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Adult granulosa cell tumors (AGCTs) are rare ovarian tumors with generally good prognosis after surgical resection; however, they do have recurrence potential. Therapeutic and management options for recurrences are currently limited, and the need for expanded adjuvant therapies is increasingly recognized. Anti-hormonal therapy is being explored as an option, which relies on the detection and assessment of hormone receptor expression (androgen, estrogen, and progesterone receptors) as a biomarker and therapeutic target. Our study identifies several clinicopathologic characteristics with significant associations for recurrence of AGCT, which were younger age, higher stage, and larger tumor size. Our study also demonstrates that androgen receptor (AR) expression may be utilized as a potential biomarker for hormonal therapy and that detection of AR expression in AGCT by immunohistochemistry (IHC) varies depending on the antibody clone used for testing. AR was detected in 95% of samples tested with antibodies derived from clone AR27. This detection rate is much higher than previously reported.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

High-grade serous carcinoma, accounts for up to 70% of all ovarian cases. Furin, a proprotein convertase, is highly expressed in high-grade serous carcinoma of ovarian cancer patients, and its expression is even higher in tumor omentum than in normal omentum, the preferred site of ovarian cancer metastasis. The proteolytic actions of this cellular endoprotease help the maturation of several important precursors of protein substrates and its levels increase the risk of several cancer. We show that furin activates the IGF1R/STAT3 signaling axis in ovarian cancer cells. Conversely, furin knockdown downregulated IGF1R-β and p-STAT3 (Tyr705) expression. Further, silencing furin reduced tumor cell migration and invasion in vitro and tumor growth and metastasis in vivo. Collectively, our findings show that furin can be an effective therapeutic target for ovarian cancer prevention or treatment.

Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137was further validated in additional endometrial primary tumors. Hypermethylation of miR-137was found in both endometrioid and serous endometrial cancer (P< 0.01), and it led to the loss of miR-137expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137grew more slowly and formed smaller tumors (P< 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137were less proliferative (P< 0.05), partly due to inhibition of EZH2 and LSD1 expression (P< 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137targets EZH2 and LSD1. These results suggest that miR-137is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated.

Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137was further validated in additional endometrial primary tumors. Hypermethylation of miR-137was found in both endometrioid and serous endometrial cancer (P< 0.01), and it led to the loss of miR-137expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137grew more slowly and formed smaller tumors (P< 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137were less proliferative (P< 0.05), partly due to inhibition of EZH2 and LSD1 expression (P< 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137targets EZH2 and LSD1. These results suggest that miR-137is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated. The authors aimed to identify epigenetic aberrations involving microRNAs (miRNAs) whose genes become hypermethylated in endometrial primary tumors. They found that that miR-137 is hypermethylated and loses expression in human endometrial tumors. Increasing miR-137 expression suppresses endometrial cancer cell growth in vitro and xenograft tumor growth in nude mice, partly because miR-137 targets EZH2, which participates in histone methylation, and LSD1, a histone demethylation enzyme.

MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer-derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR-34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16(+) and HPV18(+) cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G(0)/G(1) phase cells. Ectopic expression of miR-34a in HPV18(+) HeLa cells and HPV(-) HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer.

Promising molecular techniques may allow for testing of novel and complex hypotheses such as defining gene expression profiles in specific cells, tumors, or their microenvironments. For most large cancer epidemiologic and population-based studies, however, application of such promising techniques may not be possible owing to constraints of specimen preservation from paraffin-embedded tissues. Alternative methods would ideally preserve tissue morphology and not degrade DNA or RNA. We conducted a comparison of snap-freezing (freezing with liquid nitrogen), ethanol-fixation with low melt polyester wax embedding, and RNAlater-preservation techniques to determine which method was optimal for subsequent assessment of gene expression changes in cervical cancer. From each of 15 women with cancer and 30 without, we procured 3 pieces of cervical tissue and compared snap-freezing, ethanol-fixation, and RNAlater-preservation techniques. Despite slight loss in morphologic quality from snap-frozen cervix tissues, RNA quality was equivalent to or better than RNAlater-preserved tissues and significantly exceeded that from ethanol-fixedpolyester wax embedded tissue. In conclusion, despite the moderate logistical constraints in set-up that required either liquid nitrogen or dry ice on-site for snap-freezing tissue, the ease of downstream processing and consistent high quality RNA made it preferable to the other 2 methods.

The study was undertaken to determine the safety and efficacy of the monoclonal, antivascular endothelial growth factor antibody bevacizumab in combination with cytotoxic chemotherapy for women with platinum‐refractory ovarian cancer.A retrospective analysis of women who received bevacizumab in combination with a cytotoxic agent was performed. Response was determined by measurable disease or assessment of serial cancer antigen (CA) 125 measurements.Twenty‐three patients were identified. The patients were heavily pretreated with a median of 7 prior regimens including a median of 3 prior platinum regimens. The combination regimen included cyclophosphamide in 15 (65%), 5‐fluorouracil (5‐FU) in 6 (26%), docetaxel in 1 (4%), and gemcitibine/liposomal doxorubicin in 1 (4%). Two (9%) women developed chylous ascites during treatment. CTC Grade 4–5 toxicities occurred in 4 (17%) subjects. Gastrointestinal perforation occurred in 2 (9%) patients. Measurable disease was present in 22. The overall best response rate was 35% and all 8 were partial responses (PRs). Stable disease was found in a further 10 (44%) women, whereas progressive disease was observed in 5 (22%). The median time to progression was 5.6 months in patients with a PR and 2.3 months in subjects with stable disease. Three (13%) women experienced a progression‐free interval (PFI) of >6 months. At last follow‐up, 8 (35%) subjects had died of disease, whereas 15 (65%) women were alive with disease.Combination bevacizumab therapy demonstrated activity in heavily pretreated women with ovarian cancer. Gastrointestinal perforations were identified in 9%. Despite the toxicity of the regimen, prospective studies, particularly in less heavily pretreated patients, are warranted. Cancer 2006. © 2006 American Cancer Society.

Increasing evidence has documented the value of positron emission tomography (PET) in oncology, but only limited data are available comparing PET findings with the pathologic status of regional lymph nodes in patients with cervical carcinoma. The objective of this study was to determine the sensitivity and specificity of PET in detecting lymph node metastasis in women with early‐stage cervical carcinoma.The authors performed a retrospective review of all patients with Stage IA–IIA cervical carcinoma who underwent PET before surgery from 1999 to 2004. The status of the regional lymph nodes was correlated with lymph node pathology.Fifty‐nine patients were identified. Pelvic lymph node metastases were present in 32% of the patients and were detected by PET with a sensitivity of 53%, a specificity of 90%, a positive predictive value (PPV) of 71%, and a negative predictive value (NPV) of 80%. Paraaortic lymph node disease was present in 9% of patients and was detected by PET with a sensitivity of 25%, a specificity 98%, a PPV of 50%, and an NPV of 93%. The mean size of the tumor deposits was larger in the PET‐positive pelvic nodes (15.2 mm; range, 2–35 mm) than in the PET‐negative lymph nodes (7.3 mm; range, 0.3–20 mm; P = 0.002). Computed tomography (CT) scans were obtained before surgery in 42 patients. The combined sensitivity of PET and CT in these patients was 75%. PET alone detected 9 (36%) of the positive lymph node groups, whereas CT alone detected 3 (12%) of the positive lymph node groups. Neither PET nor CT detected the positive lymph node groups in 8 patients (32%).Pathologic validation of PET imaging demonstrated a low sensitivity and a high specificity for PET in patients with early‐stage cervical carcinoma. Cancer 2005. © 2005 American Cancer Society.

