Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference.

Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.

Acute inflammatory reaction following placement of sodium hyaluronate-carboxymethylcellulose barrier in a young woman undergoing gynecologic surgery: a case report.

BACKGROUND: Hyaluronate-carboxymethylcellulose (HA-CMC) is commonly used to inhibit adhesion formation in women undergoing gynecologic surgery. CASE: A 38-year old woman underwent a bilateral salpingo-oophorectomy for the indication of persistent pelvic pain following a hysterectomy, an ovarian cyst and endometriosis. HA-CMC was placed at the time of surgery. The patient returned to the operating room on postoperative day 3 with an acute inflammatory reaction and small bowel obstruction. A mast cell infiltrate and acute serosal damage was observed on final histopathology of the resection portion of small bowel. CONCLUSION: Few case reports describing adverse events with the use of HA-CMC have been published. This patient appears to have had a paradoxical inflammatory reaction to this adhesion barrier.

The expression of hepatocyte growth factor (HGF) and c-Met in uterine serous carcinoma.

OBJECTIVE: The hepatocyte growth factor (HGF) receptor c-Met plays an important role in tumor dissemination by activating mitogenic signaling pathways. The goal of this study was to investigate immunohistochemical (IHC) staining patterns of HGF and c-Met in endometrioid endometrial cancer (EC) and uterine serous cancer (USC) and to correlate staining with patient outcomes. METHODS: A tissue microarray was created using tissue from patients with atrophic endometrium (AE), grade 1 EC, grade 3 EC, and USC. Immunohistochemistry was used to detect c-Met, phosphorylated c-Met (p-c-Met), and HGF expression. Differences between IHC staining intensity were calculated using t-tests. Correlations between staining and clinicopathologic variables were determined by Chi-square testing for categorical variables and t-tests for continuous variables. Kaplan-Meier curves were constructed to analyze survival in USC. RESULTS: Patients with cancer had more total c-Met and HGF expression than those with AE (p=0.037, p<0.001 respectively), but no difference in p-c-Met staining. Total c-Met and HGF staining was significantly different between groups (p=0.042, p<0.001 respectively). This difference was accounted for by greater c-MET expression in USC compared to AE (p=0.027). Depth of invasion, stage, and lymph node status were not significantly related to staining intensity. Patients with strong c-Met and HGF staining had decreased overall survival compared to patients with weaker staining. CONCLUSIONS: HGF and c-Met may play a role in the progression of endometrial cancer and should be studied further as prognostic and therapeutic tools.

Combination analysis of activator protein-1 family members, Sp1 and an activator protein-2alpha-related factor binding to different regions of the urokinase receptor gene in resected colorectal cancers.

PURPOSE: Studies on the transactivation of genes via promoter elements have mostly been done on cell lines rather than resected tissues. This, however, is essential to address an in vivo or clinical relevance. We have previously shown tumor-specific binding of Sp1 and an activator protein (AP)-2-related factor to promoter region -152/-135 of the metastasis-related u-PAR gene in 60% of in vivo-resected cancer tissues. Cell lines have implicated an additional role, and potential synergism, of an AP-1 region (-190/-171) in u-PAR regulation. This study was done to (a) analyze AP-1 binding to this region in resected tumor and normal tissues, and define subgroups in which it is tumor-specific, and (b) to analyze transcription factor-binding patterns to both promoter motifs in resected tissues, supporting synergism, and draw first prognostic conclusions. EXPERIMENTAL DESIGN: In 103 patients with colorectal cancer, electrophoretic mobility shift assay/supershift analysis for u-PAR promoter region -190/-171 was done in tumors and normal tissues. In 71 patients, region -152/-135 was also analyzed. U-PAR protein was measured by ELISA. RESULTS: Tumor-specific AP-1 binding to region -190/-171 of the u-PAR promoter was found in 40% of patients. Subgroup analysis showed tumor-specific binding for c-Fos in 58%, for c-Jun in 50%, for JunD in 39%, and for Fra-1 in 4% of cases. AP-1 binding correlated significantly with u-PAR protein amounts in both normal and tumor tissues (P<0.001), in contrast to a tumor-specific correlation with u-PAR of the AP-2/Sp1 region. In analyses for both promoter regions, 62% of cancers showed simultaneous binding for AP-1, AP-2, and Sp1, 11% for AP-1 and AP-2, 16% for AP-2 and Sp1, 4% for AP-2 only, 3% for AP-1 only, and 0% for Sp1 only. The binding of AP-1, AP-2, and Sp1 correlated significantly with each other (P<0.001), the combination of AP-1 and AP-2 showing the highest correlation with u-PAR (P=0.008). Preliminary survival analysis indicated a trend for poorer prognosis for binding of all three transcription factors. CONCLUSION: This is the first study differentiating transcription factor-binding to two important u-PAR promoter regions in a large series of resected tumors and normal tissues. The AP-1 site seems to be a less tumor-specific regulator than the Sp1/AP-2 motif. Nevertheless, data corroborate the hypothesis of synergism between both elements in resected tumors.

