Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer.

Involvement of the aryl hydrocarbon receptor (AHR) in carcinogenesis has been suggested in many studies. Upregulation of AHR has been reported in some cancer species, and an association between single-nucleotide polymorphisms (SNPs) of AHR and cancer risk or cancer development has also been reported. This evidence suggests the involvement of some specific SNPs in AHR transcriptional regulation in the process of carcinogenesis or cancer development, but there have been no studies to elucidate the mechanism involved. In this study, we identified the transcription factor Nuclear Factor 1-C (NF1C) as a candidate to regulate AHR transcription in a polymorphism-dependent manner. SNP rs10249788 was included in a consensus binding site for NF1C. Our results suggested that NF1C preferred the C allele to the T allele at rs10249788 for binding. Forced expression of NF1C suppressed the activity of the AHR promoter with C at rs10249788 stronger than that with T. Moreover, expression analysis of human uterine endometrial cancer (HEC) specimens showed greater upregulation of AHR and downregulation of NF1C than those of normal endometrium specimens. Sequence analysis showed HEC patients at advanced stages tended to possess T/T alleles more frequently than healthy women. We also demonstrated that NF1C suppressed proliferation, motility and invasion of HEC cells. This function was at least partially mediated by AHR. This study is the first to report that a polymorphism on the AHR regulatory region affected transcriptional regulation of the AHR gene in vitro. Because NF1C is a tumor suppressor, our new insights into AHR deregulation and its polymorphisms could reveal novel mechanisms of genetic susceptibility to cancer.

Clinical aspects and prognosis of pelvic recurrence of cervical carcinoma.

OBJECTIVE: To identify which patients with locally recurrent cervical carcinoma are potentially curable. METHOD: A total of 664 stage IB-IVA patients were examined following surgery or radiotherapy. RESULT: Among the 664 patients, 193 (29%) developed recurrence. Sixty-seven (35%) of these recurrences were located in the pelvis alone. Among these 67 recurrences, 24 (35%) were central recurrences and the remaining 43 (65%) were pelvic side-wall recurrences. Of the 24 patients with central recurrences, 8 were salvaged. Of these 8 patients, 3 underwent pelvic exenteration, and 5 received optimal radiotherapy. The recurrent tumor in these 5 survivors who received radiotherapy had consisted of a small (<2 cm) tumor. All 43 patients with pelvic wall recurrence developed progressive disease. CONCLUSION: The following patients are potentially curable: patients with a resectable, centrally located tumor who are candidates for pelvic exenteration, and patients with a small central recurrence for whom complete radiation therapy is feasible.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus.

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12-135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 - 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21-9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

Immature glandular features in squamous cell carcinoma of the uterine cervix as an independent indicator of resistance to radiotherapy.

The aim of this study was to evaluate the significance of "immature glandular features" in cervical squamous cell carcinoma (SCC) as an indicator of tumor radioresistance. Pretreatment biopsied tissue specimens of cervical SCC from 100 patients who were uniformly treated with radiotherapy alone were classified into clinically radioresistant (cR) and radiosensitive (cS) groups. Seven histologic parameters comprising glassy cells, signet ring cells, squamous differentiation, recognizable gland, nuclear atypia, stromal response, and mitotic counts were examined. Glassy cells and signet ring cells were regarded as "immature glandular features". The correlation of these seven parameters with tumor response to radiotherapy and patient prognosis was analyzed by univariate and multivariate analyses. As objective indicators of glandular differentiation, alcian-blue staining and immunostaining of cytokeratins 7 and 20 were also performed. It was revealed that immature glandular features, absence of squamous differentiation, and low nuclear atypia were significant indicators of radioresistance of the tumor and of poorer patient prognosis. Combining those histological parameters, the present SCC cases were classified into 26 pathologically radioresistant (pR) and 74 radiosensitive (pS) groups. In the pR group, 54% (14 of 26) were clinically radioresistant, whereas 20% (15 of 74) of the pS group were clinically radioresistant (P = 0.002). The overall prognosis of the pR group was much poorer than that of the pS group (P < 0.0001). This correlation also held true in cases of identical stage and age. We could not show objectively glandular differentiation of "immature glandular features". Nonetheless, the identification of "immature glandular features" was effective in predicting the radiotherapy resistance of cervical SCC and poorer patient prognosis.

Primary epithelioid sarcoma of the vulva.

A case of a 31-year-old woman with epithelioid sarcoma of the vulva which metastasized to the regional lymph node 8 years after onset of the disease is reported here. The patient first noticed a painless subcutaneous mass of 5 mm in diameter in the right labium majus at age of 21. This was excised locally at age 23, but recurred 17 months later. Although local excision was again performed, the tumor recurred and continued to enlarge very slowly. At this stage, based on the pathology of both the initial and second tumors, the diagnosis was of a benign inflammatory process. However, local recurrence and inguinal lymph node swelling occurred at age 29, and biopsy was taken. The pathology report indicated benign granulomatous changes. The slides were reconsidered and re-interpreted as epithelioid sarcoma, whereupon radical vulvectomy was performed at age 31. Vulvar epithelioid sarcoma with inguinal lymph node metastasis was first diagnosed at that time. Epithelioid sarcoma of the vulva is an exceedingly rare tumor, and only 15 cases have been reported thus far in the literature. Early diagnosis and curative treatment of this tumor may be problematic for gynecologists because of its rarity and therefore little-known characteristic clinical behavior and histology. Radical vulvectomy or extensive local excision with inguinal lymphadenectomy at the time of diagnosis is recommended as the treatment of choice.

Prognostic factors of stage IV epithelial ovarian cancer: a multicenter retrospective study.

OBJECTIVE: In the present study, we conducted a multicenter retrospective analysis to elucidate the prognostic factors of stage IV epithelial ovarian cancer. METHODS: In November 1999, 24 Japanese institutions received questionnaires regarding stage IV epithelial ovarian cancer patients. Eligibility criteria included all patients with stage IV epithelial ovarian cancer who were surgically confirmed and initially treated in each institution between January 1990 and December 1997. Data were collected regarding age, performance status, tumor histologic subtype, site of metastasis, preoperative CA125, cytoreductive surgery, residual disease after cytoreductive surgery, and response to primary chemotherapy. Survival analysis and comparisons were performed by univariate and multivariate methods. RESULTS: Two hundred twenty-five patients with stage IV ovarian cancer were identified. The median age of the patients was 54 years. The most common site of extraperitoneal disease was malignant pleural effusion (39.6%). Of the 225 patients who underwent an attempt at surgical debulking, 70 (31.1%) were optimally cytoreduced. Most patients received platinum-based combination chemotherapy for primary chemotherapy. In multivariate analysis, performance status, histology, and residual disease after cytoreductive surgery were independent prognostic predictors of outcome. The overall median survival for optimally debulked patients was 32 months compared to 16 months for suboptimally debulked patients (P < 0.0001, hazard ratio: 0.415). CONCLUSION: Optimal surgical debulking, performance status, and histology appear to be important prognostic factors of survival in patients with stage IV epithelial ovarian cancer.

Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication.

The ubiquitin-proteasome pathway plays an important role in control of the abundance of cell cycle regulators. Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-box protein (SCF) ubiquitin ligase, were generated. Although Skp2(-/-) animals are viable, cells in the mutant mice contain markedly enlarged nuclei with polyploidy and multiple centrosomes, and show a reduced growth rate and increased apoptosis. Skp2(-/-) cells also exhibit increased accumulation of both cyclin E and p27(Kip1). The elimination of cyclin E during S and G(2) phases is impaired in Skp2(-/-) cells, resulting in loss of cyclin E periodicity. Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators.

