Understanding Barriers to Guideline-Concordant Treatment in Foregut Cancer: From Data to Solutions.

BACKGROUND: A large proportion of patients with foregut cancers do not receive guideline-concordant treatment (GCT). This study sought to understand underlying barriers to GCT through a root cause analysis approach. METHODS: A single-institution retrospective review of 498 patients with foregut (gastric, pancreatic, and hepatobiliary) adenocarcinoma from 2018 to 2022 was performed. Guideline-concordant treatment was defined based on National Comprehensive Cancer Network guidelines. The Ishikawa cause and effect model was used to establish main contributing factors to non-GCT. RESULTS: Overall, 34% did not receive GCT. Root causes of non-GCT included Patient, Physician, Institutional Environment and Broader System-related factors. In decreasing order of frequency, the following contributed to non-GCT: receipt of incomplete therapy (N = 28, 16.5%), deconditioning on chemotherapy (N = 26, 15.3%), delays in care because of patient resource constraints followed by loss to follow-up (N = 19, 11.2%), physician factors (N = 19, 11.2%), no documentation of treatment plan after referral to oncologic expertise (N = 19, 11.2%), loss to follow-up before oncology referral (N = 17, 10%), nonreferral to medical oncologic expertise (N = 16, 9.4%), nonreferral to surgical oncology in patients with resectable disease (N = 15, 8.8%), and complications preventing completion of treatment (N = 11, 6.5%). Non-GCT often was a function of multiple intersecting patient, physician, and institutional factors. CONCLUSIONS: A substantial percentage of patients with foregut cancer do not receive GCT. Solutions that may improve receipt of GCT include development of automated systems to improve patient follow-up; institutional prioritization of resources to enhance staffing; financial counseling and assistance programs; and development and integration of structured prehabilitation programs into cancer treatment pathways.

Palliative Therapies in Metastatic Pancreatic Cancer: Does Medicaid Expansion Make a Difference?

BACKGROUND: The aim of this study was to evaluate the impact of medicaid expansion (ME) on receipt of palliative therapies in metastatic pancreatic cancer patients. PATIENTS AND METHODS: A difference-in-differences (DID) approach was used to analyze patients with metastatic pancreatic cancer identified from the National Cancer Database diagnosed during two time periods: pre-expansion (2010-2012) and post-expansion (2014-2016). Patients diagnosed while residing in ME states were compared with those in non-ME states. Multivariable logistic regression was used to identify predictors of receipt of palliative therapies. RESULTS: Of 87,738 patients overall, 7483(18.1%) received palliative therapies in the pre-expansion, while 10,211(21.5%) received palliative therapies in the post-expansion period. In the pre-expansion period, treatment at a high-volume facility (HVF) (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.02-1.18) and non-west geographic location were predictive of increased palliative therapies. In the post-expansion period, treatment at an HVF (OR 1.09, 95% CI 1.02-1.16), geographic location, and living in an ME state at the time of diagnosis (OR 1.14, 95% CI 1.06-1.22) were predictive of increased palliative therapies. Older age, highest quartile median income (zip-code based), and treatment at a nonacademic facility were independently associated with decreased palliative therapies in both periods. DID analysis demonstrated that patients with metastatic pancreatic cancer living in ME states had increased receipt of palliative therapies relative to those in non-ME states (DID = 2.68, p < 0.001). CONCLUSIONS: The overall utilization of palliative therapies in metastatic pancreatic cancer is low. Multiple sociodemographic disparities exist in the receipt of palliative therapies. ME is associated with increased receipt of palliative therapies in patients with metastatic pancreatic cancer.

Disparities in Access to Oncologic Care in Pancreatic Cancer: A Systematic Review.

BACKGROUND: Pancreatic cancer care is complex, and multiple disparities in receipt of therapies have been documented. The authors aimed to conduct a systematic review of the literature to critically assess and summarize disparities in access to oncologic therapies for pancreatic cancer. METHODS: A search of PubMed, Scopus, Web of Science, and Cochrane databases were performed for studies reporting disparities in access to oncologic care for pancreatic cancer. Primary research articles published in the United States from 2000 to 2020 were included. Data were independently extracted, and risk of bias was assessed using the modified Newcastle-Ottawa scale. RESULTS: The inclusion criteria were met by 47 studies. All the studies used retrospective data, with 70 % involving national database studies, 41 assessing the impact of race/ethnicity, 22 assessing the impact of socioeconomic status, 18 assessing the impact of insurance status, 23 assessing the impact of gender, 26 assessing the impact of age, and 3 assessing the impact of location on the delivery of cancer-directed therapies. Race, socioeconomic status, insurance status, gender, and age- based disparities in receipt of surgical resection, treatment at high-volume facilities and multimodal therapy for resectable pancreatic cancer, receipt of systemic chemotherapy for metastatic cancer, and receipt of expected standard-of-care treatment are reported. CONCLUSION: Significant sociodemographic disparities in access to equitable oncologic care exist along the continuum of pancreatic cancer care. Multiple patient, provider, and systemic factors contribute to these disparities. The ongoing study of these disparities is important to elucidate processes that may be targeted to improve access to equitable oncologic care for patients with pancreatic cancer.

