miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway.

Epithelial ovarian cancer is the most lethal gynecological cancer mainly due to late diagnosis, easy spreading and rapid development of chemoresistance. Cancer stem cells are considered to be one of the main mechanisms for chemoresistance, as well as metastasis and recurrent disease. To explore the stemness characteristics of ovarian cancer stem cells, we successfully enriched ovarian cancer stem-like cells from an established ovarian cancer cell line (SKOV-I6) and a fresh ovarian tumor-derived cell line (OVS1). These ovarian cancer stem-like cells possess important cancer stemness characteristics including sphere-forming and self-renewing abilities, expressing important ovarian cancer stem cell and epithelial-mesenchymal transition markers, as well as increased drug resistance and potent tumorigenicity. Microarray analysis of OVS1-derived sphere cells revealed increased expression of amphiregulin (AREG) and decreased expression of its conserved regulatory microRNA, miR-34c-5p, when compared with the OVS1 parental cells. Overexpression of AREG and decreased miR-34c-5p expression in SKOV-I6 and OVS1 sphere cells were confirmed by quantitative real-time PCR analysis. Luciferase reporter assay and mutant analysis confirmed that AREG is a direct target of miR-34c-5p. Furthermore, AREG-mediated increase of sphere formation, drug resistance toward docetaxel and carboplatin, as well as tumorigenicity of SKOV-I6 and OVS1 cells could be abrogated by miR-34c-5p. We further demonstrated that miR-34c-5p inhibited ovarian cancer stemness through downregulation of the AREG-EGFR-ERK pathway. Overexpression of AREG was found to be correlated with advanced ovarian cancer stages and poor prognosis. Taken together, our data suggest that AREG promotes ovarian cancer stemness and drug resistance via the AREG-EGFR-ERK pathway and this is inhibited by miR-34c-5p. Targeting AREG, miR-34c-5p could be a potential strategy for anti-cancer-stem cell therapy in ovarian cancer.

Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer.

Existence of humoral immunity has been previously demonstrated in malignant ascitic fluids. However, only a limited number of immunogenic tumor-associated antigens (TAAs) were identified, and few of which are associated with ovarian cancer. Here, we identified salt-inducible kinase 3 (SIK3) as a TAA through screening of a random peptide library in the phage display system. Overexpression of SIK3 markedly promoted cell proliferation, attenuated p21(Waf/Cip1) and p27(Kip) expressions in low-grade OVCAR3 cells, and permitted the cells to grow in mice. Decrease in SIK3 expression in high-grade SK-OV3 cells consistently demonstrated its tumorigenic potency by modulating the protein levels of cell cycle regulators. When the expressions of SIK3 and CA125 were compared in cancer tissues, immunohistochemical (IHC) studies indicated that cytoplasm-localized SIK3 was highly expressed in 55% of the ovarian cancer samples. In contrast, it was rarely detected in adenomyosis, leiomyoma and normal ovary tissues, showing its higher specificity (97%) to CA125 (65%) in ovarian cancer. Moreover, experiments using pharmacological inhibitors to block SIK3-induced p21(Waf/Cip1) expression revealed that activation of c-Src and phosphoinositide-3-kinase were critically required for its biological activity, suggesting that they are the downstream signaling mediators of SIK3. These data were further supported by IHC studies, showing coexpression of c-Src with SIK3 in 85% of the ovarian tumor samples stained positive for SIK3. Collectively, our findings indicate that SIK3 is a novel ovarian TAA. Overexpression of SIK3 promotes G1/S cell cycle progression, bestows survival advantages to cancer cells for growth and correlates the clinicopathological conditions of patients with ovarian cancer.

Whole-body positron emission tomography with 18F-fluorodeoxyglucose is an effective method to detect extra-pelvic recurrence in uterine sarcomas.