Advanced age often is considered a poor prognostic factor for cervical carcinoma. The authors investigated the patterns of care and treatment outcomes of elderly women with cervical carcinoma.A hospital‐based tumor registry was used to identify patients with invasive cervical carcinoma who were treated between 1986 and 2003. Patients were divided into 2 cohorts: women age < 70 years and women age ≥ 70 years. Survival was examined using the Kaplan–Meier method. Single and multivariate Cox proportional hazards modeling was used to estimate hazard ratios with 95% confidence intervals (95% CI).In total, 1582 patients were identified, including 1385 patients age < 70 years and 197 patients age ≥ 70 years. The elderly patients presented with more advanced stage tumors at diagnosis (P < 0.0001) and were more likely to have nonsquamous neoplasms (P = 0.002). A marked difference in treatment was noted for the elderly cohort, even after stratifying by disease stage. Only 16% of the older patients underwent surgical treatment compared with 54% of the younger patients (P < 0.0001). Elderly women were 9 times more likely to receive no treatment (P < 0.0001). In a multivariate model of known prognostic factors, the hazard ratio for death from any cause in women age > 70 years was 2.1 (95% CI, 1.5–3.0). The hazard ratio for death from cervical carcinoma in the elderly women was 1.6 (95% CI, 1.1–2.5).Age is an important factor in the allocation of treatment and survival for patients with cervical carcinoma. Elderly women with cervical carcinoma are more likely to receive primary radiotherapy, to forego treatment, and to die from their disease. Cancer 2005. © 2004 American Cancer Society.

We report a unique tumor of the fallopian tube that was an incidental finding in a 60-year-old woman. The tumor was characterized by nests of spindle cells embedded in a partially ossified, hyalinized stroma, that also contained amyloid and basement membrane-like material. The histologic appearance of the tumor cells suggested an epithelial nature, but no immunohistochemical or ultrastructural evidence of such was found. The circumscription of the tumor and its lack of mitotic activity and cytologic atypia suggest a benign nature, but the histogenesis and appropriate classification of the tumor remain unclear.

ABSTRACTHuman papillomaviruses (HPVs) are important in the development of human cancers, including cervical and oral tumors. However, most existing methods for HPV typing cannot routinely distinguish among the more than 100 distinct types of HPV or the natural HPV intratypic variants that have also been documented. To address this problem, we developed a novel method, general primer-denaturing high-performance liquid chromatography (GP-dHPLC), for the detection and typing of genital HPV using an automated 96-well plate format. GP-dHPLC uses general primer PCR (GP-PCR) to amplify the viral DNA and then analyzes the GP-PCR products by denaturing high-performance liquid chromatography (dHPLC). A number of different primer pairs with homology to most known genital HPV types were tested, and the L1C1-L1C2M pair specific for the L1 region of the viral genome was chosen. A set of HPV standard control patterns, consisting of those for HPV types 16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59, 6, and 11, was established for genital HPV typing. One hundred eighty-six frozen and formalin-fixed cervical cancer tissue samples were analyzed for the presence of HPV and the HPV type by this method, and 95.8% of them were found to contain HPV DNA. GP-dHPLC accurately discriminated among HPV variants that differed by as little as one nucleotide. Several new variants of HPV types 16, 18, 39, 45, 52, and 59 were identified. Moreover, multiple HPV infections were detected in 26.6% of the samples. Our results indicate that HPV typing by GP-dHPLC permits discrimination of common genital HPV types, detection of multiple HPV infections, and identification of HPV variants in clinical samples.

Objectives: The Gynecologic Oncology Group performed a randomized phase II study to determine the antitumor activity and toxicity of two different schedules of administration of bryostatin-1 in patients with persistent or recurrent squamous cell carcinoma of the cervix. Methods: Eligible patients were randomized to receive either bryostatin-1 25 μg/m2as a 1-h infusion weekly for 3 weeks followed by a 1-week rest (Regimen I) or bryostatin-1 120 μg/m2as a 72-h continuous infusion every 2 weeks (Regimen II). Results: A total of 70 patients were enrolled on this study. There were 32 eligible patients on Regimen I and 33 eligible patients on Regimen II; all but 4 had had prior chemotherapy. There were two partial responses (one on each treatment arm) among the 65 eligible patients (response rates = 3.1 and 3.0%, respectively). Ten patients on each regimen had stable disease. The most common adverse event was myalgia; 8 of 32 patients (25%) on Regimen I and 16 of 33 patients (48%) on Regimen II had any grade of myalgia. There was no significant myelosuppression on either treatment arm. Conclusions: Both of these schedules and doses of bryostatin-1 are inactive as single agents in the second-line treatment of squamous cell carcinoma of the cervix.

