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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. [ABSTRACT FROM AUTHOR]

Simple Summary: There have been a number of advances in the treatment paradigm of pancreatic ductal adenocarcinoma (PDAC) over the past two decades. Medical and surgical approaches to PDAC have continued to evolve. The individual effects of these changes have been investigated. Understanding the implementation of these changes over time and its effect on patient survival is important. While patient survival from PDAC has been reported to have modest improvements over the decades, the National Cancer Database offers the ability to study survival trends. We aim to evaluate survival trends in patients diagnosed with PDAC in the United States. 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. [ABSTRACT FROM AUTHOR]

This document is a letter published in the British Journal of Surgery. The authors comment on a recent study that investigated the use of baseline carbohydrate antigen 19-9 (CA19-9) as a predictive biomarker for patients undergoing neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC). The authors highlight the importance of predictive biomarkers in guiding personalized treatment for PDAC and discuss the findings of the study. They argue that the study's results suggest that baseline CA19-9 can be a predictive factor for the treatment effect of neoadjuvant therapy on overall survival in PDAC patients. The authors suggest that further analysis should be conducted to explore the use of neoadjuvant systemic chemotherapy in patients with high CA19-9 levels. They commend the study and encourage the incorporation of CA19-9 as a biomarker in future clinical trials. [Extracted from the article]

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of all common malignancies. Treatment is difficult and often complicated by the presence of cachexia. The clinical portrait of cachexia contributes to the poor prognosis experienced by PDAC patients and worsens therapeutic outcomes. We propose that low bone mineral density is a component of cachexia, which we explore herein through a retrospective review of all patients at our facility that underwent surgery for PDAC between 2011 and 2018 and compared to sex‐, age‐ and comorbidity‐matched control individuals. Data were abstracted from the medical record and pre‐operative computed tomography scans. Muscle mass and quality were measured at the L3 level and bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies. Patients with PDAC displayed typical signs of cachexia such as weight loss and radiologically appreciable deterioration of skeletal muscle. Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1‐ and 2‐year disease‐specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2‐year mortality with sensitivity of 76% and specificity of 58%. These data therefore identify impaired bone mineral density as a key component of cachexia and predictor of postoperative survival in patients with PDAC. The mechanisms that lead to bone wasting in tumor‐bearing hosts deserve further study. [ABSTRACT FROM AUTHOR]

Background: Disparities exist among patients with pancreatic ductal adenocarcinoma (PDAC). Non‐White race is regarded as a negative predictor of expected treatment and overall survival. Data suggest that Academic Research Programs (ARP) provide better outcomes for minorities, but ethnic/minority outcomes are underreported. We hypothesize that outcomes among racially/ethnically diverse PDAC patients may be influenced by treatment facility. Methods: The National Cancer Database was used to identify 170,327 patients diagnosed with PDAC between 2004 and 2015. Cox proportional‐hazard regression was used to compare survival between race/ethnic groups across facilities. Results: In unadjusted models, compared to non‐Hispanic Whites (NHW), non‐Hispanic Blacks (NHB) had the worst overall survival (HR = 1.05, 95%CI: 1.03‐1.06, P <.001) and Hispanics had the best overall survival (HR = 0.92, 95%CI: 0.90‐0.94, P <.001). After controlling for socioeconomic and clinical covariates, NHB (HR = 0.95, 95%CI: 0.93‐0.96, P <.001) had better overall survival compared to NHW, and Hispanics continued to have the best comparative outcomes (HR = 0.84, 95%CI: 0.82‐0.86, P <.001). Among Hispanics, Dominicans and South/Central Americans lived the longest, at 10.25 and 9.82 months, respectively. The improved survival in Hispanics was most pronounced at ARP (HR = 0.80, 95%CI: 0.77‐0.84, P <.001) and Integrated Network Cancer Programs (HR = 0.78, 95%CI: 0.73‐0.84, P <.001). NHB had improved survival over NHW at Comprehensive Community Care Programs (HR = 0.96, 95%CI: 0.93‐0.98, P =.002) and ARP (HR = 0.96, 95%CI: 0.94‐0.98, P =.001), which was influenced by income, education, and surgical resection. Conclusion: Survival was improved at ARP for all populations. Hispanics had the best comparative overall survival. NHB had improved overall survival at higher volume centers, but this was dependent upon income, education, and surgical resection. [ABSTRACT FROM AUTHOR]

• EV cargo packaging is not a random process, but is selectively controlled. • The active exchanges of EV cargoes between cancer cells and the associated surrounding cells in PDAC TME impact cancer biology. • The identification of EV cargo molecules as biomarkers for sensitive and specific PDAC detection remains an ongoing challenge. Virtually all cells release various types of vesicles into the extracellular environment. These extracellular vesicles (EVs) transport molecular cargoes, performing as communicants for information exchange both within the tumor microenvironment (TME) and to distant organs. Thus, understanding the selective packaging of EV cargoes and the mechanistic impact of those cargoes - including metabolites, lipids, proteins, and/or nucleic acids - offers an opportunity to increase our knowledge of cancer biology and identify EV cargoes that might serve as cancer biomarkers in blood, saliva, or urine samples. In this review, we collect and organize recent advances in this field with an emphasis on pancreatic cancer (pancreatic adenocarcinoma, PDAC) and the concept that cells selectively package cargo into EVs. These studies demonstrate PDAC EV cargoes signal to reprogram and remodel the TME and impact distant organs. EV cargoes identified as potential PDAC diagnostic and prognostic biomarkers are summarized. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Perceived threats to established social order can influence the willingness of those in authority to inflict punishments as well as the severity of those punishments. Our article explores that proposition in the case of summary punishment by flogging in the Royal Navy. In the Royal Navy commanders were given the power to inflict flogging for a host of offenses. Prevailing penal thinking emphasized general deterrence, whereby punishment of a few serious offenders would deter the body of seamen. Eighteenth-century reforms were intended to rationalize and normalize flogging and limit its severity. Qualitative evidence indicates that naval commanders saw the established order under attack after 1789 and, emphasizing moral offenses, imposed tighter discipline on their crews. The evidence we have assembled based on a randomly selected sample of ships between 1740 and 1820 shows that flogging aboard ships was moderate up until the “Age of Revolution” that began after 1789 but increased dramatically in its frequency and severity in the wake of the French Revolution. Multivariate analysis shows that greater penal severity is associated with several factors, including a period effect associated with the onset of the revolutionary age. Our findings are consistent with existing research that suggests that disorder influences the willingness to punish. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

What are the origins of belief in conspiracy theories? The dominant approach to studying conspiracy theories links belief to social stresses or personality type, and does not take into account the situational and fluctuating nature of attitudes. In this study, a survey experiment, subjects are presented with a mock news article designed to induce conspiracy belief. Subjects are randomly assigned three manipulations hypothesized to heighten conspiracy perceptions: a prime to induce anxiety; information about the putative conspirator; and the number and identifiability of the victim(s). The results indicate that conspiratorial perceptions can emerge from both situational triggers and subtle contextual variables. Conspiracy beliefs emerge as ordinary people make judgments about the social and political world. [ABSTRACT FROM PUBLISHER]

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 mm² 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Endoscopic ultrasound-guided fine-needle aspiration fails to diagnose up to 25% of patients with pancreatic ductal adenocarcinoma (PDAC). Proteomics can help to overcome this clinical dilemma. We hypothesized that soluble protein signatures can differentiate PDAC from benign tissues.Study Design: Tissues were obtained from resected surgical specimens, lysed, and homogenates collected for analysis with a 41-protein multiplex assay. Analyte concentrations were normalized to total protein. Statistical analysis was performed to evaluate for differences in PDAC vs benign tissue.Results: Tissues were obtained from 159 patients, 82 patients with PDAC naïve to therapy and 77 with benign pancreatic pathology. Fourteen analytes had a receiver operating characteristic curve area of >0.75 for predicting PDAC vs benign tissue. A recursive partitioning model using only 2 analytes, interleukin 1 receptor antagonist and transforming growth factor-α, provided an accuracy, sensitivity, and specificity of 91.2%, 90.2%, and 92.2%, respectively. A penalized logistic regression model found 12 analytes that provide diagnostic value to a protein signature. The mean area under the receiver operating characteristic after 50 tenfold cross-validations was 0.951. Accuracy, sensitivity, and specificity of this model were 91.2%, 87.8%, and 94.8%, respectively. Applying the scenario of 80% disease prevalence in patients undergoing endoscopic ultrasound with fine-needle aspiration for a pancreatic head mass, positive predictive value is 98.5% (95% CI 93.0% to 99.7%) and negative predictive value is 66.0% (95% CI 54.9% to 75.6%).Conclusions: Protein signatures from pancreatic specimens can differentiate PDAC from benign tissue. Additional work to validate these findings in a unique sample set is warranted. [ABSTRACT FROM AUTHOR]

Neoadjuvant therapy prior to resection of adenocarcinoma of the pancreatic head increases time to surgery and thus the possibility of biliary complications. We hypothesized that biliary complications during neoadjuvant therapy negatively impact clinical outcomes. We completed a retrospective study of a cohort of borderline resectable patients consistently treated with neoadjuvant therapy from May 2014 through March 2019. Biliary complications were defined as new-onset biliary obstruction, existing stent failure, cholecystitis, and cholangitis. Of 59 patients that met inclusion criteria, 34 (57.6%) went on to resection. Biliary complications affected 16 patients (27%); 8 (50%) of these patients went on to surgical resection. Of those 43 patients who did not have a biliary intervention, 26 went on to surgical resection (60.4%). There was no significant effect of a biliary complication on total number of chemotherapy cycles (p = 0.12), proceeding to surgical resection (p = 0.56) or on median survival (p = 0.23). Among patients who did proceed to surgery, there was a notable difference in median survival for patients who required a biliary intervention (17.9 vs 31.0 months) that did not reach significance (p = 0.35). The need for further biliary interventions during neoadjuvant therapy for pancreatic adenocarcinoma is common, but does not appear to have a significant effect on number of cycles of neoadjuvant therapy or proceeding to surgical resection. Larger studies are necessary to determine if these events compromise overall survival. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rebellious collective action is rare, but it can occur when subordinates are severely discontented and other circumstances are favorable. The possibility of rebellion is a check—sometimes the only check—on authoritarian rule. Although mutinies in which crews seized control of their vessels were rare events, they occurred throughout the Age of Sail. To explain the occurrence of this form of high-risk collective action, this article holds that shipboard grievances were the principal cause of mutiny. However, not all grievances are equal in this respect. We distinguish between structural grievances that flow from incumbency in a subordinate social position and incidental grievances that incumbents have no expectation of suffering. Based on a case-control analysis of incidents of mutiny compared with controls drawn from a unique database of Royal Navy voyages from 1740 to 1820, in addition to a wealth of qualitative evidence, we find that mutiny was most likely to occur when structural grievances were combined with incidental ones. This finding has implications for understanding the causes of rebellion and the attainment of legitimate social order more generally. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 KRASinduced, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Distinct changes in gene expression of the IL-1 axis are found in PDAC. • IL-1 axis expression is correlated with changes in immune checkpoint proteins. • Changes in the IL-1 axis impact the tumor immune milieu. • Low tumor expression of IL1B is associated with decreased overall survival. Interleukin-1 (IL-1) plays a key role in carcinogenesis and several IL-1-targeted therapeutics are under investigation for the treatment of pancreatic ductal adenocarcinoma (PDAC). We sought to broaden our understanding of how the family of IL-1 ligands and receptors impact the tumor immune landscape and patient survival in PDAC. Gene expression data and DNA methylation data for IL1A, IL1B, IL1RN, IL1R1, IL1R2, and IL1RAP was attained from The Cancer Genome Atlas (TCGA) database and cross validated using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Immune cell-type abundance was estimated using CIBERSORTx. Further confirmatory soluble protein analysis and peripheral blood immunophenotyping were performed on available tissue samples from our institution. 169 PDAC patients and 50 benign pancreatic TCGA-based samples were analyzed. IL1A (p < 0.001), IL1RN (p < 0.001), IL1R2 (p < 0.001), and IL1RAP (p = 0.006) were markedly increased in PDAC tumor tissue compared to benign pancreatic tissue. Furthermore, expression of IL1A, IL1B and IL1R1 were positively correlated with gene expression of immune checkpoints PVR, CD274, CD47, CD80, and HLA-A/B/C (p < 0.001). IL1B and IL1R1 were correlated to expression of PDCD1, CD86, CTLA4 and IDO1 (<0.001). Low expression of IL1RN (p = 0.020), IL1R2 (p = 0.015), and IL1RAP (p = 0.003) and high expression of IL1B (p = 0.031) were correlated with increased patient survival. At the protein level, IL-1β was correlated with increased peripheral central memory CD4+ and CD8+ T-cells as well as decreased Th2 cells. These findings suggest that the IL-1 axis plays a complex and pivotal role in the host immune response to PDAC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: The practice of ambulatory surgery has expanded greatly as a result of advances in surgical technology and rising financial pressures. We sought to characterize the utilization of ambulatory surgical practices for common general surgical procedures in Michigan. Materials and methods: We identified 33,655 patients within the Michigan Surgery Quality Collaborative clinical registry undergoing general surgical procedures performed on an ambulatory basis between 25% and 75% of the time. Our primary outcome was the incidence of ambulatory surgery. Using multilevel mixed-effects logistic regression models, we adjusted ambulatory surgery utilization rates for patient comorbidities, procedure composition, and hospital characteristics. We then assessed the incidence of postoperative complications across hospitals grouped by their ambulatory surgery utilization rates. Results: Adjusted utilization rates of ambulatory surgery varied widely across 34 hospitals from 29%–75% (mean = 54%). Risk-adjusted complication rates for ambulatory cases were similar between hospitals performing the least (2.2%) and the most ambulatory surgery (2.3%, P = 0.365). Patient factors and hospital characteristics accounted for 23.3% of the between-hospital variability in ambulatory surgery utilization, whereas most variation was explained by effects at the surgeon level. Conclusions: Despite wide variation in ambulatory surgery utilization for general surgical procedures, we were unable to explain observed differences by patient comorbidities, case mix, or hospital characteristics. These data suggest that understanding factors associated with ambulatory surgery utilization may represent a novel avenue for quality improvement within our statewide surgical collaborative. [Copyright &y& Elsevier]

The oxidative electrochemistry of luminescent rhenium (I) complexes of the type Re(CO)3(LL)Cl, 1, and Re(CO)3(LL)Br, 2, where LL is an α-diimine, was re-examined in acetonitrile. These compounds undergo metal-based one-electron oxidations, the products of which undergo rapid chemical reaction. Cyclic voltammetry results imply that the electrogenerated rhenium (II) species 1+ and 2+ disproportionate, yielding [Re(CO)3(LL)(CH3CN)]+, 7, and additional products. Double potential step chronocoulometry experiments confirm that 1+ and 2+ react via second-order processes and, furthermore, indicate that the rate of disproportionation is influenced by the basicity and steric requirements of the α-diimine ligands. The simultaneous generation of rhenium (I) and (III) carbonyl products was detected upon the bulk oxidation of 1 using infrared spectroelectrochemistry. The rhenium (III) products are assigned as [Re(CO)3(LL)Cl2]+, 5; an inner-sphere electron-transfer mechanism of the disproportionation is proposed on the basis of the apparent chloride transfer. Chemically irreversible two-electron reduction of 5 yields 1 and Cl-. No direct spectroscopic evidence was obtained for the generation of rhenium (III) tricarbonyl bromide disproportionation products, [Re(CO)3(LL)Br2]+, 6; this is attributed to their relatively rapid decomposition to 7 and dibromine. In addition, the 17-electron radical cations, 7+, were successfully characterized using infrared spectroelectrochemistry. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has provided durable clinical responses in a number of human malignancies, but not in patients with pancreatic cancer. Efforts to understand mechanisms of resistance and increase efficacy of immune checkpoint blockade in pancreatic cancer require the use of appropriate preclinical models in the laboratory. Here, we discuss the benefits, caveats, and potentials for improvement of the most commonly used models, including murine-based and patient-derived models. The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and genetically-engineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens. [ABSTRACT FROM AUTHOR]