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Radical nephroureterectomy (RNU) is the gold standard treatment for upper tract urothelial carcinoma (UTUC), but the usefulness of this surgery for older patients is rarely discussed. The prognosis following RNU for patients ≥80 years old remains controversial. We retrospectively investigated the prognosis of UTUC in patients ≥80 years old who underwent RNU.Between January 1990 and December 2015, 451 patients with UTUC underwent RNU at six hospitals affiliated with Kitasato University (Kanagawa, Japan), eight patients who underwent neoadjuvant chemotherapy and two patients with metastases before surgery were excluded. Patients were divided into three groups according to their age at the time of RNU: ≤64 years (n = 135), 65-79 years (n = 254), and ≥80 years (n = 52). Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) curves were estimated using Kaplan-Meier analysis for all patients and each pT stage. Independent prognostic factors for survival were examined via multivariate analysis.RFS and CSS did not significantly differ between the three groups, but OS was significantly poorer in patients ≥80 years old. Stratification by pT stage (≤pT1, ≥pT2, and ≥pT3) yielded the same results. In the multivariate analysis for OS, an age of ≥80 years was a significant independent risk factor (hazard ratio: 3.01, p = .01), but RFS and CSS did not significantly differ.Oncological outcomes showed the same anticancer effects in patients ≥80 years old who underwent RNU for UTUC compared with those of younger patients. Our study suggests that surgical treatment is a beneficial option for older patients who can tolerate radical surgery.

Little data on the preoperative prognostic factors in radical cystectomy (RC) patients have made it difficult to choose the appropriate type of urothelial diversion (UD). This study aimed to investigate the prognostic role of UD, with a subgroup analysis of that of preoperative renal function. From 1990 to 2015, 279 patients underwent RC for bladder cancer at six hospitals affiliated with Kitasato University in Japan. All patients were divided into three groups: cutaneous ureterostomy (CU; n = 54), ileal conduit (IC; n = 139), and orthotopic neobladder (NB; n = 86). Patients were also stratified into three groups based on preoperative estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2): normal eGFR (> 60 mL/min/1.73 m2; n = 149), moderately reduced eGFR (45–60 mL/min/1.73 m2; n = 66), and severely reduced eGFR (

Background/aims Endoscopic submucosal dissection (ESD) of recurrent esophageal carcinoma is technically difficult to perform due to submucosal fibrosis that develops after definitive chemoradiation therapy. Therefore, our aim was to evaluate the usefulness of clip-with-thread traction for ESD of esophageal lesions with submucosal fibrosis. Materials and methods Four endoscopists excised 16 lesions by ESD in an ex vivo pig training model. Mock lesions (30 mm in diameter) were created, including a 10-mm area of submucosal fibrosis in the center of each lesion. Each endoscopist performed two ESDs with traction (ESD-T) and two without traction (ESD-N). The primary outcome was the time required for submucosal dissection. Secondary outcomes were the rate of en bloc (complete) resection and perforation during the procedure, and the total amount of solution injected. Results All esophageal ESDs were completed. The median dissection time was significantly shorter for the ESD-T group (median 12.5 min, interquartile range 10.2-14.5) when comparing to the ESD-N group (median 18.0 min, interquartile range 14.6-19.2) (P=0.040). The en bloc resection rate was 100% in both groups, with a rate of complete resection of 87.5% and a rate of perforation of 37.5% for both groups. The median amount of solution injected was not significantly different between the ESD-T (18.0 ml) and ESD-N (20.5 ml) groups (P=0.526). Conclusion Clip-with-thread traction improved the performance of ESD for lesions with submucosal fibrosis. However, the method might not reduce the risk of perforation, which remains an important clinical issue to resolve.

Background In patients experiencing disease recurrence after radical cystectomy (RC) for bladder cancer, data about the impact of clinicopathologic factors, including salvage treatment using cytotoxic chemotherapy, on the survival are scarce. We investigated the prognostic value of clinicopathologic factors and the treatment effect of salvage cytotoxic chemotherapy (SC) in such patients. Methods In this retrospective study, we evaluated the clinical data for 86 patients who experienced recurrence after RC. Administration of SC or of best supportive care (BSC) was determined in consultation with the urologist in charge and in accordance with each patient’s performance status, wishes for treatment, and renal function. Statistical analyses explored for prognostic factors and evaluated the treatment effect of SC compared with BSC in terms of cancer-specific survival (CSS). Results Multivariate analyses showed that liver metastasis after RC (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.17 to 3.85; P = 0.01) and locally advanced disease at RC (HR 1.92; 95% CI 1.06 to 3.46; P = 0.03) are independent risk factors for worse CSS in patients experiencing recurrence after RC. In a risk stratification model, patients were assigned to one of two groups based on liver metastasis and locally advanced stage. In the high-risk group, which included 68 patients with 1–2 risk factors, CSS was significantly better for patients receiving SC than for those receiving BSC (median survival duration: 9.4 months vs. 2.4 months, P = 0.005). The therapeutic effect of SC was not related to a history of adjuvant chemotherapy. Conclusions The present study indicated the potential value of 1st-line SC in patients experiencing recurrence after RC even with advanced features, such as liver metastasis after RC and locally advanced disease at RC.

Intravesical recurrence (IVR) after nephroureterectomy for upper tract urothelial carcinoma (UTUC) is relatively frequent, occurring in about 30-50% of patients. The aim of this study was to investigate the differences of the prognosis and IVR between open and laparoscopic surgery and to elucidate the risk factor of IVR.We retrospectively analyzed data from 403 patients with UTUC treated with laparoscopic or open nephroureterectomy at six affiliated hospitals between 1990 and 2015. The clinicopathological factors of each group were examined using Kaplan-Meier plots, and univariate and multivariate analyses.There was no difference in recurrence and cancer-specific mortality between open and laparoscopic surgery in univariate and multivariate analyses. There was no significant difference in IVR rate between the laparoscopic and open groups (p = .22). Among the patients with IVR, 84% of patients relapsed within 2 years. Univariate analysis of IVR showed a significant increase in patients with low-grade (p = .03, HR = 1.64) or low-stage urothelial carcinoma (pT1 or lower, p = .006, HR = 1.77) with no lymph node involvement (p = .002, HR = 10.3) or lymphovascular invasion (p = .009, HR = 1.79). Surgical modality was not an independent factor. In multivariate analysis, there was no independent predictive factor for IVR.There was no difference in recurrence, cancer-specific mortality, and IVR between open and laparoscopic surgery. On the other hand, our results suggested that the low malignant potential tumor may be a risk factor for IVR. This finding provides insight into IVR, which may help with the development of personalized prevention and treatment strategies.