Pegylated liposomal doxorubicin (PEG-LD) and docetaxel have single-agent activity in several malignancies. The authors conducted a Phase I trial to evaluate the maximum tolerated dose (MTD), toxicities, and effect of dose sequencing of this combination in patients with advanced malignancies. Twenty-two patients were enrolled in this two-arm, accelerated, dose escalation trial. Both drugs were administered on Days 1 and 15 of a 28 day cycle. In Arm A, dose escalation proceeded from a sequence and starting dose of 15 mg/m² PEG-LD and 30 mg/m² docetaxel. In Arm B, dose escalation proceeded from a sequence and starting dose of 30 mg/m² docetaxel and 15 mg/m²PEG-LD. In both arms, the dose of each drug was increased alternately by 5 mg/m² at each dose level. The MTD for Arm A was 20 mg/m² PEG-LD and 40 mg/m² docetaxel, both of which were administered on Days 1 and 15 of a 28-day cycle. The MTD for Arm B was 35 mg/m² docetaxel and 20 mg/m² PEG-LD, both of which were administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicities were Grade 3 (according to the National Cancer Institute Common Toxicity Criteria) skin toxicity and thrombocytopenia. One partial response was observed and stable disease was documented for three patients. The recommended sequence and dose is 20 mg/m² PEG-LD followed by 40 mg/m² docetaxel on Days 1 and 15 of a 28-day cycle in Phase II trials for patients with breast and ovarian carcinoma to establish the efficacy of this well tolerated regimen. Cancer 2003;98:610–7. © 2003 American Cancer Society. DOI 10.1002/cncr.11547

Loss of DNA mismatch repair occurs in a variety of malignancies and is associated with genome-wide instability of microsatellite repeats, a molecular phenotype referred to as microsatellite instability (MSI). MSI is a consistent feature of colorectal and endometrial tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC). Sporadic colorectal and endometrial cancers that exhibit MSI frequently have methylation of the MLH1 promoter. We undertook a detailed family and medical history study to compare family cancer risk for women with MSI-positive and -negative endometrial cancers. The MLH1 promoter methylation status was determined for all cancers. Family histories were developed for 80 probands (40 with MSI-positive and 40 with MSI-negative tumors). The numbers of reported cancers in first- and second-degree relatives of the 2 groups were similar. There was a modest increase in familial cancer clustering for MSI-positive probands. When MSI-positive tumors were subclassified according to MLH1 promoter methylation, a clear association between methylation status and familial cancer risk was evident. Women with MSI-positive endometrial cancers in which the MLH1 promoter was unmethylated had a 7-fold relative risk (RR) of demonstrating familial clustering of cancers [RR 7.07 (95% confidence interval 2.29–21.81)]. The women with MSI-positive, MLH1-unmethylated tumors were significantly younger than the rest of the study population (56.1 years vs. 65.4, p ≤ 0.01). Age of onset and tumor MSI not associated with MLH1 promoter methylation may point to women with a genetic susceptibility to malignancies. © 2002 Wiley-Liss, Inc.

Surgery is curative for the majority of patients with endometrial carcinoma: Consequently, the use of adjuvant therapy has been controversial. More effective methods to identify patients who are at risk for recurrence and who would benefit from adjuvant therapy are needed. The objective of this study was to investigate the prognostic significance of ribosomal DNA (rDNA) methylation in patients with endometrial carcinoma. rDNA methylation was assessed in 215 endometrial tumors by Southern blot analysis of HpaII-digested DNA using a probe corresponding to the 5.8 and 28S ribosomal subunits. Tumor rDNA methylation status was correlated with patient outcome. The majority of tumors demonstrated high levels of rDNA methylation (rDNA-high; 74%). Both disease free survival and overall survival were significantly worse for patients with low-level rDNA methylation (rDNA-low; P &lt; 0.0001). African-American patients were more likely to have rDNA-low tumors than Caucasian patients (P = 0.002). Among the subpopulation of patients with endometrial carcinoma for whom the use of adjuvant therapy is most controversial (148 women with Stage I–II endometrioid tumors), survival was significantly worse for the patients with rDNA-low tumors (P &lt; 0.0001); and, using multivariate analyses, tumor rDNA level was the only significant prognostic factor for both disease free survival and overall survival (hazard ratios, 11.0 and 26.3, respectively; P &lt; 0.01 for both). rDNA methylation is an independent prognostic indicator for patients with endometrial carcinoma that may serve to identify women with early-stage disease at who are at high risk for recurrence. Racial differences in DNA methylation may explain the historically observed disparity in survival between African-American patients and Caucasian patients. Cancer 2002;94:2941–52. © 2002 American Cancer Society. DOI 10.1002/cncr.10559

