Trend in unequal geographical distribution of dentists by age and gender in Japan from 1996-2014.

OBJECTIVES: To evaluate the relationship between dentists' demographic changes and their uneven geographical distribution. METHODS: Secondary analysis of nationwide government surveys, to assess trends in the geographical distribution of dentists by gender and age from 1996 to 2014 in Japan. RESULTS: The Gini-coefficient for the number of dentists per population from 47 prefectures decreased from 0.084 in 1996 to 0.069 in 2014. The coefficients for female (0.124-0.144) were higher than for male dentists (0.058-0.081). Coefficients for dentists aged 60 and older were lower than those for dentists younger than 40 in 2014 (male: 0.060 vs. 0.112; female: 0.107 vs. 0.169). CONCLUSION: The geographical maldistribution of dentists in Japan has improved. Demographic changes among dentists, including the increasing number of female dentists, could moderate this improvement.

Characterization of two cell lines with distinct phenotypes and genotypes established from a patient with renal cell carcinoma.

Two human renal carcinoma cell lines have been established from the same patient. One cell line (CCF-RC1) was obtained from the primary tumor and the second (CCF-RC2) was established from cells of the renal vein effluent of the perfused tumorous kidney. Although they were established from the same patient, the cell lines differed in certain biological properties. They have been passaged up to 50 times in vitro for about two years. Each has an epithelial morphology and exhibits mutilayering. Cell cycle time of CCF-RC1 and CCF-RC2 was 34 and 36 h, respectively. They exhibited anchorage independent growth, and the plating efficiency of CCF-RC2 in soft agar was higher than that of CCF-RC1. Both lines induced tumors in nude mice at the site of s.c. injection closely resembling the original tumor in histological examination. Electron microscopic features of both tumors in nude mice were consistent with epithelial origin. Doubling time of CCF-RC1 and CCF-RC2 in nude mice was 11 and 12 days, respectively. CCF-RC1 and CCF-RC2 have hypotetraploid karyotype and modal numbers of 83 and 73, presenting two and three marker chromosomes, respectively. Immunocytology with commercial monoclonal antibodies against renal carcinoma (URO-3) and cytokeratin (Mac 6) showed positive reactions with both lines, suggesting that these cell lines derived from renal epithelium. A murine monoclonal antibody (2E11) was generated against CCF-RC2 by the hybridoma technique; 2E11 reacted with CCF-RC2, but not with CCF-RC1. These cell lines may provide a useful model for the study of tumor heterogeneity and its relationship to metastasis.

Comparison of drug sensitivity among tumor cells within a tumor, between primary tumor and metastases, and between different metastases in the human tumor colony-forming assay.

The human tumor colony-forming assay was used to compare chemosensitivity among tumor cells within a primary tumor, between primary tumor and metastases, and between different metastases. No significant differences in cloning efficiency were found in any of the three comparison studies. However, considerable differences in chemosensitivities were observed between different parts of the same tumor and between the primary tumor and metastases. Two different parts of the same tumor were comparably assayed for nine primary tumors. In nine paired samples which allowed in vitro drug sensitivity testing, there was no satisfactory correlation of sensitivity to cytostatic drugs. Cell suspensions were prepared from 28 primary tumors and from metastases taken from the same patient. In 14 paired samples which formed sufficient colonies for determination of drug effect, the data showed no satisfactory correlation of chemosensitivity between a primary tumor and its metastases. Both tumor samples from different metastatic sites of the same patient formed sufficient colonies in seven of eight instances. In the seven paired samples, there was strong association of chemosensitivity (p less than 0.005). The results indicate that the reported discrepancies of in vitro and in vivo results in clinical trials using the tumor colony-forming assay for predicting resistance or sensitivity to cytostatic drugs may be due to therapeutic heterogeneity among tumor colony-forming units within a primary tumor and between a primary tumor and its metastases.

A physiological role of interferon (IFN)-beta derived from tumor: tumor growth of a mouse bladder carcinoma line MBT-2 is partially suppressed by autocrine IFN-beta.

