Rapid diagnosis and tumor margin assessment during pancreatic cancer surgery with the MasSpec Pen technology.

Intraoperative delineation of tumor margins is critical for effective pancreatic cancer surgery. Yet, intraoperative frozen section analysis of tumor margins is a time-consuming and often challenging procedure that can yield confounding results due to histologic heterogeneity and tissue-processing artifacts. We have previously described the development of the MasSpec Pen technology as a handheld mass spectrometry-based device for nondestructive tissue analysis. Here, we evaluated the usefulness of the MasSpec Pen for intraoperative diagnosis of pancreatic ductal adenocarcinoma based on alterations in the metabolite and lipid profiles in in vivo and ex vivo tissues. We used the MasSpec Pen to analyze 157 banked human tissues, including pancreatic ductal adenocarcinoma, pancreatic, and bile duct tissues. Classification models generated from the molecular data yielded an overall agreement with pathology of 91.5%, sensitivity of 95.5%, and specificity of 89.7% for discriminating normal pancreas from cancer. We built a second classifier to distinguish bile duct from pancreatic cancer, achieving an overall accuracy of 95%, sensitivity of 92%, and specificity of 100%. We then translated the MasSpec Pen to the operative room and predicted on in vivo and ex vivo data acquired during 18 pancreatic surgeries, achieving 93.8% overall agreement with final postoperative pathology reports. Notably, when integrating banked tissue data with intraoperative data, an improved agreement of 100% was achieved. The result obtained demonstrate that the MasSpec Pen provides high predictive performance for tissue diagnosis and compatibility for intraoperative use, suggesting that the technology may be useful to guide surgical decision-making during pancreatic cancer surgeries.

Clinical Translation and Evaluation of a Handheld and Biocompatible Mass Spectrometry Probe for Surgical Use.

BACKGROUND: Intraoperative tissue analysis and identification are critical to guide surgical procedures and improve patient outcomes. Here, we describe the clinical translation and evaluation of the MasSpec Pen technology for molecular analysis of in vivo and freshly excised tissues in the operating room (OR). METHODS: An Orbitrap mass spectrometer equipped with a MasSpec Pen interface was installed in an OR. A "dual-path" MasSpec Pen interface was designed and programmed for the clinical studies with 2 parallel systems that facilitated the operation of the MasSpec Pen. The MasSpec Pen devices were autoclaved before each surgical procedure and were used by surgeons and surgical staff during 100 surgeries over a 12-month period. RESULTS: Detection of mass spectral profiles from 715 in vivo and ex vivo analyses performed on thyroid, parathyroid, lymph node, breast, pancreatic, and bile duct tissues during parathyroidectomies, thyroidectomies, breast, and pancreatic neoplasia surgeries was achieved. The MasSpec Pen enabled gentle extraction and sensitive detection of various molecular species including small metabolites and lipids using a droplet of sterile water without causing apparent tissue damage. Notably, effective molecular analysis was achieved while no limitations to sequential histologic tissue analysis were identified and no device-related complications were reported for any of the patients. CONCLUSIONS: This study shows that the MasSpec Pen system can be successfully incorporated into the OR, allowing direct detection of rich molecular profiles from tissues with a seconds-long turnaround time that could be used to inform surgical and clinical decisions without disrupting tissue analysis workflows.

The Landmark Series: Mitigation of the Postoperative Pancreatic Fistula.

Pancreatic fistula has been the defining complication and challenge of pancreatic surgery. Better awareness and mitigation of postoperative pancreatic fistulas has led to significant improvements in morbidity and mortality of pancreatic surgery. The definition and management of pancreatic fistulas has sequentially progressed over the last three decades; the literature ranges from retrospective, observational studies to prospective multicenter randomized controlled trials. The landmark literature contributions driving the perioperative management of pancreatic fistulas are detailed in this article.

Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms.

BACKGROUND: With advances in cross-sectional imaging, pancreatic cysts are more frequently diagnosed and have become a common indication for pancreatectomy. The impact of pancreatectomy in these patients is important. The purpose of this study was to assess short-term outcomes, long-term nutritional status, quality of life (QOL), and pancreas function after pancreatectomy for cystic neoplasms. MATERIALS AND METHODS: At a single institution, patients at least 3 y post-pancreatectomy for benign cystic neoplasms were identified. Using a validated questionnaire, short-term outcomes, long-term outcomes including endocrine and exocrine insufficiency, long-term nutritional status, and preoperative and postoperative QOL were compared based on operation and indication for resection. RESULTS: Among 102 eligible patients, 70 had valid contact information and 51 (72.9%) agreed to participate. Median follow-up was 6 (4-8) y. Patients undergoing pancreatoduodenectomy for benign cysts had higher morbidity than a similar cohort resected for pancreatic adenocarcinoma (patients with at least 1 ≥ grade 2 complication [49.0% versus 31.6%, P = 0.038]). After long-term follow-up, pancreatectomy did not significantly affect perceived QOL. Half of patients had mild-moderate or severe malnourishment, but pancreatic enzyme replacement was reported by only 4 (7.8%) patients. New-onset diabetes was present in 15 (29.4%) patients with median time-to-diagnosis of 6 (1-12) mo after resection. CONCLUSIONS: Pancreatectomy for benign cysts did not negatively impact patients' perceived QOL. However, after long-term follow-up, malnutrition and pancreatic insufficiency occurred in a significant percentage and may be greater than previously estimated. Consideration of short- and long-term outcomes should factor into preoperative counseling, especially in cysts with minimal risk of progression to malignancy.

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens.

BACKGROUND: Identification of incidental pancreatic lesions is increasing because of advancements in imaging. Diagnosis remains a challenge for clinicians, with intrapancreatic accessory spleens (IPAS) posing a unique dilemma. IPAS are frequently resected because of inability to exclude alternate diagnoses, subjecting patients to unnecessary risk. The purpose of this study was to examine our institutional experience with IPAS and develop a multidisciplinary algorithm to improve preoperative diagnosis. MATERIALS AND METHODS: Patients who underwent a distal pancreatectomy at a single institution from 2005 to 2018 were identified from a prospectively maintained database. Examination of final pathology for a diagnosis of IPAS yielded the final cohort. Demographics, preoperative workup, and operative course were reviewed and analyzed. A diagnostic algorithm was composed based on the consensus of a panel of expert pancreatic surgeons, a radiologist, and a pathologist. RESULTS: Ten patients of 303 patients who underwent a distal pancreatectomy were identified with a final pathology of IPAS. The average age was 54 y, 80% were white, and 60% were male. Lesions ranged in size from 7 mm to 5.1 cm in largest diameter (mean 2.2 cm). Lesions were described as round, well-marginated, and enhancing masses within the pancreatic tail. Preoperative workup was variable in terms of imaging and laboratory testing. Diagnostic workups were examined and combined with multidisciplinary input to create a diagnostic algorithm. CONCLUSIONS: Incidental pancreatic lesions like IPAS remain a diagnostic challenge for clinicians. Employing a diagnostic algorithm as proposed may aid in the distinction of malignant and premalignant pathology and prevent unwarranted pancreatic resections.

Evidence Versus Practice in Early Drain Removal After Pancreatectomy.

BACKGROUND: Early drain removal when postoperative day (POD) one drain fluid amylase (DFA) was ≤5000 U/L reduced complications in a previous randomized controlled trial. We hypothesized that most surgeons continue to remove drains late and this is associated with inferior outcomes. METHODS: We assessed the practice of surgeons in a prospectively maintained pancreas surgery registry to determine the association between timing of drain removal with demographics, comorbidities, and complications. We selected patients with POD1 DFA ≤5000 U/L and excluded those without drains, and subjects without data on POD1 DFA or timing of drain removal. Early drain removal was defined as ≤ POD5. RESULTS: Two hundred and forty four patients met inclusion criteria. Only 90 (37%) had drains removed early. Estimated blood loss was greater in the late removal group (190 mL versus 100 mL, P = 0.005) and pathological findings associated with soft gland texture were more frequent (97 [63%] versus 35 [39%], P < 0.0001). Patients in the late drain removal group had more complications (84 [55%] versus 30 [33%], P = 0.001) including pancreatic fistula (55 [36%] versus 4 [4%], P < 0.0001), delayed gastric emptying (27 [18%] versus 3 [3%], P = 0.002), and longer length of stay (7 d versus 5 d, P < 0.0001). In subset analysis for procedure type, complications and pancreatic fistula remained significant for both pancreatoduodenectomy and distal pancreatectomy. CONCLUSIONS: Despite level one data suggesting improved outcomes with early removal when POD1 DFA is ≤ 5000 U/L, experienced pancreas surgeons more frequently removed drains late. This practice was associated with known risk factors (estimated blood loss, soft pancreas) and may be associated with inferior outcomes suggesting potential for improvement.

Venous thrombosis following pancreaticoduodenectomy with venous resection.

BACKGROUND: Addition of en bloc segmental venous reconstruction (VR) to pancreaticoduodenectomy (PD) for venous involvement of pancreatic tumors increases the complexity of the operation and may increase complications. The long-term mesenteric venous patency rate and oncologic outcome has not been well defined. METHODS: Our prospective database was reviewed to assess 90-day postoperative outcomes for patients who underwent PD or PD + VR (September 2004-June 2016). Two independent observers reviewed CT scans to determine long-term vein patency. In patients with pancreatic ductal adenocarcinoma, the impact of VR on 5-year overall survival was assessed using multivariate Cox proportional hazards regression. Student's t-test was used to evaluate continuous variables and the chi-square test for categorical variables. RESULTS: Three hundred ninety-three patients underwent PD (51 PD + VR). Patients undergoing PD + VR had longer operations (561 ± 119 versus 433 ± 89 min, P < 0.00001) and greater blood loss (768 ± 812 versus 327 ± 423 cc, P < 0.00001). There was no difference in 90-day mortality, overall postoperative complication rates, complication severity grades, reoperation, readmission, or length of stay. 26.7% experienced venous thrombosis. Most thromboses occurred in the first year after surgery, but we also observed late thrombosis in 1 patient after 89-month follow-up. Among 135 patients with pancreatic ductal adenocarcinoma, survival was significantly longer in the PD-alone group (31.3 months [95% confidence interval: 22.9-40.0] versus 17.0 [95% confidence interval: 13.0-19.1], plog-rank = 0.013). CONCLUSIONS: PD + VR does not increase short-term morbidity, but venous thrombosis is frequent and can occur long after surgery. Survival is inferior when VR is required especially in the absence of neoadjuvant chemotherapy.

Sequential drain amylase to guide drain removal following pancreatectomy.

BACKGROUND: Although used as criterion for early drain removal, postoperative day (POD) 1 drain fluid amylase (DFA) ≤ 5000 U/L has low negative predictive value for clinically relevant postoperative pancreatic fistula (CR-POPF). It was hypothesized that POD3 DFA ≤ 350 could provide further information to guide early drain removal. METHODS: Data from a pancreas surgery consortium database for pancreatoduodenectomy and distal pancreatectomy patients were analyzed retrospectively. Those patients without drains or POD 1 and 3 DFA data were excluded. Patients with POD1 DFA ≤ 5000 were divided into groups based on POD3 DFA: Group A (≤350) and Group B (>350). Operative characteristics and 60-day outcomes were compared using chi-square test. RESULTS: Among 687 patients in the database, all data were available for 380. Fifty-five (14.5%) had a POD1 DFA > 5000. Among 325 with POD1 DFA ≤ 5000, 254 (78.2%) were in Group A and 71 (21.8%) in Group B. Complications (35 (49.3%) vs 87 (34.4%); p = 0.021) and CR-POPF (13 (18.3%) vs 10 (3.9%); p < 0.001) were more frequent in Group B. CONCLUSIONS: In patients with POD1 DFA ≤ 5000, POD3 DFA ≤ 350 may be a practical test to guide safe early drain removal. Further prospective testing may be useful.

A Prospective Randomized Multicenter Trial of Distal Pancreatectomy With and Without Routine Intraperitoneal Drainage.

OBJECTIVE: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. BACKGROUND: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. METHODS: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. RESULTS: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. CONCLUSIONS: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

A randomized prospective multicenter trial of pancreaticoduodenectomy with and without routine intraperitoneal drainage.

OBJECTIVE: To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. BACKGROUND: Some surgeons have abandoned the use of drains placed during pancreas resection. METHODS: We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. RESULTS: There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. CONCLUSIONS: This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Phase II study of induction fixed-dose rate gemcitabine and bevacizumab followed by 30 Gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.

BACKGROUND: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC. METHODS: This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%. RESULTS: Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection. CONCLUSIONS: Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.

MUC1 Expressions and Its Prognostic Values in US Gastric Cancer Patients.

This study aims to evaluate the prognostic value of MUC expression in US GC patients. A total of 70 tumor specimens were collected from GC patients who underwent surgery or endoscopic resection between 2013 and 2019 at a tertiary referral center in the US. MUC expression status including MUC1, MUC2, MUC5AC, and MUC6 was evaluated by immunohistochemical staining. The positive rates of MUC1, MUC2, MUC5AC, and MUC6 were 71.4%, 78.6%, 74.3%, and 33.3%, respectively. Patients with positive MUC1 expression had a significantly higher rate of aggressive pathologic features including diffuse-type cancer (42.0% vs. 0%; p < 0.001), advanced GC (80.0% vs. 30.0%, p < 0.001), lymph node metastasis (62.0% vs. 20.0%; p = 0.001), and distant metastasis (32.0% vs. 5.0%; p = 0.017) compared with those with negative MUC1 expression. However, the differences in the pathologic features were not observed according to MUC2, MUC5AC, and MUC6 expression status. In early gastric cancer (EGC), patients with a high level of MUC1 expression showed a higher rate of lymphovascular invasion (71.4% vs. 21.4%; p = 0.026) and EGC meeting non-curative resection (85.7% vs. 42.9%; p = 0.061) than those with negative MUC1. In US GC patients, MUC1 expression is associated with aggressive pathological features, and might be a useful prognostic marker.

Pretreatment Health-Related Quality-of-Life Status and Survival in Pancreatobiliary Surgical Patients.

BACKGROUND: Pancreatobiliary (PB) disorders, especially cancer, negatively affect patients' health-related quality of life (HRQoL). However, the influence of baseline, preintervention HRQoL on perioperative and oncologic outcomes has not been well defined. We hypothesized that low baseline HRQoL is associated with worse perioperative and long-term survival outcomes for PB surgical patients. STUDY DESIGN: Pretreatment Functional Assessment of Cancer Therapy - Hepatobiliary Survey results and clinical data from PB patients (2008 to 2016) from a single center's prospective database were analyzed. Survey responses were aggregated into composite scores and divided into quintiles. Patients in the highest quintile of HRQoL were compared to patients in the bottom four quintiles combined. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. Logistic and Cox regressions were used to determine associations between quintiles of HRQoL scores and 30-day complications and long-term survival, respectively. RESULTS: Of 162 patients evaluated, 99 had malignancy, and 63 had benign disease. Median follow-up was 31 months. Baseline HRQoL scores were similar for benign and malignant disease (p = 0.42) and were not associated with the development of any (p = 0.08) or major complications (p = 0.64). Patients with highest quintile HRQoL scores had improved 3-year OS (84.6 vs 61.7%, p = 0.03) compared to patients in the lowest four quintiles of HRQoL. Among cancer patients only, those with the highest quintile scores had improved 3-year OS (81.6 vs 47.4%, p = 0.02). On multivariable analysis, highest quintile HRQoL scores were associated with longer OS and DFS for patients with malignancy. CONCLUSIONS: Pretreatment HRQoL was associated with both OS and DFS among PB patients and might have prognostic utility. Future studies are necessary to determine whether patients with poorer HRQoL may benefit from targeted psychosocial interventions.

Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer.

Introduction: Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy. Methods: Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression. Results: 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort. Discussion: Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Interobserver Variability and Challenges in Intraoperative Frozen Section Evaluation of Pancreatic Margins in Pancreatectomy Specimens.

OBJECTIVE: Frozen-section evaluation of the pancreatic margin is challenging. We aimed to determine interobserver variability among gastrointestinal pathologists for the assessment of frozen sections of pancreatic margins with marked chronic pancreatitis and to determine the challenging histological features in discrepant cases. METHODS: We identified 45 patients who underwent pancreas resection for pancreatic ductal adenocarcinoma and showed marked chronic pancreatitis at pancreatic margin. Deidentified first levels of frozen-sections of the pancreatic margins from all cases were independently reviewed by 5 experienced gastrointestinal pathologists for the presence of carcinoma and/or high-grade dysplasia. RESULTS: Interobserver agreement among pathologists was calculated as kappa coefficients ([Formula: see text]). A consensus diagnosis for discordant cases was obtained after group review and discussion. Interobserver agreement for adenocarcinoma diagnosis was 87%, and there was "substantial agreement" (Fleiss [Formula: see text]=0.78, P<0.01) and "almost perfect agreement" (Brennan-Prediger [Formula: see text]=0.86, P<0.01). Using the final diagnosis based on frozen and permanent sections as the gold standard and the concordant read of at least 3 of 5 pathologists for comparison, the diagnosis of adenocarcinoma was made in frozen-sections of pancreas margins, with accuracy 98%, sensitivity 83%, specificity 100%, negative predictive value 97%, positive predictive value 100%, false negative rate 9%, and false positive rate 0%. CONCLUSIONS: We showed excellent interobserver agreement among gastrointestinal pathologists for diagnosis of adenocarcinoma on frozen sections of pancreatic margins with marked chronic pancreatitis. Missed adenocarcinoma at the margin was mainly caused by freezing or cautery artifacts or by overlooking a tiny focus of perineural invasion in a background of marked chronic pancreatitis. The evaluation of deeper levels led to perfect agreement.

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer.

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention. SIGNIFICANCE: Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell-mediated tumor regression. See related commentary by DelGiorno, p. 977.

Factors associated with inability to return to intended oncologic treatment in pancreatic cancer.

BACKGROUND: Return to Intended Oncologic Treatment (RIOT) has been proposed as a quality metric in the care of cancer patients. We sought to define factors associated with inability to RIOT in Pancreatic Ductal Adenocarcinoma (PDAC) patients. METHODS: The NCDB was queried for patients who underwent pancreaticoduodenectomy for pathologic stage IB, IIA, or IIB PDAC from 2010 to 2016. Multivariable binary logistic regression models identified factors associated with failure to RIOT, and Kaplan-Meier survival analysis and Cox multivariable regression models demonstrated the impact of failure to RIOT on survival. RESULTS: Increasing age (p < .001), Hispanic race (p = .002), pathological stage IB (p = .004) and IIA (p = .001) as compared to IIB, increasing hospital stay (p < .001), and open surgical approach (p = .024) were associated with increased risk of inability to RIOT. Male sex (p < .001), Charlson-Deyo scores of 0 (p < .001) and 1 (p = .001) as compared to >2, negative surgical margins (p = .048), receiving care at academic institutions (p = .001), and increasing institutional case volume (p = .001) were associated with improved odds of RIOT. CONCLUSIONS: Patient features can impact RIOT and should be considered when designing multi-modality treatment strategies.

A risk-adjusted analysis of drain use in pancreaticoduodenectomy: Some is good, but more may not be better.

BACKGROUND: Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF. METHODS: The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach. RESULTS: A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P < .001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone. CONCLUSION: In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.