Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa

The T315I BCR-ABL mutation in chronic myelogenous leukemia (CML) patients is responsible for up to 20% of all clinically observed resistance. This mutation confers resistance not only to imatinib, but also to second-generation BCR-ABL tyrosine kinases, such as nilotinib and dasatinib. A number of strategies have been implemented to overcome this resistance, but allogeneic stem cell transplantation remains the only established therapeutic option for a cure. A 61-year-old male was diagnosed with Philadelphia chromosome-positive chronic-phase CML in 2002. He was initially treated with imatinib and complete cytogenetic response (CCyR) was achieved 12 months later. However, after 18 months, a loss of CCyR was observed and a molecular study at 24 months revealed a T315I mutation of the BCR-ABL gene. At 30 months, imatinib/interferon-alfa (IFNα) combination therapy was initiated in an effort to overcome the resistance. Thirty months later, he re-achieved CCyR, and the T315I BCR-ABL mutation disappeared at 51 months. To our knowledge, this is the first case report showing the effectiveness of imatinib/IFNα combination therapy for CML patients bearing the T315I BCR-ABL mutation.     

Simple and reproducible hepatectomy in the mouse using the clip technique

AIM: To investigate the reliability of massive hepatectomy models by using clip techniques.METHODS: We analyzed anatomical findings in 100 mice following massive hepatectomy induced by liver reduction > 70%. The impact of various factors in the different models was also analyzed, including learning curves, operative time, survival curves, and histopathological findings.RESULTS: According to anatomical results, models with 75%, 80%, and 90% hepatectomy produced massive hepatectomy. Learning curves and operative times were most optimal with the clip technique. Each hepatectomy performed using the clip technique produced a reasonable survival curve, and there were no differences in histopathological findings between the suture and clip techniques.CONCLUSION: Massive hepatectomy by the clip technique is simple and can provide reliable and relevant data.     

Effect of specific activation of γ‐aminobutyric acid receptor in vivo on oxidative stress‐induced damage after extended hepatectomy

Aim: γ‐Aminobutyric acid (GABA) is a multifunctional molecule with various physiological effects throughout the body. The regulation of GABA receptor (GABAR) plays a key role in reducing the damage mediated by oxidative stress (OS). Extended hepatectomy causes fatal OS‐induced injury in the liver remnant. We aimed to investigate the effect of a GABAR agonist in extended hepatectomy. Methods: Saline or a GABAR agonist (43.56 nmol/g bodyweight of muscimol) was administrated intravenously at 4 h preoperatively. C57BL/6 mice were divided into three groups: laparotomy only, 90% hepatectomy with saline and 90% hepatectomy with a GABAR agonist. Liver samples were obtained at 6 h after surgery. Results: Survival curves were prolonged by the GABAR agonist. Histopathological findings and biochemical profiles showed that the GABAR agonist reduced liver damage. Immunohistological assessment demonstrated that the GABAR agonist prevented apoptotic induction. As shown by 4‐hydroxynonenal, which reflects OS‐induced damage, 90% hepatectomy caused OS and the GABAR agonist reduced OS. We measured ataxia‐telangiectasia mutated kinase (ATM), H2AX, Akt and free radical scavenging enzymes because they may be affected by GABAR regulation, and found that Akt was greatly decreased after 90% hepatectomy, but it recovered with the GABAR agonist. Conclusion: GABAR is activated by a specific agonist in the liver in vivo. This activation reduces OS‐mediated damage after extended hepatectomy in vivo, and the mechanism via an Akt‐dependent pathway may be a key.     

Weight-based high- and low-dose ribavirin in combination with peginterferon α-2b therapy for genotype 2 chronic hepatitis C: A randomized trial

Aim: The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. Methods: We compared the efficacy and tolerability of the 24‐week peginterferon α‐2b (1.5 µg/kg/week) therapy in combination with a weight‐based higher dose (600–1000 mg) and lower dose (400–800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. Results: A total of 120 patients were randomized to a higher‐dose or a lower‐dose group. Sustained virological response (SVR) by intention‐to‐treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6–89.5) patients in the higher‐dose group and 41/60 (68.3%, 90% CI: 58.5–78.2) patients in the lower‐dose group (difference, ?12.7%; 90% CI, ?25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher‐dose and the lower‐dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs <9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41–7.92; P = 0.006). Twenty‐one (36.2%) in the higher‐dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower‐dose group (P < 0.01). Three of the higher‐dose group and two of the lower‐dose group required premature termination of therapy. Conclusions: Weight‐based lower‐dose ribavirin regimen was not equivalent to the higher‐dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low‐dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight‐based higher dose (600–1000 mg) remains the standard‐of‐care treatment for this genotype.     

Visual acuity outcomes of anti-VEGF treatment for neovascular age-related macular degeneration in clinical trials

Japanese Journal of Ophthalmology - Anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) has been evaluated in clinical trials. To select the best anti-VEGF drug and the best...     

Association of calcium urolithiasis with urokinase P141L and 3′-UTR C>T polymorphisms in a Japanese population

This was a case–control study to analyze the associations between calcium urolithiasis and the urokinase polymorphisms, P141L (rs2227564) and 3′-UTR C>T (rs4065), in a Japanese population. Cases consisted of 232 patients with urinary calcium stones (174 men and 58 women) who presented to a general hospital between April 2009 and June 2011. Among these cases, 115 (49.6 %) patients had calcium oxalate stones alone, and 113 (48.7 %) patients had calcium oxalate stones mixed with calcium phosphate stones. Controls consisted of 454 subjects who had a routine health check-up in the same prefecture. The two polymorphisms were genotyped via polymerase chain reaction with confronting two-pair primers. In the control group, the genotype frequencies of P141L were 0.573 for PP, 0.375 for PL, and 0.052 for LL, and those of 3′-UTR C>T were 0.835 for CC, 0.165 for CT, and TT was not identified. Neither of the polymorphisms was significantly associated with urolithiasis. The age- and sex-adjusted odds ratios of urolithiasis were 0.96 [95 % confidence interval (CI), 0.66–1.41] for PL and 1.22 (0.58–2.57) for LL as compared with PP genotype of P141L, and 1.01 (0.62–1.64) for CT as compared with CC genotype of 3′-UTR C>T. When compared with the PP genotype of P141L, the frequency of PL was significantly lower in female cases with a family history of urolithiasis than in females without such family history (p = 0.028). P141L and 3′-UTR polymorphisms of the urokinase gene are not associated with urolithiasis in a Japanese population.