Hypercalcemia due to parathyroid hormone-related protein produced by primary ovarian clear cell adenocarcinoma: case report.

OBJECTIVE: Amongovarian carcinomas, clear cell adenocarcinoma is one of the most common histologic subtypes associated with hypercalcemia. However, the mechanisms of hypercalcemia in clear cell adenocarcinoma are still unclear. In the following case report, we tried to determine the etiology of hypercalcemia and also to demonstrate the management of hypercalcemia diagnosed preoperatively. CASE: A 49-year-old woman was diagnosed as having a malignant ovarian tumor with hypercalcemia caused by elevated serum parathyroid hormone-related protein (PTHrP) prior to her primary surgery. Treatment with disodium incadronate promptly normalized the serum calcium level. An immunohistochemical study demonstrated PTHrP expression in the primary ovarian lesion, but not in the metastatic lesion. A Northern blot analysis of the cancer cells from the ovarian tumor confirmed the presence of PTHrP mRNA. CONCLUSION: Humoral hypercalcemia of malignancy in this case has been conclusively shown to be due to the production of PTHrP at the primary ovarian tumor, based on both immunohistochemical and molecular analyses.

A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: a Japanese cooperative study.

BACKGROUND: This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Japanese patients with advanced ovarian cancer. PATIENTS AND METHODS: Docetaxel was administered at a dose of 70 mg/m2 intravenously to patients with platinum pretreated advanced ovarian cancer. Treatment was repeated every three weeks. No routine corticosteroid premedication was given. RESULTS: Ninety patients with advanced ovarian cancer were entered and sixty were assessable for response. The overall response rate was 28% in the assessable patients (95% confidence interval (95% CI): 17.54%-41.4%). CA125 responses were seen in 8 (24%) of 34 assessable patients for CA125 criteria. The 36 platinum-refractory patients had a response rate of 25% compared with 33% in the platinum-sensitive patients. The predominant toxicity was neutropenia, with 86% of the patients experiencing grade 3 or 4. Hypersensitivity reactions occurred in 37% of the patients and were not life threatening. Edema was mild and infrequent. CONCLUSION: Docetaxel at 70 mg/m2 demonstrated effectiveness as a treatment of both platinum-sensitive and platinum-refractory ovarian cancer patients, with a low incidence of severe hypersensitivity reactions and edema.

[Clinical evaluation and significance of measurement of airway hyperresponsiveness in COPD].

Airway hyperresponsiveness (HR) is one of the clinical characteristics of bronchial asthma and COPD. HR of COPD has been known to correlate with progress of pulmonary function in COPD. In order to evaluate the necessity of HR measurement, HR of COPD alone, COPD with asthma, asthma and control subjects was compared. Patients with COPD alone exhibited weak HR, while COPD with asthma represented severe HR, which was the same degree with asthmatics. From these results, we should be cautious in measurement of HR in COPD. Especially patients with FEV1 less than 1 L should be prevented from HR test.

Quantitative reduction of type I adenylyl cyclase in human alcoholics.

The amounts of adenylyl cyclase type I (AC I) were examined in various parts of the postmortem brains from alcoholics who prior to death had been abstinent from alcohol for at least 6 months and compared with controls using immunoblot analysis with anti-AC I specific antibody. It was revealed that a significant reduction of AC I was observed in both frontal and temporal cortices. On the other hand, in other areas (occipital cortex, caudate nucleus, putamen, and hippocampus) the amounts were comparable between alcoholics and controls. In the next step, we examined two subtypes of human AC mRNA levels (AC I and AC VIII) in blood cells by quantitative RT-PCR using [alpha-32P]dCTP with two sets of the synthetic oligonucleotide primers based on the DNA sequences reported elsewhere (Villacres, E.C. et al., Genomics 16 (1993) 473-478; J. Parma et al., Biochem. Biophys. Res. Commun. 179 (1991) 455-462). The amounts of amplified DNAs of both AC I and AC VIII were significantly smaller in alcoholics than in controls. On the other hand, the amounts of amplified DNA of beta-actin DNA were almost equal between alcoholics and controls. It appears from these results that a reduction in the amount of AC subtypes may be a biological marker for alcoholics.

