Citations

BACKGROUNDAngiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC.METHODSPatients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6‐month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor‐2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05).RESULTSA total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6‐month progression rate was 72% versus 64%. The median progression‐free survival (PFS) was 2.9 months (range, 0.5 months‐32.5 months) versus 2.7 months (range, 0.8 months −65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months‐22 months).CONCLUSIONSThe current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6‐month progression rate. Open‐label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib. Cancer 2014;120:692–701. © 2013 American Cancer Society.

Abstract A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [ 18 F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies.

Total hip replacement (THR) after acetabular fracture presents unique challenges to the orthopaedic surgeon. The majority of patients can be treated with a standard THR, resulting in a very reasonable outcome. Technical challenges however include infection, residual pelvic deformity, acetabular bone loss with ununited fractures, osteonecrosis of bone fragments, retained metalwork, heterotopic ossification, dealing with the sciatic nerve, and the difficulties of obtaining long-term acetabular component fixation. Indications for an acute THR include young patients with both femoral head and acetabular involvement with severe comminution that cannot be reconstructed, and the elderly, with severe bony comminution. The outcomes of THR for established post-traumatic arthritis include excellent pain relief and functional improvements. The use of modern implants and alternative bearing surfaces should improve outcomes further. Cite this article: Bone Joint J 2013;95-B, Supple A:11–16.

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long‐term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 × 106/L, an absolute neutrophil count >1,000 × 106/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60–84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1–26). The median duration of response has not been reached and median progression‐free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single‐agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM. Am. J. Hematol. 89:237–242, 2014. © 2013 Wiley Periodicals, Inc

AbstractSirolimus is used in heart transplant patients with CAV and CNI‐induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus‐based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI‐free sirolimus‐based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI‐induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1–21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow‐up was available for a mean of 2.5 yr after conversion (range 0.5–8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient‐year (total of five episodes), compared with 0.03 rejection episodes per patient‐year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow‐up (from 86 ± 37 mL/min to 130 ± 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI‐free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles.

The objective of this study was to assess the potential for noninvasively identifying viscoelastic material properties in arterial vessels using ultrasound radiation force and modern computational inverse problem techniques. A rubber tube embedded in gelatin was excited at different points along the axis using impulsive ultrasound radiation force. The resulting mechanical waves were measured using a laser vibrometer and pulse-echo ultrasound. The inverse problem was cast as an optimization problem, in which the discrepancy between the measured dynamic response and the computed finite element model response was minimized with respect to viscoelastic material parameters. The model was very sensitive to the tube’s viscoelastic parameters and relatively insensitive to those of the gelatin. The viscoelastic properties of the tube obtained from the inverse problem were compared to the results obtained from a dynamic mechanical analyzer (DMA). For the overlapping range of frequencies (130–190 Hz), the results of the inverse problem gave an equivalent modulus that range from 7.3–8.5 MPa, while the DMA values range from 6.0–9.2 MPa. These results have important implications for using ultrasound radiation force in noninvasive characterization of the viscoelastic properties of arteries in vivo. [This work was supported in part by Grant No. EB002640 from NIH.]

BACKGROUNDBurnout is a syndrome affecting the entirety of work life and characterized by cynicism, detachment, and inefficacy. Despite longstanding concerns about burnout in hospital medicine, few data about burnout in hospitalists have been published.PURPOSEA systematic review of the literature on burnout in inpatient‐based and outpatient‐based physicians worldwide was undertaken to determine whether inpatient physicians experience more burnout than outpatient physicians.DATA SOURCESFive medical databases were searched for relevant terms with no language restrictions. Authors were contacted for unpublished data and clarification of the practice location of study subjects.STUDY SELECTIONTwo investigators independently reviewed each article. Included studies provided a measure of burnout in inpatient and/or outpatient nontrainee physicians.DATA EXTRACTIONFifty‐four studies met inclusion criteria, 15 of which provided direct comparisons of inpatient and outpatient physicians. Twenty‐eight studies used the same burnout measure and therefore were amenable to statistical analysis.DATA SYNTHESISOutpatient physicians reported more emotional exhaustion than inpatient physicians. No statistically significant differences in depersonalization or personal accomplishment were found. Further comparisons were limited by the heterogeneity of instruments used to measure burnout and the lack of available information about practice location in many studies.CONCLUSIONSThe existing literature does not support the widely held belief that burnout is more frequent in hospitalists than outpatient physicians. Better comparative studies of hospitalist burnout are needed. Journal of Hospital Medicine 2013;8:653–664. © 2013 Society of Hospital Medicine

The head-gimbal assembly suspension is a cantilever-like structure that holds the heads on a hard drive. We will discuss a noncontact method for modal testing, of suspensions in air, that utilizes the radiation force at the difference frequency generated by two intersecting ultrasound beams. The resulting low-frequency excitations were measured using a scanning vibrometer. This excitation technique has been demonstrated for MEMS and other small devices. There are several unique advantages of the ultrasound radiation force relative to mechanical shakers. Since the ultrasound radiation force is noncontact, a specialized test fixture was not needed; the technique was relatively insensitive to distracting resonances of fixtures and support structures. Another advantage is broadband excitation; a 550-kHz confocal ultrasound transducer excited suspension resonance frequencies from under 1 kHz to over 50 kHz. Other advantages include the ability to selectively excite different modes. For example, the amplitude of the suspension’s 2.28-kHz transverse mode was suppressed by an order of magnitude by shifting the modulation phase between the two ultrasound beams by 90. In another test, the amplitude of the 6.01-kHz torsional mode was doubled by moving the ultrasound focus point from near the center to near the edge of the suspension.