Charting the Course: Insights into Neuroendocrine Tumor Dynamics in the United States.

OBJECTIVE: To explore changing trends and characteristics in neuroendocrine tumors (NETs) epidemiology, focusing on demographics, clinical aspects, and survival, including the impact of social determinants of health (SDOH) on outcomes. BACKGROUND: The escalating incidence and prevalence of NETs underscore the pressing need for updated epidemiologic data to reveal the evolving landscape of this condition. Access to current information is imperative for informing clinical strategies and public health initiatives targeting NETs. METHODS: A retrospective, population-based study analyzed NET patient data from 1975 to 2020, using the Surveillance, Epidemiology, and End Results (SEER 8, 12, 18) program. We calculated annual age-adjusted incidence, prevalence, and 5-year overall survival (OS) rates. Survival trends from 2000 to 2019 were examined, employing the Fine-Gray model to evaluate cancer-specific mortality. RESULTS: NETs' age-adjusted incidence rate quadrupled from 1.5 per 100,000 in 1975 to 6.0 per 100,000 in 2020. A decline in incidence occurred from 6.8 per 100,000 in 2019 to 6.0 per 100,000 in 2020. All-cause survival multivariable analysis demonstrated high grade (HR: 2.95, 95% CI: 2.63-3.09, P<0.001), single patients (HR: 1.49, 95% CI: 1.45-1.54, P<0.001), and Black patients (HR: 1.17, 95% CI:1.13-1.22, P<0.001) all had worse survival than their controls. CONCLUSION: In conclusion, our study shows a steady increase in NETs incidence until 2019, with a decline in 2020. Understanding the reasons behind this trend is vital for improved management and public health planning. Further research should focus on the factors driving these changes to enhance our understanding of NET epidemiology.

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.

BACKGROUND: Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. METHODS: We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. RESULTS: A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. CONCLUSIONS: In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Adjusting Drain Fluid Amylase for Drain Volume Does Not Improve Pancreatic Fistula Prediction.

INTRODUCTION: Drain fluid amylase (DFA) levels have been used to predict clinically relevant postoperative pancreatic fistula (CR-POPF) and guide postoperative drain management. Optimal DFA cutoff thresholds vary between studies, thereby prompting investigation of an alternative assessment technique. As DFA measurements could, in theory, be distorted by variations in ascites fluid production, we hypothesized that adjusting DFA for volume corrected drain fluid amylase (vDFA) would improve CR-POPF predictive models. METHODS: A single-institution retrospective cohort study of patients, who underwent pancreatoduodenectomies (PD) and distal pancreatectomies (DP) between 2013 and 2019, was performed. DFAs and vDFAs were measured on postoperative day (POD) 3. Clinicopathologic variables were compared between cohorts by univariable and multivariable analyses and Receiver operating characteristic (ROC) curves. RESULTS: Patients developing a CR-POPF were more likely to be male and have elevated DFA, vDFA, and body mass index (BMI). vDFA use did not contribute to a superior CR-POPF predictive model compared to DFA-a finding consistent on subanalysis of surgery type PD versus DP. In CR-POPF predictive models, DFA, vDFA, and male sex significantly improved CR-POPF predictive models when considering both surgery subtypes, while only DFA and vDFA significantly improved models when cohorts were segregated by surgery type. CONCLUSIONS: Postoperative DFA remains a preferred method of predicting CR-POPF as the proposed vDFA assessment technique only adds complexity without increased discriminability.

Are Lymph Node Metastases Associated With Survival in Black Patients With Pancreatic Cancer?

