Metastasis of cervical cancer indicated by elevation of serum CA125 produced by mediastinal lymph nodes: a case report.

BACKGROUND: In patient assessment for recurrence of neoplasia, a biomarker that shows an elevated serum value before the first treatment is a candidate for follow-up examination. The biomarker squamous cell carcinoma antigen is usually utilized for follow-up of squamous cell cancer of the cervix. CASE PRESENTATION: We herein report a 30-year-old Japanese woman of postoperative metastasis of cervical squamous cell cancer to the mediastinal and supraclavicular lymph nodes as indicated by an elevated serum cancer antigen 125 concentration and not by the squamous cell carcinoma antigen value. After chemoradiotherapy and chemotherapy, the serum cancer antigen 125 concentration decreased to a normal value. Squamous cell carcinoma antigen was found to be distributed in both the squamous cell cancer tissue of the cervix and the supraclavicular lymph node metastatic tissue. By contrast, cancer antigen 125 was distributed in the supraclavicular lymph node metastatic tissue but not in the original squamous cell cancer tissue of the cervix. CONCLUSION: In this case, metastasis of cervical cancer to the mediastinal and supraclavicular lymph nodes was shown by the biomarker cancer antigen 125, which was not present in the original neoplasia.

Two cases of vasa previa diagnosed prenatally using three-dimensional ultrasonography.

We report two cases in which we describe the impact of sonography (US) in the management of vasa previa. In the first case, with two-dimensional US, the diagnosis of vasa previa was made at 21 weeks gestation. In the second case, using three-dimensional US, the diagnosis of vasa previa was made at 19 weeks gestation. An elective Cesarean section was carried out at 34 weeks in both cases. Diagnosis of vasa previa is critical when low-lying placenta or velamentous insertion of the umbilical cord is detected during the pregnancy.

Establishment and characterization of novel human uterine leiomyosarcoma cell lines.

Patients with unresectable advanced uterine leiomyosarcoma have a very poor prognosis because no effective chemotherapeutic protocols exist. There are currently few established primary human uterine leiomyosarcoma cell lines that can be used to investigate effective therapies. To overcome this problem, we carried out long-term in vitro cell culture and/or nude mouse transplantation and successfully established novel human uterine leiomyosarcoma cell lines from extrauterine and intrauterine tumors that were surgically excised from a single patient. The established cells were characterized by flow cytometry, anticancer drug-sensitivity assays and karyotyping analyses. All the established cell lines showed unstable multiple chromosome abnormalities. Since the cells can proliferate in vitro and in vivo, they will be useful for developing new therapeutic strategies for advanced uterine leiomyosarcoma patients.

Use of 18F-fluorodeoxyglucose positron emission tomography for diagnosis of uterine sarcomas.

We evaluated the use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of uterine sarcomas. FDG-PET combined with serum lactate dehydrogenase (LDH) levels were compared with FDG-PET alone for the diagnosis of leiomyosarcomas (LMS), which are the most difficult uterine sarcomas to diagnose. FDG-PET imaging of endometrial cancer (EC) was used as a reference. Immunoreactivity for glucose transporter-1 (GLUT-I) correlated with FDG uptake was evaluated in sarcomas and leiomyomas (LM), including cases not examined by FDG-PET. FDG was injected after at least 5 h fasting and standardized uptake values (SUVs) were analyzed quantitatively 50-70 min after injection. Immunohistochemical expression of GLUT-1 was studied in paraffin sections of tumors using anti-GLUT-1 antibodies and GLUT-1 expression scores were derived based on staining intensities. FDG-PET was performed preoperatively in a total of 53 patients including 10 with sarcomas, 19 with EC and 24 with LM. Immunohistochemical examination was performed in 17 sarcomas, 6 EC and 9 LM [6 usual LM, 1 uterine smooth muscle tumor of uncertain malignant potential (UMP), and 2 bizarre LM (BLM)]. SUVs for uterine sarcomas and EC were significantly higher (p=0.0001) than those for LMs. There were no significant differences in SUVs among ECs, carcinosarcomas (CS) and LMS. Significant differences in SUVs existed between LM and LMS (p=0.003). However, the diagnostic accuracy for LMS was only 73%. The diagnostic accuracy of FDG-PET combined with serum LDH was 100%. GLUT-1 expression scores were significantly higher in sarcomas and EC than in LM (p<0.0001). Intermediate GLUT-1 scores were found in two of the three cases of UMP and BLM. In conclusion, FDG-PET is useful for diagnosing uterine sarcomas, while FDG-PET combined with serum LDH is useful for diagnosing LMS. Immunohistochemical examination of GLUT-1 confirmed the high FDG uptake in LMS patients.

Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition.

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

Immunohistochemical localization of inhibin and activin subunits, activin receptors and Smads in ovarian endometriosis.

We previously reported that activin A, not inhibin, was localized to endometrial tissues, and that the endometrium might be a major source of activin A during the menstrual cycle, using an immunohistochemical method. However, there are few detailed reports concerning the expression of inhibin subunits, activin receptors and Smad proteins in the ectopic endometrial tissues of endometriosis. In this study, our purpose was to evaluate the immunohistochemical localization of inhibin alpha-, betaA-subunits, activin A, activin receptor, and Smad proteins in ovarian endometriosis. Tissue samples from ovarian endometriosis were obtained from 13 women. Normal endometrial tissues were obtained during the proliferative phase from 5 premenopausal women without endometriosis who were undergoing a hysterectomy for the treatment of uterine cervical intraepithelial neoplasia 3. We examined the immunohistochemical localization of inhibin/activin alpha-, betaA-subunit, activin A, activin receptors types IA, IB, IIA, IIB, Smad2, Smad3 and Smad4 using an avidin-biotin-peroxidase complex technique. No immunostaining for the alpha-subunit of inhibin was observed in ovarian endometriosis and the normal endometrium. Positive immunostaining for the betaA-subunit of inhibin, activin A, activin receptors types IA, IB, IIA, IIB, Smad2, Smad3 and Smad4 was observed in ovarian endometriosis and the normal endometrium. In conclusion, these results suggest that activin A, but not inhibins, is produced by ovarian endometriosis and the normal endometrium, and that the activin signal transduction system exists in both ovarian endometriosis and the normal endometrium.

Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase.

Although death-associated protein kinase (DAPK) is a Ca2+/calmodulin-regulated serine/threonine kinase that plays important roles in various types of apoptotic cell death, there have been no reports of its tissue distributions and functions in female reproductive organs. By comparing C57BL/6 wild-type mice with DAPK-mutant mice lacking the 74-amino acid catalytic kinase domain of DAPK, the cellular distributions and biological functions of DAPK in murine ovaries were investigated. In situ hybridization analyses with sense and antisense riboprobes revealed that DAPK mRNA was selectively and highly expressed in granulosa cells in the ovaries of both types of mice. There were no significant differences in the body weights, ovarian weights and unstimulated ovarian follicular numbers between the wild-type and DAPK-mutant mice. Intraperitoneal injection of CPT-11, an anticancer topoisomerase I inhibitor that causes granulosa cell-specific apoptosis partly through Fas-Fas ligand (FasL) interactions in MCH mice, induced follicular apoptosis in both the wild-type and DAPK-mutant mice. However, the numbers of apoptotic follicles were significantly reduced in the DAPK-mutant mice. The Fas and FasL expression levels in the CPT-11-injected mice did not differ significantly between the wild-type and DAPK-mutant mice. These results indicate that DAPK positively regulates intracellular signaling pathways for CPT-11-induced granulosa cell apoptosis.

Phase I study of combination chemotherapy with irinotecan hydrochloride and nedaplatin for cervical squamous cell carcinoma: Japanese gynecologic oncology group study.

The aim of this study (JGOG1063) was to determine the recommended dose (RD) for combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin (NDP) for advanced cervical squamous cell carcinoma. CPT-11 was given intravenously in fixed doses of 60 mg/m2 on days 1 and 8 and NDP, in escalating doses, on day 1, every 4 weeks. A total of 15 patients were enrolled in the study. At level 1 (NDP: 50 mg/m2), one of the 3 patients developed grade 3 diarrhea, so 3 additional patients were enrolled at this level. As none of the 3 additional patients exhibited dose-limiting toxicity, level 1 was elevated to level 2 (NDP: 60 mg/m2). The maximum tolerated dose was not reached, even at the highest dose level (level 4; NDP: 80 mg/m2). No further dose escalation was carried out, and level 4 (CPT-11: 60 mg/m2, NDP: 80 mg/m2) was determined as the RD.

Remodeling of the human endometrial epithelium is regulated by laminin and type IV collagen.

We investigated the expression and function of laminin and type IV collagen (COL-4) in the human endometrial epithelium throughout the menstrual cycle. Their expression was demonstrated by immunohistochemistry, while cytological analysis of the human endometrial epithelial cell line HHUA cultured on laminin- or COL-4-coated plates provided information on their roles in cell proliferation, structure and apoptosis. Laminin and COL-4 were detected in subepithelial basement membrane-like structures and their expression levels varied throughout the menstrual cycle. Laminin expression was significantly decreased in secretory phase endometrial surface epithelium, while COL-4 expression was significantly decreased in late proliferative phase endometrial epithelium and in vascular endothelium. The morphology of proliferating HHUA cells varied depending on the extracellular matrix component coated on the culture plates. COL-4 strongly inhibited cell proliferation of HHUA cells and enhanced Fas antigen (CD95)-mediated apoptosis, while laminin inhibited Fas-mediated apoptosis. These results indicate that the cyclic expression of laminin and COL-4 in basement membrane-like structures of endometrial epithelium may regulate the endometrial epithelial remodeling and embryo implantation during the menstrual cycle.

Danazol enhances Fas-mediated apoptosis in human endometrial epithelial cells within normal physiology.

Local danazol therapy reduces the signs and symptoms of endometriosis without inhibition of regular ovulation and menstruation and without atrophic changes to the endometrium or vaginal wall. It has been suggested that danazol has possible non-cytotoxic direct actions on eutopic endometrial cells and endometriotic cells. We have investigated the direct effects of danazol on a human endometrial epithelial cell line, HHUA, which is believed to retain many normal intracellular signaling pathways. A thoroughly dissolved solution of danazol enhanced Fas-mediated apoptosis in HHUA cells without inhibiting cell proliferation. Semi-quantitative flow cytometric analysis revealed that danazol did not enhance cell surface expression of Fas antigens. The enhancement of Fas-mediated apoptosis by endometrial cytokines such as EGF, IL-1beta and interferon-gamma was not additively enhanced by danazol; nor did danazol enhance growth suppression by anticancer drugs such as paclitaxel, carboplatin and 5-fluorouracil. Moreover, danazol did not enhance the irradiation-induced cell growth suppression of radiation-sensitive human cervical squamous cancer ME180 cells. These results indicate that danazol may regulate endometrial epithelial cell proliferation and apoptosis within normal physiology.

Direct effects of CPT-11 and SN38 on ovarian granulosa cells.

This study aimed to clarify the mechanism by which apoptosis and Fas ligand (FasL) expression are induced in the ovarian granulosa cells of mice injected with irinotecan HCl (CPT-11). To this end, the direct effects of CPT-11 and its active metabolite, SN38, on granulosa cells were investigated. Normal ovarian tissue fragments obtained from 8-week-old female MCH mice were cultured in vitro with CPT-11 or SN38 and paraffin-embedded. After sectioning, the ovarian fragments were analyzed by TUNEL staining to detect apoptotic cells and by immunohistochemistry with an anti-FasL antibody to detect FasL expression. The results revealed no increase in TUNEL-positive granulosa cells in the ovarian tissue fragments cultured with CPT-11 or SN38. Furthermore, CPT-11 and SN38 did not induce FasL expression in the ovarian fragments. In conclusion, apoptosis and FasL expression induced in the ovarian granulosa cells of mice injected with CPT-11 is not caused by direct stimulation with CPT-11 or SN38. Therefore, systemic CPT-11 administration appears to induce apoptosis and FasL expression in granulosa cells via currently unknown endogenous FasL-inducing factors or by active metabolites of CPT-11 other than SN38.

Phase I study of irinotecan combined with mitomycin-C and 5-fluorouracil for gynecological malignancies: the JGOG study.

BACKGROUND: A phase I study to evaluate combined therapy with irinotecan (CPT-11), mitomycin-C (MMC), and 5-fluorouracil (5-FU) was performed in patients with gynecological malignancy, especially non-squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS: Eligibility for the study included patients with previously untreated, chemotherapy-naïve cervical and ovarian carcinoma. CPT-11 and MMC were administered on days 1 and 15 by intravenous infusion, while 5-FU was given on days 3 to 7. This regimen was repeated after 5 weeks. Four escalating dose levels were carried out (CPT-11/MMC: 120/5, 120/6, 150/6, and 150/7 mg/m2; 5-FU 600 mg/m2 fixed). RESULTS: Fourteen patients were enrolled in the study. Although all the patients had no previous chemotherapy, three patients had undergone a simple hysterectomy and nine had a radical hysterectomy performed before this chemotherapy. The maximum tolerated dose was not reached by using CPT-11 150 mg/m2, MMC 7 mg/m2, and 5-FU 600 mg/m2 because none of the patients experienced any hematological or non-hematological toxicities of grade 4 during the first cycle. CONCLUSION: The recommended doses of this new regimen are CPT-11 150 mg/m2, MMC 7 mg/m2, and 5-Fu 600 mg/m2 which can be well tolerated for gynecological malignancies.

Autocrine/paracrine regulation of human endometrial stromal remodeling by laminin and type IV collagen.

The biological roles of laminin and type IV collagen in human endometrial stromal tissues were investigated by the evaluation of the expression levels in human endometrial tissues using immunohistochemistry. In addition, normal human endometrial stromal cells were cultured in vitro on laminin- or type IV collagen-coated plates and subjected to cytological analyses. Cyclic production of laminin and type IV collagen were detected and the two productions were significantly increased in late proliferative and late secretory endometrial stromal cells. Unstimulated endometrial stromal cells proliferated with specific growth structures that varied depending on the extracellular matrix component coated on the culture plates. The expression levels of integrin subunits on endometrial stromal cells were sufficiently enhanced by 8Br-cAMP treatment to mask any differences in the growth structures induced by the extracellular matrix components. 8Br-cAMP-stimulating stromal cells exhibited significant survival on laminin-coated plates, while 8Br-cAMP-deprived stromal cells, after 8Br-cAMP stimulation, showed significant survival on type IV collagen-coated plates. In conclusion, human endometrial stromal cells produce laminin and type IV collagen, and these productions are possibly regulated by ovarian estrogen and progesterone. Human endometrial stromal cells specifically bind to laminin and type IV collagen via integrins, and regulate endometrial stromal cell structures, viability and differentiation. Thus, laminin and type IV collagen may autoregulate human endometrial stromal remodeling during the menstrual cycle in an autocrine and paracrine fashion.

Leptin regulates the proliferation and apoptosis of human endometrial epithelial cells.

The biological functions of leptin in the human endometrial epithelium were investigated using the human endometrial epithelial cell line, HHUA. Specifically, the effects of leptin on the proliferation and apoptosis of HHUA cells induced by treatment with anti-Fas IgM or anticancer drugs were examined. RT-PCR detected the expression of four leptin receptor isoform mRNAs in the cells and flow cytometric analysis revealed cell surface expression of the leptin receptor molecules. Leptin stimulated HHUA cell proliferation in a dose-dependent manner at concentrations below the normal serum leptin level. Leptin enhanced anti-Fas IgM-mediated growth inhibition and DNA fragmentation, but did not enhance the expression of either Fas antigen or Fas ligand. Moreover, leptin had no effect on anticancer drug-induced apoptosis. Based on these results, leptin at a physiological serum concentration, may regulate the remodeling of the human endometrial epithelium by stimulating cell proliferation and enhancing the Fas-specific intracellular apoptotic signaling pathway.

Experimental characterization of recurrent ovarian immature teratoma cells after optimal surgery.

Minimal optimal surgery without chemotherapy is often performed for patients with ovarian immature teratoma, which frequently occurs in young women who hope for future pregnancies. If tumors recur after the operation, anticancer drug chemotherapy is often administered, although few studies have highlighted differences between the recurrent and the primary tumor cells. Therefore, we have established experimental animal models of recurrent ovarian immature teratoma cells after optimal surgery and characterized the anticancer drug sensitivity and antigenicity of the recurrent tumors. Surgically-excised tumor cells of a grade II ovarian immature teratoma were cultured in vitro and transplanted into nude mice to establish stable cell lines. Differential drug sensitivity and antigenicity of the tumor cells were compared between the primary and the nude mouse tumors. Nude mouse tumor cells showed a normal 46XX karyotype. Cultured primary cells showed a remarkably high sensitivity to paclitaxel, docetaxel, adriamycin and pirarubicin, compared to peritoneal cancer cells obtained from a patient with ovarian adenocarcinomatous peritonitis. The drug sensitivity of teratoma cells to 5-fluorouracil, bleomycin or peplomycin was also significantly higher. However, there was no significant difference in sensitivity to platinum drugs between the primary teratoma and the peritoneal adenocarcinoma cells. As for nude mouse tumor cells, sensitivity to 12 anticancer drugs was significantly lower than that of the primary tumor cells, while there was little difference in sensitivity to carboplatin or peplomycin between the primary and nude mouse tumor cells. Flow cytometry showed that the expression of smooth muscle actin (SMA) significantly decreased in nude mouse tumor cells when compared to cultured primary cells. In conclusion, ovarian immature teratomas with normal karyotypes have a malignant potential to recur after minimal surgery. During nude mouse transplantation, SMA-overexpressing cells appeared to be selectively excluded and nude mouse tumor cells were less sensitive to the majority of anticancer drugs than the primary tumor cells. These results indicate that after optimal surgery for ovarian immature teratoma, recurrent cells can be more resistant to anticancer drugs than the primary tumors. Therefore, it is likely that adjuvant chemotherapy lowers the risk of ovarian immature teratomas recurring after optimal surgery. BEP and PBV regimens are frequently given to teratoma patients. However, paclitaxel/carboplatin or docetaxel/carboplatin, which are the most effective chemotherapy treatments for epithelial ovarian cancer patients, are considered to be an alternative regimen, especially in the prevention of reproductive toxicity.

A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis.

Clinical use of CPT-11 combination chemotherapy frequently induces ovarian dysfunction in premenopausal and perimenopausal cancer patients, but its mechanism remains unclear. Mouse experiments were performed to clarify the molecular mechanism of CPT-11-induced ovarian dysfunction. Clinically therapeutic doses of CPT-11 were injected intraperitoneally into 8-week-old female MCH mice, and their ovaries were examined by the TUNEL assay to detect dead cells. Immunohistochemical examinations were simultaneously performed to detect the expression of activated caspase 3, Fas antigen and Fas ligand (FasL). Furthermore, normal murine ovarian tissue fragments were incubated with recombinant soluble FasL in organ cultures and stained by the TUNEL assay to detect apoptotic cells. Intraperitoneal CPT-11 injections induced specific TUNEL-positive cells and cell death with cleaved caspase 3 expression among large ovarian follicular granulosa cells. Apoptotic follicles (follicles containing >/=10 TUNEL-positive cells per ovarian section) were only found among large follicles. The final apoptotic follicle ratios were approximately 30% of the total follicles independent of the CPT-11 dose, while CPT-11 dose-dependently enhanced apoptotic processes in murine ovarian follicles. Fas antigen was expressed in most ovarian cells, with extremely high expression levels detected in luteal cells. CPT-11 injections did not significantly increase the Fas expression levels in ovarian cells. Although no FasL expression was detected in normal ovarian tissues, CPT-11 injections significantly induced specific FasL expression in granulosa cells. Incubation of organ-cultured normal murine ovarian tissue fragments with recombinant mouse soluble FasL significantly increased the numbers of TUNEL-positive granulosa and luteal cells. In conclusion, CPT-11 dose-dependently induced specific FasL expression in granulosa cells of developing ovarian follicles. The induced FasL reacted with the Fas antigen constitutively expressed on granulosa cells, such that apoptosis can only be enhanced and induced in granulosa cells in an autocrine and/or paracrine manner. This cell lineage-specific and differentiation stage-specific apoptosis in granulosa cells is thought to be the main molecular mechanism of the ovarian dysfunction induced by CPT-11 combination chemotherapy.

Irinotecan HCl, an anticancer topoisomerase I inhibitor, frequently induces ovarian failure in premenopausal and perimenopausal women.

The effects of irinotecan HCl (CPT-11) combination chemotherapies on the hypothalamus-pituitary-ovary endocrine system were examined clinically. The incidences of typical menopausal malaises and/or endocrinological findings were investigated in 32 gynecological cancer patients treated by CPT-11 combination chemotherapies. Patients who complained of menopausal malaises or had been treated by hormone replacement therapy before chemotherapy were excluded from the study. Menopausal malaise-like symptoms (MMLS) appeared in 6 of 32 patients (18.8%) during CPT-11 combination chemotherapy, and these symptoms were completely cured within a few days by administration of conjugated estrogen tablets (0.625 mg/day). All the MMLS cases were perimenopausal patients (47-57 years of age), and MMLS were not found in any of the postmenopausal patients who had exceeded 3 years since endocrinological menopause or patients who had recurrent cancer after pelvic radiotherapy. After exclusion of these 3-year-postmenopausal patients and postirradiation patients, 6 of 7 patients aged 45-59 years complained of MMLS during CPT-11 combination chemotherapy. The incidence of CPT-11-induced MMLS showed no relationships with the anticancer drugs combined with CPT-11, mean total CPT-11 dose, mean number of CPT-11 injections, mean individual CPT-11 dose, grade of CPT-11-specific diarrhea or anticancer effects of each CPT-11 combination chemotherapy. The perimenopausal cancer patients with CPT-11-induced MMLS showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. A young patient with CPT-11-induced secondary amenorrhea showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. None of the postmenopausal patients with high FSH and LH levels showed any significant differences in their serum FSH, LH, PRL and TSH levels during CPT-11 combination chemotherapy. No differences in the results of LHRH and TRH tests during chemotherapy were found for postmenopausal patients. Histopathological examinations of normal ovarian tissues surgically removed from 4 young cervical cancer patients treated with preoperative CPT-11 combination chemotherapies revealed no growing ovarian follicles in the ovarian tissues. CPT-11 injections can induce estrogen-rescued MMLS in cancer patients aged approximately 50 years at a very high rate and may induce secondary amenorrhea in young women. The endocrinological and histopathological studies revealed that CPT-11 causes ovarian follicular loss and ovarian failure within a short time without affecting hypothalamic and pituitary hormone secretion. These clinical results indicate that CPT-11 has strong ovarian toxicity and that repeated CPT-11 administrations may frequently induce ovarian follicular loss and premature ovarian failure, even in young women.

Alterations of the K-ras and p53 genes in Tamoxifen-associated endometrial carcinoma.

To better understand the molecular mechanisms of carcinogenesis induced in uterine endometrium by therapeutic anti-estrogenic Tamoxifen (TAM) exposure, 27 uterine tumors (4 benign endometrial polyps and 23 carcinomas) associated with TAM exposure were analyzed for the presence and spectrum of p53 and K-ras mutations. Although there was no significant difference between TAM-associated endometrial carcinomas and sporadic endometrial tumors in the frequency of these mutations, the spectrum of p53 mutations was characteristically unique to the TAM-associated tumors. The median duration of TAM exposure was significantly longer in patients with p53 mutations than those without p53 mutations (62 vs. 30 months, p=0.028). Our observation suggests that prolonged TAM exposure may directly inactivate the p53 gene by acting as a mutagen in a significant fraction of TAM-associated endometrial carcinomas.

Neoadjuvant chemotherapy with irinotecan and mitomycin-C for locally advanced squamous cell carcinoma of the uterine cervix.

BACKGROUND: The efficacy and toxicity of combined therapy with irinotecan (CPT-11) and mitomycin-C (MMC) in a neoadjuvant setting were evaluated in patients with locally advanced squamous cell carcinoma (SCC) of the uterine cervix. PATIENTS AND METHODS: Eligibility included patients with previously untreated cervical carcinoma. CPT-11 (100 mg/m2) was administered on days 1, 8 and 15 intravenously (i.v.), while MMC (10 mg/m2 i.v.) was given on day 1. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 35 eligible patients, 3 showed a complete response and 27 a partial response, with an overall response rate of 85.7%. No patient showed progressive disease. Thirty-three patients were able to undergo radical surgery after neoadjuvant chemotherapy and only 2 patients (stage IIIb) received radiotherapy without the optimal surgery. The median disease-free survival (DFS) period was 42 months (range 5-73). The median overall survival (OAS) period was 44 months (range 17-74). Two-year DFS and OAS rates were 74.3% and 91.4%, respectively. Of the 58 treatment cycles administered, grade 3 or 4 neutropenia and thrombocytopenia were observed in 50% and 9% of the treatment cycles, respectively. Grade 3 or 4 diarrhea was observed in 6%. CONCLUSION: Neoadjuvant chemotherapy with CPT-11 and MMC can be effective and well-tolerated against locally advanced SCC of the uterine cervix.