Naim Rashid

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.

Differential and limited expression of mutant alleles in multiple myeloma

Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications.

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM–BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

Trends and predictors of resection of the primary tumor for patients with stage IV colorectal cancer

Over 130,000 patients are diagnosed with colorectal cancer annually, with approximately 20% presenting with unresectable metastatic disease. Recent consensus guidelines recommend against primary tumor resection for asymptomatic patients with unresectable metastases. Our goal was to examine the trends and predictors of surgical resection.

Radiation Therapy for Unresectable Pancreatic Adenocarcinoma: Population-Based Trends in Utilization and Survival Rates in the United States

From the DOD perspective, federal programs such as this promote readiness and currency skills for military personnel, maintain services during operations, and support the vascular surgery graduate medical education program. From the VA perspective, such programs provide a sophisticated, cost-effective capacity to meet demand while simultaneously serving the VA’s educational mission. Previous regional JIF endeavors include programs in nephrology, neurosurgery, and cardiothoracic surgery with returns on investment ranging from 10% to 284%. The challenges to the development of the program have been the implementation of minimally integrated electronic medical record systems and the coordination of vascular care over a large geographical area. At the same time, encouraging clinical and financial outcomes led to additional VA-DOD collaborations. Specifically, an approved JIF Triage and Federal Care Initiative established an administrative-clinical management hub for prompt triage consultations and as a regional transfer center. The JIF-hired clinical specialists are able to access dual-system information and electronic health records with adjacent VA and DOD computers. This ensures access to care goals with prompt assignment to facility and health care provider, and assists in returning beneficiaries in community hospitals back to federal facilities. The joint VA-DOD vascular surgery program successfully used shared personnel, facilities, and resources to care for patients in VA and DOD health care systems. The benefits of JIF have been substantial, with considerable fiscal savings for the federal government. Importantly, collaboration has provided our nation’s veterans and military personnel with improved access to complex vascular and endovascular surgical care.