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Figure S1 is related to Figure 1 and shows image cytometry gating strategies used in multiplex IHC analysis

Supplemental Tables and Figures

File contains supplementary Materials & Methods, supplementary References, and Supplementary Tables S1-S10.

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

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell–cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC.Significance:A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.

Supplementary Figures

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.

PDF file - 90K, Supplementary Table 1: Adjusted Association between LNR Status and Outcomes in Untreated T3N0 Colon Cancer Undergoing Molecular Staging; Supplementary Table 2: Unadjusted and adjusted association between LNR status and TTR, OS, and DFS within pMMR subgroup (N = 262).

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.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell–cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. Significance: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.

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.

Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones. A wide range of clinical behavior can be seen, with the primary prognostic indicator being tumor grade as defined by the Ki67 proliferation index and mitotic index. Surgery is the primary treatment modality for PNETs. While functional PNETs should undergo resection for symptom control as well as potential curative intent, nonfunctional PNETs are increasingly managed nonoperatively. There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance. Evidence supports surgical management of metastatic disease if possible, and occasionally even surgical management of the primary tumor in the setting of widespread metastases. In this review, we highlight the evolving surgical management of local and metastatic PNETs.

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.

Purpose: Emerging evidence implicates the microbiome in the development of pancreatic cancer. We investigated whether increased levels of microbial-related metabolites in circulation are associated with pancreatic cancer risk. Methods: We applied metabolomics profiling to sera from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cohort to quantify and build a model based on 14 microbial-related metabolites. The study involved samples collected from 172 subjects within five years prior to diagnosis and 863 matched controls. Data from five PLCO centers were used for training and from two centers for validation and model selection. The model was subsequently tested using samples from three independent centers. The contributions of non-microbial-associated metabolites as well as CA19-9 was also assessed. Results: A 3-marker microbial-related metabolite panel yielded in the PLCO testing set an AUC of 0.64 (95% CI: 0.53-0.76) for 5-year probability of pancreatic cancer. Five additional non-microbial metabolites were identified that when combined with the microbiome panel yielded an AUC of 0.79 (95% CI: 0.71-0.88) for 5-year probability of pancreatic cancer in the PLCO testing set. The combined metabolite panel and CA19-9 yielded an AUC of 0.86 (95% CI: 0.77-0.95) for 2-year probability of pancreatic cancer in the PLCO testing set, which was improved compared to CA19-9 alone (AUC: 0.70 (95% CI: 0.57-0.82), p< 0.001). Conclusion: We developed a metabolite panel derived in part from the microbiome for risk assessment of pancreatic cancer, which has relevance to prevention and early detection. Citation Format: Johannes F. Fahrmann, Ehsan Irajizad, Ana Kenney, Tiffany Tang, Jody Vykoukal, Ranran Wu, Jennifer B. Dennison, Marta Sans Escofet, James P. Long, Maureen Loftus, John A. Chabot, Michael D. Kluger, Fay Kastrinos, Lauren Brais, Ana Babic, Kunal Jajoo, Linda S. Lee, Thomas E. Clancy, Kimmie Ng, Andrea Bullock, Jeanine M. Genkinger, Anirban Maitra, Kim-Anh Do, Bin Yu, Brian M. Wolpin, Samir Hanash. Contribution of the microbiome to a metabolomic signature predictive of risk for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P076.

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

Disparities based on socioeconomic factors such as race, ethnicity, marital status, and insurance status are associated with pancreatic cancer resection, but these disparities are usually not observed for survival after resection. It is unknown if there are disparities when patients undergo their treatment in a non-fee-for-service, equal-access healthcare system such as the Veterans Health Administration (VHA).Patients having T1-T3 M0 pancreatic adenocarcinoma diagnosed between 2006 and 2017 were identified from the VHA Corporate Data Warehouse. Socioeconomic, demographic, and tumor variables associated with resection and survival were assessed.In total, 2580 patients with early-stage pancreatic cancer were identified. The resection rate was 36.5%. Surgical resection was independently associated with younger age [odds ratio (OR) 0.94, p 0.001], White race (OR 1.35, p = 0.028), married status (OR 1.85, p = 0.001), and employment status (retired vs. unemployed, OR 1.41, p = 0.008). There were no independent associations with Hispanic ethnicity, geographic region, or Social Deprivation Index. Resection was associated with significantly improved survival (median 21 vs. 8 months, p = 0.001). Among resected patients, survival was independently associated with younger age (HR 1.019, p = 0.002), geographic region (South vs. Pacific West, HR 0.721, p = 0.005), and employment (employed vs. unemployed, HR 0.752, p = 0.029). Race, Hispanic ethnicity, marital status, and Social Deprivation Index were not independently associated with survival after resection.Race, marital status, and employment status are independently associated with resection of pancreatic cancer in the VHA, whereas geographic region and employment status are independently associated with survival after resection. Further studies are warranted to determine the basis for these inequities.

Major abdominal surgery and malignancy lead to a hypercoagulable state, with a risk of venous thromboembolism (VTE) of approximately 3% after pancreatic surgery. No guidelines exist to assist surgeons in managing VTE prophylaxis or anticoagulation in patients undergoing elective pancreatic surgery for malignancy or premalignant lesions. A systematic review specific to VTE prophylaxis and anticoagulation after resectional pancreatic surgery is herein provided.Six topic areas are reviewed: pre- and perioperative VTE prophylaxis, early postoperative VTE prophylaxis, extended outpatient VTE prophylaxis, management of chronic anticoagulation, anti-coagulation after vascular reconstruction, and treatment of VTE. A Medline and PubMED search was completed with systematic medical literature review for each topic. Level of evidence was graded and strength of recommendation ranked according to the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system for practice guidelines.Levels of evidence and strength of recommendations are presented.While strong data exist to guide management of chronic anticoagulation and treatment of VTE, data for anticoagulation after reconstruction is inconclusive and support for perioperative chemoprophylaxis with pancreatic surgery is similarly limited. The risk of post-pancreatectomy hemorrhage often exceeds that of thrombosis. The role of universal chemoprophylaxis must therefore be examined critically, particularly in the preoperative setting.

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.

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

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

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