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.

Does race affect the long-term survival benefit of systemic therapy in pancreatic adenocarcinoma?

BACKGROUND: Systemic therapy is a key management component of pancreatic ductal adenocarcinoma(PDAC). Racial disparities exist in PDAC, often linked to socioeconomic variables. We investigated the impact of race in PDAC patients who had undergone systemic therapy and surgical resection. METHODS: A retrospective analysis was performed for all patients who underwent surgical resection for PDAC from 2010 to 2018. RESULTS: 234 patients (78.2% White; 21.8% Black) were included. Black patients presented at a younger age with larger tumors. White patients benefited from systemic therapy with longer overall survival (35vs20 months, p = 0.002). This survival advantage was not present in Black patients (21vs15 months, p = 0.15). Black patients receiving systemic therapy had similar survival as White patients who did not (p = 0.81). CONCLUSION: Black PDAC patients present at younger ages and with larger initial tumors. In our population, White patients had a longer overall survival after both surgical and systemic therapy. These findings may indicate differences in tumor biology. Further prospective studies are needed.

The Fate of Resectable Pancreatic Adenocarcinoma After Neoadjuvant Chemotherapy.

OBJECTIVES: Pancreatic cancer continues to be a major cause of cancer-related mortality. There has been a greater implementation of up-front chemotherapy for pancreatic adenocarcinoma patients. Although there are many theoretical benefits to neoadjuvant chemotherapy, its clinical impact is uncertain. We sought to understand the outcomes of patients with resectable and borderline-resectable pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy. METHODS: Patients were collected in a secure database from September 2018 to May 2020. Patients were excluded if they presented with locally advanced or metastatic disease, inability to complete chemotherapy, or if they were not a surgical candidate. RESULTS: Sixty-six patients with resectable disease underwent chemotherapy. Folinic acid/5-fluorouracil/irinotecan/oxaliplatin was used in 41 patients (62.1%) and gemcitabine-based regimens in 28 patients (42.4%, greater than 100% as some patients underwent both regimens). After restaging, 47 patients (71.2%) were thought to have resectable disease. Of these patients, 36 have been successfully resected to date. Metastatic disease was found in 12 patients (18.2%) and 6 patients (9.1%) had locally advanced disease. CONCLUSIONS: Most patients with resectable pancreatic cancer are resected after neoadjuvant chemotherapy, but a subset will develop local or distant progression. Further studies will be needed to determine which patients will progress locally and may benefit from an up-front surgical approach.

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.

Perceived Institutional Barriers Among Clinical and Research Professionals: Minority Participation in Oncology Clinical Trials.

PURPOSE: In general, participation rates in cancer clinical trials are very low. However, participation rates are especially low among the socially disadvantaged and racial and ethnic minority groups. These groups have been historically under-represented in cancer clinical trials. Although many patient-related barriers have been studied, institutional factors that are essential for building clinical research infrastructure around the clinical trial enterprise in academic medical centers have been underexplored. MATERIALS AND METHODS: We assessed perspectives of cancer center professional stakeholders on the institutional factors that can potentially influence racial and ethnic minority recruitment for cancer clinical trials. Ninety-one qualitative interviews were conducted at five US cancer centers among four stakeholder groups: cancer center leaders, principal investigators, referring clinicians, and research staff. Qualitative analyses examined response data focused on institutional factors related to minority recruitment for cancer clinical trials. RESULTS: Four prominent themes emerged regarding institutional barriers among clinical and research professionals. (1) There are no existing programs currently being used to recruit or retain minorities to clinical trials. (2) Institutional efforts are needed to increase trial participation and are not specific to potential minority participants. (3) Access to cancer clinical trials and navigation within an Academic Medical Center need to be simplified to better facilitate recruitment of minority patients. (4) Community outreach by cancer centers will increase clinical research awareness in the community. CONCLUSION: Our research highlights the need to address institutional barriers to improve the success of minority recruitment. To increase participation among minority populations, medical centers must address mutable institutional barriers such as setting specific minority recruitment goals for cancer clinical trials, ensuring that cancer clinical trials are accessible, especially to minority patients, and supporting sustained community outreach programs to increase clinical research awareness.

New Insights Into the Cancer-Microbiome-Immune Axis: Decrypting a Decade of Discoveries.