Phase II dose escalation: a novel approach to balancing efficacy and toxicity of anticancer agents. Japanese Docetaxel Ovarian Cancer Study Group.

BACKGROUND: Small patient numbers in phase I trials may result in a safe but ineffective dose being recommended for phase II trials. A phase II dose escalation study may identify a dose that is both safe and effective. The Japanese phase I recommended dose of 60 mg/m2 of docetaxel (Taxotere) had been ineffective in phase II trials in ovarian carcinoma. PATIENTS AND METHODS: Patients previously treated with one platinum-based regimen for ovarian cancer received docetaxel (Taxotere) every 3 weeks. The first dose tested was 70 mg/m2. If none of the first 5 evaluable patients responded, the dose was increased. If at least one patient responded, 10 more patients were enrolled. Also, if fewer than 3 of these first 15 evaluable patients responded, the dose was increased. If at least 3 patients responded, another 15 patients were scheduled to be enrolled to confirm efficacy. Unacceptable toxicity in 4 of 5, or 10 of 15 patients would stop escalation. RESULTS: Dose escalation from 70 mg/m2 was not required because responses were noted with acceptable toxicity levels. Overall response in 25 evaluable patients treated at 70 mg/m2 was 24.0% (95% CI = 9.4-45.1%). CONCLUSION: Docetaxel 70 mg/m2 without premedication was identified as a safe and effective dose. Further testing of the phase II dose escalation design is worthwhile.

Clinicopathological factors predicting retroperitoneal lymph node metastasis and survival in endometrial cancer.

BACKGROUND: By clarifying the significance of clinicopathological factors for retroperitoneal lymph node metastasis and survival of patients with endometrial cancer, we suggest ideas for optimal treatment of this disease. METHODS: A retrospective study was conducted in 310 women with endometrial cancer who underwent surgery with retroperitoneal lymphadenectomy. To evaluate retroperitoneal lymph node metastasis, age-adjusted and multivariable analyses were carried out for six clinicopathological factors including pathological grade, myometrial invasion, cervical invasion, peritoneal cytology, lymphatic permeation and vascular invasion. To evaluate survival, besides the above factors, a positive rate of metastasis of dissected retroperitoneal lymph nodes was included. RESULTS: In 40 patients (13%) with nodal metastasis, the average positive rate of metastasis of dissected retroperitoneal lymph nodes was 22%. For retroperitoneal lymph node metastasis, the odds ratio of deep myometrial invasion, cervical invasion and severe lymphatic permeation were 5.97, 2.72 and 12.01, respectively. For survival, the hazard ratios of the positive rates of metastasis of dissected retroperitoneal lymph nodes (both 25% and < 25%), positive peritoneal cytology and poor pathological grade were 7.10, 3.24, 3.82 and 3.27, respectively, and 5-year survival rates for them were 0, 50, 72 and 77%, respectively. CONCLUSIONS: For retroperitoneal lymph node metastasis, lymphatic permeation, deep myometrial invasion and cervical invasion were the independent prognostic factors. For survival, retroperitoneal lymph metastasis, poor pathological grades and positive peritoneal cytology were the independent prognostic factors. The positive rate of metastasis of dissected retroperitoneal lymph metastasis plays an important role in predicting survival of endometrial cancer. Lymph node biopsy is insufficient in treatment of this disease.

Prognostic value of p53 protein accumulation in cancer cell nuclei in adenocarcinoma of the uterine cervix.

