The association between progesterone receptor expression and survival in women with adult granulosa cell tumors.

BACKGROUND: Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT. METHODS: A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models. RESULTS: FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0-8) and 9 (range 0-15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5-5.5) and decreased overall survival (HR = 3.7, CI 1.3-10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6-2.0 and p = 0.06, HR = 1.1, 95% CI 0.4-2.9, respectively). CONCLUSIONS: Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.

Factors associated with an increased risk of recurrence in women with ovarian granulosa cell tumors.

INTRODUCTION: Studies demonstrate that patient factors such as race, body composition, medical co-morbidities, and medications may be associated with cancer related outcomes independent of the patient's malignancy and related therapies for the cancer. The goal of this study is to determine demographic and prognostic factors affecting disease recurrence in women with early stage ovarian granulosa cell tumors (GCT). MATERIALS AND METHODS: This study used a dual-institution retrospective analysis of women diagnosed with GCT between 1995 and 2010. Demographics including age, race, body mass index (BMI), stage, diabetes (DM), adjuvant treatment, and progression-free survival (PFS) were extracted. Hazard ratios for recurrence were estimated by univariate and multivariate Cox regression models. RESULTS: One hundred and four women were identified with a median age of 50 years (range 12-87 years). Fifty-five (58.5%) were Caucasian, 29 (30.9%) African American, and 10 (10.2%) others. Median BMI was 29 kg/m(2) (range 12-57 kg/m(2)). Twenty-one patients had DM. The majority of women had clinical stage I disease (95.0%), 5 (6.4%) had stage II/III disease, and 5 were unstaged. In univariate analysis among early stage disease, DM showed the strongest association with recurrence (HR=3.37, 95% CI=1.38-8.20). In multivariate analysis, DM was associated with an HR of 3.19 for recurrence (95% CI=1.08-9.44). CONCLUSIONS: Our results emphasize that diabetes is one of the strongest predictors of recurrent disease in patients with ovarian GCTs. As this disease is characterized by long disease-free intervals prior to recurrence, this may serve as a potential chemopreventive strategy in patients felt to be at higher risk for recurrence.

Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors.

OBJECTIVE: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12-87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist.

Discussion: 'Ovarian epithelial carcinoma with pelvic endometriosis,' by Wang et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis.

Smokeless tobacco: how exposed are our schoolchildren?

The use of smokeless tobacco (ST) is linked to poor health outcomes, including oral and esophageal cancers. Adolescents who use ST are also more likely to use cigarettes and develop lung cancer later in life. Evidence shows that proximity to tobacco retailers increases youth initiation of use. We assessed availability of ST in neighborhoods surrounding ten high schools in New York City. Three hundred and twenty-one retailers were visited. Sixty-three percent of likely tobacco-selling businesses surrounding schools sold cigarettes. About 20 % sold snus, while 3 % sold snuff. Culturally-linked ST products, such as paan and gutka, were largely confined to ethnic neighborhoods, while snuff was more prevalent in neighborhoods with predominantly US born residents. A variety of ST products are easily accessible to adolescents and are located within close proximity to schools, perhaps facilitating use, as has been documented with youth smoking. Further research is needed on adolescent use of culturally-linked ST products. This research can serve as a foundation for development of interventions to reduce ST use among adolescents and for policy recommendations.

Discussion: 'Surgical staging in early ovarian carcinoma' by Garcia-Soto et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research.

A Systematic Review of the Long-Term Trajectory of Hemodynamics and Body Composition in Childhood Obesity.

Obesity has long been cited as a significant risk factor for high blood pressure, with long-term exposure linked with an increased incidence of carotid artery atherosclerosis. However, as obesity is becoming more common in young-aged children, it is important to recognize combinational factors like lifestyle, socioeconomic, and genetic factors as a cause. Increasing weight during childhood, on the other hand, is a clinically significant challenge for many physicians. It is critical to identify these risk factors since early prevention (primordial prevention) or treatment (primary prevention) to reverse the potential risks is much more likely to be effective. The objective of this review was to explore the relationship between lifestyle, anthropometric, and genetic factors and cardiometabolic risk factors. We are hopeful that our findings may aid in the primary prevention of hypertension in children and the prevention of any related cardiovascular complications that may arise later in life as a result of obesity. The synthesis of this systematic review includes a total of 15 studies using defined criteria, published up to October 2021. In addition, a total of 2,397 articles were found through an initial electronic database search and included a total of 38,182 participants. Studies explored included one or more of the following cardiovascular risk factors: body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). The findings of this study support the notion that childhood obesity may be a risk factor for a variety of adult cardiovascular disease risk factors. Several behavioral, genetic, and anthropometric factors are linked to the development of obesity during early ages, overall creating challenges in cardiovascular health during adulthood. As a result, addressing the risk factors for childhood hypertension would be advantageous for the primary prevention of its sequelae in adulthood.

Preoperative pathologic findings associated with residual disease at radical hysterectomy in women with stage IA2 cervical cancer.

OBJECTIVE: To correlate findings on pathologic examination of loop electroexcisional procedure (LEEP) or cone biopsy specimens with residual disease in radical hysterectomy specimens in patients with stage IA2 cervical cancer to determine whether a subset of such patients may be eligible for conservative, fertility-sparing treatment. METHODS: We performed a retrospective chart review of patients diagnosed with stage IA2 cervical cancer who had undergone LEEP or cone biopsy before radical hysterectomy. Surgicopathologic features of LEEP and cone biopsy specimens were correlated with the presence or absence of residual tumor in radical hysterectomy specimens. RESULTS: Forty-two patients met the inclusion criteria. At radical hysterectomy, 22 patients (52%) had no residual tumor, while 20 patients (48%) had residual disease. Margin status was the only statistically significant predictor of the presence or absence of residual disease at radical hysterectomy; positive margins predicted the presence of residual disease (P<0.001). CONCLUSION: Women with stage IA2 cervical cancer and negative margins on LEEP or cone biopsy specimens should be counseled that they may be at low risk for having residual disease in the final radical hysterectomy specimen.

Laparoscopic Allograft Spacer Placement to Minimize Bowel Dose During Re-irradiation with Interstitial Brachytherapy.

In primary or re-irradiation of gynecologic malignancies, achieving optimal dosimetry with adjacent normal tissue becomes challenging. Surgical spacers are tissue-equivalent materials placed within the patient to protect organs at risk from long-term radiation effects and are commonly used in prostate cancer. We report the use of an allograft mesh to protect adhesed bowel from high-dose radiation for definitive treatment of recurrent endometrial cancer. An 88-year-old female was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer after she developed urinary frequency, hesitancy, and hematuria. She underwent neoadjuvant chemoradiation, followed by laparoscopic hysterectomy with bilateral salpingo-oophorectomy and adjuvant vaginal cuff brachytherapy. She developed 1.8 cm bilateral vaginal cuff recurrence and was dispositioned for interstitial brachytherapy. An allograft mesh spacer was placed laparoscopically before repeat, high dose rate brachytherapy to protect nearby structures. Dose-escalation was achieved without compromising normal tissue constraints. The patient tolerated the procedure without evidence of long-term toxicity at one year. Multidisciplinary discussion may help identify patients who would benefit from spacer placement before select dose-escalated radiation therapy. Laparoscopic allograft mesh is one of many types of surgical spacers available for such patients.

The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer.

Our objective was to evaluate the effect of the COX-2 inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX-2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women.

Predictive factors of late venous aortocoronary graft failure: ultrastructural studies.

BACKGROUND: Venous aortocoronary graft arterialization may precede a preterm occlusion in some coronary artery bypass grafting (CABG) patients. The aim of the present study was to identify ultrastructural variations in the saphenous vein wall that may have an impact on the development of venous graft disease in CABG patients. METHODS: The study involved 365 consecutive patients with a mean age of 62.9 ± 9.4 years who underwent isolated CABG. The thickness and area of the whole venous wall, the tunica intima, the tunica media and the adventitia and the number and shape (length, thickness and length/thickness ratio) of the nuclei in the medial smooth muscle cells nuclei in the distal saphenous vein segments were evaluated by ultrastructural studies. Patients were followed up for 41 to 50 months (mean 45.1 ± 5.1). Saphenous vein graft patency was assessed by follow-up coronary angiography. Logistic regression models were used to identify independent risk factors for late graft failure. RESULTS: In 71 patients significant lesions in the saphenous vein grafts were observed. The whole venous wall thickness (437.5 µm vs. 405.5 µm), tunica media thickness (257.2 µm vs. 211.5 µm), whole venous wall area (2.23 mm(2) vs. 2.02 mm(2)) and tunica media area (1.09 mm(2) vs. 0.93 mm(2)) were significantly larger for this group of patients than for those without graft disease. In the latter group more elongated smooth muscle cell nuclei (higher length/thickness ratio) were found in the tunica media of the saphenous vein segments. Thickening of the saphenous vein tunica media and chunky smooth muscle cell nuclei were identified as independent risk factors for graft disease development. CONCLUSIONS: Saphenous vein tunica media hypertrophy (resulting in wall thickening) and chunky smooth muscle cell nuclei might predict the development of venous graft disease.

Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities.

OBJECTIVE: To estimate the incidence of genetic counseling referral for ovarian cancer patients who are at substantial risk for a BRCA1 or BRCA2 mutation. METHODS: An analysis was performed of new ovarian cancer patients who were seen at a comprehensive cancer center from January 1, 1999, through December 31, 2007. Patients at substantial (more than 20-25%) risk for a BRCA1 or BRCA2 mutation were identified and records reviewed for referral to genetic counseling. Time to referral was estimated using the Kaplan-Meier method. RESULTS: A total of 3,765 epithelial ovarian cancer patients were seen during the 9-year period. On average, 23.8% of patients met substantial-risk criteria for BRCA mutations. In 1999, only 12% of patients at substantial-risk were referred. Referral improved over time with 48% referred in 2007 (P<.001). Newly diagnosed patients were more often referred for genetic counseling than new patients with recurrent disease or those seen as second opinions. African-American women meeting substantial-risk criteria were less likely to be referred than were white or Hispanic women (P=.009). CONCLUSION: Although dictated family history was accurate, interpretation of risk for BRCA1 or BRCA2 mutations and subsequent referral to genetic counseling was poor. Although there was significant improvement over time, 50% of substantial-risk patients still were missed. Systematic efforts to identify those ovarian cancer patients at substantial risk for a BRCA1 or BRCA2 are necessary.