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Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma., (© 2021. The Author(s).)

Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.

Hydroxyurea is a chemotherapeutic agent that is used in the treatment of various hematological diseases including chronic myelogenous leukemia, polycythemia vera, and sickle cell anemia. Hydroxyurea is also used to treat psoriasis. Drug-induced hyperpigmentation is a known cutaneous side effect of hydroxyurea along with xerosis, dermal ulcers, and dermatomyositis-like eruptions. Hyperpigmentation has been observed in the oral mucosa, nails, and in a generalized or a diffuse pattern. The mechanism of hyperpigmentation related to hydroxyurea is believed to be correlated with increased melanin. Classically, clinical types of diffuse hyperpigmentation owing to iron deposition in the dermis have been associated with minocycline and not with hydroxyurea. We report a novel case in which hydroxyurea hyperpigmentation is associated with iron deposition.

Objective: To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea., Methods: The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted., Results: Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups., Conclusion: In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.

Aim: To assess the efficacy and safety of long-term treatment with nucleos(t)ide analogues in patients with chronic hepatitis B., Materials and Methods: We conducted an observational study in 101 chronic hepatitis B (HBeAg-negative and HBeAg-positive) patients treated (≥3 years) with entecavir, tenofovir or telbivudine., Results: Treatment with entecavir and tenofovir was associated with high rate of virologic and biochemical response (>95%) and HBeAg seroconversion (93% and 67%, respectively). Cumulative rate of virologic resistance was 0; 3.1% and 43.5% for tenofovir, entecavir and telbivudine, respectively. Long-term nucleos(t)ide analogues treatment resulted in a regress of liver fibrosis (from 8.92 to 7.18 kPa, р<0.0001) and reduction in the number of patients with advanced fibrosis (from 48.1% to 13.8%, р<0.0001). Entecavir and tenofovir were safe and well tolerated, while treatment with telbivudine was associated with development of myopathy in 13% of cases., Conclusion: Entecavir and tenofovir might be recommended for the treatment of chronic hepatitis B because of having potent antiviral effect, high genetic barriers against resistance and good safety.

Background: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage., Objectives: To assess the benefits and harms of DAAs in people with chronic HCV., Search Methods: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016., Selection Criteria: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE., Main Results: We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma)., Authors' Conclusions: The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-α), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-α) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats.

Background: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications., Objectives: To assess the benefits and harms of DAAs in people with chronic HCV., Search Methods: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016., Selection Criteria: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE., Main Results: We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn or discontinued DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, then the meta-analysis result showed no evidence of a difference.DAAs on the market or under development seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I² = 77%, 6886 participants, 32 trials, very low-quality evidence) and Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).Withdrawn or discontinued DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I² = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I² = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.Most of all outcome results were short-term results; therefore, we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma)., Authors' Conclusions: Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

The purpose of this study was to evaluate the predictability and stability of laser-assisted subepithelial keratectomy (LASEK) with mitomycin C (MMC) in correction of high myopia (≤-6.0 diopters [D]) as compared to low-to-moderate myopia (>-6.0 D).This is a retrospective, comparative, cohort study which included 43 eyes of 43 consecutive patients who underwent LASEK with MMC in a private hospital in Hong Kong by a single surgeon. Twenty-five eyes had high myopia (mean spherical equivalent [SE] = -8.53 ± 1.82 D) and 18 eyes had low-to-moderate myopia (mean SE = -3.99 ± 1.37 D) before surgery.In terms of refractive predictability, mean SE was significantly better in eyes with preoperative low-to-moderate myopia than high myopia at 6 months (0.04 ± 0.23 vs 0.31 ± 0.52 D, P = .035). In terms of refractive stability, between 1 and 3 months, both groups had mean absolute change of SE of around 0.25 D. Between 3 and 6 months, preoperative low-to-moderate myopia group had significantly less absolute change of SE compared to high myopia group (0.07 vs 0.23 D, P = .003). More eyes with preoperative high myopia changed SE by more than 0.25 D than those with low-to-moderate myopia between 3 and 6 months (32.0% vs 5.6%, P = .057).In conclusion, LASEK with MMC is more unpredictable and unstable in correction of high myopia than low-to-moderate myopia. The refractive outcome of most low-to-moderate myopia correction stabilizes at 3 months. Stability is not achieved until after 6 months in high myopia correction.

Hydroxyurea is a medication with many well-described cutaneous side effects, notably the dermatomyositis-like eruption known as hydroxyurea dermopathy. Although systemic lupus erythematosus has been reported with hydroxyurea use, cutaneous lupus has not. We report a novel case of chronic cutaneous lupus induced by hydroxyurea and propose that this is a side effect that is distinct from hydroxyurea dermopathy., (© 2016 Wiley Periodicals, Inc.)

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome., (© 2015 John Wiley & Sons Ltd.)

Inducing remission in nephrotic children on anti-tubercular therapy is difficult due to the increased metabolism of prednisolone induced by rifampicin. We report a child with nephrotic syndrome treated successfully with an increased dose of steroids without discontinuing anti-tubercular therapy.

Introduction: Oral nucleoside/ nucleotide analogues (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects associated with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking., Areas Covered: Significant adverse effects associated with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno-protective effect of telbivudine are also discussed., Expert Opinion: Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring.

Background and Aims: Refractory benign gastrointestinal (GI) strictures represent a difficult management problem given the limited therapeutic interventions available. We performed a systematic review of all published cases using mitomycin C in the treatment of GI strictures., Methods: Searches of MEDLINE and Embase databases were performed to identify studies reporting application of mitomycin C for GI strictures. Review of titles/abstracts, full review of potentially relevant studies, and data abstraction were performed independently by 2 authors., Results: Of 549 citations, 24 studies with 145 patients (74% pediatric and 26% adult) met inclusion criteria. Esophageal strictures were the most common (79%) site of refractory strictures treated with mitomycin C, with caustic injury the most common underlying etiology. The concentration (range, 0.1 to 2 mg/mL; median, 0.4 mg/mL), number of applications (range, 1 to 12; median, 1), duration of applications (range, 1 to 5; median, 2 min), and technique of application (cotton pledget, spray, injection, special catheters) varied among studies. Ninety-one patients (73%; children: 80%, adults: 59%) had a complete response; 26 (21%) had a partial response. Only 1 (0.7%) adverse event was reported: cutaneous sclerosis attributed to microperforation and mitomycin C extravastion after injection. Mean follow-up was 23 (4 to 60) months., Conclusions: Local mitomycin C application seems to be a safe and effective therapy for benign refractory GI strictures of varying etiology in both pediatric and adult populations. Although the results of this systematic review are highly encouraging, it should be considered investigational. Additional randomized trials and larger prospective studies are needed to confirm these results and to better define the optimal dose, concentration, duration and technique of mitomycin C application.

Oxalate nephropathy is an uncommon cause of acute kidney injury. Far rarer is its association with scleroderma, with only one other published case report in the literature. We report a case of a 75-year-old African-American female with a history of systemic scleroderma manifested by chronic pseudo-obstruction and small intestinal bacterial overgrowth (SIBO) treated with rifaximin, who presented with acute kidney injury with normal blood pressure. A renal biopsy demonstrated extensive acute tubular injury with numerous intratubular birefringent crystals, consistent with oxalate nephropathy. We hypothesize that her recent treatment with rifaximin for SIBO and decreased intestinal transit time in pseudo-obstruction may have significantly increased intestinal oxalate absorption, leading to acute kidney injury. Oxalate nephropathy should be considered in the differential diagnosis of acute kidney injury in scleroderma with normotension, and subsequent evaluation should be focused on bowel function to include alterations in gut flora due to antibiotic administration.

Purpose: To compare the surgical results of trabeculectomy and Ahmed glaucoma valve implantation after a previous failed trabeculectomy., Methods: A retrospective comparative case series review was performed on 31 eye surgeries in 20 patients with primary congenital glaucoma who underwent trabeculectomy or Ahmed glaucoma valve implantation after a previous failed trabeculectomy with mitomycin C., Results: The preoperative mean intraocular pressure was 25.5 mmHg in the trabeculectomy group and 26.9 mmHg in the Ahmed glaucoma valve implantation group (p = 0.73). The 48-month postoperative mean intraocular pressure was 19.6 mmHg in the trabeculectomy group and 20.2 mmHg in the Ahmed glaucoma valve implantation group (p = 0.95). The 12-month trabeculectomy success rate was 69%, compared with 64% for Ahmed glaucoma valve implantation, and the 48-month success rates were 42% and 36% for trabeculectomy and valve implantation, respectively. The success rates following the entire follow-up period were not significantly different between the two groups (p > 0.05 by log rank test). Postoperative complications occurred in 25% of the trabeculectomy-operated eyes and 9% of the Ahmed-implanted eyes (p = 0.38)., Conclusions: There was no significant difference in surgical outcome between the trabeculectomy and Ahmed glaucoma valve implantation groups, neither of which had favorable results. However, the trabeculectomy group demonstrated a higher prevalence of adverse complications such as post-operative endophthalmitis.

Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT., Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy., Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses)., Conclusion: For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Purpose: The purpose of this report is to present a case of hepatotoxicity secondary to off-label rifampin therapy for the treatment of chronic central serous choroidopathy., Methods: Case report., Results: A patient with chronic central serous chorioretinopathy was treated with oral rifampin. Three weeks after the initiation of therapy, fatigue, nausea, and malaise associated with elevated liver enzyme elevations were noted. Symptoms resolved and liver enzymes normalized after discontinuing rifampin., Conclusion: Rifampin-induced hepatic injury can occur during therapy for chronic central serous chorioretinopathy. Potential hepatotoxicity must be considered and followed closely during off-label rifampin treatment.

The treatment of hepatitis C virus (HCV) has made significant advances with the development of new direct-acting antivirals. Nucleotide polymerase inhibitors are one class of these new medications that have been shown to be highly effective, safe and well tolerated as part of an antiviral regimen. Sofosbuvir has become the first drug in this class to be approved for clinical use, supported by results from extensive phase II and phase III clinical trials. This review will further discuss nucleotide polymerase inhibitors, including the data supporting their use as part of interferon-free HCV treatment regimens., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of fidaxomicin (FDX)., Data Sources: A search of PubMed using the terms "fidaxomicin," "OPT-80," "PAR-101," "OP-1118," "difimicin," "tiacumicin," and "lipiarmycin" was performed. All English-language articles from 1983 to November 2013 were reviewed for relevance. Bibliographies of all articles were reviewed as well as the manufacturer's Web site to further identify relevant information., Study Selection: All English-language articles from 1983 to November 2013 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches., Data Synthesis: FDX is the first macrolide antibiotic with a narrow spectrum of activity targeted against Clostridium difficile. It is administered orally without regard to food. The primary route of elimination is fecal excretion. Advanced age, hepatic dysfunction, or renal impairment do not alter its disposition. Phase III clinical trials have demonstrated that FDX 200 mg twice daily for 10 days is noninferior to vancomycin 125 mg four times daily for 10 days in the treatment of adults with C. difficile infection and is associated with lower recurrence rates. FDX has a favorable side effect profile and a low potential for drug interactions., Conclusion: FDX has been shown to be safe and effective in the treatment of adults with C. difficile infection. Further research and pharmacoeconomic studies are needed to clarify and refine its role in the treatment of patients at high risk for recurrence.

Background: Hydroxyurea at a relatively low dose is frequently prescribed to induce hemoglobin F production in patients with sickle cell and β-thalassemia diseases because of its good efficacy and safety profiles. However, a potentially fatal gastrointestinal ulceration was recently found and herein reported., Case Presentation: A thirty-seven-year-old man with transfusion dependent hemoglobin E/β-thalassemia disease was treated with hydroxyurea to induce hemoglobin F production since 2007 without incident. From 2008 to April 2010, episodes of hematochezia, mucous diarrhea and epigastric pain intermittently manifested. Four colonoscopies done during the period repeatedly showed ulcerative lesions from the terminal ileum to the ascending colon with a non-specific histo-pathologic finding. Subsequently, ulcerative lesions also developed at the pharynx, histo-pathologic findings of which were not different from those in the colon. These ulcerative lesions resolved within a month after discontinuing hydroxyurea in April 2010 and have not recurred since., Conclusion: The findings suggested role of hydroxyurea in the pathogenesis of these ulcers, and that it must be immediately discontinued to prevent further damage to the digestive mucosa.

Background: No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy., Methods: In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221., Findings: Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment., Interpretation: Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy., Funding: National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background & Aims: Chemotherapy induces an increase of intestinal permeability that is partially related to an alteration of tight junction proteins, occludin and zonula occludens-1 (ZO-1). Protective effects of glutamine on intestinal barrier function have been previously shown but the effects of other amino acids remained poorly documented. Thus, we aimed to evaluate the effects of nine amino acids on intestinal permeability during methotrexate (MTX) treatment in Caco-2 cells., Methods: Caco-2 cells were incubated in culture medium supplemented with glutamine, arginine, glutamate, leucine, taurine, citrulline, glycine, histidine or cysteine during 24 h and then treated with MTX (100 ng/ml). The dose of each amino acid was 16.6 fold the physiological plasma concentrations. Barrier function was assessed by transepithelial electrical resistance (TEER), FITC-dextran paracellular flux, occludin and ZO-1 expression and localization. Signaling pathways were also studied., Results: Only glutamine, glutamate, arginine and leucine reversed the decrease of TEER observed after MTX treatment (P < 0.05). Interestingly, the addition of 6-diazo-5-oxo-1-norleucine, an inhibitor of glutaminase, blunted the effect of glutamine on MTX-treated cells (P < 0.05). Glutamine and arginine combination restored TEER and FITC-dextran flux to a similar extent than glutamine alone. In addition, pretreatment of Caco-2 cells with glutamine and arginine, alone or combined, differently limited the decrease of ZO-1 and occludin expression (P < 0.05) and the alteration of their cellular distribution, through c-Jun N-terminal kinase (JNK), Extracellular signal-regulated kinase (ERK) and nuclear factor kappa B (NF-κB) pathways., Conclusions: Glutamine prevented MTX-induced barrier disruption in Caco-2 cells. Arginine also had protective effects but in a lesser extent. The effect of glutamine and arginine should be evaluated in vivo., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Nilotinib, a second-generation tyrosine kinase inhibitor with 20- to 30-fold greater potency than imatinib, was developed to overcome imatinib intolerance or resistance. Recently, nilotinib has been approved as a first-line treatment for chronic myelogenous leukemia in the US and Japan. Tumor lysis syndrome (TLS) is an extremely rare adverse event that can occur during treatment with nilotinib, with only a few reported cases to date. Herein, we report two patients who developed TLS soon after the start of treatment with nilotinib. While in the first case, which co-presented with underlying mild-to-moderate renal insufficiency due to polycystic kidney disease, the TLS resolved on discontinuation of the drug, the second patient, who had an exceedingly high white blood cell count, presented with disseminated intravascular coagulation and severe liver injury triggered by TLS that developed after the start of nilotinib treatment, and died of multiple organ failure. Therefore, caution is necessary when this drug is used in the first-line setting in patients with renal insufficiency or a high tumor burden.

The association of essential thrombocythemia and multiple myeloma is extremely rare, with only three patients previously treated with hydroxyurea reported in the literature until now. In this paper, we report the case of a 66 year old male who developed IgG-kappa M six years after the diagnosis of essential thrombocythemia, for which he had received hydroyurea. The possible etiological and pathogenic link between both these entities is here discussed.

Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients., (© 2013 John Wiley & Sons Ltd.)

Object: The authors conducted a study to evaluate the effects and the safety of locally applied mitomycin C (MMC) on epidural fibrosis after microendoscopic discectomy (MED)., Methods: Seventy-five patients undergoing single-level unilateral MED for lumbar disc herniation were randomly assigned to receive cotton wool impregnated with either 0.5 mg/ml MMC or saline applied at the site of discectomy for 5 minutes. Outcome measures included degrees of pain severity, functional disability, physical symptoms, and quantitative evaluation of postoperative epidural fibrosis shown on follow-up lumbar contrast-enhanced MRI., Results: Sixty-two patients completed the follow-up. Neither serious drug adverse effects nor clinically significant laboratory adverse effects were observed. Patients in both groups showed similar clinical recoveries postoperatively. A statistically significant difference (p < 0.05) between the 2 treatments was shown in a quantitative evaluation of postoperative MRI-documented epidural fibrosis in the MMC group and the saline group using a modified grading system. The mean cross-sectional areas of epidural fibrosis were 7.32-70.06 mm(2) in the MMC group and 22.94-90.48 mm(2) in the saline group. The epidural fibrosis index ranged from 0.0296 to 0.3267 in the MMC group and from 0.1191 to 0.3483 in the saline group. A significant difference was also observed using the Ross grading system to evaluate postoperative MR images., Conclusions: Although no benefit was observed clinically, the authors observed a notable reduction of epidural fibrosis after MED radiologically, with 0.5 mg/ml MMC locally applied and no clinical side effects.

Objective: To evaluate the possible effect of methotrexate (MTX) on rat ovaries by measuring serum antimullerian hormone (AMH), the novel marker of the ovarian reserve., Methods: Pretreatment serum AMH levels were measured in 15 Wistar albino rats. MTX was given in 1 mg/kg dose in days 1, 3, 5, and 7. Serum AMH levels were measured twenty-four hours after each MTX administration. Pre- and post-treatment serum AMH levels were compared., Results: Pretreatment median serum AMH was 102.4 ng/mL (25%: 41.9; 75%: 179.8). The median serum AMH levels were 70.6 ng/mL (25%: 54.08; 75%: 125.5); 136.1 ng/mL (25%: 57.3; 75%: 223.09); 121.2 ng/mL (25%: 52.5; 75%: 151.5); and 104.7 ng/mL (25%: 65.8; 75%: 265.5) after the first, second, third, and fourth methotrexate administrations, respectively. The ratio of the final (eighth day) median serum AMH level to the pretreatment median AMH level was 1.27 (25%: 0.84 and 75%: 2.57). Wilcoxon related samples test showed that final AMH was significantly higher as compared to the second day AMH measurement (p = 0.041)., Conclusion: MTX administration did not cause a statistically significant change between pretreatment and final serum AMH levels in rats. There was no decrease in AMH levels indicating a decrease in ovarian reserve.

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, has been reported to exert an anti-tumor effect in various cancer cells. However, the effect of TB on oral cancer has not been evaluated. Herein we demonstrate that TB (0-60 µM) concentration-dependently decreased cell number in cultured human oral squamous cell carcinoma (OSCC), KB cells. The anti-proliferation effect of TB was also observed in two other OSCC cell lines, SAS and SCC 15. TB (60 µM) was not cytotoxic and its inhibition on KB cell growth was reversible. [(3) H]thymidine incorporation and flow cytometric analyses revealed that TB-inhibited DNA synthesis and induced the G0/G1 cell-cycle arrest. The TB-induced cell-cycle arrest occurred when the cyclin-dependent kinase 2 activity was inhibited just as the protein levels of p21(cip1) and p27(kip1) were increased. The TB-induced G0/G1 cell-cycle arrest was completely blocked when the expressions of p21(cip1) and p27(kip1) were knocked-down together. Taken together, these results suggest that the p21(cip1) - and p27(kip1) -associated signaling pathways might be involved in the TB-induced anti-proliferation in KB cells. In vivo, TB (50 mg/kg, i.p.) significantly inhibited the KB tumor size. In these TB-treated tumors, increases in the levels of p21(cip1) and p27(kip1) protein and decreases in the number of proliferating cell nuclear antigen-positive cells and the microvessel density were observed. These findings demonstrate for the first time that TB might have potential to serve as a therapeutic tool in the treatment of oral cancer., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Packed red blood cell (PRC) transfusion with iron chelation is the mainstay of treatment for β-thalassemia major. This prospective interventional trial serves as a follow up to our similar earlier study that evaluated the efficacy and safety of hydroxyurea (HU) in minimizing PRC transfusions in patients with β-thalassemia major., Methods: One hundred fifty-two patients with β-thalassemia major received HU at a mean dose of 16 mg/kg/d. The results were analyzed at the end of 24 months. Transfusion requirement during the 6 months preceding the study was considered as the control., Results: One hundred forty-six of 152 patients were evaluated after 24 months of follow up; 6 patients were either lost to follow-up or withdrew consent. Grade 1 myelosuppression was observed in 4 patients and diarrhea in 2 patients. Sixty children (41%) did not require any transfusion after using HU; 57 patients (39%) showed partial response with greater than 50% reduction in PRC transfusion; and 29 patients (20%) were nonresponders with less than 50% reduction in PRC transfusion. The mean volume of PRC transfused was reduced for all patients., Conclusions: HU was found to be safe in patients with β-thalassemia major, and resulted in the reduction of transfusion requirement and in an increase in the interval between transfusions.

Objective: To review the literature concerning the role of rifampin in the combination treatment of Legionella pneumophila pneumonia., Data Sources: A search of MEDLINE and Ovid databases was conducted (January 1970-May 2011) using the search terms Legionella pneumophila, pneumonia, Legionnaires' disease, rifampin or rifampicin, macrolide, fluoroquinolone, erythromycin, clarithromycin, levofloxacin, ciprofloxacin, and moxifloxacin, Study Selection and Data Extraction: In vivo studies published in English that compared antimicrobial therapies including rifampin for the treatment of Legionella pneumonia, as well as in vitro studies including an assessment of rifampin bioactivity, were included., Data Synthesis: Macrolides and fluoroquinolones have been effective as monotherapy in the treatment of L. pneumophila pneumonia. This review includes evidence summaries from 4 bioactivity evaluations, 6 clinical studies, and 6 reported cases of combination rifampin use. Combined with supporting evidence, the role of combination rifampin therapy is further delineated., Conclusions: Interpretation of the data is limited by the potential for selection bias and lack of consistent comparators. Rifampin therapy should be considered only for patients with severe disease or significant comorbid conditions (eg, uncontrolled diabetes, smoking, or obstructive lung disease) including immunocompromised hosts and those refractory to conventional monotherapy regimens. Caution for significant adverse drug events and drug-drug interactions should be taken with the addition of rifampin.

Adrenal insufficiency is rarely associated with adrenal haemorrhage. In this report, a case of polycythaemia vera with adrenal haemorrhage and insufficiency has been presented.

Standardized criteria of response to treatment and a unified definition of resistance/intolerance to hydroxycarbamide (HC) in essential thrombocythaemia (ET) have been proposed by the European LeukaemiaNet (ELN). We have retrospectively evaluated such criteria in 166 ET patients treated with HC for a median of 4·5 years. Overall, 134 patients achieved a complete clinicohaematological response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n = 15) or intolerance (n = 21) to HC. Fifteen cases developed anaemia with thrombocytosis, which was associated with a high incidence of myelofibrosis and death from any cause. Other definitions of resistance were less useful. Factors determining the thrombotic risk were a history of prior thrombosis and a baseline leucocyte count >10 × 10⁹/ l. Of note, patients achieving a CR, even if sustained during the entire follow-up, did not benefit from a lower incidence of thrombosis or an improved survival. In conclusion, most ET patients respond to HC, but the achievement of response, as defined by the ELN, does not correlate with the patients' outcome. The best discriminating ELN criterion of resistance to HC was the detection of anaemia, which also identified a subgroup of patients with poor prognosis., (© 2010 Blackwell Publishing Ltd.)

Objective: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial., Methods: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1-T2) and then every 2 months throughout treatment (T3-T10) and posttreatment periods (T11-T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC)., Results: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had -1.88 for GMFM (p = 0.11), -0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function., Conclusion: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia., Classification of Evidence: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.

Purpose: To examine the rates of intermediate-term intraocular pressure (IOP) control after trabeculectomy with adjunctive mitomycin C (MMC) and assess for associated complications., Methods: Medical records of patients undergoing primary trabeculectomy with MMC at Concord Repatriation Hospital, Sydney between January 1997 and December 2005 were reviewed. All eyes with a minimum of 2-year follow up were included. Follow-up data were collected in a standardized form on postoperative IOP, bleb-related and other complications. Success was measured as IOP ≤ 18 mmHg and ≥ 6 mmHg (criteria 1) with (qualified success) or without (absolute success) the use of glaucoma medications. A secondary outcome measure was an IOP reduction of greater than 20% from baseline (criteria 2). Eyes with preoperative IOP of 18 mmHg or less were included, but also analysed separately to those eyes with preoperative IOP above 18 mmHg., Results: Sixty eyes from 42 patients were included in the study, with 3-year follow up on 48 eyes. Mean preoperative IOP was 25.3 mmHg (range 8-45) and mean postoperative IOP was 14.0 mmHg at 1- and 2-year follow up, and 14.7 mmHg at 3 years (ranges: 3-31, 4-30 and 8-45 mmHg respectively). Cumulative success for criteria 1 was 85.0% at 2 years and 83.3% at 3 years, and for criteria 2 it was 80.0% and 79.2%, respectively. The number of eyes on glaucoma medications was reduced from 51 preoperatively to 30 at 3 years. Complications were infrequent. There was one eye with a shallow anterior chamber beyond the immediate postoperative period. One eye required cataract surgery at 1-year follow up. Subgroup analysis was performed using the first operated eye only, and results did not differ significantly from overall results., Conclusion: MMC-augmented trabeculectomy can significantly reduce IOP in the short and intermediate term, with a favourable safety profile., (© 2010 The Authors. Clinical and Experimental Ophthalmology © 2010 Royal Australian and New Zealand College of Ophthalmologists.)

Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic HCV infection. An estimated 180 million people worldwide are infected with HCV and at risk of developing chronic liver diseases that can lead to cirrhosis or hepatocellular carcinomas. HCV infection is the main cause of liver transplantation in industrialized nations. Filibuvir is a potent and specific inhibitor of the virally-encoded NS5B polymerase, and inhibited genotype 1 subgenomic HCV replication in the cell-based replicon system. Filibuvir demonstrated a good pharmacokinetic profile and oral bioavailability in preclinical animal studies, which is consistent with twice-daily dosing in humans. In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. The incidence and severity of adverse events were similar to SoC and placebo. At the time of publication, phase I pharmacokinetic clinical trials were ongoing in healthy volunteers and a phase IIb clinical trial was assessing filibuvir in combination with SoC for up to 24 weeks in treatment-naïve patients infected with genotype 1 HCV. Results of this trial will help to characterize the potential of this drug class for the treatment of HCV infections.

Objective: To illustrate the association between hydroxyurea and the development of ulcers., Method: A case study is presented, in which histological changes, mean corpuscular volume (MCV) and transcutaneous oxygen tension (TcPO2) were all measured and analysed, both during hydroxyurea treatment and following it's discontinuation., Results: Two months following the cessation of hydroxyurea therapy, the patient's ulcer had healed completely. Biopsy specimens taken before and after its discontinuation showed a considerable improvement in vascularity, with a capillary density 6.28 times higher after discontinuation of the drug. TcPO2 was just 8mmHg at the first measurement, and this increased to 65mmHg at the second., Conclusion: These findings suggest deficient neovascularisation and circulation during hydroxyurea treatment. Changes in MCV also appeared to have an effect on the progress of wound healing, which supports the hypothesis that macroerythrocytosis may be involved in the development of these rare ulcers, via impairment of the microcirculatory rheology.

Background: Chronic hydroxyurea therapy is associated with numerous cutaneous adverse effects. While hydroxyurea-associated nonmelanoma skin cancers are known to be associated with significant morbidity and occasional mortality, to date, dermatomyositis-like eruption has been considered a benign entity, other than its ability to mimic true dermatomyositis leading to inappropriate immunosuppression. More recently, hydroxyurea-associated squamous dysplasia has been characterized as a premalignant precursor to hydroxyurea-associated nonmelanoma skin cancers and shown to manifest abnormal p53 expression., Observations: An elderly woman receiving chronic hydroxyurea therapy for myelodysplasia developed a dermatomyositis-like eruption that was misdiagnosed as true dermatomyositis, leading to continuation of hydroxyurea. Years later she developed severe hydroxyurea-associated nonmelanoma skin cancers resulting in discontinuation of hydroxyurea, poor control of her myelodysplasia, and death. Re-evaluation with immunohistochemical analysis of tissue from her original dermatomyositis-like eruption revealed focal confluent nuclear expression of p53 along the lower layers of the epidermis, suggestive of a premalignant state., Conclusions: We suggest that dermatomyositis-like eruption and hydroxyurea-associated squamous dysplasia represent similar clinical manifestations of a common underlying chronic phototoxic process involving aberrant keratinocyte p53 expression mediated by hydroxyurea's antimetabolite properties and UV radiation exposure. Accordingly, we suggest that dermatomyositis-like eruption, previously considered a benign entity, may represent a premalignant precursor of hydroxyurea-associated nonmelanoma skin cancers warranting discontinuation of hydroxyurea therapy.

Not much is known about the side effects of mitomycin C (MMC), an anti-fibrogenetic agent, in the upper aerodigestive tract. However, its use in ophthalmology is widely known and without quantitatively important side effects. A literature review was performed for side effects of MMC in the upper aerodigestive tract. Forty-six articles, describing the use of MMC to prevent scarring, were retracted from PubMed. Thirty-two are human studies. MMC is used in different concentrations (0.1-10 mg/ml) with different application times (2-5 min) and frequencies (up to 4 times). Five hundred and thirty-eight patients were included in those publications, of whom 19 developed side effects (3.53%). No side effects developed in studies, where post-application irrigation with saline was reported. The longest mean follow-up period is 75.5 months. Direct relations between the reported side effects and MMC seem absent in most studies. Serious complications seem to occur when MMC is used in high concentrations. Unfortunately, sometimes crucial information is lacking. One patient was described who supposedly developed laryngeal carcinoma after repeated treatment of hyperkeratosis and anterior commissure webbing. Animal studies show that excessive fibrin production can lead to acute airway obstruction. In conclusion, topical application of MMC on a wound with consecutive irrigation with saline can be performed safely to prevent scar formation in circular structures of the upper aerodigestive tract. Long-term yearly control of the application site seems advisable.

A 74-year-old patient, suffering for 20 years from polycythemia rubra vera, was treated with hydroxyurea for 2 years. Intensive xerosis (ichthyosis-like) and violaceous papules on the dorsal hand surfaces were observed. There was also reddish purple periorbital erythema resembling "heliotrope erythema". Such a disease pattern has been described as "hydroxyurea-induced dermatomyositis-like eruption" - a drug-adverse reaction associated with hydroxyurea therapy. The reaction has typical dermal features of dermatomyositis without any systemic symptoms (in the case of our patient, antinuclear antibodies absent and creatine phosphokinase within the normal range). The above reaction is associated with chronic hydroxyurea uptake and, after withdrawing the drug, alleviation of skin lesions usually takes place after 10 days to 18 months with no recurrences. In the case of our patient, we observed clinical improvement after 3 months; xerosis decreased, heliotrope erythema vanished, and there was also a decrease in both the number and intensity of violaceous papules on the dorsal hand surfaces.

Purpose: To report a possible association between fluoroquinolones and diplopia., Design: Database study., Participants: A total of 171 subjects were studied., Methods: Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, World Health Organization, and Food and Drug Administration were collected on fluoroquinolones and diplopia., Main Outcome Measures: Data garnered from the spontaneous reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data., Results: A total of 171 case reports of diplopia associated with fluoroquinolones were reported, including 76 men, 91 women, and 4 case reports in which the gender was not specified. The median age was 51.6 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 9.6 days (range 1 day to 5 months). Seventeen subjects also had concomitant tendinitis, 49 patients were 60 years or older, 1 patient had renal cysts, and 4 patients were taking systemic anti-inflammatory steroids. There were 53 positive dechallenge and 5 positive rechallenge case reports., Conclusions: According to World Health Organization criteria, the relationship between fluoroquinolone therapy and diplopia is "possible." This causality assessment is based on the time relationship of drug administration and ADR development, the multiple positive dechallenge and rechallenge reports, and the plausible mechanism by which diplopia could occur: possible tendinitis of the extraocular muscles., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

We describe a patient who was treated with high-dose intravenous and intrathecal methotrexate for acute lymphoblastic leukemia, and who manifested a false photosensitivity reaction with no prior evidence of sun exposure. This patient later experienced delayed transient hemiparesis following methotrexate administration, although without long-term sequelae. The etiology of these events is obscure, but suggestive of a vasculitic or immune-mediated reaction to methotrexate., (Copyright 2009 Wiley-Liss, Inc.)