Bovine and human endometrium-derived hydrogels support organoid culture from healthy and cancerous tissues.

Organoid technology has provided unique insights into human organ development, function, and diseases. Patient-derived organoids are increasingly used for drug screening, modeling rare disorders, designing regenerative therapies, and understanding disease pathogenesis. However, the use of Matrigel to grow organoids represents a major challenge in the clinical translation of organoid technology. Matrigel is a poorly defined mixture of extracellular matrix proteins and growth factors extracted from the Engelbreth-Holm-Swarm mouse tumor. The extracellular matrix is a major driver of multiple cellular processes and differs significantly between tissues as well as in healthy and disease states of the same tissue. Therefore, we envisioned that the extracellular matrix derived from a native healthy tissue would be able to support organoid growth akin to organogenesis in vivo. Here, we have developed hydrogels from decellularized human and bovine endometrium. These hydrogels supported the growth of mouse and human endometrial organoids, which was comparable to Matrigel. Organoids grown in endometrial hydrogels were proteomically more similar to the native tissue than those cultured in Matrigel. Proteomic and Raman microspectroscopy analyses showed that the method of decellularization affects the biochemical composition of hydrogels and, subsequently, their ability to support organoid growth. The amount of laminin in hydrogels correlated with the number and shape of organoids. We also demonstrated the utility of endometrial hydrogels in developing solid scaffolds for supporting high-throughput, cell culture-based applications. In summary, endometrial hydrogels overcome a major limitation of organoid technology and greatly expand the applicability of organoids to understand endometrial biology and associated pathologies.

Proteomic and functional characterization of intra-tumor heterogeneity in human endometrial cancer.

Endometrial cancer is one of the most frequently diagnosed gynecological cancers worldwide, and its prevalence has increased by more than 50% over the last two decades. Despite the understanding of the major signaling pathways driving the growth and metastasis of endometrial cancer, clinical trials targeting these signals have reported poor outcomes. The heterogeneous nature of endometrial cancer is suspected to be one of the key reasons for the failure of targeted therapies. In this study, we perform a sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based comparative proteomic analysis of 63 tumor biopsies collected from 20 patients and define differences in protein signature in multiple regions of the same tumor. We develop organoids from multiple biopsies collected from the same tumor and show that organoids capture heterogeneity in endometrial cancer growth. Overall, using quantitative proteomics and patient-derived organoids, we define the heterogeneous nature of endometrial cancer within a patient's tumor.

Nucleotide excision repair protein ERCC1 and tumour-infiltrating lymphocytes are potential biomarkers of neoadjuvant platinum resistance in high grade serous ovarian cancer.

OBJECTIVE: ERCC1 is a nucleotide excision repair protein that may have a role in drug resistance in high grade serous ovarian cancer (HGSOC). We hypothesized that ERCC1 expression and tumour infiltrating lymphocytes (TILS) are induced by chemotherapy in HGSOC, which may be prognostically useful. METHODS: 115 HGSOC patients were used for this study. 92 (80%) of the tissue analysed had not been exposed to platinum chemotherapy. The remaining 20% (n = 23) of cases received combination or monotherapy with carboplatin before tissue was collected. Immunohistochemistry was used to score for ERCC1 expression and morphology to score for TILs. Correlation analysis of all clinical parameters, TILs and ERCC1 and Kaplan-Meier survival analysis was performed using the ERCC1 and TILs scoring parameters (0, 1, 2 or 3). RESULTS: ERCC1 expression was 2-fold higher in the neoadjuvant chemotherapy group compared to the primary cytoreductive surgery group (p < 0.0001). The mean overall survival for the neoadjuvant group with high ERCC1 was 141.6 ±â€¯20.2 months which was significantly longer than absent ERCC1 survival of 61 + 22.6 months (p = 0.028). ERCC1 score strongly correlated with TILs score across the whole cohort (0.349, p = 1.3 × 10-4) suggesting there is a relationship between ERCC1 expression and TILs, but this requires further investigation. CONCLUSION: In conclusion, ERCC1 was identified as a potential biomarker of platinum response overall survival in HGSOC undergoing neoadjuvant HGSOC treatment.

