Comparing Paclitaxel-Carboplatin with Paclitaxel-Cisplatin as the Front-Line Chemotherapy for Patients with FIGO IIIC Serous-Type Tubo-Ovarian Cancer.

The use of weekly chemotherapy for the treatment of patients with advanced-stage serous-type epithelial Tubo-ovarian cancer (ETOC), and primary peritoneal serous carcinoma (PPSC) is acceptable as the front-line postoperative chemotherapy after primary cytoreductive surgery (PCS). The main component of dose-dense chemotherapy is weekly paclitaxel (80 mg/m2), but it would be interesting to know what is the difference between combination of triweekly cisplatin (20 mg/m2) or triweekly carboplatin (carboplatin area under the curve 5-7 mg/mL per min [AUC 5-7]) in the dose-dense paclitaxel regimen. Therefore, we compared the outcomes of women with Gynecology and Obstetrics (FIGO) stage IIIC ETOC and PPSC treated with PCS and a subsequent combination of dose-dense weekly paclitaxel and triweekly cisplatin (paclitaxel-cisplatin) or triweekly carboplatin using AUC 5 (paclitaxel-carboplatin). Between January 2010 and December 2016, 40 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC EOC, FTC, or PPSC were enrolled, including 18 treated with paclitaxel-cisplatin and the remaining 22 treated with paclitaxel-carboplatin. There were no statistically significant differences in disease characteristics of patients between two groups. Outcomes in paclitaxel-cisplatin group seemed to be little better than those in paclitaxel-carboplatin (median progression-free survival [PFS] 30 versus 25 months as well as median overall survival [OS] 58.5 versus 55.0 months); however, neither reached a statistically significant difference. In terms of adverse events (AEs), patients in paclitaxel-carboplatin group had more AEs, with a higher risk of neutropenia and grade 3/4 neutropenia, and the need for a longer period to complete the front-line chemotherapy, and the latter was associated with worse outcome for patients. We found that a period between the first-time chemotherapy to the last dose (6 cycles) of chemotherapy >21 weeks was associated with a worse prognosis in patients compared to that ≤21 weeks, with hazard ratio (HR) of 81.24 for PFS and 9.57 for OS. As predicted, suboptimal debulking surgery (>1 cm) also contributed to a worse outcome than optimal debulking surgery (≤1 cm) with HR of 14.38 for PFS and 11.83 for OS. Based on the aforementioned findings, both regimens were feasible and effective, but maximal efforts should be made to achieve optimal debulking surgery and following the on-schedule administration of dose-dense weekly paclitaxel plus triweekly platinum compounds. Randomized trials validating the findings are warranted.

Palliative home parenteral nutrition in patients with ovarian cancer and malignant bowel obstruction: experiences of women and family caregivers.

BACKGROUND: Malnutrition is a problem in advanced cancer, particularly ovarian cancer where malignant bowel obstruction (MBO) is a frequent complication. Parenteral nutrition is the only way these patients can received adequate nutrition and is a principal indication for palliative home parenteral nutrition (HPN). Giving HPN is contentious as it may increase the burden on patients. This study investigates patients' and family caregivers' experiences of HPN, alongside nutritional status and survival in patients with ovarian cancer and MBO. METHODS: This mixed methods study collected data on participant characteristics, clinical details and body composition using computed tomography (CT) combined with longitudinal in-depth interviews underpinned by phenomenological principles. The cohort comprised 38 women with ovarian cancer and inoperable MBO admitted (10/2016 to 12/ 2017) to a tertiary referral hospital. Longitudinal interviews (n = 57) were carried out with 20 women considered for HPN and 13 of their family caregivers. RESULTS: Of the 38 women, 32 received parenteral nutrition (PN) in hospital and 17 were discharged on HPN. Nutritional status was poor with 31 of 33 women who had a CT scan having low muscle mass, although 10 were obese. Median overall survival from admission with MBO for all 38 women was 70 days (range 8-506) and for those 17 on HPN was 156 days (range 46-506). Women experienced HPN as one facet of their illness, but viewed it as a "lifeline" that allowed them to live outside hospital. Nevertheless, HPN treatment came with losses including erosion of normality through an impact on activities of daily living and dealing with the bureaucracy surrounding the process. Family caregivers coped but were often left in an emotionally vulnerable state. CONCLUSIONS: Women and family caregivers reported that the inconvenience and disruption caused by HPN was worth the extended time they had at home.