PURPOSE OF INVESTIGATION: To assess the clinical use of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the post-therapy surveillance of uterine sarcoma. METHODS: Eight whole-body FDG-PET studies were performed in seven women with previously treated uterine sarcoma. Conventional image studies (computed tomography) and physical examinations were performed for follow-up. All FDG-PET studies were indicated to localize suspected recurrences noted by conventional methods. RESULTS: The per case sensitivity of the FDG-PET studies and CT scans was 85.7% (6/7) and 100% (7/7), respectively (p = 0.174). FDG-PET was able to detect seven extrapelvic metastastic sites below the diaphragm (7/7, sensitivity: 100%), including the liver, spleen, paraaortic lymph node, spine and paracolic gutter, as well as pulmonary lesions in five patients, while the CT scan detected only three lesions (3/7, sensitivity: 42.9%; p = 0.070). FDG-PET detected only four recurrent pelvic lesions (4/6) and CT scan detected six (6/6) recurrent pelvic lesions (66.7% vs 100%, p = 0.455). CONCLUSIONS: The FDG-PET showed a better detection rate than the abdominal CT scan for extrapelvic metastatic lesions and a similar detection rate as well as abdominal CT scan. FDG-PET can serve as a useful detection tool for patients with uterine sarcomas because nearly 80% of recurrence involve an extrapelvic site.

Presumed Stage IA primary epithelial ovarian carcinoma: the role of complete staging surgery.

PURPOSE: Proper staging is warranted in any patient with primary epithelial ovarian carcinoma (PEOC), but sometimes it cannot always be performed. The prognosis of patients with and without complete staging surgery is to be determined. METHODS: We retrospectively evaluated 61 patients with presumed Stage IA PEOC between January 1970 and December 1993. Inclusion criteria were: being referred patients; no ascites; an intact ovarian tumor without extra-spillage or rupture before, during or after operation; conventional regular exploratory laparotomy without urgency; more than a 5-year follow-up, except for recurrent diseases; a detailed pathology review; and no other systemic disease. Tumors of lower malignant potential (LMP) and cystectomy for removing tumor were excluded. Of the 61 patients, 17 patients received a close observation (Group A), and the others (44 patients) received a re-exploratory laparotomy to complete the staging surgery (Group B). RESULTS: The mean follow-up time was 7.4 years, ranging between 5.4 and 11.1 years, in Group A, and 8.1 years, ranging from 5.6 to 12.7 years, in Group B. Two patients (11.8%) in Group A and seven patients (15.9%) in Group B suffered from recurrence. Two patients finally died of disease, and both were in Group B. CONCLUSIONS: Based on the observation in this study that the recurrence rate of the two groups was not statistically different, close follow-up for patients with presumed Stage IA EOC, but without complete surgical staging surgery, might be acceptable when these patients are treated with postoperative adjuvant chemotherapy.

Improved early detection of cervical intraepithelial lesions by combination of conventional Pap smear and speculoscopy.

PURPOSE: To evaluate the efficacy of the addition of speculoscopy to a Pap smear in cervical cancer screening. METHODS: All women were screened using the Pap smear plus speculoscopy (PapSure) and colposcopy in the multicenter trial. The final diagnosis of each patient was based on a histological evaluation of the colposcopic target biopsy. Results were analyzed using a proportional compare test, sensitivity, specificity and predictive value with significant value determined at less than 0.05. RESULTS: Of 1,717 eligible cases, 26 cases had LGSIL and 16 cases had HGSIL. Of the Pap smears, five cases had LSIL and 14 cases had HGSIL. Of the combination of the PapSure, 23 cases had LGSIL and 16 cases had HGSIL. The sensitivity of the Pap smear to that of PapSure was calculated at 45.2% and 92.9%, respectively (p < 0.001). The estimated cost to detect a cervical lesion using PapSure is less than that of the Pap smear. CONCLUSION: The addition of speculoscopy along with a Pap smear screening results in early detection of cervical lesions in comparison to the Pap smear alone. This screening combination is also more cost-effective and requires fewer visits to the clinic in comparison to a Pap smear screening alone.

