Citations

AbstractHairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Abstract Motivation Testing SNP–SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP–SNP interactions are underdeveloped. Results We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA_Full, Geno_Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR, EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP–SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns. Availability and Implementation The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/. Supplementary information Supplementary data are available at Bioinformatics online.

Objectives: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. Patients and Methods: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m 2 of gemcitabine (on days 1, 8), 650 mg/m 2 of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. Results: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P =0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P =0.39). Conclusions: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.

ABSTRACT We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) foreign body-associated osteomyelitis and used it to compare tedizolid alone and in combination with rifampin against rifampin alone, vancomycin plus rifampin, and vancomycin alone. A clinical strain of MRSE was inoculated into the proximal tibia, and a stainless steel wire with a precolonized MRSE biofilm was implanted. Following a 1-week infection period, 92 rats received either no treatment ( n = 17) or 14 days of intraperitoneal tedizolid ( n = 15), tedizolid plus rifampin ( n = 15), rifampin ( n = 15), vancomycin plus rifampin ( n = 15), or vancomycin ( n = 15). Quantitative bone and wire cultures were performed after treatment completion and also 1 week after infection in a separate group of five rats. The median quantity of staphylococci in bone after the 1-week infection period was 4.89 log 10 CFU/g bone (interquartile range, 3.83 to 5.33 log 10 CFU/g bone); staphylococci were recovered from all associated wires. A median quantity of staphylococci of 3.70 log 10 CFU/g bone was detected in bones of untreated control rats after 3 weeks. Quantities of staphylococci in bones of all treatment groups except the group receiving vancomycin alone (2.78 log 10 CFU/g) were significantly lower than those for untreated controls, with no staphylococci being detected in the groups receiving rifampin monotherapy, tedizolid-plus-rifampin combination therapy, and vancomycin-plus-rifampin combination therapy. Quantities of staphylococci on wires from all treatment groups that included rifampin were significantly lower than those for untreated controls. No resistance to rifampin, tedizolid, or vancomycin was detected. Tedizolid combined with rifampin was active in a rat model of MRSE foreign body-associated osteomyelitis.

SummaryThe clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real‐world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community‐, 17 academic‐, and 3 government‐based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient‐level observational data that represent real‐world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment ofGBMincluding the tightly controlled interface between the bloodstream and central nervous system termed the ‘neurovascular unit,’ a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal ofGBMtherapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified asGBMtargets include the transferrin receptor, low‐density lipoprotein receptor‐related protein, αvβ3integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR),EGFRvariantIII, interleukin‐13 receptor α chain variant 2, and fibroblast growth factor‐inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the keyGBMtargets with the goal of advancing the understanding and development of targeted nanotherapeutics forGBM.WIREs Nanomed Nanobiotechnol2017, 9:e1439. doi: 10.1002/wnan.1439This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging TechnologiesTherapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

AbstractBackgroundEducators in pediatric hematology–oncology lack rigorously developed instruments to assess fellows’ skills in humanism and professionalism.ProcedureWe developed a novel 15‐item self‐assessment instrument to address this gap in fellowship training. Fellows (N = 122) were asked to assess their skills in five domains: balancing competing demands of fellowship, caring for the dying patient, confronting depression and burnout, responding to challenging relationships with patients, and practicing humanistic medicine. An expert focus group predefined threshold scores on the instrument that could be used as a cutoff to identify fellows who need support. Reliability and feasibility were assessed and concurrent validity was measured using three established instruments: Maslach Burnout Inventory (MBI), Flourishing Scale (FS), and Jefferson Scale of Physician Empathy (JSPE).ResultsFor 90 participating fellows (74%), the self‐assessment proved feasible to administer and had high internal consistency reliability (Cronbach's α = 0.81). It was moderately correlated with the FS and MBI (Pearson's r = 0.41 and 0.4, respectively) and weakly correlated with the JSPE (Pearson's r = 0.15). Twenty‐eight fellows (31%) were identified as needing support. The self‐assessment had a sensitivity of 50% (95% confidence interval [CI]: 31–69) and a specificity of 77% (95% CI: 65–87) for identifying fellows who scored poorly on at least one of the three established scales.ConclusionsWe developed a novel assessment instrument for use in pediatric fellowship training. The new scale proved feasible and demonstrated internal consistency reliability. Its moderate correlation with other established instruments shows that the novel assessment instrument provides unique, nonredundant information as compared to existing scales.