Nutritional Interventions to Improve Clinical Outcomes in Ovarian Cancer: A Systematic Review of Randomized Controlled Trials.

Among all gynaecological neoplasms, ovarian cancer has the highest rate of disease-related malnutrition, representing an important risk factor of postoperative mortality and morbidity. Hence, the importance of finding effective nutritional interventions is crucial to improve ovarian cancer patient's well-being and survival. This systematic review of randomized controlled trials (RCTs) aims at assessing the effects of nutritional interventions on clinical outcomes such as overall survival, progression-free survival, length of hospital stay (LOS), complications following surgery and/or chemotherapy in ovarian cancer patients. Three electronic bibliographic databases (MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials) were used to conduct a systematic literature search based on fixed inclusion and exclusion criteria, until December 2018. A total of 14 studies were identified. Several early postoperative feeding interventions studies (n = 8) were retrieved mainly demonstrating a reduction in LOS and an ameliorated intestinal recovery after surgery. Moreover, innovative nutritional approaches such as chewing gum intervention (n = 1), coffee consumption (n = 1), ketogenic diet intervention (n = 2) or fruit and vegetable juice concentrate supplementation diet (n = 1) and short-term fasting (n = 1) have been shown as valid and well-tolerated nutritional strategies improving clinical outcomes. However, despite an acceptable number of prospective trials, there is still a lack of homogeneous and robust endpoints. In particular, there is an urgent need of RCTs evaluating overall survival and progression-free survival during ovarian oncology treatments. Further high-quality studies are warranted, especially prospective studies and large RCTs, with more homogeneous types of intervention and clinical outcomes, including a more specific sampling of ovarian cancer women, to identify appropriate and effective nutritional strategies for this cancer, which is at high risk of malnutrition.

Therapeutic value of selective lymphadenectomy in interval debulking surgery for stage IIIc and IV epithelial ovarian cancer.

OBJECTIVE: The role of selective lymphadenectomy at the time of interval debulking surgery in patients with advanced ovarian cancer remains a topic of debate. This study aimed to evaluate the value of selective lymphadenectomy during interval debulking surgery in patients with radiologic evidence of lymph node metastasis at initial diagnosis that ultimately become negative on imaging after neoadjuvant chemotherapy. METHODS: A retrospective analysis including patients with stage IIIC-IV epithelial ovarian cancer and suspicious pelvic or para-aortic lymph node metastasis by imaging at diagnosis that resolved after neoadjuvant chemotherapy. The study was conducted from January 1996 to June 2016 with R0 interval debulking surgery. The patients with disease progression after neoadjuvant chemotherapy were excluded. Suspicious metastatic lymph nodes at initial diagnosis by computed tomography/magnetic resonance imaging were excised by selective lymphadenectomy. Survival curves were constructed by the Kaplan-Meier method, and a multivariate analysis was performed using Cox regression. RESULTS: There were a total of 330 patients included in the analysis. Selective lymphadenectomy of suspicious nodes (Group 1) was performed in 145 patients. Systematic lymphadenectomy (Group 2) was performed in 118 patients. Sixty-seven patients did not undergo lymphadenectomy (Group 3). There were no significant differences in clinicopathologic features among the groups. Median progression-free survival was 28, 30.5, and 22 months in Groups 1, 2, and 3, respectively (log-rank, p=0.049). No-lymphadenectomy was an independent factor affecting progression-free survival (Cox analysis, HR=1.729, 95% CI 1.213 to 2.464, p=0.002), with no difference between Groups 1 and 2 (Cox analysis, HR=1.097, 95% CI 0.815 to 1.478, p=0.541). Median overall survival was 50, 59, and 57 months in Groups 1, 2, and 3, respectively (Cox analysis, p=0.566). Patients who underwent selective lymphadenectomy had lower 1-year frequencies of lower extremity lymphedema and lymphocysts than those with systematic lymphadenectomy (6.2% vs 33.1%, p<0.001, and 6.2 % vs 27.1%, p<0.001, respectively). CONCLUSIONS: Extent of lymphadenectomy (systematic or selective) had no significant impact on progression-free survival or overall survival. In addition, the risks of lower extremity lymphedema and lymphocysts were lower in patients who underwent selective lymphadenectomy.

