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.

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.

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.

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.

Resection Versus Observation for Small (≤2 cm) Pancreatic Neuroendocrine Tumors.

BACKGROUND: We hypothesized that those patients with pancreatic neuroendocrine tumors (pNETs) ≤2 cm managed nonoperatively would have comparable disease progression to individuals undergoing an operation. METHODS: Patients diagnosed with nonfunctional pNETs ≤ 2 cm who were evaluated at a single comprehensive cancer center from 2010 to 2017 were selected from a cancer registry database. Clinicopathologic variables were obtained via retrospective chart review. Primary outcomes were overall and disease specific survival. Variables were compared between the 2 groups using chi-square and independent t-test. RESULTS: Fifty-two individuals had tumors ≤2 cm, of whom 75% had an operation, while 25% were observed. Each treatment arm had similar distributions of gender, race, and tumor location. The most common operation was distal pancreatectomy (n = 29) followed by pancreatoduodenectomy (n = 6). Nine patients had grade III postoperative complications and 4 had grade IV under Clavien-Dindo classification. The observation group was noted to have a mean disease progression interval of 80.9 months, while those who underwent an operation had a mean disease progression interval of 94.6 months (P = .246). CONCLUSIONS: Overall disease progression in patients with pNETs ≤ 2 cm without evidence of metastasis at the time of presentation is not different between those who underwent operation compared to those observed.

Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma.

There is a complete lack of highly sensitive and specific biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis, limiting multi-modal therapeutic options. Mitochondrial DNA (mtDNA) is an excellent resource for biomarker discovery because of its high copy number and increased mutational frequency in cancer cells. We examined if mtDNA mutations can be detected in circulating extracellular vesicles (EVs) of PDAC patients and used for discerning between cancer and non-cancer subjects. A greater yield of circulating EVs (~ 1.4 fold; p = 0.002) was obtained in PDAC patients (n = 20) than non-cancer (NC) individuals (n = 10). PDAC-EVs contained a higher quantity of total DNA (~ 5.5 folds; p = 0.0001) than NC-EVs and had greater enrichment of mtDNA (~ 14.02-fold; p = 0.0001). PDAC-EVs also had higher levels of cardiolipin (a mitochondrial inner-membrane phospholipid), suggestive of their mitochondrial origin. All mtDNA mutations in PDAC-EVs were unique and frequency was remarkably higher. Most mtDNA mutations (41.5%) in PDAC-EVs were in the respiratory complex-I (RCI) (ND1-ND6), followed by the RCIII gene (CYTB; 11.2%). Among the non-coding genes, D-Loop and RNR2 exhibited the most mutations (15.2% each). Altogether, our study establishes, for the first time, that mtDNA mutations can be detected in circulating EVs and potentially serve as a tool for reliable PDAC diagnosis.

Developing 3D Organoid Raft Cultures from Patient-Derived Xenografts as Rapid Models to Screen Efficacy of Experimental Therapeutics.

Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed "organoid raft cultures" (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological structure. The ORCs were developed from patient-derived xenografts (PDXs) of colon cancers excised from immune-deficient mice (NOD/SCID/IL2Rgammanull). We utilized these new models to evaluate the efficacy of an investigational drug, Navitoclax (ABT-263). We tested the efficacy of ABT-263, an inhibitor of BCL-2 family proteins, in these ORCs derived from a PDX that showed high expression of antiapoptotic BCL2 family proteins (BCL-2, BCL-XL, and BCL-W). Hematoxylin and eosin staining evaluation of PDXs and corresponding ORCs indicated the retention of morphological and other histological integrity of ORCs. ORCs treated with ABT-263 showed decreased expression of antiapoptotic proteins (BCL2, BCL-XL and BCL-W) and increased proapoptotic proteins (BAX and PUMA), with concomitant activation of caspase 3. These studies support the usefulness of the ORCs, developed from PDXs, as an alternative to PDXs and as faster screening models.

Fragmentation of Care in Pancreatic Cancer: Effects on Receipt of Care and Survival.

BACKGROUND: The impact of fragmentation of care (FC), i.e., receipt of care at > 1 institution, on treatment of pancreatic cancer is unknown. The purpose of this study was to determine factors associated with FC in curative-intent treatment of pancreatic cancer (PDAC) patients and evaluate how FC affects survival outcomes. METHODS: Using the National Cancer Database (NCDB), data on stage I-III PDAC patients diagnosed 2006-2016 were extracted. Multiple logistic regression analyses were performed to identify factors predictive of FC and survival. RESULTS: Of the 20,013 patients identified, 24.1% had FC. Factors predictive of FC were stage-III tumors (odds ratio [OR] 1.36; p = 0.014), higher median-income [third quartile (OR 1.38; p = 0.006) and highest-quartile (OR 1.50; p = 0.003)], care at high-volume facility (OR 1.47; p < 0.001), and receipt of multi-modal therapy (OR 1.69; p < 0.001). In contrast, age > 80 years (OR 0.82; p = 0.018), Black (OR 0.85; p = 0.013) or Asian race (OR 0.76; p = 0.033), Charlson comorbidity-index 2 (OR 0.85; p = 0.033), treatment at non-academic facility (OR 0.87; p = 0.041), and non-private insurance were negatively predictive of FC. FC independently predicted decreased 30-day [OR 0.57; p < 0.001] and 90-day mortality [OR 0.61; p < 0.001] and improved overall survival [hazard ratio 0.91; p < 0.001]. DISCUSSION: Sociodemographic factors are significantly associated with FC in curative-intent treatment of PDAC patients. FC was found to predict improved 30-day, 90-day, and overall survival outcomes.

Diet as a Risk Factor for Early-Onset Colorectal Adenoma and Carcinoma: A Systematic Review.

Background: Colorectal cancer in adults 50 years old and younger is increasing in incidence worldwide. Diet may be a modifiable risk factor. The objective of this study was to examine evidence regarding the association between diet and the risk of developing early-onset colorectal cancer (EOCRC) and early-onset colorectal adenomas in young adults. Methods: PUBMED, Web of Science, and Embase were systematically searched for studies examining dietary intake as a risk factor for EOCRC and early-onset colorectal adenomas. Results were synthesized narratively due to the heterogeneity of the studies. Results: Of the 415 studies identified, ten met the inclusion criteria. Of these ten studies, four provided data on dietary risk factors for early-onset colorectal adenomas and six provided data on dietary risk factors for EOCRC. The four studies that measured colorectal adenoma occurrence reported an increased incidence with high sugar sweetened beverage intake, a higher pro-inflammatory diet, a higher Western diet score and higher sulfur microbial diet score. A protective effect against early-onset colorectal adenomas was observed in those who had a higher Prudent diet score or higher adherence to other health dietary approaches (Dietary Approaches to Stop Hypertension, Alternative Healthy Eating Index-2010, or the alternative Mediterranean diet). Those who consumed large amounts of deep-fried foods, refined foods, followed a high fat diet, consumed large amounts of sugary drinks and desserts, and had low folate and fiber consumption had a significantly higher occurrence of EOCRC. A protective effect against EOCRC was observed for those who consumed more fruits and vegetables, high amounts of micronutrients and those who adhered to a vegetarian diet. Conclusions: The results of this study reveal various dietary habits may be risk factors or protective against early-onset colorectal cancer and adenomas. Future research should focus on large prospective cohort studies with long-term follow-up to confirm published results and further examine whether differences in diet quality are associated with EOCRC risk.

Engineered colorectal cancer tissue recapitulates key attributes of a patient-derived xenograft tumor line.

The development of physiologically relevantin vitrocolorectal cancer (CRC) models is vital for advancing understanding of tumor biology. Although CRC patient-derived xenografts (PDXs) recapitulate key patient tumor characteristics and demonstrate high concordance with clinical outcomes, the use of thisin vivomodel is costly and low-throughput. Here we report the establishment and in-depth characterization of anin vitrotissue-engineered CRC model using PDX cells. To form the 3D engineered CRC-PDX (3D-eCRC-PDX) tissues, CRC PDX tumors were expandedin vivo, dissociated, and the isolated cells encapsulated within PEG-fibrinogen hydrogels. Following PEG-fibrinogen encapsulation, cells remain viable and proliferate within 3D-eCRC-PDX tissues. Tumor cell subpopulations, including human cancer and mouse stromal cells, are maintained in long-term culture (29 days); cellular subpopulations increase ratiometrically over time. The 3D-eCRC-PDX tissues mimic the mechanical stiffness of originating tumors. Extracellular matrix protein production by cells in the 3D-eCRC-PDX tissues resulted in approximately 57% of proteins observed in the CRC-PDX tumors also being present in the 3D-eCRC-PDX tissues on day 22. Furthermore, we show congruence in enriched gene ontology molecular functions and Hallmark gene sets in 3D-eCRC-PDX tissues and CRC-PDX tumors compared to normal colon tissue, while prognostic Kaplan-Meier plots for overall and relapse free survival did not reveal significant differences between CRC-PDX tumors and 3D-eCRC-PDX tissues. Our results demonstrate high batch-to-batch consistency and strong correlation between ourin vitrotissue-engineered PDX-CRC model and the originatingin vivoPDX tumors, providing a foundation for future studies of disease progression and tumorigenic mechanisms.

Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis.

Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity-a worldwide public health concern-is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas-Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.

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.