy. On multivariable analysis, NLR ≥5 (HR 2.46 [1.08–5.60 CI], p = 0.032), PLR ≥ 220 (HR 2.10 [1.04–4.23 CI], p = 0.037), and greater than 2 liver metastases (HR 2.41 [1.06–5.45 CI], p = 0.035) were associated with reduced overall survival. Conclusions PLR ≥ 220 and NLR ≥ 5 may have utility as preoperative prognostic markers for overall survival in patients with resectable CLM.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24–2.44; Ptrend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00–1.92; Ptrend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03–8.96, comparing extreme tertiles; Pinteraction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

Neoadjuvant therapy has shown value in various cancer types. The role of neoadjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), however, remains unknown. The aim of the present work is to evaluate the effect of neoadjuvant therapy on the survival of patients with borderline-resectable PDAC. Between 2004 and 2015, 7730 patients with resectable PDAC and 1980 patients with borderline-resectable PDAC were identified from the National Cancer Database (NCDB). Survival was compared between resectable and borderline-resectable patients. Survival and pathologic characteristics were also compared within borderline-resectable patients who received neoadjuvant therapy and those who received adjuvant therapy alone. Kaplan–Meier method and Cox proportional-hazard models were used for analysis. Median overall survival (mOS) of all patients with resectable PDAC was similar to that of patients with borderline-resectable disease treated with neoadjuvant therapy (26.5 versus 25.7 months, p = 0.78). Patients with borderline-resectable disease treated with neoadjuvant therapy had improved mOS compared with borderline-resectable patients treated with adjuvant therapy alone (25.7 versus 19.6 months, p

Background Many patients with borderline resectable/locally advanced pancreatic ductal adenocarcinoma (borderline resectable [BR]/locally advanced [LA] pancreatic ductal adenocarcinoma [PDAC]) undergoing resection will have positive resection margins (R1), which is associated with poor prognosis. It might be useful to preoperatively predict the margin (R) status. Methods Data from patients with BR/LA PDAC who underwent a pancreatectomy between 2008 and 2018 at Brigham and Women’s Hospital were retrospectively reviewed. Logistic regression analysis was used to evaluate the association between R status and relevant preoperative factors. Significant predictors of R1 resection on univariate analysis ( P < .1) were entered into a stepwise selection using the Akaike information criterion to define the final model. Results A total of 142 patients with BR/LA PDAC were included in the analysis, 60(42.3%) had R1 resections. In stepwise selection, the following factors were identified as positive predictors of an R1 resection: evidence of lymphadenopathy at diagnosis (OR = 2.06, 95% CI: 0.99-4.36, P = .056), the need for pancreaticoduodenectomy (OR = 3.81, 96% CI: 1.15-15.70, P = .040), extent of portal vein/superior mesenteric vein involvement at restaging (70% (all 5 factors). Conclusions Relevant preoperative clinicopathological characteristics accurately predict positive resection margins in patients with BR/LA PDAC before resection. With further development, this model might be used to preoperatively guide surgical decision-making in patients with BR/LA PDAC.

PURPOSE. While abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress anti-tumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. EXPERIMENTAL DESIGN. To generate spatially-resolved tumor and immune cell data at single cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, interferon regulatory factor 5 (IRF5), MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of co-localization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. RESULTS. In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15(+)ARG1(+) immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. CONCLUSIONS. A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially-resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy. TRANSLATIONAL RELEVANCE. Using multiplex immunofluorescence combined with digital image analysis and supervised machine learning, we comprehensively evaluated the composition, spatial characteristics and prognostic significance of myeloid cells in the PDAC microenvironment in a multi-institutional cohort of >300 patients with resected pancreatic ductal adenocarcinoma (PDAC). Myeloid cells were highly abundant in the human PDAC microenvironment with large inter-tumor heterogeneity. Not only the densities but also the spatial locations of myeloid immune cells were associated with patient outcomes, revealing PDAC microenvironmental complexity with important implications for design and interpretation of immunotherapy clinical trials.

Surgeons are being increasingly called upon to operate on the very elderly. This study aimed to evaluate outcomes following hepatectomy in patients ≥80 years of age at two tertiary care centers.All adult patients who underwent liver resection from 2001 to 2017 were included. Primary outcome was 90-day postoperative mortality. Secondary outcomes included 30-day postoperative mortality and postoperative complications.Between 2001 and 2017, 2397 patients underwent liver resection. On unadjusted analysis, patients ≥80 years of age had higher rates of 90-day mortality (13.3% vs. 3.6%, p 0.001), 30-day mortality (5.6% vs. 1.8%, p = 0.01), MI (7.9% vs. 3.5%, p = 0.04), and UTI (10.0% vs. 4.5%, p = 0.02). On multivariable analysis, age ≥80 years was significantly associated with 90-day postoperative mortality (OR 4.51, 95%CI 2.11-9.67, p 0.001).Across these two major referral tertiary care centers, very elderly patients had higher rates of 90-day and 30-day postoperative mortality on both unadjusted and adjusted analyses.

Summary Background Many women with increased lifetime risk of developing breast cancer, due to pathogenic gene variants or family history, choose to undergo bilateral risk reducing mastectomies (BRRM). Patient reported outcome measures (PROMS) are an increasingly important part of informed consent but are little studied in women undergoing BRRM. Methods We used a validated PROMS tool for breast reconstruction (BREAST-Q) in 297 women who had BRRM and breast reconstruction, 81% of whom had no malignancy (Benign Group, BG) and 19% in whom a perioperative breast cancer was diagnosed (Cancer Group, CG). 128 women also completed a Hospital Anxiety & Depression Score (HADS) questionnaire to test if preoperative HADS score could predict PROMS outcomes. Results Women in the CG had lower PROMS scores for satisfaction with their breasts, nipple reconstruction and sexual wellbeing. Both groups reported equal satisfaction with BRRM outcome and psychosocial well-being. Physical well-being PROMS of the abdomen and chest were high in women in both groups as were scores for satisfaction with the care they received. The CG group reported suboptimal quality of patient information. A higher presurgical HADS anxiety score predicted less favourable postoperative psychosocial well-being despite similar levels of satisfaction with aesthetic outcome. Conclusion We show a high degree of patient reported satisfaction by woman undergoing BRRM and reconstruction. There was a negative association with a cancer diagnosis on quality of life PROMS and higher preoperative anxiety levels negatively affected postoperative psychosocial well-being. These important findings should be part of the informed consent process during preoperative counselling.

Background & Aims There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. Methods CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. Results In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. Conclusion CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.

Summary Design of tissue-specific contrast agents to delineate tumors from background tissues is a major unmet clinical need for ultimate surgical interventions. Bioconjugation of fluorophore(s) to a ligand has been mainly used to target overexpressed receptors on tumors. However, the size of the final targeted ligand can be large, >20 kDa, and cannot readily cross the microvasculature to meet the specific tissue, resulting in low targetability with a high background. Here, we report a small and hydrophilic phenoxazine with high targetability and retention to pancreatic neuroendocrine tumor. This bioengineered fluorophore permits sensitive detection of ultrasmall (, Graphical Abstract, Highlights • Bioengineered near-infrared fluorescent small molecules for PNET imaging • Highlight tumors within a minute after a single bolus injection with improved retention • Sensitive and specific detection of ultrasmall ectopic tumors • Intraoperative image-guided navigation provides a surgical margin, Histology; Chemistry; Cancer

Background The clinicopathologic factors associated with the survival of patients with pancreatic ductal adenocarcinoma (PDAC) during the different phases of neoadjuvant treatment (NT)—at diagnosis, restaging, or postoperatively—remain unclear. Methods Data of patients with PDAC who underwent pancreatic resection after NT between 2008 and 2018 were retrospectively collected. Clinicopathologic characteristics and outcomes were compared stratified by resection margin status. Three multivariable regression models (at diagnosis, restaging, and postoperatively) were constructed to assess the temporal impact of different prognostic factors on all-cause survival (ACS) and disease-free survival (DFS). Results All patients were diagnosed with a nonmetastatic PDAC and were appropriate candidates for NT according to the current National Comprehensive Cancer Network guidelines. From a total of 83 patients, 57 (68.7%) had a negative resection margin >1 mm (R0), whereas 26 patients (31.3%) had a positive resection margin (R1). At diagnosis, planned procedure (P = 0.017) and CA19-9 >100 U/mL (P = 0.047) were independent prognostic factors of decreased ACS. At restaging, planned procedure (P = 0.017), FOLFIRINOX (P = 0.026), and tumor size >30 mm (P = 0.030) were independent prognostic factors for increased and decreased ACS, respectively. Postoperatively, R0 was an independent prognostic factor for improved ACS (P = 0.005) and DFS (P = 0.002), whereas adjuvant therapy (P = 0.006) was associated with increased ACS. Lymph node involvement (P = 0.019) was associated with decreased DFS. Conclusions At diagnosis, restaging, and postoperatively, different, relevant clinicopathologic factors significantly impact the survival of patients with nonmetastatic PDAC undergoing NT. An R0 resection remains the most important prognostic factor and therefore should be the primary goal of surgical treatment in the neoadjuvant setting.

OBJECTIVE Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs. METHODS Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses. RESULTS Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death. CONCLUSIONS Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.

Background Hepatopancreatobiliary (HPB) Fellowship training in the Americas consists of 3 distinctive routes with variable curricula: Surgical Oncology Fellowship via the Society of Surgical Oncology (SSO), Abdominal Transplant Surgery Fellowship via the American Society of Transplant Surgeons (ASTS), and HPB Fellowship via the Americas Hepato-Pancreato-Biliary Association (AHPBA). Our objective was to establish a pan-American consensus among HPB surgeons, surgical oncologists, abdominal transplant surgeons, and general surgery residency program directors (GSPDs) on a core knowledge curriculum for HPB fellowship, and to identify topics appropriate for general surgery residency and subspecialty beyond HPB fellowship. Study Design A 3-round modified Delphi process was used. Baseline statements were developed by the Education and Training Committee of the AHPBA, in collaboration with representatives of the SSO, ASTS, and GSPDs. The expert panel, consisting of members of the 3 societies together with GSPDs, rated the statements on a 5-point Likert scale and suggested editing or adding new statements. A statement was included in the final curriculum when Cronbach’s alpha value was ≥ 0.8 and ≥ 80% of the panel agreed on inclusion. Results The response rate was 100% for the first round, and 98% for the second and third rounds. Eighty-nine of 138 proposed statements were included in the final HPB fellowship curriculum. Curricula for general surgery residency and subspecialty beyond HPB fellowship included 50 and 29 statements, respectively. Conclusions A multinational consensus on core knowledge for an HPB fellowship curriculum was achieved via the modified Delphi method. This core curriculum may be used to standardize HPB fellowship training across different pathways in the Americas.

Purpose The anatomic variability of the hepatic artery has important implications in the treatment of periampullary cancers. The purpose is of this report is to describe the importance of the replaced right hepatic artery originating from the gastroduodenal artery, which is typically removed during a pancreatic head resection, and to demonstrate how this variant can markedly alter treatment planning and intraoperative decision making. Materials and methods In this report, two cases of a replaced right hepatic artery originating from the gastroduodenal artery are described in the setting of a borderline-resectable pancreatic adenocarcinoma identified on preoperative CT imaging. Results The importance of identifying this variant preoperatively is highlighted. In addition, the implications involved in preserving the replaced right hepatic artery are emphasized, requiring preservation of a portion of the gastroduodenal artery within the pancreatic parenchyma during pancreaticoduodenectomy. Conclusion The location of this variant in the setting of a pancreatic head malignancy mandates its attention by a multidisciplinary team of radiologists, radiation oncologists, medical oncologists, and surgeons, prior to pancreaticoduodenectomy.

The economic implications of relevant clinicopathologic factors on the surgical approach to distal pancreatectomy (DP) should be clearly defined and understood to potentially allow the implementation of cost reduction strategies.Administrative and clinical datasets of patients undergoing a DP between 2012 and 2016 were merged and queried. Univariate and multivariate analyses were used to identify clinicopathologic predictors of cost differentials for minimally invasive DP (MIDP) relative to open DP (ODP). Time trends in cost were also assessed to identify opportunities for cost containment.Among two hundred and twenty five patients, 128 underwent an ODP (57%) and 97 a MIDP (43%). The DP groups were comparable with regard to relevant perioperative and disease characteristics. Total hospitalization and total OR costs for MIDP were significantly lower (- 12%, P = 0.0048) and higher (+ 16%, P 0.0001) respectively, compared to ODP. On univariate analysis, age 60 (- 12%, P = 0.0262), BMI 25 (- 10%, P = 0.0222), ASA class ≥ 3 (- 11%, P = 0.0045), OpTime 230 min (- 16%, P = 0.0004), and T stage ≥ 3 (- 8%, P = 0.0452) were associated with decreased total costs after MIDP compared to ODP. Linear regression analysis revealed that BMI 25 (Estimate - 0.31, SE 0.15, P = 0.0482), ASA class ≥ 3 (Estimate - 0.36, SE 0.17, P = 0.0344), and T stage ≥ 3 (Estimate - 0.57, SE 0.26, P = 0.0320) were associated with decreased hospitalization costs after MIDP compared to ODP. Overtime, total hospitalization cost for MIDP increased from - 21 to 1% (P = 0.0197), while OR costs for MIDP decreased from + 41% to - 2% (P = 0.0049), nearly equalizing the cost differences between ODP and MIDP.Relevant clinicopathologic factors predicted decreased hospitalization costs after MIDP relative to ODP. In equivalent stages of disease, optimizing the surgical approach to DP based on specific clinicopathologic characteristics may afford significant cost-saving opportunities.

