Sarah Adams

Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of ≈15% and at least ≈36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis

OBJECTIVE The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols. METHOD Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I(2) statistics. RESULTS Ten suitable studies comprising 1815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71-2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified. CONCLUSIONS Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies.

Surgical outcomes of robotic-assisted surgical staging for endometrial cancer are equivalent to traditional laparoscopic staging at a minimally invasive surgical center

OBJECTIVE To compare peri- and post-operative complications and outcomes of robotic-assisted surgical staging with traditional laparoscopic surgical staging for women with endometrial cancer. METHODS A retrospective chart review of cases of women undergoing minimally invasive total hysterectomy and pelvic and para-aortic lymphadenectomy by a robotic-assisted approach or traditional laparoscopic approach was conducted. Major intraoperative complications, including vascular injury, enterotomy, cystotomy, or conversion to laparotomy, were measured. Secondary outcomes including operative time, blood loss, transfusion rate, number of lymph nodes retrieved, and the length of hospitalization were also measured. RESULTS 275 cases were identified-102 patients with robotic-assisted staging and 173 patients with traditional laparoscopic staging. There was no significant difference in the rate of major complications between groups (p=0.13). The mean operative time was longer in cases of robotic-assisted staging (237 min vs. 178 min, p<0.0001); however, blood loss was significantly lower (109 ml vs. 187 ml, p<0.0001). The mean number of lymph nodes retrieved were similar between groups (p=0.32). There were no significant differences in the time to discharge, re-admission, or re-operation rates between the two groups. CONCLUSION Robotic-assisted surgery is an acceptable alternative to laparoscopy for minimally invasive staging of endometrial cancer. In addition to the improved ease of operation, visualization, and range of motion of the robotic instruments, robotic surgery results in a lower mean blood loss, although longer operative time. More data are needed to determine if the rates of urinary tract injuries and other surgical complications can be reduced with the use of robotic surgery.

Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer.

The aim of the study was to determine whether tumor‐infiltrating lymphocytes and/or tumor mitotic activity could identify subgroups of patients with advanced serous epithelial ovarian cancer who would maximally benefit from aggressive surgical cytoreduction.

CTLA-4 blockade synergizes therapeutically with PARP-inhibition in BRCA1-deficient ovarian cancer

PARP inhibitors improve progression-free survival in BRCA1-deficient ovarian cancer. In a mouse model, checkpoint blockade with anti–CTLA-4, but not anti–PD-1, synergized with PARP inhibition to establish protective immune memory and achieve long-term survival. Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA− ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1− cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1− cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1− tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. Cancer Immunol Res; 3(11); 1257–68. ©2015 AACR.

Robotic-assisted surgery in gynecologic oncology: A Society of Gynecologic Oncology consensus statement: Developed by the Society of Gynecologic Oncology's Clinical Practice Robotics Task Force

The Society of Gynecologic Oncologys (“SGO”) Clinical Practice Committee has developed a series of Clinical Documents designed to improve the overall quality of womens cancer care; reduce the use of unnecessary, ineffective or harmful interventions; as well as facilitate the optimal treatment of patients with a goal to maximize the therapeutic benefit, and minimize the risk of harm, at acceptable cost. In developing clinical documents, SGO follows a rigorous process to assure that any conflicts of interest are disclosed and appropriately addressed and that relationships with manufacturers and other third parties do not influence the development process. More specifically, SGO adheres to the principles adopted by the Council of Medical Specialty Societies (“CMSS”) in developing, adopting and promulgating clinical guidelines and consensus statements. Consistent with CMSS principles, SGO received no funding from any manufacturer to support the development of this Consensus Statement nor any other clinical consensus statement or practice guideline developed and published by SGO. In accordance with CMSS principles, SGO requires that its clinical documents be subject to multiple levels of review beginning with a review by SGOs full Clinical Practice Committee. After review and approval by the Clinical Practice Committee, Consensus Statements are submitted to the SGO Council which is SGOs governing body which reviewed and approved the Consensus Statement for submission to SGOs Journal. None of the members of the SGO Council has a financial or other relationship with Intuitive. In accordance with those principles, each member of the Robotics Clinical Task Forcewhich developed the Consensus Statement executed a detailed disclosure statement prior to participating in the Task Force. There is currently only one manufacturer of robotic gynecology technology, Intuitive Surgical Inc., of Sunnyvale, California (“Intuitive”). Onemember of the thirteenmembers of the Robotics Clinical Task Force has a consulting relationship with Intuitive and receives honoraria from Intuitive for teaching advanced courses at his institution. SGO has received unrestricted educational grants from Intuitive to provide educational support for its annual and winter meetings at approximately

Vaginal cuff dehiscence after robotic total laparoscopic hysterectomy.

25,000 a year over 5 years. All content for these educational programs was developed in accordance with ACCME standards. Clinical Documents are intended to be educational devices that provide information that may assist healthcare providers in caring for patients. This Clinical Document is not a rule and should not be construed as establishing a legal standard of care or as encouraging,

A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer

BACKGROUND: Vaginal cuff dehiscence with small bowel evisceration after hysterectomy is a rare event that may be occurring more frequently with the advent of robotic laparoscopic hysterectomies. CASES: Two women underwent robotic total laparoscopic hysterectomy for menorrhagia and stage I endocervical adenocarcinoma, respectively. Each presented 7–8 weeks postoperatively with abdominal pain and vaginal pressure after intercourse. The small bowel protruded into the vagina through the dehisced vaginal cuff. Both cuffs were repaired vaginally with delayed absorbable suture. One repair required revision 7 weeks after the initial repair. CONCLUSION: Robotic total laparoscopic hysterectomy may be associated with increased risk of vaginal cuff dehiscence and small bowel evisceration. This observation may be because of thermal spread and cuff tissue damage from electrosurgery used for colpotomy.

Robotic-assisted laparoscopic exenteration in recurrent cervical cancer Robotics improved the surgical experience for 2 women with recurrent cervical cancer.

OBJECTIVE Ten percent of ovarian cancer is attributed to hereditary syndromes, most commonly to mutations in the BRCA1 or BRCA2 genes. These cancers are characterized by a prolonged sensitivity to platinum agents in spite of presentation at advanced stages. We hypothesized that women with BRCA-associated ovarian cancer would also show a high response rate to pegylated liposomal doxorubicin (Doxil). METHODS A retrospective cohort study was conducted to compare the response rate, progression-free, and overall survival among women with BRCA-associated or sporadic ovarian cancer who were treated with Doxil. RESULTS A response to Doxil was seen in 13 of 23 patients with BRCA mutations (56.5%; 3 by RECIST criteria and 10 by CA125 levels) compared with only 8 of 41 women with non-hereditary cancers (19.5%; 2 by RECIST criteria and 6 by CA125 levels; p=0.004). This was associated with an improved progression-free and overall survival as measured from the time of Doxil administration. Notably, platinum sensitivity did not directly correlate with a response to Doxil. CONCLUSIONS Women with BRCA-associated ovarian tumors demonstrate a greater sensitivity to cytotoxic therapy with Doxil than has previously been reported in unselected cases.

Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18

Pelvic exenteration can be used to cure women with a central pelvic recurrence or persistence of gynecologic malignancy after initial definitive therapy. Refinements in patient selection, operative techniques, and surgical instrumentation have significantly improved outcomes over the past 60 years, but the procedure is still associated with significant mortality, morbidity, and recovery time. New technologies have made it possible to approach radical gynecologic surgeries in a minimally invasive fashion. We present 2 patients successfully treated with robotic-assisted anterior pelvic exenteration for treatment of persistent or recurrent cervical cancer after definitive radiotherapy.