HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression.

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.

Intraoperative Indocyanine Green Dye Use in Ovarian Torsion: A Feasibility Study.

STUDY OBJECTIVE: To determine the feasibility of  intravenous indocyanine green (ICG) dye use in patients with adnexal torsion to intraoperatively evaluate ovarian perfusion after detorsion. DESIGN: A prospective multicenter single-arm feasibility study. SETTING: A teaching hospital. PATIENTS: A total of 12 nonpregnant patients, 18 to 45 years old with surgically confirmed adnexal torsion. INTERVENTIONS: Torsion was surgically confirmed, the involved adnexa were untwisted laparoscopically, and ICG dye was injected intravenously. The absence or presence of ICG perfusion was documented, and the clinical decision for ovarian conservation or removal was determined by the surgeon. MEASUREMENTS AND MAIN RESULTS: The primary outcome was feasibility of using ICG dye including measures such as time to visualized perfusion and operative time. Secondary outcomes included presence or absence of ovarian preservation and postoperative follow-up measures. Intraoperative visualization of ICG perfusion to the detorsed adnexa was achieved in 10 patients (83%) in a median time of 1 minute (0, 2), resulting in entire (n = 9) or partial (n = 1) ovarian conservation. Perfusion was absent in 2 cases, and postoophorectomy histologic necrosis was confirmed in one case. Median operative time was 74 minutes (48, 94). There were no adverse events related to ICG dye use. CONCLUSION: Intraoperative ICG dye use in this study was logistically feasible and conservation of the entire or partial ovary was observed in 83% of patients, including one case where preoperative Doppler flow was absent.

Postoperative outcomes after continent versus incontinent urinary diversion at the time of pelvic exenteration for gynecologic malignancies.

OBJECTIVE: To compare outcomes of patients undergoing continent or incontinent urinary diversion after pelvic exenteration for gynecologic malignancies. METHODS: Data on patients who underwent pelvic exenteration for gynecologic malignancies at The University of Texas MD Anderson Cancer Center between January 1993 and December 2010 were collected. A multivariate logistic regression model was used and statistical significance was P<0.05. RESULTS: A total of 133 patients were included in this study. The mean age at exenteration was 47.6 (range, 30-73) years in the continent urinary diversion group and 57.2 (range, 27-86) years in the incontinent urinary diversion group (P<0.0001). Forty-six patients (34.6%) had continent urinary diversion, and 87 patients (65.4%) had incontinent urinary diversion. The rates of postoperative complications in patients with continent and incontinent urinary diversion, respectively, were as follows: pyelonephritis, 32.6% versus 37.9% (P=0.58); urinary stone formation, 34.8% versus 2.3% (P<0.001); renal insufficiency, 4.4% versus 14.9% (P=0.09); urostomy stricture, 13.0% versus 1.2% (P=0.007); ureteral (anastomotic) leak, 4.4% versus 6.9% (P=0.71); ureteral (anastomotic) stricture, 13.0% versus 23% (P=0.25); fistula formation, 21.7% versus 19.5% (P=0.82); and reoperation because of complications of urinary diversion, 6.5% versus 2.3% (P=0.34). Among patients with continent urinary diversion, the incidence of incontinence was 28.3%, and 15.2% had difficulty with self-catheterization. CONCLUSION: There were no differences in postoperative complications between patients with continent and incontinent conduits except that stone formation was more common in patients with continent conduits.

The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes.

Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.

Bowel perforation associated with temsirolimus use in a recently irradiated patient.

PURPOSE: A probable case of bowel perforation associated with temsirolimus use in a patient with uterine leiomyosarcoma is reported. SUMMARY: A 45-year-old Hispanic woman reported acute abdominal pain one day after receiving her third weekly i.v. infusion of temsirolimus, a mammalian target of rapamycin inhibitor increasingly used against a variety of cancers, including renal cell carcinoma and soft tissue sarcomas. Temsirolimus had been initiated three weeks previously in an attempt to control retroperitoneal metastases of uterine leiomyosarcoma, which had progressed despite surgical resection, six cycles of adjuvant chemotherapy, and pelvic irradiation. A computed tomography scan revealed a large pelvic mass with foci of gas, fluid collection, and other findings highly suggestive of an abscess due to bowel perforation. Application of the adverse drug reaction probability scale of Naranjo et al. in this case indicated a probable relationship between the bowel perforation and temsirolimus use; a literature search identified no other reported cases of temsirolimus-associated bowel perforation in association with uterine leiomyosarcoma. It is suspected that the patient's recent course of pelvic radiotherapy may have played a role in predisposing her to bowel perforation during temsirolimus use. While the mechanism of bowel perforations associated with temsirolimus therapy remains unclear, it is possible that due to its inhibitory effects on vascular endothelial growth factor (VEGF), temsirolimus use may result in gastrointestinal stresses and weaknesses similar to those attributed to bevacizumab, a VEGF-targeted angiogenesis inhibitor that has been linked to chemotherapy-induced bowel perforation. CONCLUSION: A woman who recently received pelvic radiation experienced a bowel perforation after three infusions of temsirolimus for the treatment of metastatic leiomyosarcoma.