Citations

Abstract Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR. See related commentary by Voss and Hsieh, p. 2320

Non‐invasive tests to identify age and early disease‐associated pathology within the kidney are needed. Specific populations of urinary extracellular vesicles (EVs) could potentially be used for such a diagnostic test. Random urine samples were obtained from age‐ and sex‐stratified living kidney donors before kidney donation. A biopsy of the donor kidney was obtained at the time of transplantation to identify nephron hypertrophy (larger glomerular volume, cortex per glomerulus and mean profile tubular area) and nephrosclerosis (% fibrosis, % glomerulosclerosis and arteriosclerosis). Renal parenchymal‐derived EVs in cell‐free urine were quantified by digital flow cytometry. The relationship between these EV populations and structural pathology on the kidney biopsy was assessed. Clinical characteristics of the kidney donors (n=138, age range: 20–70 years, 50% women) were within the normative range. Overall, urine from women contained more EVs than that from men. The number of exosomes, juxtaglomerular cells and podocyte marker–positive EVs decreased (p<0.05) with increasing age. There were fewer total EVs as well as EVs positive for mesangial cell, parietal cell, descending limb of Henle's loop (simple squamous epithelium), collecting tubule‐intercalated cell and monocyte chemoattractant protein‐1 markers (p<0.05) in persons with nephron hypertrophy. The number of EVs positive for intercellular adhesion molecule‐1, juxtaglomerular cell, podocyte, parietal cell, proximal tubular epithelial cell, distal tubular epithelial cell and collecting duct cells were fewer (p<0.05) in persons with nephrosclerosis. EVs carrying markers of cells from the renal pelvis epithelium did not associate with any indices of nephron hypertrophy or nephrosclerosis. Therefore, specific populations of EVs derived from cells of the glomerulus and nephron associate with underlying kidney structural changes. Further validation of these findings in other cohorts is needed to determine their clinical utility.

BACKGROUNDLeukoreduced (LR) or cytomegalovirus (CMV)‐seronegative cellular blood components are commonly used to reduce the risk of transfusion‐transmitted CMV infection in high‐risk patients.STUDY DESIGN AND METHODSWe performed a systematic review and meta‐analysis to evaluate the evidence for the use of LR cellular blood components with or without concurrent CMV testing of donor units in patients undergoing chemotherapy or solid organ and hematopoietic stem cell transplantation, in pregnant women, in very‐low‐birthweight infants, and in patients with primary immunodeficiency. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1980 through February 2015. Studies were included if they had a comparison group. Two independent reviewers selected and appraised studies. Meta‐analysis was performed when appropriate.RESULTSOf 457 studies screened, 11 were eligible. One study was excluded from the meta‐analysis because the comparison performed differed significantly from the others. Meta‐analysis of five studies that compared leukoreduction to transfusing CMV‐untested blood components showed no significant difference in clinical CMV infection (relative risk [RR], 0.26; 95% confidence interval [CI], 0.04‐1.57) or laboratory CMV infection (RR, 0.33; 95% CI, 0.08‐1.37). Meta‐analysis of three studies that compared leukoreduction to transfusing CMV‐seronegative cellular components showed no significant difference in laboratory CMV infection (RR, 2.18; 95% CI, 0.96‐4.98). Meta‐analysis of two studies that compared adding CMV testing to leukoreduction (vs. leukoreduction alone) showed no significant difference in clinical or laboratory CMV infection. The certainty in estimates was low for all comparisons.CONCLUSIONAt present, the scientific evidence does not favor a single strategy for reducing the risk of transfusion‐related CMV infection in high‐risk patients.

Key Points HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation. HERC4 suppresses MM cell proliferation and delays MM tumor growth.

Abstract Background. The objectives of this study were to estimate the incidence and evaluate risk factors for development of minocycline-induced cutaneous hyperpigmentation in patients with orthopedic infections. Methods. Patients with orthopedic infections evaluated at Mayo Clinic (Rochester, MN) and treated with minocycline from 1 January 2002 to 31 December 2011 were retrospectively identified. Long-term minocycline suppression was defined as daily minocycline use for at least 3 months. A proportional hazards model was used to evaluate potential risk factors. Results. Of 291 patients receiving long-term minocycline suppression, 54% (156 of 291) developed hyperpigmentation after a mean follow-up of 4.8 years (range, 0.3–13.2 years); 88% involved blue-gray pigmentation of normal skin that appeared most commonly in the lower (75%) and upper extremities (44%). The mean duration of minocycline therapy before hyperpigmentation was 1.5 years (range, 0.1–9 years) with a mean cumulative dosage of 107.3 g (range, 8.6–657 g). Notable risk factors include a history of vitamin D deficiency (relative risk [RR], 6.29; 95% confidence interval [CI], 1.91–15.27; P = .0052), presence of a shoulder prosthesis (RR, 3.2; 95% CI, 1.23–6.56; P = .0062), noncirrhotic liver pathology (RR, 3.63; 95% CI, 1.11–8.75; P = .0359), and use of a concurrent medication also known to cause hyperpigmentation (RR, 4.75; 95% CI, 1.83–10.1; P = .0029). Conclusions. Hyperpigmentation associated with the use of long-term minocycline suppression in patients with orthopedic infections is common.