Citations

AbstractBackground & AimsAntiviral drugs are safe and effective in the third trimester to prevent intrauterine transmission of hepatitis B virus, and are recommended for hepatitis B virus (HBV) infected gravid mothers (between weeks 28 and 32) with high viral load, followed by postnatal hepatitis B immunization in the newborn. We estimated the comparative efficacy of antiviral drugs for prevention of vertical transmission of HBV, through a network meta‐analysis of clinical trials.MethodsWe conducted a comprehensive search of MEDLINE, EMBASE and published proceedings from major liver meetings from January 1980 to November 2014. We conducted pair‐wise meta‐analyses and Bayesian framework using Markov chain Monte Carlo methods, combining direct and indirect evidence for any given pair of treatments.ResultsSeventeen clinical trials involving 2764 newborns of hepatitis B surface antigen seropositive mothers were eligible for analysis. There were no clinical trials involving tenofovir or entecavir. On pair‐wise meta‐analyses, telbivudine (hazard ratio, HR 0.12, 95% confidence interval (CI) 0.04–0.37; I2 = 0%), and Lamivudine (HR 0.40, 95% CI 0.24–0.65; I2 = 0%), were more effective than placebo in reducing vertical transmission of HBV in high viremic hepatitis B e antigen (HBeAg)‐positive chronic Hepatitis B Chinese patients. Sensitivity analyses limited to studies with HBeAg seropositive mothers revealed similar results.ConclusionsBased on a Bayesian network meta‐analysis of clinical trials, combining direct and indirect treatment comparisons, telbivudine appears to be more effective than Lamivudine for preventing vertical transmission of HBV infection. Trials assessing the efficacy of tenofovir or entecavir compared to placebo or other antiviral drugs are lacking.

Abstract Background: In United States there will be an estimated 74,690 new diagnoses and 15,580 deaths in 2014 due to bladder cancer. Lack of reliable markers of early disease and limited chemotherapy options have resulted in poor patient outcomes. A better approach is to treat patients with early intervention using targeted therapy. Arginine metabolic pathway has been identified to be deregulated in bladder cancer. Arginine is either derived from the microenvironment or synthesized by cells containing arginosuccinate synthase I (ASS1). Arginine undergoes subsequent conversion to nitric oxide (NO), which which can activate numerous intracellular signaling mediators, including guanylate cyclase (GC). We evaluated dual targeting of this metabolic pathway by arginine deprivation (ADI-PEG 20, Polaris Pharmaceuticals, San Diego, CA) and NO chelation (Cobinamide) as a therapy for bladder cancer. Experimental Design: Expression of arginine-NO pathway components in FFPE tissue sections was assessed by IHC and correlated with histopathology, outcomes and progression to identify pathway activation during early and late disease and stratified based on moderate to strong expression (2+, 3+) compared to absent to weak expression (0, 1+). In addition, a panel of bladder cell lines was screened for arginine-NO pathway components by immunoblotting and representative ASS1 negative and positive cells were used to evaluate the effects of arginine deprivation and/or NO chelation in vitro on colony formation and cell viability by clonogenic and MTT assays. Effects of NO production on bladder cancer survival and motility was assessed utilizing siRNA gene silencing and small molecule inhibitors. Effects of arginine deprivation by ADI-PEG 20 treatment in vivo was assessed by a mouse xenograft model. Results: Analysis of human tumors showed that ASS1 loss and increase in NOS occurred early in the course of bladder neoplastic progression. We identified loss of the ASS1 enzyme in bladder cancer cells and compensatory dependence on extracellular arginine, which can be successfully targeted using arginine removal to induce bladder cancer cell death, both in vitro and in vivo. We also identified increased nitric oxide synthase (NOS; the enzyme that catalyzes NO production) and GC activation in invasive bladder cancer cell lines. We characterized the effects of NO production on bladder cancer cell survival, growth and motility. Disruption of the NO pathway through gene silencing and small molecule inhibitors resulted in decreased cell survival, migration and invasion. Conclusions: Thus, dual targeting of this metabolic pathway using arginine chelation by the arginine degrading enzyme ADI-PEG20 and NO scavenging by a novel compound Cobinamide can be a potential mechanism to prevent development and/or progression of early bladder neoplasia. Citation Format: Divya Sahu, Sounak Gupta, Andrew M. Hau, Paul Elson, John Bomalaski, Gerry R. Boss, Donna E. Hansel. Targeting the arginine-nitric oxide pathway to arrest development and progression of invasive bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2015-4712

Abstract Glioblastoma multiforme (GBM) is an aggressive and fatal disease commonly treated with radiation and temozolomide (TMZ), but emergence of therapy resistance invariably limits treatment efficacy. Inhibition of Poly-ADP ribose polymerases 1 and 2 (PARP1/2) sensitizes GBM cells, and inhibitors of PARP are emerging as combination partners with TMZ. However, limited brain penetration precludes use of several promising PARP inhibitors in GBM. BGB-290 is a relatively new and potent PARP inhibitor that crosses the blood brain barrier with a brain to plasma ratio of ∼0.2. The focus of the present study was to evaluate antitumor effects of BGB-290, as single agent or in combination with TMZ, in patient derived GBM xenografts and glioma cell lines. In a biochemical assay, low doses (30-100 nM) of BGB-290 suppressed PARP activity, while single agent anti-tumor activity of BGB-290 was modest and restricted to concentrations above 3 μM. Combinations of 0.1 μM BGB-290 with 10 μM TMZ significantly diminished primary neurosphere formation in a patient-derived xenograft line, GBM12, decreasing relative neurosphere count to 3.1 ± 1.3% as compared to 9.2 ± 3.1% with TMZ alone, p = 0.03. Consistent with a mechanism involving disruption of DNA repair, treatment of GBM12 cells with TMZ and BGB-290 combination resulted in robust γH2AX foci formation and a synergistic increase in DNA damage signaling as compared to TMZ or BGB-290 alone. TMZ-sensitizing effects of BGB-290 were heterogeneous in TMZ-resistant (GBM12TMZ) sublines that were developed previously by in vivo selection of parental GBM12 with cyclical TMZ therapy. The average neurosphere formation across 4 resistant sublines lacking MGMT expression after 100 μM TMZ only was 75.3 ± 9.0% versus 14.9 ± 7.4% with TMZ and 0.1 μM BGB-290, p<0.01. In contrast, 2 MGMT overexpressing sublines were much less sensitive to the combination with relative neurospheres 91.9 ± 5.2% versus 73.2 ± 9.2% respectively, p< 0.01. Next Gen Sequencing revealed discrete non-synonymous somatic mutations in the mismatch repair pathway of GBM12TMZ sublines lacking MGMT, which led us to examine the relationship between mismatch repair and sensitizing effects of PARP inhibition. Silencing Msh2 resulted in marked TMZ resistance in U251 cells (94.7± 5.4% relative growth with 100 μM TMZ), while co-treatment with 0.1 μM BGB-290 and 100 μM TMZ decreased growth to 23.5 ± 9.6% (p<0.01), which is similar sensitivity to TMZ alone in U251 parental cells. In an initial in vivo study with orthotopic GBM12 xenografts, administration of BGB-290 at 3 mg/kg twice per day combined with 25 mg/kg TMZ extended survival of animals beyond 300 days (80% survival at day 320), while in the group treated with TMZ alone 80% animals were moribund before day 150. In conclusion, BGB-290 is a promising PARP inhibitor with high potency, cytotoxicity and favorable in vivo efficacy in TMZ sensitive and possibly a subset of recurrent TMZ resistant GBM. Citation Format: Shiv K. Gupta, Brett L. Carlson, Mark A. Schroeder, Katrina K. Bakken, Ann C. Tuma, Jann N. Sarkaria. Inhibition of PARP activity by BGB-290 potentiates efficacy of temozolomide in patient derived xenografts of glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3505. doi:10.1158/1538-7445.AM2015-3505

Objectives: The most common reason for reoperation following arthroscopic hip surgery is conversion to total hip arthroplasty (THA). The purpose of this study was to identify clinical and radiographic risk factors for early conversion to THA. Methods: Data were prospectively collected on all hip arthroscopy patients from January 2009 through December 2011. Inclusion criteria for the study group were patients undergoing hip arthroscopy for a labral tear who eventually converted to THA. Patients were then compared to a control group of patients who underwent hip arthroscopy for a labral tear and did not convert to THA during the same period. Exclusion criteria were patients with previous hip conditions such as Legg-Calves-Perthes, slipped capital femoral epiphysis, pigmented villonodular synovitis, and avascular necrosis. A bivariate analysis of 41 preoperative and intraoperative variables was performed. Results: A total of 792 patients met inclusion and exclusion criteria. A total of 72 (9%) converted to THA. The control group consisted of 720 patients who did not convert to THA. Bivariate analysis demonstrated that the study group had significantly higher means or frequencies than the control group for the following variables: male gender, age at time of surgery, BMI, back pain, previous back surgery, Tönnis grade above 0, acetabular inclination angle, alpha angle, Seldes combined-type labral tear, labral tear size, chondral injury, traction time, labral debridement (versus repair), number of anchors used repair or reconstruction, and capsular release (versus repair). The study group had significantly lower means or frequencies than the control group for the following variables: preoperative patient reported outcome scores, crossover sign, lateral center edge angle, and psoas release. A statistically significant difference in average joint space was not observed. Conclusion: Multiple risk factors are possible preoperative and intraoperative risk factors for conversion to THA following hip arthroscopy. The clinician and patient should be aware of these variables.

Purpose To detail our early experience using concomitant hip arthroscopy and periacetabular osteotomy (PAO) for the treatment of acetabular dysplasia. Methods We prospectively collected and retrospectively reviewed the surgical and outcome data of 17 patients who underwent concomitant hip arthroscopy and PAO between October 2010 and July 2013. Preoperative and postoperative range of motion, outcome and pain scores, and radiographic data were collected. Intraoperative arthroscopic findings and postoperative complications were recorded. Results The group consisted of 3 male and 14 female patients with a mean follow‐up period of 2.4 years. Three patients had undergone previous surgery on the affected hip. Chondrolabral pathology was identified in all 17 patients. Twelve patients underwent labral repair, and five patients underwent partial labral debridement. No patient was converted to total hip arthroplasty or required revision surgery at short‐term follow‐up. All 4 patient‐reported outcome scores showed statistically significant changes from baseline to latest follow‐up ( P < .001). An excellent outcome was obtained in 82% of patients (13 of 16). The lateral center‐edge angle averaged 11° preoperatively and 29° postoperatively. The acetabular inclination averaged 18° preoperatively and 3° postoperatively. The anterior center‐edge angle averaged 7° preoperatively and 27° postoperatively. At most recent radiographic follow‐up, 1 patient had progression of arthritic changes but remained asymptomatic. No other patient showed any radiographic evidence of progression of arthritis. Complications included 3 superficial wound infections, 1 pulmonary embolism, and 1 temporary sciatic neurapraxia. Conclusions Our initial experience with concomitant hip arthroscopy and PAO has been favorable. We noted that all our patients have evidence of chondrolabral damage at the time of PAO when the joint is distracted and evaluated. All patients in this series had intra‐articular pathology treated arthroscopically and showed satisfactory mean clinical improvement. Hip arthroscopy with PAO did not appear to introduce complications beyond the PAO alone. Level of Evidence Level IV, therapeutic case series.

Abstract The labrum of the hip is recognized as being important to the stability of the hip and a major cause of hip pain. Damage to the labrum may result in increased joint stress and articular damage. Labral damage is often treated through various methods, among them simple stitch repair, base refixation, and debridement. Labral reconstruction becomes necessary when the labrum is too damaged to salvage, which renders labral repair improbable and labral debridement ineffective. In contrast to other methods that have been described for this treatment, our technique uses a semitendinosus allograft as a graft source, allowing for arthroscopic hip labral reconstruction. This technique has many advantages and is easily reproducible. It has shown promising results in patients with labral damage. The purpose of this article is to detail the step‐by‐step surgical technique of labral reconstruction using a semitendinosus allograft, in addition to the indications, pearls, and pitfalls of the technique. Technique Video video See video under supplementary data.

BackgroundWhile central obesity increases gastroesophageal reflux (GER) by mechanically disrupting the anti‐reflux barrier, limited data exist on pathways by which central obesity may potentiate esophageal injury by non‐mechanical means. Obesity has been associated with an impaired epithelial intestinal barrier.ObjectiveWe aimed to assess the influence of central obesity and reflux on the squamous esophageal epithelial intercellular space diameter (ICSD).MethodsThe ICSD was measured using electron microscopy in esophageal biopsies from individuals who underwent ambulatory pH monitoring and endoscopy. Anthropometric measurements were obtained on all participants. Participants were classified into four groups: with and without central obesity and reflux.ResultsSixteen individuals were studied with four in each study group. The mean ICSD was almost three‐fold greater (p < 0.001) in the group with central obesity without reflux, compared to controls without central obesity and reflux. It was also comparable to the ICSD in groups with acid reflux only and those with both reflux and central obesity.ConclusionsThere is evidence of esophageal squamous ICSD increase in individuals with central obesity who do not have evidence of acid and nonacid reflux on ambulatory pH monitoring. This may reflect a mechanism by which central obesity potentiates reflux‐induced esophageal injury and inflammation.

We present a case of a patient with a diagnostic dilemma who was referred for possible faecal microbiota transplantation (FMT) for refractory diarrhoea secondary to Clostridium difficile infection (CDI). On detailed history, the patient was exposed to ipilimumab concomitantly while being treated for CDI, and was instead diagnosed with diarrhoea secondary to superimposed ipilimumab-associated colitis. Ipilimumab is an anti-CTLA4 monoclonal antibody approved for use in metastatic melanoma and under trial for other indications. Ipilimumab is associated with several immune-related adverse effects, of which diarrhoea and colitis are the most common. While FMT has shown tremendous efficacy in managing recurrent and refractory CDI, it was not offered in this case due to negative C. difficile testing showing a high degree of suspicion for ipilimumab-associated colitis due to recent drug use. Our patient was successfully managed with fluid resuscitation and steroids, and remains symptom free at last follow-up at 9 months.

Abstract Background. The purpose of this study was to determine the risk of prosthetic joint infection (PJI) as a complication of routine genitourinary (GU) procedures in patients with total hip arthroplasty (THA) or total knee arthroplasty (TKA) and to study the impact of antibiotic prophylaxis administered prior to these procedures. Methods. We conducted a prospective, single-center, case-control study between December 1, 2001 and May 31, 2006. Case patients were hospitalized with total hip or knee PJI. Control subjects underwent a THA or TKA and were hospitalized during the same period on the same orthopedic floor without a PJI. Data regarding demographic features and potential risk factors were collected. The outcome measure was the odds ratio (OR) of PJI after GU procedures performed within 2 years of admission. Results. A total of 339 case patients and 339 control subjects were enrolled in the study. Of these, 52 cases (15%) and 55 controls (16%) had undergone a GU procedure in the preceding 2 years. There was no increased risk of PJI for patients undergoing a GU procedure with or without antibiotic prophylaxis (adjusted OR [aOR] = 1.0, 95% confidence interval [CI] = 0.2–4.5, P = .95 and aOR = 1.0, 95% CI = 0.6–1.7, P = .99, respectively). Results were similar in a subset of patients with a joint age less than 6 months, less than 1 year, or greater than 1 year. Conclusions. Genitourinary procedures were not risk factors for subsequent PJI. The use of antibiotic prophylaxis before GU procedures did not decrease the risk of subsequent PJI in our study.