Dasatinib in chronic myeloid leukemia: A limited Indian experience

Aim: To report our experience of the use of dasatinib in various phases of chronic myeloid leukemia (CML). Methods: Ten patients in various phases of CML, not responding to imatinib and started on dasatinib, were included and analyzed. The baseline characteristics of the patients and their salient features including the duration and response to initial therapy as well as to dasatinib, were noted. Results: Before starting dasatinib three patients were in chronic phase of CML while seven others were in the progressive phase (accelerated and blast phase) of CML. Half the patients developed transient grade 3 and 4 toxicities to dasatinib. Overall, the tolerability of the drug in all 10 patients was acceptable and none discontinued treatment. Three patients died due to progressive disease while the remaining seven are continuing the drug with the disease still under cytogenetic or hematological remission. Of the 10 patients, seven achieved complete hematological response and two of the accelerated phase/blast crisis patients achieved complete cytogenetic response. Overall, dasatinib was able to control disease for a median of 20.6 months. Conclusion: Despite small sample size and insufficient information on mutational analysis, dasatinib is effective in CML in INdia. Cost limits the use of second‐generation tyrosine kinase inhibitors in India. Our observation is not suitable for survival analysis but the difference made by dasatinib in progressive disease and its tolerability needs to be acknowledged.     

Potential role of platelet FcgammaRIIA in collagen-mediated platelet activation associated with atherothrombosis

Increased levels of hemostatic factors may play a role in the pathogenesis of myocardial infarction by triggering thrombin formation. We measured factor XII (FXII), factor XI (FXI), plasma prekallikrein (PK) and high-molecular-weight kininogen (HK) in 200 patients having survived myocardial infarction for at least 2 months, and in 100 healthy controls. We found significantly elevated levels of FXI clotting activity (FXI:C), HK:C and of the amidolytic activity of PK (PK:Am) among the patients as compared to the controls. Plasma levels of FXI:C, HK:C and PK:Am in the highest quartile were associated with an odds ratio of 1.9 (95% CI: 1.0-3.8), 2.0 (95% CI: 1.0-4.0) and 5.4 (95% CI: 2.6-11.2), respectively, compared to the respective plasma levels in the lowest quartile. After correction for established clinical and laboratory risk factors, the association between PK:Am plasma levels and myocardial infarction remained significant (P=0.0007). Combination of high PK:Am plasma levels and smoking or arterial hypertension, respectively, resulted in a more than additive relative risk for myocardial infarction.     

Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study

The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression.     

Initial default among diagnosed sputum smear-positive pulmonary tuberculosis patients in Andhra Pradesh, India

BACKGROUND: Under the Indian Revised National TB Control Programme (RNTCP), smear-positive pulmonary tuberculosis (PTB) patients not confirmed as starting treatment are reported as 'initial defaulters'. SETTING: Twenty districts of Andhra Pradesh State, India. OBJECTIVE: To evaluate reasons for treatment non-initiation in smear-positive PTB patients diagnosed and reported as initial defaulters by the NTP. DESIGN: A cross-sectional survey conducted of all reported initial defaulters during the period July-September 2006. RESULTS: Of 1304 reported initial defaulters, 619 (47.5%) had been placed on treatment, having been incorrectly reported due to poor documentation of patients referred for treatment in the same district or whose treatment initiation was delayed until the subsequent quarter. Of the 685 (4.5% of the total diagnosed) who were confirmed initial defaulters, 350 (51%) were untraceable, 152 (22%) had died before treatment initiation, 38 (5.5%) were treated privately, 93 (13.5%) had other reasons (e.g., refusal of treatment, chronic case, etc.) and no data were available for 52 (8%). CONCLUSIONS: Nearly 5% of smear-positive PTB patients diagnosed in the study period were confirmed as not having initiated treatment under the RNCTP. Improvements in address recording may assist efforts to retrieve these patients for treatment. Additional evaluations are needed of improved counselling of TB suspects to prevent initial default, and of reasons for death before treatment initiation.     

Coronary steal syndrome with coil embolization of a large LIMA side branch: radionuclide evidence for reversible ischemia.

This case presents the controversy over coronary artery steal syndrome following bypass surgery when a large branch of the left internal mammary artery (LIMA) is not ligated. A discussion of previous attempts to understand the physiology of this anatomy is compared with case reports of objective evidence for ischemia that resolves following occlusion of the LIMA side branch.     