Background: Endoscopic submucosal dissection (ESD) is a standard treatment for tumors of the gastrointestinal tract. We developed a self-completion method of ESD using Endosaber to eliminate the need for an additional device or human assistance during the procedure. The aim of this study was to evaluate the technical feasibility and outcomes of this method in an ex vivo porcine training model. Methods: This was a pilot study, and the procedures were performed by 4 experts. Mock lesions measuring 15 mm in diameter were prepared at the posterior wall in the middle or lower esophagus obtained from domestic pigs. Each operator performed ESD on the mock lesions in 3 models. The primary outcome was ESD completion rate using the self-completion method. The secondary outcomes were procedure time, en bloc resection rate, perforation rate, and number of injections during the procedure. Results: All 12 ESDs were completed using the self-completion method. The median procedure time (interquartile range) was 483.5 (399–619.3) s (median incision time: 240.4 [168.3–332.5] s; median dissection time: 222 [182.8–257] s). En bloc resection rate was 100%. No perforation was noted during any of the procedures. The median number of injections was 10.5 (9–14.3). The procedure time decreased significantly with increase in experience (p = 0.020). Conclusions: The self-completion ESD method using one Endosaber without any assistance achieved a 100% en bloc resection rate without any perforation. The need for an additional device or assistance was successfully eliminated. This method may prove to be a simple and cost-effective ESD procedure for lesions in humans.

BACKGROUND Chemotherapy is a standard strategy for stage IV gastric cancer patients. However, some cases cannot undergo conversion surgery because of their frailty, even if the patients had response to chemotherapy. For these patients, local tumor progression is a problem. We report here the case of a patient whose residual gastric cancer was resected through endoscopic submucosal dissection (ESD) after concomitant chemotherapy for metastatic gastric cancer. CASE SUMMARY An 85-year-old male complained of difficulty swallowing, and examination revealed gastric cancer with multiple liver metastases. Although he received concomitant chemotherapy, a residual tumor was observed in the primary lesion while the metastatic lesions disappeared completely. Conversion surgery was considered optional treatment; however, he could not undergo that because of advanced age and comorbidities. Thus, we performed ESD to treat the residual tumor. As a result, we resected the residual lesion completely. The patient has been alive for 29 mo since ESD, without recurrence. CONCLUSION We achieved local control using ESD, and these findings may provide therapeutic improvements both in local control and patient survival outcomes.

Background: Radical nephroureterectomy (RNU) is the standard treatment for patients with upper tract urothelial carcinoma (UTUC). However, approximately 25% of patients experience recurrence or metastasis after RNU. This study evaluated the clinical outcome and efficacy of salvage chemotherapy (SC) after recurrence or metastasis. Patients and Methods: Of the 441 nonmetastatic UTUC patients who underwent RNU, 147 patients with recurrent or metastatic lesions were analyzed; patients with bladder cancer recurrence were excluded. Time from disease recurrence or metastasis to cancer-specific survival (CSS) was estimated by the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. Results: The median time from RNU to disease recurrence or metastasis was 13.2 months. In the recurrent or metastatic sites, 31 cases (21%) were liver. In multivariate analyses, pT stage (≥pT3), time to recurrence (p < 0.001). Conclusion: Two or more risk factors defined the high-risk group for patients with recurrence or metastasis after RNU. SC was associated with improved survival in patients with high-risk UTUC.

AIM To investigate the association of perioperative estimated glomerular filtration rate (eGFR) with prognosis in patients with upper urinary tract urothoelial caicinoma (UTUC). METHODS A total of 433 patients underwent radical nephroureterectomy with excision of the bladder cuff (RNU) at six hospitals affiliated with Kitasato University in Japan. Patients were divided into three groups each in terms of preoperative eGFR: normal eGFR (>60 mL/min/1.73 m2 ; n = 172), moderately reduced eGFR (45-60 mL/min/1.73 m2 ; n = 147) and severely reduced eGFR ( 30% decreased; n = 129). Statistical analyses were performed to investigate the association between perioperative eGFR and prognosis. RESULTS Patients in the preoperative normal and moderately reduced eGFR group had significantly better progression-free survival (PFS) and cancer-specific survival (CSS) than those in the severely reduced eGFR group (both; P

Aim To evaluate the impact of body mass index (BMI) on the oncological outcomes of urothelial carcinoma (UC) patients. Patients and methods We retrospectively analyzed data from 818 patients with upper tract urothelial cancer (UTUC) and bladder cancer (BC) who were treated with radical nephroureterectomy (RNU) or radical cystectomy (RC) between 1990 and 2015 at six different institutions in Japan. Patients with distant metastasis at diagnosis and those who received neoadjuvant therapies were excluded, leaving 727 eligible patients (UTUC: n = 441; BC: n = 286). Patients were classified into four groups according to World Health Organization BMI criteria: underweight (BMI 30 kg/m2 ). Results Overweight UTUC and BC patients achieved significantly better cancer-specific survival (CSS) than the other three groups. However, obese UTUC and BC patients had significantly worse CSS than the other three groups (UTUC: P = 0.031; BC: P = 0.0019). Multivariate analysis of BC patients demonstrated that obesity was an independent predictor of unfavorable CSS (hazard ratio [HR] = 7.47; P = 0.002) and that being underweight was an independent predictor of favorable CSS (HR = 0.37; P = 0.029). However, BMI was not a prognostic factor for CSS in UTUC patients according to multivariate analysis. Conclusions Obesity was an independent predictor of BC patients requiring RC. Conversely, being underweight was associated with a favorable prognosis for BC patients. However, BMI was not an independent prognostic factor in patients with upper urinary tract cancer.

A 37-year-old man developed abdominal pain and the frequency of severe abdominal pain steadily increased to once a month. He was therefore admitted to our hospital. Abdominal CT showed bowel obstruction. It revealed transient stenosis in the small intestine. There were no symptoms such as fever or weight loss, it seemed unlikely that the patient had inflammatory bowel disease. Considering the history of recurrent abdominal pain, Familial Mediterranean Fever (FMF) was considered. As a result, a genetic analysis revealed mutations in exons 3 and 8 of the MEFV gene. We herein report the first known case of FMF with transient small bowel stenosis in Japan.

