Mitchell I. Edelson

Tumor Cell-Specific BRCA1 and RASSF1A Hypermethylation in Serum, Plasma, and Peritoneal Fluid from Ovarian Cancer Patients

Because existing surgical and management methods can consistently cure only early-stage ovarian cancer, novel strategies for early detection are required. Silencing of tumor suppressor genes such as p16INK4a, VHL, and hMLH1 have established promoter hypermethylation as a common mechanism for tumor suppressor inactivation in human cancer and as a promising target for molecular detection in bodily fluids. Using sensitive methylation-specific PCR, we screened matched tumor, preoperative serum or plasma, and peritoneal fluid (washes or ascites) DNA obtained from 50 patients with ovarian or primary peritoneal tumors for hypermethylation status of the normally unmethylated BRCA1 and RAS association domain family protein 1A tumor suppressor genes. Hypermethylation of one or both genes was found in 34 tumor DNA (68%). Additional examination of one or more of the adenomatous polyposis coli, p14ARF, p16INK4a, or death associated protein-kinase tumor suppressor genes revealed hypermethylation in each of the remaining 16 tumor DNA, which extended diagnostic coverage to 100%. Hypermethylation was observed in all histologic cell types, grades, and stages of ovarian tumor examined. An identical pattern of gene hypermethylation was found in the matched serum DNA from 41 of 50 patients (82% sensitivity), including 13 of 17 cases of stage I disease. Hypermethylation was detected in 28 of 30 peritoneal fluid DNA from stage IC-IV patients, including 3 cases with negative or atypical cytology. In contrast, no hypermethylation was observed in nonneoplastic tissue, peritoneal fluid, or serum from 40 control women (100% specificity). We conclude that promoter hypermethylation is a common and relatively early event in ovarian tumorigenesis that can be detected in the serum DNA from patients with ovary-confined (stage IA or B) tumors and in cytologically negative peritoneal fluid. Analysis of tumor-specific hypermethylation in serum DNA may enhance early detection of ovarian cancer.

Prevalence and Predictors of Psychological Distress Among Women With Ovarian Cancer

PURPOSE To identify the prevalence of psychological distress among women with ovarian cancer and to examine the association between these symptoms of distress and demographic and medical variables. PATIENTS AND METHODS Participants were 143 women with ovarian cancer. Forty-eight percent of participants had been diagnosed with advanced-stage disease (stage III or IV) and most (80%) were currently receiving treatment. Psychological distress was assessed with the following measures: the Beck Depression Inventory, the Mental Health Inventory, the Impact of Events Scale, and a questionnaire regarding mental health service use. RESULTS Approximately one fifth of women reported moderate to severe levels of distress, and more than half reported high stress responses to their cancer and its treatment. Most participants (60%) were not using any mental health services or psychotropic medications. There was also evidence to suggest that younger patients, patients with more advanced or recurrent disease, and patients who had more recently been diagnosed with ovarian cancer experienced greater psychological distress. CONCLUSION These findings indicate that psychological distress and high stress responses to cancer are prevalent among women with ovarian cancer, suggesting they should be carefully evaluated to determine whether treatment for these symptoms is warranted.

Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. METHODS The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. RECOMMENDATIONS All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki.

Coping and communication-enhancing intervention versus supportive counseling for women diagnosed with gynecological cancers.

This study compared the efficacy of 2 psychological interventions, a coping and communication-enhancing intervention (CCI) and supportive counseling (SC), in reducing depressive symptoms and cancer-specific distress of women diagnosed with gynecological cancer. Demographic, medical, and psychological moderators of intervention effects were evaluated. Three hundred fifty-three women with gynecological cancer were randomly assigned to 7 sessions of CCI, 7 sessions of SC, or usual care. Intent-to-treat growth curve analyses indicated that participants assigned to CCI and SC reported lower depressive symptoms than participants assigned to usual care at the 6- and 9-month follow-ups. Women with greater than average increases in physician-rated physical symptoms and/or women who were more expressive of positive emotions benefited more from SC than women with lower than average increases in symptom scores and/or women who were less expressive of positive emotions. These findings suggest that both interventions may be effective in treating depressive symptoms among patients with gynecological cancer. Future research should evaluate whether bolstering both psychological interventions with additional intervention sessions and topics in the disease trajectory will result in persistent long-term effects.

Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline ☆

PURPOSE To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. METHODS The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are non-inferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. RECOMMENDATIONS All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to <1cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to <1cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki.

