Citations

Abstract Background: We recently have reported that co-mutations within KRAS-mutated lung adenocarcinoma (LUAD) define a distinct biological phenotype and may offer insights into therapeutic targeting using this classification system. The analysis revealed striking differences in checkpoint ligand expression and T cell infiltration between TP53 and STK11 (LKB1) co-mutated KRAS LUAD. We, therefore, hypothesized that loss of LKB1promotes an immune-suppressed phenotype in KRAS LUAD. To test this, we analyzed 100 immune-related genes from The Cancer Genome Atlas datasets, as well as three other sets of resected tumors from NSLC patients from MD Anderson Cancer Center. Results: Our results revealed that tumors lacking LKB1 (LKB1-loss), as defined by mutation or gene-expression signature, resulted in a down regulation of: tumor associated immunosuppressive ligands, PD-L1, PD-L2, B7-H3, B7-H4, HVEM; T cell associated immunosuppressive ligands PD-1, CTLA-4, BTLA; co-stimulation ligands such as CD80, -86, -40L, and -40. We further examined if this loss of immunosuppression and co-stimulation resulted in changes in markers of T cell phenotypes. Indeed, tumors lacking LKB1-loss tumors demonstrated a distinct lack absence of several T cell markers including CD3, -4, & -8, but also RORC, T-bet, GATA-3, and FoxP3. To determine if myeloid cell populations, known mediators of immune suppression, were also diminished in LKB1-loss tumors, we analyzed expression of CD11c, -103, -11b, -68, and CD33. Consistent with T cell makers and suppressive ligand markers, myeloid markers were down regulated in LKB1-loss tumors. Because common immune suppression markers were lost, we then examined the expression of antigen presentation (HLA-I, HLA-II) and amino acid transporters as possible alternative methods for immune suppression. In LKB1-loss tumors, both HLA-I and HLA-II markers were down regulated, compared to tumors with intact LKB1 expression. Furthermore, genes associated with the antigen presentation complex, LMP2, TAP1&2, and B2M were also down regulated. In contrast to the immune markers described above, cationic transporters (SLC7A2), anionic transporters (SLC7A11), and neutral transporters (SLC3A2) were universally upregulated in LKB1-loss tumors. Conclusions: LKB1 loss is associated with an inert immune phenotype. Our data suggests that reduced antigen presentation and amino acid depletion, but not checkpoint factors or MDSCs, are likely mediator of this phenotype. Citation Format: Warren L. Denning, Ferdinandos Skoulidis, Li Shen, Vassiliki Papadimitrakopoulou, Lixia Diao, Yanyan Lou, Lauren A. Byers, Jing Wang, Jaime R. Canales, Ignacio I. Wistuba, John Weinstein, Don L. Gibbons, John V. Heymach. Loss of LKB1 mediates an immune inert phenotype in human lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4137.

Abstract Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel treatment. There is conflicting data on the benefits and harms of supplement use for the treatment and prevention of CIPN. We examined dietary supplement use before diagnosis and during treatment in relation to CIPN among breast cancer patients registered to a clinical trial (SWOG 0221; ClinicalTrials.gov Identifier: NCT00070564) before diagnosis and during treatment in relation to CIPN. Methods. At trial registration (baseline), breast cancer patients (n = 1,225) completed questionnaires to capture use before and at diagnosis of multivitamins and other dietary supplements. Of these patients, 1,068 completed a 6-month follow-up questionnaire to capture use during treatment. We examined the use of multivitamins, vitamins C, D, E, B6, and B12, folic acid, iron, calcium, glucosamine, and combined fish oil, eicosapentaenoic acid (EPA), omega-3, flaxseed and cod liver oil at these timepoints in relation to CIPN. CIPN was assessed via the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios and 95% confidence intervals were computed using unconditional logistic regression. Results. Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE adjusted OR = 0.60, 95% CI = 0.42-0.87; FACT/GOG-Ntx adjusted OR = 0.78, 95% CI = 0.61-1.00). Although in a similar direction as use prior to diagnosis, multivitamin use during treatment was less strongly associated with CIPN (CTCAE adjusted OR = 0.73, 95% CI = 0.49-1.08; FACT/GOG-Ntx 0.77, 95% CI = 0.60-0.99). Other supplement use, either before diagnosis or during treatment, was not associated with CIPN. Conclusions. Our results indicate that supplement use during treatment may not appreciably affect experience of CIPN symptoms. Future analyses of the relationships between supplement use and survival outcomes will better inform patient decision making. Acknowledgments: supported by R01 CA116395 (CBA); S0221 supported, in part, by National Cancer Institute/Division of Cancer Prevention SWOG NCORP Research Base grant 5UG1CA189974-02; National Cancer Institute (NCI), National Clinical Trials Network (NCTN): CA180888, CA180819; and in part by Amgen, Inc. Citation Format: Gary R. Zirpoli, Susan E. McCann, Lara E. Sucheston-Campbell, Dawn L. Hershman, Gregory Ciupak, Warren Davis, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Robert B. Livingston, Gabriel N. Hortobagyi, Julie R. Gralow, Daniel F. Hayes, G. Thomas Budd, Kathy S. Albain, Christine B. Ambrosone. Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3413.

An effort over 3 years to conduct a data pooling project regarding the association between smoking and lung cancer treatment outcomes has shown that, of 32 completed studies of lung cancer treatments in 1 National Cancer Institute Cooperative Group, only a minority have usable data concerning smoking‐related variables. Clinical trials research is needed to inform patients with cancer and their physicians about the impact of smoking, and how smoking cessation may affect the course of their disease.

Educators, policy makers, and health systems leaders are calling for significant reform of undergraduate medical education (UME) and graduate medical education (GME) programs to meet the evolving needs of the health care system. Nationally, several schools have initiated innovative curricula in both classroom and workplace learning experiences to promote education in health systems science (HSS), which includes topics such as value-based care, health system improvement, and population and public health. However, the successful implementation of HSS curricula across schools is challenged by issues of curriculum design, assessment, culture, and accreditation, among others. In this report of a working conference using thematic analysis of workshop recommendations and experiences from 11 U.S. medical schools, the authors describe seven priority areas for the successful integration and sustainment of HSS in educational programs, and associated challenges and potential solutions. In 2015, following regular HSS workgroup phone calls and an Accelerating Change in Medical Education consortium-wide meeting, the authors identified the priority areas: partner with licensing, certifying, and accrediting bodies; develop comprehensive, standardized, and integrated curricula; develop, standardize, and align assessments; improve the UME to GME transition; enhance teachers’ knowledge and skills, and incentives for teachers; demonstrate value added to the health system; and address the hidden curriculum. These priority areas and their potential solutions can be used by individual schools and HSS education collaboratives to further outline and delineate the steps needed to create, deliver, study, and sustain effective HSS curricula with an eye toward integration with the basic and clinical sciences curricula.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn’s disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft- versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials.