Novel Approach for 2-Port Laparoscopic Hysterectomy.

Background and Objectives. To describe a novel technique for a port-reducing laparoscopic hysterectomy. The 2-port laparoscopic hysterectomy (TPH) is performed through two 5-mm ports without the use of any multiport channels. We demonstrate outcomes via a large case series. We also describe and provide a video showing the TPH technique. Methods. Retrospective comparative study between the newly developed TPH and the conventional 4-port hysterectomy techniques. Variables of patients who underwent a TPH with fellowship-trained gynecologic surgeons at a single academic university hospital were collected through electronic medical records chart review. Results. Forty-five patients underwent a TPH. Mean age was 39.4, body mass index was 28.5 kg/m2, and uterine weight was 170.0 g. Our outcomes of interest were operative time (98.4 minutes, mean), estimated blood loss (65.6 mL, mean), conversion to 3-port (1/45), and intraoperative (0/45) and postoperative (5/45) complications. By comparing the TPH to the conventional 4-port laparoscopic hysterectomy within a similar setting, we provide insight into variables that prompt the minimally invasive gynecologic surgeon to perform a port-reducing procedure. Patients were more likely to be allocated for a TPH if they were younger (37.8 vs 44.7, P = .005), had a lower body mass index (29.0 vs 32.5, P = .07), smaller uterus (143.1 vs 672.3 g, P < .001), and were white (56.8% and 22.4%, P < .001). Conclusions. The TPH is a novel port-reducing hysterectomy that is safe in a subset of patients with small uteri and limited surgical history who require no other surgical interventions at the time of hysterectomy.

Epigenetic therapy for ovarian cancer: promise and progress.

Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer.

Survival Disparities by Hospital Volume Among American Women With Gynecologic Cancers.

PURPOSE: We describe survival disparities among women with uterine, ovarian, or cervical cancer by cancer-specific mean annual hospital volume. METHODS: National Cancer Database 1998-2011 uterine (n = 441,863), ovarian (n = 223,017), and cervical (n = 146,698) cancer data sets were used. Cancer-specific mean annual hospital volumes were calculated. Overall survival (OS) was plotted by hospital volume using restricted mean OS times from Cox regression. RESULTS: Uterine, ovarian, and cervical cancers were reported from 1,651, 1,633, and 1,600 hospitals, respectively. Median values of mean annual hospital volumes among hospitals were 8.6 (interquartile range [IQR], 2.6 to 20.8), 4.4 (IQR, 1.4 to 10.3), and 2.4 (IQR, 0.6 to 6.6) for uterine, ovarian, and cervical cancers, respectively. Increased hospital volume was associated with increased OS among women with stage III to IV high-grade serous ovarian cancer, stage II to IV squamous or adenocarcinoma cervical cancer, and stage I to IV endometrioid, clear cell, serous, or carcinosarcoma uterine cancers (all P < .03). Differential OS between women treated at higher- versus lower-volume cancer centers exceeded 5, 5, and 13 months among women with advanced endometrial, ovarian, or cervical cancer, respectively (all P < .001). Hospital volume was not associated with OS among patients with stage II to IV cervical cancer treated with brachytherapy ( P = .17). Use of adjuvant therapies decreased OS disparities by hospital volume among women with advanced ovarian or endometrial cancer. CONCLUSION: Increased delivery of brachytherapy for treatment of cervical cancer may decrease survival disparities by hospital volume. Standardization of adjuvant therapies may diminish survival disparities by hospital volume among women with advanced ovarian or endometrial cancer. In addition, survival of American women with gynecologic cancer may be increased by centralization of care.

Wnt Signaling and Survival of Women With High-Grade Serous Ovarian Cancer: A Brief Report.

OBJECTIVE: Ovarian cancer is the gynecologic malignancy with the highest case-fatality rate due to the development of chemotherapy resistance. Predictors of chemotherapy response are needed to guide chemotherapy selection and improve survival for patients with ovarian cancer. Wnt signaling may impact chemoresistance in ovarian cancer. METHODS: We studied The Cancer Genome Atlas patients with ovarian cancer treated with intraperitoneal or intravenous-only adjuvant chemotherapy. Cox regression tested associations of expression of 26 Wnt pathway genes with progression-free survival and overall survival. Permutation tests compared survival between chemotherapy groups stratified by expression. P values are two-tailed. RESULTS: Increased FZD3 was associated with increased survival (intraperitoneal group, overall survival: hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.72, P = 0.009; progression-free survival: HR, 0.58; 95% CI, 0.37-0.92, P = 0.020) (intravenous-only group, overall survival: HR, 0.85; 95% CI, 0.72-0.99, P = 0.039; progression-free survival: HR, 0.83; 95% CI, 0.73-0.95, P = 0.006). Low FZD3 predicted decreased overall survival after intraperitoneal versus intravenous-only chemotherapy (21.7 vs 33.3 months, P < 0.0001). Increased APC2 was associated with decreased overall survival (HR, 1.22; 95% CI, 1.05-1.42; P = 0.009) and progression-free survival (HR, 1.28; 95% CI, 1.12-1.45; P = 0.0002). CONCLUSIONS: Up-regulated tumor Wnt signaling predicts increased ovarian cancer survival. FZD3 may predict benefit from intraperitoneal chemotherapy.

Discovery of candidate tumor biomarkers for treatment with intraperitoneal chemotherapy for ovarian cancer.

Tumor mRNA expression was used to discover genes associated with worse survival or no survival benefit after intraperitoneal (IP) chemotherapy. Data for high grade serous ovarian cancer patients treated with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Progression free survival (PFS) and overall survival (OS) were compared between IP and IV groups using Kaplan-Meier analysis and Cox regression. Validations were performed by analyses of microarray and RNA-Seq mRNA expression data. PFS and OS were compared between IP and IV groups by permutation testing stratified by gene expression. P-values are two-tailed. IP chemotherapy increased PFS (26.7 vs 16.0 months, HR 0.43 (0.28-0.66), p = 0.0001) and OS (49.6 vs 38.2 months, HR 0.46 (0.25-0.83), p = 0.01). Increased expression of NCAM2 and TSHR and decreased expression of GCNT1 was associated with decreased PFS and OS after IV chemotherapy (p < 0.05). High tumor expression of LMAN2, FZD4, FZD5, or STT3A was associated with no significant PFS increase after IP compared to IV chemotherapy. Low expression of APC2 and high expression of FUT9 was associated with 5.5 and 7.2 months, respectively, decreased OS after IP compared to IV chemotherapy (p ≤ 0.007).

Survival of patients with structurally-grouped TP53 mutations in ovarian and breast cancers.

The objective of this study was to determine if ovarian cancer patients with a TP53 mutation grouped by location of the mutation within the p53 protein structure exhibit differential survival outcomes. Data from patients with high grade serous ovarian cancer (HGS OvCa) (N = 316) or breast cancer (BrCa) (N = 981) sequenced by The Cancer Genome Atlas (TCGA) was studied by Kaplan-Meier and Cox proportional hazards survival analysis. A TP53 DNA binding domain (BD) missense mutation (MM) occurred in 58.5% (185/316) of HGS OvCas and 16.8% (165/981) of BrCas. Patients with a TP53 DNA BD MM grouped by structural location had significantly different overall survival (OS) and progression free survival (PFS). Median OS (months) of HGS OvCa patients by structural group were: Sheet-loop-helix stabilizers, 31.1; DNA minor groove residue R248, 33.6; Wild-type, 34.2; all other MMs, 44.5; DNA major groove residues, 84.1, and zinc ion coordinating residues, 87.0 (log-rank p = 0.006). PFS of DNA major groove MM cases was longer than TP53 wild-type cases (19.1 versus 10.1 months, log-rank p = 0.038). HGS OvCa and BrCa patients with structurally-grouped TP53 DNA BD MMs have different survival outcomes.

Metastatic Uterine Leiomyosarcoma Involving Bilateral Ovarian Stroma without Capsular Involvement Implies a Local Route of Hematogenous Dissemination.

Uterine sarcomas spread via lymphatic and hematogenous dissemination, direct extension, or transtubal transport. Distant metastasis often involves the lungs. Ovarian metastasis is uncommon. Here we present an unusual case of a large, high-grade uLMS with metastatic disease internal to both ovaries without capsular involvement or other abdominal diseases, and discovered in a patient with distant metastases to the lungs, suggesting likely hematogenous dissemination of uLMS to the ovaries in this case. Knowledge of usual uLMS metastases may influence surgical management in select cases.

TP53 hot spot mutations in ovarian cancer: selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas.

OBJECTIVE: To test if TP53 hot spot mutations (HSMs) confer differential chemotherapy resistance or survival outcomes, the effects of microtubule stabilizers on human ovarian carcinoma cells (OCCs) expressing TP53 HSMs were studied in vitro. Survival outcomes of patients with high grade serous epithelial ovarian carcinoma (HGS EOC) expressing matched HSMs were compared using The Cancer Genome Atlas (TCGA) data. METHODS: Growth inhibition of OCCs transfected with a HSM (m175, m248 or m273) was measured during treatment with paclitaxel, epothilone B (epoB), or ixabepilone. Effects of epoB on p53 expression, phosphorylation, and acetylation, as well as p53-regulated expression of p21 and mdm2 proteins, were determined by Western blot analysis. Expression of p53 target genes P21, GADD45, BAX, PIDD, NF-kB2, PAI-1, and MDR1 was measured by RT-PCR. cBioPortal.org identified patients with codon R175, R248 or R273 HSMs from TCGA data. Survival outcomes were characterized. RESULTS: p53-m248 confers chemoresistance and is not acetylated during epoB treatment. m273 demonstrated high MDR1 expression and resistance to paclitaxel. P21, GADD45 and PAI-1 expression were down-regulated in mutant OCCs. Optimally cytoreduced patients with codon R273 (n=17), R248 (n=13), R175 (n=7) HSMs, or any other TP53 mutation demonstrated median 14.9, 17.6, 17.8 and 16.9months (p=0.806) progression free survival and 84.1, 33.6, 62.1 and 44.5months (p=0.040) overall survival, respectively. CONCLUSIONS: Human OCCs harboring different TP53 HSMs were selectively resistant to microtubule stabilizers. Patients with different HSMs had significantly different overall survival. Both in vitro data and clinical experience support further studying the outcomes of particular TP53 HSMs.

Delayed and clinically isolated port site carcinosarcoma recurrence as an early indicator of disseminated disease.

A 71-year-old woman with suspected endometrial cancer underwent robotic-assisted hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, and infracolic omentectomy revealing a stage II uterine carcinosarcoma with components of serous adenocarcinoma and undifferentiated spindle cell sarcoma. There was no evidence of distant metastasis at the time of surgery. However pelvic washings were positive for malignant cells. She received adjuvant chemotherapy and vaginal cuff brachytherapy. Forty months later she developed a subcutaneous mass at the location of previous port site which was confirmed to be recurrence of the uterine primary. She subsequently developed additional distant metastases to the abdominal wall, lungs, and bone. Port site metastasis (PSM) was the earliest indicator of disseminated metastatic disease in this patient. We review challenges in the management of patients with PSM and propose that PSM be considered as a sign of systemic disease even when presenting as an apparently isolated recurrence.

Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm.

IMPORTANCE Sebaceous neoplasms (SNs) define the Muir-Torre syndrome variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality.Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SNs can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis are limited.OBJECTIVE To characterize the utility of IHC screening of SNs in identification of germline MMR mutations confirming LS.DESIGN, SETTING, AND PARTICIPANTS Retrospective study at 2 academic cancer centers of 86 adult patients referred for clinical genetics evaluation after diagnosis of SN.MAIN OUTCOMES AND MEASURES Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC testing in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and Muir-Torre syndrome, and family history characteristics were compared between mutation carriers and noncarriers.RESULTS Of 86 patients with SNs, 25 (29%) had germline MMR mutations confirming LS.Among 77 patients with IHC testing on SNs, 38 (49%) had loss of staining of 1 or more MMR proteins and 14 had germline MMR mutations. Immunohistochemical analysis correctly identified 13 of 16 MMR mutation carriers, corresponding to 81% sensitivity. Ten of 12 patients(83%) with more than 1 SN had MMR mutations. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 11 of 25 (44%) did not meet the clinical definition of Muir-Torre syndrome. CONCLUSIONS AND RELEVANCE Immunohistochemical screening of SNs is effective in identifying patients with germline MMR mutations and can be used as a first-line test when LSis suspected. Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has substantial limitations,suggesting that universal IHC screening of SNs merits further study. Clinical genetics evaluation is warranted for patients with abnormal IHC test results, normal IHC test results with personal or family history of other LS-associated neoplasms, and/or multiple SNs.

Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome.

OBJECTIVE: Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age ≥ 35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies. METHODS: The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices. RESULTS: In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1-70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk-reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing. CONCLUSIONS: Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers.

CLINICAL MANAGEMENT OF FAMILIES WITH HEREDITARY COLORECTAL CANCER SYNDROMES.

Hereditary colorectal cancer syndromes can be associated with a lifetime risk of CRC of >70% in the absence of specialized surveillance. Diagnosing a genetic predisposition to cancer allows clinicians to tailor cancer prevention strategies for patients and families at highest risk. Once a genetic syndrome has been identified in a family, communication with family members, timely implementation of screening tests and/or surgeries, and psychosocial support are all instrumental for effective cancer prevention.Molecular screening of tumors, computerized risk assessment models, and genetic testing can help clinicians identify individuals at risk for hereditary cancer syndromes. This review discusses some of the complexities involved in the diagnosis and management of families with hereditary CRC syndromes and provides strategies for coordinating clinical care.