Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.

OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment.

RATIONALE: Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. OBJECTIVES: The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. MATERIALS AND METHODS: The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. RESULTS: In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. CONCLUSIONS: The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Prediction of the bulking phenomenon in wastewater treatment plants

The control and prediction of wastewater treatment plants poses an important goal: to avoid breaking the environmental balance by always keeping the system in stable operating conditions. It is known that qualitative information — coming from microscopic examinations and subjective remarks — has a deep influence on the activated sludge process. In particular, on the total amount of effluent suspended solids, one of the measures of overall plant performance. The search for an input–output model of this variable and the prediction of sudden increases (bulking episodes) is thus a central concern to ensure the fulfillment of current discharge limitations. Unfortunately, the strong interrelationbetween variables, their heterogeneity and the very high amount of missing information makes the use of traditional techniques difficult, or even impossible. Through the combined use of several methods — rough set theory and artificial neural networks, mainly — reasonable prediction models are found, which also serve to show the different importance of variables and provide insight into the process dynamics

The "reversed" treatment approach for synchronous liver metastases and colorectal cancer. Feasability and first results

Background: The « reversed treatment» approach inverts the treatment sequence of¦advanced synchronous colorectal liver metastases - i.e. the liver metastasis is¦treated first, followed by resection of the primary tumor. Chemotherapy is performed¦before and after liver surgery. We recently started to use a reversed treatment¦approach in selected patients. The aim of this study is to critically assess this new¦treatment modality.¦Methods: Nine patients (7 male, 2 female, mean age 62 years) benefited from this¦new treatment between November 2008 and May 2010. The data were collected¦retrospectively.¦Results: All patients responded to the neoadjuvant chemotherapy. The median¦number of liver metastases was 6 (range 1 - 22). The median size of the largest liver¦metastases was 4.3 cm (range 2.6 - 13 cm). Three patients had portal vein¦embolization prior to liver surgery. Two patients could not complete the treatment.¦One had to undergo emergency surgery for occluding colonic tumor. The second one¦showed liver recurrence before starting the adjuvant chemotherapy. The seven¦patients who completed the treatment are still alive after a median time of 27 months¦(range 17 - 37 months). Seven of them had recurrence (1 rectal, 6 liver). The median¦disease-free survival was 9 months (range 0 - 17 months).¦Conclusion: Based on our preliminary experiences, the reversed strategy shows¦encouraging results for the treatment of advanced synchronous colorectal liver¦metastases in well selected patients. The treatment was generally well tolerated and¦long term survival seems to be prolonged.

Patient versus general practitioner perception of problems with treatment adherence in type 2 diabetes: from adherence to concordance.

OBJECTIVES: To determine the prevalence of problems with treatment adherence among type-2 diabetic patients with regards to medication, dietary advice, and physical activity; to identify the associated clinical and psychosocial factors; and to investigate the degree of agreement between patient-perceived and GP-perceived adherence. METHODS: Consecutive patients were solicited during visits to 39 GPs. In total, 521 patients self-reported on treatment adherence, anxiety and depression, and disease perception. The GPs reported clinical and laboratory data and patients' adherence. A multivariate analysis identified the factors associated with adherence problems. RESULTS: Problems of adherence to medication, dietary advice, and physical activity recommendations were reported by 17%, 62%, and 47% of the patients, respectively. Six independent factors were found associated with adherence problems: young age, body-mass index (BMI) > 30 kg/m(2), glycosylated haemoglobin (HbA(1c)) > 8%, single life, depression, and perception of medication as a constraint. Agreement between patients' and GPs' assessments of treatment problems reached 70%. CONCLUSION: In type 2 diabetes, problems with dietary advice or physical activity are far more frequent than problems with medication, and not all physicians are fully aware of patients' problems. More active listening and shared decision-making should enhance adherence and improve outcomes.

Contribution of PaTrin-2 in Radiotherapy with Temozolomide for the Treatment of Glioblastoma Expressing MGMT

Purpose/Objective(s): Current standard treatment of glioblastoma is radiotherapy (RT) concomitant with temozolomide (TMZ), an alkylating agent. O6-methylguanine-DNA methyltransferase (MGMT) expression is a major mechanism of resistance to Proceedings of the alkylating agent chemotherapy, and MGMT gene promoter methylation (present in 30-45 % of tumors) has been shown to be predictive for tumor response to TMZ therapy. MGMT, an exhaustible repair protein can be depleted by specific inhibitors such as O6- benzylguanine or the non-toxic O6-(4-bromothenyl)guanine (PaTrin-2). Here we have studied the efficacy of the combination of TMZ, RT, and PaTrin-2 to improve the treatment outcome in glioblastoma expressing MGMT. Materials/Methods: 3 glioblastoma lines were chosen: LN18 and T98G expressing MGMT and U251 lacking MGMT expression. A shRNA approach was used to selectively and permanently knockdown level of MGMT in LN18 line. Cells were treated with 10 mM PaTrin-2. After 2 h, various concentrations of TMZ were added, cells were incubated for 24 h, and clonogenic assays were performed. After the same PaTrin-2 pretreatment and 100 mM TMZ exposure, cells were plated 4 h before irradiation with increasing RT doses of up to 6 Gy. Clonogenic survival was assessed after 14 days. Results: Western blot analysis confirmed that reduction of MGMT expression was achieved in LN18A1 expressing MGMT-targeting shRNA. The shRNA non-targeting control sequence did not influenceMGMTprotein level (LN18NT). PaTrin-2 showed no toxicity at 10 mMon the 5 cell lines. TMZ induced up to 70 and 97%of cell death on LN18A1 and U251, respectively, but was not toxic up to 50 mMfor T98G, LN18, and LN18NT. Up to 53%increased TMZ toxicity was observed on the 5 cell lines when treated with the 2 drugs. Irradiation of the 5 lines treated or not with PaTrin-2 showed no survival difference at any irradiation dose. When LN18A1 and U251 cells were irradiated post TMZ treatment, an up to 2.5 and 139.4 fold increase in toxicity, respectively, was observed compared to un-pretreated controls. By contrast, TMZ pretreatment did not increase irradiation toxicity on T98G, LN18, and LN18NT. When cells were incubated with PaTrin-2 and TMZ before the irradiation, up to 3.7, 3.9, 5.8, 6.6 and 348.5 fold increase in toxicity was observed compared to controls on LN18, LN18NT, LN18A1, T98G and U251, respectively. Conclusions: We present here results of TMZ and PaTrin-2 combination ± RT on glioblastoma lines. U251 and LN18A1 cells were much more sensitive to TMZ than LN18, LN18NT, and T98G. PaTrin-2 enhanced the toxicity of TMZ on the MGMT expressing glioblastoma lines. RT further increased TMZ and PaTrin-2 efficacy. These results are encouraging for the treatment of patients with glioblastoma expressing MGMT who have the worst prognosis and respond poorly to RT combined with TMZ.

Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.

BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98). CONCLUSIONS: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.).

Acceptance of inflammatory bowel disease treatment recommendations based on appropriateness ratings : do practicing gastroenterologists agree with experts?

BACKGROUND: Appropriateness criteria for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) have been developed by experts' panels. Little is known about the acceptance of such recommendations by care providers. The aim was to explore how treatment decisions of practicing gastroenterologists differ from experts using a vignette case study and a focus group. METHODS: Seventeen clinical vignettes were drawn from clinical indications evaluated by the expert panel. A vignette case questionnaire asking for treatment options in 9-10 clinical situations was submitted to 26 practicing gastroenterologists. For each vignette case, practitioners' answers on treatments deemed appropriate were compared to panel decisions. Qualitative analysis was made based on focus group discussion to explore acceptance and divergence reasons. RESULTS: 239 clinical vignettes were completed, 98 for CD and 141 for UC. Divergence between proposed treatments and results from panels was more frequent for CD (34%) than for UC (27%). Among UC clinical vignettes, the main divergences with the panel were linked to 5-ASA failure assessment and to situations where stopping treatment was the main decision. For CD, the care provider propositions diverged with the panel in mild-to-moderate active disease, where practitioners were more prone to an accelerated step up than the panel's recommendations. CONCLUSIONS: In about one third of vignettes cases, IBD treatment propositions made by practicing gastroenterologists diverged as compared to expert recommendations. Practicing gastroenterologists may experience difficulties in applying recommendations in daily practice.

Age and adverse drug reactions from psychopharmacological treatment: Data from the AMSP drug surveillance programme in Switzerland.

QUESTION UNDER STUDY: The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years. METHODS: Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP. RESULTS: A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions. CONCLUSION: The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

Treatment of penile carcinoma: to cut or not to cut?