Image-guided vulvovaginal interstitial brachytherapy in the treatment of primary and recurrent gynecological malignancies

PurposeEvaluation of interstitial high-dose-rate brachytherapy (HDRB) to the vulvovaginal region both alone and in combination with external beam radiotherapy (EBRT) for primary or recurrent gynecological malignancy.Methods and MaterialsFrom 1998 to 2009, 37 women with a mean age of 68 years were treated with transperineal interstitial HDRB. Fifteen patients (40.5%) were treated for primary disease, whereas 22 (59.5%) patients were treated for recurrent disease. Median time to local recurrence was 31 months (2–312 months). Primary sites included endometrium (12), vulva (11), vagina (10), vulvovagina (1), cervix (1), and bladder (2). Thirty-one patients (83.7%) in this series were treated with radical intent, whereas 6 (16.3%) were treated with palliative intent. Radically treated patients received between 45 and 60 Gy (median, 45 Gy) of EBRT. The median number of days from EBRT to HDR boost was 5 days (1–35 days). The HDRB doses ranged from 11 Gy in two fractions to 42 Gy in six fractions (dose per fraction varied from 4 to 8.5 Gy) and fractions were given at least 6–8 h apart.ResultsEight of the 31 patients (26%) treated with radical intent relapsed locally. Eleven of 37 patients (30%) treated with either radical or palliative intent recurred locally. The 2- and 5-year local progression-free survival was 74% and 63.4%, respectively. The total progression-free survival, which includes local, locoregional/nodal, and distant recurrence, at 2 and 5 years, was 73.6% and 45.6%, respectively. With a mean follow-up of 27 months (3.8–111.9 months), the median survival for the patient group was 16.6 months with a 2- and 5-year overall survival of 47.7% and 36.4%, respectively. Acute Grade 3 toxicity was seen in 13 (35%) of the 37 patients (skin: 10, urinary: 2, genital: 2, gastrointestinal: 0). No acute Grade 4 toxicities were seen. A total of 10 of the 37 patients (27%) developed late Grade 3 toxicities. Five of the 22 patients (22%) treated for recurrent disease with radical intent developed Grade 3 toxicity (skin: 4, urinary: 2, genital: 1, radiation-induced fracture of acetabulum: 1, and gastrointestinal: 0), whereas 1 of the 6 patients treated with palliative intent had Grade 3 toxicity affecting skin. No late Grade 4 toxicities were seen.ConclusionThis retrospective series suggests that interstitial perineal HDRB is a safe and effective treatment option for primary or locally recurrent gynecological malignancies. It is a valuable option in patients who have received previous EBRT to the pelvis, achieving good local control with acceptable late treatment-related side effects.     

Methylphenidate Hydrochloride Modified-Release in Adults with Attention Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Trial

Introduction

Treatment options for adults with attention deficit hyperactivity disorder (ADHD) are limited. The study was conducted to confirm the clinically effective and safe dose of methylphenidate hydrochloride modified-release (MPH-LA) in adults with ADHD and evaluate the maintenance of effect of MPH-LA.

Methods

The study consisted of three treatment phases. The double-blind dose-confirmation phase: 9-week double-blind period (3-week titration period, 6-week fixed dose) with randomization to MPH-LA 40, 60, or 80 mg/day or placebo. The real-life dose-optimization phase: a 5-week re-titration period to optimal dose; and the double-blind maintenance of effect phase, a 6-month double-blind randomized placebo-controlled maintenance of effect phase. The three co-primary endpoints were change in Diagnostic and Statistical Manual of Mental Disorders-IV ADHD Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores from baseline to end of 9-week confirmation phase and the percentage of treatment failures during the 6-month maintenance of effect phase.

Results

725 of 863 screened patients were randomized to 40 (N = 181), 60 (N = 182), or 80 mg (N = 181) MPH-LA or placebo (N = 181), and 584 (80.6%) completed. 489 (83.7%) of completers were re-randomized to the double-blinded maintenance of effect phase and 235 (48.1%) of them completed. Improvement from baseline in DSM-IV ADHD RS (P < 0.0001 for all comparisons) and SDS (40 mg, P = 0.0003; 60 mg, P = 0.0176; 80 mg, P < 0.0001) total scores was significantly greater vs. placebo for all MPH-LA doses. Treatment failure rate was significantly lower with MPH-LA (21.3%) versus placebo (49.6%) during the 6-month maintenance of effect phase. Safety profile was consistent with the profile for MPH-LA in children; percentage of serious adverse events was comparable between all MPH-LA arms (1.3%) and placebo (1.5%), while percentage of adverse events was higher in MPH-LA arms.

Conclusion

MPH-LA provided and maintained significant symptomatic and functional improvement in adult ADHD patients.