Alfred Guirguis

Optimal surgical debulking in uterine papillary serous carcinoma affects survival

OBJECTIVE UPSC is similar to papillary serous ovarian carcinoma in its histology and pattern of spread. The survival advantage with optimal debulking for ovarian cancer has been demonstrated. We examined our experience with UPSC. METHODS Seventy-eight UPSC patients were seen between 1995 and 2008 at Rush University Medical Center for surgery and/or adjuvant treatment. Information was obtained retrospectively from the Rush computer system, National Death Registry, and charts from chemotherapy, radiation, and gynecologic oncology. RESULTS Mean survival was 67.1 months for all stages (95% CI 52.8-81.2), 47.6 months for stage III (95% CI 26.7-68.3), and 21.7 months for stage IV (95% CI 14.5-29.1). No deaths occurred in stages I and II. No significant survival difference was found between African-Americans and Whites (log-rank test, p=0.62), nor between full serous and mixed pathology (log-rank test, p=0.52). Optimally debulked stage IV patients had a mean survival of 30.9 months, compared to 10.3 months in suboptimally debulked patients (p<0.001). Optimal debulking had no significant effect on stage III survival (p=0.47). Although weight was not statistically significant (p=0.059), there was a trend associated with suboptimal debulking. The mean time to recurrence for stage I was 79.9 months (95% CI 12.8-54.9), stage III was 27.4 months (95% CI 7.8-47.1), and stage IV was 20.2 months (95% CI 11.1-29.4) (p<0.001). There were no recurrences in stage II. CONCLUSION Our results suggest that UPSC should be optimally debulked. Weight is a risk factor for suboptimal debulking, which decreases mean survival and time to recurrence.

Interleukin 16 expression changes in association with ovarian malignant transformation

OBJECTIVE Long-term unresolved inflammation has been suggested as a risk factor for the development of various malignancies. The goal of this study was to examine whether the expression of interleukin (IL)-16, a proinflammatory cytokine, changes in association with ovarian cancer (OVCA) development. STUDY DESIGN In an exploratory study, changes in IL-16 expression in association with OVCA development and progression were determined using ovarian tissues and serum samples from healthy subjects (n = 10) and patients with benign (n = 10) and malignant ovarian tumors at early (n = 8) and late (n = 20) stages. In the prospective study, laying hens, a preclinical model of spontaneous OVCA, were monitored (n = 200) for 45 weeks with serum samples collected at 15-week interval. Changes in serum levels of IL-16 relative to OVCA development were examined. RESULTS The frequency of IL-16-expressing cells increased significantly in patients with OVCA (P < .001) compared to healthy subjects and patients with benign ovarian tumors. The concentration of serum IL-16 was higher in patients with benign tumors (P < .05) than in healthy subjects and increased further in patients with early-stage (P < .05) and late-stage (P < .03) OVCA. Increase in tissue expression and serum levels of IL-16 in patients with early and late stages of OVCA were positively correlated with the increase in ovarian tumor-associated microvessels. Prospective monitoring showed that serum levels of IL-16 increase significantly (P < .002) even before ovarian tumors become grossly detectable in hens. CONCLUSION This study showed that tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression.

A Delay from Diagnosis to Treatment Is Associated with a Decreased Overall Survival for Patients with Endometrial Cancer

Objectives While Caucasian women are more likely to be diagnosed with endometrial cancer compared to African-American women, the rate of mortality is higher for African Americans. The cause of this disparity is unknown. We analyzed the time interval from diagnosis of endometrial cancer to treatment as it pertains to race and socioeconomic factors and its possible impact on survival. Methods This was a retrospective, single institution chart review using a cancer registry database. We identified 889 patients who were diagnosed with endometrial cancer between January 2005 and June 2012. Clinicopathologic characteristics, demographics, insurance status, distance from medical center, body mass index (BMI), dates of diagnosis, and treatment were obtained from the medical records. Survival and association was determined by a one-way ANOVA test. Results At the time of the study, 699 patients were alive and 190 dead. The average age was noted to be 62 years (24–91 years). Stages I–IV disease accounted for 69, 6, 15, and 10%, respectively. White race accounted for 64%, African Americans 24%, and Hispanics 7% of our study population. Majority of patients were privately insured (n = 441) followed by Medicare (n = 375). The mean interval time from diagnosis to treatment was 47.5 days (0–363). A statistically significant difference was noted for this time interval with regard to both race and insurance status: white and African Americans (42.6 vs. 57.3 days, p = 0.048), privately insured and Medicare (38.4 vs. 54.1 days, p < 0.001). There was a significant association with increased risk of death with a longer delay (43.3 vs. 64.8 days, p < 0.001). No statistically significance was noted for distance from medical center or BMI. Conclusion A significant increase in interval of time from diagnosis to treatment of endometrial cancer was seen in both race and insurance status. A longer interval from diagnosis to treatment was associated mortality. The causes of these delays are likely multifactorial but deem further investigation given these data.