Background and objectives Various treatment options exist for patients with metastatic pancreatic neuroendocrine tumors (PNETs). Surgical resection with pancreaticoduodenectomy (PD) typically reserved for patients with limited disease. Definitive data are lacking to support either the resection of primary PNET in the metastatic setting or for surgical debulking of metastatic lesions. Methods We conducted an analysis of the National Cancer Database (NCDB) using the pancreatic cancer Participant User File. Thirty- and 90-day mortality rates and survival rates were determined for patients undergoing PD for primary tumor resection and compared with patients who had no surgery or metastasectomy. The Kaplan-Meier method was used to compare survival time. Cox regression models were used to assess factors independently associated with overall survival time. Results Resection of the primary tumor or metastatic disease each significantly improved overall survival time compared with no resection. Adding metastasectomy to PD resulted in an incremental increase in overall survival time. Both PD and metastasectomy are independently associated with overall survival time. Conclusions Our report highlights the potential for survival time benefit in appropriately selected patients who undergo PD in the setting of metastatic PNET.

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096–111. ©2018 AACR. See related commentary by Collisson, p. 1062. This article is highlighted in the In This Issue feature, p. 1047

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Background Diagnostic imaging plays a critical role in the initial diagnosis and therapeutic monitoring of pancreatic adenocarcinoma. Over the past decade, the concept of ‘borderline resectable’ pancreatic cancer has emerged to describe a distinct subset of patients existing along the spectrum from resectable to locally advanced disease for whom a microscopically margin-positive (R1) resection is considered relatively more likely, primarily due to the relationship of the primary tumor with surrounding vasculature. Materials and methods This review traces the conceptual evolution of borderline resectability from a radiological perspective, including the debates over the key imaging criteria that define the thresholds between resectable, borderline resectable, and locally advanced or metastatic disease. This review also addresses the data supporting neoadjuvant therapy in this population and discusses current imaging practices before and during treatment. Results A growing body of evidence suggests that the borderline resectable group of patients may particularly benefit from neoadjuvant therapy to increase the likelihood of an ultimately margin-negative (R0) resection. Unfortunately, anatomic and imaging criteria to define borderline resectability are not yet universally agreed upon, with several classification systems proposed in the literature and considerable variance in institution-by-institution practice. As a result of this lack of consensus, as well as overall small patient numbers and lack of established clinical trials dedicated to borderline resectable patients, accurate evidence-based diagnostic categorization and treatment selection for this subset of patients remains a significant challenge. Conclusions Clinicians and radiologists alike should be cognizant of evolving imaging criteria for borderline resectability given their profound implications for treatment strategy, follow-up recommendations, and prognosis.

Robotic surgery is gaining acceptance for distal pancreatectomy (DP). Nevertheless, no multi-institutional data exist to demonstrate the ideal clinical circumstances for use and the efficacy of the robot compared to the open or laparoscopic techniques, in terms of perioperative outcomes. The 2014 ACS-NSQIP procedure-targeted pancreatectomy data for patients undergoing DP were analyzed. Demographics and clinicopathological and perioperative variables were compared between the three approaches. Univariate and multivariable analyses were used to evaluate outcomes. One thousand eight hundred fifteen DPs comprised 921 open distal pancreatectomies (ODPs), 694 laparoscopic distal pancreatectomies (LDPs), and 200 robotic distal pancreatectomies (RDPs). The three groups were comparable with respect to demographics, ASA score, relevant comorbidities, and malignant histology subtype. Compared to the ODP group, patients undergoing RDP had lower T-stages of disease (P = 0.0192), longer operations (P = 0.0030), shorter hospital stays (P

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 64-year-old woman with a history of hypertension and type 2 diabetes had been in her usual state of health until she developed symptoms of diarrhea, abdominal bloating, and discomfort in the midepigastrium. Evaluation with a contrast-enhanced abdominopelvic computed tomography (CT) scan demonstrated a mass in the pancreatic body that was approximately 3.1 cm × 2 cm × 2.1 cm in size with abutment of the portal vein–superior mesenteric vein confluence for less than 180°. The confluence was narrowed but without thrombosis. No tumor–vessel interface was noted at the superior mesenteric artery, celiac artery, or common hepatic artery. Several peripancreatic lymph nodes were observed that measured up to 11 mm × 5 mm. No evidence for distant spread of disease was identified. An upper endoscopy with endoscopic ultrasound was performed and fine-needle aspirates of the pancreas mass were positive for malignant cells that were consistent with adenocarcinoma. Chest CT scan without intravenous contrast demonstrated no evidence of metastatic disease. The patient came to the clinic to discuss management of her newly diagnosed malignancy.

On the basis of SEER data, in which most gastric cancer patients had limited lymph node dissection, node ratio-based staging system (TNrM) has been shown to have better accuracy than the AJCC TNM system. This study is to validate the result with patients from Taiwan, where D2 lymphadenectomy is routinely performed.A total of 1405 consecutive gastric cancer patients treated at National Taiwan University Hospital between 1998 and 2010 were included. To evaluate the performance of the AJCC system, each TNM stage was stratified by TNrM stages. The homogeneity of patients' survival across TNrM strata was evaluated using the log-rank test. The performance of the TNrM system was evaluated with the same approach.Five of the 7 evaluable AJCC stages (IA, IIA, IIIA, IIIB, and IIIC) contained TNrM subgroups with statistically heterogenous survival (P=0.003, 0.04, 0.002, 0.04, and0.001, respectively). Thirty-six percent of patients (506/1405) were misclassified by the AJCC TNM system. However, of the assessable 6 TNrM stages, none of the AJCC subgroups showed significantly heterogenous survivals (P0.05). About 19% of patients (264/1405) were misclassified by using the TNrM system.Lymph node ratio significantly decreases the stage migration caused by inadequate examined lymph nodes. The advantage of TNrM was validated with a patient cohort from the Eastern medical center.

Current literature emphasizes post-operative complications as a leading cause of post-pancreatectomy readmissions. Transitional care factors associated with potentially preventable conditions such as dehydration and failure to thrive (FTT) may play a significant role in readmission after pancreatectomy and have not been studied.Thirty-one post-pancreatectomy patients, who were readmitted for dehydration or FTT between 2009 and 2014, were compared to 141 nonreadmitted patients. Medical record review and a questionnaire-based survey, specifically designed to assess transitional care, were used to identify predictors of readmissions for dehydration or FTT. Logistic regression models were used to evaluate outcomes.On multivariable analysis, the strongest predictors of readmission for dehydration and FTT were the patient's lower educational level (P = 0.0233), the absence of family during the delivery of discharge instructions (P = 0.0098), episodic intermittent nausea at discharge (P = 0.0019), uncertainty about quantity, quality, or frequency of fluid intake (P = 0.0137), and the inability or failure to adhere to the clinician's instructions in the outpatient setting (P = 0.0048).Transitional-care-related factors are found to be associated with post-pancreatectomy readmission for dehydration and FTT. Using these results to identify high-risk patients and implement focused preventive measures combining efficient communication and optimal inpatient and outpatient management could potentially decrease readmission rates.

Objectives Endoscopic necrosectomy is effective in the treatment of walled-off necrosis (WON), and is preferred to surgical approaches, however complication and mortality rates remain high with few centers regularly employing the technique. Lack of a standardized approach may also contribute to these limitations. Methods Prior to the study, a multidisciplinary team applied standardized care assessment and management plan principles to develop and optimize a systematic approach for the management of WON. Preoperative, postoperative, and endoscopic management were standardized. Patient preparation, room set-up, technical features (EUS-guidance, cold-access with balloon dilation, fragmentation of necrosis on the initial procedure, antibiotic lavage, double pigtail stents), and discontinuation of PPIs to encourage auto-digestion of necrosis were included. This study employed a consecutive prospective clinical registry to assess the clinical outcomes of this standardized approach. Results 60 consecutive patients underwent 1.58 ± 0.1 necrosectomies, with debridement accomplished on the initial procedure in 98.3%. 39 patients (65%) required only one session. Clinical resolution occurred in 86.7%, with radiologic confirmation. Percutaneous drainage was required in 8 patients during follow-up, and 4 of these later required surgery. Serious adverse events occurred in 3.3% of patients, and there was no mortality. Conclusions The standardized technique employed in this series was associated with lower rates of adverse events, morbidity, and mortality than prior large series. Use of a systematic approach, and integrating elements of this method may improve the risk profile of endoscopic necrosectomy and allow broader adoption.

Background: Neoadjuvant therapy (neoTX) may improve survival for patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the impact of neoTX on the tumor immune microenvironment is incompletely understood, hampering efforts to identify optimal treatment combinations and predictive markers to guide patient selection. Design: We employed digital image analysis and three multiplex immunofluorescence (mIF) assays, comprising 15 immune cell markers, to identify T cell subpopulations, macrophage polarization and myeloid cell subpopulations in primary resected PDAC. A multi-institution cohort of untreated tumors (n=299) was analyzed to characterize the baseline tumor immune microenvironment, while resected tumors after FOLFIRINOX-based neoTX (n=36) or upfront surgery (n=30) were analyzed to identify immune microenvironmental change due to neoTX. Multivariable Cox proportional hazard regression models were used to assess associations with patient outcomes. Results: Macrophages, T lymphocytes, and granulocytes were all abundant in the previously-untreated PDAC microenvironment, yet their densities exhibited substantial heterogeneity across patient tumors. In the untreated multi-institutional cohort, higher CD3+ T cell density was associated with longer disease-free survival (DFS) and overall survival (OS), while M2-polarized macrophages and CD15+ARG1+ immunosuppressive granulocytes were associated with shorter survival times. In particular, a higher ratio of CD3+CD8+ T cells to CD15+ARG1+ immunosuppressive granulocytes was associated with longer DFS (Q4 vs. Q1 HR 0.46, Ptrend=0.002) and OS (Q4 vs. Q1 HR 0.70, Ptrend=0.02). While neoTX did not alter overall CD3+ density, it increased the relative proportion of CD3+CD8+ cells, resulting in a lower CD4/CD8 ratio (p Citation Format: Andressa Dias Costa, Sara Väyrynen, Akhil Chawla, Jinming Zhang, Juha P. Väyrynen, Mai Chan Lau, Hannah L. Williams, Chen Yuan, Vicente Morales-Oyarvide, Douglas A. Rubinson, Thomas E. Clancy, Lauren K. Brais, Emma Reilly, Margaret M. Kozak, David C. Linehan, Richard F. Dunne, Daniel T. Chang, Aram F. Hezel, Albert C. Koong, Andrew J. Aguirre, Brian M. Wolpin, Jonathan A. Nowak. Neoadjuvant therapy is associated with altered composition of immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-001.

567 Background: Fibroblast growth factor receptor (FGFR) pathway alterations have been identified in approximately 20% of patients (pts) with intrahepatic cholangiocarcinoma (IHCC), most commonly by FGFR2 fusions. Early phase clinical trials have demonstrated encouraging efficacy of FGFR inhibitors in pts with FGFR2-translocated cholangiocarcinoma, but efficacy in pts with other FGFR2 activating alterations is less clear. Methods: Pts with cholangiocarcinoma underwent CLIA-certified next generation DNA sequencing (NGS) to identify actionable alterations. FGFR2 fusions and other FGFR2 genomic events were assessed, with genomic characterization performed before and after treatment with FGFR inhibitors in appropriate pts. Novel extracellular domain in-frame deletions (INDELs) of FGFR2 and apparent resistance mutations were investigated for oncogenic activity and inhibitor resistance in vitro and in vivo. Results: Cholangiocarcinomas from 284 pts (136 male, 148 female; median age, 64 [20-89], including 139 IHCCs, were sequenced. Among the IHCCs, 16 (11.5%) had FGFR2 fusions, with 9 different gene partners. Surprisingly, 5 (3.6%) IHCCs harbored extracellular domain FGFR2 INDELs. Two of these IHCCs harbored an exon 5 deletion FGFR2 p.H167_N173del. Expression of FGFR2 p.H167_N173del in 3T3 cells resulted in oncogenic transformation. In the clinic, two pts with FGFR2 p.H167_N173del were treated with Debio1347, an oral FGFR-1/2/3 inhibitor. Both patients achieved a durable partial response (PR) of 11 months, with one of the pts still on active treatment with Debio-1347. The patient who developed acquired resistance underwent repeat biopsy, and NGS identified a secondary mutation ( FGFR2 p. L617F) in the kinase domain. In vitro studies demonstrated that this mutation confers resistance to Debio1347. This patient was subsequently treated with another FGFR inhibitor and again experienced a PR lasting 17 months. A third biopsy after disease progression demonstrated a previously undetected L597Q BRAF mutation. Conclusions: Extracellular domain FGFR2 in-frame deletions are a novel genomic alteration in IHCC that are transforming and predict clinical sensitivity to FGFR inhibitors.

Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Abstract: Neuroendocrine tumors are relatively uncommon neoplasms presenting with a wide spectrum of clinical behavior. Many patients may present with or develop liver metastases from neuroendocrine tumors, which significantly influences prognosis and the potential for symptoms. Data suggest that some patients may have symptomatic relief and oncologic benefit from liver-directed therapy for neuroendocrine tumor metastases. Surgical resection, tumor ablation, transarterial therapy such as bland embolization, chemoembolization and radioembolization, as well as liver transplantation have been studied as liver-directed therapies. Data continue to emerge to help guide selection of treatment modality for an individual patient. The spectrum of behavior of neuroendocrine metastases and heterogeneity in the literature are a challenge to arriving at cohesive recommendations for all patients.

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome with a 60-80% lifetime risk of colorectal cancer. We assessed the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) in LS families and explored novel methods for informing and engaging at-risk relatives. Uptake of predictive testing was explored using Kaplan-Meier analysis and engagement with colorectal screening was ascertained. A questionnaire was distributed to 216 general practitioners (GPs) of registered LS family members to determine their prior experience and opinion of an enhanced role. Of 591, 329 (55.7%) FDRs had undergone predictive testing. Uptake was significantly lower in males (p = 0.012) and individuals

Purpose Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown. Patients and Methods We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage. Results In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival. Conclusion Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.

Importance Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. Objective To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants This study analyzed protein expression and DNA alterations for theKRAS,CDKN2A,SMAD4, andTP53genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women’s Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. Main Outcomes and Measures The DFS and OS among patients with resected pancreatic adenocarcinoma. Results Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients withKRASmutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients withKRASwild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients withKRASG12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status ofSMAD4was not associated with DFS or OS, whereasTP53status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75;P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59;P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94;P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. Conclusions and Relevance Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

OBJECTIVES The aims of this study were to compare the safety, efficacy, and patients' quality of life with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDIs) in type 3c diabetes mellitus (T3cDM) following total pancreatectomy (TP) and pancreatic enzyme usage. METHODS Thirty-nine patients with T3cDM (18 CSII patients vs 21 MDI patients) who underwent TP between 2000 and 2016 at 3 Harvard-affiliated hospitals and the University of Minnesota returned prospectively obtained questionnaires examining quality of life and both endocrine and exocrine pancreatic functions. RESULTS Main indications for TP were as follows: chronic pancreatitis (n = 19), intraductal papillary mucinous neoplasm (n = 12), and adenocarcinoma (n = 4). Median hemoglobin A1c using MDIs was 8.1% versus 7.3% in CSII. Severe hypoglycemic events using MDIs were increased compared with CSII (P = 0.02). There were no significant differences in quality-of-life measures with CSII versus MDIs. Pancreatic enzyme dose per meal (P < 0.05) differed between the hospitals. Gastrointestinal symptoms and unintended weight loss (P < 0.01) were more common with low doses of pancreatic enzymes. CONCLUSIONS After TP, CSII therapy is safe compared with MDIs in T3cDM and not associated with an increase in severe hypoglycemic events. Pancreatic enzyme replacement therapy is highly variable with low doses associated with unintentional weight loss and gastrointestinal symptoms.

Background: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). Methods: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. Results: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend

Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07–5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99–3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36–1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24–5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Clin Cancer Res; 20(16); 4361–9. ©2014 AACR.

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.