Enfortumab Vedotin for Elderly Advanced Urothelial Carcinoma Patients or Those With a Poor Performance Status.

BACKGROUND/AIM: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear. PATIENTS AND METHODS: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023. RESULTS: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001). CONCLUSION: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated.

Clinical Outcomes of Enfortumab Vedotin in Advanced Urothelial Carcinoma With Prior Avelumab Versus Pembrolizumab Therapy.

BACKGROUND/AIM: This study retrospectively evaluated whether enfortumab vedotin (EV) monotherapy is effective as a late-line treatment according to prior treatment type in patients with advanced urothelial carcinoma (UC). PATIENTS AND METHODS: We assessed consecutive patients from the Uro-Oncology Group in the Kyushu study population with lower and upper urinary tract cancer treated with EV monotherapy after platinum-based chemotherapy and immune checkpoint inhibitor therapy failure between December 2021 and March 2024. In particular, patients receiving avelumab maintenance or pembrolizumab therapy before EV for advanced UC were analyzed and compared according to the response rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 80 enrolled patients, 31 and 49 received avelumab and pembrolizumab before EV therapy, respectively. The avelumab and pembrolizumab groups had comparable objective response rates (48.4% vs. 44.9%, p=0.820) and disease control rates (77.4% vs. 67.3%, p=0.448). These two groups showed no significant difference in PFS from the initiation of EV (median: 6.4 months vs. 4.2 months, p=0.184); meanwhile, the avelumab group had better OS from the initiation of EV than the pembrolizumab group (median: 16.0 months vs. 10.2 months, p=0.019). Moreover, the median OS after first-line chemotherapy initiation was longer in the avelumab group than in the pembrolizumab group (40.3 months vs. 24.7 months, p=0.054). On multivariate analysis, avelumab maintenance therapy before EV reduced the mortality risk by 47% (95% confidence interval=0.27-1.03; p=0.059). CONCLUSION: EV monotherapy after avelumab maintenance therapy provides favorable survival outcomes in patients with advanced UC.

Efficacy and safety of Vibegron for the treatment of residual overactive bladder symptoms after laser vaporization of the prostate: A single-center prospective randomized controlled trial (VAPOR TRIAL).

OBJECTIVES: This study aimed to evaluate the efficacy and safety of Vibegron for the treatment of residual overactive bladder (OAB) symptoms after laser vaporization of the prostate (photo-selective vaporization of the prostate, contact laser vaporization of the prostate, and thulium laser vaporization). METHODS: This randomized, open-label, parallel-group, single-center superiority trial with a 12-week observation (jRCTs071190040) enrolled male patients with OAB aged 40 years or older who had undergone laser vaporization of the prostate for not less than 12 weeks and not more than 1 year earlier. Patients were allocated to receive Vibegron 50 mg once daily or follow-up without treatment for 12 weeks. RESULTS: Forty-seven patients were enrolled between January 2020 and March 2023. The median age (interquartile range) was 75.5 (72.5-78.5) years for the Vibegron group and 76.5 (71.0-81.0) years for the control group. The intergroup difference in the mean change (95% confidence interval) in the 24-hour urinary frequency at 12 weeks after randomization was -3.66 (-4.99, -2.33), with a significant decrease for the Vibegron group. The Overactive Bladder Symptom Score, International Prostate Symptom Score, IPSS storage score, and Overactive Bladder Questionnaire score significantly improved for the Vibegron group. Voided volume per micturition also increased for the Vibegron group. CONCLUSIONS: The administration of 50 mg of Vibegron once daily for 12 weeks showed significant improvement compared with follow-up without treatment in bladder storage (OAB) symptoms after laser vaporization of the prostate for symptomatic benign prostatic hyperplasia.

Organ-Specific Tumor Response to Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: To evaluate the organ-specific therapeutic effect of enfortumab vedotin (EV) after chemotherapy and immunotherapy failed for advanced urothelial carcinoma. MATERIALS METHODS: At 6 institutions between December 2021 and July 2023, we retrospectively analyzed patients with metastatic upper and lower urinary tract cancer who received EV monotherapy after platinum-based chemotherapy and immune checkpoint blockade therapy. Objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: This study analyzed 58 patients with 210 tumor lesions, of which 24% were females and 48% had upper urinary tract cancer. The ORR and disease control rate were 53.5% and 74.1%. Moreover, we found 15 target lesions in the primary site, 7 in local recurrence, 93 in the lymph nodes, 46 in the lung, 29 in the liver, and 20 in the bone, with OSRRs of 40%, 71.4%, 61.1%, 70.6%, 90.9%, and 18.2%, respectively. Over time from baseline, the reduction rate (median) in tumor burden was 50% or more in the lymph node, lung, and liver metastases. CONCLUSION: The organ-specific tumor response to EV in patients with metastatic urothelial carcinoma was almost favorable. The antitumor activity of EV monotherapy may be less in bone metastasis than in other organ sites. Conversely, EV showed remarkably high efficacy against liver metastasis.

Cutaneous and Renal Toxicities of Enfortumab Vedotin for Advanced Urothelial Carcinoma: The UROKYU Study.

BACKGROUND/AIM: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. PATIENTS AND METHODS: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. RESULTS: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). CONCLUSION: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study.

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC.

Early Phase Persistent Changes in the White Blood Cell Fraction in Patients With Advanced Urothelial Carcinoma Treated With Pembrolizumab: A Multicenter Retrospective Study.

BACKGROUND/AIM: The association of clinical outcomes with posttreatment persistent changes in eosinophils and other white blood cell (WBC) subtypes in patients with advanced urothelial cancer (UC) treated with pembrolizumab after the failure of platinum-based chemotherapy is unclear. PATIENTS AND METHODS: We retrospectively analyzed 87 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The changes in WBC subtypes from pretreatment were evaluated three and six weeks after pembrolizumab administration. The association between the changes in the WBC subtypes and clinical outcomes was then evaluated using the Kaplan-Meier method and a Cox regression model. RESULTS: Among WBC subtypes, significant changes in the absolute (AEC) and relative eosinophil count (REC) and the neutrophil-to-eosinophil ratio (NER) were observed at three and six weeks compared with pretreatment (p<0.001). Multivariable Cox regression analyses revealed that a persistent decrease in AEC and REC and a persistent increase in NER were associated with poor overall survival. CONCLUSION: Persistent increase in AEC and REC and decrease in NER in the early phase after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab.

Cigarette Smoking, Smoking Cessation, and Bladder Cancer Risk: A Pooled Analysis of 10 Cohort Studies in Japan.

BACKGROUND: Although cigarette smoking is an established risk factor for bladder cancer, assessment of smoking impact on bladder cancer in Asian populations has been hindered by few cohort studies conducted in Asian populations. Therefore, we investigated the risk of bladder cancer associated with smoking status, cumulative smoking intensity, and smoking cessation in Japan. METHODS: We analyzed data for 157,295 men and 183,202 women in 10 population-based cohort studies in Japan. The risk associated with smoking behaviors was estimated using Cox regression models within each study, and pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for the incidence of bladder cancer were calculated. RESULTS: During 4,729,073 person-years of follow-up, 936 men and 325 women developed bladder cancer. In men, former smokers (HR 1.47; 95% CI, 1.18-1.82) and current smokers (HR 1.96; 95% CI, 1.62-2.38) had higher risk than never smokers. In women, current smokers had higher risk than never smokers (HR 2.35; 95% CI, 1.67-3.32). HRs in men linearly increased with increasing pack-years. Risk decreased with increasing years of smoking cessation in men, with a significant dose-response trend. Former smokers with a duration of more than 10 years after smoking cessation had no significantly increased risk compared with never smokers (HR 1.26; 95% CI, 0.97-1.63). CONCLUSION: Data from a pooled analysis of 10 population-based cohort studies in Japan clearly show an association between cigarette smoking and bladder cancer risk. The risk of smokers may approximate that of never smokers following cessation for many years.

A prospective, single-center, randomized clinical trial to evaluate the efficacy of three types of laser vaporization surgeries using a 180-W GreenLight XPS laser, a 300-W diode laser, and a 200-W thulium laser for the treatment of benign prostatic hyperplasia.

OBJECTIVES: This study aimed to compare the safety and efficacy of three different laser prostate vaporization surgeries, which were photoselective vaporization of the prostate (PVP), diode laser vaporization (DVP), and thulium laser vaporization (ThuVAP), for the treatment of benign prostatic hyperplasia (BPH) in a randomized clinical trial. METHODS: A total of 71 consecutive patients with BPH were included; 23 patients were treated with PVP, 23 with DVP, and 25 with ThuVAP. Patients were evaluated with disease-related symptomatic questionnaires, Quality of Life (QOL) Index, and maximum urinary flow rate (Qmax ) for 12 months. Patients were monitored to record operation/vaporization time, 24-hour hemoglobin/sodium drop, length of catheterization/hospitalization, and perioperative/postoperative complications. RESULTS: In all three groups, patients showed significant and comparable improvements in symptom scores, QOL Index, and Qmax during the 12-month follow-up period. The mean operation/vaporization time was equivalent across all three groups at 69/23 (PVP), 81/34 (DVP), and 76/32 minutes (ThuVAP), while the applied laser energy was lower for PVP at 157 kJ compared to the other two techniques (DVP at 358 kJ, ThuVAP at 240 kJ). The mean vaporization rates per unit energy were significantly different between the three groups (PVP 0.16, DVP 0.09, and ThuVAP 0.09 mL/kJ). There were no significant differences in the main safety profiles between the three groups. CONCLUSIONS: Our study demonstrated that these three types of laser surgeries are similar in terms of complications and outcomes, with excellent hemostasis and high patient satisfaction. It was suggested that sufficient tissue vaporization could be achieved using less energy through PVP surgery.

The role of adipocytokines and their receptors in bladder cancer: expression of adiponectin or leptin is an independent prognosticator.

Adipocytokines such as leptin and adiponectin have functions in metabolism as well as the development and progression of various types of malignancies. However, little is known about their role in bladder cancer. In this study, we investigated whether leptin, adiponectin, and their receptors have an impact on bladder cancer outgrowth and the mechanisms involved. We performed immunohistochemistry for leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors (AdipoR1, AdipoR2) in bladder cancer tissue microarrays. Wound healing assay and western blot were then performed in human bladder cancer lines. The positive rates (0 vs 1+/2+/3+) of Ob-R (P=0.004), adiponectin (P<0.001), AdipoR1 (P=0.016), and AdipoR2 (P<0.001) expression were significantly higher in bladder tumors than in benign urothelial tissues. Strong (3+) leptin expression tended to be present more often in tumors (10.2%; P=0.079) than in benign tissues (3.2%). Multivariate analysis revealed a lower risk of recurrence (hazard ratio [HR]=0.432; 95% confidence interval [CI]=0.198-0.942; P=0.034) in patients with an adiponectin-positive non-muscle-invasive tumor and a higher risk of progression (HR=5.148, 95% CI=1.190-22.273; P=0.028) in patients with a leptin-positive muscle-invasive tumor. Treatment of two bladder cancer cell lines with a synthetic adiponectin inhibited their migration and the expressions of phospho-NF-κB, NF-κB, snail, slug, Y-box-binding protein 1, and COX-2, whereas leptin showed reverse effects. Downregulation of adiponectin expression and upregulation of leptin expression were independent predictors for the recurrence of non-muscle-invasive bladder tumors and progression of muscle-invasive bladder tumors, respectively. In summary, synthetic adiponectin might exhibit antitumor activity against bladder cancer.

Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer.

BACKGROUND: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. METHODS: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index. RESULTS: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206-0.922; p = 0.028). CONCLUSIONS: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.

Alcohol Drinking and Bladder Cancer Risk From a Pooled Analysis of Ten Cohort Studies in Japan.

BACKGROUND: The association of alcohol drinking with bladder cancer risk remains unclear in East Asian populations. Aldehyde dehydrogenase 2 (ALDH2) enzyme oxidizes alcohol-metabolized carcinogenic acetaldehyde into acetate. It is well known that the inactive ALDH2 carriers, specific to East Asian populations, have an increased risk of several cancer types because of increased exposure to acetaldehyde after alcohol consumption. The aim of this study was to examine the association between alcohol drinking and bladder cancer risk using data from ten population-based prospective cohort studies in Japan, where approximately 40% of the population has inactive ALDH2 enzyme. METHODS: We analyzed 340,497 Japanese participants with average follow-up of 13.4 years. The association between alcohol drinking and bladder cancer risk was evaluated using Cox regression models within each study, and random-effects models were used to estimate pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). RESULTS: During 4,729,071 person-years, 936 men and 325 women were newly diagnosed with bladder cancer. Our results showed no evidence of significant association between alcohol drinking and bladder cancer risk even among men who consumed alcohol of ≥69 g/week, with HR of 1.02 (95% CI, 0.79-1.33). The null result was observed consistently among women. CONCLUSIONS: Our findings do not support an association between alcohol drinking and bladder cancer risk in the Japanese, at least without consideration of the polymorphisms of alcohol-metabolizing enzymes.

Association between ALDH2 and ADH1B polymorphisms, alcohol drinking and gastric cancer: a replication and mediation analysis.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer. METHODS: We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways. RESULTS: ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04-6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (Pinteraction = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed. CONCLUSION: The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.

Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study.

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95,915 subjects (45,649 men and 50,266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non-drinkers and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (p for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted.

Potential overtreatment among men aged 80 years and older with localized prostate cancer in Japan.

Despite treatment guidelines recommending observation for men with low-risk prostate cancer with life expectancy <10 years, a majority of elderly patients choose active treatment, which may result in overtreatment. Given the growing burden of prostate cancer among men aged ≥80 years (super-elderly men), accumulation of survival data for evaluation of overtreatment among super-elderly patients is imperative. Here, we report results of a population-based cohort study to clarify potential overtreatment of super-elderly men with localized prostate cancer. We used cancer registry data from the Monitoring of Cancer Incidence in Japan project, which covers 47% of the Japanese population. The subjects were men diagnosed with prostate cancer between 2006 and 2008. Follow-up period was 5 years. We calculated 5-year relative survival rates among the active treatment and observation groups after imputation for missing values. Of the 48 782 patients with prostate cancer included in the analysis, 15.1% were super-elderly men. The 5-year relative survival rates of super-elderly men with localized cancer were 105.9% and 104.1% among the active treatment and observation groups, respectively. This excellent relative survival rate in the observation group remained consistent even after stratification by tumor grade. Of the 2963 super-elderly men with localized cancer, 252 (8.5%) with curative treatment and 1476 (49.8%) with hormone therapy were assumed to have been overtreated. The proportion of overtreatment was estimated to reach 80% after imputation. These specific survival data in super-elderly men in the observation group can be useful in shared decision-making for these patients and may lead to a reduction in overtreatment.

Combination of ALDH2 and ADH1B polymorphisms is associated with smoking initiation: A large-scale cross-sectional study in a Japanese population.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms are known to strongly influence alcohol　drinking behavior. Given evidence of an association between smoking and drinking behaviors, we hypothesized that ALDH2/ADH1B polymorphisms might also be associated with smoking initiation, and conducted a cross-sectional study to examine this hypothesis. METHODS: Study subjects were first-visit outpatients diagnosed not to have cancer at Aichi Cancer Center Hospital between 2001 and 2005, including 4141 never smokers and 2912 ever smokers. Unconditional logistic regression models were applied to estimate odds ratios (OR) and 95% confidence intervals (CI) for smoking initiation by comparing ever smokers with never smokers. RESULTS: Excessive alcohol drinking was associated with a higher likelihood of ever smoking. After adjustment for drinking behaviors, compared to individuals with ALDH2 Glu/Glu, the ORs of ever smoking were 1.71 (95% CI, 1.49-1.95) and 2.28 (1.81-2.87) among those with ALDH2 Glu/Lys and Lys/Lys, respectively. Combination of ALDH2 Lys/Lys and ADH1B His/His (i.e., the most alcohol-intolerant subpopulation) showed the highest OR [2.44 (1.84-3.23)], whereas combination of ALDH2 Glu/Glu and ADH1B Arg/Arg (i.e., the most alcohol-tolerant subpopulation) showed the lowest OR [0.83 (0.57-1.21)] compared with ALDH2 Glu/Glu and ADH1B His/His. CONCLUSION: Besides the amount and frequency of alcohol drinking, the combination of ALDH2 and ADH1B polymorphisms predicts smoking initiation. This study suggests that alcohol tolerance regulated by ALDH2 and ADH1B polymorphisms is associated with smoking initiation, and facilitates the development of targeted interventions to reduce smoking prevalence.

Aldehyde Dehydrogenase 2 Polymorphism Is a Predictor of Smoking Cessation.

INTRODUCTION: Smoking cessation has been known to be associated with drinking behaviors, which are influenced by polymorphisms in genes encoding alcohol metabolizing enzymes. The aim was to evaluate the impact of aldehyde dehydrogenase 2 (ALDH2, rs671) and alcohol dehydrogenase 1B (ADH1B, rs1229984) polymorphisms together with drinking behaviors on smoking cessation. METHODS: We conducted a cross-sectional study with 1137 former smokers and 1775 current smokers without any cancer at Aichi Cancer Center Hospital between 2001 and 2005. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for successful smoking cessation by comparing former smokers (quitters) with current smokers (non-quitters). RESULTS: Older age, lower amount of cumulative smoking exposure, lower number of cigarettes per day, younger age of smoking initiation, shorter smoking duration, longer time to first cigarette in the morning, and lower amount of drinking among ever drinkers were predictors of smoking cessation. After careful adjustment for age, sex, smoking patterns, and drinking status, the ORs for smoking cessation among subjects with ALDH2 Glu/Lys and Lys/Lys were 1.02 (95% CI 0.84-1.23) and 1.78 (95% CI 1.23-2.58) compared with those with ALDH2 Glu/Glu, respectively Mediation analyses confirmed that the effect of ALDH2 Lys/Lys on smoking cessation was independent by dinking behaviors. No statistically significant association between ADH1B polymorphism and smoking cessation was observed. CONCLUSIONS: In our Japanese population, ALDH2 polymorphism predicts smoking cessation, independent by drinking behaviors. Interventions for promoting smoking cessation by ALDH2 polymorphism may be useful in Asian populations. IMPLICATIONS: We newly show that subjects with ALDH2 Lys/Lys genotype in a functional polymorphism, rs671, are more likely to quit smoking than those with ALDH2 Glu allele in a Japanese population. Our finding suggests that ALDH2 polymorphism may be useful for promoting smoking cessation in those specific populations as East Asian ones with frequent ALDH2 Lys allele carriers.

Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.

Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001].

Cigarette smoking and bladder cancer risk: an evaluation based on a systematic review of epidemiologic evidence in the Japanese population.

OBJECTIVE: Although several epidemiological studies have demonstrated that cigarette smoking is an important risk factor for bladder cancer, no systematic review in the Japanese population has yet been performed. Accurate evaluation of bladder cancer risk in relation to smoking for Japanese populations can provide necessary information for Japanese policy-makers and doctors to enlighten the importance of smoking cessation. We reviewed epidemiologic data to estimate the strength of the association between cigarette smoking and bladder cancer in the Japanese population. METHODS: We identified previous cohort and case-control studies, extracting data from databases in the MEDLINE (PubMed) and Ichushi. The magnitude of association and strength of evidence were evaluated in each study, and a meta-analysis was conducted to obtain summary estimates for the overall magnitude of association. RESULTS: Three cohort and eight case-control studies were identified. Except for one case-control study, all studies showed a strong positive association between cigarette smoking and bladder cancer. The summary relative risk for ever smokers relative to never smokers was 2.14 (95% confidence interval 1.87-2.44) in a fixed-effect model. CONCLUSIONS: We conclude that cigarette smoking is a convincing risk factor for bladder cancer among Japanese.

Decompressive craniectomy for arteriovenous malformation-related intracerebral hemorrhage.

Arteriovenous malformation (AVM)-related intracerebral hemorrhage (ICH) is the cause of approximately 2-3% of ICH and is an important factor in the significant morbidity and mortality in patients with AVM. Decompressive craniectomy (DC) is a surgical procedure to relieve malignant elevation of intracranial pressure. The use of DC to treat patients with AVM-ICH has been much less common. The present study describes our experience with DC for AVM-ICH and discusses the safety of this procedure. The present retrospective analysis compared 12 consecutive patients treated with DC for AVM-ICH with 23 patients treated with DC for hypertensive ICH. Nine patients were male and three were female, aged from 11 to 53 years (mean, 31.7 years). Hematoma volumes ranged from 50 to 106 ml (mean, 75.8 ml). The outcomes were good recovery in one patient, moderate disability in three, severe disability in seven, and vegetative state in one. Complications after DC included subdural hygroma in four patients, hydrocephalus in one, intracranial infection in two, and intracranial hemorrhage in one. No significant difference was found in the incidence of complications between DC for large AVM-ICH and DC for hypertensive ICH. In conclusion, the present study found no significant difference in the incidence of complications between DC for large AVM-ICH and DC for hypertensive ICH. Further investigations including a prospective randomized trial are needed to confirm the safety and efficacy of DC for the treatment of large AVM-ICH.