Breast Cancer Awareness and Screening Perceptions of Women in Yerevan, Armenia.

Objectives: Breast cancer is the leading cause of female cancer mortality in Armenia. The government is considering covering breast cancer screening, but prevailing attitudes towards it are unknown. This cross-sectional study assessed Armenian women's awareness and perceptions of breast cancer screening. Methods: We administered a validated telephone survey to women ages 35-65 registered in Yerevan's polyclinic system between 2019-2021, assessing sociodemographic characteristics, breast cancer exposure and screening attitudes, using an adapted Champion's Health Belief Model Scale (CHBMS). We analyzed the association, unadjusted and adjusted, between sociodemographic characteristics, screening exposure, and CHBMS scores. Results: 170 women completed surveys. Most (82.9%) were aware of screening, 48.5% knew someone with breast cancer, but only 42.5% had undergone screening, predominantly without their physician's recommendation (63.2%). Despite elevated awareness, 76.2% had never discussed screening with their provider. Barriers included cost and mistreatment concerns. Education consistently predicted prior screening and most CHBMS scores. Conclusion: Armenian women are highly exposed to breast cancer, but knowledge and prior screening primarily emanate from non-physician sources. Results highlighted the influence of education, patient-provider relationships, and healthcare costs, underscoring the importance of multi-level interventions.

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Validation of an Eastern Armenian breast cancer health belief survey.

With the fourth highest breast cancer mortality rate in the world, breast cancer prevention and early detection is a priority for Armenia. The Ministry of Health recently initiated efforts to expand access to breast cancer screening. However, little is known about the population's understanding and perception of breast cancer screening programs. This cross-sectional telephone-based study sought to develop and validate an Eastern Armenian language version of the Champion's Health Belief Model Scale (CHBMS) for future use. The English-language CHBMS survey was first rigorously translated by two Armenian nationals and evaluated for face validity. Telephone surveys were then administered to randomly-selected women of approximately screening age (35-65 years) with no prior history of breast cancer living in Armenia's capital between 2019-2020 (n = 103). The translated survey's psychometric properties were evaluated, examining (1) content equivalence, (2) test-retest reliability and (3) internal consistency. Content equivalence and test-retest reliability of the Armenian CHBMS were characterized using correlational analysis with Pearson's coefficient ranging from 0.76-0.97 (p<0.001) and 0.72-0.97 (p<0.001), respectively, for all five CHBMS domains. The translated survey's internal consistency was comparable to the original English-language CHBMS with a Cronbach's alpha greater than 0.7 for all five domains (0.75-0.94 (p<0.001). The translated Eastern Armenian version of CHBMS is a valid, internally-consistent, and reliable research tool that is ready for imminent use among screening-age women to investigate breast cancer perceptions and beliefs as the Armenian government seeks to expand screening access.

Higher Numbers of Examined Lymph Nodes Are Associated with Increased Survival in Resected, Treatment-Naïve, Node-Positive Esophageal, Gastric, Pancreatic, and Colon Cancers.

BACKGROUND OR PURPOSE: The role of extended lymphadenectomy as part of resection for lymph node (LN)-positive gastrointestinal (GI) malignancies remains controversial with no clear clinical guidance. The purpose of this retrospective study is to determine whether the number of LNs examined as part of GI malignancy resections affects overall survival (OS) among patients with node-positive esophageal, gastric, pancreatic, and colon cancers. METHODS: Participants with LN-positive GI cancers who were diagnosed between 2004 and 2015 and underwent oncologic resections were selected from National Cancer Database (NCDB). The primary predictor was the number of examined LNs categorized in tertiles. The effect on OS was measured by hazard ratio (HR) derived from multivariate Cox regression analyses. RESULTS: From 2004 to 2015, 1877, 10,086, 18,193, and 102,500 patients with LN-positive esophageal, gastric, pancreatic, and colon adenocarcinomas who did not receive neoadjuvant treatment and underwent oncologic tumor resection were registered in the NCDB. Using multivariate Cox proportional hazard modeling, greater LNs examined in surgically resected LN-positive GI cancers were found to be associated with increased OS for all histologies. This association was the strongest (as compared to the lowest tertile) for gastric cancer (middle tertile: HR = 0.91, 95% CI, 0.86-0.96, p = 0.001; highest tertile: HR = 0.73, 95% CI, 0.69-0.78, p < 0.001), followed by colon (highest tertile: HR = 0.86, 95% CI, 0.84-0.88, p < 0.001), esophageal (highest tertile: HR = 0.83, 95% CI, 0.72-0.95, p = 0.01), and pancreatic (highest tertile: HR = 0.93, 95% CI, 0.89-0.98, p = 0.002) cancers. DISCUSSION AND CONCLUSION: In patients with surgically resected node-positive GI malignancies who did not receive neoadjuvant systemic therapy, a higher number of examined LNs is associated with increased OS. This association is the strongest for gastric cancer, followed by colon, esophageal, and pancreatic cancers respectively.

STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

Postoperative Physician Phone Calls as a Method to Decrease Urgent Care and Emergency Department Returns After Ambulatory General Surgery.

Unplanned returns after ambulatory surgery pose a burden to patients and health care providers alike. We hypothesized that a postoperative phone call by a physician would decrease avoidable returns to urgent care (UC) or the emergency department (ED) in the week after anorectal (AR), laparoscopic cholecystectomy (LC), inguinal hernia repair (IHR), and umbilical hernia repair (UHR) operations. A retrospective analysis from 1/2011 to 12/2015 across 14 Kaiser hospitals was conducted to determine baseline UC/ED return rates of patients pre-call. Between 10/2017 and 06/2019, physicians placed phone calls to patients within postoperative days (PODs) 1-4. The cohorts were compared using chi-squared analysis with significance determined at P < .05. In total, 276 patients received a call, with the majority placed on PODs 1-3. There were no statistically significant differences in return rates between the pre- and post-call groups. All of the AR, 50.0% of LC, 66.7% of IHR, and 50.0% of UHR patients returned prior to phone call placement. Our data indicate that a physician phone call does not help in decreasing UC/ED returns. However, it is noteworthy that many of the returns occurred pre-call placement. Future directions should be aimed at placing earlier postoperative phone calls.

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

Pasireotide does not prevent postoperative pancreatic fistula: a prospective study.

BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.

Conserved role for Gga proteins in phosphatidylinositol 4-kinase localization to the trans-Golgi network.

Phosphoinositides serve as key membrane determinants for assembly of clathrin coat proteins that drive formation of clathrin-coated vesicles. At the trans-Golgi network (TGN), phosphatidylinositol 4-phosphate (PtdIns4P) plays important roles in recruitment of two major clathrin adaptors, Gga (Golgi-localized, gamma-adaptin ear homology, Arf-binding) proteins and the AP-1 (assembly protein-1) complex. The molecular mechanisms that mediate localization of phosphatidylinositol kinases responsible for synthesis of PtdIns4P at the TGN are not well characterized. We identify two motifs in the yeast phosphatidylinositol 4-kinase, Pik1, which are required for binding to the VHS domain of Gga2. Mutations in these motifs that inhibit Gga2-VHS binding resulted in reduced Pik1 localization and delayed accumulation of PtdIns4P and recruitment of AP-1 to the TGN. The Pik1 homolog in mammals, PI4KIIIß, interacted preferentially with the VHS domain of GGA2 compared with VHS domains of GGA1 and GGA3. Depletion of GGA2, but not GGA1 or GGA3, specifically affected PI4KIIIß localization. These results reveal a conserved role for Gga proteins in regulating phosphatidylinositol 4-kinase function at the TGN.

Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.

Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.