Primary Cutaneous Epithelioid Mesenchymal Tumor With a Novel ATP2B4::GLI1 Gene Fusion.

ABSTRACT: GLI1 gene alterations (rearrangement or amplification) have been found in several bone and soft tissue tumors including pericytic tumors, gastric plexiform fibromyxoma, gastroblastoma, and a various group of epithelioid tumors with regional recurrence or distant metastasis. In this article, we describe a case of primary cutaneous epithelioid mesenchymal tumor harboring hitherto not reported ATP2B4::GLI1 gene fusion. A 42-year-old man presented with a growing firm lesion on the left postauricular scalp. Microscopically, the shave biopsy specimen revealed a dermal-based nodular proliferation of relatively monotonous epithelioid cells with round to ovoid nuclei and pale eosinophilic cytoplasm, accompanied by prominent stromal vasculature. Significant cytologic atypia, necrosis, and mitotic activity were absent. The tumor cells were partially positive for CD34 and S-100 protein, but were negative for other markers, including SOX-10, keratins, and myogenic markers. An ATP2B4::GLI1 gene fusion was identified by next-generation sequencing. Array CGH was also performed, but it did not show relevant chromosomal copy number changes. Awareness of this rare cutaneous tumor, and thus, reporting of additional cases is necessary for further delineating its full clinicopathologic spectrum.

Invasive and Noninvasive Progression After Resection of Noninvasive Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To define frequencies, pattern of progression (invasive vs noninvasive), and risk factors of progression of resected noninvasive intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: There is a risk of progression in the remnant pancreas after resection of IPMNs. METHODS: Four hundred forty-nine consecutive patients with resected IPMNs from 1995 to 2018 were included to the study. Patients with invasive carcinoma or with follow-up <6 months were excluded. Noninvasive progression was defined as a new IPMN, increased main pancreatic duct size, and increased size of an existing lesion (5 mm compared with preoperative imaging). Invasive progression was defined as development of invasive cancer in the remnant pancreas or metastatic disease. RESULTS: With a median follow-up of 48.9 months, progression was identified in 124 patients (27.6%); 108(24.1%) with noninvasive and 16(3.6%) with invasive progression. Median progression follow-up was longer for invasive progression (85.4 vs 55.9 months; P = 0.001). Five-and 10-year estimates for a cumulative incidence of invasive progression were 6.4% and 12.9% versus 26.9% and 41.5% for noninvasive progression. After risk adjustment, multifocality (HR 4.53, 95% CI 1.34-15.26; P = 0.02) and high-grade dysplasia (HGD) in the original resection (HR 3.60, 95% CI 1.13-11.48; P = 0.03) were associated with invasive progression. CONCLUSIONS: Progression to invasive carcinoma can occur years after the surgical resection of a noninvasive IPMN. HGD in the original resection is a risk factor for invasive progression but some cases of low-grade dysplasia also progressed to cancer. Patients with high-risk features such as HGD and multifocal cysts should be considered for more intensive surveillance and represent an important cohort for future trials such as anti-inflammatory or prophylactic immunotherapy.

The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection: Long-Term Follow-Up Analysis.

OBJECTIVE: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN). SUMMARY BACKGROUND DATA: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection. METHODS: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing. RESULTS: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years. CONCLUSION: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.

Minimal main pancreatic duct dilatation in small branch duct intraductal papillary mucinous neoplasms associated with high-grade dysplasia or invasive carcinoma.

BACKGROUND: The aim of this study was to determine the incidence of high-grade dysplasia (HGD) or invasive carcinoma in patients with small branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). METHODS: 923 patients who underwent surgical resection for an IPMN were identified. Sendai-negative patients were identified as those without history of pancreatitis or jaundice, main pancreatic duct size (MPD) <5 mm, cyst size <3 cm, no mural nodules, negative cyst fluid cytology for adenocarcinoma, or serum carbohydrate antigen 19-9 (CA 19-9) <37 U/L. RESULTS: BD-IPMN was identified in 388 (46.4%) patients and 89 (22.9%) were categorized as Sendai-negative. Overall, 68 (17.5%) of BD-IPMN had HGD and 62 (16.0%) had an associated invasive-carcinoma. Among the 89 Sendai-negative patients, 12 (13.5%) had IPMNs with HGD and only one patient (1.1%) had invasive-carcinoma. Of note, older age (OR 1.13, 95% CI 1.03-1.23; P = 0.008) and minimal dilation of MPD (OR 11.3, 95% CI 2.40-53.65; P = 0.002) were associated with high-risk disease in Sendai-negative patients after multivariable risk adjustment. CONCLUSION: The risk of harboring a high-risk disease remains low in small BD-IPMNs. However, Sendai-negative patients who are older than 65 years old and those with minimal dilation of MPD (3-5 mm) are at greater risk of high-risk lesions and should be given consideration to be included as a "worrisome feature" in a future guidelines update.

Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases.

OBJECTIVE: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS: A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS: In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS: We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.

Main Duct Dilatation Is the Best Predictor of High-grade Dysplasia or Invasion in Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: The purpose of this study is to determine preoperative factors that are predictive of malignancy in patients undergoing pancreatic resection for intraductal papillary mucinous neoplasms (IPMN). SUMMARY BACKGROUND DATA: IPMN of the pancreas may be precursor lesions to pancreatic cancer (PC) and represent a target for early diagnosis or prevention. While there has been much effort to define preoperative risk factors for malignant pathology, guidelines are ever-changing and controversy remains surrounding which patients would benefit most from resection. METHODS: We performed a retrospective analysis of 901 consecutive patients obtained from two tertiary referral centers who underwent pancreatic resection for histologically proven IPMN between 2004 and 2017. Collected data included patient demographic characteristics, preoperative symptoms, radiological findings, and laboratory data. RESULTS: Main pancreatic duct (MPD) dilatation was the only variable that was significantly associated with increased probability of malignancy (defined high-dysplasia or invasion) on both univariate and multivariate analysis. Even middle-range MPD dilatation from 5 mm to 9.9 mm (n = 286) was associated with increased odds of HG-IPMN (OR = 2.74; 95% CI = 1.80-4.16) and invasion (OR = 4.42; 95% CI = 2.55-7.66). MPD dilatation >10 mm (n = 150) had even greater odds of HG-IPMN (OR = 6.57; 95% CI = 3.94-10.98) and invasion (OR = 15.07; 95% CI = 8.21-27.65). A cutoff of 5 to 7 mm MPD diameter was determined to be the best predictor to discriminate between malignant and benign lesions. CONCLUSIONS: In agreement with current IPMN management guidelines, we found MPD dilatation, even low levels from 5 mm to 9.9 mm, to be the single best predictor of HG-IPMN or invasion, highlighting the critical role that MPD plays in the selection of surgical candidates.

Follicular cholecystitis: clinicopathologic associations.

Follicular cholecystitis (FC) is a relatively rare entity with uncertain causal associations. In this study, we aimed to explore different clinicopathologic associations of FC, and to better characterize the entity. A retrospective review of archival hematoxylin and eosin slides and pertinent clinical information was undertaken for all cholecystectomy cases with a rendered diagnosis of "follicular cholecystitis," from 1991 to 2017. Concurrent conventional chronic cholecystitis (CC) and lymphocytic cholecystitis (LC) were documented. Forty-three consecutive patients were confirmed to have FC. The majority of the patients (88.4%) had at least one other histologic association in the gallbladder (LC, CC, or both). Remarkably, functional distal biliary obstruction (from choledocholithiasis, sclerosing cholangitis, distal biliary strictures, or malignancies of the pancreatic head or ampulla) was found in 76.7% of the patients, irrespective of the presence of other concurrent histologic findings. FC associated with CC was relatively more common in females (61%) and strongly associated with cholelithiasis (70%). However, those without CC were predominantly males (70%) and had a significant association with LC (75%). All four cases of FC without any other histologic associations who had clinical information available showed some form of distal biliary obstruction. FC cases without concurrent LC were often associated with CC (74%). FC is strongly associated with extrahepatic biliary obstruction distal to the gallbladder. Therefore, this finding at routine cholecystectomy may warrant further evaluation to rule out a cause for distal biliary tract obstruction. Additionally, it is commonly associated with other concomitant histologic abnormalities in the gallbladder such as CC and/or LC.

Colorectal Liver Metastases: Does the Future of Precision Medicine Lie in Genetic Testing?

Colorectal liver metastases (CRLM) present an important clinical challenge in both surgical and medical oncology. Despite improvements in management, survival among patients undergoing resection of CRLM is still very variable and there is a paucity of clinical trial data and reliable biomarkers that could guide prognostic forecasts, treatment selection, and follow-up. Fortunately, recent advances in molecular biology and tumor sequencing have identified a number of critical genetic loci and proliferation markers that may hold the key to understanding the biologic behavior of CRLM; specifically, mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki-67, and the presence of microsatellite instability appear to have a decisive impact on prognosis and response to treatment in patients with CRLM. While the applicability of genetic biomarkers in everyday clinical practice remains conditional on the development of inexpensive bedside sequencing, targeted therapies, and the conduct of appropriate clinical trials, the promise of personalized treatment may be closer to realization than ever before.

Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology.

Visualizing pathologies in three dimensions can provide unique insights into the biology of human diseases. A rapid and easy-to-implement dibenzyl ether-based technique was used to clear thick sections of surgically resected human pancreatic parenchyma. Protocols were applicable to both fresh and formalin-fixed, paraffin-embedded tissue. The penetration of antibodies into dense pancreatic parenchyma was optimized using both gradually increasing antibody concentrations and centrifugal flow. Immunolabeling with antibodies against cytokeratin 19 was visualized using both light sheet and confocal laser scanning microscopy. The technique was applied successfully to 26 sections of pancreas, providing three-dimensional (3D) images of normal pancreatic tissue, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, and infiltrating pancreatic ductal adenocarcinomas. 3D visualization highlighted processes that are hard to conceptualize in two dimensions, such as invasive carcinoma growing into what appeared to be pre-existing pancreatic ducts and within venules, and the tracking of long cords of neoplastic cells parallel to blood vessels. Expanding this technique to formalin-fixed, paraffin-embedded tissue opens pathology archives to 3D visualization of unique biosamples and rare diseases. The application of immunolabeling and clearing to human pancreatic parenchyma provides detailed visualization of normal pancreatic anatomy, and can be used to characterize the 3D architecture of diseases including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and pancreatic ductal adenocarcinomas.

Postoperative complications after resection of borderline resectable and locally advanced pancreatic cancer: The impact of neoadjuvant chemotherapy with conventional radiation or stereotactic body radiation therapy.

BACKGROUND: The impact of neoadjuvant stereotactic body radiation therapy on postoperative complications for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma remains unclear. Limited studies have compared neoadjuvant stereotactic body radiation therapy versus conventional chemoradiation therapy. A retrospective study was performed to determine if perioperative complications were different among patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant stereotactic body radiation therapy or chemoradiation therapy. METHODS: Patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma who underwent neoadjuvant chemotherapy with stereotactic body radiation therapy or chemoradiation therapy followed by pancreatectomy at the Johns Hopkins Hospital between 2008 and 2015 were included. Predictive factors for severe complications (Clavien grade ≥ III) were assessed by univariate and multivariate analyses. RESULTS: A total of 168 patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma underwent neoadjuvant chemotherapy and RT followed by pancreatectomy. Sixty-one (36%) patients underwent stereotactic body radiation therapy and 107 (64%) patients received chemoradiation therapy. Compared with the chemoradiation therapy cohort, the neoadjuvant stereotactic body radiation therapy cohort was more likely to have locally advanced pancreatic ductal adenocarcinoma (62% vs 43% P = .017) and require a vascular resection (54% vs 37%, P = .027). Multiagent chemotherapy was used more commonly in the stereotactic body radiation therapy cohort (97% vs 75%, P < .001). Postoperative complications (Clavien grade ≥ III 23% vs 28%, P = .471) were similar between stereotactic body radiation therapy and chemoradiation therapy cohort. No significant difference in postoperative bleeding or infection was noted in either group. CONCLUSION: Compared with chemoradiation therapy, neoadjuvant stereotactic body radiation therapy appears to offer equivalent rates of perioperative complications in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma despite a greater percentage of locally advanced disease and more complex operative treatment.

Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: To describe accurately the pattern, timing, and predictors of disease recurrence after a potentially curative resection for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: After surgery for PDAC, most patients will develop disease recurrence. Understanding the patterns and timing of disease failure can help guide improvements in therapy. METHODS: Patients who underwent pancreatectomy for PDAC at the Johns Hopkins Hospital between 2000 and 2010 were included. Exclusion criteria were incomplete follow-up records, follow-up <24 months, and neoadjuvant therapy. The first recurrence site was recorded and recurrence-free survival (RFS) was estimated using Kaplan-Meier curves. Predictive factors for specific recurrence patterns were assessed by univariate and multivariate analyses using Cox-proportional hazard regression models. RESULTS: From the identified cohort of 1103 patients, 692 patients had comprehensive and detailed follow-up data available. At a median follow-up of 25.3 months, 531 (76.7%) of the 692 had recurred after a median RFS of 11.7 months. Most patients recurred at isolated distant sites (n = 307, 57.8%), while isolated local recurrence was seen in 126 patients (23.7%). Liver-only recurrence (n = 134, 25.2%) tended to occur early (median 6.9 mo), while lung-only recurrence (n = 78, 14.7%) occurred later (median 18.6 mo). A positive lymph node ratio >0.2 was a strong predictor for all distant disease recurrence. Patients receiving adjuvant chemotherapy or chemoradiotherapy had fewer recurrences and a longer RFS of 18.0 and 17.2 months, respectively. CONCLUSIONS: Specific recurrence locations have different predictive factors and possess distinct RFS curves, supporting the hypothesis that unique biological differences exist among tumors leading to distinct patterns of recurrence.

Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium.

OBJECTIVE: Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA: IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS: Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS: We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS: For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

Multi-institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-risk Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72-4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

Intraductal Papillary Mucinous Neoplasm of the Pancreas in Young Patients: Tumor Biology, Clinical Features, and Survival Outcomes.

AIM: The aim of this paper is to describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in young patients. METHODS: We evaluated 1693 patients from the Pancreatic Surgery Consortium who underwent resection for IPMN and classified them as younger or older than 50 years of age at the time of surgery. We assessed the relationship of age with clinical, radiological, pathological, and prognostic features. RESULTS: We identified 90 (5%) young patients. Age was not associated with differences in main pancreatic duct size (P = 0.323), presence of solid components (P = 0.805), or cyst size (P = 0.135). IPMNs from young patients were less likely to be of gastric type (37 vs. 57%, P = 0.005), and more likely to be of oncocytic (15 vs. 4%, P = 0.003) and intestinal types (44 vs. 26%, P = 0.004). Invasive carcinomas arising from IPMN were less common in young patients (17 vs. 27%, P = 0.044), and when present they were commonly of colloid type (47 vs. 31% in older patients, P = 0.261) and had better overall survival than older patients (5-year, 71 vs. 37%, log-rank P = 0.031). CONCLUSION: Resection for IPMN is infrequent in young patients, but when they are resected, IPMNs from young patients demonstrate different epithelial subtypes from those in older patients and more favorable prognosis.

Preoperative bevacizumab and volumetric recovery after resection of colorectal liver metastases.

BACKGROUND AND OBJECTIVES: While preoperative treatment is frequently administered to CRLM patients, the impact of chemotherapy, with or without bevacizumab, on liver regeneration remains controversial. METHODS: The early and late regeneration indexes were defined as the relative increase in liver volume (RLV) within 2 and 9 months from surgery. Regeneration rates of the preoperative treatment groups were compared. RESULTS: Preoperative chemotherapy details and volumetric data were available for 185 patients; 78 (42.2%) received preoperative chemotherapy with bevacizumab (Bev+), 46 (24.8%) received chemotherapy only (Bev-), and 61 (33%) received no chemotherapy. Patients in the Bev+ and Bev- groups received similar chemotherapy cycles (4 [3-6] vs 4 [4-6]; P = 0.499). Despite the comparable clinicopathological characteristics and Resected Volume/Total Liver Volume (TLV) at surgery (P = 0.944) of both groups, Bev+ group had higher early and late regeneration (17.2% vs 4.3%; P = 0.035 and 14.0% vs 9.4%; P = 0.091, respectively). Of note, early and late regeneration rates (3.7% and 10.9% vs 6.6% and 5.5%, respectively) were comparable between the no chemotherapy and Bev- groups (all P > 0.05). In multivariable analysis -adjusted for gender, age, portal vein embolization, preoperative chemotherapy, resected liver volume, tumor number, postoperative chemotherapy, fibrosis, steatosis- bevacizumab independently predicted early liver regeneration (P = 0.019). CONCLUSION: Our findings suggest that preoperative bevacizumab administered along with chemotherapy was associated with enhanced volumetric restoration. Interestingly, this effect was more pronounced among patients who received oxaliplatin-based regimens and bevacizumab compared to those treated with irinotecan-based regimens and bevacizumab.

Neoadjuvant therapy prior to surgical resection for previously explored pancreatic cancer patients is associated with improved survival.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently referred to tertiary centers after unsuccessful attempted resections at other institutions. The outcome of these patients who are ultimately resected is not well understood. METHODS: We performed a retrospective review of patients with PDAC who underwent re-exploration between 1995 and 2013 at a single high volume tertiary care institution. We aimed to evaluate the association of neoadjuvant therapy prior to re-exploration on pathologic findings and clinical outcome in previously explored patients with PDAC. RESULTS: Between 1995 and 2013, 50 of the 2,062 patients who were surgically explored underwent pancreatic resection following a previous exploration where they were deemed unresectable. The most common reason for unresectability at initial operation was vascular invasion (80%) and a presumed R2 resection. Thirty-seven (74%) patients received neoadjuvant therapy. Neoadjuvant therapy was associated with improved TNM stage (P=0.002), fewer positive lymph nodes (0 vs. 2, P=0.025), and improved median survival (24 vs. 13 months, P=0.044). Compared to R2 resected patients with PDAC who had not previously been explored, re-explored patients had significantly lower pathologic T and N stages (P<0.001) and a longer median survival (19 vs. 10 months, P<0.001). CONCLUSIONS: Patients with PDAC deemed unresectable may warrant re-exploration. Treatment with neoadjuvant therapy between operations is associated with improved pathological stage and survival. In this highly selected group of patients, successful resection is associated with improved survival compared to R2 resections.

Duodenal Involvement is an Independent Prognostic Factor for Patients with Surgically Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The current staging system for pancreatic ductal adenocarcinoma (PDAC) includes information about size and local extension of the primary tumor (T stage). The value of incorporating any local tumor extension into pancreatic staging systems has been questioned because it often is difficult to evaluate tumor extension to the peri-pancreatic soft tissues and because most carcinomas of the head of the pancreas infiltrate the intra-pancreatic common bile duct. This study sought to evaluate the prognostic implications of having PDAC with local tumor extension. METHODS: A single-institution, prospectively collected database of 1128 patients who underwent surgical resection for PDAC was queried to examine the prognostic significance of extra-pancreatic tumor involvement ("no involvement," "duodenal involvement," and "extensive involvement"; e.g., gastric, colon or major vein involvement). RESULTS: The median overall survival for the patients without extra-pancreatic involvement was 26 months versus 19 months for the patients with duodenal involvement and 16 months for the patients with extensive involvement (p < 0.001). In the multivariable analysis, duodenal and extensive involvement independently predicted increased risk of death compared with no involvement (hazard ratio [HR] 1.30; 95% confidence interval [CI] 1.08-1.57 and 1.78; 95% CI 1.25-2.55, respectively). A multivariable model combining duodenal and extensive extra-pancreatic involvement, tumor grade, lymph node ratio, and other prognostic features had the highest c-index (0.67). CONCLUSIONS: Inclusion of duodenal involvement in the staging of PDAC adds independent prognostic information.

Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.