INTRODUCTION: Despite aggressive surgical care and systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Recent studies show that racial disparities in outcome also exist. We sought to investigate the association lymph node (LN) metastases had with survival between Black and White patients with PDAC after resection. METHODS: Retrospective analysis of 226 PDAC patients who underwent resection at a single institution from 2010 to 2018 was performed with attention to LN metastasis and patient race. The number of patients who received chemotherapy was also evaluated. RESULTS: One Hundred Seventy Five (77.4%) PDAC patients were White and 51 (22.6%) were Black. 130 (59.3%) patients had LN metastasis (LN+). LN+ and LN- groups were similar in race (P = 0.93), sex (P = 0.10) and age at the time of diagnosis (P = 0.45). Patients with LN + disease were more likely to present with larger tumors (3.4 versus 2.8 cm, P = 0.02) and higher T status (P = 0.001). White and Black patients had similar rates of LN metastasis (59% versus 58.8%, P = 1.0). The median survival for LN- Black and White patients were similar (43.2 versus 30.2 mo, P = 0.82). LN + Black patients trended towards receiving more systemic therapy than White LN + patients (55% versus 42%, P = 0.10). The median survival for LN + Black patients was significantly less than LN + White patients (17.5 versus 24.6 mo, P = 0.04). CONCLUSIONS: Black LN + PDAC patients have an inferior survival rate after resection when compared to their White counterparts. Our disparity in outcome cannot be solely explained by a difference in systemic treatment. Further investigation is warranted to determine racial differences in tumor biology or response to chemotherapy.

Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance.

Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

BACKGROUND: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells.

In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.

Significance of radiographic splenic vessel involvement in the pancreatic ductal adenocarcinoma of the body and tail of the gland.

BACKGROUND AND OBJECTIVES: Unlike pancreatic head tumors, little is known about the biological significance of radiographic vessel involvement with pancreatic body/tail adenocarcinoma. We hypothesized radiographic splenic vessel involvement may be an adverse prognostic factor. METHODS: All distal pancreatectomies performed for resectable pancreatic adenocarcinoma between 2000 and 2016 were reviewed and clinicopatholgic data were collected, retrospectively. Preoperative computed tomography imaging was re-reviewed and splenic vessel involvement was graded as none, abutment, encasement, or occlusion. RESULTS: Among a total of 71 patients, splenic artery or vein encasement/occlusion was present in 41% (29 of 71) of patients, each. There were no significant differences in tumor size or grade, margin positivity, and perineural or lymphovascular invasion. However, splenic artery encasement/occlusion (P = 0.001) and splenic vein encasement/occlusion (P = 0.038) both correlated with lymph node positivity. Splenic artery encasement was associated with a reduced median overall survival (20 vs 30 months, P = 0.033). Multivariate analysis also showed that splenic artery encasement was an independent risk factor of worse survival (hazard ratio, 2.246; 95% confidence interval, 1.118-4.513; P = 0.023). CONCLUSION: Patients with cancer of the body or tail of the pancreas presenting with radiographic encasement of the splenic artery, but not the splenic vein, have a poorer prognosis and perhaps should be considered for neoadjuvant therapy before an attempt at curative resection.

The Role of Notch3 in Cancer.

The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue-specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling. IMPLICATIONS FOR PRACTICE: The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity.

Posterior 'superior mesenteric artery first' approach for resection of locally advanced pancreatic cancer.

