Sarvari Venkata Yellapragada

Epigenetics in Prostate Cancer

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Hypomethylating agents for urologic cancers

Silencing of tumor suppressor genes by promoter-region methylation as an epigenetic mechanism of gene regulation is increasingly recognized as beneficial in cancer. Initially developed as cytotoxic high-dose therapies, azacitidine and decitabine are now being reinvestigated in lower-dose cancer treatment regimens with a different paradigm - hypomethylation. Recent evidence for benefit in myelodysplastic syndromes and acute myeloid leukemias has renewed interest in hypomethylation as a therapeutic option in epithelial cancers. In this article, we describe the mechanistic aspects of DNA methylation, which alters gene expression, and review the evidence for hypomethylation as a therapeutic option in urologic cancers. Potential correlative studies that may assist in developing tailored therapy with hypomethylating agents are reviewed. Given that the population with urologic cancers is typically elderly with multiple comorbidities, the excellent tolerability of lower-dose hypomethylating agents provides a high therapeutic index and rational development is warranted, bearing in mind that the cytostatic and delayed activity present challenges in the choice of appropriate trial end points.

State-of-the-Art Imaging and Staging of Plasma Cell Dyscrasias.

Monoclonal gammopathy of unknown significance (MGUS) is a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. Smoldering multiple myeloma, also called asymptomatic multiple myeloma, is an intermediate stage between MGUS and symptomatic multiple myeloma. As the name implies, extraosseous or extramedullary myeloma refers to the presence of myeloma deposits outside the skeletal system. Waldenström macroglobulinemia is a distinct subtype of plasma cell dyscrasia characterized by lymphoplasmacytic lymphoma in the bone marrow with an associated IgM monoclonal gammopathy. Amyloidosis is a condition characterized by extracellular deposition of fibrils composed of a variety of normal serum proteins.

Significant improvement in overall survival among patients diagnosed with low‐risk myelodysplastic syndrome treated with selective serotonin reuptake inhibitors

Low risk myelodysplaastic syndrome (LR-MDS) is observed in elderly patients and characterized by symptomatic cytopenias. Molecular studies highlight a central role for apoptosis and immune deregulation. The capacity of cytokines, such as IL6, TNFa and INF-ү to sustain ineffective haematopoiesis suggests that intervention in this pathway could provide benefit. Similar to LR-MDS, deregulated cytokine signalling is observed in both depression and rheumatoid arthritis and selective serotonin reuptake inhibitors (SSRIs) abrogate the symptoms of these disorders in part by modulating cytokine abnormalities (Sutcigil et al, 2007; Baharav et al, 2012; Taraz et al, 2013). We hypothesized that SSRIs could delay disease progression and prolong survival in LR-MDS patients. After Institutional Review Board approval, 118 primary MDS patients aged 18 years and older were identified from the Michael E. DeBakey VA Medical Center cancer registry. Eighty-seven patients had a low or intermediate-1 International Prognostic Scoring System score (i.e., lower-risk). LR-MDS patients were considered to be in the SSRI+ group if they had received at least 6 months of an SSRI (including fluoxetine, sertraline, paroxetine or citalopram) during the 12 months prior to and/or after MDS diagnosis. The primary outcome was defined as overall survival (OS), in days, from bone marrow diagnosis to death from any cause. Univariate and multivariate analysis of SSRI effect were performed using the Cox proportional hazards regression model. Statistical analyses were performed with SPSS 22.0 (IBM Corp., Armonk, NY, USA). P values were considered statistically significant when <0 05. Among the 87 patients with low risk disease, balanced baseline characteristics were observed (15 SSRI+ vs. 72 SSRI ). The risk of death in the non-SSRI group was almost 2 4 times higher than that observed in the treated group [Hazard ratio (HR) = 2 38, 95% confidence interval (CI) = 1 20–4 71, P = 0 0128]. The estimated median OS for patients with lower-risk disease was 57 5 months in the SSRI+ group and 23 9 months in the SSRI group (Fig 1A). Multivariate analysis identified SSRI use, white blood cell (WBC) count and haemoglobin (Hb) as independent predictors of survival. A Cox multivariate model containing all 3

Pulmonary Complications of Azanucleoside Therapy in Patients with Myelodysplastic Syndrome and Acute Myelogenous Leukemia.

Our primary aim was to identify potential risk factors and clinical outcome of azanucleoside induced pulmonary complications in patients with myelodysplastic syndrome (MDS) and Acute Myelogenous Leukemia (AML). We present an 89-year-old female with MDS derived AML who developed fatigability, hypoxemia, and bilateral lung infiltrates indicating interstitial lung disease after 11 cycles of azanucleoside. In addition, we describe a cohort of six MDS patients with fever, cough, dyspnea, and pulmonary infiltrates at early time point during azanucleoside treatment. Early and late onset of pulmonary manifestations suggest different pathogenic mechanisms. Brief azanucleoside discontinuation and steroids led to rapid improvement in symptoms.

HIV-related Refractory Hodgkin Lymphoma: A Case Report of Complete Response to Nivolumab

We present a case of a veteran with well-controlled human immunodeficiency virus (HIV) infection and primary refractory classical Hodgkin lymphoma (HL) who, after multiple prior lines of therapy, received nivolumab with a complete response. He also developed autoimmune diabetes mellitus after 6 months of nivolumab. HIV-associated HL is currently treated under the same algorithm as HL in the general population, but its unique biology, particularly the near-universal association with Epstein-Barr virus, regardless of histology, suggests that immunotherapy may have an important role in the management of this disease. Most clinical trials highlighting checkpoint inhibitors have excluded HIV-infected patients. More prospective data is clearly needed to delineate the risks and benefits of immunotherapy in this population with increased autoimmunity at baseline.

Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor

Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS) who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD) and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA) therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E) in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS.

Gelatinous Marrow Transformation Associated with Imatinib: Case Report and Literature Review

Gelatinous marrow transformation (GMT) is a rare condition observed in severe illness or malnutrition, in which the bone marrow contains amorphous “gelatinous” extracellular material, and histopathology demonstrates varied degrees of fat cell atrophy and loss of hematopoietic elements. An association of GMT with imatinib use in chronic myeloid leukemia (CML) has been reported recently. The objective of this study is to describe a case of GMT associated with imatinib use and review the existing similar cases in the literature to identify epidemiological patterns and potential imatinib-induced mechanisms leading to gelatinous conversion.