Objective: Several prognostic factors for biochemical recurrence after radical prostatectomy have been reported, including initial prostate-specific antigen level, Gleason score, positive surgical margin, and seminal vesicle invasion. Here we investigate whether Gleason pattern 5 is a predictor for biochemical recurrence. Methods: This retrospective study included 168 patients who underwent laparoscopic radical prostatectomy from 2006 to 2015. The relationship between biochemical recurrence after laparoscopic radical prostatectomy and the presence of Gleason pattern 5, even as a tertiary pattern, was investigated. Biochemical recurrence was defined when the prostate-specific antigen level rose to >0.2 ng/ml after having decreased to

No definitive evidence exists regarding the clinical significance of histologic variants (HV) in upper urinary tract cancer. We investigated the impact of HV on prognosis in patients with upper urinary tract cancer following radical surgery. We retrospectively analyzed 451 patients with upper urinary tract cancer who underwent radical nephroureterectomy at six affiliated hospitals from 1990 to 2015. Patients with distant metastatic disease prior to surgery and those who received neoadjuvant chemotherapy were excluded, leaving 441 eligible patients. Patients were classified into two groups: pure urothelial carcinoma (UC) and HV. The clinicopathological variables of each group were examined using Kaplan–Meier plots and proportional Cox hazard ratios (HR) to compare the oncological outcomes between the two groups. HV included 37 patients (8%). Compared with the pure UC patients, HV patients had significantly worse recurrence-free survival (RFS) and cancer-specific survival (CSS; RFS p = 0.0002, CSS p = 0.0001). Multivariate analysis for RFS revealed HV were independent predictors (HR 1.92; p = 0.026), but the association did not remain significant for CSS. There was no significant difference in CSS between the adjuvant chemotherapy (AC) group and the non-AC group for all HV patients, except in patients with ≥ pT3 tumor or positive lymph node status where the AC group had significantly favorable CSS. HV in upper urinary tract cancer are independent predictors for RFS, but not for CSS. AC improved CSS for HV patients with ≥ pT3 tumor or positive lymph node status.

SUMMARY The Clutch Cutter was invented as a scissor-type knife for endoscopic submucosal dissection (ESD) of gastrointestinal neoplasms. ESD with the scissor-type knife (ESD-S) may be considered a technically easier procedure than ESD with non-scissor-type knives (ESD-NS). Therefore, this study aimed to compare the technical outcomes of ESD-S with those of ESD-NS for superficial esophageal cancer. This was a multicenter retrospective study. Patients with superficial esophageal cancer treated with ESD between October 2015 and March 2018 at three hospitals were retrospectively reviewed. The ESD-S group had 48 patients and the ESD-NS group had 114 patients. A propensity score matching analysis was performed to compensate for the confounding bias between both groups. Multivariate analyses and propensity score matching were used to adjust for age, sex, the tumor size, tumor location, tumor depth, degree of tumor circumference, operator level, usage of the traction method, and the sedation method. The primary outcome was the procedure time of the ESD. Secondary outcomes were the rate of en-bloc/complete resection and the rate of complications including perforation, delayed bleeding, and stricture. Propensity score matching analysis provided 36 matched pairs. Median procedure time in the ESD-S group was significantly shorter than that in the ESD-NS group (44.0 min vs. 66.5 min, P = 0.020). In addition, the treatment outcomes were similar in both groups (en-bloc resection: 100% vs. 97.2%, P = 1; complete resection: 88.9% vs. 86.1%, P = 1; curative resection: 80.6% vs. 77.8%, P = 1; perforation: 0% vs. 5.6%, P = 0.49; delayed bleeding: 0% in both groups; stricture: 2.8% vs. 8.3%, P = 0.61). ESD-S was associated with a shorter procedure time than ESD-NS, without an increase in the incidence of complications. Therefore, the scissor-type knife should be considered as an endo-knife for ESD of superficial esophageal cancers.

Background The prognostic value of histologic variants (HV) after radical cystectomy (RC) remains controversial. We evaluated the clinicopathological features and prognosis in patients with pure urothelial carcinoma (UC) and HV following RC. Methods From 1990 to 2015, 286 patients with bladder cancer were treated with RC at six Kitasato University-affiliated hospitals. All patients were divided into two groups: pure UC and HV, which contained pure variants and mixed-type UC with variant pattern. A comparison of patient characteristics between the two groups was made to assess the clinicopathological features, and statistical analyses were performed to investigate prognosis in the two groups. Results Of the 286 patients, 226 (79%) had pure UC, while 60 (21%) had HV. Of all HV, pure variants accounted for 45% (n = 27). The prevalence of lymph node involvement, locally advanced stage (≥ pT3), positive soft tissue surgical margin and lymphovascular invasion were significantly higher in patients with HV than in those with pure UC. Patients with HV showed worse disease-free survival and cancer-specific survival than those with pure UC (P = 0.009 and 0.003, respectively). In multivariate analysis, HV and lymph node involvement were independent predictors of worse disease-free survival (P = 0.017 and 0.001, respectively). HV, locally advanced stage, lymph node involvement, and positive soft tissue surgical margin were also confirmed as independent predictors of worse cancer-specific survival (P = 0.011, 0.012, 0.003 and 0.010, respectively.). Conclusions HV was associated with greater biological aggressiveness and worse prognosis than pure UC.

AIM To compare the outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms using Clutch Cutter (ESD-C) or other knives (ESD-O). METHODS This was a single-center retrospective study. Gastric neoplasms treated by ESD between April 2016 and October 2017 at Kitakyushu Municipal Medical Center were reviewed. Multivariate analyses and propensity score matching were used to reduce biases. Covariates included factors that might affect outcomes of ESD, including age, sex, underlying disease, anti-thrombotic drugs use, tumor location, tumor position, tumor size, tumor depth, tumor morphology, tumor histology, ulcer (scar), and operator skill. The treatment outcomes were compared among two groups. The primary outcome was ESD procedure time. Secondary outcomes were en bloc, complete, and curative resection rates, and adverse events rates including perforation and delayed bleeding. RESULTS A total of 155 patients were included in this study; 44 pairs were created by propensity score matching. Background characteristics were quite similar among two groups after matching. Procedure time was significantly shorter for ESD-C (median; 49 min) than for ESD-O (median; 88.5 min) (P < 0.01). However, there was no significant difference in treatment outcomes between ESD-C and ESD-O including en bloc resection rate (100% in both groups), complete resection rate (100% in both groups), curative resection rate (86.4% vs 88.6%, P = 0.730), delayed bleeding (2.3% vs 6.8%, P = 0.62) and perforation (0% in both groups). CONCLUSION ESD-C achieved shorter procedure time without an increase in complication risk. Therefore, ESD-C could become an effective ESD option for gastric neoplasms.

A 59-year-old woman was referred to our hospital with the finding of an incidentaloma in her right kidney. Computed tomographyand magnetic resonance imaging showed a solid tumor, approximately8 cm in diameter, at the lower pole of the right kidney. Partial nephrectomy was performed without a renal vessel clamp. Histopathologically, fibroblast-like spindle cells were proliferating with rich collagenous fibers, and tumor cells were infiltrated into the renal parenchyma. The tumor cells were stained positive with CD34, CD99, and bcl-2. The tumor was diagnosed as solitaryfibrous tumor originating from the kidney based on these histopathological findings. The patient was followed 3 years after surgery with neither recurrence nor metastasis.

Background No definitive evidence exists regarding use of adjuvant chemotherapy (AC) for high-risk cases after radical nephroureterectomy (RNU), and the benefit of AC remains controversial. The aims of this study were to evaluate the efficacy of AC in patients with upper tract urothelial carcinoma (UTUC) and to determine those who qualified for AC. Patients and Methods From 1990 to 2015, 449 patients with nonmetastatic UTUC underwent RNU at 6 Kitasato University-affiliated hospitals. Eight patients who received neoadjuvant chemotherapy were excluded from this study. One hundred patients (23%) received platinum-based AC for a median of 3 courses. Disease-free survival and cancer-specific survival (CSS) were estimated using the Kaplan–Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. Results The median age was 69 years, and the median follow-up period was 35.7 months. In multivariate analyses, factors independently predictive of poorer survival included pT stage (≥pT3), lymph node status (pN+), tumor grade (Grade 3), lymphovascular invasion, and soft tissue surgical margin. For the risk stratification model, patients were categorized into 3 groups on the basis of these 5 risk factors. In the high-risk group (at least 3 risk factors, 83 patients), 41 patients (49%) were treated with AC, and the 5-year CSS rate was higher in the AC group compared with the non-AC group (P = .02). Conclusion Having more than 3 risk factors defined the high-risk group among UTUC patients after RNU. AC was associated with improved CSS in patients with high-risk UTUC.

Aims: Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is a clinically and histologically uncommon benign tumor that can be easily mistaken for a malignant neoplasm. We sought to determine whether immunohistochemical staining would be evaluated IMT of the urinary bladder. We have also shown the literatures that imminohistochemical staining of IMT was investigated to distinguish malignant lesions using PubMed data base. Methods: Immunohistochemical staining, including anaplastic lymphoma kinase (ALK), p53, cytokeratin, vimentin, desmin, alpha-smooth muscle actin, myoglobin, smooth muscle myosin and S100, was carried out on serial sections from archival specimens of three patients who underwent transurethral resection and partial cystectomy. Results: Immunohistchemical staining in all patients was positive for ALK and weak positive for p53 protein. In the literatures, positive rates of ALK and p53 inthe IMT of the urinary bladder were 60.9% and 53.1%, respectively. Sarcoma and carcinosarcoma were shown in the pathological specimens with negative ALK and strongly positive p53 inthe same data base. Conclusions: Both ALK and p53 were potentially useful protein markers to distinguish between IMT and sarcoma. However, this study was small sample size. Further study was warranted an investigation of the availability of these proteins in IMT.

Zymomonas mobilis ZmCytC as a peroxidase bearing three heme c-binding motifs was investigated with ΔZmcytC constructed. The mutant exhibited filamentous shapes and reduction in growth under a shaking condition at a high temperature compared to the parental strain and became hypersensitive to exogenous H2O2. Under the same condition, the mutation caused increased expression of genes for three other antioxidant enzymes. Peroxidase activity, which was detected in membrane fractions with ubiquinol-1 as a substrate but not with reduced horse heart cytochrome c, was almost abolished in ΔZmcytC. Peroxidase activity was also detected with NADH as a substrate, which was significantly inhibited by antimycin A. NADH oxidase activity of ΔZmcytC was found to be about 80% of that of the parental strain. The results suggest the involvement of ZmCytC in the aerobic respiratory chain via the cytochrome bc1 complex in addition to the previously proposed direct interaction with ubiquinol and its contribution to protection against oxidative stress.

OBJECTIVES Tissue-specific expression is of key importance in gene therapy and can be achieved by using tissue-specific promoters to drive therapeutic gene expression. The uroplakin (UP) promoter is a powerful tool for bladder cancer gene therapy, but the role of UP protein in the bladder remains unknown. This study aimed to detect UP III expression in transitional cell carcinoma (TCC) of the bladder and to determine whether the role of UP III heterogeneity is associated with predicting disease recurrence and patient survival. METHODS Immunohistochemical staining for UP III was carried out in 92 archival radical cystectomy and 38 normal specimens and correlated with pathologic features and clinical outcomes. RESULTS UP III expression was significantly decreased in bladder cancer tissues compared with normal controls (P

Zymomonas mobilis is an alternative microorganism to Saccharomyces cerevisiae for ethanol production. To find a thermotolerant Z. mobilis strain, the growth and ethanol production of four isolates in Thailand were compared with those of the efficient strain ZM4 (NRRL B-14023) at different temperatures. One of the selected strains, TISTR 405, was found to grow and produce ethanol even at 39°C to an extent similar to that at 30°C, and the growth and ethanol productivity at 39°C were better than those of ZM4 at 30°C, suggesting that TISTR 405 is suitable for ethanol fermentation at high temperatures. Analysis of genes directly related to ethanol formation or degradation, adhA, adhB and pdc, encoding alcohol dehydrogenase (Adh) A, AdhB and pyruvate decarboxylase, respectively, revealed that these genes were highly conserved in both strains. Comparison of their gene expression and activity of the products in both TISTR 405 and ZM4 at different temperatures or growth phases indicated that there was not a great difference at the transcriptional level, but the total activity of AdhA and AdhB in TISTR 405 was higher than that in ZM4. Both strains showed a significant increase in AdhB activity in the stationary phase.

Objectives: We report that a combination of gemcitabine and paclitaxel will effectively treat patients with advanced urothelial carcinoma (UC) who have been previously treated with methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). The objective of this study was to assess the tumor responses, toxicity, and overall survival of these patients as second-line treatment. Methods: Ten eligible patients were enrolled in this study. All patients had been previously treated with MVAC. Patients received paclitaxel 200 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1, 8, and 15. The treatment was repeated every 21 days. Tumors were assessed every two cycles by imaging study. Results: The median number of treatment courses was 4 (range 2–7). Two patients had complete response and five patients had partial response after two courses of treatment. Median overall survival was 10.3 months. Median overall survival from the first MVAC was 19.1 months. Median progression-free survival was 4.1 months. Of the seven responders, median progression-free survival was 7.4 months. Myelosuppresion was the most common toxicity. Nonhematologic toxicity consisted of hypersensitivity reactions to paclitaxel. There were no therapy-related deaths. Conclusions: Gemcitabine and paclitaxel chemotherapy is a favorable therapeutic alternative for patients with advanced or metastatic UC who have previously been treated with MVAC chemotherapy. Given the safety and benefit profile seen in this study, a large prospective research study is warranted to consider the potential role of gemcitabine and paclitaxel chemotherapy as a second-line treatment for urothelial cancer.

PURPOSE To evaluate the clinicopathological outcomes of 8 months of neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy for high-risk prostate cancer. PATIENTS AND METHODS A multi-institutional prospective trial was performed between July 2000 and May 2003 involving high-risk prostate cancer patients without metastasis, including 21 who received 8 months of NHT before radical prostatectomy. High-risk group was defined as clinical stage > or =T2c and/or prostate-specific antigen (PSA) >20 ng/ml and/or Gleason score > or =8. PSA values were considered elevated (biochemical failure) if values of 0.1 ng/ml or greater were obtained. RESULTS Median of initial PSA levels before prostate biopsy was 27.6 ng/ml (8.5-80.7 ng/ml), and median of pre-operative PSA levels after NHT was 0.28 ng/ml (0.02-4.2 ng/ml). There were 5 patients (23.8%) with lower limit of PSA detection (less than 0.02 ng/ml) in 8 months after NHT. The clinical T stage was T1c in 9 patients (42.9%), T2a-b in 8 patients (38.1%), T2c in 3 patients (14.3%), and T3a in 1 patient (4.8%). The median follow-up was 25 months (range 4 to 37). There were 2 patients (9.5%) in pT0, 5 patients (23.8%) with positive surgical margin, 5 patients (23.8%) with extracapsular extension (ECE) and 3 patients (14.3%) with seminal vesicle involvement (SVI). Biochemical failure was occurred in 9 of 21 (42.9%) including of one pT0. Range of time to postoperative biochemical failure was 2 to 25 months (median 6 months) and most of biochemical failure was found within 12 months after surgery. Biochemical failure rate was significantly higher in patient with positive SVI (p = 0.0308) and higher in patients with pre-operative PSA levels of more than 0.1 ng/ml (p = 0.0836), positive ECE (p = 0.0545) and positive surgical margin (p = 0.0545). CONCLUSION Biochemical failure was frequent after this combined treatment, even in a pT0 case. Long-term follow-up of patients is needed to assess the impact of this therapy on mortality.

To evaluate the biochemical disease-free survival (DFS), predictors of clinical outcome and morbidity of patients with localized prostate cancer treated with high-intensity focused ultrasound (HIFU), a noninvasive treatment that induces complete coagulative necrosis of a tumour at depth through the intact skin.In all, 63 patients with stage T1c-2bN0M0 localized prostate cancer underwent HIFU using the Sonablate system (Focus Surgery, Inc., Indianapolis, IN, USA). None of the patients received neoadjuvant and/or adjuvant therapy. Biochemical recurrence was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology consensus definition, i.e. three consecutive increases in prostate-specific antigen (PSA) level after the nadir. The median (range) age, PSA level and follow-up were 71 (45-87) years, 8.5 (3.39-57.0) ng/mL and 22.0 (3-63) months, respectively.The overall biochemical disease-free rate was 75% (47 patients). The 3-year biochemical DFS rates for patients with a PSA level before HIFU of10, 10.01-20 and20 ng/mL were 82%, 62% and 20% (P0.001), respectively. The 3-year biochemical DFS rates for patients with a PSA nadir of0.2, 0.21-1 and1 ng/mL were 100%, 74% and 21% (P0.001), respectively. Final follow-up sextant biopsies showed that 55 (87%) of the patients were cancer-free. Multivariate analysis showed that the PSA nadir (P0.001) was a significant independent predictor of relapse.HIFU therapy appears to be a safe, effective and minimally invasive therapy for patients with localized prostate cancer, and the PSA nadir is a useful predictor of clinical outcome.

To perform systemic 22-core transperineal ultrasound-guided template prostate biopsies in patients with previous negative transrectal ultrasound-guided prostate biopsy findings and evaluate the cancer core distribution.Between April 2001 and December 2003, 128 men underwent systemic ultrasound-guided biopsy using the transperineal template technique. All patients had undergone at least one previous set of biopsies. Prostate biopsy was performed transperineally using an 18-gauge biopsy needle driven by a spring-loaded device. Four biopsies were obtained anterior to posterior from each of four coronal planes in the mid-region, and three biopsies were obtained anterior to posterior from each of two coronal planes in the apical region.Of the 128 patients, 29 (22.7%) had cancer according to an extended transperineal biopsy. Patients with prostate cancer had significantly greater prostate-specific antigen (PSA) levels (11.4 versus 7.6 ng/mL, P = 0.0125), smaller transition zone volumes (12.7 versus 21.2 cm3, P = 0.0012), smaller prostate glands (31.5 versus 44.0 cm3, P = 0.0015), and greater PSA density (0.36 versus 0.19 ng/mL/cm3, P0.0001). The cancer core rates in the mid and apical parts of the anterior region (5.3% and 8.0%) were significantly greater than in the mid and apical parts of the posterior region (3.3% and 3.6%, P = 0.0297 and P = 0.0132, respectively).The results of our study have shown that transperineal approaches are appropriate for sampling from the anterior half of the prostate gland. In patients in whom the diagnosis of prostate cancer is suspected, we believe that systemic 22-core transperineal ultrasound-guided template prostate biopsy might be the next optional diagnostic step after an initial negative prostate biopsy.

Purpose The analgetic efficacy of intraurethral instillation of anesthetic jelly in rigid cystoscopic examination for men is not clearly confirmed. This study evaluated the usefulness of intraurethral instillation of anesthetic jelly by questionnaires regarding the pain and uncomfortable feelings during and after the cystoscopic examination. Materials and methods A total of 62 men were enrolled in the study. Sixteen patients had not received cystoscopy previously (first cases), and 46 had prior experiences of cystoscopy more than twice (repeat cases). These patients were sequentially divided into two groups; one group (jelly-group) received intraurethral instillation of oxybuprocaine hydrochroride jelly (Benoxil jelly) prior to cystoscopic examination, and the other group (no-jelly-group) did not receive the jelly instillation. Pain during the jelly instillation to examination, and uncomfortable feelings at micturition after the examination was evaluated by questionnaires. Results Instillation of the jelly itself caused considerable pain, which almost similar to that of scope insertion. There was no significant difference in pain score between jelly-group and no-jelly-group during the insertion of the scope to examination. The miction pain after examination was significantly severer in the jelly-group than in the no-jelly-group in repeat cases. In addition, 75% of repeat cases felt better comfortableness when jelly was not instilled, and 96% of repeat cases did not want jelly instillation for their future examination. Conclusions Intraurethral instillation of anesthetic jelly had no efficacy for reducing the pain during cystoscopy. Instillation of the jelly itself caused considerable pain, and it made pain and uncomfortable feelings after the examination worse. These results suggested that the instillation of anesthetic jelly before rigid cystoscopy in men might not be useful enough for reducing the uncomfortable feeling during the examination.

Cancer prevention in people occupationally exposed to carcinogens that cause bladder cancer has focused on early cancer detection by use of traditional screening methods including hematuria testing, urinary cytology, and cystoscopy. However, these screening methods showed limitations in terms of reducing mortality from bladder cancer. Currently, several molecular substances have shown potential as screening markers for bladder cancer. This article reviews epidemiologic cohort studies, hematuria screening, and the biologic molecular markers for bladder cancer related to occupational carcinogenicity. Considering the long latency period, new cases of occupational bladder cancer have been expected to occur more frequently. Because of recent advances in molecular techniques, biologic markers have a potential role in screening for and monitoring of occupational bladder cancers.

山岳トンネル掘削に伴う山体内の地下水位の挙動の変化は, 掘削時の安全性だけでなく, 地元住民の生活や周辺の自然環境など多岐に亘って影響を及ぼす. これらの影響評価の上で基本的な指標となる地下水位変動の影響圏とトンネル内湧水流量を予測するためには, いくつかの簡易的な方法が提案されている. しかし, これらの簡易的な手法は何らかの仮定に基づいて提案されたものである. そこで, 本研究では従来から提案されている方法とその前提条件について明らかにするとともにとともに, これらの方法では取扱っていなかった降雨と透水係数を入力条件とした影響圏の簡易推定法を提案する. また, これらの結果をもとに, 浸透流解析においてモデル化すべき領域の設定方法について論述する.

Background: Open pyeloplasty has been the gold standard for surgical treatment of ureteropelvic junction (UPJ) obstruction, enjoying a long-term success rate exceeding 90%. Unfortunately, this procedure requires a muscle incision that entails some degree of morbidity. We have, therefore, investigated the feasibility of laparoscopic pyeloplasty for UPJ obstruction and report here the outcomes of our early cases. The median follow up is 25 months (range, 12–42 months). Methods: Between March 1999 and September 2001 we performed laparoscopic pyeloplasty on 12 ureters in 11 patients presenting with symptomatic hydronephrosis, secondary to a short stenosis of the UPJ or to ventrally crossing vessels; bilateral pyeloplasty was performed as a single procedure in one patient. We performed dismembered Anderson–Hynes pyeloplasty, Fenger plasty and Y-V plasty in eight, two and two ureters, respectively. All procedures were carried out transperitoneally. Results: The procedure was completed successfully in all cases. Crossing vessels were noted in six of 12 ureters (50.0%). Mean operative time and blood loss in 11 patients (including one bilateral case) were 272.8 min (range, 175–480 min) and 96.4 mL (range, 20–340 mL), respectively. Postoperative complications were noted in two patients (18.2%): one instance of prolonged urine leakage and one anastomotic re-stricture. Eleven of 12 ureters (91.6%) demonstrated a patent UPJ on excretory urography and/or improvement of renal function on diuretic renography at a minimum follow up of 12 months. Conclusion: Although the procedure requires advanced laparoscopic skills, it can be safely and successfully completed as frequently as the conventional open procedure. Laparoscopic pyeloplasty seems to be a valuable alternative to open pyeloplasty for UPJ obstruction.

The efficacy of various currcntly available therapeutic strategies for bladder cancer is not always suffcient, especially for the advanced disease, recurrent superficial cancer, and treatment-resistant carcinoma in situ. Advances in genetic and molecular biology have led to novel approaches for cancer treatment. Gene therapy is currently one of the most promising strategies against various malignancies, and several clinical trials have been approved worldwide. Various strategies for modulating the genetic state have been applied in bladder cancer treatment, and encouraging results have been demonstrated both in vitro and in vivo. Although the therapeutic genes work dramatically when the transgenes are effectively expressed in the targeted cells, however, a sufficient rate of transduction cannot always be achieved. The most significant obstacle for clinical application of cancer gene therapy might be the method for sufficient delivery and expression of the therapeutic genes. Bladder is an easily accessible organ because of its anatomy; however, a glycosaminoglycan (GAG) layer on the bladder mucosa may protect integration of exo-delivered genetic vectors. Various strategies are applied for improving the transduction efficacy of the therapeutic genes into the bladder cancer cells. These strategies include the modification of adenoviral fibers, cotransduction of the materials for enhancing the viral infectivity, and disruption of the GAG layer. Recent advances in the field of gene therapy for bladder cancer are briefly summarized in this review.

Objectives. To evaluate the therapeutic efficacy of bacille Calmette-Guerin (BCG) for carcinoma in situ (CIS) of the urothelium involving the upper urinary tract when the vaccine was administered by way of the bladder using vesicoureteral reflux created by a double-pigtail (DP) catheter. Methods. Thirteen upper urinary tracts of 9 patients with cytologically diagnosed CIS, with concomitant bladder CIS in 4, were treated by intravesical BCG instillation. A DP catheter was placed retrogradely, and the appearance of vesicoureteral reflux was confirmed by cystography. BCG (1 to 2 mg/mL) in a volume sufficient to fill the renal caliceal system was administered into the bladder weekly for 6 weeks. The mean follow-up was 36 months (range 8 to 97). Results. The voided urine cytology turned negative in all 9 patients at a mean of 86 days after the first administration of BCG. The voided urine cytology returned positive afterward in 3 patients, and positive cytology in the upper urinary tract was confirmed in 1 of 13 treated urinary tracts, which were successfully treated by another course of BCG therapy with the DP catheter. Minor adverse effects related to BCG and the DP catheter were seen in 5 patients. Conclusions. BCG therapy for the CIS involving the upper urinary tract using a DP catheter might have the potential to be an effective procedure preserving renal units and could be adopted not only as an imperative, but also as an elective, treatment option.

Purpose Enterovesical fistula in patients with Crohn's disease is intractable. Although there are some reports that the enterovesical fistula were successfully treated conservatively, closure of the fistula cannot always be achieved and surgical intervention may required for those patients. Since surgical closure of entero-entero fistula has a high risk of relapse, the strategy for treating enterovesical fistula has not been established. We evaluated the clinical findings especially in management of enterovesical fistula in Crohn's disease. Patients and methods Two hundred two patients (mean age was 28.4 year old, range 12-69; 152 men and 50 women) were diagnosed as Crohn's disease during a period of 15 years between 1986 and 2000 in our institute. The incidence and the clinical results regarding the diagnosis and the treatment of enterovesical fistula in these patients were retrospectively evaluated. Results Seven in 202 patients were diagnosed to have an enterovesical fistula (3.5%, 6 men and 1 woman). The period from the initial diagnosis of Crohn's disease to the recognition of the enterovesical fistula was 11 to 204 months (mean 92.1 months). Enterovesical fistula was revealed and/or visualized by radiological enterography in 6, cystography in 2, cystoscopy in 6, and CT in 4 patients. Surgical interventions were finally conducted in all 7 patients after the failure of conservative treatment for 10 to 146 days (mean 68.2 days). Surgical procedures performed for closing the enterovesical fistula were partial cystectomy with fistulectomy in 5, fistulectomy with bladder wall overlay-suture in 2, and bladder wall overlay-suture alone in 1. No relapse of enterovesical fistula was recognized in any patient in the average observation of 41.6 months. Conclusion Although the treatment of Crohn's disease has been advanced, enterovesical fistula is shown to be resistant to conservative treatment options and it makes patients in unfavorable status for relatively long duration. Our evaluation shown here demonstrated the sufficient surgical results on the closure of enterovesical fistula without any relapse, and was different from the high relapse rate after the surgical management of entero-entero fistula in similar observation period. Surgical interventions of enterovesical fistula caused by Crohn's disease might have an advantage to make diseased patients improved in shorter duration.

Purpose: To evaluate the efficacy and invasiveness of retroperitoneoscopic radical nephrectomy for renal-cell carcinoma (RCC) in patients with chronic renal failure (CRF), a group known to have relatively high surgical risk. Patients and Methods: Between May 1996 and September 1999, six CRF patients maintained on hemodialysis underwent retroperitoneoscopic radical nephrectomy for clinically localized RCC by the posterior lumber approach. The excised kidneys were evacuated via a posterior skin incision (5 cm) between two port sites; the muscle layers were not incised. Results: The procedure was completed in all patients with no major complications. The mean operative time was 162 (range 135-210) minutes, and the estimated blood loss was 58 (15-100) mL; none of the patients required a blood transfusion. Regular hemodialysis was restarted on postoperative day 2 or 3. Conclusions: This procedure seems to be minimally invasive and suitable for the treatment of small RCC in atrophic kidneys, especially in patie...

HER-2/neu is overexpressed in 25-30% of human breast cancers. We prepared an anti-HER-2/neu hammerhead ribozyme expressed by a recombinant adenovirus (rAdHER-Rz). Human breast cancer cell lines were transduced with high efficiency, resulting in decreased HER-2/neu expression. In vivo injections of rAdHER-Rz into BT-474 tumors established in nude mice inhibited tumor growth to 20% of mock-treated controls. Similar in vivo effects were shown in MCF-7 cells, which do not overexpress HER-2/neu. The growth inhibitory effects of rAdHER-Rz were greater than those of an antisense-expressing vector. These results suggest the utility of anti-HER-2/neu ribozymes as a rational strategy for gene therapy of breast cancer. Gene Therapy (2000) 7, 241-248.

Culture and international relations have come closer in the past twenty years. Still many areas are open to further research. As part of Cold War studies, historians have explored the links between national culture and strategic and political thinking. Some of them now question traditional international relations periodization and favor macro-historic themes such as globalization (leading to studies on migrations as well as international non-governmental organisations). One wonders whether the very ideas of culture and international relations are not altered by the coming of an “international civil society” just as thinking on globalization raises the issue of “americanization.”, Histoire culturelle et histoire des relations internationales — liens et perspectives d’intégration — Depuis vingt ans, de nombreux rapprochements se sont opérés entre la culture et les relations internationales ; des pistes fructueuses peuvent encore être explorées. Les historiens de la Guerre froide se sont intéressés aux liens entre culture nationale et élaboration des stratégies et politiques. On remet aujourd'hui en cause la périodisation habituelle des relations internationales pour aborder des thèmes macro-historiques (comme la globalisation, qui comprend l'étude des migrations, comme les travaux sur les Organisations non-gouvernementales internationales). Il faut se demander si les notions mêmes de culture et de relations internationales ne sont pas affectées par l'émergence d'une «société civile internationale», alors que les réflexions sur la globalisation posent le problème de l'«américanisation»., Irie Akira. Cultural History and International History — How they Have Connected, How they May be Further Integrated. In: Cahiers Charles V, n°28, juin 2000. Transmission des valeurs nationales: théories, individus, institutions (domaine anglo-américain) pp. 13-31.

Ras oncogenes are thought to play a critical role in cellular proliferation and tumorigenesis. Reversal of the malignant phenotype, inhibition of tumor growth, and decreased tumorgenicity have been demonstrated with the use of anti-H-ras ribozymes. In this study, the therapeutic efficacy of a hammerhead ribozyme targeting the mutated H-ras oncogene was investigated in an experimental bladder cancer model using a recombinant adenovirus as delivery vehicle. Tumors were established in nude mice by subcutaneous injection of EJ human bladder carcinoma cells harboring a point mutation of the H-ras gene. The tumors were treated with intralesional injections of an adenovirus expressing an anti-H-ras ribozyme (rAd-Hras Rz) by different schedules at serial titers, and the tumor inhibition efficacy was analyzed. The viral infection efficacy and kinetics of ribozyme expression were also evaluated. Intralesional injection of rAd-Hras Rz resulted in significant antineoplastic effects in a dose-dependent fashion. Complete regression of the tumor was achieved by rAd-Hras Rz in several cases without recurrence during the 50-day observation period. Although there was moderate vector-associated cytotoxicity in this cell line, complete regressions were not observed in the cases treated with control adenovirus vectors or vectors expressing an inactive anti-H-ras ribozyme or anti-H-ras antisense oligonucleotides. These results suggest the efficacy of a ribozyme-encoding adenovirus in the experimental gene therapy of human bladder cancer.

The tumor suppressor gene BRCA1 on chromosome 17q21 has been characterized and shown to be mutated in patients with familial breast and ovarian cancer. Several studies examined the relatives of women with breast cancer and noted an association with ovarian and prostate cancer. This study investigated 24 human prostate cancer specimens for BRCA1 gene mutations and loss of heterozygosity (LOH) on chromosome 17q21 assessed by the polymerase chain reaction. LOH was identified using 7 highly polymorphic tandem repeat markers on chromosome 17q21, in addition to an analysis of the whole coding region of the BRCA1 gene. Four of the 24 prostate cancer specimens showed LOH at one or more loci, all of which were histologically poorly differentiated (4 of 11) and stage D (4 of 15). One of the 24 cases showed a germ-line mutation of the BRCA1 gene, and a sister of this patient died of ovarian cancer. It appears that the BRCA1 gene is not frequently involved in the development of primary prostate cancer.

We consider a global optimization problem of minimizing a linear function subject to p linear multiplicative constraints as well as ordinary linear constraints. We show that this problem can reduce to a 2p-dimensional reverse convex program, and present an algorithm for solving the resulting problem. Our algorithm converges to a globally optimal solution and yields an e-approximate solution in finite time for any e > 0. We also report some results of computational experiment.

BACKGROUND During the past decade, studies of human cancer have begun to yield molecular information on the identify of the multiple genetic changes in the development and progression of tumorigenesis. We investigated alterations of p53 and genomic instability in testicular tumors. MATERIALS AND METHODS Polymerase chain reaction (PCR) single-strand conformation polymorphism was performed for analysis from exons 5 to 8 of p53 gene in 22 cases and PCR-microsatellite instability analysis using 8 microsatellite markers were conducted in 19 cases of testicular tumor. RESULTS No mutations were noted for exons 5 to 8 of the p53 gene. Differences in unrelated microsatellites for tumor and corresponding normal DNA were detected in 5 of 19 (26.3%) cases examined. Alterations noted in more than 2 microsatellites were observed in 3 of 19 (15.8%) and categorized as replication error (RER) phenotype. Two of 7 (28.6%) seminomatous and 1 of 12 (8.3%) non-seminomatous testicular tumors patients showed RER. Two of 16 (12.5%) stage T1-3N0M0 and 1 of 3 (33.3%) stage T1-3N1-3M0-1 showed RER. CONCLUSIONS Alterations in microsatellite instability may be involved in the development of testicular tumor.

Laparoscopic cystectomy and bilateral ureteric ligation were performed on a 52-year-old woman with end-stage renal disease on hemodialysis (HD) for muscle-invasive bladder cancer. Her volume of urine production was approximately 100 mL/day. Excisions of the bladder and uterus with ligation of the bilateral ureter were conducted completely laparoscopically. Total operative time was 280 min and the amount of blood loss was 60 mL. No complications were seen perioperatively and no adverse events regarding ureteric ligation arose. HD was performed on the second postoperative day. At a 12-month follow-up, the patient showed no evidence of disease.

To investigate the safety and efficacy of a maintenance regimen of bacillus Calmette-Guérin therapy including 6-week induction and 2-week maintenance instillation for patients with recurrent or multiple Ta, T1 tumors or carcinoma in situ of the urinary bladder.This study was performed as single-arm multi-institutional study. The enrolled patients had been diagnosed with urothelial carcinoma of the bladder, including the presence of at least two bladder tumors, single tumors recurring within 12 months of follow-up, any Grade 3 Stage Ta or T1 tumor, and primary or recurrent biopsy proven carcinoma in situ. Patients received 81 mg intravesical bacillus Calmette-Guérin (Connaught strain). The instillation was repeated once a week for another 5 weeks, followed by once a week for 2 weeks at months 3, 6, 12, 18, 24, 30 and 36, for a total of 20 instillations in 3 years.From 28 hospitals, 202 patients were registered. A total of 186 patients matched the inclusion criteria: 139 patients in the Ta/T1group and 47 patients in the carcinoma in situ group. At the 4-year median point of follow-up, recurrence-free survival rates in the Ta/T1 group and the carcinoma in situ group were 76.7 and 77.7%, respectively. Completion rates for maintenance therapy in both groups at months 3, 6, 12, 24 and 36 were 81.7, 68.9, 58.1, 42.5 and 35.0%, respectively. Common toxicities were pain on urination, urinary frequency and gross hematuria. There was no treatment-related death.This regimen may be feasible in patients with Ta/T1 tumor or carcinoma in situ; however, future Phase III randomized study is needed to determine whether this regimen would be truly safe and effective compared with 3-week maintenance regimen.