BACKGROUND: En bloc resection of the superior mesenteric vein (SMV), portal vein (PV), and/or splenic vein (SV) with concomitant venous reconstruction is required in 11-65 % of cases of locally advanced pancreatic cancer.1 Early retropancreatic dissection of the superior mesenteric artery (SMA) from behind the pancreatic head utilizing an 'artery first' approach has been reported to be an efficient and safe approach to pancreaticoduodenectomy when SMA involvement is suspected.2 Additionally, this technique has been shown to reduce blood loss and result in shorter PV clamp times.3 While there are multiple variations to 'artery first' resection,4 this video will illustrate the critical steps of using the 'posterior approach' in patients with locally advanced pancreatic cancer. This approach has the benefit of early identification of a replaced right hepatic artery, but may be difficult in obese patients or those with extensive peripancreatic inflammation. These difficulties may be overcome by utilizing an 'inferior supracolic (anterior) approach', but this necessitates early division of the pancreatic neck and stomach.5 METHODS: Select video clips were compiled from several pancreatoduodenectomies to demonstrate this technique. A variety of bipolar devices were utilized for dissection depending on surgeon preference. All patients were diagnosed with locally advanced pancreatic cancer by Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology (AHPBA/SSO) consensus criteria, confirmed by biopsy, and completed neoadjuvant chemotherapy. Patients were restaged by pancreas protocol computed tomography scan at the end of chemotherapy and offered local resection if the tumor did not progress and they were medically fit. No Institutional Review Board approval was required. RESULTS: The operation begins by dividing the attachment of the transverse mesocolon to the right perinephric area and extending this down to the white line of Toldt, followed by a wide Kocher maneuver. The lateral attachments to the pancreatic head are then divided, thereby exposing the left renal vein. The lesser sac is entered directly over the uncinate, allowing for a full visceral rotation of the pancreatic head, and further facilitating exposure of the left renal vein. In the setting of malignancy, the SMA may now be palpated posterior to the pancreatic head and/or neck to confirm it is free of tumor. If tumor is invading the SMA, the pancreaticoduodenectomy is aborted prior to performing any gastrointestinal or pancreatic transections. If the SMA is free, the dissection is then carried on to the inferior aspect of the pancreatic neck. Here the SMV (jejunal and ileal branches), middle colic vein, and the gastroepiploic vein are identified and the latter is ligated and transected. Following this, dissection of the portal structures (hepatic arteries, gastroduodenal artery, common bile duct, and PV) is performed. The jejunum is then divided, the ligament of Treitz is taken down, and the jejunum is then mobilized to the patient's right side. This allows for clear visualization of the pancreatic head/uncinate/SMV relationship. At this point, proximal and distal control of the PV, SMV, and SV should be obtained using vessel loops or umbilical tape. The dissection then proceeds laterally along the SMA border (posterior to the pancreatic head). This is often facilitated by use of a bipolar sealing device due to a rich lymphovascular network. Once the lateral border of the SMA is clearly exposed, dissection along its longitudinal axis is performed utilizing the jejunum for traction. Following this dissection, larger vessels such as the inferior pancreaticoduodenal artery can be more readily identified and ligated to fully mobilize the pancreatic head. After the head is completely separated from the SMA, the neck is divided. This leaves the specimen attached solely by the PV and SMV, which greatly facilitates venous resection and reconstruction when necessary. CONCLUSION: The 'artery first' approach has been shown to be safe and feasible in pancreatic resections. This technique should be considered whenever tumor is thought to involve the SMV and/or PVs as a means to facilitate safe venous resection and reconstruction while preserving sound oncologic principles.

Extended neoadjuvant chemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival.

BACKGROUND: The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined. Herein we report the outcomes of an extended neoadjuvant chemotherapy regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head. METHODS: Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospectively maintained registry. Included patients were initiated on a 24-week course of neoadjuvant chemotherapy. Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent. Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed. RESULTS: Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy. Thirty-nine (61 %) met resection criteria and underwent operative exploration with curative intent, and 31 (48 %) were resected. Of the resected patients, 18 (58 %) had positive lymph nodes, 15 (48 %) required en-bloc venous resection, 27 (87 %) had a R0 resection, and 3 (10 %) had a complete pathologic response. There were no postoperative deaths at 90 days, 16 % of patients had a severe complication, and the 30-day readmission rate was 10 %. The median overall survival of all 64 patients was 23.6 months, whereas that of unresectable patients was 15.4 months. Twenty-five of the resected patients (81 %) are still alive at a median follow-up of 21.6 months. CONCLUSIONS: Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma, selects a subset of patients for curative surgery with low perioperative morbidity, and is associated with favorable survival.

An Analysis on the Effect of Income Changes in the Resection of Early-Stage Pancreatic Adenocarcinoma.

INTRODUCTION: The impact of socioeconomic inequalities on cancer care and outcomes has been well recognized and the underlying causes are likely multifactorial. Income is regarded as a cornerstone of socioeconomic status and has been assumed to correlate with access to care. We therefore sought to investigate whether income and changes in income would affect the rate of patients undergoing surgical resection for early-stage pancreatic cancer. METHODS: Inflation-adjusted income data were obtained from the United States Census Bureau from 2010 to 2019. The cancer data were obtained from the SEER database. Counties present in both data sets were included in the analysis. Patients with stage I or II pancreatic cancer who underwent formal resection were deemed to have undergone appropriate surgical management. Patients were grouped into an early (2010-2014) and late (2015-2019) time period. RESULTS: The final analysis included 23968 patients from 173 counties across 11 states. The resection rate was 45.1% for the entire study and rose from 42.8% to 47.4% from the early to late time periods (P < .001). The median change in income between the two time periods was an increase by $2387. The rate of resection was not dependent on income class or income change in our study population. CONCLUSION: Our surgical care of pancreatic cancer is improving with more patients undergoing resection. In addition, there are now fewer disparities between patients of lower-income and higher-income groups with respect to receiving surgical intervention. This implies that our access to care has improved over the past decade. This is an encouraging finding with regards to reducing health care disparities.