PURPOSE: The aim of this study was to assess the outcome in patients with penile cancer. METHODS AND MATERIALS: A total of 60 patients with penile carcinoma were included. Of the patients, 45 (n = 27) underwent surgery, and 51 underwent definitive (n = 29) or postoperative (n = 22) radiotherapy (RT). Median follow-up was 62 months. RESULTS: Median time to locoregional relapse was 14 months. Local failure was observed in 3 of 23 patients (13%) treated with surgery with or without postoperative RT vs. in 19 of 33 patients (56%) given organ-sparing treatment (p = 0.0008). Of 22 local failures, 16 (73%) were salvaged with surgery. Of the 33 patients treated with definitive RT (n = 29) and the 4 patients refusing RT after excisional biopsy, local control was obtained with organ preservation in 13 (39%). In the remaining 20, 4 patients with local failure underwent salvage conservatively, resulting in an ultimate penis preservation rate of 17 of 33 (52%) patients treated with definitive RT. The 5-year and 10-year probability of surviving with an intact penis was 43% and 26%, respectively. There was no survival difference between the patients treated with definitive RT and primary surgery (56% vs. 53%; p = 0.16). In multivariate analysis, independent factors influencing survival were N-classification and pathologic grade. Surgery was the only independent predictor for better local control. CONCLUSION: Based on our study findings, in patients with penile cancer, local control is superior with surgery. However, there is no difference in survival between patients treated with surgery and those treated with definitive RT, with 52% organ preservation.

Prevalence of cardiovascular risk factors in a middle-income country and estimated cost of a treatment strategy.

BACKGROUND: We assessed the prevalence of risk factors for cardiovascular disease (CVD) in a middle-income country in rapid epidemiological transition and estimated direct costs for treating all individuals at increased cardiovascular risk, i.e. following the so-called "high risk strategy". METHODS: Survey of risk factors using an age- and sex-stratified random sample of the population of Seychelles aged 25-64 in 2004. Assessment of CVD risk and treatment modalities were in line with international guidelines. Costs are expressed as USD per capita per year. RESULTS: 1255 persons took part in the survey (participation rate of 80.2%). Prevalence of main risk factors was: 39.6% for high blood pressure (> or =140/90 mmHg or treatment) of which 59% were under treatment; 24.2% for high cholesterol (> or =6.2 mmol/l); 20.8% for low HDL-cholesterol (<1.0 mmol/l); 9.3% for diabetes (fasting glucose > or =7.0 mmol/l); 17.5% for smoking; 25.1% for obesity (body mass index > or =30 kg/m2) and 22.1% for the metabolic syndrome. Overall, 43% had HBP, high cholesterol or diabetes and substantially increased CVD risk. The cost for medications needed to treat all high-risk individuals amounted to USD 45.6, i.e. 11.2 dollars for high blood pressure, 3.8 dollars for diabetes, and 30.6 dollars for dyslipidemia (using generic drugs except for hypercholesterolemia). Cost for minimal follow-up medical care and laboratory tests amounted to 22.6 dollars. CONCLUSION: High prevalence of major risk factors was found in a rapidly developing country and costs for treatment needed to reduce risk factors in all high-risk individuals exceeded resources generally available in low or middle income countries. Our findings emphasize the need for affordable cost-effective treatment strategies and the critical importance of population strategies aimed at reducing risk factors in the entire population.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network.

PURPOSE: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

The appropriate use of neurostimulation: avoidance and treatment of complications of neurostimulation therapies for the treatment of chronic pain.

INTRODUCTION: The International Neuromodulation Society (INS) has determined that there is a need for guidance regarding safety and risk reduction for implantable neurostimulation devices. The INS convened an international committee of experts in the field to explore the evidence and clinical experience regarding safety, risks, and steps to risk reduction to improve outcomes. METHODS: The Neuromodulation Appropriateness Consensus Committee (NACC) reviewed the world literature in English by searching MEDLINE, PubMed, and Google Scholar to evaluate the evidence for ways to reduce risks of neurostimulation therapies. This evidence, obtained from the relevant literature, and clinical experience obtained from the convened consensus panel were used to make final recommendations on improving safety and reducing risks. RESULTS: The NACC determined that the ability to reduce risk associated with the use of neurostimulation devices is a valuable goal and possible with best practice. The NACC has recommended several practice modifications that will lead to improved care. The NACC also sets out the minimum training standards necessary to become an implanting physician. CONCLUSIONS: The NACC has identified the possibility of improving patient care and safety through practice modification. We recommend that all implanting physicians review this guidance and consider adapting their practice accordingly.