A point mutation of the ED1 gene in a Japanese family with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (EDA) is characterized by the hypoplasia or absence of hair, teeth and sweat glands. In this study, the authors investigated the ED1 gene in a Japanese family with X-linked hypohidrotic ectodermal dysplasia. The only affected male fulfils the diagnostic criteria for this disorder. His parents were not consanguineous and both of them were healthy. After informed consent, genomic DNA was isolated from the peripheral blood lymphocytes or oral buccal epithelial cells of all members of the family. A polymerase chain reaction fragment containing exon 9 of the ED1 gene was amplified using primers. The patient's amplified fragment, as well as those from his father, mother and sister, were directly sequenced. The sequence from the patient revealed a point mutation (G1149A) in exon 8 of the ED1 gene, which changes codon 291 from glycine to arginine. Heterozygosity was demonstrated in his mother and sister. This mutation has not been reported previously. The amino acid substitution is predicted to disrupt the transmembrane domain, which strongly implies that this is the disease-causing mutation in the family.

Prognostic value of thymidine phosphorylase immunostaining in patients with uterine cervical cancer treated concurrently with doxifluridine, radiotherapy and immunotherapy.

Thymidine phosphorylase (dThdPase) is reportedly identical to platelet-derived endothelial cell growth factor (PD-ECGF). We conducted immunohistochemical staining of dThdPase to assess correlation between its expression in cancer tissue and efficacy of a combination therapy with 5'-DFUR, radiotherapy and sizofilan (SPG) in uterine cervical cancer patients. No difference in response rates was observed between dThdPase positive and negative tumor and stromal cells. Survival curves significantly differed between stromal dThdPase positive and negative groups (p=0.032). Results showed that dThdPase immunostaining is possibly prognostic and predictive in determining success of the combination therapy.

Effects of concomitant use of doxifluridine, radiotherapy and immunotherapy in patients with advanced cervical cancer.

Clinical effects of doxifluridine (group A, 600 mg/body/day; group B, 800 mg/body/day) combined with radiotherapy and immunotherapy were evaluated in patients with advanced cancer of the uterine cervix. Response rates were 84.2% (16/19 patients) in group A and 100% (18/18 patients) in group B, respectively (p=0.230). There was no significant difference in adverse reaction incidence between the methods but significantly higher grade adverse reaction were observed in group B than in group A (p=0.048). Time to progression (TTP) was longer in group B than in group A (p=0.081). The optimal 5'-DFUR dose was 800 mg/body (group B), by which higher grade adverse reactions were fully controlled and TTP was prolonged.

[A pilot trial of high dose CEP (cyclophosphamide, epirubicin, cis-platinum) therapy in patients with advanced and recurrent ovarian cancer].

We evaluated the feasibility of high-dose CEP (cyclophosphamide 750 mg/m2, epirubicin 90 mg/m2, cis-platinum 70 mg/m2) therapy, with granulocyte colony-stimulating factor support every 21 days, in 18 patients with advanced and recurrent ovarian cancer. Ten patients (56%) received 6 cycles of this regimen as planned. Toxicities more than grade 3/4 on' the WHO scale of neutropenia and thrombocytopenia were observed in all cases. Nausea, vomiting, mucositis, malaise, alopecia, hepatotoxicity, and fever were common adverse effects. The average relative dose intensity of cyclophosphamide, epirubicin, cis-platinum was 0.77, 0.77, 0.79 respectively, and each RDI decreased in the last two cycles. These data suggest that this regimen could be performed safely with careful consideration on hepatotoxicity and thrombocytopenia.

Serum MAGE-4 protein in ovarian cancer patients.

OBJECTIVE: We measured serum levels of MAGE-4 protein in patients with ovarian cancer to investigate the relationship between serum MAGE-4 positivity and prognosis. METHODS: Serum levels of MAGE-4 protein were measured with an ELISA system. RESULTS: Serum levels of MAGE-4 in patients with ovarian cancer were significantly higher than levels in patients with benign diseases. Serum MAGE-4 protein was considered positive in 22% of primary ovarian cancer patients. The positive rate was the highest in sera of patients with surface epithelial-stromal tumors, particularly serous adenocarcinomas (24%). The survival time after a primary surgical operation in ovarian cancer patients with serum MAGE-4 positivity was significantly shorter than that of MAGE-4-negative cases. CONCLUSION: These results suggest that serum MAGE-4 protein is a potential prognostic factor of reduced survival in ovarian cancer patients.

Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced or recurrent cervical cancer.

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The patients' median age was 57 years (range 35-75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16-62 days). The median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

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.

Phase II clinical study on the effects of recombinant human interleukin-3 on thrombocytopenia after chemotherapy for advanced ovarian cancer. SDZ ILE 964 [IL-3] Study Group.

The efficacy, safety, and optimum clinical dose of recombinant human interleukin-3 (rhIL-3) was examined in ovarian cancer patients with thrombocytopenia after cancer chemotherapy. In cases with a platelet count < 75,000/mm3 during the control observation period, rhIL-3 was administered subcutaneously at a dose of 5 or 10 micrograms/kg, once a day for 10 days starting from day 4 of the subsequent chemotherapy course. Comparison between the control observation period and the rhIL-3 administration period showed a significant improvement or a tendency toward improvement in increasing the nadir platelet count and the recovery of the platelet count. The major adverse reactions were pyrexia, fatigue, and headache, which were well controlled by the use of antipyretics, analgesics, and antiinflammatory agents. Adverse reactions were for the most part transient and disappeared quickly during or after rhIL-3 administration. Although severe adverse reactions were not observed, the incidence of grade 2 and 3 adverse reactions according to a World Health Organization (WHO) Toxicity Scale were slightly higher in the 10 micrograms/kg/d group. As a consequence, the 5 micrograms/kg/d dose was considered to have a slightly better safety profile than the 10 micrograms/kg/d dose. Although there was no significant difference in the efficacy (the platelet count) between the two doses, the safety profile of the 5 micrograms/kg/d dose was slightly better than the 10 micrograms/kg/d group. Therefore, the 5 micrograms/kg/d was considered to be the optimum clinical dose.

Topoisomerase-I activity and response to second-line chemotherapy consisting of camptothecin-11 and cisplatin in patients with ovarian cancer.

The aim of the present study was to clarify the relationship between topoisomerase-I (topo-I) activity and sensitivity to second-line chemotherapy consisting of cisplatin and camptothecin-11 (CPT-11) in patients with ovarian cancer. Thirty Japanese women with relapsed epithelial ovarian cancer who received treatment at Tottori University Hospital or Kurume University Hospital between 1992 and 1997 were included in this study. All patients had initially undergone chemotherapy consisting of cisplatin, doxorubicin and cyclophosphamide (CAP). All subjects exhibited measurable lesions and received second-line chemotherapy consisting of 50 to 60 mg/m(2) CPT-11 on days 1, 8 and 15 and 60 mg/m(2) cisplatin on day 1. Tumor samples were obtained in the period between initial and second-line chemotherapy. Topo-I activity was assayed by relaxation of supercoiled plasmid substrate DNA. Of the 30 patients, 18 responded to second-line chemotherapy and 12 did not. We found no significant difference in patient characteristics in responders and non-responders. The interval from the end of the initial course of chemotherapy to the beginning of the second-line chemotherapy did not significantly differ in the 2 groups. The minimum amount of extraction showing complete DNA relaxation in non-responders was significantly greater than that in responders (201.7 +/- 92.5 vs. 124.1 +/- 59.4 ng; p = 0.0164). In 8 cases whose samples could be obtained before and after CAP, the amount of protein significantly decreased after CAP therapy (286.4 +/- 142.1 vs. 138.5 +/- 97.8 ng; p = 0.0294). Topo-I activity, which is enhanced by CAP therapy, can play an important role in sensitivity to CPT-11.

Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer.

To evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m(-2)) was administered intravenously on days 1, 8 and 15, followed by cisplatin (60 mg m(-2)) given intravenously on day 1. Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% (95% confidence interval 58-90%). Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated.

Radical surgery after neoadjuvant intra-arterial chemotherapy in stage IIIb squamous cell carcinoma of the cervix.

We examined the efficacy and safety of neoadjuvant intra-arterial chemotherapy (NAC) followed by radical hysterectomy and/or radiotherapy in patients with stage IIIb cervical cancer. Treatment consisted of bilateral internal iliac artery infusion of cisplatin or carboplatin and peplomycin every 21 days for two courses. Patients who responded to NAC underwent radical surgery. Patients who did not respond to NAC were treated with pelvic radiotherapy. Complete response was achieved in 2 (7.1%) of 28 patients, while a partial response was observed in 17 (60.7%) and stable disease in 9 (32.1%) patients. Sixteen patients (57.2%) were able to undergo surgery. The median blood loss (674 ml) and operating time (232 min) for radical surgery in patients with stage IIIb disease was similar to that in patients with stages Ib to IIb disease. No intra-operative or immediate postoperative complications were observed. The 5-year disease-free survival (DFS) for patients who underwent surgery (81.3%) was higher than for patients who underwent radiotherapy after NAC (31.3%). Radical surgery after NAC for stage IIIb disease was safe, and a survival benefit followed by surgery with or without radiotherapy.

Serous adenocarcinofibroma of the ovary--report of two cases and review of the literature.

We investigated the clinical and histologic characteristics of patients with ovarian serous adenocarcinofibroma. Because the tumors in both cases contained fibroma components; they were hard and clinically indistinguishable from uterine myoma, even by computed tomography. Both patients experienced relapses associated with tumors that originated outside the abdominal cavity (the subcutaneous abdominal wall in case 1, and the inguinal lymph nodes in case 2). The serum level of CA125 was normal or only moderately elevated at the first onset and relapse. The present cases suggest that the diagnostic features and clinical course differ between ovarian serous adenocarcinoma and serous adenocarcinofibroma.

[Trends in comprehensive treatment for gynecologic malignancies].

Advances in many areas, including oncology-epidemiology, chemotherapy, diagnosis, surgery, radiology, and clinical research have all had a positive impact on the treatment of gynecologic malignancies, so that today we have achieved an improved quality of life concomitant with increased survival rates in patients. The improvements in therapy for gynecologic malignancies have been in diagnostic procedures, such as tumor markers, molecular biologic methods, and image analysis. Considerable progress has been made in surgical management, from focal excision of primary lesions to minimal debulking surgery after the initial chemotherapy for advanced cancer. Chemotherapy has advanced markedly after the introduction of cisplatin, and various regimens or anticancer drug-analogs of cisplatin, camptotesin, and paclitaxel have been introduced. In recent years, the quality of life of patients with malignancies has been one of the most important factors in treatment. Intensive and combination therapies will be put to greater use for gynecologic malignancy in the future.

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.

The horizontally impacted maxillary canine situated in a labial position.

Surgical management of unerupted teeth depends upon a thorough understanding of anatomic, physiologic and pathologic factors. Attention has been given to problems of eruption in the maxillary anterior region. It is a region where a variety of anomalies occur. Since the maxillary anterior region influences appearance so greatly, early detection of difficulties and careful planning and treatment can be extremely beneficial to patients. The purpose of this case report is to present a case of maxillary permanent canine impaction in a horizontal displacement that developed after loss of the deciduous canine to chronic apical periodontitis, and incomplete root resorption of the deciduous canine.

Solitary splenic recurrence of ovarian cancer: case report and review of the literature.

We report a rare case of solitary recurrence of ovarian cancer in the spleen which developed 4 years after initial treatment. Only six cases have been reported in the literature and all were serous carcinoma. Our patient had a splenectomy without any complications but developed a liver metastasis 10 months after splenectomy.

[Early phase II trial of oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer. ETP 21 Study Group--Cervical-Ovarian Cancer Group].

We conducted multi-site early phase II trial or oral etoposide administered for 21 consecutive days in patients with cervical or ovarian cancer in cooperation with 19 institutes. Fifty mg/body of oral etoposide was administered daily for 21 consecutive days. Cycles were repeated every 28 days. In cervical cancer, 24 patients were enrolled and 17 of them were evaluated. The overall response rate including CR and PR was 23.5% (4/17). In ovarian cancer, 18 patients out of 21 enrolled were evaluated. The overall response rate was 16.7% (3/18). The primary toxicity observed was myelosuppression such as leukopenia, neutropenia, hemoglobin decrease and thrombocytopenia. Other adverse effects were anorexia, nausea, vomitting, fatigue, alopecia and stomatitis. From these results we concluded that oral etoposide administered for 21 consecutive days was effective against cervical cancer.

Effects of a gonadotropin-releasing hormone agonist on rat ovarian adenocarcinoma cell lines in vitro and in vivo.

To evaluate the biologic effects of the gonadotropin-releasing hormone (GnRH) agonist buserelin on rat ovarian adenocarcinoma cells in vivo and in vitro, female Wistar rats with primary ovarian adenocarcinoma induced by 7, 12-dimethylbenz(a)anthracene (DMBA) and the DMBA-OC-1 cell line established from a DMBA-induced rat tumor were used in this study. In vivo, daily administration of buserelin significantly suppressed the release of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and progesterone as compared with controls. Buserelin did not inhibit the growth of DMBA-induced tumors. However, histopathologically, there was increased central necrosis and a decrease in the number of neoplastic cells, with proliferation of connective tissue, in the group treated with buserelin. In vitro, FSH-induced proliferation of DMBA-OC-1 cells was suppressed by buserelin. Thus, this basic experimental study supports the potential use of a GnRH agonist to suppress the growth of ovarian cancer.

Two cases of endometrial adenocarcinoma arising from atypical polypoid adenomyoma.

Atypical polypoid adenomyoma (APA) most frequently presents as an endometrial polyp in premenopausal women and is believed to follow a benign course. In hysterectomy specimens from postmenopausal Japanease women, the endometrium contained an APA with an area of endometrial adenocarcinoma. A convincing transition zone between the APA and the adenocarcinoma was seen in our cases, suggesting that APA may develop into endometrial adenocarcinoma in postmenopausal women.

Histologic characterization of rat ovarian carcinoma induced by intraovarian insertion of a 7,12-dimethylbenz[a]anthracene-coated suture: common epithelial tumors of the ovary in rats?

BACKGROUND: The surface epithelium of the human ovary simulates the mullerian form in tumor formation. In experimental animals, however, such a phenomenon has not previously been observed. METHODS: A chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), was heated, and the central portion of a 3-0 silk suture was immersed in the melted carcinogen. After vaginal cytology, the DMBA-coated silk was inserted into the ovaries of 40 Wistar strain rats age 7 weeks. The animals were sacrificed when a tumor mass became large enough to extend the abdominal wall. The experimental period lasted for 60 weeks. The tumor histology was compared with that in human counterparts and the mullerian derivatives in rats. RESULTS: In 19 rats, including 4 animals with cornified vaginal smears at the time of DMBA treatment, an ovarian carcinoma developed within 36 weeks. In 17 epithelial tumors, the neoplastic cells proliferated to form papillary or glandular structures, and the lining epithelium consisted of flattened or cuboidal cells and columnar cells, often with pseudostratified nuclei. Adenocarcinoma components transformed into squamous cells in two cases. The remaining two neoplasms were pure mesenchymal tumors with histology of a fibrosarcomatous tumor, and one of them contained heterologous malignant osteoid components. In the remaining 21 rats, including 5 with cornified smears, no tumors developed during the experimental period. CONCLUSIONS: The histologies of DMBA-induced rat ovarian carcinoma simulated the epithelia of rat ovarian surface, fallopian tube, endometrium, and uterine cervix. The results of this study suggest that the surface epithelium of rat ovary also simulates the mullerian form in tumor formation.