Immunohistochemical characterization of squamous differentiation and morular metaplasia in uterine endometrioid adenocarcinoma.

Squamous differentiation (SD) and morular metaplasia (MM) are frequently present in uterine endometrioid adenocarcinoma (EAC) and can mimic areas of solid tumor. We used immunohistochemical stains to further characterize these lesions, and to determine which markers would help to distinguish these metaplasias from areas of solid growth in EAC. The pathology database was searched for diagnoses of EAC from 1997 to 2007, the hematoxylin and eosin-stained slides were reviewed, and 143 cases with SD, MM, or both (SD+MM) were identified. A panel of immunohistochemical stains was performed. In particular, we were interested in PAX2 and PAX8, recently studied markers of Müllerian tissue as potential markers for differentiation of metaplasias and tumor. In addition, estrogen receptor and progesterone receptor, and Her-2/neu, were examined to determine whether there was a differential expression between the metaplasias and solid tumor that may be diagnostically useful. In addition, to further characterize MM and SD, bcl-2 as a marker of cell regulation and inhibition of apoptosis, p16 as a surrogate marker for human papillomavirus, and p63 as a marker of mature SD were studied. Adjacent normal endometrium (NEM), when present, and 20 EAC cases (FIGO Grades 1–3) without SD or MM served as controls. PAX2 was positive in NEM (58/61, 95%) and was lost in SD (15/136, 11%), MM (1/25, 4%), and EAC (57/163, 35%), whereas PAX8 was positive in all NEM (61/61, 100%) and in the majority of SD (125/136, 92%), MM (19/25, 73%), and EAC (162/163, 99%). The estrogen receptor and the progesterone receptor were expressed by the majority of EAC (148/163, 91% and 144/163, 88%, respectively), whereas both were markedly diminished in SD (56/136, 41% and 58/136, 43%) and MM (4/25, 16% and 2/25, 8%). Approximately half of the MM was positive for bcl-2 (12/25, 48%), making it an unreliable marker. Her-2/neu was negative in all cases (0%). p16 was patchy in SD (111/136, 82%), MM (22/25, 88%), and EAC (154/163, 94%), whereas p63 was predominantly positive only in SD (96/136, 71%). Estrogen receptor and progesterone receptor, PAX2, and PAX8 were helpful in differentiating MM from SD, EAC, or NEM (P<0.05). In addition, p63 distinguished between SD and MM, supporting the theory that morules do not show characteristic mature SD.

Central-type primitive neuroectodermal tumor of the uterus: Case report of remission of stage IV disease using adjuvant cisplatin/etoposide/bevacizumab chemotherapy and review of the literature

Highlights • Bevacizumab was an effective agent in one case of advanced uterine PNET.• VEGF was expressed by the tumor, supporting a mechanism for effectiveness.• Cisplatin/etoposide/bevacizumab should be further studied in clinical trials.• Patient remains disease-free forty-eight months following intervention.

Evaluation and Management of Adnexal Masses

The adnexa refers to the region that usually contains the ovary, fallopian tube, any associated vessels, ligaments, and connective tissue. At times, pathology coming from the uterus, bowel, retroperitoneum, and/or metastatic disease may also be within the adnexal region. Although variable, the prevalence of adnexal masses is highest during premenopausal years at approximately 6–8 % and decreases in the menopausal state. Of utmost concern with these adnexal masses is to rule out malignancy.