The past decade has witnessed groundbreaking advances in the field of microbiome research. An area where immense implications of the microbiome have been demonstrated is tumor biology. The microbiome affects tumor initiation and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. It can also determine response to cancer therapies and predict disease progression and survival. Modulation of the microbiome can be harnessed to potentiate the efficacy of immunotherapies and decrease their toxicity. In this review, we comprehensively dissect recent evidence regarding the interaction of the microbiome and anti-tumor immune machinery and outline the critical questions which need to be addressed as we further explore this dynamic colloquy.

Racial and socioeconomic disparity associates with differences in cardiac DNA methylation among men with end-stage heart failure.

Heart failure (HF) is a multifactorial syndrome that remains a leading cause of worldwide morbidity. Despite its high prevalence, only half of patients with HF respond to guideline-directed medical management, prompting therapeutic efforts to confront the molecular underpinnings of its heterogeneity. In the current study, we examined epigenetics as a yet unexplored source of heterogeneity among patients with end-stage HF. Specifically, a multicohort-based study was designed to quantify cardiac genome-wide cytosine-p-guanine (CpG) methylation of cardiac biopsies from male patients undergoing left ventricular assist device (LVAD) implantation. In both pilot (n = 11) and testing (n = 31) cohorts, unsupervised multidimensional scaling of genome-wide myocardial DNA methylation exhibited a bimodal distribution of CpG methylation found largely to occur in the promoter regions of metabolic genes. Among the available patient attributes, only categorical self-identified patient race could delineate this methylation signature, with African American (AA) and Caucasian American (CA) samples clustering separately. Because race is a social construct, and thus a poor proxy of human physiology, extensive review of medical records was conducted, but ultimately failed to identify covariates of race at the time of LVAD surgery. By contrast, retrospective analysis exposed a higher all-cause mortality among AA (56.3%) relative to CA (16.7%) patients at 2 yr following LVAD placement (P = 0.03). Geocoding-based approximation of patient demographics uncovered disparities in income levels among AA relative to CA patients. Although additional studies are needed, the current analysis implicates cardiac DNA methylation as a previously unrecognized indicator of socioeconomic disparity in human heart failure outcomes.NEW & NOTEWORTHY A bimodal signature of cardiac DNA methylation in heart failure corresponds with racial differences in all-cause mortality following mechanical circulatory support. Racial differences in promoter methylation disproportionately affect metabolic signaling pathways. Socioeconomic factors are associated with racial differences in the cardiac methylome among men with end-stage heart failure.

Does health insurance protect against risk of financial catastrophe for pancreatic tumor care? A cost-based review of patients undergoing pancreatic resection at an academic institution.

BACKGROUND: Pancreatic cancer is a leading cause of financial insolvency and cancer related deaths in the United States. The risk of catastrophic health expenditure (CHE) was calculated for patients undergoing pancreatic resection at an academic institution. METHODS: Patients who underwent pancreatic resection between 2013 and 2017 were identified through an institutional cancer registry. A CHE was an out-of-pocket payment (OOP) > 10% of the estimated median household income. RESULTS: 319 patients met inclusion criteria. Hospital median charge was $76,700. 99% of patients had insurance and hospital bill adjustments. As a result, 61% (n = 193) made no OOP. Only 3 patients risked CHE. For all tumors combined there were no differences in survival outcomes by OOP. CONCLUSION: This is the first study to use institutional financial data to calculate CHE risk for pancreatic resection patients. Insurance adjustments to hospital charges that accompany health insurance and voluntary hospital adjustments for the uninsured protect patients against CHE.

Benchmarking Accomplishments of Leaders in American Surgery and Justification for Enhancing Diversity and Inclusion.

OBJECTIVE: To comprehensively assess the level of achievement and demographics of national surgical society presidents. BACKGROUND: Data on the accomplishments needed to rise to positions of national surgical leadership is scarce and merit alone does not always yield such opportunities. Recognizing the shortcomings of sex and ethnic diversity within academic surgical leadership, the American College of Surgeon (ACS), American Surgical Association (ASA), Association of Women Surgeons (AWS), and the Society of Black Academic Surgeons (SBAS) partnered to address these challenges by performing a comprehensive assessment of their presidents over the last 16 years. METHODS: ACS, ASA, AWS, and SBAS presidents' CVs, at the time of their presidential term, were assessed for demographics and scholastic achievements. Regression analyses controlling for age were performed to determine relative differences across societies. RESULTS: A total of 62 of the 64 presidents' CVs were received and assessed (97% response rate). There was a large discrepancy in the average age in years of ACS (70) and ASA (66) presidents compared to the AWS (51) and SBAS (53) presidents. For the ACS and ASA cohort, 87% were male and 83% were White, collectively. After controlling for age (52), the AWS and SBAS presidents' scholastic achievements were comparable to the ACS (and ASA) cohort in 9 and 12 of the 15 accessed metrics, respectively. CONCLUSION: The ACS and ASA presidents' CVs displayed unsurpassed scholastic achievement, and although not equivalent, both the AWS and the SBAS presidents had comparable attainment. These findings further substantiate that women and ethnic minority surgeons are deserving of additional national leadership consideration as organized medicine pursues a more diverse and reflective physician workforce.

