Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Prognostic impact of Dynamin related protein 1 (Drp1) in epithelial ovarian cancer.

BACKGROUND: The mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin-dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA). Thus, we examined the expression of Drp1, CaMKI and their phosphorylated forms and their prognostic impact in epithelial OVCA patients. METHODS: Expression analysis was performed by immunohistochemistry (IHC) of paraffin-embedded tumor samples from 49 patients with epithelial OVCA. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score (IRS) of 0-12. The expression scores calculated were correlated with clinicopathological parameters and patient survival. RESULTS: High immunoreactivity of phospho-Drp1Ser637 was significantly correlated with high-grade serous carcinoma (HGSC) (p = 0.034), residual postoperative tumor of > 1 cm (p = 0.006), and non-responders to adjuvant chemotherapy (p = 0.007), whereas high expression of CaMKI was significantly correlated with stage III/IV [International Federation of Gynecologists and Obstetricians (FIGO)] (p = 0.011) and platinum-resistant recurrence (p = 0.030). ROC curve analysis showed that Drp1, phospho-Drp1Ser637 and CaMKI could significantly detect tumor progression with 0.710, 0.779, and 0.686 of area under the curve (AUC), respectively. The Kaplan-Meier survival curve showed that patients with high Drp1, phospho-Drp1Ser637 and CaMKI levels had significantly poorer progression free survival (PFS) (p = 0.003, p < 0.001 and p = 0.017, respectively). Using multivariate analyses, phospho-Drp1Ser637 was significantly associated with PFS [p = 0.043, hazard ratio (HR) 3.151, 95% confidence interval (CI) 1.039-9.561]. CONCLUSIONS: Drp1 and CaMKI are novel potential candidates for the detection and prognosis of epithelial OVCA and as such further studies should be performed to exploit their therapeutic significance.

Pattern of recurrence in patients with endometrial cancer: A retrospective study.

INTRODUCTION: Endometrial cancer (EC) known prognostic factors are not sufficient to predict either outcome or recurrence rate/site: to investigate EC recurrence patterns according to ESMO-ESGO-ESTRO risk classes, could be beneficial for a more tailored adjuvant treatment and follow-up schedule. METHODS: 758 women diagnosed with EC, and a 5-years follow-up, were enrolled: they were divided into the ESMO-ESGO-ESTRO risk classes (low LR, intermediate IR, intermediate-high I-HR, and highrisk HR) and surgically treated as recommended, followed by adjuvants therapies when appropriate. RESULTS: Higher recurrence rate (RR) was significantly detected (p < 0,001) in the HR group (40,3%) compared to LR (9,6%), IR (16,7%) and I-HR (17,1%). Recurrences were detected more frequently at distant sites (64%) compared to pelvic (25,3%) and lymph nodes (10,7%) recurrences (p < 0,0001): only in LR group, no differences were detected between local and distant recurrences. 5-Year distant-free (LR 99%, IR 94%,I-HR 86%, HR 88%) and local-free survivals (LR 99%, IR 100%,I-HR 98%, HR 95%) significantly differ between groups (p < 0,0001 and p = 0,003, respectively). Adjuvant therapy modifies RRs only in LR group (p = 0,01). CONCLUSION: To identify biological factors to stratify patients at higher risk of relapse is needed. Distant site relapse could be the main reason of endometrial cancer failure follow-up, independently or in addition to their risk class prognosis.

G Protein-Coupled Receptor 30 Mediates the Anticancer Effects Induced by Eicosapentaenoic Acid in Ovarian Cancer Cells.

PURPOSE: While numerous epidemiological studies have indicated that omega-3 polyunsaturated fatty acids have anticancer properties in various cancers, the effects and mechanisms of eicosapentaenoic acid (EPA) in ovarian cancer cell growth are poorly understood. MATERIALS AND METHODS: ES2 ovarian clear cell carcinoma cells and SKOV3 adenocarcinoma cells were treated with palmitic acid or EPA, followed by flow cytometry and cell counting to measure apoptosis and proliferation, respectively. A modified protein lipid overlay assay was used to further verify whether EPA was a ligand of G protein-coupled receptor 30 (GPR30) in ES2 cells. The levels of apoptosis-related genes, phosphorylated AKT, and phosphorylated ERK1/2 were detected to explore the underlying mechanism. Finally, inhibitory effect of EPA on tumor growth via GPR30 was determined in vitro and in vivo. RESULTS: EPA suppressed ES2 ovarian clear cell carcinoma cells growth via GPR30, a novel EPA receptor, by inducing apoptosis. As a ligand of GPR30, EPA activated the GPR30-cAMP- protein kinase A signaling pathway. When GPR30 was suppressed by siRNA or its inhibitor G15, the antiproliferative action of EPA was impaired. Furthermore, EPA inhibited tumor growth by blocking the activation of AKT and ERK. In the mouse xenograft model, EPA decreased tumor volume and weight through GPR30 by blocking tumor cell proliferation. CONCLUSION: These results confirm that EPA is a tumor suppressor in human ovarian clear cell carcinoma cells and functions through a novel fatty acid receptor, GPR30, indicating a mechanistic linkage between omega-3 fatty acids and cancers.

[Radiotherapy of oligometastases: Sequences and interactions with systemic therapies, example of kidney cancer]. / Radiothérapie des oligométastases : interactions/séquences avec thérapies systémiques, exemple du cancer du rein.

This article is a review of the literature that aims to clarify the place of systemic and locoregional treatments, with a focus on radiotherapy and surgery in the management of patients with oligometastatic kidney cancer. We have selected articles of interest published in Medline indexed journals. We have also analysed the related guidelines: National Comprehensive Cancer Network (NCCN) 2019, European Association of Urology (EAU) 2019, European Society of Medical Oncology (ESMO) 2019, Association française d'urologie (Afu) 2018 as well as some abstracts of international congresses. The main treatments evaluated were surgery and radiotherapy. We defined the different scenarios conventionally encountered in clinical practice. The evolution of systemic therapies (increased overall survival and response rate) is likely to increase the number of patients potentially accessible to locoregional treatments. The complete analysis of the literature underlines the place of locoregional treatments whatever the scenarios mentioned. Data on stereotactic radiotherapy found a local control rate consistently above 70% in all studies with a maintained response and positive impact on overall survival and progression-free survival. The improvement of overall survival by sequential use of the various therapeutic classes confirms the need for optimization of locoregional treatments in the model of oligometastatic kidney cancer. The dogma of radioresistance must definitely be set aside with current irradiation techniques.

Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma.

INTRODUCTION: PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2. MATERIALS AND METHODS: cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry. RESULTS: Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P < 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death. CONCLUSION: A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.

Minimally invasive hysterectomy surgery rates for endometrial cancer performed at National Comprehensive Cancer Network (NCCN) Centers.

OBJECTIVES: Minimally invasive surgery (MIS) is a quality measure for endometrial cancer (EC) established by the Society of Gynecologic Oncology and the American College of Surgeons. Our study objective was to assess the proportion of EC cases performed by MIS at National Comprehensive Cancer Network (NCCN) centers and evaluate perioperative outcomes. METHODS: A retrospective cohort study of women who underwent surgical treatment for EC from 2013 to 2014 was conducted at four NCCN centers. Multivariable mixed logistic regression models analyzed factors associated with failure to perform MIS and perioperative complications. RESULTS: In total 1621 patients were evaluated; 86.5% underwent MIS (robotic-assisted 72.5%, laparoscopic 20.9%, vaginal 6.6%). On multivariable analysis, factors associated with failure to undergo MIS were uterine size >12cm (Odds Ratio [OR]: 0.17, 95% CI 0.03-0.9), stage III (OR: 0.16, 95% CI 0.05-0.49) and IV disease (OR: 0.07, 95% CI 0.02-0.22). For stage I/II disease, complications occurred in 5.1% of MIS and 21.7% of laparotomy cases (p<0.01). Laparotomy was associated with increases in any complication (OR: 6.0, 95% CI 3.3-10.8), gastrointestinal (OR: 7.2, 95% CI 2.6-19.5), wound (OR: 3.7, 95% CI 1.5-9.2), respiratory (OR 37.5, 95% CI 3.9-358.0), VTE (OR 10.5, 95% CI 1.3-82.8) and 30-day readmission (OR: 2.6, 95% CI 1.4-4.9) compared to MIS. CONCLUSIONS: At NCCN-designated centers, the MIS hysterectomy rate in EC is higher than the published national average, with low perioperative complications. Previously identified disparities of age, race, and BMI were not observed. A proposed MIS hysterectomy benchmark of >80% in EC care is feasible when performed at high volume centers.

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

OBJECTIVE: Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. RESULTS: Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. CONCLUSIONS: This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted.

Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women.

OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.

Long-Term Survival for Platinum-Sensitive Recurrent Ovarian Cancer Patients Treated with Secondary Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: To analyze the 5- and 7-year survival outcomes for women with platinum-sensitive recurrent epithelial ovarian cancer (REOC) who underwent secondary cytoreductive surgery (SCS) plus platinum-based hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From the electronic databases of the Department of Obstetrics and Gynecology at the Catholic University of the Sacred Heart of Rome and of the S. Orsola Hospital, University of Bologna, a consecutive series of REOC patients were selected using the following inclusion criteria: primary platinum-free interval (PFI-1) of 6 months or longer, completeness of secondary cytoreduction score (CC) of 1 or lower, minimum follow-up period of 48 months, Eastern Cooperative Group (ECOG) performance status at recurrence of 1 or less, and platinum-based HIPEC. Progression-free survival (PFS) and post-relapse survival (PRS) were calculated as the time between SCS + HIPEC and secondary recurrence or death, respectively. RESULTS: The final study population included 70 women with platinum-sensitive REOC. The median follow-up time was 73 months (range 48-128 months), and the median PFI-1 was 19 months (range 6-100 months). At the time of recurrence, the median peritoneal cancer index was 7 (range 1-21), and a CC score of 0 was achieved for 62 patients (88.6 %). As the HIPEC drug, we used oxaliplatin in 17 cases (38.6 %) and cisplatin in 43 cases (61.4 %). No postoperative deaths were observed, and the complication rate for grades 3 and 4 disease was 8.6 %. The median PFS duration was 27 months (range 5-104 months), and the 5- and 7-year PRS rates were respectively 52.8 and 44.7 %, (median PRS 63 months). CONCLUSIONS: The current study demonstrated favorable 5- and 7-year PRS rates for platinum-sensitive REOC patients undergoing SCS + HIPEC, which encourages the inclusion of patients in randomized clinical trials for definitive conclusions to be drawn.

Coumestrol suppresses proliferation of ES2 human epithelial ovarian cancer cells.

Coumestrol, which is predominantly found in soybean products as a phytoestrogen, has cancer preventive activities in estrogen-responsive carcinomas. However, effects and molecular targets of coumestrol have not been reported for epithelial ovarian cancer (EOC). In the present study, we demonstrated that coumestrol inhibited viability and invasion and induced apoptosis of ES2 (clear cell-/serous carcinoma origin) cells. In addition, immunoreactive PCNA and ERBB2, markers of proliferation of ovarian carcinoma, were attenuated in their expression in coumestrol-induced death of ES2 cells. Phosphorylation of AKT, p70S6K, ERK1/2, JNK1/2, and p90RSK was inactivated by coumestrol treatment in a dose- and time-dependent manner as determined in western blot analyses. Moreover, PI3K inhibitors enhanced effects of coumestrol to decrease phosphorylation of AKT, p70S6K, S6, and ERK1/2. Furthermore, coumestrol has strong cancer preventive effects as compared to other conventional chemotherapeutics on proliferation of ES2 cells. In conclusion, coumestrol exerts chemotherapeutic effects via PI3K and ERK1/2 MAPK pathways and is a potentially novel treatment regimen with enhanced chemoprevention activities against progression of EOC.

