Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016.

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation.

BACKGROUND: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival. METHODS: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies. RESULTS: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057). CONCLUSIONS: The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.

Diagnostic performance of chromoendoscopy and narrow band imaging for colonic neoplasms: a meta-analysis.

AIM: We conducted a meta-analysis to compare the diagnostic test performance of chromoendoscopy and narrow band imaging (NBI) for colonic neoplasms. METHOD: MEDLINE, EMBASE and the Cochrane Library were searched (1966 to March 2009). Articles were included if: (i) chromoendoscopy or NBI was used, (ii) sensitivity and specificity were reported; (iii) absolute numbers of true-positive, false-positive, true-negative and false-negative results were provided or could be calculated; and (iv) pathology was used as the reference standard. Sensitivity and specificity were pooled using random effects model. Secondary analyses were conducted by limiting the studies in which magnifying endoscopy was used alone as a diagnostic modality, and polyp size and macroscopic appearance of lesions were not considered. RESULTS: Of 1342 screened articles, 27 met the inclusion criteria. Pooled sensitivity for chromoendoscopy and NBI was 0.94 (95% CI, 0.92-0.95) and 0.94 (0.91-0.97), and specificity was 0.82 (0.77-0.88) and 0.86 (0.83-0.89), respectively. There were no differences in sensitivity (P = 0.99) or specificity (P = 0.54) between the two methods. In the secondary analysis, pooled sensitivity for choromoendoscopy and NBI was 0.93 (95% CI, 0.90-0.97) and 0.96 (0.93-0.99) and specificity was 0.80 (0.73-0.87) and 0.85 (0.78-0.92). respectively. Overall, the pooled false-negative rate was 0.057 (95% CI, 0.040-0.73) for chromoendoscopy and 0.057 (95% CI, 0.028-0.085) for NBI. CONCLUSION: Chromoendoscopy and NBI had similar diagnostic test characteristics in the assessment of colonic neoplasms; however, the false-negative rate for both methods of 5.7% is an unacceptably high rate and currently therefore, neither method is ready for general use.

Effect of HMG-CoA reductase inhibitors on blood pressure in hypertensive patients treated with blood pressure-lowering agents: retrospective study using an anti-hypertensive drug database.

BACKGROUND AND OBJECTIVES: We used a Japanese antihypertensive drug database to investigate the blood pressure-lowering effect of statins in hypertensive patients receiving antihypertensive medication. We also examined the class effect of antihypertensive drugs on blood pressure lowering by statins. MATERIAL AND METHODS: The Risk/Benefit Assessment of Drugs-Analysis and Response (RAD-AR) Council has developed an antihypertensive drug database which contains the results of post-marketing surveillance for various antihypertensive agents from 143,509 antihypertensive users in clinical settings. Antihypertensive patients in the database with concurrent hyperlipidemia were grouped into statin users and non-users, and changes in systolic and diastolic blood pressure over a three-month period were compared. Further, the class effects of antihypertensive drugs on the lipid lowering effects of statins were also investigated. RESULTS: A total of 1070 statin users and 1974 non-users were analyzed. Changes in systolic blood pressure were significantly greater in the statin user than in the non-user group (mean difference: 1.63 mmHg, p = 0.03). In contrast, no significant effect of statin use was observed on the change in diastolic blood pressure (DBP) (0.87 mmHg, p = 0.08). When stratified by antihypertensive class, reductions in blood pressure were greater in statin user groups for all antihypertensive classes without statistical significance, except for a significant change in DBP in those receiving beta-blockers (mean difference: 2.98 mmHg, p = 0.03). DISCUSSION: The present study documented that statin's effect on blood pressure in hypertensive patients with hyperlipidemia in clinical setting is statistically significant but has a minimal significance. With regard to class differences among antihypertensive agents, the decrease was greatest in the DBP of patients treated with beta-blockers. In contrast, no significant changes were seen in the ACE inhibitor or Ca antagonist subgroups. One possible explanation for the differential effects of antihypertensive class in our study might be the lack of a vasodilatation effect.

[Diagnosis of pheochromocytoma by 131I-MIBG scintigraphy].

Between February, 1984, and June, 1988, 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy was performed on 48 patients with suspected pheochromocytoma at our hospital. Whole body image and/or spot images were obtained 24, 48 and 72 hours after injection of 0.5 mCi of 131I-MIBG. In 10 of 12 patients with surgically proven pheochromocytoma, 131I-MIBG was accumulated in the primary and metastatic tumor. 131I-MIBG scintigraphy was negative in 2 patients. One case of renal cyst had the accumulation of 131I-MIBG but the disease could be confirmed. By 131I-MIBG scintigraphy sensitivity was 83% (10/12), and specificity was 97% (35/36). Heart intensity was much higher in patients with nonpheochromocytoma than those with pheochromocytoma. Thus 131I-MIBG scintigraphy proved to be safe, non-invasive and specific in the diagnosis of pheochromocytoma.

[Fibroepithelial polyp of the prostatic urethra: report of two cases and review of the literature].

Two cases of Fibroepithelial polyp in 47-and 74-year-old males complaining of gross hematuria are described. In the foreign literature, this polyp most commonly occurs in infancy and childhood in the first decade of life, but rarely occurs in aged male. Ten cases of this disease could be accumulated in the Japanese literatures, in which this polyp more commonly occurs in older generation compared with younger one. Urethral polyp should be considered in the differential diagnosis of gross hematuria.

[Use of Nd:YAG laser and flexible cystoscope in outpatient treatment of recurrent superficial bladder tumors].

Nd:YAG laser irradiation and flexible cystoscopy were used in the outpatient management of 16 cases (21 sessions) with superficial bladder tumors. Irradiation of tumors was accomplished in all cases except 3 in which the visual field was affected by bleeding after the cup biopsy of tumors. Tumors at the bladder neck were easily irradiated through the flexible cystoscope. No tumor recurred at or near the previously irradiated site. This method provided a safe and cost-effective means to treat superficial bladder tumors in selected cases.

[A case of urinary ascites probably caused by spontaneous bladder rupture].

The patient was a 68-year-old woman, who had underwent radical hysterectomy and postoperative radiation therapy thirteen years ago, and suffered from typical symptoms of panperitonitis in 1992 and 1993. Based upon laboratory findings of ascites, intraperitoneal urinary extravasation was suspected as the cause of panperitonitis. However, IVP, cystography, cystoscopy could not show the direct evidence of extravasation. On urodynamic study, poor flow rate, large postvoided residual urine, disturbance of the bladder sensation, and low compliance were present. We considered the neurogenic bladder dysfunction and detrusor weakness due to the previous radical hysterectomy and radiation therapy as the possible causal factors of spontaneous bladder rupture causing urinary extravasation from the bladder in this case.

[An overview of clinical trials in endocrine therapy for cancer].

To obtain information for published clinical trials in endocrine therapy for cancer in Japan, a computerized literature search of MEDLINE, EMBASE and IGAKU-CHUO-ZASSHI (CD-ROM) was done. We found four articles on randomized trials for prostate cancer and two for breast cancer. In order to obtain information for ongoing randomized phase III trials in endocrine therapy for cancer in the United States and Europe, a search of PDQ (Physician's Data Query) was done. In PDQ, 13 active trials started after January 1990 in endocrine therapy for breast cancer and six active trials started after January 1990 in endocrine therapy for prostate cancer were registered. Out of 13 trials for breast cancer, projected sample sizes were over 1,000 in eight trials, and QOL was selected as an end point in six trials. Out of six trials for prostate cancer, projected sample sizes were over 500 in three trials, and QOL or sexual function was selected as an end point in three trials.

[Comparison of clinical effects between granisetron alone and combination of granisetron and methylprednisolone against the nausea and vomiting induced by CDDP chemotherapy--comparative study by the cross-over trial. University of Tsukuba Antiemetics Study Group].

A cross-over clinical trial was carried out to compare the antiemetic effect and safety between granisetron alone (40 micrograms/kg) and the combination of granisetron and methylprednisolone (MP: 10 mg/kg) in urological cancer patients treated with cisplatin. Forty-eight courses were given with granisetron alone and 47 courses with both granisetron and MP. The antiemetic effect of nausea and vomiting was evaluated in the acute emetic phase. during the 24 hours following the CDDP administration, and in the delayed emetic phase, 2 to 7 days after the administration. Combination therapy of granisetron and MP demonstrated a greater antiemetic effect during the 72 hours following the CDDP administration than by granisetron alone. But there was no significant difference in antiemetic effect between combination therapy and granisetron alone after the 3rd day. Combination therapy also demonstrated more efficacy in complete antiemetic effect, with no emesis and less than moderate nausea, than by granisetron alone. Both treatments showed no side effects and were safe.

[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development].

A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product.

