Krishna, Somashekar G

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

AbstractBackgroundObesity worsens various gastrointestinal pathologies. While bariatric surgery ameliorates obesity, it substantially modifies the gastrointestinal system depending on surgery type, with limited data on subsequent impact on obesity‐related gastrointestinal admissions.MethodsUsing the 2012–2014 Nationwide Readmission Database, we included individuals with obesity who received vertical sleeve gastrectomy (VSG), Roux‐en‐Y gastric bypass (RYGB), or hernia repair (HR–control surgery). Our main focus was the adjusted odds ratio (aOR) for gastrointestinal inpatient admissions within 6 months following surgery compared to the 6 months preceding it, while controlling for several confounding factors. Gastrointestinal admissions were grouped into postoperative complications or obesity‐associated gastrointestinal conditions.ResultsOur cohort included 140,103 adults with RYGB, 132,253 with VSG, and 12,436 HR controls. Postoperative gastrointestinal complications were most common after RYGB, prominently obstruction (aOR = 33.17, 95%CI: 18.01, 61.10), and Clostridium difficile infection (aOR: 12.52, 95%CI: 6.22, 25.19). VSG also saw significantly increased but less frequent similar conditions. Notably, for gastrointestinal conditions associated with obesity, acute pancreatitis risk was higher post‐VSG (aOR = 6.26, 95%CI: 4.02, 9.73). Post‐RYGB patients were most likely to be admitted for cholelithiasis with cholecystitis (aOR: 4.15, 95% CI: 3.24, 5.31), followed by chronic liver disease (aOR: 3.00, 95% CI: 2.33, 3.87). The risk of noninfectious colitis admissions was threefold higher after RYGB and VSG. No gastrointestinal conditions showed an increase after HR.ConclusionDespite weight loss, bariatric surgery was associated with an increased risk of hepato‐pancreatobiliary and colitis admissions related to obesity in the first six postoperative months, with considerable variations in rates of gastrointestinal conditions by surgery type.

Despite the increasing rate of detection of incidental pancreatic cystic lesions (PCLs), current standard-of-care methods for their diagnosis and risk stratification remain inadequate. Intraductal papillary mucinous neoplasms (IPMNs) are the most prevalent PCLs. The existing modalities, including endoscopic ultrasound and cyst fluid analysis, only achieve accuracy rates of 65–75% in identifying carcinoma or high-grade dysplasia in IPMNs. Furthermore, surgical resection of PCLs reveals that up to half exhibit only low-grade dysplastic changes or benign neoplasms. To reduce unnecessary and high-risk pancreatic surgeries, more precise diagnostic techniques are necessary. A promising approach involves integrating existing data, such as clinical features, cyst morphology, and data from cyst fluid analysis, with confocal endomicroscopy and radiomics to enhance the prediction of advanced neoplasms in PCLs. Artificial intelligence and machine learning modalities can play a crucial role in achieving this goal. In this review, we explore current and future techniques to leverage these advanced technologies to improve diagnostic accuracy in the context of PCLs.

A combination of several factors, including the increasing use of cross-sectional imaging and an aging population, has led to pancreatic cystic lesions (PCLs) becoming the most detected incidental pancreatic lesions. Accurate diagnosis and risk stratification of PCLs is challenging. In the last decade, several evidence-based guidelines have been published addressing the diagnosis and management of PCLs. However, these guidelines cover different subsets of patients with PCLs and offer varying recommendations regarding diagnostic assessment, surveillance, and surgical resection. Further, recent studies comparing the accuracy of various guidelines have reported significant variations in the rate of missed cancer versus unnecessary surgical resections. In clinical practice, it is challenging to decide which guideline to follow specifically. This article reviews the varying recommendations of the major guidelines and results of comparative studies, provides an overview of newer modalities not included in the guidelines, and offers perspectives on translating the guidelines into clinical practice.

Radiomics, also known as quantitative imaging or texture analysis, involves extracting a large number of features traditionally unmeasured in conventional radiological cross-sectional images and converting them into mathematical models. This review describes this approach and its use in the evaluation of pancreatic cystic lesions (PCLs). This discipline has the potential of more accurately assessing, classifying, risk stratifying, and guiding the management of PCLs. Existing studies have provided important insight into the role of radiomics in managing PCLs. Although these studies are limited by the use of retrospective design, single center data, and small sample sizes, radiomic features in combination with clinical data appear to be superior to the current standard of care in differentiating cyst type and in identifying mucinous PCLs with high-grade dysplasia. Combining radiomic features with other novel endoscopic diagnostics, including cyst fluid molecular analysis and confocal endomicroscopy, can potentially optimize the predictive accuracy of these models. There is a need for multicenter prospective studies to elucidate the role of radiomics in the management of PCLs.

Abstract Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Abstract Background and study aims Endoscopic biliary intervention (BI) is often difficult to perform in patients with prior bariatric surgery (BRS). We sought to analyze outcomes of patients with prior BRS undergoing endoscopic and non-endoscopic BI. Patients and methods The Nationwide Inpatient Sample (2007 – 2011) was reviewed to identify all adult inpatients (≥ 18 years) with a history of BRS undergoing BI. The clinical outcomes of interest were in-patient mortality, length of stay (LOS), and total hospital charges. Results There were 7,343 patients with prior BRS who underwent BIs where a majority were endoscopic (4,482 vs. 2,861, P < 0.01). The mean age was 50±30.8 years and the majority were females (80.5 %). Gallstone-related disease was the most common indication for BI and managed more often with primary endoscopic management (2,146 vs. 1,132, P < 0.01). Inpatient mortality was not significantly different between patients undergoing primary endoscopic versus non-endoscopic BI (0.2 % vs. 0.7 %, P = 0.2). Patients with sepsis were significantly more likely to incur failed primary endoscopic BI (OR 2.74, 95 % CI 1.15, 6.53) and were more likely to be managed with non-endoscopic BI (OR 2.13, 95 % CI 1.3, 3.5). Primary non-endoscopic BI and failed endoscopic BI were both associated with longer LOS (by 1.77 days, P < 0.01 and by 2.17 days, P < 0.01, respectively) and higher hospitals charges (by $11,400, P < 0.01 and by $ 14,200, P < 0.01, respectively). Conclusion Primary endoscopic management may be a safe and cost-effective approach for patients with prior BRS who need BI. While primary endoscopic biliary intervention is more common, primary non-endoscopic intervention may be used more often for sepsis.

Objectives Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. Methods Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. Results Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76–2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09–2.87). Conclusions Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.