Citations

Disease overview: Hodgkin lymphoma (HL) is an uncommon B‐cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States.Diagnosis: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte‐predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte‐rich HL are subgroups under the designation of classical HL.Risk stratification: An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy.Risk‐adapted therapy: Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved‐field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy.Management of relapsed/refractory disease: High‐dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. Am. J. Hematol. 89:772–779, 2014. © 2014 Wiley Periodicals, Inc.

ABSTRACT Rothia spp. are Gram-positive cocco-bacilli that cause a wide range of serious infections, especially in immunocompromised hosts. Risk factors for Rothia mucilaginosa (previously known as Stomatococcus mucilaginosus ) bacteremia include prolonged and profound neutropenia, malignancy, and an indwelling vascular foreign body. Here, we describe 67 adults at the Mayo Clinic in Rochester, MN, from 2002 to 2012 with blood cultures positive for Rothia . Twenty-five of these patients had multiple positive blood cultures, indicating true clinical infection. Among these, 88% (22/25) were neutropenic, and 76% (19/25) had leukemia. Common sources of bacteremia were presumed gut translocation, mucositis, and catheter-related infection. One patient died with Rothia infection. Neutropenic patients were less likely to have a single positive blood culture than were nonneutropenic patients. Antimicrobial susceptibility testing was performed on 21% of the isolates. All of the tested isolates were susceptible to vancomycin and most beta-lactams; however, four of six tested isolates were resistant to oxacillin. There was no difference between the neutropenic and nonneutropenic patients in need of intensive care unit care, mortality, or attributable mortality.

Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness.

SummaryBackgroundThe presence of germline mutations in sporadic pheochromocytomas and paragangliomas (SPPs) may change the clinical management of both index patients and their family members. However, the frequency of germline mutations in SPPs is unknown.ObjectiveTo describe the frequency of germline mutations in SPPs and to determine the value of testing index patients and their family members for these mutations.MethodsWe searched databases through June 2012 for observational studies of patients with SPPs who underwent germline genetic testing. The criteria used to define sporadic tumours were (i) the absence of a family history of PCC/PG, (ii) the absence of syndromic features, (iii) the absence of bilateral disease and (iv) the absence of metastatic disease.ResultsWe included 31 studies including 5031 patients (mean age 44). These patients received tests for any of these ten mutations: SDHAF2, RET, SDHD, SDHB, SDHC, VHL, TMEM127, MAX, Isocitrate Dehydrogenase Mutation (IDH) and NF1. The overall frequency of germline mutation in SPP was 551 of 5031 or 11%; when studies with patients fulfilling four criteria for sporadic tumours were used, the frequency was 171 of 1332 or 13%. The most common germline mutation was SDHB 167 of 3611 (4·6%). Little outcome data were available to assess the benefits of genetic testing in index cases and family members.ConclusionsThe frequency of germline mutations in SPPs is approximately 11–13% and the most common mutations affect less than 1 in 20 patients. The value of testing for germline mutations in patients with SPPs and their family members is unknown, as the balance of potential benefits and harms remains unclear.

Significance: Metabolism-dependent generation of reactive oxygen species (ROS) and associated oxidative damage have been traditionally linked to impaired homeostasis and cellular death. Beyond the adverse effects of ROS accumulation, increasing evidence implicates redox status as a regulator of vital cellular processes. Recent Advances: Emerging studies on the molecular mechanisms guiding stem cell fate decisions indicate a role for energy metabolism in regulating the fundamental ability of maintaining stemness versus undergoing lineage-specific differentiation. Stem cells have evolved protective metabolic phenotypes to minimize reactive oxygen generation through oxidative metabolism and support antioxidant scavenging through glycolysis and the pentose phosphate pathway. Critical Issues: While the dynamics in ROS generation has been correlated with stem cell function, the intimate mechanisms by which energy metabolism regulates ROS to impact cellular fate remain to be deciphered. Future Directions: Decoding the linkage between nutrient sensing, energy metabolism, and ROS in regulating cell fate decisions would offer a redox-dependent strategy to regulate stemness and lineage specification. Antioxid. Redox Signal . 21, 1648–1659.

AbstractGhrelin is a gut hormone processed from the proghrelin peptide acting as the endogenous ligand of the GH secretagogue receptor 1a. The regulatory role of endogenous ghrelin on pulsatile GH secretion and linear growth had to be established. The aim of the present study was to delineate the endogenous actions of preproghrelin on peripheral and central components of the GH axis. Accordingly, the ultradian pattern of GH secretion was measured in young and old preproghrelin-deficient males. Blood samples were collected by tail bleeding every 10 minutes over a period of 6 hours. Analysis of the GH pulsatile pattern by deconvolution showed that GH was secreted in an ultradian manner in all genotypes, with major secretory peaks occurring at about 3-hour intervals. In older mice, the peak number was reduced and secretion was less irregular compared with younger animals. Remarkably, in young Ghrl−/− mice, the amplitude of GH secretory bursts was significantly reduced. In older mice, however, genotype differences were less significant. Changes in GH pulsatility in young Ghrl−/− mice were associated with a tendency for reduced GH pituitary contents and plasma IGF-I concentrations, but with only a minor impact on linear growth. In Ghrl+/− mice, despite reduced Acyl ghrelin to des-acyl ghrelin ratio, GH secretion was not impaired. Ghrelin deficiency was not associated with a reduction in hypothalamic GHRH content or altered response to GHRH stimulation. Therefore, reduction in GHRH production and/or sensitivity do not primarily account for the altered GH pulsatile secretion of young Ghrl−/− mice. Instead, GHRH expression was elevated in young but not old Ghrl−/− mice, suggesting that differential compensatory responses resulting from the absence of endogenous ghrelin is occurring according to age. These results show that endogenous ghrelin is a regulator of GH pulse amplitude in growing mice but does not significantly modulate linear growth.