[Early detection and prevention of cancers in various therapeutic areas. Discussion].

As illustrated by prostate cancer screening provides an opportunity for early intervention and treatment. However the screening test needs to detect patients with cancer with a low rate of false positives and at a stage which can be treated. Recently the concept of treating patients at high risk of developing breast cancer or suffering a recurrence has been highlighted by the western studies with Nolvadex (tamoxifen). Thus roundtable discussion (held in Tokyo) discussed the different strategies in Japan compared to US & Europe for screening & early intervention/prevention of cancer for breast, prostate, bladder, liver, lung, gynaecological & GI cancers. The range of strategies for cancer screening, how it is funded, whether it is appropriately targeted and whether there is any evidence for a beneficial effect on morbidity or mortality & future prospects for improved sensitivity through new methodology or markers were discussed. Although the relative rates of cancer vary between Japan & the West, the same factors seem to influence cancer development & the data on intervention were seen to be valid. The changing patterns of cancer in Japan suggest a clear opportunity for reducing, the incidence of cancer through lifestyle modification. For some cancers, e.g. cervical & bladder where there is a clear link between abnormal cytology & development cancer true prevention is already practiced. In other cases, preventive treatment is limited by the efficacy of available therapies. As far as drug treatment is concerned, funding of healthcare in Japan does not recognise the concept of prevention although there is, in practice, no barrier to the use of interventions where there is a clear link between biochemical/histological markers & development of cancer.

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling.

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P=0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P=0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of beta-catenin. Knockdown of CXXC4 induced the nuclear translocation of beta-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

Serum creatinine level during chemotherapy for testicular cancer as a possible predictor of bleomycin-induced pulmonary toxicity.

BACKGROUND: Bleomycin is one of the key drugs used in induction chemotherapy for testicular cancer. Pulmonary toxicity is the major and potentially fatal adverse side-effect of this drug. METHODS: To evaluate the risk factors for bleomycin pulmonary toxicity, we retrospectively analyzed the cases of 20 men treated for metastatic testicular cancer at Tsukuba University Hospital between 1990 and 1996. All patients were treated with two to four cycles of a PVB regimen or BEP regimen. Recombinant human granulocyte colony-stimulating factor was used in all but one case. With a logistic procedure, we evaluated the age, total bleomycin dose, total cisplatin dose, renal injury, leukocytosis, smoking history, lung metastases and drug regimen as risk factors for a decrease in the diffusing capacity. RESULTS: Diffusing capacity was decreased to below 75% of the predicted values in nine patients. Elevation of the serum creatinine level was the most significant risk factor (P = 0.018) by the chi-squared test. A logistic regression analysis also indicated that the elevation of serum creatinine level was an independent risk factor for a decrease in the diffusing capacity (odds ratio 22.3, 95% Cl 1.02-487.3, P = 0.049). CONCLUSIONS: We recommend a pulmonary function assessment of patients receiving a relatively low dose of bleomycin, especially when an elevated serum creatinine level is seen during chemotherapy.

Intravesical chemotherapy for maximum prophylaxis of new early phase superficial bladder carcinoma treated by transurethral resection: a combined analysis of trials by the Japanese Urological Cancer Research Group using smoothed hazard function.

BACKGROUND: The effect of intravesical instillation of doxorubicin or epirubicin after transurethral resection (TUR) was estimated from the data of five randomized clinical trials in Japan. The authors provided the estimated hazard function plots with a smoothing technique, to evaluate the prophylactic effect of an intravesical therapy over time and to estimate the natural history of superficial bladder carcinoma. METHODS: Data on a total of 1732 patients from 5 studies of the Japanese Urological Cancer Research Group who were eligible to receive doxorubicin and epirubicin were analyzed. The patients were divided into four subgroups based on their background characteristics. Their tumors were categorized as "primary and solitary," "primary and multiple," "recurrent and solitary," or "recurrent and multiple." RESULTS: Multivariate analysis revealed that intravesical instillation reduced the risk of recurrence to about one-half to two-thirds compared with the controls. The shapes of the graphs that estimated the hazard function for patients with no prophylaxis indicated that multiple tumors showed an earlier peak of recurrence than solitary tumors and recurrent tumors had a higher hazard of recurrence than primary tumors. Graphic presentation of the hazard function in each subgroup suggested that the effect of prophylaxis continued for 500 days after TUR but not for longer. CONCLUSIONS: This analysis indicated that there are two patterns of tumor recurrence of superficial bladder carcinoma after TUR, namely, early phase and late phase. Intravesical chemotherapy may be effective mainly in reducing the hazard for recurrence in the early phase.

Bacillus Calmette-Guérin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group.

BACKGROUND: Intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) has become a standard treatment for carcinoma in situ (CIS) of the urinary bladder. However, there have been few reports concerning the direct effect of BCG on existing tumors classified as Ta or T1. In the first stage of this clinical study, 157 patients were treated with BCG intravesical instillation (Tokyo 172 strain [BCG Co. Ltd., Tokyo, Japan]; 80 mg weekly for eight times) by our Study Group. The efficacy on existing tumors was a complete response (CR) rate of 84.4% and 66.4% and a partial response (PR) of 6.3% and 20.8% for 32 cases of CIS and 125 cases of Ta or T1 tumors, respectively. METHODS: In the second stage of this study, the authors investigated the outcome of the 138 patients who had achieved CR or PR in the first stage. One hundred twenty (87.0%) of the patients were followed fully. Of those patients, 52 were randomized to receive prophylactic (maintenance) therapy consisting of BCG of 40 mg monthly for 12 times (Group A), whereas 55 were randomized to an untreated control group (Group B). Thirteen other patients refused to be randomized and were followed without prophylactic instillation. RESULTS: The median follow-up period was 48 months for Group A and 42 months for Group B. In Groups A and B, the beneficial effect of the BCG therapeutic instillation persisted for a long time, and the 3-year nonrecurrence rate was 77.6% in Group A and 74.2% in Group B. Disease progression was observed rarely. CONCLUSION: For patients in whom transurethral resection of tumors of the bladder (TUR-Bt) alone is unlikely to eliminate the tumor, intravesical BCG is potentially the treatment of choice.

Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group.

BACKGROUND: To evaluate the antitumor activity in patients with T3b, T4 or metastatic urothelial carcinoma treated with MEC or M-VAC chemotherapy, by performing a multi-center randomized prospective study. METHODS: From 1991 to 1995, 89 patients with T3b, T4 or metastatic urothelial carcinoma were randomly allocated to a methotrexate, epirubicin and cisplatin chemotherapy group (arm 1: S-MEC therapy; n = 29), a dose-intensified MEC therapy combined with G-CSF group (arm 2: I-MEC therapy; n = 30) or a methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy (arm 3: M-VAC therapy; n = 30). At the registration center, the patients were stratified into previously untreated patients and patients with recurrence after radical operation and then randomly allocated to the treatment groups. In each arm, two or more courses of chemotherapy (4-week cycles) were performed. RESULTS: Of the 88 eligible patients, four treated with S-MEC therapy and two treated with I-MEC therapy showed CR. The response rates (CR + PR) were 52% (15/29) with S-MEC therapy, 76% (22/29) with I-MEC therapy and 47% (14/30) with M-VAC therapy. The response rate with I-MEC therapy was significantly higher than that with M-VAC therapy (P = 0.02). Although the incidence of leukopenia was low with I-MEC therapy, the incidence of thrombocytopenia was high with this therapy. CONCLUSION: MEC therapy used in this study is promising in terms of the antitumor effects.

Argyrophilic nucleolar organizer region in proliferating cell has a predictive value for local recurrence in superficial bladder tumor.

PURPOSE: It has been shown in many carcinomas that the proliferation rate and number of argyrophilic nucleolar organizer regions (AgNOR) are associated with tumor aggressiveness. However, in bladder tumor the significance of the correlation between the number of AgNOR and tumor behavior remains controversial. Therefore, it would be helpful if a new technique could be developed that would allow for more accurate AgNOR counting in association with tumor behavior. We established the simultaneous staining technique of AgNOR with Ki-67 labeling to reveal the significance of AgNOR count in superficial bladder tumor. MATERIALS AND METHODS: A total of 50 paraffin sections of superficial bladder tumor were stained with AgNOR and Ki-67 (MIB-1). The numbers of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed. RESULTS: The AgNOR count in proliferating cells was significantly higher than that in resting cells (p<0.01), and the count significantly increased with tumor grade (p<0.01). Based on recurrence-free survival analyses the local recurrence rate was significantly higher in patients with high proliferating cell NOR but not for those with resting or whole cells. However, no AgNOR score helped to select patients at high risk for disease progression. CONCLUSIONS: Proliferating cell NOR had a predictive value for local recurrence in patients with superficial bladder tumor.