William C. McBee

Endometrial stromal sarcoma: Analysis of recurrence following adjuvant treatment

OBJECTIVE Endometrial stromal sarcoma (ESS) is a rare and indolent form of uterine cancer with ill-defined post-operative treatment guidelines. The goal of this study was to evaluate the rate of recurrence and the effect of various adjuvant treatment modalities. METHODS Patients with ESS at 4 institutions were identified (1986-2007). Patient demographics, pathology, treatment, and follow-up information were collected. Chi-square statistical analysis was performed. RESULTS Forty-three patients with ESS were identified. All patients initially underwent hysterectomy. Twenty-eight (66.7%) had early stage, 12 (28.6%) had advanced stage ESS, and 2 (4.8%) had no staging information. Eight patients received pelvic and or vaginal cuff radiation treatment, with or without chemotherapy. Sixteen of 43 patients experienced a recurrence at an average of 100.5months. Thirty-three patients were treated with progestin therapy alone or followed expectantly. Complete outpatient records were available for 28 of these patients. Sixteen patients (57%) were followed expectantly while 12 (43%) received progestins. Patients receiving progestins vs. expectant management had a lower rate of recurrence in stage 1 (14.3% vs 38.5%, p=0.26) and all stages (33% vs 50%, p=0.38). Twenty-three of 28 (82.1%) patients underwent initial oophorectomy. Eight of 23 (34.8%) had a recurrence, compared to 4 of 5 (80%) in those who retained their ovaries (p=0.06). CONCLUSIONS ESS is a rare cancer that is difficult to study. We found removal of the adnexa and post-operative treatment with progestin therapy decreased recurrence rates. These two treatment strategies should be considered in the treatment of patients with all stages of ESS.

Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications

OBJECTIVE Combination intravenous/intraperitoneal (IV/IP) chemotherapy has been shown in three randomized trials to be superior to IV therapy alone in the treatment of advanced ovarian cancer with respect to overall survival (OS). We sought to evaluate the effect of dose modification of IP therapy on completion rates. METHODS From November 1999 until August 2008, all optimally debulked, advanced stage ovarian cancer patients who received adjuvant IP chemotherapy at a single institution were reviewed. The primary endpoint was completion of 6 cycles of IP chemotherapy. This rate was compared to published results from GOG 172. A secondary analysis evaluated completion of chemotherapy based on IP catheter type. Statistical analysis was performed with a chi square test with a significance level of p<0.05. RESULTS One hundred and three patients received IP chemotherapy during this period. Seventy-five patients received the modified IV/IP chemotherapy regimen. Sixty-two patients (83%) completed all 6 cycles in our cohort compared to 119 patients (42%) reported in GOG 172 (p=0.0001). Fifty-five patients had a fenestrated catheter (F) and 48 had a non-fenestrated (NF) catheter. Eight patients in each cohort discontinued treatment, for a completion rate of 85.5% in NF and 82.3% in F (p=0.79). CONCLUSIONS The dose modifications utilized in this study allowed for completion of 6 cycles of adjuvant IP chemotherapy in 83% of patients. Choice of catheter type did not affect completion rates. Continued monitoring of outcomes is planned to compare PFS and OS. The high completion rate may increase acceptance of IP chemotherapy in the community setting.

Radical hysterectomy for early stage cervical cancer: laparoscopy versus laparotomy.

Laparoscopic radical hysterectomy appears to be a feasible alternative to laparotomy for early stage cervical cancer with similar surgical outcomes and lessened morbidity.

MicroRNA Analysis in Human Papillomavirus (HPV)-Associated Cervical Neoplasia and Cancer

Background: MicroRNAs (miRNAs) are ~22 nt single-stranded, non-coding RNAs that generally negatively regulate their target mRNAs at a posttranscriptional level. Differential expression of miRNAs has been observed in many human cancers. Methods: To study their potential role in the pathogenesis of human papillomavirus (HPV) type 16-associated cervical neoplasia and cancer, we analyzed miRNA expression in cervical tissue from the normal cervix, moderate/ severe dysplasia, and invasive squamous cell carcinoma. Results: Using RNA from six cervical cancers, three dysplasias, and four normal samples and the TaqMan® MicroRNA Arrays, we found that 18 miRNAs were overexpressed and 2 underexpressed in cervical cancer compared to normal cervical tissue. We further demonstrated via individual TaqMan® MicroRNA Assays that 8 miRNAs (miRs- 16, 21, 106b, 135b, 141, 223, 301b, and 449a) were significantly overexpressed and 2 miRNAs (miRs-218 and 433) were significantly underexpressed in cervical cancer compared to normal cervical tissue. MiR-21, miR-135b, miR- 223, and miR-301b were overexpressed in cervical cancer compared to both cervical dysplasia and normal tissue. MiR-218 was similarly underexpressed in cervical cancer compared to dysplasia and normal tissue. Conclusions: Our results suggest that ten miRNAs can delineate cervical cancer from normal cervical tissue, and five miRNAs may have potential as markers for progression from dysplasia to invasive cervical disease.

MicroRNA analysis in human papillomavirus (HPV)-associated cervical neoplasia and cancer

Background: MicroRNAs (miRNAs) are ~22 nt single-stranded, non-coding RNAs that generally negatively regulate their target mRNAs at a posttranscriptional level. Differential expression of miRNAs has been observed in many human cancers. Methods: To study their potential role in the pathogenesis of human papillomavirus (HPV) type 16-associated cervical neoplasia and cancer, we analyzed miRNA expression in cervical tissue from the normal cervix, moderate/ severe dysplasia, and invasive squamous cell carcinoma. Results: Using RNA from six cervical cancers, three dysplasias, and four normal samples and the TaqMan® MicroRNA Arrays, we found that 18 miRNAs were overexpressed and 2 underexpressed in cervical cancer compared to normal cervical tissue. We further demonstrated via individual TaqMan® MicroRNA Assays that 8 miRNAs (miRs- 16, 21, 106b, 135b, 141, 223, 301b, and 449a) were significantly overexpressed and 2 miRNAs (miRs-218 and 433) were significantly underexpressed in cervical cancer compared to normal cervical tissue. MiR-21, miR-135b, miR- 223, and miR-301b were overexpressed in cervical cancer compared to both cervical dysplasia and normal tissue. MiR-218 was similarly underexpressed in cervical cancer compared to dysplasia and normal tissue. Conclusions: Our results suggest that ten miRNAs can delineate cervical cancer from normal cervical tissue, and five miRNAs may have potential as markers for progression from dysplasia to invasive cervical disease.

Intraperitoneal chemotherapy for recurrent epithelial ovarian cancer is feasible with high completion rates, low complications, and acceptable patient outcomes.

Objectives Three large randomized clinical trials have shown a survival benefit for patients treated with intraperitoneal (IP) compared with intravenous chemotherapy for advanced stage epithelial ovarian cancer (EOC). However, the use of IP chemotherapy in recurrent EOC is controversial. The purpose of this study was to determine outcomes, completion rates, and frequency of complications in patients with platinum-sensitive recurrent EOC treated with IP chemotherapy. Methods A retrospective, single-institution analysis of women who received IP chemotherapy for recurrent EOC from January 2003 to April 2010 was conducted. Study patients were identified from the Tumor Registry and office records. Demographic factors, stage, histology, surgical findings, cytoreduction status, and subsequent therapies were abstracted. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier methods. Results Fifty-six women who received IP chemotherapy for their first EOC recurrence were identified. The mean age of patients was 56.7 years (range, 40–79 y). Fifty-five patients (98.3%) had previously completed at least 6 cycles of intravenous chemotherapy. Of all patients, 87.5% were initially diagnosed with advanced stage disease (stage IIA–IV). All patients underwent secondary cytoreduction at the time of IP port placement. Moreover, 67.9% of patients were considered optimally cytoreduced (<1 cm residual disease) at the end of the secondary debulking surgery. Forty-two patients (75%) were able to successfully complete at least 6 cycles of IP chemotherapy. Reasons for noncompletion were disease progression, allergic reaction, renal failure, pain, severe nausea and vomiting, death, and patient refusal. Six patients (10.7%) developed port complications including pain around port site, port malfunction, and port erosion into small bowel. Median PFS since the initiation of IP chemotherapy was 10.5 months (95% confidence interval, 7.5–16.4 months) and median OS was 51 months (95% confidence interval, 40.8–61.1 months). Conclusions Intraperitoneal chemotherapy is a feasible option for patients with recurrent EOC, with high completion rates, low frequency of complications, and acceptable PFS and OS.

Metastatic ovarian serous carcinoma presenting as inflammatory breast cancer: a case report.

A 42-year-old woman presented with localized irritation, erythema and sharp pain in the one breast. After unsuccessful treatment for mastitis, an oncology consultation was obtained. A breast biopsy revealed an invasive carcinoma and a diagnosis of inflammatory breast cancer was made. The patient was treated with neo-adjuvant chemotherapy and subsequently underwent bilateral mastectomy. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was also performed at the same time due to the presence of a pelvic mass. Morphologic and immunohistochemical examination of the specimens helped to clarify the correct diagnosis of primary ovarian carcinoma with widespread metastases to bilateral breasts.

Intraperitoneal catheter leads to prolongation of the time to normalization of serum CA125 levels.

Objective: The intraperitoneal (IP) catheter has the potential to cause peritoneal irritation, which may contribute to an elevated CA125 level. We hypothesize that patients undergoing IP chemotherapy may have elevated CA125 values when compared with patients receiving intravenous (IV) chemotherapy. Methods: From February 2006 to July 2007, optimally debulked patients with stage III and stage IV ovarian carcinoma from a single institution were offered an outpatient IV/IP chemotherapy regimen modified from Gynecologic Oncology Group 172. They were matched to a cohort of similar patients who received IV paclitaxel and carboplatin. Demographic data and CA125 levels were collected before each cycle of chemotherapy and after the removal of the IP catheter. Statistical analysis was completed using a χ2 test with a significance level of P < 0.05. Results: Fifty patients received the standard IV regimen, and 38 patients completed the modified IV/IP regimen. There was no statistical difference in the median CA125 values between the 2 groups during the treatment. After 6 cycles of therapy, 68.4% (26/38) of the IP cohort had a normal CA125 level before IP catheter removal compared with 78% (39/50) in the IV chemotherapy cohort (P = 0.44). After removal of the IP catheter, 86.8% (33/38) of the patients had a normal CA125 value (68.4% vs 86.8%, P = 0.049). Conclusions: After removal of the IP catheter, an additional 18.2% (7/38) of patients in the IP group had normalized their CA125 level. Because CA125 levels at the end of the treatment have prognostic significance, the role of the IP catheter in an elevated CA125 level must be considered.

Abstract B57: Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers

Introduction : Invasive cancer of the uterine cervix (ICC) is a leading cause of cancer death in women worldwide. ICC incidence and mortality rates are especially high among women from Appalachia. In addition to lifestyle and social-behavioral factors and HPV infections, hereditary predispositions may mediate cervical cancer risk. Polymorphic alleles within the Transforming Growth Factor Beta (TGFB) signaling cascade, an important regulator of epithelial cell growth, have been implicated in modifying cancer susceptibility. The contributions of these factors within a gene-environment model have not been well characterized in Appalachian ICC patients. Hypothesis : High-risk genomic variants of TGFB signaling pathway components will be overrepresented in Appalachian women diagnosed with ICC compared to their healthy Appalachian counterparts. Methods : A case-control study was conducted with 163 cases, women diagnosed with ICC, and 842 controls, women with normal Pap tests from Appalachia Ohio, West Virginia, and Kentucky. Inclusion criteria were (i) women residing in Appalachian counties who were ≥18 years, (ii) spoke English, (ii) not cognitively impaired, (iii) able to provide informed consent. Three distinct groups were considered, representing (i) prevalent invasive cervical cancer cases, (ii) newly diagnosed invasive cervical cancer cases, and (iii) healthy controls. Targeted genomic variance analysis of 9 SNPs (rs1800469, rs1800470, rs3917200, rs7034462, rs11568785, rs868, rs1042522, rs750749, rs1800566) and a polymorphic repeat variant was conducted on blood DNA. Behavioral and environmental factors were collected using a comprehensive, self-administered questionnaire completed at the time of enrollment. Characteristics between cases and controls were compared by a two sample t-test, assuming unequal variance for continuous variables and by Fisher9s exact test for categorical variables. Associations between disease status, polymorphism and behavioral or environmental characteristics were estimated via multivariable logistic regression. Results : Never smokers with TGFB1 rs1800469 overdominant allele types A/A-G/G had 0.4 (95% CI: 0.22-0.73, p=0.003) times the odds of cervical cancer compared to never smokers with A/G genotype. This effect was not observed in ever smokers (interaction p=0.02). While there was a suggestion of an increased risk of cervical cancer for never smokers with TGFB1 rs1800469 recessive A/G-A/A genotypes compared to G/G non9A genotype CD83 dominant T/T compared to C/C-C/T, or overdominant C/C -T/T compared to C/T alleles, there were no strong interaction effects identified. The effect of dominant TP53 rs1042522 allele type (C/C C/G versus G/G) differed by smoking status. There was a significant 3-fold increase in the odds of cervical cancer (aOR: 3.1, 95% CI: 1.1-8.5, p=0.03) for never smokers with TP53 rs1042522 G/G compared to never smokers with C/C-C/G genotypes. A similar increase was not observed in ever-smokers (smoking status by genotype interaction effect p=0.02). In codominant types, there was a similar increased adjusted odds (aOR: 3.65, 95% CI: 1.21-11.0, p=0.021) of cervical cancer for never smokers with G/G genotypes compared to never smokers with C/G genotypes. This effect was not observed in ever smokers (interaction effect p=0.06). Conclusions : Genetic susceptibility may contribute to the overall cervical cancer risk associated with the Appalachian population, especially among non-smokers. Inclusion of additional demographic and social-behavioral features, as well as other genetic events, may further define this evolving cervical cancer risk model. Citation Format: Thomas J. Knobloch, Steve Oghumu, Marta Sears, Zhaoxia Zhang, Blessing Ogbemudia, Joe Perrault, David Cohn, Cecilia R. DeGraffinreid, Bo Lu, Juan Peng, Erinn M. Hade, Michael A. Schiano, Byron C. Calhoun, William McBee, Jr., Jamie Lesnock, Holly Gallion, Jondavid Pollock, Mack T. Ruffin, IV, Christopher M. Weghorst, Electra D. Paskett. Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B57.