Monali K. Vasekar

ACE Inhibitor–Induced Angioedema

Much has been written about hereditary angioedema (HAE) in recent literature; however, the prevalence of angiotensin-converting enzyme inhibitor–induced angioedema (ACEiIA) far exceeds that of HAE. Similarly, multiple therapies have been developed for HAE, yet no definitive therapy is available for ACEiIA. In this article, we discuss the mechanism, prevalence, pathophysiology, and management of ACEiIA, with focus on newer therapies recently approved for HAE and how they may be effective for ACEiIA.

Targeted immunotherapy for non-small cell lung cancer.

Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer (NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.

Novel immunotherapies for hematological malignancies

The successful treatment of hematological malignancies remains challenging. Prognosis is often dismal given the frequency of disease relapse or treatment refractory disease. Cytotoxic and cytostatic chemotherapy remain mainstream therapeutics for most hematological malignancies. However, improved understanding of tumor immunobiology is providing appealing anti-cancer strategies targeting selected component of immune response. Since approval of rituximab for treating B cell malignancies in 1997, availability of monoclonal antibodies against tumor specific surface molecules has driven the development of the emerging field of cancer immunotherapy. This strategy of modulating the immune response is taking an increasingly prominent role in the treatment of hematological malignancies with several new antibody-based therapeutics becoming available for patients with leukemia/lymphoma. In addition, with an increasingly appreciated role for T cell immunity in cancer pathogenesis, strategies enhancing T cell activation as well as inhibiting T cell suppression mechanisms are under active development. Therapeutic vaccines to improve efficacy of antigen processing and presentation, agonists for co-stimulatory molecules, adoptive transfer of genetically-modified T cells, as well as agents that suppress negative regulatory pathways for T cell function are all under active clinical investigation. Although most of these studies are in early stages, preliminary data are very promising. Availability of additional immune-based therapeutic options for patients with hematological malignancies is anticipated in the near future.

Relationship of smoking status to genomic profile, chemotherapy response and clinical outcome in patients with advanced urothelial carcinoma

Smoking has been linked to urothelial carcinoma (UC), but the implications on genomic profile and therapeutic response are poorly understood. To determine how smoking history impacts genomic profile and chemotherapy response, clinicopathologic data was collected for patients with metastatic UC (mUC) across 3 academic medical centers and comprehensive genomic profiling (CGP) was performed through a CLIA-certified lab. Unsupervised hierarchical clustering based on smoking status was used to categorize the frequency of genomic alterations (GAs) amongst current smokers (CS), ex-smokers (ES) and non-smokers (NS), and survival was compared in these subsets. Fishers exact test identified significant associations between GAs and smoking status. Amongst 83 patients, 23%, 55% and 22% were CS, ES, and NS, respectively, and 95% of patients had stage IV disease. With a median follow up of 14.4 months, the median overall survival (OS) was significantly higher in NS and ES (combined) as compared to CS (51.6 vs 15.6 months; P = 0.04). Of 315 cancer-related genes and 31 genes often related to rearrangement tested, heatmaps show some variations amongst the subsets. GAs in NSD1 were more frequent in CS as compared to other groups (P < 0.001). CS status negatively impacts OS in patients with mUC and is associated with genomic alterations that could have therapeutic implications.

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

Background Mutations of DNA repair genes, e.g. ATM/RB1, are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.