Hyperthermic Intraperitoneal Chemotherapy after Secondary Cytoreduction in Epithelial Ovarian Cancer: A Single-center Comparative Analysis.

BACKGROUND: Although the standard of care after recurrence of epithelial ovarian cancer (EOC) is chemotherapy, increasing data suggest that combining cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising option for patients with recurrent EOC. Our aim was to determine the prognostic value of the addition of HIPEC to secondary cytoreductive surgery (SCR) in recurrent EOC. METHODS: We analyzed a series of 79 patients with platinum-sensitive recurrent EOC who were treated from May 2000 to January 2014. Fifty patients who underwent SCR were compared to 29 who had SCR in combination with HIPEC. RESULTS: The SCR group had a higher median age (58.4 years) compared to the SCR + HIPEC group (51.6 years) (p = 0.006). The median hospital stay length was longer for SCR + HIPEC versus SCR patients (11 and 8 days, respectively; p = 0.009). More subjects experienced National Cancer Institute grade III-IV morbidity in the SCR + HIPEC group (34.5 %) compared to the SCR group (10.6 %) (p = 0.015). Conversely, there were no deaths in the SCR + HIPEC group and 2 (4.0 %) deaths the SCR group. The median disease-free survival did not differ between SCR and SCR + HIPEC patients (18.6 and 15.8 months, respectively; p = 0.82); nor did median overall survival (59.3 and 58.3 months, respectively; p = 0.95). The presence of carcinomatosis was the only variable that remained linked to a higher risk of recurrence and death in the multivariate analysis. CONCLUSIONS: Our data suggest that the addition of HIPEC to cytoreduction in patients with recurrent platinum-sensitive EOC does not improve survival.

Impact of guideline adherence on patient outcomes in early-stage epithelial ovarian cancer.

AIM: The aim of this study was to evaluate the effects of adherence to National Comprehensive Cancer Network (NCCN) guidelines on survival outcomes in patients with early-stage epithelial ovarian cancer. METHODS: Our institutional cancer registry data on 266 patients with Stage I epithelial ovarian cancer was reviewed retrospectively and compliance with treatment guidelines for surgery and adjuvant treatment was determined. Patients were categorized according to adherence or non-adherence. The primary endpoints were recurrence-free survival and disease-specific survival. Hazard ratios (HRs) for survival were estimated with a Cox proportional hazards model. RESULTS: Of the 266 patients, 71 (26.7%) underwent adequate surgical staging in accordance with the guidelines. The guidelines for adjuvant chemotherapy were followed adequately in all 71 patients that were adherent to surgical staging and in 163 of the 195 patients with non-adherence to surgical staging (83.6%). Multivariate analysis, adjusted for prognostic factors, identified higher recurrence-free survival (HR, 0.36; 95% CI, 0.15-0.88) and disease-specific survival (HR, 0.42; 95% CI, 0.16-1.12) among patients whose treatment adhered to both surgical and chemotherapy guidelines, although disease-specific survival was not statistically significant. When excluding clear cell histology from the cohort, the guideline-adherent group had significantly better disease-specific survival than the non-adherent group (HR, 0.13; 95% CI, 0.02-0.94). CONCLUSION: The results of this study suggest that adherence to NCCN guidelines may improve survival outcomes in patients with early-stage epithelial ovarian cancer, particularly in cases other than clear cell histology.

Chylous ascytis causing abdominal distension after laparoscopic radical nephrectomy.

OBJECTIVE: To report a case of large chylous ascytis as a late complication of a laparoscopic nephrectomy for renal tumor. METHODS: A 62 year old patient was admitted with general deterioration and abdominal distension due to chylous ascites. Abdominal ultrasound and CT led to the diagnosis. Paracentesis confirmed the presence of a large peritoneal chylous fluid effusion. RESULTS: The patient was treated by punction and placement of a percutaneous drainage. A large amount of lymphatic fluid was obtained after punction with a progressive decrease. Medical treatment included low sodium and low fat diet, together with medium chain fast absorbing triglycerides, protein supplements, diuretics and somatostatin analogues (octeotride). The patient's progress was satisfactory after several days of treatment. CONCLUSIONS: Chylous ascites is a rare complication of laparoscopic nephrectomy, but it has a favorable course if managed conservatively. Meticulous clipping of the retroperitoneal lymph vessels is recommended to prevent the formation of chylous ascites, especially when discharging the renal vascular pedicle during nephrectomy or extensive lymphadenectomy.

The influence of comorbid conditions on racial disparities in endometrial cancer survival.

OBJECTIVE: There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race. STUDY DESIGN: Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival. RESULTS: Black women experienced a higher hazard of death from any cause (hazard ratio [HR] 1.51; 95% confidence interval [CI], 1.22-1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63-3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94-1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39-3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23-0.98; and HR, 0.35; 95% CI, 0.19-0.67, respectively). CONCLUSION: The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed.

Reasons for failure to deliver National Comprehensive Cancer Network (NCCN)-adherent care in the treatment of epithelial ovarian cancer at an NCCN cancer center.

OBJECTIVE: The National Comprehensive Cancer Network (NCCN) has established guidelines for treating epithelial ovarian cancer (EOC) which includes cytoreductive surgery and platinum and taxane-based chemotherapy (CT). The objective of this study was to determine the reasons for failure to deliver NCCN-adherent care at an NCCN cancer center serving a diverse racial and socioeconomic population. METHODS: Medical records of women with EOC diagnosed between 2004 and 2009 were reviewed for demographic, clinical, tumor, treatment, and survival data. Independent reviewers determined if their treatment met criteria for being NCCN-adherent. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Meier estimates and compared with the log-rank test. RESULTS: 367 patients were identified. 79 (21.5%) did not receive NCCN-adherent care. Non-adherent CT in 75 patients was the most common reason for failure to receive NCCN-adherent care. 39 patients did not complete CT due to treatment toxicities or disease progression. 12 patients received single agent CT only and 4 received no CT due to comorbidities. 2 patients declined CT. 18 patients died in the postoperative period without receiving CT. 8 patients did not undergo cytoreduction due to disease progression or comorbidities. PFS and OS were improved in the NCCN-adherent cohort (PFS: 5.7 vs. 18.3 months, p<.005) (OS: 11.4 vs. 49.5 months, p<.005). CONCLUSIONS: The vast majority of patients at an NCCN cancer center received NCCN-adherent treatment. Reasons for failure to receive NCCN-adherent care were variable, but most did not receive chemotherapy in accordance with guidelines due to comorbidities or disease progression.

Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy.

Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life-threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia.

Two cases of recurrent ovarian clear cell carcinoma treated with sorafenib.

Sorafenib is an oral multikinase inhibitor targeting Raf and other kinases. The anti-tumor effect of sorafenib is thought to be mediated through its inhibition of the RAS-Raf-Erk pathway, as well as its inhibition of VEGFR and PDGFR. Sorafenib has been effective at treating patients with renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer. OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC. Using a microarray database, the gene expression profile of OCCC was similar to that of RCC. The effects of sorafenib against human OCCC are unknown. Therefore, we used sorafenib to treat two patients with recurrent chemoresistant OCCC, and observed good effect in both of them without severe side effects. We believe that sorafenib is an effective agent against OCCC. Given the chemoresistant nature of this tumor, this drug appears to be very valuable.