Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma.

Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).

Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes.

AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases.

PCB contamination assessment of yusho patients by using preserved human umbilical cord.

PCB concentrations in umbilical cord preserved from the time when Yusho patients and healthy subjects gave birth were examined. The total concentration of the 12 DL-PCB isomers ranged from 130 to 12,000 pg/g in the umbilical samples, was about 700 pg/g around 1950 but began to increase in the mid 1960s, reached about 12,000 pg/g between 1968 and 1970 immediately after the Yusho incident. However, the DL-PCB concentration was high between 1968 and 1970 in not only the designated Yusho patients but also healthy subjects, and the maximum DL-PCB concentration was close between the two groups.

Dentinal defects in Hyp mice not caused by hypophosphatemia alone.

The Hyp mouse is a murine homolog of human X-linked hypophosphatemic rickets and displays hypo-mineralization in bone and dentin due to a defect of the phosphate-regulating gene with homology to endopeptidase on the X chromosome (Phex) gene. It has long been considered that the bone and dentin defects in Hyp mice are caused by hypophosphatemia alone, however, several recent studies have indicated the possibility that intrinsic defects are present in Hyp mice osteoblasts. Further, we previously found a hyper-expression of osteocalcin (OC) mRNA in Hyp mouse odontoblasts and suggested the possibility of the presence of intrinsic defects. In the present study, we evaluated morphological features and OC mRNA expression levels in tooth germs of Nor mice with a normal phex gene and a low concentration of serum phosphate, and compared them to those in Hyp and wild-type mice. Nor mice exhibited low serum phosphate levels, however, did not show the characteristic features of dentin defects seen in Hyp mice, such as widened predentin and hyper-expression of OC mRNA. These results suggest that the hypo-mineralization of dentin in Hyp mice is not dependent on serum phosphate level, but rather is affected by intrinsic defects in odontoblasts.

Wide use of skin-lightening soap may cause mercury poisoning in Kenya.

In a previous study, we speculated that some of the high mercury levels observed in head hair from a total of 14 subjects who resided around Lake Victoria, Tanzania, might be attributable to the habitual use of toilet soap containing considerable amounts of mercury (Harada et al. Sci Total Environ 1999;227:249-256). In August 1998, the current study was conducted to investigate if such mercury-containing soap was also available in the surroundings of Lake Victoria, Kenya, and if so, its toxic effects. A total of nine goldminers, 44 fishermen and their families, and 12 residents of Kisumu City, Kenya, volunteered for the study. Fourteen types of toilet soap were collected in Kisumu. Total mercury content was very significantly higher than in European-made soap (0.47-1.7%, as mercury iodide) compared with Kenya-made soap (0.41 x 10(-4)-6.2 x 10(-4)%). Indeed, all the subjects with a high hair mercury level (> 36.1 ppm) had made habitual use of European-made soap, accompanied by various symptoms, such as tremor, lassitude, vertigo, neurosthenia, and black and white blots, suggesting inorganic-mercury poisoning. On the other hand, any subject who had used soap other than the European-made soap, did not exceed a mercury level of 10 ppm in hair that is well within normal limits (Harada et al. Sci Total Environ 1999:227:249-256). The findings obtained suggest that the mercury-containing soap must be barred from circulation without delay, and that the residents' health in addition to the environmental pollution in Lake Victoria (Kenya as well as Tanzania) should be kept under close observation.

Allelochemicals of the tropical weed Sphenoclea zeylanica.

Nine plant growth inhibitors were isolated from the tropical weed Sphenoclea zeylanica, which shows allelopathic properties. Those compounds hitherto not reported from any plant source were the isomers of cyclic thiosulfinate, (1S,3R,4R)-(+)- and (1R,3R,4R)-(+)-4-hydroxy-3-hydroxymethyl-1,2-dithiolane-1-oxides, and (2R,3R,4R)-(-)- and (2S,3R,4R)-(+)-4-hydroxy-3-hydroxymethyl-1,2-dithiolane-2-oxides. These were named zeylanoxide A, epi-zeylanoxide A, zeylanoxide B and epi-zeylanoxide B, respectively. The absolute configurations at C-3 and C-4 were elucidated by chemical synthesis of both enantiomers from L- and D-glucose. Two of the inhibitors were secologanic acid and secologanoside. and three other inhibitors were by known secoiridoid glucosides formed as artifacts during extraction with methanol. The cyclic thiosulfinates and secoiridoid glucosides completely inhibit the root growth of rice seedlings at 3.0 mM. While the specific activity of the inhibitors was not high, since they accumulated to circa 0.61% S. zelanica by dry weight, this suggests that the inhibitors are nervertheless potent allelochemicals in this weed.

[Effective administration of recombinant granulocyte colony-stimulating factor to prevent granulocytopenia due to combination chemotherapy for testicular germ cell tumors].

