Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.

There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.

A protein-based machine learning approach to the identification of inflammatory subtypes in pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: The inherently immunosuppressive tumor microenvironment along with the heterogeneity of pancreatic ductal adenocarcinoma (PDAC) limits the effectiveness of available treatment options and contributes to the disease lethality. Using a machine learning algorithm, we hypothesized that PDAC may be categorized based on its microenvironment inflammatory milieu. METHODS: Fifty-nine tumor samples from patients naïve to treatment were homogenized and probed for 41 unique inflammatory proteins using a multiplex assay. Subtype clustering was determined using t-distributed stochastic neighbor embedding (t-SNE) machine learning analysis of cytokine/chemokine levels. Statistics were performed using Wilcoxon rank sum test and Kaplan-Meier survival analysis. RESULTS: t-SNE analysis of tumor cytokines/chemokines revealed two distinct clusters, immunomodulating and immunostimulating. In pancreatic head tumors, patients in the immunostimulating group (N = 26) were more likely to be diabetic (p = 0.027), but experienced less intraoperative blood loss (p = 0.0008). Though there were no significant differences in survival (p = 0.161), the immunostimulating group trended toward longer median survival by 9.205 months (11.28 vs. 20.48 months). CONCLUSION: A machine learning algorithm identified two distinct subtypes within the PDAC inflammatory milieu, which may influence diabetes status as well as intraoperative blood loss. Opportunity exists to further explore how these inflammatory subtypes may influence treatment response, potentially elucidating targetable mechanisms of PDAC's immunosuppressive tumor microenvironment.

It's more than just cancer biology: Health disparities in patients with pancreatic neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs. METHODS: A retrospective review of patients with PNETs in the National Cancer Database was performed for 2004-2014. Approximately 16 605 patients with PNETs and available vital status were identified. Survival was compared by race/ethnicity and socioeconomic status using Kaplan-Meier methods and Cox regression. RESULTS: There were no significant differences in survival between Non-Hispanic, White; Hispanic, White; or Non-Hispanic, Black patients on univariate analysis. Kaplan-Meier analysis showed that patients from communities with lower median household income and education level had worse survival (p < 0.001). Patients age less than 65 without insurance, similarly, had worse survival (p < 0.001). Multivariable modeling found no association between race/ethnicity and risk of mortality (p = 0.37). Lower median household income and lower education level were associated with increased mortality (p < 0.001). CONCLUSIONS: Unlike most other malignancies, race/ethnicity is not associated with survival differences in patients with PNETs. Patients with lower socioeconomic status had worse survival. The presence of identifiable health disparities in patients with PNETs represents a target for intervention and opportunity to improve survival in patients with this malignancy.

The Proteome of Pancreatic Cancer-Derived Exosomes Reveals Signatures Rich in Key Signaling Pathways.

Exosomes are membrane-bound vesicles that traffic small molecular cargos. These cargos participate in cell-cell communication and contribute to the pathogenesis of many disease including cancer. How these mechanisms contribute to communication within the pancreatic adenocarcinoma (PDAC) microenvironment and how they contribute to PDAC biology are poorly understood. Performed in this study are comprehensive, quantitative comparisons of the proteomes of three PDAC cell lines to those of the exosomes they produce. Approximately 35% of whole cell proteins sort into exosomes. Analysis of composition of microbiomes (ANCOM) determined a cluster of 98 enriched pancreatic cancer exosome core proteins (ePC-ECPs). Further, these proteins are predicted by ingenuity pathway analysis (IPA) as actively involved in signaling pathways regulating cell death and survival, cellular movement, and cell-to-cell signaling and interaction in particular (top three p-value significant pathways). Significant enrichment of canonical pathways of acute phase response signaling (inflammatory response signaling pathways) and FXR and RXR activation in biosynthetic pathways are also predicted; 97 ePC-ECPs are associated with cancer and among them, 34 are specifically associated with PDAC. In conclusion, exosomes from PDAC are enriched with cancer-associated signaling proteins. Further assessment of these proteins as PDAC biomarkers or therapeutic targets is warranted.

Postoperative surgical trainee opioid prescribing practices (POST OPP): an institutional study.

BACKGROUND: Increasing mortality from opioid overdoses has prompted increased focus on prescribing practices of physicians. Unfortunately, resident physicians rarely receive formal education in effective opioid prescribing practices or postoperative pain management. Data to inform surgical training programs regarding the utility and feasibility of formal training are lacking. METHODS: Following Institutional Review Board approval, a single institution's resident physicians who had completed at least one surgical rotation were surveyed to assess knowledge of pain management and evaluate opioid prescribing practices. RESULTS: Fifty-three respondents (68% males and 32% females) completed the survey. Most respondents denied receiving formal instruction in opioid pain medication prescribing practices during either medical school (62.3%) or residency (56.6%); however, nearly all respondents stated they were aware of the side effects of opioid pain medications, and a majority felt confident in their knowledge of opioid pharmacokinetics and pharmacodynamics. Of the respondents, 47% either "agreed" or "strongly agreed" that they prescribed more opioid medications than necessary to patients being discharged following a surgical procedure. Individual case scenario responses demonstrated variability in the number of morphine milligram equivalents prescribed across scenarios (P < 0.001). Male and nonsurgical specialty respondents reported prescribing significantly fewer overall morphine milligram equivalents in these scenarios. CONCLUSIONS: This pilot study shows wide variability in opioid prescribing practices and attitudes toward pain management among surgical trainees, illustrating the potential utility of formal education in pain management and effective prescribing of these medications. A broader assessment of surgical trainees' knowledge and perception of opioid prescribing practices is warranted to facilitate the development of such a program.

Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine.

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

Morphometric age and survival following kidney transplantation.

BACKGROUND: As patients with chronic kidney disease become older, there is greater need to identify who will most benefit from kidney transplantation. Analytic morphomics has emerged as an objective risk assessment tool distinct from chronologic age. We hypothesize that morphometric age is a significant predictor of survival following transplantation. METHODS: A retrospective cohort of 158 kidney transplant patients from 2005 to 2014 with 1-year preoperative imaging was identified. Based on a control population comprising of trauma patients and kidney donors, morphometric age was calculated using the validated characteristics of psoas area, psoas density, and abdominal aortic calcification. The primary outcome was post-transplant survival. RESULTS: Cox regression showed morphometric age was a significant predictor of survival (hazard ratio, 1.06 per morphometric year [95% confidence interval, 1.03-1.08]; P < .001). Chronological age was not significant (hazard ratio, 1.03 per year [0.98-1.07]; P = .22). Among the chronologically oldest patients, those with younger morphometric age had greater survival rates compared to those with older morphometric age. CONCLUSIONS: Morphometric age predicts survival following kidney transplantation. Particularly for older patients, it offers improved risk stratification compared to chronologic age. Morphomics may improve the transplant selection process and provide a greater assessment of prospective survival benefits.

Sarcopenia and failure to rescue following liver transplantation.

INTRODUCTION: Sarcopenic liver transplant recipients have higher rates of mortality, but mechanisms underlying these rates remain unclear. Failure to rescue (FTR) has been shown to be a primary driver of mortality following major general and vascular surgery. We hypothesized that FTR is common in sarcopenic liver transplant recipients. METHODS: We retrospectively reviewed 348 liver transplant recipients with perioperative CT scans. Analytic morphomic techniques were used to assess trunk muscle size via total psoas area (TPA). One-yr major complication and FTR rates were calculated across TPA tertiles. RESULTS: The one-yr complication rate was 77% and the FTR rate was 19%. Multivariate regression showed TPA as a significant predictor of FTR (OR = 0.27 per 1000 mm(2) increase in TPA, p < 0.001). Compared to patients in the largest muscle tertile, patients in the smallest tertile had 1.4-fold higher adjusted complication rates (91% vs. 66%) and 2.8-fold higher adjusted FTR rates (22% vs. 8%). DISCUSSION: These results suggest that mortality in sarcopenic liver transplant recipients may be strongly related to FTR. Efforts aimed at early recognition and management of complications may decrease postoperative mortality. Additionally, this work highlights the need for expanded multicenter collaborations aimed at collection and analysis of postoperative complications in liver transplant recipients.

Cigarette smoking in living kidney donors: donor and recipient outcomes.

BACKGROUND: Living kidney donor pools are expanding with the use of "medically complex" donors. Whether or not to include cigarette smokers as living kidney donors remains unclear. The aim of this study was to determine the relationship between donor smoking and recipient outcomes. We hypothesized that donor smoking would increase donor complications and decrease allograft and recipient survival over time. METHODS: The charts of 602 living kidney donors and their recipients were retrospectively reviewed. Kaplan-Meier survival analysis and Cox modeling were used to assess the relationships between smoking and recipient and allograft survival. RESULTS: No difference in postoperative complications was seen in smoking versus non-smoking donors. Donor smoking at time of evaluation did not significantly decrease allograft survival (HR = 1.19, p = 0.52), but recipient smoking at evaluation did reduce allograft survival (HR = 1.74, p = 0.05). Both donor and recipient smoking decreased recipient survival (HR = 1.93, p < 0.01 vs HR = 1.74, p = 0.048). DISCUSSION: When controlled for donor and recipient factors, cigarette smoking by living kidney donors significantly reduced recipient survival. This datum suggests that careful attention to smoking history is an important clinical measure in which to counsel potential donors and recipients. Policy efforts to limit donors with a recent smoking history should be balanced with the overall shortage of appropriate kidney donors.

Dorsal muscle group area and surgical outcomes in liver transplantation.

INTRODUCTION: Better measures of liver transplant risk stratification are needed. Our previous work noted a strong relationship between psoas muscle area and survival following liver transplantation. The dorsal muscle group is easier to measure, but it is unclear if they are also correlated with surgical outcomes. METHODS: Our study population included liver transplant recipients with a preoperative CT scan. Cross-sectional areas of the dorsal muscle group at the T12 vertebral level were measured. The primary outcomes for this study were one- and five-yr mortality and one-yr complications. The relationship between dorsal muscle group area and post-transplantation outcome was assessed using univariate and multivariate techniques. RESULTS: Dorsal muscle group area measurements were strongly associated with psoas area (r = 0.72; p < 0.001). Postoperative outcome was observed from 325 patients. Multivariate logistic regression revealed dorsal muscle group area to be a significant predictor of one-yr mortality (odds ratio [OR] = 0.53, p = 0.001), five-yr mortality (OR = 0.53, p < 0.001), and one-yr complications (OR = 0.67, p = 0.007). CONCLUSION: Larger dorsal muscle group muscle size is associated with improved post-transplantation outcomes. The muscle is easier to measure and may represent a clinically relevant postoperative risk factor.

Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer.

Metastatic colorectal cancer remains a deadly malignancy and is the third leading cause of cancer-related death. The mainstay of treatment for metastatic colorectal cancer is chemotherapy, but unfortunately, even with recent progress, overall survival is still poor. Colorectal cancer is a heterogeneous disease, and the underlying genetic differences among tumors can define the behavior and prognosis of the disease. Given the limitations of cytotoxic chemotherapy, research has focused on developing targeted therapy based on molecular subtyping. Since the early 2000s, multiple targeted therapies have demonstrated efficacy in treating metastatic colorectal cancer and have received FDA approval. The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have demonstrated promising results for targeted therapies. As new gene mutations and proteins involved in the oncogenesis of metastatic colorectal cancer are identified, new targets will continue to emerge. We herein provide a summary of the updated literature regarding targeted therapies for patients with mCRC.

Hepatic adenoma: evolution of a more individualized treatment approach.

BACKGROUND: Hepatic adenomas (HAs) are benign, solid liver lesions, which carry a risk of hemorrhage and malignant transformation. This review article highlights the advances in the diagnosis and management of HAs. METHODS: A comprehensive review was performed using MEDLINE/PubMed and Web of Science databases with a search period ending on September 30, 2023. Using PubMed, the terms "hepatocellular," "hepatic," and "adenoma" were searched. RESULTS: HA has been classified into at least 8 subtypes based on molecular pathology, each exhibiting unique histopathologic features, clinical considerations, and risk of malignant transformation. The most common subtype is inflammatory HA, followed by hepatocyte nuclear factor 1α-inactivated HA, ß-catenin exon 3-mutated HA (ßex3-HA), ß-catenin exon 7- or 8-mutated HA, sonic hedgehog HA, and unclassified HA. Magnetic resonance imaging is the best imaging method for diagnosis and can distinguish among HA subtypes based on fat and telangiectasia pathologic characteristics. The risk of malignant transformation varies among molecular subtypes, ranging from <1% to approximately 50%. Up to 42% of HAs present with spontaneous intratumoral hemorrhage and peritoneal hemorrhage. In general, only 15% to 20% of patients require surgery. HA larger than 5 cm are more likely to be complicated by bleeding and malignant transformation, regardless of subtype, and should generally be resected. In particular, ßex3-HA carries a high risk of malignant transformation and can be considered a true precancerous lesion. CONCLUSION: The management of HAs is based on a multidisciplinary approach. Clinical decision-making should integrate information on gender, tumor size, and HA subtyping. In the future, patients with HA will benefit from novel medical therapies tailored to the individual molecular subtypes.

Resident and Fellow Performance and Supervision in Surgical Oncology Procedures.

BACKGROUND: Previous research has highlighted concerns among trainees and attendings that general surgery training and fellowship are inadequately preparing trainees for practice. Providing trainees with supervision that matches their proficiency may help bridge this gap. We sought to benchmark operative performance and supervision levels among senior surgery residents (post-graduate year 4 or 5) and fellows performing general surgical oncology procedures. STUDY DESIGN: Observational data were obtained from the Society for Improving Medical Procedural Learning (SIMPL) OR application for core general surgical oncology procedures performed at 103 unique residency and fellowship programs. Procedures were divided into breast and soft tissue, endocrine, and hepatopancreatobiliary (HPB). Case evaluations completed by trainees and attendings were analyzed to benchmark trainee operative performance and level of supervision. RESULTS: There were 4,907 resident cases and 425 fellow cases. Practice-ready performance, as assessed by trainees and faculty, was achieved by relatively low proportions of residents and fellows for breast and soft tissue cases (residents: 38%, fellows: 48%), endocrine cases (residents: 22%, fellows: 41%), and HPB cases (residents: 10%, fellows: 40%). Among cases in which trainees did achieve practice-ready performance, supervision only was provided for low proportions of cases as rated by trainees (residents: 17%, fellows: 18%) and attendings (residents: 21%, fellows 25%). CONCLUSION: In a sample of 103 residency and fellowship programs, attending surgeons rarely provided senior residents and fellows with levels of supervision commensurate to performance for surgical oncology procedures, even for high performing trainees. These findings suggest a critical need for surgical training programs to prioritize providing greater levels of independence to trainees that have demonstrated excellent performance.

Infiltration of CD3+ and CD8+ lymphocytes in association with inflammation and survival in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins. METHODS: Tissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples. RESULTS: Our findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC. CONCLUSION: In this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment.

Changing Practice Patterns and Improving Survival for Patients with Pancreatic Ductal Adenocarcinoma.

Over the last two decades, there have been many reported advances in the clinical management of pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate changes in survival for patients diagnosed with PDAC between 2004 and 2017. The National Cancer Database was queried for patients diagnosed with PDAC between 2004 and 2017. There were 55,401 patients who underwent surgery and 109,477 patients who underwent non-surgical treatment for PDAC between 2004 and 2017. Patients were categorized into four groups by year of diagnosis. Median survival improved from 15.5 months to 25.3 months for patients treated with surgery between the years 2016 and 2017 compared with between 2004 and 2007 (p < 0.001). Median survival improved from 7.2 months to 10.1 months for patients treated without surgery during the same years (p < 0.001). On multivariable analysis, the hazard ratio for death was estimated to multiply by 0.975 per year for patients treated with surgery and 0.959 per year for patients treated without surgery (p < 0.001). This increase in survival in the setting of evolving care validates continued efforts aimed at improving survival for patients with this devastating disease.

Surgical resident experience with common bile duct exploration and assessment of performance and autonomy with formative feedback.

BACKGROUND: Common bile duct exploration (CBDE) is safe and effective for managing choledocholithiasis, but most US general surgeons have limited experience with CBDE and are uncomfortable performing this procedure in practice. Surgical trainee exposure to CBDE is limited, and their learning curve for achieving autonomous, practice-ready performance has not been previously described. This study tests the hypothesis that receipt of one or more prior CBDE operative performance assessments, combined with formative feedback, is associated with greater resident operative performance and autonomy. METHODS: Resident and attending assessments of resident operative performance and autonomy were obtained for 189 laparoscopic or open CBDEs performed at 28 institutions. Performance and autonomy were graded along validated ordinal scales. Cases in which the resident had one or more prior CBDE case evaluations (n = 48) were compared with cases in which the resident had no prior evaluations (n = 141). RESULTS: Compared with cases in which the resident had no prior CBDE case evaluations, cases with a prior evaluation had greater proportions of practice-ready or exceptional performance ratings according to both residents (27% vs. 11%, p = .009) and attendings (58% vs. 19%, p < .001) and had greater proportions of passive help or supervision only autonomy ratings according to both residents (17% vs. 4%, p = .009) and attendings (69% vs. 32%, p < .01). CONCLUSIONS: Residents with at least one prior CBDE evaluation and formative feedback demonstrated better operative performance and received greater autonomy than residents without prior evaluations, underscoring the propensity of feedback to help residents achieve autonomous, practice-ready performance for rare operations.

Transcriptomic analysis of pancreatic adenocarcinoma specimens obtained from Black and White patients.

In pancreatic cancer clinical trials, Black patients are under-represented while having higher morbidity and mortality rates as compared to other racial groups. Multiple factors, including socioeconomic and lifestyle factors may contribute to this disparity, but genomic contributions remain unclear. In an exploratory project to identify genes that may contribute to differences in survival between Black (n = 8) and White (n = 20) patients with pancreatic cancer, transcriptomic sequencing of over 24,900 genes was performed in human pancreatic tumor and non-tumor tissue obtained from Black and White patients. Over 4,400 genes were differentially expressed in tumor and non-tumor tissue, irrespective of race. To validate these results, the expression of four genes (AGR2, POSTN, TFF1, and CP) reported to be up-regulated in pancreatic tumor tissue as compared to non-tumor tissue were confirmed using quantitative PCR. Transcriptomic analysis that compared pancreatic tumor tissue from Black and White patients revealed differential expression in 1,200 genes, while a comparison of the non-tumor and tumor gene expression differences within each race revealed over 1,500 tumor-specific differentially expressed genes in pancreatic tumor and non-tumor tissue from Black patients. We identified TSPAN8 as a potential tumor-specific gene significantly overexpressed in pancreatic tumor tissue in Black patients as compared to White patients. Using Ingenuity Pathway Analysis software to compare the race-associated gene expression profiles, over 40 canonical pathways were identified to be potentially impacted by the gene expression differences between the races. Heightened expression of TSPAN8 was associated with poor overall survival, suggesting TSPAN8 as one potential genetic factor contributing to the differential outcomes in Black patients with pancreatic cancer, supporting the potential utility of larger genomic studies to further explore the role of TSPAN8 in pancreatic cancer.

A simulation curriculum for laparoscopic common bile duct exploration, balloon sphincterotomy, and endobiliary stenting: Associations with resident performance and autonomy in the operating room.

BACKGROUND: Laparoscopic common bile duct exploration is safe and effective for managing choledocholithiasis, but laparoscopic common bile duct exploration is rarely performed, which threatens surgical trainee proficiency. This study tests the hypothesis that prior operative or simulation experience with laparoscopic common bile duct exploration is associated with greater resident operative performance and autonomy without adversely affecting patient outcomes. METHODS: This longitudinal cohort study included 33 consecutive patients undergoing laparoscopic common bile duct exploration in cases involving postgraduate years 3, 4, and 5 general surgery residents at a single institution during the implementation of a laparoscopic common bile duct exploration simulation curriculum. For each of the 33 cases, resident performance and autonomy were rated by residents and attendings, the resident's prior operative and simulation experience were recorded, and patient outcomes were ascertained from electronic health records for comparison among 3 cohorts: prior operative experience, prior simulation experience, and no prior experience. RESULTS: Operative approach was similar among cohorts. Overall morbidity was 6.1% and similar across cohorts. The operative performance scores were higher in prior experience cohorts according to both residents (3.0 [2.8-3.0] vs 2.0 [2.0-3.0]; P = .01) and attendings (3.0 [3.0-4.0]; P < .001). The autonomy scores were higher in prior experience cohorts according to both residents (2.0 [2.0-3.0] vs 2.0 [2.0-2.0]; P = .005) and attendings (2.5 [2.0-3.0] vs 2.0 [1.0-2.0]; P = .001). Prior simulation and prior operative experience had similar associations with performance and autonomy. CONCLUSION: Simulation experience with laparoscopic common bile duct exploration was associated with greater resident operative performance and autonomy, with effects that mimic prior operative experience. This illustrates the potential for simulation-based training to improve resident operative performance and autonomy for laparoscopic common bile duct exploration.