Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity. Significance: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511

BACKGROUND. Tissue inhibitor of metalloproteinase‐1 (TIMP‐1) has paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of matrix metalloproteinases and apoptosis as well as promotion of angiogenesis and tumor growth. Elevated TIMP‐1 levels have been associated with a poorer prognosis in multiple cancers. METHODS. Ethylenediaminetetraacetic acid plasma TIMP‐1 was determined in 362 castration‐resistant prostate cancer (PC) patients using a TIMP‐1 enzyme‐linked immunosorbent assay. All patients with castration‐resistant PC and available plasma were identified from an institutional database. Overall survival was analyzed using the Kaplan‐Meier method and Cox modeling on plasma TIMP‐1 tertiles. RESULTS. Patients were evaluated in pilot (n = 60) and primary (n = 302) sets. Median follow‐up from diagnosis was 5.8 and 6.6 years, respectively. Median plasma TIMP‐1 levels were 335 and 183 ng/mL in the pilot and primary sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP‐1 in both datasets (P<.001). For the primary cohort, hazard ratio of (HR) death and median survival by plasma TIMP‐1 tertile levels were: low, HR 1.0, 43 months; middle, HR 1.7, 27 months; high, HR 2.4, 19 months. In the primary set, significant covariates in the adjusted Cox regression model were: TIMP‐1 level (mid or high vs low tertile), prostate‐specific antigen (>20 vs ≤20 ng/mL), alkaline phosphatase (>102 vs ≤102 U/L), Eastern Cooperative Oncology Group performance status (1 + vs 0), and Gleason score (7 or 8 vs ≤6). CONCLUSIONS. Elevated plasma TIMP‐1 levels predicted decreased survival in metastatic castration‐resistant PC patients, independent of known prognostic markers. Cancer 2011. © 2010 American Cancer Society.

The aim of our study is to evaluate the role of electrosurgery and vaginal closure technique in the development of postoperative vaginal cuff dehiscence. From prospective surgical databases, we identified 463 patients who underwent total laparoscopic hysterectomy (TLH) for benign disease and 147 patients who underwent laparoscopic-assisted vaginal hysterectomy (LAVH) for cancer. All TLHs and LAVHs were performed entirely by use of electrosurgery, including colpotomy. Colpotomy in the TLH group was performed with Harmonic Ace Curved Shears (Ethicon Endo-Surgery, Cincinnati, OH, USA), and in the LAVH group, it was performed with a monopolar electrosurgical pencil. The main surgical difference was vaginal cuff closure--laparoscopically in the TLH group and vaginally in the LAVH group. Although patients in the LAVH group were at increased risk for poor healing (significantly older, higher body mass index, more medical comorbidities, higher blood loss, and longer operative time), there were no vaginal cuff dehiscences in the LAVH group compared with 17 vaginal cuff dehiscences (4%) in the TLH group (P = .02). It does not appear that the increased vaginal cuff dehiscence rate associated with TLH is due to electrosurgery; rather, it is due to the vaginal closure technique.