Single-agent pulse dactinomycin has only modest activity for methotrexate-resistant gestational trophoblastic neoplasia.

OBJECTIVES: To determine the effectiveness of single-agent pulse dactinomycin for methotrexate-resistant low-risk gestational trophoblastic neoplasia (GTN). METHODS: Ten patients with low-risk GTN (WHO/FIGO score <8) previously treated with uterine evacuation and single-agent methotrexate were treated with pulse dactinomycin 1.25 mg/m(2) every 2 weeks. RESULTS: Patients had antecedent pregnancies of complete mole (7), partial mole (1), missed abortion (1), and choriocarcinoma (1). One patient underwent hysterectomy during methotrexate treatment. The mean hCG level and WHO score before dactinomycin was 1476 and 4.1, respectively. Six of 10 (60%) patients achieved complete remission with single-agent pulse dactinomycin. Two others responded to a 5-day regimen of dactinomycin, 1 responded to a multidrug regimen, and 1 had chemo-resistant disease dying of metastatic choriocarcinoma. After median follow-up of 11.9 months, 9 of 10 patients remain without relapse. A mean of 3.3 (1-6) cycles were given-4.5 (3-6) for responders and 1.5 (1-2) for nonresponders. In 33 cycles of chemotherapy administered, there were 46 toxicity events: all events were graded as 1. While WHO scores were comparable between responders and nonresponders (mean 3.8 vs. 4.5), hCG levels were lower in responders (mean 37 vs. 3634) but the sample size was too small to reach statistical significance. CONCLUSIONS: Although remission rates of 80-90% have been reported for pulse dactinomycin, patients with methotrexate-resistant GTN had only a 60% remission rate. Prediction of remission may be more closely associated with hCG levels than with WHO score alone.

Tumor-specific transcription factor binding to an activator protein-2/Sp1 element of the urokinase-type plasminogen activator receptor promoter in a first large series of resected gastrointestinal cancers.

PURPOSE: Evidence for transactivation of genes via specific promoter elements has been derived from studies on tumor cell lines but rarely on resected tumors. However, the proof of an in vivo relevance and the identification of patients with a potential tumor-specific gene expression is essential to transfer molecular-targeting strategies into clinical applications. This study gives the first clinical evidence that urokinase-type plasminogen activator receptor (u-PAR) gene expression is tumor-specifically regulated via an activator protein (AP)-2/Sp1 promoter element in a large patient subpopulation. EXPERIMENTAL DESIGN: In 145 gastrointestinal cancer patients, electrophoretic mobility shift analysis and supershift assays for u-PAR-promoter region -152/-135 were performed in tumors and corresponding normal tissues. u-PAR protein levels were measured by ELISA. RESULTS: Binding of Sp1 to region -152/-135 in tumors in contrast to corresponding normal mucosae was observed in 55% of colorectal and in 52% of gastric cancer patients. Tumor-specific binding of an AP-2-related factor was seen in 59% of colorectal and in 63% of gastric cancer patients. A significant correlation between AP-2 (P < 0.0001) and Sp1 (P = 0.0003) binding with a high u-PAR expression was observed in tumors but not in normal mucosae. Tissues of five nontumor patients did not show transcription factor binding to this region. CONCLUSIONS: This is the first study to show the tumor-specific binding of trans-activators to the u-PAR promoter region (-152/-135) biochemically in a large series of resected tumors. For the subpopulation of approximately 60% of patients with tumor-restricted u-PAR-transactivation, a molecular targeting of this region or its activating pathways should be pursued as a new antimetastasis therapy approach.