Association of Medicaid Expansion with Pancreatic Cancer Treatment and Outcomes: Evidence from the National Cancer Database.

BACKGROUND: Socioeconomic- and demographic-based disparities exist in the treatment of pancreatic adenocarcinoma (PDAC). Medicaid expansion (ME) may have an impact on these disparities. Analyses of patients with PDAC from the National Cancer Database (NCDB) were performed to examine the impact of ME on access to treatment and outcomes. METHODS: Patients with non-metastatic PDAC diagnosed between 2006 and 2016 were identified. Multiple logistic regression analyses were performed to evaluate factors associated with curative-intent surgical resection, multimodal therapy, treatment at a high-volume facility (HVF), and survival. RESULTS: The study identified 41,876 patients who met the criteria. Medicaid expansion was independently associated with curative-intent resection (odds ratio [OR] 1.54; 95 % confidence interval [CI] 1.43-1.67; p < 0.001). In a multivariable analysis, ME was independently associated with multimodal therapy (OR 1.60; 95 % CI 1.44-1.76; p < 0.001) and treatment at an HVF (OR 1.57; 95 % CI 1.42-1.74; p < 0.001). Medicaid expansion was independently associated with improved 30-day mortality (OR 0.49; 95 % CI 0.34-0.79) and 90-day mortality (OR 0.48 95 % CI 0.35-0.59). Cox regression analysis demonstrated that after adjustment for other variables, ME status was associated with improved overall survival (hazard ratio [HR], 0.82; 95 % CI 0.73-0.90; p < 0.001). CONCLUSIONS: Medicaid expansion is associated with increased use of care processes that improve outcomes in PDAC, operative outcomes, and overall survival. The study data suggest that ME has helped to improve disparities in PDAC in ME states.

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal ß-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype.

UNLABELLED: Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs. OBJECTIVE: To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes. DESIGN: Retrospective study. SUBJECTS AND MEASUREMENTS: Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing. RESULTS: Mutation frequencies were as follows: KCNJ5, 37·1%; CACNA1D, 10·3%; ATP1A1, 8·2%; ATP2B3, 3·1%; and CTNNB1, 2·1%. Previously unidentified mutations included I157K, F154C and two insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0·007). On computed tomography, KCNJ5-mutant tumours displayed significantly greater diameter (P = 0·023), calculated area (P = 0·002) and lower precontrast Hounsfield units (P = 0·0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 × 10(-6) vs non-KCNJ5 mutant and P = 0·0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. CONCLUSIONS: KCNJ5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations.

Graduating general surgery resident operative confidence: perspective from a national survey.

BACKGROUND: General surgical training has changed significantly over the last decade with work hour restrictions, increasing subspecialization, the expanding use of minimally invasive techniques, and nonoperative management for solid organ trauma. Given these changes, this study was undertaken to assess the confidence of graduating general surgery residents in performing open surgical operations and to determine factors associated with increased confidence. METHODS: A survey was developed and sent to general surgery residents nationally. We queried them regarding demographics and program characteristics, asked them to rate their confidence (rated 1-5 on a Likert scale) in performing open surgical procedures and compared those who indicated confidence with those who did not. RESULTS: We received 653 responses from the fifth year (postgraduate year 5) surgical residents: 69% male, 68% from university programs, and 51% from programs affiliated with a Veterans Affairs hospital; 22% from small programs, 34% from medium programs, and 44% from large programs. Anticipated postresidency operative confidence was 72%. More than 25% of residents reported a lack of confidence in performing eight of the 13 operations they were queried about. Training at a university program, a large program, dedicated research years, future fellowship plans, and training at a program that performed a large percentage of operations laparoscopically was associated with decreased confidence in performing a number of open surgical procedures. Increased surgical volume was associated with increased operative confidence. Confidence in performing open surgery also varied regionally. CONCLUSIONS: Graduating surgical residents indicated a significant lack of confidence in performing a variety of open surgical procedures. This decreased confidence was associated with age, operative volume as well as type, and location of training program. Analyzing and addressing this confidence deficit merits further study.

Hepatocellular carcinoma: a comprehensive overview of surgical therapy.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a rising incidence in the United States. The increase in medical and locally ablative therapies have improved prognosis, however surgery, either liver resection or transplantation, remains the mainstay of therapy. An increased understanding of liver anatomy, improved imaging modalities and refinements of surgical technique have all led to improved outcomes after surgery. Both resection and transplantation may be used in a complementary manner. Resection remains the treatment of choice for HCC when feasible. Liver transplantation, which removes both the tumor and the underlying diseased liver offers excellent outcomes in patients that meet the Milan criteria. While both these modalities have relatively well defined roles, the treatment of these patients must be tailored individually, using a multidisciplinary approach, to maximize survival, quality of life and allocation of scarce organs.

Pediatric thymomas: report of two cases and comprehensive review of the literature.

PURPOSE: Thymomas are rare pediatric malignancies with indolent behavior. There are fewer than 50 reported cases and no comprehensive review. We sought to evaluate our recent experience with pediatric thymomas, and comprehensively review the extant literature. METHODS: A systematic search of the PubMed database was performed using keywords: "thymoma", "pediatric", "juvenile", "childhood", and "child". Additional studies were identified by a manual search of the reference list. RESULTS: We report two patients with thymomas. We identified 22 case reports or series that described 48 patients; 62 % were male, 15 % presented with myasthenia gravis. Fifty percent were Masaoka Stage I, 15 % were Stage II, 13 % were Stage III, and 23 % were Stage IV. Four patients with early stage (I or II) disease were treated with adjuvant therapies in addition to surgical excision, while five patients with late stage (III or IV) disease treated with surgical excision alone. Of studies reporting at least 2-year follow-up, survival was 71 %. CONCLUSION: Pediatric thymomas are rare tumors with a slight male predominance. Wide variations were observed in the treatment of thymomas across all stages. Our review indicates a need for large database and multi-institutional studies to clearly elucidate clinical course, prognostic factors and outcome.

Evaluation of a recently described risk classification scheme for pancreatic fistulae development after pancreaticoduodenectomy without routine post-operative drainage.

BACKGROUND: Post-operative pancreatic fistula (POPF) formation occurs frequently after a pancreaticoduodenectomy (PD). Recently, a 10-point Fistula Risk Score (FRS) evaluating the likelihood of clinically relevant POPF (CR-POPF) development has been described and validated. This scheme has yet to be evaluated in PD patients managed without intra-operative drain placement. METHODS: Among patients undergoing PD at an academic centre since 2003, a retrospective analysis calculating FRS and its correlation with CR-POPF development was evaluated by logistic regression. Secondary analysis examined presentation and management of CR-POPF in undrained PD patients. RESULTS: FRS was calculated for 265 patients; 97.7% were managed without operative drains. The overall incidence of CR-POPF was 7.9%. Logistic regression revealed a 1.6-fold increase in CR-POPF risk per 1-point increase in FRS [95% confidence interval (CI) 1.2-2.0]. The negative predictive value in patients with FRS <3 was 100%, whereas the positive predictive value of FRS >6 was 16.7%. The median time to CR-POPF diagnosis was 18 days [interquartile range (IQR) 13-23]; 70.0% required readmission and 10.0% required a laparotomy. CONCLUSIONS: Among patients without operative drainage, CR-POPF often has delayed presentations but most are managed non-operatively. The predictive value of high-risk FRS appears limited; conversely, a low-risk FRS accurately predicts the absence of CR-POPF and seems an appropriate metric for guiding care.

Time Kills: Impact of Socioeconomic Deprivation on Timely Access to Guideline-Concordant Treatment in Foregut Cancer.

BACKGROUND: Receipt of guideline-concordant treatment (GCT) is associated with improved prognosis in foregut cancers. Studies show that patients living in areas of high neighborhood deprivation have worse healthcare outcomes; however, its effect on GCT in foregut cancers has not been evaluated. We studied the impact of the area deprivation index (ADI) as a barrier to GCT. STUDY DESIGN: A single-institution retrospective review of 498 foregut cancer patients (gastric, pancreatic, and hepatobiliary adenocarcinoma) from 2018 to 2022 was performed. GCT was defined based on National Comprehensive Cancer Network guidelines. ADI, a validated measure of neighborhood disadvantage was divided into terciles (low, medium, and high) with high ADI indicating the most disadvantage. RESULTS: Of 498 patients, 328 (66%) received GCT: 66%, 72%, and 59% in pancreatic, gastric, and hepatobiliary cancers, respectively. Median (interquartile range) time from symptoms to workup was 6 (3 to 13) weeks, from diagnosis to oncology appointment was 4 (1 to 10) weeks, and from oncology appointment to treatment was 4 (2 to 10) weeks. Forty-six percent were diagnosed in the emergency department. On multivariable analyses, age 75 years or older (odds ratio [OR] 0.39 [95% CI 0.18 to 0.87]), Black race (OR 0.52 [95% CI 0.31 to 0.86]), high ADI (OR 0.25 (95% CI 0.14 to 0.48]), 6 weeks or more from symptoms to workup (OR 0.44 [95% CI 0.27 to 0.73]), 4 weeks or more from diagnosis to oncology appointment (OR 0.76 [95% CI 0.46 to 0.93]), and 4 weeks or more from oncology appointment to treatment (OR 0.63 [95% CI 0.36 to 0.98]) were independently associated with nonreceipt of GCT. CONCLUSIONS: Residence in an area of high deprivation predicts nonreceipt of GCT. This is due to multiple individual- and system-level barriers. Identifying these barriers and developing effective interventions, including community outreach and collaboration, leveraging telehealth, and increasing oncologic expertise in underserved areas, may improve access to GCT.

Epigenetic silencing of RASSF1A deregulates cytoskeleton and promotes malignant behavior of adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with high mutational heterogeneity and a generally poor clinical outcome. Despite implicated roles of deregulated TP53, IGF-2 and Wnt signaling pathways, a clear genetic association or unique mutational link to the disease is still missing. Recent studies suggest a crucial role for epigenetic modifications in the genesis and/or progression of ACC. This study specifically evaluates the potential role of epigenetic silencing of RASSF1A, the most commonly silenced tumor suppressor gene, in adrenocortical malignancy. RESULTS: Using adrenocortical tumor and normal tissue specimens, we show a significant reduction in expression of RASSF1A mRNA and protein in ACC. Methylation-sensitive and -dependent restriction enzyme based PCR assays revealed significant DNA hypermethylation of the RASSF1A promoter, suggesting an epigenetic mechanism for RASSF1A silencing in ACC. Conversely, the RASSF1A promoter methylation profile in benign adrenocortical adenomas (ACAs) was found to be very similar to that found in normal adrenal cortex. Enforced expression of ectopic RASSF1A in the SW-13 ACC cell line reduced the overall malignant behavior of the cells, which included impairment of invasion through the basement membrane, cell motility, and solitary cell survival and growth. On the other hand, expression of RASSF1A/A133S, a loss-of-function mutant form of RASSF1A, failed to elicit similar malignancy-suppressing responses in ACC cells. Moreover, association of RASSF1A with the cytoskeleton in RASSF1A-expressing ACC cells and normal adrenal cortex suggests a role for RASSF1A in modulating microtubule dynamics in the adrenal cortex, and thereby potentially blocking malignant progression. CONCLUSIONS: Downregulation of RASSF1A via promoter hypermethylation may play a role in the malignant progression of adrenocortical carcinoma possibly by abrogating differentiation-promoting RASSF1A- microtubule interactions.

Omental vein catheter thrombolysis for acute porto-mesenteric vein thrombosis.

Mesenteric venous thrombosis (MVT) is an uncommon clinical condition with potential high morbidity. We report here a patient who presented with acute-onset MVT and bowel infarction, which was successfully ameliorated with intramesenteric vein thrombolytic therapy.

Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors.

The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.

Association between Rural Residence and Processes of Care in Pancreatic Cancer Treatment.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is an aggressive malignancy associated with poor outcomes. Surgical resection and receipt of multimodal therapy have been shown to improve outcomes in patients with potentially resectable PDAC; however treatment and outcome disparities persist on many fronts. The aim of this study was to analyze the relationship between rural residence and receipt of quality cancer care in patients diagnosed with non-metastatic PDAC. METHODS: Using the National Cancer Database, patients with non-metastatic pancreatic cancer were identified from 2006-2016. Patients were classified as living in metropolitan, urban, or rural areas. Multivariable logistic regression was used to identify predictors of cancer treatment and survival. RESULTS: A total of 41,786 patients were identified: 81.6% metropolitan, 16.2% urban, and 2.2% rural. Rural residing patients were less likely to receive curative-intent surgery (p = 0.037) and multimodal therapy (p < 0.001) compared to their metropolitan and urban counterparts. On logistic regression analysis, rural residence was independently associated with decreased surgical resection [OR 0.82; CI 95% 0.69-0.99; p = 0.039] and multimodal therapy [OR 0.70; CI 95% 0.38-0.97; p = 0.047]. Rural residence independently predicted decreased overall survival [OR 1.64; CI 95% 1.45-1.93; p < 0.001] for all patients that were analyzed. In the cohort of patients who underwent surgical resection, rural residence did not independently predict overall survival [OR 0.97; CI 95% 0.85-1.11; p = 0.652]. CONCLUSIONS: Rural residence impacts receipt of optimal cancer care in patients with non-metastatic PDAC but does not predict overall survival in patients who receive curative-intent treatment.