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Background: Many veterans have dual Veterans Administration (VA) and Medicare healthcare coverage. We compared 3-year overall and cancer event-free survival (EFS) among patients with nonmetastatic colon cancer who obtained substantial portions of their care in both systems and those whose care was obtained predominantly in the VA or in the Medicare fee-for-service system.Methods: We conducted a retrospective observational cohort study of patients older than 65 years with stages I to III colon cancer diagnosed from 1999 to 2001 in VA and non-VA facilities. Dual use of VA and non-VA colon cancer care was categorized as predominantly VA use, dual use, or predominantly non-VA use. Extended Cox regression models evaluated associations between survival and dual use.Results: VA and non-VA users (all stages) had reduced hazard of dying compared with dual users [e.g., for stage I, VA HR 0.40, 95% confidence interval (CI): 0.28–0.56; non-VA HR 0.54, 95% CI: 0.38–0.78). For EFS, stage I findings were similar (VA HR 0.47, 95% CI: 0.35–0.62; non-VA HR 0.64, 95% CI: 0.47–0.86). Stage II and III VA users, but not non-VA users, had improved EFS (stage II: VA HR 0.74, 95% CI: 0.56–0.97; non-VA HR 0.92, 95% CI: 0.69–1.22; stage III: VA HR 0.73, 95% CI: 0.56–0.94; non-VA HR 0.81, 95% CI: 0.62–1.06).Conclusions: Improved survival among VA and non-VA compared with dual users raises questions about coordination of care and unmet needs.Impact: Additional study is needed to understand why these differences exist, why patients use both systems, and how systems may be improved to yield better outcomes in this population. Cancer Epidemiol Biomarkers Prev; 21(12); 2231–41. ©2012 AACR.

PDF file - 51K, Administrative codes used to define comorbidities, colon cancer treatment, and colon events

All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of genes encoding high-affinity leucine transporters and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. Elevated expression of KDM3B targets is associated with reduced survival in a subset of human cancers and ID represses mTORC1 in patient-derived tumor cells and sensitizes cancer cells to chemotherapy. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

Introduction: The utility of circulating tumor DNA (ctDNA) as a biomarker in localized pancreatic ductal adenocarcinoma (PDAC) remains unclear. We aimed to characterize the detection of ctDNA by targeted next-generation sequencing (NGS) during treatment for localized PDAC and to evaluate the clinical implication of detection. Methods: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine Cancer Centers between September 2020 and May 2022. During treatment, blood was drawn for targeted NGS ctDNA assessment utilizing the Tempus xF 105 gene panel assay. Three timepoints during the course of treatment were evaluated: at diagnosis prior to treatment, after neoadjuvant chemotherapy (NAC), and after local therapy, which included surgery with or without radiotherapy, or radiotherapy alone. The effect of NAC and local therapy on ctDNA mutational status and its relationship with serum CA19-9 was analyzed. Results: 32 patients who underwent NAC were included in the analysis. 66% of patients received FOLFIRINOX and 34% received Gemcitabine/nab-paclitaxel. The mean length of NAC was 3.1 months. TP53 mutations were the most common mutation detected by targeted NGS (41%), followed by KRAS (G12D/V/R, 13%) and ATM mutations (13%). In 24 patients assessed prior to treatment, 10 (42%) were found to have detectable ctDNA. 11 of 32 (34%) patients had detectable ctDNA following completion of NAC. 22 patients underwent surgery, of which 6 (27%) had detectable ctDNA following NAC and surgery. Of the 10 patients who had detectable ctDNA prior to treatment, 4 (40%) cleared ctDNA after treatment. Patients with detectable ctDNA prior to treatment had higher CA19-9 levels following NAC compared with those with undetectable ctDNA prior to treatment (1244.83 U/ml vs 60.42 U/ml, p = 0.0299). Following NAC, patients with detectable ctDNA had higher CA19-9 levels than those with undetectable ctDNA after NAC (1121.05 U/ml vs 58.89 U/ml, p = 0.0231). 6 of 32 (19%) patients were found to have unresectable disease following NAC and underwent definitive radiotherapy for local control; none of these patients had ctDNA clearance. Conclusion: This is the first reported study demonstrating the value of targeted NGS as a biomarker in the treatment of localized pancreatic cancer. Treatment led to clearance of detectable ctDNA, although the effect was not seen in all patients. Patients with detectable ctDNA prior to treatment had higher levels of CA19-9 following NAC, suggesting that pre-therapy detection may be a predictor of poor serum CA19-9 response after NAC. Given that after NAC, patients with detectable ctDNA had significantly higher serum CA19-9 levels, ctDNA assessment by targeted NGS may be an additional biomarker of treatment response. Taken together, ctDNA detected by targeted NGS is a potential biomarker of treatment response in localized PDAC. Citation Format: Dhavan Shah, Amy Wells, Kevin Dawravoo, John Abad, Arlene D'Souza, Grace Suh, Robert Bayer, Sohail Chaudhry, David Bentrem, Akhil Chawla. Evaluating circulating tumor DNA by targeted next generation sequencing as a biomarker in the treatment of localized pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR014.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. While a number of BET inhibitors are currently in preclinical development or in early phase clinical trials, BET inhibitors show limited single-agent activity. Thus, there is increasing interest in identifying combination regimens to enhance the efficacy of BET inhibitors. Since MNK kinases can enhance the efficacy of BET inhibitors in vitro and in vivo, in this report we evaluated whether targeting effectors downstream of MNK kinases can enhance the efficacy of BET inhibitors. We show that there is co-expression of the BET protein BRD4 and the MNK effector hnRNPA1 in human tumors. We show that hnRNPA1 knockdown can potentiate the effects of BET inhibitors, with enhanced apoptosis and suppression of proliferation and sphere-forming ability by cancer cells. We also show that the plant flavonoid Quercetin, which reduces hnRNPA1 protein levels in cancer cells, can enhance the efficacy of BET inhibitors. Co-treatment with BET inhibitors and Quercetin results in enhanced apoptosis, further suppression of proliferation, and decreased sphere-forming ability by cancer cells. Significantly, Quercetin synergizes with BET inhibitors at suppressing tumor growth in vivo. Together, these results demonstrate that targeting the MNK effector hnRNPA1 can enhance the efficacy of BET inhibitors, and we identify combination therapy with BET inhibitors and Quercetin for the treatment of cancer patients. Citation Format: Thao Pham, Sophie Stempel, Mario Shields, Christina Spaulding, Krishan Kumar, David Bentrem, Hidayatullah Munshi. Targeting the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2086.

Near-infrared fluorescence (NIRF) endoscopy has a great potential for efficient early detection of dysplastic lesions in the colon. For preclinical studies, we developed a small animal NIRF endoscope and successfully used this device to identify dysplastic lesions in a murine model of chronic colitis. In this chapter, we present a step-by-step protocol for using NIRF endoscopy to examine the location, the size, and the borders of the dysplastic lesions developed in murine colitis. Our studies suggest that NIRF endoscopy is a specific and sensitive technique that provides a unique opportunity to analyze early stages of tumorigenesis in animal models of colon cancer and to perform surveillance colonoscopy in patients with colitis-associated colon cancer.

Gallbladder carcinoma (GBC) is the most common biliary epithelial malignancy, with an estimated 10,910 new cases and 3700 deaths per year (Siegel et al. in CA Cancer J Clin 65:5–29, 2015 [1]). This disease’s insidious nature and typically late presentation place it among the most lethal of invasive neoplasms. Gallbladder cancer spreads early by lymphatic or hematogenous metastasis and by direct invasion into the liver. While surgery may well be curative at early stages, both surgical and nonsurgical treatments remain largely unsuccessful in patients with more advanced disease.

We have advanced the view that estrogens activate the estrogen receptor (ER) alpha complex differently. A group of planar (estradiol, genistein, and coumestrol) and nonplanar (methoxychlor and its mono- and didemethylated phenolic metabolites) environmental estrogens, which are all full estrogens in MCF-7 breast cancer cell proliferation assays, was shown to segregate discretely into planar and nonplanar groups. These groups were delineated using a novel assay of mutant ER cDNAs stably transfected into MDA-MB-231 cells and the activation of the transforming growth factor alpha target gene in situ that putatively describes the external shape of the ER complex. Planar compounds activate estrogen action through the two traditional activation functions (AFs), AF1 and AF2, in the ER. In contrast, nonplanar compounds can activate estrogen action through AF1 and the amino acids Asp-351 and Asp-538, which are exposed when helix 12 silences AF2. The observation that class I (planar) and class II (nonplanar) compounds have different mechanisms of estrogen action may have important implications for tissue selective modulation of the ER.

Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands.Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.