Favorable Effects of a Ketogenic Diet on Physical Function, Perceived Energy, and Food Cravings in Women with Ovarian or Endometrial Cancer: A Randomized, Controlled Trial.

Ketogenic diets (KDs) are gaining attention as a potential adjuvant therapy for cancer, but data are limited for KDs' effects on quality of life. We hypothesized that the KD would (1) improve mental and physical function, including energy levels, (2) reduce hunger, and (3) diminish sweet and starchy food cravings in women with ovarian or endometrial cancer. Participants were randomized to a KD (70:25:5 energy from fat, protein, and carbohydrate) or the American Cancer Society diet (ACS: high-fiber, lower-fat). Questionnaires were administered at baseline and after 12 weeks on the assigned diet to assess changes in mental and physical health, perceived energy, appetite, and food cravings. We assessed both between-group differences and within-group changes using ANCOVA and paired t-tests, respectively. After 12 weeks, there was a significant between-group difference in adjusted physical function scores (p < 0.05), and KD participants not receiving chemotherapy reported a significant within-group reduction in fatigue (p < 0.05). There were no significant between-group differences in mental function, hunger, or appetite. There was a significant between-group difference in adjusted cravings for starchy foods and fast food fats at 12 weeks (p < 0.05 for both), with the KD group demonstrating less frequent cravings than the ACS. In conclusion, in women with ovarian or endometrial cancer, a KD does not negatively affect quality of life and in fact may improve physical function, increase energy, and diminish specific food cravings. This trial was registered at ClinicalTrials.gov as NCT03171506.

Feasibility of structured endurance training and Mediterranean diet in BRCA1 and BRCA2 mutation carriers - an interventional randomized controlled multicenter trial (LIBRE-1).

BACKGROUND: Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. METHODS: We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility. Intervention comprised a structured, individualized endurance training alongside nutrition education based on the Mediterranean diet (MD) for 3 months, plus monthly group training and regular telephone contact during the subsequent 9 months. The CG attended one session on healthy nutrition and the benefits of physical activity. Primary endpoints were feasibility, acceptance and satisfaction over 12 months. Furthermore, effects on physical fitness, diet profile, body mass index (BMI), quality of life and perceived stress were investigated. RESULTS: Sixty-eight participants (mean age 41, mean BMI 23.2 kg/m2) were enrolled, of whom 55 (81%, 26 IG, 29 CG) completed 12 months. 73% (n = 26) participated in at least 70% of all intervention sessions. Predictors for drop-outs (19%; n = 13) or non-adherence (27%; n = 7) were not found. 73% rated the program highly and 80% would participate again. Severe adverse events did not occur. Positive effects in the IG compared to the CG were observed for secondary endpoints: BMI, MD eating pattern and stress levels. CONCLUSIONS: This lifestyle intervention was feasible, safe and well accepted. Positive results on eating habits, physical fitness and stress levels warrant a larger randomized trial. TRIAL REGISTRATION: The study has been retrospectively registered at ClinicalTrials.gov (reference: NCT02087592 ) on March 12, 2014. The first patient was included on February 24, 2014.

Methoxyphenyl chalcone sensitizes aggressive epithelial cancer to cisplatin through apoptosis induction and cancer stem cell eradication.

