Biological Insights into Chemotherapy Resistance in Ovarian Cancer.

The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance.

Postoperative readmissions following ileostomy formation among patients with a gynecologic malignancy.

OBJECTIVES: Ileostomy results in a relatively poorer water reabsorption and is associated with dehydration and renal injury. These problems may be exacerbated in the setting of gynecologic cancers owing to both patient and disease-related factors. We evaluated the rate and reasons for hospital readmission within 30 days of ileostomy creation in patients with a gynecologic malignancy. METHODS: We performed a retrospective review of women with gynecologic malignancies who underwent ileostomy creation between 2002 and 2013. RESULTS: Fifty-three patients were eligible for analysis. The mean age was 63.3 years. Most patients had ovarian cancer (86.5%). Indications for ileostomy included small bowel obstruction (45.3%), as part of primary debulking (18.9%), or treatment of an anastomotic leak (15.1%). The 30-day readmission rate was 34%. Co-morbid diseases such as hypertension (p=0.008) and chronic kidney disease (p=0.010) were more common among women who were readmitted. The most common reasons for readmission were dehydration (38.9%) and acute renal failure (33.3%); women readmitted for these conditions had higher average serum creatinine levels at initial postoperative discharge (1.00 mg/dL versus 0.71 mg/dL, p=0.017) than women who did not require readmission. Readmitted women had a trend toward shorter overall survival (0.41 years versus 1.67 years, p=0.061). CONCLUSIONS: Readmission rates for gynecologic oncology patients undergoing ileostomy were similar to, but higher than those previously reported in the colorectal literature. In our population, patients with preexisting cardiovascular or renal disease were at the highest risk of readmission and may benefit from preemptive strategies to decrease high ostomy output and dehydration.

Neoadjuvant chemotherapy (NACT) is an effective way of managing elderly women with advanced stage ovarian cancer (FIGO Stage IIIC and IV).

BACKGROUND: To compare outcomes in women ≥ age 70 who receive neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC) followed by cytoreductive surgery with those undergoing upfront cytoreductive surgery followed by the same chemotherapy. METHODS: A retrospective cohort study was performed for women ≥ age 70 with Stage IIIC or Stage IV EOC from 1996 to 2009. RESULTS: Sixty-two patients who underwent upfront cytoreductive surgery and 42 patients who received NACT were eligible for analysis. Patients receiving NACT were significantly more likely to have Stage IV disease (P = 0.004). Cytoreduction to no macroscopic disease was achieved in 71.4% of women who received NACT and 28.1% of women undergoing upfront surgery (P < 0.001). NACT patients had significantly less blood loss at surgery (P = 0.01), required fewer small bowel resections (P = 0.009), had shorter ICU stays (P = 0.02) and fewer hospital days (P = 0.04). NACT patients experienced a trend toward an improved progression-free survival (P = 0.078); however, no statistically significant differences were found in either the progression-free or overall survival analyses. CONCLUSION: NACT is associated with reduced perioperative morbidity in elderly patients with advanced stage ovarian cancer.

Expression of tissue factor in adenocarcinoma and squamous cell carcinoma of the uterine cervix: implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor.

BACKGROUND: Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology. METHODS: Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-51chromium-release-assays against cervical cancer cell lines in vitro. RESULTS: Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (p=0.0023 qRT-PCR; p=0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing±SD, 56.2%±15.9%, range, 32.4%-76.9%, p<0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p=0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p=0.597). CONCLUSIONS: TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.

Impact of age on preoperative and postoperative urinary incontinence quality of life.

OBJECTIVE: The objective of the study was to estimate the effect of age on quality of life in women with urinary incontinence before and following antiincontinence surgery. STUDY DESIGN: We performed a retrospective cohort study of women who underwent surgery for stress urinary incontinence from December 2003 to August 2005. Younger women were defined as age younger than 60 years and older women were defined as age 60 years or older. Quality of life was measured using Incontinence Impact Questionnaire (IIQ)-7 and Urogenital Distress Inventory (UDI)-6 questionnaires pre- and postoperatively. Multiple linear regression was performed to estimate the effect of age on improvement in quality-of-life scores. RESULTS: One hundred sixty-eight younger women and 81 older women were included. Older women had lower mean baseline IIQ-7 scores (P < .01) and had less improvement in IIQ-7 scores postoperatively (P = .02) when compared with younger women. After adjusting for baseline IIQ-7 score using multiple linear regression, age was no longer associated with decreasing improvements in quality-of-life scores following surgical treatment. CONCLUSIONS: Antiincontinence surgery is associated with improved quality of life in both older and younger women.

Aggressive Angiomyxoma of the Vulva and Bladder.

BACKGROUND: Aggressive angiomyxoma is a rare, locally infiltrative tumor, frequently occurring in female patients. Although wide local excision is considered standard therapy, radical surgery may be needed. CASE: A 49-year-old woman presented with an aggressive angiomyxoma involving the vulva and bladder. Given the hormone receptor status and size of the tumor, the patient was initially treated with fulvestrant and goserelin acetate in an attempt to reduce the size of the mass. She was followed up at 1- to 3-month intervals; after 6 months of treatment, owing to increasing size of the mass and worsening symptoms, the decision was made to proceed with radical surgery. CONCLUSION: Although a less radical surgical approach is preferred, radical surgery is possible for treatment of aggressive angiomyxoma when needed.

Enhanced Recovery Program and Length of Stay After Laparotomy on a Gynecologic Oncology Service: A Randomized Controlled Trial.

OBJECTIVE: To estimate whether a rapid recovery program would reduce length of stay among patients undergoing laparotomy on a gynecologic oncology service. METHODS: We conducted a prospective, randomized, controlled trial comparing an enhanced recovery after surgery protocol with routine postoperative care among women undergoing laparotomy on the gynecologic oncology service. Protocol elements included: preoperative counseling, regional anesthesia, intraoperative fluid restriction, and early postoperative ambulation and feeding. A sample size of 50 per group (N=100) was planned to achieve 80% power to detect a two-day difference in our primary outcome, length of hospital stay; secondary outcomes included: total daily narcotics used, time to postoperative milestones, and complications. RESULTS: A total of 112 women were enrolled between 2013 and 2015. Nine patients did not undergo laparotomy and were excluded, leaving 52 and 51 patients in the control and intervention groups, respectively. There was no difference in length of stay between the two groups (median 3.0 in both groups; P=.36). Enhanced recovery after surgery patients used less narcotics on day 0 (10.0 compared with 5.5 morphine equivalents in the control and intervention arms, respectively, P=.09) and day 2 (10.0 compared with 7.5 morphine equivalents, respectively; P=.05); however, there was no statistically significant difference between groups in any of the secondary outcomes. Post hoc analysis based on actual anesthesia received also failed to demonstrate a difference in time to discharge. CONCLUSION: When compared with usual care, introducing a formal enhanced recovery after surgery protocol did not significantly reduce length of stay. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01705288.

Long term follow-up of a phase II trial of multimodal therapy given in a "sandwich" method for stage III, IV, and recurrent endometrial cancer.

BACKGROUND: Our objective was to determine if previously reported overall survival (OS) and progression-free survival (PFS) rates are maintained long term following multimodal therapy for advanced and recurrent endometrial cancer and to assess the lymphedema rates associated with this therapy. METHODS: Women with advanced-stage or recurrent endometrial cancer were recruited between 9/2004 and 6/2009 to our previously published Phase II trial. Patients received intravenous docetaxel (75 mg/m2) and carboplatin (AUC = 6) every 3 weeks for 3 cycles before and after radiation therapy. Patient outcomes were updated in July 2014. Data abstracted included presence of lymphedema, disease progression, and death. OS and PFS estimates at 5 years were calculated using Kaplan-Meier methods. RESULTS: Of the 41 patients enrolled, 10 (24 %) had stage IIIA and 21 (51 %) had stage IIIC disease; 32 (78 %) had endometrioid histology; and 35 (85 %) completed the protocol. With a median follow-up of 5 years, 15 of 41 patients have died. The Kaplan-Meier estimate and 95 % CI for OS at 5 years was 70 % (53-82 %). Excluding the two patients with recurrent disease at enrollment, 15 of 39 patients progressed or died during follow-up. The Kaplan-Meier estimate and 95 % CI for PFS at 5 years was 66 % (48-78 %). Fifteen patients (37 %) had medical record documentation of lymphedema following treatment. CONCLUSIONS: After additional follow-up, OS and PFS estimates remain high and in-field recurrences low following "sandwich" therapy. The "sandwich" method remains efficacious for women with stage III-IV or recurrent endometrial cancer.

Class III ß-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel.

Critics have suggested that neoadjuvant chemotherapy (NACT) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. ß-tubulins are chemotherapeutic targets of taxanes and epothilones. Class III ß-tubulin overexpression has been linked to chemoresistance and hypoxia. Herein, we describe changes in class III ß-tubulin in patients with advanced ovarian carcinoma in response to NACT, in relationship to clinical outcome, and between patients who underwent NACT versus primary debulking; we characterize in vitro chemosensitivity to paclitaxel/patupilone of cell lines established from this patient population, and class III ß-tubulin expression following repeated exposure to paclitaxel. Using immunohistochemistry, we observed among 22 paired specimens obtained before/after NACT decreased expression of class III ß-tubulin following therapy within stroma (p=0.07), but not tumor (p=0.63). Poor median overall survival was predicted by high levels of class III ß-tubulin in both tumor (HR 3.66 [1.11,12.05], p=0.03) and stroma (HR 4.53 [1.28,16.1], p=0.02). Class III ß-tubulin expression by quantitative-real-time-polymerase-chain-reaction was higher among patients who received NACT (n=12) compared to primary cytoreduction (n=14) (mean±SD fold-change: 491.2±115.9 vs. 224.1±55.66, p=0.037). In vitro subculture with paclitaxel resulted in class III ß-tubulin upregulation, however, cell lines that overexpressed class III ß-tubulin remained sensitive to patupilone. Overexpression of class III ß-tubulin in patients dispositioned to NACT may thus identify an intrinsically aggressive phenotype, and predict poor overall survival and paclitaxel resistance. Decreases in stromal expression may represent normalization of the tumor microenvironment following therapy. Epothilones warrant study for patients who have received neoadjuvant carboplatin and paclitaxel.