Resection Versus Observation for Small (≤2 cm) Pancreatic Neuroendocrine Tumors.

BACKGROUND: We hypothesized that those patients with pancreatic neuroendocrine tumors (pNETs) ≤2 cm managed nonoperatively would have comparable disease progression to individuals undergoing an operation. METHODS: Patients diagnosed with nonfunctional pNETs ≤ 2 cm who were evaluated at a single comprehensive cancer center from 2010 to 2017 were selected from a cancer registry database. Clinicopathologic variables were obtained via retrospective chart review. Primary outcomes were overall and disease specific survival. Variables were compared between the 2 groups using chi-square and independent t-test. RESULTS: Fifty-two individuals had tumors ≤2 cm, of whom 75% had an operation, while 25% were observed. Each treatment arm had similar distributions of gender, race, and tumor location. The most common operation was distal pancreatectomy (n = 29) followed by pancreatoduodenectomy (n = 6). Nine patients had grade III postoperative complications and 4 had grade IV under Clavien-Dindo classification. The observation group was noted to have a mean disease progression interval of 80.9 months, while those who underwent an operation had a mean disease progression interval of 94.6 months (P = .246). CONCLUSIONS: Overall disease progression in patients with pNETs ≤ 2 cm without evidence of metastasis at the time of presentation is not different between those who underwent operation compared to those observed.

Preclinical safety evaluation of continuous UV-A lighting in an operative setting.

BACKGROUND: Germicidal ultraviolet (UV-C) light has been shown as an effective modality for disinfection in laboratory settings and in the operative room. Traditionally, short-wavelength UV-C devices, which have previously been shown to cause DNA damage, are utilized only for disinfection in pre- and post-operative settings and are not continuously active during operations. Continuous use of intraoperative UV light has potential to decrease pathogens and subsequent surgical site infections (SSIs), which arise in approximately 5-15% of operative cases. SSIs are a significant determinant of patient morbidity, readmission rates, and overall cost. Therefore, a method of UV light disinfection with a low risk of DNA damage is needed so that greater antimicrobial protection can be afforded to patients during the entirety of their surgical procedures. A new disinfection device that harnesses longer-wavelength UV-A light to disinfect the surgical field throughout the entirety of the procedure, including pre- and post-operation has been developed. METHODS: This study aimed to determine if UV-A light administered intraoperatively was safe, as defined by the minimal presence of DNA damage and safe amounts of reflection upon medical personnel. Using in vitro models, we examined the differential impacts of UV-C and UV-A light on DNA damage and repair pathways. In a murine model, we looked at the production of DNA damage photoproduction in relation to UV-A versus UV-C exposure. RESULTS: Our results show UV-A light does not induce a significant amount of DNA damage at the cellular or tissue level. Furthermore, a preclinical porcine study showed that surgical personnel were exposed to safe levels of UV-A irradiance from an overhead UV-A light used during an operation. The amount of UV-A transmitted through surgical personal protective equipment (PPE) also remained within safe levels. CONCLUSIONS: In conclusion, we found that UV-A may be safe for intraoperative use.

Management of neuroendocrine tumor liver metastases.

BACKGROUND: Neuroendocrine Tumors (NETs) are a group of tumors that arise from neuroendocrine cells, and are increasing in incidence worldwide. These tumors often metastasize to the liver, and management of these neuroendocrine tumor liver metastases (NELMs) requires a multi-disciplinary approach. We aim to provide a comprehensive update for treatment of NELMs. METHODS: We completed a comprehensive systemic review of papers involving the diagnosis, treatment, and outcomes of NELMs. We identified 1612 records via Scopus database literature search. Two independent authors reviewed these records, with 318 meeting criteria for inclusion in the final systemic review. RESULTS: Primary tumor resection with resection of liver metastases is the treatment of choice for patients with NELMs. Liver-directed therapies and liver transplantation can be considered for patients with unresectable liver metastases. Systemic medical therapy is used for managing tumor burden and symptoms caused by NELMs. CONCLUSIONS: Advancement in liver-directed and targeted systemic therapies provide improved options for patients with unresectable tumors. Given the complexity of NELMs, management of NELMs necessitates multidisciplinary teams at comprehensive health centers.

Understanding risk factors and microbial trends implicated in the development of Whipple-related surgical-site infections.

Objective: The purpose of this study is to understand the role of risk factors and postoperative complications seen in patients undergoing Whipple procedures in the development of surgical site infections. Our secondary goal was to evaluate whether microbial patterns differed between preoperative antibiotic classes, offering insight into the effectiveness of current practices while promoting antibiotic stewardship. Design: We performed a retrospective cohort study comparing patients with and without SSIs. Setting: This study was conducted at a tertiary-care center in the southeastern United States. Participants: Patients who underwent a Whipple procedure between 2012 and 2021 were acquired from the National Surgical Quality Improvement Program (NSQIP) database. Results: Patients with a bleeding disorder reported higher SSI rates (P = .04), whereas patients with a biliary stent reported lower surgical site infection (SSI) rates (P = .02) Those with postoperative complications had higher SSI rates, including delayed gastric emptying (P < .001) and pancreatic fistula (P < .001). Patients with longer operative times were 1.002 times more likely to develop SSIs (adjusted odds ratio [aOR], 1.002; 95% confidence interval [CI], 1.001-1.004; P = .006) whereas surgical indications for malignancy correlated with decreased SSIs risk (aOR, 0.578; 95% CI, 0.386-866) when adjusting for body mass index, surgical indication, and duration of surgical procedure. Conclusions: Optimizing preoperative management of modifiable risk factors for patients undergoing pancreatoduodenectomies and decreasing operative times may reduce SSI rates and patient and hospital burden. Further research is needed to understand whether stent placement reduces SSI risk in pancreatoduodenectomy.

Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid.

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28-30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. Methods: Thirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. Results: Significant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. Conclusions: Patients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implications: Using serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.

High-Throughput Analysis to Identify Activators of Notch Signaling.

The Notch pathway regulates many cellular functions in a context-dependent manner. Depending on the cell type, either the activation or inhibition of Notch signaling can influence many processes such as cellular proliferation, specification, differentiation, and survival. The activation of Notch signaling has been shown to have therapeutic advantages in some cancers, thus having a method to identify Notch-activating compounds is needed. In this chapter we outline a method for high-throughput analysis of potential Notch pathway activators in a pancreatic neuroendocrine tumor cell line as an example. We also include the steps for subsequent validation of results and preclinical testing.

External validation of four Pancreatic Fistula Risk Score models in the Deep South US: Do racial disparities affect pancreatic fistula prediction?

BACKGROUND: Fistula Risk Score (FRS) models often lack adequate discrimination for clinically relevant postoperative pancreatic fistula (CR-POPF) on external validation. We tested four FRS models in the Deep South United States and sought to determine if CR-POPF discrimination was affected by racial disparities. METHODS: A single-institution retrospective cohort study of patients who underwent pancreatoduodenectomies between 2013 and 2019 was performed. FRS discrimination for CR-POPF was assessed using ROC curves for both the entire patient population, and for Black vs White patients. RESULTS: The Alternative FRS maintains adequate CR-POPF discrimination when considering the patient population as a whole, but inadequately predicts CR-POPF when applied to the Black patient population. The Sun-FRS provides adequate CR-POPF discrimination for Black patients when considering risk grade. Only soft pancreatic gland texture and small duct size were significantly associated with CR-POPF in this patient population. DISCUSSION: Institutions should assess their preferred FRS model to determine if it provides adequate CR-POPF discrimination among a racially diverse patient population. Further studies are needed to determine how racial disparities influence CR-POPF prediction to better guide postoperative management.