Adipose-Derived VEGF-mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women.

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.Implications: Adipocyte-derived VEGF-mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309-21. ©2017 AACR.

Examining word association networks: A cross-country comparison of women's perceptions of HPV testing and vaccination.

In this study, we examined the perceptual associations women hold with regard to cervical cancer testing and vaccination across two countries, the U.S. and Australia. In a large-scale online survey, we presented participants with 'trigger' words, and asked them to state sequentially other words that came to mind. We used this data to construct detailed term co-occurrence network graphs, which we analyzed using basic topological ranking techniques. The results showed that women hold divergent perceptual associations regarding trigger words relating to cervical cancer screening tools, i.e. human papillomavirus (HPV) testing and vaccination, which indicate health knowledge deficiencies with non-HPV related associations emerging from the data. This result was found to be consistent across the country groups studied. Our findings are critical in optimizing consumer education and public service announcements to minimize misperceptions relating to HPV testing and vaccination in order to maximize adoption of cervical cancer prevention tools.

Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer.

BACKGROUND: Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. OBJECTIVES: To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. SEARCH METHODS: We searched the Gynaecological Cancer Review Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010, May 2011 and September 2015. In addition, we handsearched and cascade searched the major gynaecological oncology journals up to May 2011. SELECTION CRITERIA: The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. DATA COLLECTION AND ANALYSIS: We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. MAIN RESULTS: Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less likely to die if they received an IP component to chemotherapy (eight studies, 2026 women; HR = 0.81; 95% confidence interval (CI): 0.72 to 0.90). Intraperitoneal component chemotherapy prolonged the disease-free interval (five studies, 1311 women; HR = 0.78; 95% CI: 0.70 to 0.86). There was greater serious toxicity with regard to gastrointestinal effects, pain, fever and infection but less ototoxicity with the IP than the IV route. AUTHORS' CONCLUSIONS: Intraperitoneal chemotherapy increases overall survival and progression-free survival from advanced ovarian cancer. The results of this meta-analysis provide the most reliable estimates of the relative survival benefits of IP over IV therapy and should be used as part of the decision making process. However, the potential for catheter related complications and toxicity needs to be considered when deciding on the most appropriate treatment for each individual woman. The optimal dose, timing and mechanism of administration cannot be addressed from this meta-analysis. This needs to be addressed in the next phase of clinical trials.

Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer.

BACKGROUND: Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. OBJECTIVES: To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. SEARCH METHODS: We searched the Gynaecological Cancer Review Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010 and May 2011. In addition, we handsearched and cascade searched the major gynaecological oncology journals. SELECTION CRITERIA: The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. DATA COLLECTION AND ANALYSIS: We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. MAIN RESULTS: Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less likely to die if they received an IP component to chemotherapy (eight studies, 2026 women; HR = 0.81; 95% confidence interval (CI): 0.72 to 0.90). Intraperitoneal component chemotherapy prolonged the disease-free interval (five studies, 1311 women; HR = 0.78; 95% CI: 0.70 to 0.86). There was greater serious toxicity with regard to gastrointestinal effects, pain, fever and infection but less ototoxicity with the IP than the IV route. AUTHORS' CONCLUSIONS: Intraperitoneal chemotherapy increases overall survival and progression-free survival from advanced ovarian cancer. The results of this meta-analysis provide the most reliable estimates of the relative survival benefits of IP over IV therapy and should be used as part of the decision making process. However, the potential for catheter related complications and toxicity needs to be considered when deciding on the most appropriate treatment for each individual woman. The optimal dose, timing and mechanism of administration cannot be addressed from this meta-analysis. This needs to be addressed in the next phase of clinical trials.

Positron emission tomography and granulosa cell tumor recurrence: a report of 2 cases.

Two case reports of women with recurrent granulosa cell tumors identified initially by increasing levels of inhibin. As part of their investigation to assess the extent of the recurrence, an abdominopelvic computed tomography and a positron emission tomography scans were performed. Interestingly, the recurrent tumors were identified on the abdominopelvic computed tomography but not on the positron emission tomography scan. These recurrences were confirmed at surgery, and the histopathologic findings were identical to the original lesion.