Adenocarcinoma of the uterine cervix (CxAd) is one of the most distressing malignancies of the female reproductive system because of its tendency to spread aggressively and to be resistant to radiation and systemic therapies. To clarify the prognostic significance of p53 alteration in CxAd, we immunohistochemically examined the incidence of p53 nuclear accumulation, which is considered to be mostly parallel with p53 gene mutation, and its association with clinicopathological parameters in 26 patients with CxAd. The overall incidence of p53 nuclear accumulation was 46% (12 of 26), being higher in groups with clinically advanced disease, higher degrees of cellular atypia, and deeper myometrial invasion, but significantly lower in patients with integration of human papillomavirus (HPV) type 16 or 18 DNA. Nuclear p53 immunoreactivity as well as lymph node status, depth of invasion and the absence of HPV-DNA integration were significant indicators of a poor prognosis. Examination of p53 nuclear accumulation could be applied to biopsy material, and would be of practical assistance in predicting the prognosis of CxAd both preoperatively and postoperatively.

Frequent occurrence of c-Ki-ras gene mutations in well differentiated endometrial adenocarcinoma showing infiltrative local growth with fibrosing stromal response.

The frequency of c-Ki-ras mutation was examined by polymerase chain reaction (single-strand conformation polymorphism and direct sequencing analysis) and its association with histological parameters was analyzed in 110 endometrial adenocarcinoma hysterectomy specimens. The c-Ki-ras mutation was detected in 24 cases (22%). It occurred irrespective of tumor size, stage or histological grade, and was more frequent in tumors associated with endometrial hyperplasia (11 of 20, 55%) than in those without (10 of 73, 14%). In addition, the frequency of the mutation was significantly higher in tumors showing an infiltrative growth pattern accompanied by a stromal response consisting of edematous fibrous tissue (19 of 58, 33%), than in those which revealed an expansive growth pattern without such a stromal reaction (five of 52, 10%). Even among tumors showing the infiltrative growth pattern, the frequency of c-Ki-ras mutation was especially high (48%) in grade I cases in comparison with grade II or III cases (20% and 19%). Mutational activation of the c-Ki-ras gene may act at two points in the developmental pathway of endometrial adenocarcinoma by enhancing evolution of hyperplasia to adenocarcinoma, and by producing an infiltrative growth with a fibrosing stromal response.

High dose rate brachytherapy for carcinoma of the uterine cervix: comparison of two different fractionation regimens.

PURPOSE: There is no consensus as to the best dose-fractionation regimen in high dose rate (HDR) brachytherapy for cervix cancer. Since 1983, two fractionation regimens have been used in different time periods at National Cancer Center Hospital, and their treatment results have been compared in terms of 5-year survival, local control, and complication rate to find the better therapeutic regimen. METHODS AND MATERIALS: From November 1983 to October 1990, 130 patients with uterine cervix carcinoma were treated with HDR intracavitary brachytherapy using a remote afterloading system. There were 21 Stage Ib patients, 5 Stage IIa, 29 Stage IIb, 2 Stage IIIa, 68 Stage IIIb, and 5 Stage IVa. The median age was 64 years. The median follow-up time was 50 months. Radiotherapy consisted of external beam irradiation to the pelvis (mean dose of 50 Gy), combined with HDR brachytherapy (mean dose of 20 Gy to point A) given 5 Gy per session twice weekly (group A: 54 patients) or 6 Gy once weekly (group B: 76 patients). RESULTS: The overall 5-year survival was 52% in group A and 72% in group B. Local recurrence rate was 11%, and distant failure rate was 21%, with no difference between the two groups. The complication rate was significantly lower in group B (37%) than in group A (55%). Multivariate analysis has shown that factors affecting survival were stage, brachytherapy dose, and local control status. No factor was predictive of local control, but the external beam radiation dose significantly influenced the risk of complications. CONCLUSION: The once-weekly HDR intracavitary applications combined with properly adjusted external beam pelvic irradiation is a safe and effective treatment for patients with uterine cervix cancer.

