Prospective Evaluation of Circulating Tumor DNA using Next Generation Sequencing as a Biomarker during Neoadjuvant Chemotherapy in Localized Pancreatic Cancer.

OBJECTIVE: In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation-sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Circulating tumor DNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear. METHODS: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor agnostic NGS utilizing the Tempus x|F 105 gene panel at three timepoints: pre-therapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9, and the prognostic significance of ctDNA detection were analyzed. RESULTS: 56 patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs. 30.0, P=0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0 U/mL vs. 31.5 U/mL; P=0.01), while those with ctDNA present at diagnosis did not (198.1 U/mL vs. 113.8 U/mL; P=0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free-survival. CONCLUSION: This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.

The Racial Divide: A Follow Up Study on Racial Disparity Amongst COVID-19 Survivors in an Urban Community.

Background: Studies have shown that COVID-19 has had a disproportionate effect on minority groups in both the clinical and social settings in America. We conducted a follow up study on patients previously diagnosed with COVID-19 one year ago in an urban community in New Jersey. The purpose of the study was to evaluate the socioeconomic impact of COVID-19 as well as assess for receptiveness towards COVID-19 vaccination amongst various ethnic groups. Methods: This was a prospective cohort study consisting of patients who had recovered from COVID-19 one year prior. The patients included in the study had a confirmed COVID-19 diagnosis in the months of March and April of 2020. This was a single institutional study conducted at St. Joseph's University Medical Center in Paterson, NJ from the months of March to April of 2021. Patients included in the study were either male or female aged 18 years or older. Patients who met criteria for inclusion were contacted by telephone to participate in a telephone survey. After informed consent was obtained, the patients completed a survey which obtained sociodemographic information pertaining to their diagnosis with COVID-19. Statistical analysis was performed using chi-square testing and multivariable logistic regression analysis. Results: Of the 170 patients enrolled in the study, the most common ethnicity was Hispanic (79/170 [46.47%]), followed by African American (46/170 [27.05%]). The gender distribution was 83 male (83/170 [48.82%]) and 87 female (87/170 [51.18%]) with a mean age of 51.5. Caucasians were the most willing to receive a COVID-19 vaccine (28/30 [93.3%]), followed by Asians (13/14 [92.8%]), Hispanics (63/78 [80.7%]) and African Americans (29/46 [63.0%]). Hispanics had the highest rate of job loss (31/79 [39.24%]), followed by of African Americans (16/46 [34.7%]). Hispanics were found to be in the most financial distress (31/79 [39.2%]), followed by African Americans (17/46 [36.9%]). Chi square analysis revealed Hispanics and African Americans were more likely to lose their jobs after being diagnosed with COVID-19 (p: 0.04). Hispanics and African Americans were also more likely to refuse vaccination with any of the available COVID-19 vaccines (p: 0.02). Multivariable Logistic regression analysis was then performed comparing both Hispanics and African Americans to Caucasians. Hispanics were more likely to lose their jobs compared to Caucasians (odds ratio, 4.456; 95% CI, 1.387 to 14.312; p: 0.0121). African Americans were also more likely to lose their jobs when compared to Caucasians (odds ratio, 4.465; 95% CI, 1.266 to 15.747; p: 0.0200). Discussion: Overall Hispanics reported the highest rates of financial distress after their diagnosis with COVID-19. Nearly 40% of the Hispanic lost their jobs following their diagnosis with COVID-19 which was the highest in our study group. African Americans were similarly affected with about 37% of all patients experiencing job loss and financial distress following diagnosis with COVID-19. Hispanics and african americans were the two ethnic groups who were least willing to receive COVID-19 vaccination. Only 63% of African Americans were willing to receive the vaccine, with 80.7% of Hispanics willing to become vaccinated. The most common reason for not receiving any of the COVID-19 vaccines was due to lack of trust in the vaccine. Both Hispanics and African Americans were more statistically likely to lose their jobs as well as refuse COVID-19 vaccination following diagnosis with COVID-19.

Acute Pancreatitis-Induced Euglycemic Diabetic Ketoacidosis.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications utilized for the treatment of diabetes mellitus by mechanisms promoting incretin release and insulin production. Although poorly understood, cases of acute pancreatitis have been observed in patients taking GLP-1 RAs. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are another class of diabetic medications inhibiting renal glucose reabsorption which have been associated with rare cases of euglycemic ketoacidosis. Acute pancreatitis itself has been an observable cause of diabetic ketoacidosis, although typically in a hyperglycemia state. In this case report, we present a patient on SGLT-2is and GLP-1 RAs who developed acute pancreatitis, which may have precipitated euglycemic diabetic ketoacidosis (eu-DKA).

Encapsulating peritoneal sclerosis in liver transplant.

Encapsulating peritoneal sclerosis occurs due to chronic irritation of the peritoneal surface resulting in inflammation and fibrosis. Encapsulating peritoneal sclerosis usually occurs in patients requiring peritoneal dialysis (PD); however, it may also occur in liver transplant patients. The fibrosis in encapsulating peritoneal sclerosis could be severe enough to cause small bowel obstruction (SBO). Herein, we report a case of encapsulating peritoneal sclerosis secondary to liver transplantation that presented with SBO. The patient was started on Tamoxifen for encapsulating peritoneal sclerosis and evaluated at follow-up without any other intestinal obstruction episodes. This case demonstrates that encapsulating peritoneal sclerosis can occur as a liver transplant complication and present with small bowel obstruction.

Encapsulating peritoneal sclerosis in liver transplant

Encapsulating peritoneal sclerosis occurs due to chronic irritation of the peritoneal surface resulting in inflammation and fibrosis. Encapsulating peritoneal sclerosis usually occurs in patients requiring peritoneal dialysis (PD); however, it may also occur in liver transplant patients. The fibrosis in encapsulating peritoneal sclerosis could be severe enough to cause small bowel obstruction (SBO). Herein, we report a case of encapsulating peritoneal sclerosis secondary to liver transplantation that presented with SBO. The patient was started on Tamoxifen for encapsulating peritoneal sclerosis and evaluated at follow-up without any other intestinal obstruction episodes. This case demonstrates that encapsulating peritoneal sclerosis can occur as a liver transplant complication and present with small bowel obstruction.

Novel cell-specific and dominant negative anti-apoptotic roles of p73 in transformed leukemia cells.

Although extensive homology exists between related genes p53 and p73, recent data suggest that the family members have divergent roles. We demonstrate that the differential regulatory roles of p53 family member p73 are highly cell-context and promoter-specific. Full-length p73 expressed in the transformed leukemia cell line Jurkat behaves as a specific dominant negative transcriptional repressor of the cell cycle inhibitor gene p21 and blocks p53-mediated apoptosis. These findings provide evidence for a new mechanism in oncogenesis through which the functional properties of p73 can be altered in an inheritable and cell-specific fashion independent of transcriptional coding.

Cross-regulation of T cell growth factor expression by p53 and the Tax oncogene.

In this study, we demonstrate that p53 directly inhibits expression of the T cell growth factor (IL-2) in activated T cells. This repression is independent of the intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this repression through coordinate targeting of p300, CREB, and the NF-kappaB pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead, mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and resistant to Tax reversal. The p300 structure-function studies show that these effects are linked to competitive associations among p53, Tax, and mdm2 with multiple domains of p300. The functional outcome of these antagonistic associations is revealed further by the observation that Tax and p53 induce apoptosis in activated T cells through separate and mutually exclusive pathways. Interestingly, both pathways are abrogated by mdm2. These results provide evidence that a dynamic interplay, between Tax and specific elements of the p53 network, mediates growth factor expression and programmed cell death in activated T cells.