Abstract POSTER-BIOL-1343: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) prevents ovarian cancer progression

Abstracts: 10th Biennial Ovarian Cancer Research Symposium; September 8-9, 2014; Seattle, WA Background: The lack of information on the molecular etiology associated with ovarian malignant transformation hinders the prevention of ovarian cancer (OVCA) as well as its early detection. Longstanding unresolved chronic inflammation has been suggested as a risk factor for carcinogenesis. Ovarian surface epithelium (site of ovulatory rupture) and fimbrial surface epithelium (site of receiving of ovulated ovum) are exposed to inflammatory agents due to ovulation as well as ovarian autoimmune conditions. Sustained exposure to chronic inflammation leads to the inactivation of PPAR-γ, a member of steroid receptor superfamily. PPAR-γ has been shown to be tumor suppressive in several malignancies. However, systematic studies on the role of PPAR-γ in OVCA development and progression have not been performed. Herbs are used in traditional medicine as anti-tumor agents. The herb Ashwagandha (Withania somnifera, ASH), has long been used as anti-inflammatory and anti-oxidant in traditional medicine. However, its role in prevention of OVCA-associated change in PPAR-γ function is not known. Objective: The goals of this study were to determine (i) if PPAR-γ expression changes in association with OVCA development and progression and (ii) if dietary supplementation of ASH enhances PPAR-γ expression in laying hens, a preclinical model of spontaneous OVCA. Materials and Methods: Changes in PPAR-γ expression in association with OVCA development and progression were determined in an exploratory study by immunohistochemistry (IHC), gene expression, and proteomic studies using normal ovaries (n=10) and ovaries with cancer at early (n=7) and late stages (n= 20) of OVCA. In the prospective study, hens with or without early stage OVCA were selected by ultrasound scanning and grouped into control (basal diet), 1% and 2% ASH root powder supplemented diet. 30 hens (25 healthy, 5 with early stage OVCA) were grouped in each dietary category. Hens were provided with feed and water ad libitum and maintained for 90 days. At the end of 90-days, hens were euthanized, normal and cancerous ovaries were processed for PPAR-γ expression as mentioned above. Results: Compared with early stage OVCA, the expression of PPAR-γ was significantly lower in approximately 75% of OVCA cases at late stages. This decrease in tissue expression of PPAR-γ was associated with decreased in gene expression. Furthermore, decreased PPAR-γ expression was more pronounced in poorly differentiated tumors than well differentiated ones. In the prospective study, compared with control and 1%, OVCA incidences and tumor metastasis were reduced markedly in hens supplemented with 2% dietary ASH. Reduction in OVCA incidence and progression was associated with the increased expression of PPAR-γ in the tumor tissues. ASH treatment enhanced gene expression of PPAR-γ in hens supplemented with 2% ASH. Conclusion: The expression of PPAR-γ was inversely associated with ovarian tumor development and progression. Dietary supplementation of ASH increased the expression of PPAR-γ significantly and reduced the incidence of OVCA as well as its metastasis. These results will form a foundation for a clinical study. Support: Dept. of Defense award # W81XWH-12-1-0460. Citation Format: Lauren E. Rosen, Animesh Barua, Janice M Bahr, Sanjib Basu, Sameer Sharma, Seby E Edassery, Alfred S Guirguis, Pincas Bitterman. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) prevents ovarian cancer progression [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1343.

Use of cervical mucus to screen for gynecological malignancies: a pilot study.

High-grade malignancies are the leading cause of death from gynecological tumors. Unfortunately, no efficient screening method is available for these tumors. In this paper we report the results of a pilot study based on the frequency of TP53 mutations in these cancers. Mucus from the cervix of 32 hysterectomy specimens with no grossly visible cervical or serosal involvement were included in this study. TP53 exons 5–9 mutations were screened for mutations using single strand conformation polymorphism (SSCP). Immunostain for p53 protein was performed in all fallopian tubes and in a sample from the tumors that were identified prospectively. A total of 32 cases including 19 malignant, and 13 benign cases were included. P53 immunostain was positive in only 5 cases including 3 high grade malignant tumors and 2 precancerous lesions (serous tubal intraepithelial lesion or p53 signature) in the fallopian tubes. A TP53 mutation band pattern was detected by SSCP in 2/3 and 2/2 cases respectively. Twenty-seven cases were negative for p53 imunostain, 4 of which were positive for TP53 mutation by SSCP including 3 low-grade malignancies. The results of this study provide evidence that DNA from precursor lesions of high grade ovarian, fallopian tube and endometrial carcinomas can be detected in cervical mucus. Further studies using different markers, in preoperative setting and large scale screening studies will determine the utility of using cervical mucus to screen for gynecological malignancies.