Person:

Garrett, Leslie

Background: Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. Methods: The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589. The effect of LBH589 on cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Serially transplanted primary human high-grade serous ovarian adenocarcinoma tissue was utilized to generate xenografts in 6-week old female NOD/SCID mice. The mice were then randomized into one of 4 treatment groups: (1) vehicle control; (2) paclitaxel and carboplatin (P/C); (3) LBH589; or (4) P/C + LBH589. Mice were treated for 21 days and tumor volumes and mouse weights were obtained every 3 days. These experiments were performed in triplicate with three different patient derived tumors. Wilcoxan rank-sum testing was utilized to assess tumor volume differences. Results: In vitro treatment with LBH589 significantly reduced the viability of both taxol-sensitive and taxol-resistant ovarian cancer cell lines (p < 0.01). In vivo treatment with LBH589 alone appeared tumorstatic and reduced tumor growth when compared to vehicle treatment (p < 0.007) after 21 days. This single agent activity was confirmed in two additional experiments with other PDX tumors (p < 0.03, p < 0.05). A potential additive effect of LBH589 and P/C, manifested as enhanced tumor regression with the addition of LBH589 compared to vehicle (p < 0.02), in one of the three analyzed serous PDX models. Conclusions: Our findings suggest that pan-HDAC inhibition with panobinostat precludes the growth of ovarian cancer cell lines in vitro and PDXs in vivo. Added benefit of LBH589 to standard P/C therapy was observed in one of three PDX models suggesting improved response in a subset of serous ovarian cancers.

Skin metastasis of ovarian cancer is rare, often nodular in appearance, and conveys a poor prognosis. This patient developed an unusual maculo-papular rash which was biopsy-proven to be metastatic endometrioid adenocarcinoma. Pruritic symptoms from skin metastases should be palliated; SSRIs, local radiation, and topical creams all may play a role.

Background: Acquired arteriovenous malformations (AVMs) can develop after uterine instrumentation. The increased risks of vascular changes, including abnormal placentation, after repeated cesarean sections are well studied. Herein, we describe a patient with delayed hemorrhage from a uterine AVM, following dilation and curettage for a cesarean scar pregnancy. Case: A 32-year-old G3P2 presented with a cesarean scar ectopic pregnancy managed with dilation and curettage, which incurred a 1,500-ml blood loss. Within 6 weeks, she returned with 2 episodes of vaginal bleeding. Initial angiography demonstrated a high-flow arteriovenous fistula, which was coiled. Vaginal hemorrhage recurred; repeat angiography demonstrated a large AVM. Gelfoam embolization of the bilateral internal iliac arteries reduced the vascularity of the AVM. The AVM's location, starting at the left lateral apex of the cesarean scar and extending into the parametrium, necessitated a radical hysterectomy. Pathologic examination revealed a placenta percreta extending into the parametrium. Conclusion: The prevalence of uterine AVMs has increased with the rise in surgical obstetrics. In patients with a failed prior interventional procedure, surgical management is necessary to prevent life-threatening hemorrhage. The location of the AVM within the abnormal uterine scar tissue requires familiarity with radical pelvic surgical techniques that are normally used in cancer surgery in order to definitively treat this delayed obstetrical complication.