Although some tumor cells endogenously produce a wide variety of cytokines, their physiological roles remain to be fully understood. In this study, we found that mouse subcutaneous tumor induced by inoculation of bladder tumor MBT-2 cells into syngeneic mice secreted a significant amount of interferon (IFN), whereas the cells exhibited no IFN production in in vitro cell culture. Typing experiment using IFN-specific neutralizing antibodies showed that the tumor-derived IFN was exclusively beta type. Since the MBT-2 tumor tissues were homogenous and not infiltrated by immune cells, MBT-2 cells themselves were considered to be IFN-beta producers. By intraperitoneal injection of neutralizing anti-IFN-beta antibodies into MBT-2 cell-inoculated mice, the tumor growth was substantially precipitated and survival days of the tumor-bearing mice were shortened. As the in vitro cell growth of MBT-2 cells was dose-dependently inhibited by IFN-beta, it was suggested that apparent immunogenicity of MBT-2 tumor is partially mediated by tumor suppression by autocrine IFN-beta.

Induction of specific anti-tumour immunity by interferon-gamma gene-transferred murine bladder carcinoma MBT-2.

Tumour cell-targeted cytokine gene therapy of cancer has been proposed using various cytokine genes including interferon (IFN)-gamma gene. In the course of the experimental approach using IFN-gamma gene, we established two IFN-gamma gene-transferred clonal sublines, IFN-gamma producer and non-producer, from a murine bladder tumour line MBT-2 via retroviral transfer of mouse IFN-gamma cDNA, and studied the influence of local secretion of IFN-gamma on tumour progression. While cell growth in vitro was not affected by gene transfer, expression of major histocompatibility complex (MHC) class I antigens was increased in both sublines. The IFN-gamma producing cells injected subcutaneously into syngeneic mice could not induce tumours but the non-producing cells tended to induce tumours. Thus the increase in MHC class I expression was not enough to cause tumour regression, and IFN-gamma secretion over a certain amount was needed for tumour suppression, probably in addition to MHC class I expression. Mice that rejected IFN-gamma producers established a specific anti-tumour immunity and spleen cells derived from the mice contained populations of CD8+ effector T cells against MBT-2 cells. These results supported previous reports that IFN-gamma gene transfer into tumour cells apparently abrogated the tumorigenicity by augmenting the host anti-tumour immunity, and were encouraging for a promising execution of the tumour cell-targeted IFN-gamma gene therapy against human bladder cancers.

[A case of spontaneous rupture of renal cell carcinoma].

A case of spontaneous rupture of renal cell carcinoma is reported. A 53-year old man was admitted with the chief complaint of sudden gross hematuria and right flank pain on December 28, 1979. On the following day, the clinical impression was right ruptured kidney, and therefore right nephrectomy was done. Pathological diagnosis was renal cell carcinoma. He received the post-operative irradiation of a total of 5,000 rads. He was seen five years later, at which time there was no evidence of local recurrence or distant metastasis of cancer. Thirty three cases of spontaneous rupture of renal cell carcinoma were collected from Japanese and English literature. Most common chief complaint is abdominal or flank pain. Excretory urography, ultrasonography, CT scan and angiography are useful, but it is difficult to diagnose preoperatively when the tumor is small. Therefore, it is important to suspect occult cancer when a reasonable cause of rupture is undetermined. In these indeterminate cases primary nephrectomy should be considered strongly.

Geriatric ureteropelvic junction obstruction: the possible role of an arteriosclerotic lower pole branch of renal artery: report of two cases.

An 83-year-old woman presented with left flank pain and high grade fever. After left ureteral catheterization and intensive chemotherapy with hemoperfusion, surgical exploration revealed the lower pole branches of the renal vessels were obstructing the ureteropelvic junction (UPJ), and dissection of the vessels released the obstruction. An 82-year-old man presented with right flank pain. Angiography demonstrated UPJ obstruction caused by the lower pole branch of the renal artery. Arterial dissection with dismembered pyeloplasty resulted in improvement of obstruction. In both cases, the patients had a long history of hypertension with mild to severe arteriosclerosis. Arteriosclerosis associated with fixation of the UPJ, may be one of the important factors leading to progressive hydronephrosis in geriatric patients.

[Endoscopical reconstruction of traumatic urethral disruption with ureteral resectoscope: a case report].

A 19-year-old man sustained a fracture of the left ischial rami and disruption of the membranous urethra when a car hit him against a wall. A suprapubic tube was placed and was used for reconstruction of the disrupted urethra 3 months later. Eighty days after the injury, an 11.5 F ureteral resectoscope was inserted through the open cystostomy tract. Simultaneously, a 11 F pediatric cystoscope was inserted via urethra. Using the "cut to the light" procedure, the scar tissue was incised with sharp strokes of the ureteral resectoscope revealing the distal urethral lumen. Sequentially, urethral dilatation to 24 F was performed over a 0.038 Teflon-coated guide wire following insertion of a 24 F urethral catheter. The urethral catheter was removed 22 days after the operation. Direct vision urethroscopy was performed at 1- to 2-week intervals for 3 months. At present 13 months after the operation, he performs 18 F urethral self-dilation and has been free of voiding complaints. The ureteral resectoscope is useful for endoscopical reconstruction of urethral disruption.

[A case of primary localized amyloidosis of the urinary bladder].

A case of primary localized amyloidosis is reported. The patient was a 73-year-old female who suffered from miction pain and consulted our department. There was a 1.5 x 1.5 cm slightly red, nonpapillary tumor around the right ureteral orifice in cystoscopy. The diagnosis was amyloidosis with cystitis hemorrhagica histopathologically. After the treatment with antibiotics for about one month there were no symptoms and no tumors in the urinary bladder cystoscopically. The clinical course was relatively good. The treatment varies from transurethral resection to total cystectomy with urinary diversion. This case was cured by non-operative treatment, but close follow-up of the patient is necessary because of the frequency of multiple recurrence.

[Bladder hernia associated with bladder diverticulum in a female].

A 77-year-old woman with a previous history of pelvic fracture had suffered from recurrent cystitis. In the excretory urography, post-void upright film revealed the bladder hernia associated with the bladder diverticulum. Transurethral incision and fulguration of the bladder diverticulum and left inguinal herniography was performed. There has been no recurrence since then.

[Circumvention of the intrinsic multidrug-resistance in renal cell carcinoma].

Most of renal cell carcinomas (RCCs) are refractory at the start of chemotherapy. We have demonstrated that the frequently elevated expression of the multidrug resistance gene (MDR) in RCCs is associated with the intrinsic vinca alkaloids and anthracyclines resistance. The preliminary clinical trials using verapamil or amiodarone in combination with vinblastine or doxorubicin to overcome multidrug-resistant (MDR) tumors could not achieve satisfactory results owing to severe cardiovascular toxicities of such reversing agents. In the present study, we studied the sensitizing ability of bis-benzyl-isoquinoline (cepharanthine) and SDB-ethylenediamine (N-1379) in natural MDR kidney cancer cells. Cepharanthine remarkably sensitized vinblastine and doxorubicin sensitivities in those cells with high MDR RNA levels. From a clinical point of view, cepharanthine seems to be a potent and less toxic agent to treat natural MDR kidney cancers.

[Combination chemotherapy of methotrexate, etoposide, adriamycin and cisplatin (M-EAP) for advanced urothelial cancer].

Combination chemotherapy with methotrexate, etoposide, adriamycin and cisplatin (M-EAP regimen) was administered to 4 patients with advanced epithelial cancer of the urinary tract (Methotrexate 30 mg/M2 day 1, 15 and 22; Etoposide 100 mg/M2 day 1, 2, 15 and 22; Adriamycin 30 mg/M2 day 2; Cisplatin 70 mg/M2 day 2, every 4 weeks). In an attempt to improve the anti-cancer effect of the M-VAC regimen, etoposide was substituted for vinblastine. This series comprised 3 males and 1 female ranging in age from 54 to 68 years (mean age: 63), with a performance status of 1 to 2. The site of the primary lesion was bladder in 3, and left ureter in 1. The clinical response was assessed in 3 of the 4 patients: one achieved complete response and two had partial response. Two of the four died of disease 5 months after chemotherapy. Two of them have been alive for 10 and 8 months with no evidence of disease after chemotherapy. Toxicity included moderate or severe myelosuppression in two patients, and mild to moderate anorexia, vomiting, alopecia, and hiccups in all patients. These preliminary results suggest that the M-EAP regimen is effective against advanced epithelial carcinoma of the urinary tract. However, myelosuppression was a dose-limiting factor.

[A case of secondary bladder tumor the origin (gastric cancer) of which could not be identified before autopsy].

Primary bladder tumor is the most frequent malignant tumor in the field of urology, whereas the incidence of secondary bladder tumor from a distant organ is quite rare. We report here a 21-year-old female patient with metastatic bladder tumor from gastric cancer. She came to our hospital with a complaint of only bladder irritability. Cystoscopical and cytological examinations revealed rhabdomyosarcoma of the bladder. She did not respond to radiation therapy and combined chemotherapy, consisting of actinomycin D, vincristine and cyclophosphamide, and died 91 days after admission. Autopsy revealed a primary tumor of poorly differentiated scirrhus carcinoma of the stomach. Thus this was a quite rare case of metastatic bladder carcinoma characterized by bladder irritability without gastrointestinal symptoms.

[Clinical significance of stereological estimation of mean nuclear volume in human bladder carcinoma--further analysis of nuclear morphometric variables].

Recently, nuclear morphometry methods have been used to quantitatively analyze the malignant potential of cancer cells. We have previously shown that the malignant potential of human bladder carcinoma can be analyzed quantitatively through mean nuclear volume measurements. In the present study, we examined other measurements obtained from nuclear morphometry and evaluated their usefulness as indicators of the outcome of bladder carcinoma. Our subject group consisted of 161 patients with untreated bladder carcinoma. Four nuclear morphometric values were measured on each subject: the mean nuclear volume (MNV), the mean nuclear area (MNA), the nuclear roundness factor (NRF) and the variation of nuclear area (VNA). MNV, MNA and VNA values increased as the tumors progressed to a more advanced stage and grade of malignancy. Patients were then divided into two subgroups based on each morphometric value: small MNV (< 186.9 microns3) and large MNV (> or = 186.9 microns3); small MNA (< 33.6 microns2) and large MNA (> or = 33.6 microns2); low NRF (< 81.1) and high NRF (> or = 81.1); and low VNA (< 33.0) and high VNA (> or = 33.0). Survival rates were significantly higher among patients with a small MNV, a small MNA and a low NRF (5-year survival rate; 93.0, 84.9 and 84.6%), compared to patients exhibiting high values (5-year survival rate; 59.7, 61.3 and 61.9%). For patients with grade 2 tumors, those with a small MNV had a high survival rate (5-year survival rate; 95.2%), similar to that of patients with grade 1 tumors (5-year survival rate; 95.2%)(ABSTRACT TRUNCATED AT 250 WORDS)

[In vitro chemosensitivity test by human tumor colony forming assay].

In vitro chemosensitivity of urological cancers was assessed by a human tumor colony forming assay (HTCA) and a 3H-thymidine incorporation assay. Primary tumor cells from 160 of 253 (63%) urological cancers showed adequate colony growth (greater than 30 colonies per well), and there was a 57% true positive and 100% true negative rate for predicting clinical response of anticancer agents. On the other hand, cells from 37 of 45 (82%) urologic cancers incorporated a sufficient amount of 3H-thymidine (greater than 300 cpm). However, when the positive control drug (chromomycin A3 100 micrograms/ml) was used for the assay quality control, the successful assay rate of the HTCA (38%) was lower than that of the 3H-thymidine incorporation assay (75%), while there was a significant correlation in drug sensitivities between the two assays. Thus, the 3H-thymidine incorporation assay seemed to be more useful than the HTCA for evaluating the chemosensitivity of urologic cancers.

