Hina Khan

Role of DNA Methylation in the Pathogenesis and Treatment of Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myeloid leukemia (AML). Even though mutations have been shown to occur in MDS, a notable proportion of these affect genes involved in epigenetic maintenance, suggesting a dominant role of epigenomic dysregulation in the pathogenesis of MDS. Aberrant DNA methylation is the dominant and most well-studied epigenetic alteration in MDS. Various genes, including cell cycle regulators, apoptotic genes, and DNA repair genes, are epigenetically silenced and have roles in pathogenesis and transformation to leukemia. The involvement of these genes in MDS pathophysiology and prognosis is reviewed and reveals distinct methylation patterns between high- and low-risk subsets of this disease. Furthermore, DNA methyltransferase (DNMT) inhibitors azacitdine and decitabine are approved for treatment even though the optimal dosing strategies are still being developed. We have reviewed the mechanisms of action of these agents in MDS and show that demethylation may not correlate well with their efficacy, thus suggesting alternative modes of action. We also show that DNMT inhibitors may have potent anti-leukemic stem cell effects at lower doses and also review the mechanisms of resistance to these agents. Altogether, these studies show that even though DNA methylation has been studied extensively in MDS, its role in prognosis and response to therapy is still unclear. The use of deep sequencing and genome-wide methylome analysis will potentially uncover prognostic signatures and reveal the complexity of epigenetic dysregulation in this disease.

Testosterone Levels and Quality of Life in Diverse Male Patients With Cancers Unrelated to Androgens

PURPOSE Symptoms secondary to hormonal changes significantly impact quality of life (QoL) in patients with cancer. This cross-sectional study examines prevalence of hypogonadism and its correlation with QoL and sexual dysfunction. PATIENTS AND METHODS We collected blood and medical histories from 428 male patients with non-testosterone-related cancer at three cancer centers. Serum was analyzed for total testosterone (TT), free testosterone (FT), bioavailable testosterone (BAT), and sex hormone binding globulin (SHBG). The Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL questionnaire measured physical, social, emotional, and functional domains as well as sexual function. Exclusion criteria were prostate, testicular, or male breast cancer; known hypogonadism; and HIV. RESULTS Mean and median TTs were 337.46 and 310 ng/dL, respectively. The mean age of patients was 62.05 years. The crude prevalence of hypogonadism (ie, TT < 300 ng/dL) was 48%, and mean TT in hypogonadal patients was 176 ng/dL. The prevalences that were based on FT (ie, hypogonadal < 52 pg/dL) and BAT (ie, hypogonadal < 95 ng/dL) were 78% and 66%, respectively. The mean FT and BAT values in hypogonadal patients were 25 pg/dL and 45 ng/dL, respectively. Hypogonadal patients had decreased total QoL scores on FACT-P (P = .01) and decreased three-item sexual function subset (P = .003). CONCLUSION The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations.

Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: A retrospective cohort study

OBJECTIVES The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease. METHODS All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR ≥ 30mL/min/1.73m2 were included. Moderate-to-severe TID was defined as the presence of moderate-to-severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at the time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate-to-severe TID was predictive of ESRD progression. RESULTS Of the 131 LN patients with eGFR ≥ 30mL/min/1.73m2, 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR ≥ 60mL/min/1.73m2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m2. Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI: 1.4-12.1, p = 0.01 for eGFR ≥ 30mL/min/1.73m2; HR = 6.2, 95% CI: 1.7-23.2, p = 0.008 for eGFR ≥ 60mL/min/1.73m2. There was no association between tubulointerstitial inflammation (TII) and ESRD progression. CONCLUSIONS Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions.

Analysis of chronic myelogenous leukemia in an underserved, inner-city cohort shows a significant five year overall survival that is not affected by choice of tyrosine kinase inhibitor

Tyrosine kinase inhibitors (TKIs) have become the firstline treatment of choice for chronic myelogenous leukemia (CML) after imatinib was shown to offer improved and durable responses.[1,2] Second generation TKIs such as nilotinib [3,4] and dasatinib [5,6] have shown superior efficacy in achieving faster remissions in the first-line setting. Patients who achieve a complete cytogenetic response at two years have a life span similar to that of the general population as long as they receive adequate therapy and adhere to treatment.[7] Despite efficacy, the cost of TKIs created a significant financial burden which led leaders in the field to speculate on whether such prices are justifiable.[8] Individuals with ‘adequate’ healthcare coverage are not immune and may have a 20% out of pocket co-payment. Adherence to therapy is essential to achieve adequate responses.[9] Higher socioeconomic status was linked to better imatinib adherence [10] and patients with higher copayments were more likely to have poorer adherence.[11] To examine the impact of cost of TKIs on efficacy, we conducted a retrospective analysis to determine the treatment patterns in an inner-city population comprised predominantly of ethnic minorities with low socioeconomic status. We aimed to study access to different generations of TKI, reasons for switching TKIs as well as overall survival (OS). We included CML cases that presented to Montefiore Medical Center between 1997 and 2014 in the Bronx, New York. Cases were identified by a data-mining software (Clinical Looking Glass , CLG) used to search by ICD-9 diagnosis code. Records were manually reviewed to confirm diagnosis and to collect relevant demographic and CML-specific data. The population number (n value) was adjusted to reflect the number of records with available data pertaining to each variable. As such, the number of evaluable records for phase at diagnosis, first-line therapy, line of therapy at the conclusion of the study, and line of therapy at expiration was 77, 118, 125, and 20 patients, respectively. All chart review was conducted by one of the study authors and discrepancies were reviewed by at least two authors. This research was approved by our institutional review board and ethics committee. For comparison, we obtained data from the Surveillance, Epidemiology and End Results (SEER) program database. SEER collects cancer incidence, treatment, and survival information from 18 geographic areas in the United States, representing 28% of the entire population. We used direct case listings extracted by SEER*Stat software (version 8.1.5, released March 31, 2014) and included patients with a diagnosis of CML with the International Classification of Disease for Oncology, third edition, ICD-0-3 histology code 9863, 9875, 9876, 9945, 9946 until the latest follow-up recorded in the SEER submission. For analysis of categorical variables, we reported proportions and p values calculated with Pearson chi square or Fisher exact test as appropriate. Kaplan–Meier curves were used to compare survival and significance was examined using the log rank test. Statistical analyses were performed with computer software (SPSS 18, SPSS, Inc., Chicago, IL) and a two-tailed alpha of 0.05 was used to denote significance.

Tumor infiltrating lymphocytes as a prognostic and predictive biomarker in breast cancer

Tumor infiltrating lymphocytes (TILs) have been recognized in various cancers and may reflect a host immune response to malignant cells. TILs are a heterogeneous population of various types of mononuclear cells, including CD8 or CD4 + T cells and their subsets, B cells, myeloid derived suppressor cells (MDSC), macrophages, and other cells. Immunosuppressive factors in the tumor microenvironment (TME) that inhibit recruitment and function of TILs include immunosuppressive cells, cytokines secreted by tumor or mesenchymal cells, and co-inhibitory ligands expressed by tumor cells. Despite this complex interplay of immune cells and the TME, higher TIL density is associated with favorable prognosis in certain breast cancer subtypes, including HER2 overexpressing cancers, and “triple negative” cancers that do not express the estrogen and progesterone receptors or overexpress HER2. TILs infiltrating the tumor stroma (sTILs) are associated with higher rates of complete pathologic response to neoadjuvant chemotherapy, decreased recurrence and improved survival in early stage triple negative and HER2-positive breast cancer treated with adjuvant systemic therapy. An international working group has published guidelines on reporting TILs in pathology specimens. In this chapter we review the composition of TILs, mechanisms of immune evasion, recommendations for TILs measurement, and data supporting use of TILs as a prognostic and predictive biomarker in breast cancer.