[Twenty one multicentral studies on prognosis of advanced ovarian cancer; focused on correlation between primary surgical procedure following adjuvant chemotherapies and 4 year survival rates].

The treatment outcome of 778 patients with stage III ovarian cancer treated by surgery and chemotherapy between 1976 and 1990 in 21 institutions was analyzed retrospectively. Survival of patients treated between 1985 and 1990 was significantly superior to that before 1985 (Kaplan-Meier, p < 0.01). Four year survival rates were found to be distributed from 5 to 52% among institutions (p < 0.001, log-rank test). When survival rates were compared according to the relative dose intensity (RDI) of CDDP administered, patients who were given CDDP RDI > or = 0.9 had a favorable prognosis. The twenty-one institutions were divided into two groups: Standard (total abdominal hysterectomy and bilateral salpingo-oophorectomy) vs. standard+debulking (of as much gross tumor as can safely be performed) according to the operative procedure which was performed in each hospital. It was found that the four-year survival rate for patients treated in hospitals where standard surgery was done was 22.9 +/- 12.2%, whereas that in hospitals adopting standard+debulking surgery was 34.4 +/- 10.1% (p = 0.03, t-test). When the hospitals were divided into 4 groups according to combination of the operative procedure and CDDP RDI, the four year survival rates were 17.5 +/- 8.3% for standard+debulking+CDDP RDI < 0.9, 39.0 +/- 1.4% for standard+CDDP RDI > or = 0.9, 28.8 +/- 11.5% for standard+debulking+CDDP RDI < 0.9 and 37.8 +/- 8.0% for standard+debulking+CDDP RDI > or = 0.9.(ABSTRACT TRUNCATED AT 250 WORDS)

Peritoneal cytology in endometrial cancer - an investigation of the source of endometrial cancer-cells in the peritoneal-cavity.

In order to identify the source of endometrial cancer cells in the peritoneal cavity, the incidence of positive peritoneal cytology was assessed according to pTNM classification. In 74 cases free peritoneal fluid in the pelvic cavity was aspirated. In the absence of fluid smears of the cul-de-sac was made by scraping (45 cases). Five of 15 positive aspirated cases were pT1N0 or pT2N0. These five cases underwent surgery alone and are still alive with no evidence of disease. Malignant cells which supposedly gain access to the pelvic cavity via the fallopian tube have low potential for implantation.

Possible mechanisms of action of the antispasmodic agent tiropramide in the isolated detrusor from rats.

The effects of tiropramide hydrochloride on Ca(2+)-induced contraction, cytoplasmic free Ca2+ levels and tissue cyclic AMP concentrations were investigated to elucidate the mechanisms of its antispasmodic action in the isolated detrusor from rats. Tiropramide inhibited the Ca2+ (3 mM)-induced contractions of the isolated urinary bladder depolarized in a Ca(2+)-free medium, and the IC50 value was 3.3 x 10(-6) M. When tiropramide was added during the sustained phase of the K+ (60 mM)-contracture, IC50 values of tiropramide for the contraction and the increased fluorescence were 1.9 x 10(-5) M and 16.4 x 10(-5) M, respectively. On the other hand, the IC50 values for the K(+)-induced contraction and fluorescence after pretreatment of the isolated urinary bladder with tiropramide were 2.1 x 10(-5) M and 2.6 x 10(-5) M, respectively. Tissue cyclic AMP levels at 1 min after addition of 10(-5) M tiropramide were significantly increased. Papaverine, IBMX or forskolin potentiated the inhibitory effect of tiropramide on carbachol-induced contraction and its cyclic AMP-elevating effect. However, a good correlation between the degrees of potentiation of the inhibitory effect and the increase in cyclic AMP levels was not observed. The present results suggest that the smooth muscle relaxant activity of tiropramide in the isolated detrusor from rats may be intimately associated with predominant inhibition of Ca2+ influx and, to a lesser extent, an increase in intracellular cyclic AMP levels.