Thirty women who had prophylactic oophorectomy (PO) and thirty women undergoing ovarian cancer surveillance (OCS) completed a one-time in-depth telephone interview exploring information gathering and decision-making processes. There were close similarities between groups, including age, race, marital status, education, menopausal status, number undergoing genetic testing for BRCA mutations, and number of prophylactic mastectomies. The majority of participants indicated overall satisfaction with their final decision. However, many described the information gathering process as frustrating and anxiety provoking. Participants in both groups expressed a need to process medical information within the context of individual psychosocial needs and personal perceptions and experiences. There were recurrent themes with regard to informational and psychosocial needs and personal perceptions and experiences that impacted decision-making process for these women. The present paper is a companion paper to Swisher et al.(J Repr Med 2001, 46:87–94) with the focus of this paper to illustrate the medical informational processing needs identified by this group of women.

Objective.We set out to determine the factors that predict subcutaneous implanted central venous port function. Specifically, we sought to determine whether the location of the catheter tip is correlated with port failure.

The purpose of this study was to compare the clinical characteristics of endometrial carcinomas with and without microsatellite instability (MSI). The authors prospectively acquired DNA from patients with endometrial carcinomas at Washington University Medical Center. Tumors were assigned MSI (+) status when two or more of five microsatellite repeat markers revealed novel bands in tumor DNA not present in the corresponding normal DNA. Clinical characteristics and survival data of patients with and without MSI were abstracted from patient charts. Statistical significance was calculated with the chi-square test, and survival was assessed with Kaplan–Meier methods. The authors found 65 of 70 (93%) patients with MSI (+) tumors to be of white race, whereas only 124 of 159 (78%) patients with MSI (−) tumors were white (P = 0.012). Advanced disease (International Federation of Gynecology and Obstetrics Stage III–IV) was observed in 9 of 70 (13%) MSI (+) patients and 44 of 159 (28%) MSI (−) patients (P = 0.017). In addition, aggressive histologic subtypes were observed less frequently in MSI (+) tumors (6/70 [8%]) than in MSI (−) tumors (30 of 159 [19%]) (P = 0.034). Race and stage were shown by multivariate analysis to be different in MSI (+) and MSI (−) patients. Recurrence and overall survival were similar in the two groups. Patients with MSI (+) tumors were more likely to be of white race and to present with early stage disease. Further investigation is needed to explain why patients with MSI (+) tumors have similar survival to patients with MSI (−) tumors, despite presenting at earlier stages, being of white race, and being less likely to be associated with virulent histologic subtypes. Cancer 2000;89:1758–64. © 2000 American Cancer Society.

Objective. PTEN,a tumor suppressor gene shown to be frequently mutated in endometrial cancers, has been suggested to be a target of microsatellite instability (MSI)-driven mutagenesis. We set out to investigate the relationship between MSI and PTENmutation in a large series of primary endometrial carcinomas.

Family history plays an important role in breast, ovarian, and colorectal cancers. The increasing availability of genetic testing has forced women with these malignancies and their physicians to confront new questions regarding screening and prevention. This review highlights the screening for and prevention of breast, ovarian, and colorectal cancer in women at risk for malignancy.

Objective.We set out to determine whether hereditary nonpolyposis colorectal cancer (HNPCC) was responsible for cancer susceptibility in a family with gynecologic malignancies in three consecutive generations.

Purpose.A multicenter Phase II trial was conducted to evaluate the activity and toxicity of gemcitabine in patients with previously treated squamous cell carcinoma of the uterine cervix.

Objective: The role of human leukocyte antigen (HLA) DQB1 alleles and human papillomavirus (HPV) as contributing factors to invasive cervical cancer was investigated. To overcome problems of misleading causal inferences common in traditional case-control studies, a family-based test, the transmission/disequilibrium test, was used.

Objective: To estimate the morbidity, adequacy of surgery, and survival of obese women undergoing radical hysterectomy and pelvic lymphadenectomy.

Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3′ untranslated region (3′UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYCmRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.

The correlation between tumor microsatellite instability (MSI) and the accumulation of mutations in KRAS2 and TP53 is uncertain. The authors evaluated the TP53 and KRAS2 genes for mutations in sporadic endometrial carcinomas with microsatellite instability (MSI) and matched MSI negative controls to determine whether defective DNA mismatch repair impacts the patterns of mutations in two genes known to be involved in endometrial tumorigenesis. Twenty-five MSI positive endometrial tumors were matched for prognostic factors with 25 MSI negative tumors. Mutations in codon 12 and 13 of KRAS2 were assessed using a polymerase chain reaction (PCR) restriction assay. Mutations in codon 61 of KRAS2 and exons 5–8 of TP53 were evaluated using PCR amplification and single strand conformation variant (SSCV) analysis. All variants were subjected to direct DNA sequencing. KRAS2 and TP53 mutations were identified with equal frequency in the MSI positive and MSI negative groups. For TP53, the authors identified 5 mutations (20%) in the MSI positive specimens compared with 8 (32%) in the MSI negative group. For KRAS2, there were identified 8 mutations (32%) in the MSI positive specimens compared with 7 (28%) in the MSI negative tumors. The mutational spectra evident from sequence analysis of TP53 and KRAS2 variants were similar between MSI negative and MSI positive tumors. MSI negative tumors were more likely to have mutations in both KRAS2 and TP53 than MSI positive tumors, which were rarely mutant in both genes (P = 0.046). Although the overall frequency of mutations in TP53 and KRAS2 is similar, MSI positive tumors are less likely to have mutations in both genes than MSI negative sporadic endometrial carcinomas. MSI positive and MSI negative endometrial carcinomas may arise through distinct genetic pathways. Cancer 1999;85:119–26. © 1999 American Cancer Society.

Objective.Approximately 20% of endometrial tumors have a defect in DNA mismatch repair and exhibit microsatellite instability (MSI). We assessed the role of the PMS2 DNA mismatch repair gene in MSI-positive sporadic endometrial tumors.

Objective:To clarify the origin of defective mismatch repair (MMR) in sporadic endometrial cancers with microsatellite instability (MSI), a thorough mutation analysis was performed on the human mismatch repair geneMSH3.Methods:Twenty-eight MSI-positive endometrial cancers were investigated for mutations in the human mismatch repair geneMSH-3 using single-strand conformation variant (SSCV) analysis of all 24 exons. All variants were sequenced. Loss of heterozygosity was investigated at allMSH3 polymorphisms discovered. A subset of tumors were investigated for methylation of the 5′ promoter region ofMSH3 using Southern blot hybridization.Results:An identical single-base deletion (ΔA) predicted to result in a truncated protein was discovered in six tumors (21.4%). This deletion occurs in a string of eight consecutive adenosine residues (A8). Because simple repeat sequences are unstable in cells with defective MMR, the observed mutation may be an effect, rather than a cause, of MSI. Evidence of inactivation of the secondMSH3 allele in tumors with the ΔA mutation would strongly support a causal role for theseMSH3 mutations. However, there was no evidence of a second mutation, loss of sequences, or methylation of the promoter region in any of the tumors with the ΔA mutation.Conclusion:Although the ΔA mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR.

Objective: To clarify the origin of defective mismatch repair (MMR) in sporadic endometrial cancers with microsatellite instability (MSI), a thorough mutation analysis was performed on the human mismatch repair gene MSH3. Methods: Twenty-eight MSI-positive endometrial cancers were investigated for mutations in the human mismatch repair gene MSH-3using single-strand conformation variant (SSCV) analysis of all 24 exons. All variants were sequenced. Loss of heterozygosity was investigated at all MSH3polymorphisms discovered. A subset of tumors were investigated for methylation of the 5' promoter region of MSH3using Southern blot hybridization. Results: An identical single-base deletion (?A) predicted to result in a truncated protein was discovered in six tumors (21.4%). This deletion occurs in a string of eight consecutive adenosine residues (A8). Because simple repeat sequences are unstable in cells with defective MMR, the observed mutation may be an effect, rather than a cause, of MSI. Evidence of inactivation of the second MSH3allele in tumors with the ?A mutation would strongly support a causal role for these MSH3mutations. However, there was no evidence of a second mutation, loss of sequences, or methylation of the promoter region in any of the tumors with the ?A mutation. Conclusion: Although the ?A mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR.

The propensity of ovarian cancer to recur—even after initial chemotherapeutic responses—is a problem that has been given a great deal of attention during the past year in the literature dealing with the treatment of ovarian cancer. Most of the articles address techniques to improve the percent of initial and secondary treatment responses. Several studies have described cytoreductive techniques to decrease the remaining tumor size for improved chemotherapeutic response. Cross-resistance between platinum analogues has been reconfirmed. However, improved secondary responses were seen when repeat treatment with platinum agents were preceded by a longer interval from initial platinum agent therapy. Radiation therapy has been shown to offer little solution to recurrent disease except possibly in a select group of patients with microscopic disease at second-look laparotomy. Reports on the use of carboplatin continue to demonstrate good initial responses, with decreased toxicity compared with cisplatin. Granisetron has been shown to significantly decrease the nausea and vomiting caused by emetogenic chemotherapy like cisplatin.

The aim of this study was to evaluate the diagnostic potential, treatment efficacy, specimen adequacy, and acute complication rate associated with electrosurgical excision procedure (EEP) of the cervix for the management of cervical intraepithelial neoplasia (CIN). Analysis was performed retrospectively on 153 consecutive patients who underwent EEP under colposcopic guidance. Patients with negative endocervical curettage (ECC), adequate colposcopy, and biopsy-proven CIN were considered candidates for therapeutic EEP, whereas patients with a positive ECC, inadequate colposcopy, or cytology two or more grades discordant from the biopsy results underwent diagnostic EEP. Histopathologic specimens were graded as adequate, suboptimal, or inadequate. Diagnostic EEP was performed in 85 cases, and the remaining 68 procedures were performed primarily for treatment. Specimens were graded as adequate in 83%, suboptimal in 13%, and inadequate in 4% of the diagnostic EEP's. Specimen adequacy correlated most strongly with operator experience (P< 0.05). Four patients were found to have microinvasive or invasive cervical carcinoma. Complications occurred in 7% of the EEPs performed. Most consisted of immediate or delayed hemorrhage. In conclusion, EEP is a safe, well-tolerated procedure which is acceptable as both a therapeutic and diagnostic tool in the management of CIN when performed by an experienced operator. We recommend that initial EEP procedures should be performed for therapeutic indications, since adequacy of EEP specimens correlated with the level of operator experience.

Frequent loss of chromosome 10q sequences in endometrial cancers suggests the involvement of a tumorsuppressor gene. Previous loss-of-heterozygosity (LOH)studies have pointed to the 10q25–q26 region as the likely site of a tumor suppressor involved in endometrial tumorigenesis (S. L. Peifferet al.,1995,Cancer Res.55: 1922–1926; S. Nagaseet al.,1996,Br. J. Cancer74: 1979–1983; S. Nagaseet al.,1997,Cancer Res.57: 1630–1633). In an attempt to define further the localization of a tumor suppressor gene at 10q25, we screened a panel of 123 endometrioid adenocarcinomas for loss of heterozygosity of 10q25.3 sequences. Forty-three (35%) revealed LOH at one or more loci. The observed patterns of allelic loss define a minimum consensus region of deletion between D10S221 and D10S610. A sequence-ready bacterial clone contig and a long-range restriction map for a 1-Mb interval spanning the deletion region were developed as the first step in experiments directed toward the discovery the 10q25 tumor suppressor.

Objective: The familial clustering of ovarian, breast, endometrial, colon, and prostate cancer was compared in first-degree relatives of probands with invasive and borderline ovarian cancer to determine coaggregation.

Objective:The purpose of this study was to define the response rate and toxicity of topotecan in patients with ovarian cancer resistant to first-line therapy.

The familial clustering of ovarian, breast, endometrial, colon, and prostate cancer was compared in firstdegree relatives of probands with invasive and borderline ovarian cancer to determine coaggregation.

Ultrasonic surgical aspiration is a useful technique for safe and accurate tissue removal. This study was conducted to evaluate its role in noninvasive vulvar disease. From December 1988 to March 1990, 27 patients underwent ultrasonic surgery; nine patients had vulvar intraepithelial neoplasia (VIN) and 18 had condylomata acuminata. All surgical procedures were done under general anesthesia, with two patients requiring hospitalization for perineal care and pain control after extensive vulvar surgery. Recurrent or persistent disease occurred in four patients with condylomata acuminata and in two with VIN, with a mean follow-up of 50 weeks. Reepithelialization was completed within 5 weeks and no patients developed vulvar scarring. Adequate samples for histopathologic review were obtained in 26 patients. Identical histologic grading occurred in all 13 patients who had preoperative vulvar biopsies and an adequate aspiration specimen. Ultrasonic surgery permits precise and rapid removal of epithelial lesions with rapid healing, minimal patient discomfort, excellent cosmetic results, and histopathologic documentation.

We performed a multicentered, placebo-controlled, randomized, crossover study comparing the efficacy of 0.5% and 1.0% apraclonidine hydrochloride in 15 normal volunteers and 17 subjects with increased intraocular pressure. Apraclonidine 1% produced a maximum 30.4% ± 14.0% (4.7 ± 2.4 mm Hg) decrease in mean intraocular pressure in normal eyes and a 31.3% ± 16.5% (7.6 ± 4.2 mm Hg) decrease in eyes with increased pressure. Apraclonidine 0.5% produced a maximum 25.8% ± 9.7% (4.0 ± 1.7 mm Hg) decrease in mean intraocular pressure in normal eyes and a 27.4% ± 16.0% (6.8 ± 4.5 mm Hg) decrease in eyes with increased pressure. There was no statistically significant difference in mean percent intraocular pressure lowering effect between the 0.5% and 1.0% apraclonidine concentrations. Most subjects treated with apraclonidine had a ≥20% reduction in intraocular pressure from baseline. Twelve hours after instillation of apraclonidine, nine of the normal volunteers had an intraocular pressure of 10 mm Hg or less. Apraclonidine produced the same percent intraocular pressure decrease regardless of the initial level of intraocular pressure.

Proximal constriction (retinal arteries narrower near the disk than further down the stream in the retina) was present in 96 of 226 eyes (42%) with classic glaucoma or normal-tension glaucoma, but it was present in only 11 of 206 eyes (5%) that were normal, had ocular hypertension, or had retinal disease not affecting the optic nerve. In cases of glaucoma with proximal constriction over only part of the disk circumference, its location corresponded to the sector with the greatest cupping in 60 of 66 cases (91%) and likewise corresponded to the sector in which the peripapillary zone of absent retinal pigment epithelium was widest in 48 of 55 cases (87%). Proximal constriction was also present in 16 of 45 eyes (36%) with nonischemic types of nonglaucomatous optic atrophy. The nonarteritic form of anterior ischemic optic neuropathy had proximal constriction in 19 of 28 eyes (68%), which was more frequent than in those with glaucoma (P = .017). Only one of nine eyes with the arteritic form of anterior ischemic optic neuropathy had proximal constriction, which was a lower prevalence than in those with glaucoma (P = .066). General arterial narrowing (throughout the retinal course) was present in 111 of 204 (54%) of those with moderate optic nerve damage and 100 of 128 (78%) of those with severe optic nerve damage in all categories, compared with 29 of 208 (14%) of the controls with no optic nerve damage. Unlike proximal constriction, the generalized narrowing was related to severity of optic nerve damage and not to the disease category.

This paper presents a comparison of total hospital costs for the final 60 days of life for patients with ovarian cancer managed by hospice versus those who did not receive hospice care. The study subjects were 84 women who had been treated at the Barnes-Jewish Hospital for ovarian cancer who died from their disease between 1999 and 2003. Clinical and financial data were obtained from a review of the medical records of these patients.

Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the “oncostatin signaling module,” which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells.