Citations

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Objectives To present early safety and feasibility data from a multicentre prospective study (WATER II) of aquablation in the treatment of symptomatic men with large‐volume benign prostatic hyperplasia ( BPH ). Methods Between September and December 2017, 101 men with moderate‐to‐severe BPH symptoms and prostate volume of 80–150 mL underwent aquablation in a prospective multicentre international clinical trial. Baseline demographics and standardized postoperative management variables were carefully recorded in a central independently monitored database. Surgeons answered analogue scale questionnaires on intra‐operative technical factors and postoperative management. Adverse events up to 1 month were adjudicated by an independent clinical events committee. Results The mean (range) prostate volume was 107 (80–150) mL. The mean (range) operating time was 37 (15–97) min and aquablation resection time was 8 (3–15) min. Adequate adenoma resection was achieved with a single pass in 34 patients and with additional passes in 67 patients (mean 1.8 treatment passes), all in a single operating session. Haemostasis was achieved using either a Foley balloon catheter placed in the bladder under traction ( n = 98, mean duration 18 h) or direct tamponade using a balloon inflated in the prostate fossa ( n = 3, mean duration 15 h). No patient required electrocautery for haemostasis at the time of the primary procedure. The mean length of stay after the procedure was 1.6 days (range same day to 6 days). The Clavien–Dindo grade ≥2 event rate observed at 1 month was 29.7%. Bleeding complications were recorded in 10 patients (9.9%) during the index procedure hospitalization prior to discharge, and included six (5.9%) peri‐operative transfusions. Conclusions Aquablation is feasible and safe in treating men with men with large prostates (80–150 mL). The 6‐month efficacy data are being accrued and will be presented in future publications (ClinicalTrials.gov number, NCT 03123250).

Key Points There was no difference in overall survival after allogeneic transplant between patients aged 55-64 years and patients ≥65 years. Age alone should not be a determinant for allogeneic transplant eligibility among older non-Hodgkin lymphoma patients.

Background Evidence exists for racial/ethnic differences in left ventricular mass index (LVMI). How this translates to future cardiovascular disease (CVD) events is unknown. Hypothesis The impact of racial/ethnic differences in LVMI on incident cardiovascular outcomes could have potential implications for the optimization of risk stratification strategies. Methods Using the prospectively collected database of the Multi‐Ethnic Study of Atherosclerosis (MESA) involving 4 racial/ethnic groups (non‐Hispanic Whites, Chinese, Blacks, and Hispanics) free of CVD at baseline, we assessed for racial/ethnic differences in the relationship between LVMI and incident CVD using a Cox model. Results 5004 participants (mean age, 62 ± 10 years; 48% male) were included in this study. After an average follow‐up of 10.2 years, 369 (7.4%) CVD events occurred. Significant racial/ethnic differences existed in the relationship between LVMI and incident CVD ( P for interaction = 0.04). Notably, the relationship was strongest for Chinese (HR per 10‐unit increase in LVMI: 1.7, 95% CI: 1.1–2.8) and Hispanics (HR per 10‐unit increase in LVMI: 1.9, 95% CI: 1.5–2.2). Non‐Hispanic Whites demonstrated the lowest relationship (HR: 1.3, 95% CI: 1.1–1.5). LVMI values of 36.9 g/m 2.7 , 31.8 g/m 2.7 , 39.9 g/m 2.7 , and 41.7 g/m 2.7 were identified as optimal cutpoints for defining left ventricular hypertrophy (LVH) for non‐Hispanic Whites, Chinese, Blacks, and Hispanics, respectively. In secondary analysis of LVH (vs no LVH) using these optimal cutpoints, we found a similar pattern of association as above ( P for interaction = 0.04). For example, compared with those without LVH, Chinese with LVH had HR: 5.3, 95% CI: 1.6–17, whereas non‐Hispanic Whites with LVH had HR: 1.6, 95% CI: 1.2–2.1 for CVD events. Conclusions Among 4 races/ethnicities studied, LVMI has more prognostic utility predicting future CVD events for Chinese and Hispanics and is least significant for non‐Hispanic Whites.

BACKGROUNDEarly treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high‐risk group of patients with an expected 5‐year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.METHODSThis study compared autologous hematopoietic stem cell transplantation (auto‐HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo‐HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto‐HCT or allo‐HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression‐free survival, relapse, and nonrelapse mortality (NRM).RESULTSFour hundred forty FL patients had ETF (auto‐HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow‐up of 69 to 73 months, the adjusted probability of 5‐year OS was significantly higher after auto‐HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5‐year adjusted probability of NRM was significantly lower for auto‐HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5‐year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto‐HCT (58%; P < .0001).CONCLUSIONSPatients with high‐risk FL, as defined by ETF, undergoing auto‐HCT for FL have low NRM and a promising 5‐year OS rate (70%). MSD HCT has lower relapse rates than auto‐HCT but similar OS. Cancer 2018;124:2541‐51. © 2018 American Cancer Society.

Abstract Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Study Design. Systematic review and meta-analysis of observational studies. Objective. The aim of the study is to evaluate different treatment modalities in the management of sacrococcygeal chordoma. Summary of Background Data. Chordomas are primary malignant bone tumors associated with considerable morbidity and mortality. Methods. We searched MEDLINE, EMBASE, Cochrane Central-Register of Controlled Trials, and Scopus from inception to July 2015. Eligible studies included patients with sacrococcygeal chordoma treated exclusively with surgery, radiotherapy, or both. Two reviewers independently assessed the eligibility of potential studies, risk of bias, and extracted data. Outcomes of interest were all-cause mortality, progression-free survival, and metastases. We analyzed further surgical outcomes by resection margin. All outcomes were assessed at 60 months and more than 60 months following intervention. Results. We included 33 noncomparative studies reporting on 501 patients (mean age 57 years). Overall mortality rate was (16%) after surgical resection with adjuvant radiotherapy and (28%) after surgical resection, and (43%) after radiotherapy (P = 0.28). All-cause mortality following wide surgical resection was (32%) compared to (40%) after marginal resection (P = 0.51). Overall progression-free survival rate was (58%) after surgical resection with adjuvant radiotherapy and (55%) after surgery (P = 0.92). However, at more than 60 months follow-up, progression-free survival rates were significantly higher (P = 0.024) following surgical resection with adjuvant radiotherapy (74%) in comparison to surgery (55%) and radiotherapy (36%). Overall progression-free survival rates were nonsignificantly higher after wide surgical resection (66%) than marginal resection (33%) (P = 0.16). However, at 60 months follow-up, progression-free survival rates were significantly higher following wide surgical resection (73%) than marginal resection (33%) (P = 0.047). Conclusion. Sacrococcygeal chordoma is a difficult to treat disease entity. Until comparative studies become available, wide surgical resection and multidisciplinary management are the recommended approaches to improve patient outcomes. Level of Evidence: 3

Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and Results Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR ‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P <5×10 −8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS 2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P =4.17×10 −8 ). G‐allele carriers of HMGCS 2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P =0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10 −8 . HMGCS 2 , a part of the HMG ‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. Conclusions These results suggest that HMGCS 2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00246519 and NCT 01203852.