[Circumvention of the multidrug-resistance in renal cancer by bisbenzylisoquinoline].

A bisbenzylisoquinoline alkaloid, cepharanthine, significantly enhanced vinblastine, adriamycin and etoposide sensitivities in P-glycoprotein positive renal cancer cells. However, it did not show any enhancing effect on cisplatin sensitivity. Four patients with metastatic renal cell carcinomas were treated with intraarterial chemotherapy using vinblastine and/or adriamycin in combination with cepharanthine for their metastatic lesions (3 bone and 1 contralateral kidney metastases). A partial response was observed in 1 patient with femoral bone metastasis and a minor response in 1 patient with lumbar bone metastasis, although they were also treated with interferons. No adverse effects associated with cepharanthine were seen except in one patient complaining of redness and burning sense of the skin probably due to its vaso-dilatation effect.

[Clinicopathological analysis on invasion and metastasis in superficial bladder cancer].

We analyzed the clinico-pathological features of the initial tumors in 205 patients with superficial bladder cancer, admitted to Kyoto University Hospital between 1974 and 1988, to investigate the prognostic factors for progression to the muscle invasive disease or metastasis. Of 205 patients, 35 (17%) exhibited muscular invasion alone (12 patients) and/or metastasis (23 patients). Tumor multiplicity, higher grade and positive urinary cytology were the significant risk factors for later malignant progression. Expression of A, B, H-blood group isoantigens in the bladder tumor were significantly decreased from the onset in the patients with initially T1 tumor but not in those with Ta tumor. Significant loss of expression was also found at the time of progression in the initially Ta cases. Thus, loss of A, B, H-blood group antigen expression seems to be correlated with the malignant potential of superficial bladder cancer. However, more feasible and reliable diagnostic markers such as molecular genetical and biochemical markers remain to be developed to predict the malignant potential of the superficial bladder cancer.

[A case of granulomatous orchitis].

A 69-year-old man complained of a painless left scrotal swelling. The scrotal mass was enlarged to a hen's egg size with a smooth surface. The scrotal ultrasonogram showed diffuse hypoechogenicity. A testicular tumor was suspected and left high orchiectomy was performed. Histopathological diagnosis was granulomatous orchitis.

[Cancer immunotherapy by murine bladder cancer cells transfected with mouse interferon-gamma gene].

We established constitutively an interferon-gamma (IFN-gamma) producing cell line (MBT2/gamma) from a mouse bladder cancer cell line (MBT2) by retroviral transfer of a mouse IFN-gamma cDNA. Although the in vitro cell growth of these cells was unaffected by the IFN-gamma production, their subcutaneous tumor growth in syngeneic C3H/He mice was different; MBT2/gamma tumor growth was more strongly suppressed (3/20) than that of MBT2 (10/10). MBT2/gamma tumor growth was observed in nude mice (6/6). The mice immunized with MBT2/gamma were resistant to tumor growth of the parental cells (7/9; 77%), but permitted the growth of another kind of C3H/He tumor line. These findings indicate that the reduced tumorigenicity of the IFN-gamma producing line was due to the augmented specific antitumor immunity, probably as a result of the immunomodulatory effects of the IFN-gamma derived from the tumor.

[Renal or perirenal malignant lymphoma: report of three cases].

We report three cases of renal or perirenal malignant lymphoma. The patients were a 69-year-old woman presenting with lumbago, a 43-year-old man with fever and erythema, and a 69-year-old woman with general malaise. In each case, renal or perirenal tumor was discovered by abdominal ultrasound. Biopsy and microscopic examination revealed the diagnosis of non-Hodgkin's malignant lymphoma. The computerized tomography patterns of the cases were different from each other; "direct invasion" in the first case, "solitary nodule" in the second case, and "engulfment" in the third case. Chemotherapy and/or radiation therapy were performed. Only the third case is still alive at present. The computerized tomography pattern of renal or perirenal malignant lymphoma was classified into five groups; I) multiple nodules, II) solitary nodule, III) engulfment, IV) direct invasion, V) diffuse infiltration. This classification should be useful in making an accurate and early diagnosis.