Observational study of the clinical value of the canine osteoarthritis staging tool.

The aim of this multi-centred, cohort, prospective, observational study was to evaluate the clinical application of the canine osteoarthritis staging tool (COAST), in dogs affected by osteoarthritis (OA). In all dogs, a COAST stage was obtained based on the Liverpool Osteoarthritis in Dogs (LOAD) score and a complete orthopaedic and radiographic examination. The severity of OA (COAST stage) was scored as 1 (preclinical), 2 (mild), 3 (moderate), and 4 (severe). These scores were compared with the overall subjective opinion of experienced orthopaedic surgeons who examined the dogs (Clinical Opinion). Data were analysed with descriptive statistic, multiple regression analysis, chi-square and Bland-Altman tests (P < 0.05). In total, 362 evaluations were performed in 202 dogs. Clinical Opinion had a greater proportion of stage 1 and 2 cases compared to COAST (P < 0.0001). The proportion of stage 4 cases was higher in COAST compared to Clinical Opinion (P < 0.0001). The proportions of Stage 3 cases were similar in the two evaluation systems. COAST had a strong correlation (r = 0.79; P < 0.01) with Clinical Opinion. Overall, the two evaluation systems exhibited strong agreement (mean bias 0.51). Stages 1 and 2 had weaker agreement (mean bias 1.04 and 0.75, respectively), than stage 3 and stage 4 (mean bias 0.46 and 0.0, respectively).

Clinical significance of p53, MDM2 and bcl-2 expression in transitional cell carcinoma of the bladder.

We investigated the prognostic and predictive relevance of p53, MDM2, and bcl-2 protein expression in patients with transitional cell carcinoma (TCC) of the bladder. The expression of p53, MDM2 and bcl-2 protein was studied by immunohistochemical methods in paraffin-embedded specimens from 119 patients whose clinicopathologic data confirmed TCC of the bladder. Multivariate analyses of prognostic factors were performed, and correlations with classical clinicopathologic parameters were examined. Sixty-one, 12, and 17% of cases were considered positive for expression of p53, MDM2 and bcl-2, respectively. p53 expression correlated with stage (p=0.0209), but not MDM2 and bcl-2 with any clinicopathologic parameters. In Cox's regression analysis, staging demonstrated a statistically worse prognosis (hazard ratio 1.636; p=0.0059) while bcl-2 (hazard ratio 0.179; p=0.0474) expression showed favorable prognosis in stage T2-4 invasive TCC of the bladder. Co-expression with p53/MDM2 (hazard ratio 0.367; p=0.0401) and p53/bcl-2 (hazard ratio 3.487; p=0.0111) overexpression were associated with favorable and unfavorable prognosis in stage T2-4 invasive TCC of the bladder, respectively. Our results indicate that staging is the most useful parameter to predict clinical outcome in patients with TCC of the bladder. Determinations of bcl-2 and co-expression p53/MDM2 and p53/bcl-2 may be useful for predicting tumor behavior and prognosis in stage T2-4 invasive type TCC of the bladder.

[Giant cystic pheochromocytoma: a case report].

The patient, a 59-year-old woman, was referred to our University Hospital for evaluation of a left mass. Ultrasonography revealed a left adrenal cystic mass. On excretory urograms, the left kidney was pressed downward by a suprarenal mass, and computerized tomography (CT) and magnetic resonance imaging (MRI) confirmed an adrenal cyst. 131I-meta-iodo-benzylguanidine (MIBG) scintigraphy showed prominent accumulation in the left adrenal mass and the capsule. Considering the elevation of catecholamines in both blood and urine samples, we performed a left adrenalectomy with a presumptive diagnosis of pheochromocytoma (tumor size: 11.6 x 7.5 x 6.5 cm, tumor weight 720 g). The subsequent pathological examination confirmed a left giant cystic pheochromocytoma. 131I-MIBG scintigraphy was the most useful tool in the diagnosis of the cystic pheochromocytoma.

Adenoid cystic carcinoma of the prostate: a case report with immunohistochemical and in situ hybridization staining for prostate-specific antigen.

A 43-year-old man with urinary outlet obstruction was referred to our hospital. A digital rectal examination revealed an elastic hard prostate. The serum prostate-specific antigen (PSA), serum prostatic acid phosphate and gamma-seminoprotein levels were found to be within the normal range, and transrectal ultrasound sonography provided normal findings. The patient underwent a subcapsular prostatectomy under a diagnosis of benign prostatic hyperplasia. Histopathologically, the lesion was diagnosed as an adenoid cystic carcinoma of the prostate. Because a further examination revealed a pathologic extension into the urinary bladder, a radical cystoprostatectomy was performed. The expression of PSA protein and PSA mRNA was studied by means of immunohistochemistry and an in situ hybridization technique. The adenoid cystic carcinoma in the patient did not show any positive signs for PSA protein or PSA mRNA.

Anaplastic meningioma with papillary, rhabdoid, and epithelial features: a case report.

A 74-year-old man manifested disturbed consciousness and right hemiparesis. Computed tomography revealed a left frontal parasagittal meningeal tumor with extensive peritumoral brain edema and skull invasion. Subtotal removal was performed. Five years later, he underwent two more operations of massive recurrences. Pathological studies revealed anaplastic meningioma with two different histological areas. One was an epithelial and meningothelial area, and the other was a papillary and rhabdoid area. In the papillary and rhabdoid area, small tumor cells with a high nucleus/cytoplasm ratio proliferated densely around the dilated central capillaries with a pseudopapillary pattern. Many rhabdoid cells (vimentin ++, cytokeratin AE1/AE3 +, epithelial membrane antigen [EMA] + +) tended to be distributed far from the central capillaries. There were many mitotic figures near the central vessels. Dense MIB1-positive nuclei were also observed near the central vessels. The trabecular pattern of the tumor cells in the epithelial area was quite different from the histological features of chordoid meningioma.

[Malignant mesothelioma presenting as a perineal and pelvic mass--a trial of high dose intra-arterial methotrexate injection and irradiation].

A 50-year-old male with the complaints of lumbago and voiding disturbance was diagnosed to have malignant mesothelioma. Serum CA-125 was found to be elevated. The tumor was stained positive immunohistochemically only for CA-125 and epithelial membrane antigen. Magnetic resonance imaging of the pelvic demonstrated a large mass extending from the right external obturator muscle to the perineum. He was treated by two courses of methotrexate given intra-arterially (2,000 mg) followed by external beam irradiation at a total dose of 60 Gy. Disease progression was not apparent 15 months after treatment.

Relationship between p53 gene mutation and protein expression: clinical significance in transitional cell carcinoma of the bladder.

Although the mutated p53 gene has been postulated to induce immunohistochemically-detectable p53 protein, reports regarding the relationship between p53 mutation and p53 protein expression have been contradictory. This study investigated the relationship between p53 mutations and p53 expression and their clinical significance for patients with transitional cell carcinoma of the bladder. Eighty-seven transitional cell carcinoma of the bladder were analyzed by immunohistochemistry (IHC) for p53 nuclear accumulation, and the results compared to mutations detected in the p53 gene evaluated by polymerase chain reaction single-strand conformation polymorphism (SSCP) and DNA sequence analysis. By p53 IHC analysis, positive p53 staining was observed in 50 (57.5%) of the 87 tumors. The specificity of IHC, defined as a percentage of IHC negative (<20%) tumors among tumors without mutation, was 94.6%. Despite the good concordance between p53 mutation and p53 protein expression (p<0.0001), 48.0% (24/50) of the tumors showed p53 overexpression without mutation, and 2 (5.4%) tumors with mutation showed no p53 immunoreactivity. Patients with higher grade (grade 3), stage (stages pT2-4), and p53 mutations had a poorer prognosis by Kaplan-Meier survival analysis. A Cox univariate analysis found that grading (hazard ratio 3.139; p=0.002), staging (hazard ratio 3.832; p=0.0005) and p53 mutation (hazard ratio 2.498; p=0.013) were significant variables in these patients, but no variable was independently associated with an increased survival of bladder carcinoma by multivariate analysis. We found that a 20% cut-off level of p53 overexpression showed the highest correlation with prognosis and p53 mutation, however, p53 overexpression and mutation were not superior to staging as prognostic markers. These data suggest that careful assessment of the TNM staging system remains the most reliable predictive indicator of survival for patients with transitional cell carcinoma of the bladder.

Prediction of organ-confined disease by prostate-specific antigen nadir after neoadjuvant therapy.

BACKGROUND: It is not clear whether or not serum prostate-specific antigen (PSA) levels after androgen deprivation prior to radical prostatectomy (neoadjuvant therapy) have any value in the prediction of the final pathologic stage. METHODS: We conducted a study on 49 patients who underwent retropubic radical prostatectomy following neoadjuvant therapy for clinical stage T1c, T2, and T3a prostate cancer. We evaluated progression-free survival based on the PSA failure rate and the predictive value of the PSA nadir after neoadjuvant therapy and other clinical factors to determine the most important predictor of organ confinement. RESULTS: Of the 49 patients, 30 had organ-confined disease. Of 31 patients without adjuvant therapy after surgery, the PSA failure-free rates at 2 years were 81.6 and 34.3% in the subset of organ-confined disease and non-organ-confined disease, respectively (P= 0.0031). Of the 18 patients with adjuvant androgen deprivation therapy after surgery, the PSA failure-free rate at 2 years was 100% and 59.7% in patients with organ-confined disease and non-organ-confined disease, respectively. Baseline PSA (P=0.037), PSA nadir (P<0.0001) and PSA density (P=0.003) significantly correlated with organ confinement. Multivariate logistic regression analysis revealed that the PSA nadir was the only independent predictor of organ confinement (P = 0.044). CONCLUSIONS: There was a trend that the patients with non organ-confined disease had a higher probability of PSA failure than did the patients with organ-confined disease. The PSA nadir after neoadjuvant therapy was the strongest predictor of organ confinement. The predictive value of the serum PSA nadir should be validated in well-designed larger population-based studies.

Polymorphism of the beta3-adrenergic receptor gene and weight gain in pregnant diabetic women.

Inappropriate body weight gain during pregnancy has critical effects on the outcome for both mother and fetus. Therefore, body weight gain is an important issue in the management of pregnancy in women with diabetes. A Trp64Arg substitution in the beta3-AR gene has been reported to be associated with body weight gain and obesity in non-insulin-dependent diabetes mellitus (NIDDM) subjects. The aim of this study was to elucidate the contribution of the beta3-AR gene to body weight gain during pregnancy in subjects with diabetes. We analyzed 199 diabetic patients (NIDDM/IDDM; 131/68) and patient data was obtained from the first delivery of each individual. The mean age at diagnosis of diabetes was 22.9 +/- 7.5 years (mean +/- S.D.) and the mean age at delivery was 29.8 +/- 4.5 years. A polymorphism of the beta3-AR gene was detected by PCR-RFLP using Bst OI, which recognizes a Trp64Arg substitution. The frequency of the Trp64Arg allele was 0.15 in NIDDM and 0.17 in IDDM. Among the NIDDM subjects, excess weight gain during pregnancy, as defined by maximum BMI during pregnancy minus basal BMI before pregnancy exceeding five, was observed in 12.2% of the wild-type patients, 19.2% of heterozygotes and 28.6% of homozygotes. Homozygous subjects with NIDDM tended to show excess weight gain during pregnancy, however, this trend did not reach significance. None of the IDDM homozygotes showed excess weight gain. From our study, this beta3-AR gene polymorphism cannot be excluded as a contributing factor to excess weight gain during pregnancy in NIDDM subjects.

Characterization of ureteral lesions associated with impacted stones.

BACKGROUND: Few studies have addressed the various types of ureteral lesions apparent in patients treated for ureteral stones, especially in those with impacted stones. Macroscopic and microscopic analyses of ureteral lesions associated with impacted stones were therefore undertaken. METHODS: From May 1994 to October 1996, 36 patients with ureteral stones, 21 of whom showed stone impaction, were treated with transurethral ureterolithotripsy. After ureteroscopic examination, biopsied specimens were obtained from six patients with impacted stones and were examined microscopically by conventional hematoxylin and eosin staining. RESULTS: Ureteroscopy revealed two types of mucosal lesions in the patients with impacted stones: Type 1 lesions were defined as edematous or cystic hemispheric lesions and occurred in 18 patients, whereas type 2 lesions had a villous appearance and were present in three patients. Microscopically, type 1 lesions appeared as submucosal edema without specific findings, whereas type 2 lesions appeared as columnar mesenchymal tissue coated with several layers of transitional epithelium. With regard to factors that might contribute to lesion formation, duration of stone presence was significantly greater for patients with impacted stones than for those with-non-impacted stones. However, no differences in such parameters were apparent between patients with type 1 lesions and those with type 2 lesions. CONCLUSIONS: Two types of ureteral lesions associated with impacted stones were confirmed microscopically. The duration of stone presence is a potential contributing factor in the development of ureteral lesions, but factors that determine the type of ureteral lesion remain unclear.

Urinary continence following radical prostatectomy.

An examination was made of pre- and postoperative variables for predicting urinary continence following radical prostatectomy in 94 consecutive patients. Postoperative recovery of urinary continence continued for up to 18 months, when it plateaued. No pads were required in 73.0% of the patients at 18 months. The interval until recovery of urinary continence following surgery averaged 4.0 +/- 3.3 months. Clinical stage, pathologic stage, tumor grade, tumor volume, preservation of neurovascular bundles, methods of bladder neck reconstruction, internal urethrotomy for anastomotic stricture and postoperative adjuvant external beam radiation therapy provided no indication of postoperative urinary incontinence. Preoperative endocrine therapy, preoperative prostate-specific antigen level of > or = 10.0 ng/ml and age < 70 years at the time of surgery were all associated with a greater probability of urinary incontinence. Multiple factors are involved in the etiology of postprostatectomy urinary incontinence. In patients who had undergone surgery because of local progression following endocrine therapy associated with a high serum prostate-specific antigen level, a significantly inferior outcome was noted. Stricter criteria for indicating radical prostatectomy in patients with prostate cancer are needed. Surgical techniques should also be improved for better overall continence.

[A case study of metastatic renal cell carcinoma in lungs showing complete response to continuous subcutaneous injection of interferon alpha and gamma].

Previously, we reported a case of complete response (CR) of metastatic renal cell carcinoma with inhalant interferon-gamma. This inhalant therapy was considered effective against metastatic lung hilar tumors. On the other hand, metastatic tumors of the peripheral lung field tumor did not respond to the inhalation therapy. We report, a case of metastatic renal cell carcinoma in peripheral lungs showing complete response to continuous subcutaneous administration of interferon alpha and gamma. A 53-year-old woman was admitted to our hospital because of a large palpable mass in the left upper quadrant in March, 1994. Computerized tomographic (CT) scan disclosed a huge renal tumor. To reduce the tumor size, transarterial embolization, and subcutaneous administration of interferon-gamma were performed. In April 1994, the tumor was completely excised. In the post-operative course, multiple metastases were recognized in the lower peripheral lung field, subcutaneous administration of IFN-gamma and inhalation of IFN-gamma were begun, but the tumor size increased in October 1994. She underwent continuous subcutaneous administration of IFN-alpha and gamma. Three months later, the lung tumor disappeared. She has remained tumor-free as of October 1995. We concluded that this therapy may be effective against metastatic renal cell carcinoma in the lungs.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBP-1, -2 and -3) in diabetic pregnancy: relationship to macrosomia.

To evaluate the role of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) in excessive fetal growth (macrosomia) in diabetic pregnancy, 84 insulin-treated diabetic mothers and their infants were tested for serum concentrations of IGF-I, IFG-II, and IGFBP-1, -2 and -3. These parameters were correlated with the birth weight of neonates and placental weight. IGF-I and II levels were determined by specific radioimmunoassays (RIAs) after serum samples were extracted with aid-ethanol. IGFBPs were measured by Western immunoblot with specific antibodies to the respective IGFBP species. Serum concentrations of both IGF-I and IGF-II in mothers with either IDDM or NIDDM increased with the gestational period, reached a plateau at the third trimester, and returned to non-pregnant levels within 7 days after delivery. These values were not different from those in normal mothers before and throughout pregnancy. As previously reported, IGF-I concentrations in cord serum of neonates born to diabetic mothers were (P < 0.01) higher than those of newborns of normal mothers. Likewise, cord blood IGF-II levels were 2-fold higher in babies of diabetic mothers (P <0.001). Fetal IGF-I and IGF-II correlated with each other and with maternal HbA1C, and they positively correlated with either birth weight or placental weight. Cord IGFBP-3 concentrations were significantly higher in diabetic pregnancy, but IGFBP-2 concentrations were not different from those in normal pregnancy. Cord IGFBP-1 concentrations were significantly higher only in babies of mothers with IDDM. None of these cord IGFBP concentrations correlated with birth weight or placental weight. The data suggest that fetal IGF-II, like IGF-I, is involved in fetal and placental growth in diabetic pregnancy. The role of IGFBPs remained to be determined.

Mutation in the mitochondrial tRNA(leu) at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies.

Mitochondrial DNA is exclusively maternally inherited. We recently found the prevalence of diabetic patients with an A to G transition at position 3243 of leucine tRNA (3243 base pair (bp) mutation) to be nearly 1% in randomly selected Japanese subjects. Here, we report the higher prevalence of diabetic patients with the 3243 bp mutation in a specific Japanese population of women attending a diabetic pregnancy clinic. Of 102 patients with non-insulin-dependent diabetes mellitus 6 (5.9%) were positive for the mutation, 1 (8.3%) of 12 patients with gestational diabetes and 2 (5.9%) out of 34 borderline diabetic patients. In contrast, none of 64 patients (0%) with insulin-dependent diabetes mellitus had the 3243 bp mutation. Moreover, there was a difference in the prevalence of spontaneous abortions between patients with and without this mutation (27.3 vs 12.4%). Among nine probands with the mutation, four had a history of one spontaneous abortion (p = 0.0518) and two had a history of two abortions (p = 0.0479). Two probands had a spontaneous abortion even while under strict diabetic metabolic control. The 3243 bp mutation thus may cause spontaneous abortion during pregnancy.

Current status of pregnancy in diabetic women. A comparison of pregnancy in IDDM and NIDDM mothers.

Pregnancy in diabetic patients was uncommon before 1960 in Japan. It has increased recently and there has been a 3-fold increase since 1971. Only 26% of the cases of diabetic pregnancy had IDDM; the rest of cases had NIDDM. The perinatal mortality of infants decreased from 10.8% in 1971-1975 to 1.1% in 1986-1990, but the incidence of congenital malformations remained at 5.7-8.2% during this period. From 1988 to 1992, we experienced 207 deliveries at the Diabetes Center, Tokyo Women's Medical College. The ratio of IDDM to NIDDM of the mothers was 33:67. The onset of diabetes of pregnant women occurred earlier and the duration of diabetes was longer in IDDM than in NIDDM (mean onset, 17.8 vs. 26.0 years; mean duration, 11.5 vs. 5.6 years). The prevalence of maternal complications was similar between the IDDM and NIDDM mothers. Proliferative retinopathy in NIDDM was often detected for the first time during pregnancy. Major congenital malformations were found in none of the infants of IDDM mothers but in 5.8% of the infants of NIDDM mothers. This is probably related to the poor management of diabetes in NIDDM before pregnancy.

Insulin-receptor kinase is enhanced in placentas from non-insulin-dependent diabetic women with large-for-gestational-age babies.

The function of insulin receptor and IGF-1 receptor was investigated in placentas from 10 healthy control mothers, 8 diabetic mothers with appropriate-for-gestational-age babies (AGA group) and 9 diabetic mothers with large-for-gestational-age babies (LGA group). None of the diabetic mothers were obese before pregnancy; their blood glucose was well controlled during pregnancy and glycosylated HbA1c was 6.52 +/- 0.71% (M +/- S.E.). Insulin and IGF-1 receptors were partially purified from placentas using wheat germ agglutinin chromatography. The insulin-binding capacity was significantly increased in both the AGA and the LGA groups compared to the control, whereas the IGF-1 binding capacity was similar in the three groups. Autophosphorylation studies were performed with partially purified receptors equalized for similar binding capacity, then immunoprecipitated with anti-insulin receptor antibody or anti-IGF-1 receptor antibody. Insulin-stimulated 32P-incorporation into the insulin receptor beta-subunit was increased by 133% in the LGA group versus the control, whereas incorporation in the AGA group was equivalent to the control. Insulin-stimulated tyrosine kinase activity of the receptor preparation for histone H2B phosphorylation was also significantly increased in the LGA group compared to the control. 32P-incorporation into beta-subunit IGF-1 receptor and IGF-1-stimulated tyrosine kinase activity did not show any significant differences among the three groups. The data in the present study suggest that elevated insulin receptor kinase might be involved in fetal overgrowth in diabetic mothers.

Comparison of diagnostic criteria of IGT, borderline, and GDM. Blood glucose curve and IRI response.

A 75-g oral glucose tolerance test (OGTT) was performed in 615 nonobese pregnant women (mean +/- SD age 29.7 +/- 4.3 yr) who were referred to the Division of Internal Medicine at our diabetes center because of glycosuria. Seventy-seven cases were found to have urinary glucose at the first trimester, 185 at the second trimester, and 353 at the third trimester. With their 75-g OGTT results, the diagnostic criteria of borderline (formulated by the Japan Diabetes Society), impaired glucose tolerance (IGT; defined by the World Health Organization [WHO]), and gestational diabetes mellitus (GDM; determined by the Japan Society of Obstetrics & Gynecology standards) were compared through blood glucose (BG) curves and immunoreactive insulin (IRI) responses. Borderline (fasting BG greater than or equal to 6.1 and less than 7.8 mM and 2-h BG greater than or equal to 6.7 and less than 11.1 mM) is neither diabetes nor normal. IGT is as referred to by the WHO. GDM exceeds two points of fasting BG greater than or equal to 5.6 mM, 1-h BG greater than or equal to 10.0 mM, or 2-h BG greater than or equal to 8.3 mM. Diabetes mellitus (DM) is as referred to by the Japan Diabetes Society (same as the WHO). The prevalence of abnormal glucose tolerance among all 615 pregnant women was 54.6% in borderline, 24.5% in IGT, 7.3% in GDM, and 3.4% in DM. The 2-h BG levels in IGT during the first trimester were higher than in borderline (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in parameters of the coagulation-fibrinolysis system and platelet function after OKY-046 administration to patients with ruptured aneurysm of the cerebral artery.

The influence of the TXA2-synthetase inhibitor OKY-046 (Xanbon) on haematological findings for the coagulation-fibrinolysis system and platelet aggregation was investigated in patients with subarachnoid bleeding during or after the administration. Changes in alpha 2-PI activity and the levels of fibrinogen, t-PA and PAI antigen were observed. Especially, PAI activity and PAI antigen were found to be significantly increased as compared with levels before the administration. On the other hand, the platelet aggregation induced by various agents and the activity of AT-III were not greatly altered after the administration of OKY-046.