A prospective randomized study on the administration of recombinant granulocyte colony stimulating factor (rG-CSF) was conducted on 15 patients with testicular germ cell tumors. The clinical stagings of all patients except one were minimal to moderate extent according to the Indiana University staging system. Combination chemotherapy using bleomycin, etoposide and cisplatinum (BEP) was performed as the initial treatment on the eligible patients. rG-CSF was administered by two different methods; 1) routine administration on the 6th day after BEP chemotherapy (group A), and 2) the same method, but after granulocytopenia of 1,500/mm3 had developed (group B). The administration of rG-CSF in group A significantly reduced the severity of leucocytopenia and also the incidence of stomatitis compared with group B. Although rG-CSF produced no significant side effects, the thrombocytopenia was prominent in the group A patients (not significant). BEP chemotherapy itself is an easily-tolerable and well established method for treating young adult patients. The method used in group B seems to be suitable in situations where thrombocytopenia and cost effectiveness.

[Clinical study of the advanced testicular tumor non-achieved complete response by primary chemotherapy and relapse cases. The East Japan Testicular Tumor Study Group].

The East Japan Testicular Tumor Study group has studied advanced testicular tumors. Treatment and prognosis of the patients who did not achieved complete response on the primary chemotherapy were discussed in this paper. Also 8 patients who had once reached complete response by primary treatments and relapsed later have been clinically analyzed. 1. Concerning the patients non-achieving complete response on the primary chemotherapy: Two cases who had resection of the residual tumors and 4 cases who had radiation therapy had reached NED in 7 cases of seminoma stage II. Nine of 10 cases in non-seminoma stage II reached NED on resection of the residuals. Moreover, 10 out of 17 cases in stage III showed NED on excision of the residuals. On the other hand, recuperating was very difficult in the cases who could not have excision of residual tumor. The histological findings of the residual tumors after chemotherapy were necrosis and fibrosis in 13 cases, viable cells in 4 cases, teratoma in 6 cases and other 2 cases were not clear. Five out of 15 who had teratoma in the primary lesion had teratoma in the resected residuals on metastatic lesion. On the other hand 5 patients who did not have teratoma originally had no any teratoma elements in the residuals. 2. Concerning the relapse cases by primary treatments: Although relapses were possible in any stages, they were more common with stage IIIB and IIIC cases. Those who achieved complete response after chemotherapy alone fewer relapse than those who had partial response after chemotherapy and there after had excision of residual tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

[A randomized trial of PVB, VAB-6, BVP regimen versus PEB chemotherapy in patients with disseminated testicular tumors].

During 2 years and 7 months from June, 1985 to December, 1987, a randomized multi-center trial of PVB, VAB-6, BVP regimen (group A) without etoposide versus PEB chemotherapy (bleomycin, etoposide and cisplatinum) (group B) was given to patients with disseminated testicular tumors. Of 34 patients registered, 10 patients were with minimal disease in stages IIA, IIIO and IIIA and 24 with extensive disease in IIB, IIIB2 and IIIC. Seminomas were found in 10 patients, while non-seminomatous tumors in 24. Among groups A and B, there was no statistical difference in clinicopathological profiles. A group patients were given either PVB, VAB-6 or BVP according to the physician's discretion. In groups A and B, 35% and 43% of the patients achieved complete response, and 45% and 50% achieved partial response, respectively. The difference in CR rates among both groups was not statistically significant even when calculated according to the stage or histologic grouping. Salvage treatments mainly with surgical resection of residual tumors after the chemotherapy, however, were more successful in group B (88%) than group A (61%). It appears likely that the higher response of induction chemotherapy in patients with extensive disease made the salvage surgery more successful in group B than in group A. The 3 year survival rate was 100% in group B, whereas it was 76% in group A. Although the incidence of myelosuppression and alopecia was significantly higher in group B, neuropathy was significantly more frequent in group A. From the above results, PEB seems to be a better induction chemotherapy than the conventional one for advanced testicular tumors.

Application of an ovomucoid-conjugated polymer column for the enantiospecific determination of chlorprenaline concentrations in plasma.

An ovomucoid-conjugated polymer column was prepared for the liquid chromatographic resolution of racemic compounds. The column showed strong retention of acidic solutes, a characteristic attributed to the structure of the stationary phase support gel. Although the efficiency of the column was lower than that of an ovomucoid-conjugated silica gel column, enantiospecific chlorprenaline determination in plasma was achieved with solute amounts from 1.0 ng to 0.1 microgram.

[Discriminant analysis of quantification theory on prognostic factors of chemotherapeutic effects on advanced testicular cancer. East Japan Testicular Tumor Study Group].

Prognostic factors of chemotherapy against advanced testicular cancer were analysed in 33 cases studied by East Japan Testicular Tumor Study Group. In this study a discriminant analysis of quantification theory (a multivariate analysis) was adapted, taking 7 factors as comparative variables. The significant factors for complete tumor response were clinical stage, histology, and tumor markers (HCG-beta, AFP). Prognostic score was calculated in each case by quantification theory, which correctly discriminated the group with CR from that without CR, at a probability of 90.1%. The results of our study indicate that the outcome of chemotherapy on advanced testicular cancer may be predicted with probability, by patients' status and adopted treatment. It may enable one to make an adequate treatment schedule for each patient.

[Clinical significance of multiple biopsies of nontumorous bladder mucosa in patients with bladder cancer].

Multiple biopsy specimens obtained from nontumorous bladder mucosa were investigated histologically. An average of 3.6 specimens was taken in 142 transurethral resection operations for 112 patients with bladder cancer. The histological categories used were normal epithelium, metaplasia, hyperplasia and G1-G3 dysplasia. Thirty-seven patients (27.7%) had G2 less than dysplasia within normal looking bladder mucosa. In patients with high grade bladder cancer, the incidence of the association with dysplasia was 51.7%, which was significantly higher than the rates in patients with low or moderate grade bladder cancer (p less than 0.05). The tumor recurrence was observed in 45 patients of 102 patients who were followed with bladder preservation. The recurrence was seen in 13 of 19 patients (68.4%) with mucosal dysplasia in the previous operation. The rate was significantly higher than 38.6% in patients without dysplasia (p less than 0.05). Thus, the epithelial dysplasia seen in nontumorous bladder mucosa were associated with higher grade bladder tumors more often, and the histology of multiple biopsy specimens might be one of predictors for tumor recurrence in near future.

[Clinical experience of enoxacin complicated urinary tract infection].

Enoxacin (ENX) was administered to 69 patients with complicated urinary tract infections (UTI). Clinical efficacy and safety were evaluated by the criteria proposed by the UTI Committee, Japan. The overall clinical efficacy was excellent in 60.9%, moderate in 10.1% and poor in 29% of the patients. Of the 76 strains isolated from the patients 61 strains (80.3%) were eradicated. Subjective side effect was observed in one patient who complained of slight nausea. No drug-related aggravation in the laboratory test was observed. These results showed that ENX was effective and safety for the treatment of complicated urinary tract infection.

Postoperative reduction of serum beta-HCG in testicular seminoma.

Serum beta-HCG and urinary HCG were measured in 17 patients with histologically proved pure seminoma of the testis. The patients have been followed to date for 10 to 74 months after orchiectomy, and have no residual disease or recurrence of their disease. Preoperative urinary HCG levels were abnormal in 9 patients (53%). Serum beta-HCG levels were slightly elevated in 6 out of 12 patients evaluated, and were reduced after orchiectomy even in patients with preoperative normal beta-HCG levels (P less than 0.05). Preoperative levels of the tumour marker in seminoma were far lower than in patients with non-seminomatous germ cell tumours, but it would not be rare to see a small amount of HCG produced by the tumour cells in the seminoma.

Papillary adenoma of the bladder in a patient with intermittent self-catheterization.

We report a case of papillary adenoma of the bladder. The patient had had intermittent self-catheterization for the previous 3 years. The tumors developed multiply and were identified on the trigone and posterior wall of the bladder. Dysplasia of the urothelium was associated in nontumorous areas. Transurethral resection of the tumors was performed. The tumor recurred 3 times for 3 years, but no malignant changes were identified.

[Clinical evaluation of combination therapy with Fortimicin and Cefotax in the treatment of complicated urinary tract infections].

Clinical efficacy of combination therapy using Fortimicin (ASTM) and Cefotax (CTX) was studied in 63 patients with complicated urinary tract infections. The patients received 200 mg of ASTM i.m. and 1 g of CTX i.v. twice a day. The overall clinical efficacy of the treatment was evaluated by criteria proposed by the Japanese UTI Committee. The overall clinical efficacy rate was 68.3%. The rate was 67.3% in the patients with single bacterial infection and 72.7% in those with mixed infections. Subjective side effects were observed in one of the patients. Drug related aggravation in laboratory tests was observed in 8 items in 8 patients, but these were mild changes. We concluded that combination therapy with ASTM and CTX was useful for the treatment of complicated urinary tract infections.

[Clinical trial of CSF-HU (colony-stimulating factor derived from human urine: P-100) on granulocytopenia induced by anticancer therapy in urogenital cancer patients].

We examined the value of the CSF-HU preparation (colony-stimulating factor derived from human urine: P-100) to prevent or treat granulocytopenia induced by anticancer chemotherapy. Subjects were urogenital cancer patients who underwent two courses of the same chemotherapy regimen. Among these patients, we selected the subjects whose leucocyte counts were decreased to less than 2000/mm3 after the first course of anticancer chemotherapy. P-100 was administered from the following day of the end of the second course of chemotherapy at a dose of 8,000,000 units/day by intravenous drip infusion for 7 successive days. According to the global evaluation by consideration of changes in leucocyte and granulocyte counts, the utility rate by physicians was 52.4% (22/42), and that by a committee was 50.0% (18/36). No difference was seen in utility rate and efficacy rate according to P.S., cancer types and antineoplastic drugs used. Side effects were noted only in 2.3% (1/44) which was mild and transient fever. These findings suggest that P-100 is a very useful drug for prevention and/or treatment of granulocytopenia following cancer chemotherapy.