Case Report: Elevated CPK, an indicator of idiopathic inflammatory myopathy?

Polymyositis is a rare disease with incidence rates at about 1 per 100,000 people annually. In this case report we will review a case of proximal muscle weakness with an elevated creatine phosphokinase that was initially misdiagnosed twice as rhabdomyolysis. Therefore, emphasizing that idiopathic inflammatory myopathy is a potential cause of myasthenia that must be considered in the differential. The case will also describe the current treatment and treatment response in polymyositis.

THU0317 Tubuloinsterstial Damage Is An Independent Predictor of End Stage Renal Disease in Lupus Nephritis Patients with Mild To Moderate Renal Impairment

Background Tubulointerstitial damage (TID) is associated with progression to end stage renal disease (ESRD) in lupus nephritis (LN)1,2. However, it has not been established whether the association of TID and ESRD holds true in individuals with preserved or only moderately impaired renal function. Objectives To determine if TID predicts progression to ESRD in LN patients with mild to moderate renal impairment at the time of kidney biopsy. Methods We identified all adult and pediatric SLE patients (by ACR and/or SLICC criteria) who had an index biopsy consistent with LN between January 2005 and July 2015. Demographic data, comorbidities, medications, laboratory data, ESRD onset, and deaths through December 2015 were ascertained from medical chart reviews, the United States Renal Data Systemic Report, and National Death Index. Renal impairment was defined as mild (chronic kidney disease [CKD] stage 1 or 2, estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73m2), or moderate (CKD stage 2, eGFR≥30 and <60 mL/min/1.73m2). TID was defined as the presence of moderate to severe tubular atrophy and/or interstitial fibrosis as reported on the renal biopsies in accordance with the 2003 ISN/RPS criteria. Time to ESRD onset was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at time of death or the last visit. Kaplan-Meier survival curves and Cox proportional hazards models were used to evaluate whether TID was predictive of ESRD progression adjusting for eGFR (as a continuous variable) and LN class. Results Of the 131 LN patients with mild to moderate renal impairment (8 (6%) Class II, 58 (44%) Class III/IV, 38 (29%) Class V, and 27 (21%) mixed), 16 (12%) progressed to ESRD. Eighty six percent of ESRD progressors had proliferative or mixed LN vs. 51% of non-ESRD, p=0.02. There were no significant differences with respect to age, sex, race, comorbidity scores, complement levels, anti-dsDNA, or protein to creatinine ratio at index biopsy between ESRD and non-ESRD groups. Median (IQR) baseline eGFR was 65 (51, 75) mL/min/1.73m2 in the ESRD group and 97 (69, 127) mL/min/1.73m2 in the non-ESRD group, p=0.001. TID was present in 12% of biopsies with eGFR≥60 mL/min/1.73m2 and in 35% of biopsies with GFR between 30 and 60 mL/min/1.73m2. Moderate to severe TID was associated with a high risk of ESRD progression (Figure 1, log-rank p-value<0.001), HR=8.3, 95% CI: (2.6, 27), p-value<0.001, adjusted for eGFR and proliferative or mixed LN. Similarly, TID remained a significant predictor when the analyses were limited to patients with a eGFR>60 mL/min/1.73m2, HR=5.6, 95% CI: (1.3, 22.9), p=0.02, adjusted for eGFR. Conclusions TID was found in a significant proportion of clinically-indicated kidney biopsies in LN patients with mild to moderate renal impairment. The presence of TID was a strong predictor of ESRD progression in these patient independent of eGFR or biopsy class. Further studies are needed to identify factors associated with the presence of TID to develop effective prevention strategies. References Hsieh C, et al. Arthritis Care & Research Vol.63, No. 6, June 2011, pp 865–874. Yu F, et al. Kidney Int 2010; 77:820–829. Disclosure of Interest None declared