Placenta accreta diagnosed at 9 weeks' gestation.

The majority of cases of placenta accreta are unanticipated and initially identified intraoperatively. Although color Doppler ultrasound is adequate for the evaluation of placenta accreta in the third trimester, ultrasound diagnosis in the first trimester has never been reported. To our knowledge, this is the first case of placenta accreta detected at 9 weeks' gestation by ultrasound. Placenta accreta with intraplacental lacunae can be identified together with a loss of the hypoechogenic retroplacental myometrial zone. Based on this case, we found that early diagnosis of placenta accreta in the first trimester by ultrasound is possible.

Extramammary Paget's disease found by abnormal vulvar brush sampling.

INTRODUCTION: Doctors are usually reluctant to perform a vulvar biopsy on a patient with non-specific chronic vulvitis--especially because of the rarity of vulvar malignancy in young women--until the lesion is suspected of being malignant. Therefore, most cases of extramammary Paget's disease (EMPD) were originally misdiagnosed as chronic and recurrent vulvar lesions. Late diagnosis of invasive lesions occurring in elderly females have resulted in cases of death. CASE: A 37-year-old patient showed an extended lesion on the vulva and perineum. In addition, abnormal cells were found from a vulvar scrape smear, and a following punch biopsy was used to diagnose and determine the extension of the disease. CONCLUSION: Diagnosis and demarcation of EMPD remain difficult due to the multifocal lesions and subtle nature of the disease. Brush sampling taken from suspicious areas can be a guide for multiple biopsies to demarcate the lesion before major surgery. A brush biopsy is presented as a first-step method to detect vulvar malignancy.

Clinicopathologic factors related to apoptosis in retinoblastoma.

PURPOSE: To investigate the presence of apoptosis in retinoblastoma and its correlation with other pathologic and prognostic factors. METHODS: The pathologic and admission records of 25 patients with a pathologically confirmed diagnosis of retinoblastoma were reviewed. TUNEL (TdT dUTP nick end labeling) staining was used to examine apoptosis in the pathologic slides of these 25 patients. The association between apoptosis and clinicopathologic factors was examined with chi-square, Fisher's exact, and Student's t tests. RESULTS: Of the 25 specimens tested, 11 were TUNEL stain-positive for the presence of apoptotic cells. Apoptosis was found more frequently in younger patients and within rosettes, although these associations were not statistically significant. Apoptosis was not associated with tumor invasion or metastasis. CONCLUSION: Apoptotic cells were found in 11 of 25 retinoblastoma specimens. Apoptosis tends to occur in young patients and be distributed within rosettes.

Establishment and characterization of a cell line, MT-213-VGH, isolated from a mixed müllerian tumor of the uterus.

OBJECTIVE: To establish a cell line from a woman with malignant mixed müllerian tumor of the uterus and to examine the biologic properties of this cell line (MT-213-VGH). STUDY DESIGN: Cells were cloned by the limiting dilution method. Histologic staining of mixed müllerian (mesodermal) tumor (MMMT) cells was performed with May-Grünwald-Giemsa and hematoxylin and eosin stain. After more than 20 passages, cells were used to estimate the population-doubling time and colony-forming efficiency of MMMT cells. The cell line exhibited considerable variation in the degree of sensitivity to diverse chemotherapy drugs in vitro. RESULTS: MMMT cells containing antigens for vimentin and myoglobin were detected, but those for CA-125, carcinoembryonic antigen, cytoskeleton, desmin, epithelial membrane antigen and fibronectin were not found. In addition, MT-213-VGH cells contained a mucinous substance; its chromosome model number is 45. This cell line showed differential sensitivities to chemotherapeutic agents, such as bleomycin, cisplatin, 5-fluorouracil and vinblastine. CONCLUSION: The establishment and availability of the number cell line MT-213-VGH for a malignant mixed müllerian tumor of the uterus should assist in research on new methods of managing this type of gynecologic cancer.

Sonographic features of breast abscesses with emphasis on "hypoechoic rim" sign.

BACKGROUND: There are only limited reports on the ultrasound (US) features of breast abscess. The purpose of this paper is to review the US features of breast abscess with emphasis on "hypoechoic rim" sign which is more commonly seen in chronic abscess. METHODS: In a period of 10 years, 20,998 patients were referred for breast US examinations. Medical records identified 204 patients in whom breast abscess was diagnosed. All patients were examined using high-resolution real-time US scanners. The initial ultrasound reports and hard copy images were all carefully reviewed. The grading of the echogenicity of the abscess was classified from grade 0 to grade 5. The contours of the lesions were described as smooth, macrolobulated, microlobulated, irregular, zigzag, spiculate or indistinct. The wall thickness was measured to document the presence of "hypoechoic rim" which denoted a wall thickness greater than 2 mm. The associated findings and other acoustic phenomena related to the lesion were recorded. RESULTS: One hundred and thirty-six patients (136/204) having specific aspiration and/or biopsy/histopathological results were included in the study. All of the 136 patients showed abnormal US findings (100%). Most lesions showed grade 1 or grade 2 echogenicity (117, 86%). The contour of the abscess was usually smooth (42, 31%), macrolobulated (42, 31%), or irregular (22, 16%). A hypoechoic rim was noticed in 18 lesions (13%). Focal skin thickening was chiefly noticed in 91% of superficial abscesses (39/43) and 17% of intramammary abscesses (14/84). Diffuse skin thickening was exclusively evident in the breasts coexisting with mastitis. Hypoechoic interstitial streaks were not a common finding (7%), occurring in acute abscesses. The other findings included surrounding hypoechoic amorphous tissue (26%), posterior wall enhancement (71%), distal enhancement (60%) and lateral shadows (57%). CONCLUSIONS: US plays an important role in confirmation of the clinical diagnosis of breast abscess and aids significantly in the management of inflammatory breast diseases. Presence of the hypoechoic rim surrounding a fluid space or a central area of low-level echoes (i.e., grade 1 to grade 3) is indicative of a chronic abscess.

Spontaneous expulsion of a uterine submucosal leiomyoma after administration of a gonadotropin-releasing hormone agonist.

A 40-year-old primigravida presented with acute urine retention. Ultrasound examination revealed a large uterine submucosal leiomyoma and GnRH-a was administered. The leiomyoma grew to over twice its original size and protruded through the introitus. After 10 days, it was expelled completely and removed by resectohysteroscopy. The expulsion of the leiomyoma was most likely a result of GnRH-a's flare-up effect.

Clinical, virological, and pathological significance of hepatic bile duct injuries in Chinese patients with chronic hepatitis C.

PURPOSE: Hepatic bile duct injuries are characteristic histological findings in patients with chronic hepatitis C virus (HCV) infection. However, the pathogenesis and clinical significance of this phenomenon remain unclear. The aims of this study were to evaluate the prevalence and clinical significance of hepatic bile duct injuries in Chinese patients with chronic hepatitis C. METHODS: One hundred and seventeen Chinese patients with chronic hepatitis C were enrolled. Clinical, biochemical, immunological (serum autoantibodies and cryoglobulinemia), histological, and virological data (serum HCV RNA titer and HCV genotype) were compared between patients with and without hepatic bile duct injuries. RESULTS: Eighty-three (71%) of the 117 patients with chronic hepatitis C had hepatic bile duct injuries. Patients with hepatic bile duct injuries had a significantly higher frequency of HCV genotype 1b; a higher mean serum globulin level; significantly higher mean scores for histological periportal necro-inflammation, portal inflammation, and fibrosis; and more severe portal lymphoid aggregation/follicles when compared with patients without hepatic bile duct injuries (P < 0.05, all). No significant differences in the presence of serum autoantibodies, cryoglobulinemia, mean serum HCV RNA titer, or response to interferon treatment were noted between the two groups. Multivariate logistic regression analysis showed that HCV genotype 1b infection, portal inflammation, and lymphoid aggregation/follicles were significant independent predictors associated with hepatic bile duct injuries. CONCLUSIONS: The presence of hepatic bile duct injuries in Chinese patients with chronic hepatitis C was significantly correlated with HCV genotype 1b infection, and the patients with these injuries had more severe portal inflammation and formation of lymphoid aggregates/follicles.

Primary epithelial ovarian carcinoma in Taiwanese women.

PURPOSE OF INVESTIGATION: Primary epithelial ovarian carcinoma is common in industrial countries but rare in the Orient. In fact, it is still a rare disease in Taiwan. In this article, we report the general data of Taiwanese patients with primary epithelial ovarian carcinoma. METHODS: In this retrospective study we used univariate and multivariate analysis models to analyze the prognosis of patients with surgically confirmed primary epithelial ovarian carcinoma. One hundred and ninety-four patients from 1990 to 1996 were identified and enrolled in this study. RESULTS: The mean follow-up time was 44.7 months with an interval between 15.1 months and 105.9 months. Univariate analysis showed postmenopausal status, advanced stage, presence of lymph node metastasis, poor differentiation, and suboptimal surgery as risk factors for disease recurrence and subsequent deaths. Multivariate analysis demonstrated stage as the most important factor correlated with recurrent disease (risk ratio: 7.303 and 5.409, respectively), followed by optimal surgery (RR: 2.447), and cellular differentiation (RR: 1.677). CONCLUSIONS: Our data on the Taiwan population were consistent with other reports of different races. Early detection for primary epithelial ovarian cancer is of great importance because stage is still the most important predictor in disease-free survival and disease-related deaths. Application of the most reliable and acceptable methods of screening is our goal in the next century after weighing benefits over costs.

Clinical, virological, immunological, and pathological significance of GB virus C/hepatitis G infection in patients with chronic hepatitis C.

GB virus-C (GBV-C)/hepatitis G virus (HGV), a single-strand RNA virus, has been identified as a transfusion transmissible virus and categorized as a member of the Flaviridiae family. GBV-C/HGV superinfection in patients with chronic hepatitis C is not seen uncommonly, most likely because of the similar transmission routes. This study aimed to investigate the prevalence of GBV-C/HGV infection in 100 Chinese patients with histologically proven chronic hepatitis C, and to clarify the clinical, virological, immunological, and histopathological impact of GBV-C/HGV infection on chronic hepatitis C patients. Serum GBV-C/HGV RNA was positive in 22 (22%) of the 100 chronic hepatitis C patients. There were no significant differences in mean age, gender, and serum liver biochemical tests between GBV-C/HGV infected and non-infected chronic hepatitis C patients. The HCV genotype distribution and mean serum HCV RNA level were not significantly different between patients with and without GBV-C/HGV co-infection. The presence of serum autoantibodies (anti-nuclear antibody and anti-smooth muscle antibody) and cryoglobulinemia showed no significant difference between the two groups. Liver histopathological analysis revealed no significant difference in the grade of periportal, portal, and intralobular necro-inflammation, in the stage of fibrosis/cirrhosis, or in the presence of steatosis and lymphoid aggregation/follicle formation between patients with and without GBV-C/HGV infection. However, a higher degree of bile duct damage was noted in chronic hepatitis C patients co-infected with GBV-C/HGV infection than in those without infection (P=0.036). In conclusion, GBV-C/HGV infection had no apparent influence on the clinical, immunological, or virologic features of patients with chronic hepatitis C. However, the clinical significance of a higher degree of bile duct damage in patients with HCV and GBV-C/HGV co-infection deserves further investigation.

Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C.

Elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C is not uncommonly seen, but the pathogenesis of this phenomenon remains unclear. The aims of this study were to assess the prevalence of elevated serum AFP in patients with chronic hepatitis C and to evaluate the clinical, virologic, and histopathologic significance of this phenomenon. One hundred and fifteen Chinese patients with a histologic diagnosis of chronic hepatitis C were enrolled. None had evidence of hepatocellular carcinoma by image study at enrollment and for at least 2 years' follow-up. Of the 115 patients, 33 (29%) had elevated serum AFP (more than 12 ng/mL). There was a significantly lower mean serum albumin (4.0 +/- 0.1 vs. 4.3 +/- 0.1 gm/dL, p <0.001) and higher mean scores for periportal necroinflammation (3.3 +/- 0.3 vs. 2.3 +/- 0.2, p = 0.007) and fibrosis (2.3 +/- 0.2 vs. 1.1 +/- 0.1, p < 0.001) in patients with elevated serum AFP when compared with patients without elevated serum AFP. Patients with elevated serum AFP had significantly more incidences of genotype 1b infection when compared with patients without elevated serum AFP (77% vs. 51%, p = 0.021). Mean serum hepatitis C virus (HCV) RNA titer showed no significant difference between the two groups. Multivariate logistic regression analysis showed that as serum albumin of less than 4.2 gm/dL, a histology fibrotic score of more than 3, and HCV genotype 1b infection were significantly independent predictors associated with elevated serum AFP. In conclusion, elevated serum AFP levels were significantly correlated with lower serum albumin levels, advanced fibrosis/cirrhosis, and genotype 1b infection in patients with chronic hepatitis C.

Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation.

BACKGROUND AND AIMS: Hepatic steatosis is a histological characteristic in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to evaluate the prevalence of hepatic steatosis in Chinese patients with chronic hepatitis C, and to look for possible correlation with various histopathological changes and to look for possible correlation with various clinical and pathologic variables. METHODS: One hundred and six patients were enrolled, and patients with alcoholism or diabetes mellitus were excluded. Clinical, biochemical and virologic data, including HCV genotype and serum HCV-RNA titer and histological findings, were compared between patients with and without hepatic steatosis. RESULTS: Fifty-five (52%) of the 106 patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis had significantly higher mean serum levels of triglyceride and gamma-glutamyl transpeptidase, higher body mass index, and a higher incidence of obesity compared with patients without hepatic steatosis. No significant differences in serum HCV-RNA titer and HCV genotype or the response to interferon therapy were noted between the two groups. Histological analysis showed patients with hepatic steatosis had a significantly higher mean fibrotic score than patients without hepatic steatosis (1.9 +/- 1.2 vs 1.3 +/- 1.0; P = 0.016). There were no significant differences in the severity of necroinflammation, the presence of lymphoid aggregation/follicle or bile duct damage between the two groups. Multivariate logistic regression analysis showed that independent predictors associated with hepatic steatosis were obesity or a histology fibrotic score of > or = 2. CONCLUSION: It was found that 52% of Chinese patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis were more frequently obese and had more severe hepatic fibrosis.

Comparison of clinical, virologic and pathologic features in patients with acute hepatitis B and C.

BACKGROUND AND AIMS: The clinical outcomes of adult-acquired acute infection of hepatitis C virus (HCV) and hepatitis B virus (HBV) are quite different. In order to compare the clinical, biochemical, virologic and pathologic pictures in these two groups of patients, we enrolled 22 adult patients with acute hepatitis C and 16 adult patients with acute hepatitis B, on whom liver biopsies were performed within 3 months of acute onset of the illness. RESULTS: The results showed that a significantly younger age, a higher ratio of the clinical symptoms of jaundice, nausea, vomiting, and poor appetite, a higher mean serum level of alanine transaminase, aspartate transaminase, and total bilirubin were present in patients with acute hepatitis B patients than in those with acute hepatitis C (P < 0.05). There was a significantly higher degree of periportal inflammation and total necro-inflammatory activity in the acute hepatitis B patients (P = 0.002 and 0.049, respectively). Fifteen (68.2%) of the 22 patients with acute hepatitis C had detectable serum HCV-RNA, but only two (14.3%) of the 14 tested patients with acute hepatitis B had detectable serum HBV-DNA, detected by using the branched DNA signal amplification assay. Eighteen (82%) of the 22 acute hepatitis C patients and none of the 16 acute hepatitis B patients progressed into a chronic hepatitis stage (P < 0.001). CONCLUSION: The manifestations of mild clinical symptoms, lower mean serum transaminases and bilirubin levels, a lesser degree of histological periportal necroinflammation, and more patients with a high circulatory viral load among the acute hepatitis C patients, may lead to more of that group developing chronicity than patients with acute hepatitis B.

p53 mutation is infrequent in clear cell carcinoma of the ovary.

OBJECTIVE: p53 gene alteration has been extensively studied in epithelial ovarian cancer. However, its occurrence in clear cell carcinoma, an infrequent histologic subtype of epithelial ovarian cancer, is rarely reported. The aim of this study is to determine the status of p53 gene alteration in this distinct type of ovarian carcinoma. METHODS: Paraffin blocks of tumors from 38 patients with primary or recurrent ovarian clear cell carcinoma were studied for p53 alteration. All these tumors were subjected to immunohistochemical and molecular analysis. Two monoclonal antibodies (DO-7 and PAb 1801) were used for immunohistochemical staining. Genomic DNAs extracted from paraffin blocks of the 38 tumors were subscribed for a nested polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) analysis. Tumors showing band shift on SSCP were further prepared for DNA sequencing to determine the site of mutation. RESULTS: Overexpression of p53 was observed in only one stage III clear cell carcinoma. However, focal positive p53 staining was noted in another five tumors. Of the six tumors showing positive immunohistochemistry, p53 alterations were noted in four tumors. Three tumors revealed a missense point mutation: two were in exon 7 (TCT(227) --> TTT and GGC(245) --> AGC) and one was in exon 5 (CGC(156) --> CAC). Another tumor revealed a 12-bp deletion in two possible ways: it might involve the last four codons at the 3' end of exon 4 (nucleotides 12,288-12,299) or it might cross over the splice junction between exon 4 and intron 4 (nucleotides 12,290-12,301). The former would result in a predicted protein product of 389 amino acids whereas the latter would cause a frameshift in the gene sequence and would result in a truncated protein. CONCLUSION: Mutations in p53 appear to be much less frequent in clear cell carcinoma than in other histologic types of epithelial ovarian cancer. We suggest that p53 alterations may not play an important role in the development of clear cell carcinoma.

Intraperitoneal cisplatin-based chemotherapy vs. intravenous cisplatin-based chemotherapy for stage III optimally cytoreduced epithelial ovarian cancer.

OBJECTIVE: To compare the survival between intraperitoneal cisplatin-based chemotherapy (IPCT) and intravenous cisplatin-based chemotherapy (IVCT) in stage III epithelial ovarian cancer with minimal residual disease (<1 cm) after primary debulking surgery. METHOD: One hundred and thirty-two patients with stage III epithelial ovarian cancer after optimal primary debulking surgery with minimal residual disease between April 1990 and March 1995 were entered into a randomized clinical trial in which IPCT or IVCT was administered at 3-week intervals. Patients in the IPCT arm received cisplatin-based (100 mg/m(2)) intraperitoneal chemotherapy. Patients in the IVCT arm received cisplatin-based (50 mg/m(2)) intravenous chemotherapy. The tumor response was assessed every 3 months. The hematological toxicity using the South West Oncology Group (SWOG) toxicity criteria was assessed. Catheter complications associated with intraperitoneal chemotherapy were also analyzed. RESULT: The estimated median survival in the IPCT group was 43 months (95% confidence interval, 34-54) and IVCT group was 48 months (95% confidence interval, 37-59). The hazard ratio of death was not statistically significant between IPCT and IVCT (hazard ratio, 1.13; 95% CI, 0.69-1.86; P=0.317). The frequencies of hematological toxic effects were significantly lower in the IPCT group than in the IVCT group. CONCLUSION: Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery.