Citations

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and has the highest propensity to manifest as metastatic disease. Recent characterizations of the genetic signature of ccRCC have revealed several factors correlated with tumor cell migration and invasion; however, the specific events driving malignancy are not well defined. Furthermore, there remains a lack of targeted therapies that result in long-term, sustainable response in patients with metastatic disease. We show here that neuronal pentraxin 2 (NPTX2) is overexpressed specifically in ccRCC primary tumors and metastases, and that it contributes to tumor cell viability and promotes cell migration through its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR4. We propose NPTX2 as a novel molecular target for therapy for patients with ccRCC diagnosed with or at risk of developing metastatic disease. Cancer Res; 74(17); 4796–810. ©2014 AACR.

Key PointsWe identified CRBN-binding proteins and confirmed recent work implicating the Ikaros transcription factors as important members. Low IZKF1 levels predict lack of IMiD responsiveness and shorter OS; IZKF1 expression is a potential predictive biomarker for clinic application.

ABSTRACTMutations in leucine‐rich repeat kinase 2 (LRRK2) are found in a significant proportion of late‐onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2‐G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2‐G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate‐specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies. J. Comp. Neurol. 522:2465–2480, 2014. © 2014 Wiley Periodicals, Inc.

Background Shoulder arthroscopy is not common in the pediatric and adolescent population, but the frequency may be on the rise. The purpose of the study was to determine the incidence of acute complications of arthroscopic shoulder surgery in children and adolescents. Methods A retrospective, cross-sectional review was performed identifying patients aged 18 years or less who underwent an arthroscopic shoulder procedure from 1997 to 2009 at Institution 1 and 2007 to 2010 at Institution 2. Exclusion criteria included open procedures and missing records. Demographic and surgical data were collected, including intra-operative and post-operative complications during the first 6 months. The complications were divided into minor (no secondary treatment) and major (secondary treatment rendered). Results Two hundred children, mean age 15.9 years, met criteria and 73 % were boys. All procedures were performed under general anesthesia, but 51 % included inter-scalene regional anesthesia. There were 16 (8.0 %) total complications recorded. Major complications occurred in five (2.5 %) patients, including two tendinitis/bursitis requiring injections, one broken pain pump catheter requiring an accessory incision to retrieve, one pain control readmission, and one laceration of the cephalic vein requiring ligation. Minor complications occurred in 11 (5.5 %) patients, including allergic reactions, transient dysesthesias, headaches, bronchitis, syncope, transient hypotension, and uvula swelling. Conclusion Although we found no seriously deleterious outcomes, it is important to recognize that an additional service was rendered for 2.5 % of children undergoing shoulder arthroscopy. The events that did occur may be preventable and this study should serve as a baseline to improve quality and safety of shoulder arthroscopy in the pediatric population.

Key Points Methylation analysis at ZAP-70 CpG+223 in CLL provides superior prognostic information vs IGHV status or CD38 or ZAP-70 expression. A pyrosequencing method for the feasible assessment of CpG+223 methylation in CLL samples is provided.

Abstract Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

Background Aneurysmal bone cysts (ABCs) are a benign aggressive tumor that occurs rarely in the pelvis in the pediatric population. Pelvic ABCs may involve the triradiate cartilage and/or the acetabulum, which increases the technical difficulty of surgical treatment and has potential implications on the growth and development of the hip joint. This study examines the clinical presentation, rate of surgical complications, and recurrence rate, as well as, long-term clinical and functional outcomes of children with pelvic ABCs treated at a single institution by a single treatment modality. Methods Between 1988 and 2008, 142 children with histologically confirmed ABCs were treated at our institution. Seventeen (12 %) tumors were located in the pelvis. A total of 13 pelvic ABCs (5 ilium-periacetabular, 4 pubic, 3 ilium-iliac wing, and 1 ischium) were included in this study. There were eight male and five female patients with a mean age of 12.9 years (range 4.1–17.5 years) at the time of surgery. The Toronto Extremity Salvage Score (TESS), the Musculoskeletal Tumor Society 1993 (MSTS’93) score, and the Short Form Health Survey Sf-36 were obtained at a minimum 5-year follow-up in all patients (mean follow-up 11.5 years, range 5.5–19.8 years). The mean age at follow-up was 24.3 years (range 14.6–32.6 years). Results All patients were treated surgically with intralesional curettage extended with a high-speed burr and bone grafting. Eight patients received adjunctive therapy with phenol. Five patients had preoperative selective arterial embolization. Of the 13 patients, 1 had a local recurrence diagnosed at 6 months after surgery. The only complication in the cohort was a superficial wound infection. At the latest follow-up, all patients were free of disease. The mean TESS score was 95 and the mean MSTS’93 score was 93 %. The mean self-rated general health score, according to the SF-36 was 87 % of total points possible. Conclusions Extended curettage and bone grafting of pelvic ABCs in the pediatric population can yield high clinical and functional scores at an average of 11 years follow-up with a low rate of complications and recurrence. Level of evidence IV, case series.

Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus .