Association of Hospital Market Competition with Outcomes of Complex Cancer Surgery.

BACKGROUND: The association of hospital market competition, financial costs, and quality of oncologic care has not been well-defined. This study sought to evaluate variations in patient outcomes and financial expenditures after complex cancer surgery across high- and low-competition markets. METHODS: Medicare 100% Standard Analytic Files were used to identify patients with lung, esophageal, gastric, hepatopancreaticobiliary, or colorectal cancer who underwent surgical resection between 2018 and 2021. Data were merged with the annual hospital survey database, and the hospital market Herfindahl-Hirschman index was used to categorize hospitals into low- and high-concentration markets. Multi-level, multivariable regression models adjusting for patient characteristics (i.e., age, sex, comorbidities, and social vulnerability), year of procedure, and hospital factors (i.e., case volume, nurse-bed ratio, and teaching status) were used to assess the association between hospital market competition and outcomes. RESULTS: Among 117,641 beneficiaries who underwent complex oncologic surgery, the mean age was 73.8 ± 6.1 years, and approximately one-half of the cohort was male (n = 56,243, 47.8%). Overall, 63.8% (n = 75,041) of the patients underwent care within a high-competition market. Notably, there was marked geographic variation relative to market competition. High versus low market-competition hospitals were more likely to be in high social vulnerability areas (35.1 vs 27.5%; p < 0.001), as well as care for racial/ethnic minority individuals (13.8 vs 7.7%; p < 0.001), and patients with more comorbidities (≥ 2 Elixhauser comorbidities: 63.1 vs 61.1%; p < 0.001). In the multivariable analysis, treatment at hospitals in high- versus low-competition markets was associated with lower odds of achieving a textbook outcome (odds ratio, 0.95; 95% confidence interval, 0.91-0.99; p = 0.009). Patients at high-competition hospitals had greater mean index hospitalization costs ($19,462.2 [16211.9] vs $18,844.7 [14994.7]) and 90-day post-discharge costs ($7807.8 [15431.3] vs $7332.8 [14038.2]) (both p < 0.001) than individuals at low-competition hospitals. CONCLUSIONS: Hospital market competition was associated with poor achievement of an optimal postoperative outcome and greater hospitalization costs.

Surgical outcomes and healthcare expenditures among patients with dementia undergoing major surgery.

BACKGROUND: We sought to define surgical outcomes among elderly patients with Alzheimer's disease and related dementias (ADRD) following major thoracic and gastrointestinal surgery. METHODS: A retrospective cohort study was used to identify patients who underwent coronary artery bypass grafting (CABG), abdominal aortic aneurysm (AAA) repair, pneumonectomy, pancreatectomy, and colectomy. Individuals were identified from the Medicare Standard Analytic Files and multivariable regression was utilized to assess the association of ADRD with textbook outcome (TO), expenditures, and discharge disposition. RESULTS: Among 1,175,010 Medicare beneficiaries, 19,406 (1.7%) patients had a preoperative diagnosis of ADRD (CABG: n = 1,643, 8.5%; AAA repair: n = 5,926, 30.5%; pneumonectomy: n = 590, 3.0%; pancreatectomy: n = 181, 0.9%; and colectomy: n = 11,066, 57.0%). After propensity score matching, patients with ADRD were less likely to achieve a TO (ADRD: 31.2% vs. no ADRD: 40.1%) or be discharged to home (ADRD: 26.7% vs. no ADRD: 46.2%) versus patients who did not have ADRD (both p < 0.001). Median index surgery expenditures were higher among patients with ADRD (ADRD: $28,815 [IQR $14,333-$39,273] vs. no ADRD: $27,101 [IQR $13,433-$38,578]; p < 0.001) (p < 0.001). On multivariable analysis, patients with ADRD had higher odds of postoperative complications (OR 1.32, 95% CI 1.25-1.40), extended length-of-stay (OR 1.26, 95% CI 1.21-1.32), 90-day readmission (OR 1.37, 95% CI 1.31-1.43), and 90-day mortality (OR 1.76, 95% CI 1.66-1.86) (all p < 0.001). CONCLUSION: Preoperative diagnosis of ADRD was an independent risk factor for poor postoperative outcomes, discharge to non-home settings, as well as higher healthcare expenditures. These data should serve to inform discussions and decision-making about surgery among the growing number of older patients with cognitive deficits.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM: To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS: Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS: Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION: Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Median arcuate ligament release at the time of pancreaticoduodenectomy or total pancreatectomy.

BACKGROUND: Celiac artery compression can complicate the performance of pancreaticoduodenectomy or total pancreatectomy due to the need for ligation of the gastroduodenal artery. Median arcuate ligament release restores normal arterial flow to the liver, spleen, and stomach and may avoid complications related to poor perfusion of the foregut. METHODS: All patients who underwent median arcuate ligament release for celiac artery compression at the time of pancreatectomy between 2009 and 2023 were reviewed. Pre- and postoperative computed tomography was used to categorize celiac artery compression by the extent of compression (types A [<50%], B [50%-80%], and C [>80%]). RESULTS: Of 695 patients who underwent pancreatectomy, 22 (3%) had celiac artery compression, and a majority (17) were identified on preoperative imaging. Median celiac artery compression was 52% (interquartile range = 18); 8 (36%) patients had type A and 14 (64%) had type B compression with a median celiac artery compression of 39% (interquartile range = 18) and 59% (interquartile range = 14), respectively (P < .001). Postoperative imaging was available for 20 (90%) patients, and a reduction in the median celiac artery compression occurred in all patients: type A, 14%, and type B, 31%. Complications included 1 (5%) death after hospital discharge, 1 (5%) pancreatic fistula, 1 (5%) delayed gastric emptying, and 4 (18%) readmissions. No patient had evidence of a biliary leak or liver dysfunction. CONCLUSION: Preoperative computed tomography allows accurate identification of celiac artery compression. Ligation of the gastroduodenal artery during pancreaticoduodenectomy or total pancreatectomy in the setting of celiac artery compression requires median arcuate ligament release to restore normal arterial flow to the foregut and avoid preventable complications.

Precision Oncology in Hepatopancreatobiliary Cancer Surgery.

Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.

Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS: TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. CONCLUSIONS: This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.

Energy Device Preferences Among Gynecologic Surgeons.

Background and Objectives: Multiple vessel-sealing devices are available for use during laparoscopy. The objective of this study is to determine what surgeon-level and device characteristics influence the choice of advanced energy device during gynecologic laparoscopy. Methods: This is a national cross-sectional study of gynecologic surgeons conducted via social media, utilizing an online, publicly-available, anonymous survey. Gynecologic surgeons who had completed residency training were approached for participation in the survey. Survey completion was voluntary and involved no further follow-ups. The web-based survey consisted of six questions with the option to answer three additional questions if time permitted. The institutional review board determined that this study qualified for exemption. Results: There were 92 respondents who participated in the survey. Of these, 81 completed the survey and were included in the analysis. Female respondents were younger and more frequently reported a glove size of 6.5 or less. Surgeon-level characteristics, including gender, age, glove size, case volume, region, and practice setting, were not significantly associated with preferred energy devices. Device availability in the operating room was the only characteristic associated with preferred energy devices (P-value = .0076). Other device-level characteristics such as optimal thermal spread, reduced plume, ease of use, device reliability, and teachability had no statistically significant association with preferred energy devices. Conclusion: Multiple advanced energy devices are available for use during gynecologic laparoscopy. These devices have varying energy profiles, thermal spread, and device size. Despite this diversity, only device availability in the operating room influenced the surgeon's preferred device selection.

Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy.

PURPOSE/OBJECTIVES: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. MATERIALS/METHODS: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. RESULTS: 121 patients were included with a median age of 62 years (37-86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving <18 months and ≥18 months regarding the presence of lung only metastases (36% vs. 16%, p = 0.04), number of organs with metastases (≥2 vs. 1, p = 0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p = 0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p = 0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19-9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p = 0.03). In those patients that normalized their CA 19-9, median overall survival was 16 months. CONCLUSIONS: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions.

Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Automated machine learning (AutoML) can predict 90-day mortality after gastrectomy for cancer.

Early postoperative mortality risk prediction is crucial for clinical management of gastric cancer. This study aims to predict 90-day mortality in gastric cancer patients undergoing gastrectomy using automated machine learning (AutoML), optimize models for preoperative prediction, and identify factors influential in prediction. National Cancer Database was used to identify stage I-III gastric cancer patients undergoing gastrectomy between 2004 and 2016. 26 features were used to train predictive models using H2O.ai AutoML. Performance on validation cohort was measured. In 39,108 patients, 90-day mortality rate was 8.8%. The highest performing model was an ensemble (AUC = 0.77); older age, nodal ratio, and length of inpatient stay (LOS) following surgery were most influential for prediction. Removing the latter two parameters decreased model performance (AUC 0.71). For optimizing models for preoperative use, models were developed to first predict node ratio or LOS, and these predicted values were inputted for 90-day mortality prediction (AUC of 0.73-0.74). AutoML performed well in predicting 90-day mortality in a larger cohort of gastric cancer patients that underwent gastrectomy. These models can be implemented preoperatively to inform prognostication and patient selection for surgery. Our study supports broader evaluation and application of AutoML to guide surgical oncologic care.

Attitudes and Beliefs about Hysterectomy in Patients with Uterine Fibroids.

STUDY OBJECTIVE: To investigate the attitudes toward and beliefs about hysterectomy that influence the decision of women with symptomatic uterine fibroids regarding hysterectomy. DESIGN: A prospective survey study. SETTING: An outpatient clinic. PATIENTS: Patients in an urban, academic complex gynecology outpatient clinic at the age of 35 years or older with uterine fibroids and without previous hysterectomy were invited to participate. A total of 67 participants were surveyed between December 2020 and February 2022. INTERVENTIONS: Data were collected on demographics, Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QOL) Questionnaire scores, and beliefs regarding hysterectomy via a web-based survey. Participants were posed with clinical scenarios and asked to indicate a preference for hysterectomy or myomectomy and stratified into groups by acceptability of hysterectomy as a treatment option for fibroids. MEASUREMENTS AND MAIN RESULTS: Data were analyzed using chi-square or Fisher exact tests, t tests, or Wilcoxon tests as appropriate. The mean age of participants was 46.2 (SD 7.5) years, and 57% of participants self-identified as White/Caucasian. The mean UFS-QOL symptoms score was 50 (SD 26) and the mean overall health-related quality of life score was 52 (SD 28). Notably, 34% of participants preferred hysterectomy whereas 54% preferred myomectomy assuming equivalent efficacy; 44% of those who preferred myomectomy did not desire future fertility. There were no differences observed in UFS-QOL scores. Participants opting for a hysterectomy believed that it would improve their mood/emptions, relationship with partner, general quality of life, sense of femininity, feeling whole, identity/body image, sexuality, and relationships. Those who opted for a myomectomy believed all those factors would worsen with a hysterectomy, and in addition, it would worsen their vaginal moisture and their partner's experience. CONCLUSION: Many factors affect a patient's decisions regarding hysterectomy for uterine fibroids beyond those related to fertility, including factors related to body image, sexuality, and relationships. Physicians should consider these factors when counseling patients and recognize their importance to facilitate improved shared decision making.

Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

OBJECTIVE: To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. BACKGROUND: Patients with PC presenting with biliary obstruction require durable decompression before NAT. METHODS: Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. RESULTS: Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). CONCLUSIONS: During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

Endometriosis and adenomyosis: shared pathophysiology.

Endometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-ß. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.

Neoadjuvant chemotherapy for pancreatic cancer: Quality over quantity.

BACKGROUND AND OBJECTIVES: The ideal duration of neoadjuvant chemotherapy (NACT) in patients with localized pancreatic adenocarcinoma (PDAC) treated with curative intent is unclear. We sought to determine the prognostic significance of both duration of NACT and Carbohydrate Antigen 19-9 (CA19-9) normalization to NACT. METHODS: We examined patients with resectable and borderline resectable PDAC treated with NACT and chemoradiation. Patients were compared by NACT duration (2 vs. 4 months) and by CA19-9 normalization after NACT. RESULTS: Among 171 patients, 83 (49%) received 2 months of NACT, and 88 (51%) received 4 months. After NACT completion, 115 (67%) patients had persistently elevated CA19-9, and 56 (33%) had normalized. Of the 125 patients who had successful surgery, 73 (58%) had normalized CA19-9 postoperatively. Duration of NACT was not associated with overall survival (OS) while CA19-9 normalization after NACT (regardless of duration) was associated with improved OS (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35-0.89, p = 0.02). Adjuvant chemotherapy was associated with improved OS among patients without CA19-9 normalization after NACT (HR 0.42, CI 0.20-0.86, p = 0.02) but not among those that normalized, independent of duration. CONCLUSIONS: CA19-9 normalization after NACT is a clinically significant endpoint of treatment; patients without CA19-9 normalization may benefit from additional therapy.

CA19-9 Response to First-Line Neoadjuvant FOLFIRINOX and Second-Line Gemcitabine/Nab-Paclitaxel for Patients with Operable Pancreatic Cancer.

BACKGROUND: Response to second-line (2L) neoadjuvant therapy for operable pancreatic cancer (PC) is understudied. This study examined carbohydrate antigen 19-9 (CA19-9) response to first-line (1L) and 2L chemotherapy. METHODS: The study identified patients with operable PC and elevated CA19-9 (≥ 35 U/mL with total bilirubin < 2 mg/dL) who received 1L FOLFIRINOX (FFX). The patients were restaged after 2 months and based on response, received additional FFX or gemcitabine/nab-paclitaxel (GnP) as part of total neoadjuvant therapy. Response was defined as a decrease in tumor size on computed tomography (CT) imaging or a decline in CA19-9 of 50% or more and preserved performance status. RESULTS: For operable PC with an elevated CA19-9, 108 patients received 1L FFX. After 2 months of chemotherapy, the decision was made to continue FFX (FFX ≥ FFX) for 76 (70%) of the 108 patients and switch to GnP (FFX ≥ GnP)) for 32 (30%) of the patients. Of the 32 FFX ≥ GnP patients, 27 had no evidence of radiographic or biochemical (CA19-9) response to 1L FFX. Of these 27 patients, 26 (96%) demonstrated a response to 2L GnP. After 4 months of chemotherapy, 62 (82%) of the 76 FFX ≥ FFX patients had a CA19-9 response compared with 31 (97%) of the 32 FFX ≥ GnP patients (p = 0.04). CONCLUSIONS: Lack of biochemical response to 2 months of 1L FFX may identify a subgroup of patients with a very high rate of response to 2L GnP, emphasizing the importance of assessing treatment response at 2-month intervals.

Impact of Medicaid Expansion on Stage at Diagnosis for US Adults with Pancreatic Cancer: a Population-Based Study.

INTRODUCTION: We evaluated whether Medicaid expansion is associated with earlier stage at diagnosis for pancreatic cancer taking into account key demographic, clinical, and geographic factors. METHODS: We obtained Surveillance, Epidemiology, and End-Results (SEER-18) data on individuals diagnosed with pancreatic cancer from 2007 to 2016 (< 65 years of age). We defined non-metastatic as either local or regional disease (vs. metastatic disease). To estimate the association of Medicaid expansion with pancreatic cancer stage at diagnosis, we used a difference-in-differences model, at the individual level, comparing those from early-adopting states in 2014 to non-early-adopting states. We utilized cluster-robust standard errors and explored the role of demographic factors (race, sex, insurance at diagnosis), clinical indicator (disease in the head of the pancreas), and county characteristics (Urban Influence Code, Social Deprivation Index). RESULTS: In the univariable setting, the probability of non-metastatic disease at diagnosis increased by 3.9 percentage points (ppt) for those from Medicaid expansion states post-expansion (n = 36,609). After adjustment for covariates, the ppt was attenuated to 2.7. Of particular note, we observed evidence of interactions with sex and race. The beneficial effect was less pronounced for men (increase in the probability of non-metastatic stage at diagnosis by 2.1ppt) than women (3.6ppt) and non-existent for blacks (- 3.1ppt) compared to whites (4.9ppt) and other races (4.8ppt). CONCLUSION: Medicaid expansion is associated with increased probability of non-metastatic stage at diagnosis for pancreatic cancer; however, this beneficial effect is not uniform across sex and race. This underscores the need to investigate the impact of policy and implementation strategies on pancreatic cancer survival disparities.

Outcomes of a pilot virtual mentorship program for medical students interested in surgery.

BACKGROUND: Lack of mentorship may deter medical students who identify as underrepresented minorities (URM) from entering academic surgery. METHODS: 30 mentor-medical student pairs from the AWS 2020 virtual mentorship pilot-program were surveyed pre-and post-program to explore 1) feasibility of meetings, and, 2) program's perceived efficacy in fostering professional development skills. Participants responded using a 5-point Likert scale (1 = not at all; 5 = completely). Proportions of participants in each category were compared. RESULTS: Proportion of participants perceiving monthly meetings to be completely feasible did not differ from pre-to post-program surveys for mentees (75%(21/28) vs. 71%(12/17); p = 0.743) or mentors (71%(17/24) vs 71%(13/18); p = 1.00). Compared to pre-program responses, mentees endorsed "completely" (Likert scale 5) improving with regard to their elevator speech (p = 0.001), developing their curriculum vitae (p = 0.003), ability to network (p = 0.021), and acquiring skills for career advancement (p = 0.003). CONCLUSION: Virtual mentorship may be a feasible and effective means of increasing access to mentors for URM medical students.

Targeting Cellular Metabolism With CPI-613 Sensitizes Pancreatic Cancer Cells to Radiation Therapy.

Purpose: Local tumor progression is a cause of significant morbidity and mortality in patients with pancreatic ductal adenocarcinoma (PDAC) with surgically unresectable disease. Novel and effective approaches to accomplish durable local control are urgently needed. We tested whether CPI-613 (devimistat), a first-in-class investigational small molecule inhibitor of mitochondrial metabolism, was capable of altering cancer cell energy metabolism and sensitizing PDAC cells to radiation therapy (RT). Methods and Materials: The effect of a combined treatment of RT with CPI-613 on the viability of, clonogenic potential of, and cell death induction in PDAC cells (MiaPaCa-2 and Panc-1) was determined using a trypan blue dye exclusion assay, a colony formation assay, and a 7-amino-actinomycin D assay, respectively. The synergistic effects of CPI-613-RT and chemotherapeutic agents (gemcitabine or 5-fluorouracil) were measured in MiaPaCa-2 cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and spheroid formation assay. Changes in energy metabolism were determined by profiling metabolites treated with either RT, CPI-613, or both using liquid chromatography-mass spectrometry. Results: This study demonstrates that a combination of single-fraction RT (2 and 10 Gy) with CPI-613 significantly inhibits PDAC cell growth compared with RT alone. Molecular analysis revealed inhibition of α-ketoglutarate dehydrogenase at the protein level. In addition, we demonstrate enhanced cell death of PDAC cells when treated with RT-CPI-613 combination. Targeted metabolomic analysis on PDAC cells post-CPI-613-RT treatment revealed alterations in key mitochondrial metabolites, with broader target engagement by the combination treatment, indicating the sensitization of CPI-613-treated PDAC cells to RT. Furthermore, a combination treatment of CPI-613 with either gemcitabine or 5-fluorouracil in the presence of 2 Gy RT synergistically inhibits PDAC cell proliferation. Conclusions: Our results support a novel combination of CPI-613-RT that warrants further preclinical and early-phase clinical investigations. A phase 1 trial designed to identify the maximum tolerated dose of CPI-613 in combination with chemo-RT in patients with PDAC was recently initiated (NCT05325281).

Becoming a Sustainable Academic Surgeon.

INTRODUCTION: Health care facilities represent a significant source of pollution, contributing to the growing problems associated with global warming. The resulting climate change impacts our health through worsening air and water quality, diminished access to nutritious food, and safe shelter. METHODS: We outline here the not only the role of the surgeon in contributing to climate change, but also ways in which to minimize one's carbon footprint. RESULTS: Surgeons are leaders within healthcare systems. Adopting environmentally conscious practices can reduce solid waste, energy usage, and carbon emissions. Practices outside of the clinical setting can also incorporate sustainability, including the use of virtual recruitment and educational programs, as well as thoughtful and conscientious travel practices. CONCLUSIONS: Academic surgery combines clinical practice with an element of leadership, at all levels. Our recognition and action to reduce wasteful practices can help leave a better earth for generations to come.