Mediators of a Coping and Communication-Enhancing Intervention and a Supportive Counseling Intervention among Women Diagnosed with Gynecological Cancers

The authors evaluated mechanisms of change for a coping and communication-enhancing intervention (CCI) and supportive counseling (SC). They proposed that the effects of CCI on depressive symptoms would be mediated by psychological processes targeted by CCI, namely increases in the following: positive reappraisal, acceptance, planful problem solving, attempts to understand emotional reactions to cancer, emotional expression, seeking of emotional and instrumental support, and self-esteem. The authors hypothesized that the effects of SC on depressive symptoms would be mediated by the processes encouraged by SC, in this case increases in the following: expression of emotions, attempts to understand emotional reactions to cancer, and self-esteem. Three hundred fifty-three women were randomized to a CCI, SC, or usual care control group and completed measures at preintervention and 3, 6, and 9 months later. The effects of CCI were fully mediated by positive reappraisal, problem solving, and self-esteem and partially mediated by emotional expression. The effects of SC were partially mediated by positive reappraisal. These findings provide support for hypothesized mediators for CCI. The authors were less able to identify mediators for SC. Future research might benefit from identifying SC mediators.

Long-term Trajectories of Psychological Adaptation Among Women Diagnosed With Gynecological Cancers

Objective: Women diagnosed with gynecological cancers may cope with a difficult treatment regimen that includes multiple abdominal surgeries and courses of chemotherapy and/or radiation. Little attention has been paid to identifying what factors place women at risk for long-term problems with psychological adaptation. The goal of the present study was to identify a set of demographic, medical, and predisposing factors as well as cognitive and social processing strategies that predict the trajectory of psychological distress and well-being among women diagnosed with gynecological cancer. Methods: One hundred thirteen women on active treatment for gynecological cancer completed measures at baseline, 3, 6, and 9 months afterward. Results: Women with poorer physician-rated performance status and self-reported functional impairment, women who were Caucasian, women who have received previous psychological treatments, women who were less expressive of positive emotions, women who had unsupportive friends and family, and women who were less able to find something positive in the cancer experience reported poorer adaptation. Conclusions: This study identified a set of risk factors for poor long-term psychological adaptation among women diagnosed with gynecological cancers. Healthcare professionals working with these women can use these risk factors to screen for patients who may require additional psychological services. ECOG = Eastern Cooperative Oncology Group.

Primary small cell carcinoma of the vagina.

BACKGROUND Primary vaginal small cell carcinoma is extremely rare, with a total number reported in English-language journals to date of 23. Most patients die of the disease within 2 years of diagnosis from metastatic disease. CASE A 69-year-old woman presented with vaginal spotting while on Premarin. She was subsequently diagnosed with Stage I (T1N0M0) small cell carcinoma of the vagina. She underwent concurrent chemoradiation and then brachytherapy for persistent disease. Due to residual disease after the brachytherapy, surgical resection was planned but aborted because of metastatic disease. CONCLUSIONS Of the three reported cases treated with concurrent chemoradiation, ours is the first case reported with persistent local disease after therapy. Extrapolating from the available clinical trials from lung carcinoma, concurrent chemoradiation as a primary treatment approach should still be considered.

p16 Expression in Squamous Lesions of the Female Genital Tract

The aim of this study was to examine the role of p16 in the pathogenesis of squamous carcinoma of the gynecologic tract. Squamous carcinoma and carcinoma in situ from the female genital tract were examined for the expression of p16 by paraffin immunohistochemistry. About 74% (40/54) of cases showed p16 expression. By primary site, 77% (23/30) of cervical, 67% (6/9) of vaginal and 85% (11/13) of vulvar primaries expressed p16, but two endometrial primary squamous carcinomas were negative (0/2). In addition, p16 was not identified in non-dysplastic tissue and low grade dysplasia. In cases where there were matched vaginal or vulvar and cervical primaries in a given patient, there was concordant positive p16 expression. It is concluded that p16 is frequently expressed in squamous carcinoma of the cervix, vagina and vulva, but not seen in cases of benign and low grade lesions. It may be a marker of transformation from a low to a high grade lesion. More cases of endometrial primaries need to be studied to see if these evolve by a p16-independent pathway.

Immunohistochemical confirmation of pulmonary papillary adenocarcinoma metastatic to ovaries

Metastatic papillary adenocarcinomas of the ovary are rare compared to primary ovarian papillary serous carcinomas. We report a case of pulmonary papillary adenocarcinoma metastatic to the ovary and show how this tumor can be differentiated immunohistochemically from an ovarian primary. Paraffin blocks of the ovarian tumor were analyzed for carcinoembryonic antigen, CA 125, surfactant, E-cadherin, N-cadherin, and vimentin. These markers are useful in differentiating epithelial tumors of lung versus ovarian origin. The papillary tumor showed expression of carcinoembryonic antigen, surfactant, and E-cadherin, but was negative for CA 125, N-cadherin, and vimentin. These findings support a lung carcinoma metastatic to the ovary.