Bias and stereotyping among research and clinical professionals: Perspectives on minority recruitment for oncology clinical trials.

BACKGROUND: In recent years, extensive attention has been paid to the possibility that bias among health care professionals contributes to health disparities. In its 2003 report, the Institute of Medicine concluded that bias against racial minorities may affect communication or care offered. However, to the authors' knowledge, the role of bias within the context of recruitment of racial and ethnic minorities to cancer clinical trials has not been explored to date. Therefore, the authors assessed the experiences of clinical and research personnel related to factors influencing the recruitment of racial and ethnic minorities for cancer clinical trials. METHODS: A total of 91 qualitative interviews were conducted at 5 US cancer centers among 4 stakeholder groups: 1) cancer center leaders; 2) principal investigators; 3) referring clinicians; and 4) research staff. Data analysis was conducted using a content analysis approach to generate themes from the transcribed interviews. RESULTS: Five prominent themes emerged: 1) recruitment interactions with potential minority participants were perceived to be challenging; 2) potential minority participants were not perceived to be ideal study candidates; 3) a combination of clinic-level barriers and negative perceptions of minority study participants led to providers withholding clinical trial opportunities from potential minority participants; 4) when clinical trial recruitment practices were tailored to minority patients, addressing research misconceptions to build trust was a common strategy; 5) for some respondents, race was perceived as irrelevant when screening and recruiting potential minority participants for clinical trials. CONCLUSIONS: Not only did some respondents view racial and ethnic minorities as less promising participants, some respondents reported withholding trial opportunities from minorities based on these perceptions. Some providers endorsed using tailored recruitment strategies whereas others eschewed race as a factor in trial recruitment. The presence of bias and stereotyping among clinical and research professionals recruiting for cancer clinical trials should be considered when designing interventions to increase minority enrollment.

Correction to: Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia.

Following publication of the original article [1], the authors found an error in Figure 3. The middle panel of Figure 3a was inadvertently duplicated.

O-GlcNAc modification of Sox2 regulates self-renewal in pancreatic cancer by promoting its stability.

Pancreatic adenocarcinoma (PDAC) claims more than 90% of the patients diagnosed with the disease owing to its aggressive biology that is manifested by high rate of tumor recurrence. Aberrant upregulation in the transcriptional activity of proteins involved in self-renewal like Sox2, Oct4 and Nanog is instrumental in these recurrence phenomena. In cancer, Sox2 is aberrantly "turned-on" leading to activation of downstream genes those results in relapse of the tumor. Molecular mechanisms that regulate the activity of Sox2 in PDAC are not known. In the current study, we have studied the how glycosylation of Sox2 by O-GlcNAc transferase (OGT) can affect its transcriptional activity and thus regulate self-renewal in cancer. Methods: RNA-Seq analysis of CRISPR-OGTi PDAC cells indicated a deregulation of differentiation and self-renewal pathways in PDAC. Pancreatic tumor burden following inhibition of OGT in vivo was done by using small molecule inhibitor, OSMI, on subcutaneous implantation of PDAC cells. Sox2 activity assay was performed by Dual Luciferase Reporter Assay kit. Results: Our study shows for the first time that in PDAC, glycosylation of Sox2 by OGT stabilizes it in the nucleus. Site directed mutagenesis of this site (S246A) prevents this modification. We further show that inhibition of OGT delayed initiation of pancreatic tumors by inhibition of Sox2. We also show that targeting OGT in vivo with a small molecule-inhibitor OSMI, results in decreased tumor burden in PDAC. Conclusion: Understanding this mechanism of SOX2 regulation by its glycosylation is expected to pave the way for development of novel therapy that has the potential to eradicate the cells responsible for tumor-recurrence.