Current standard chemotherapy for late stage ovarian cancer is found unsuccessful due to relapse after completing the regimens. After completing platinum-based chemotherapy, 70% of patients develop relapse and resistance. Recent evidence proves ovarian cancer stem cells as the source of resistance. Therefore, treatment strategy to target both cancer stem cells and normal stem cells is essential. In this study, we developed a novel chalcone derivative as novel drug candidate for ovarian cancer treatment. We found that methoxyphenyl chalcone was effective to eliminate ovarian cancer cells when given either as monotherapy or in combination with cisplatin. We found that cell viability of ovarian cancer cells was decreased through apoptosis induction. Dephosphorylation of Bcl2-associated agonist of cell death protein was increased after methoxyphenyl chalcone treatment that led to activation of caspases. Interestingly, this drug also worked as a G2/M checkpoint modulator with alternative ways of DNA damage signal-evoking potential that might work to increase response after cisplatin treatment. In addition, methoxyphenyl chalcone was able to suppress autophagic flux and stemness regulator in ovarian spheroids that decreased their survival. Therefore, combination of methoxyphenyl chalcone and cisplatin showed synergistic effects. Taken together, we believe that our novel compound is a promising novel therapeutic agent for effective clinical treatment of ovarian cancer.

Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer.

The study reported here demonstrates that a flaxseed-supplemented diet causes ovarian tumors in the laying hen to undergo apoptosis, resulting in a reduction of tumor burden, reducing the frequency and severity of ovarian cancer. We have previously shown in normal ovaries that flaxseed and its components down-regulate ERalpha and alter the expression of enzymes that metabolize estrogen. In this study, we analyzed the effects of the two main components of whole flaxseed, ligan and omega 3 fatty acids on estrogen metabolism and the estrogen receptor in ovarian tumors. ER alpha expression was up-regulated in the ovarian tumors and was not affected by diet. Liver CYP1A1 expression was significantly increased by the whole flaxseed diet with a corresponding increase in 2-methoxyestradiol plasma levels. We also observed increased p38 and ERK 1/2 MAPK activation in the ovary as well as an increase in apoptosis in the tumor epithelium. SMAD 7, a factor involved in the 2-methoxyestradiol-mediated apoptosis pathway was also up-regulated in tumors from the whole flaxseed diet group. 2-methoxyestradiol-induced antitumor effects were further validated by in human ovarian cancer cells. This study details the effect of flaxseed diet on estrogen metabolism and demonstrates the antiovarian cancer effects of 2-methoxyestradiol.

Proof-of-Concept of Polymeric Sol-Gels in Multi-Drug Delivery and Intraoperative Image-Guided Surgery for Peritoneal Ovarian Cancer.

PURPOSE: The purpose of this study is to investigate a sol-gel transition property and content release profiles for thermosensitive poly-(D,L-lactide-co-glycolide)-block-poly-(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogels carrying paclitaxel, rapamycin, and LS301, and to present a proof-of-concept that PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, called TheranoGel, exhibit excellent theranostic activity in peritoneal ES-2-luc ovarian cancer xenograft mice. METHODS: Thermosensitive PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, individually or in combination, were prepared via a lyophilization method, characterized with content release kinetics, and assessed with theranostic activity in ES-2-luc xenograft mice. RESULTS: A thermosensitive PLGA-b-PEG-b-PLGA sol-gel system was able to entrain 3 poorly water-soluble payloads, paclitaxel, rapamycin, and LS301 (TheranoGel). TheranoGel made a sol-to-gel transition at 37°C and slowly released 3 drugs at a simultaneous release rate in response to the physical dissociation of hydrogels in vitro. TheranoGel enabled loco-regional delivery of multi-drugs by forming a gel-depot in the peritoneal cavity of ES-2-luc xenograft mice. An intraperitoneal (IP) administration of TheranoGel resulted in excellent therapeutic and diagnostic activities, leading to the improved peritoneal surgery in ES-2-luc xenograft mice. CONCLUSIONS: TheranoGel prepared via a facile lyophiliation method enabled successful IP delivery of multi-drugs and exhibited excellent theranostic activity in vivo.

Evaluación y soporte nutricional en pacientes con carcinomatosis peritoneal por cáncer de ovario con citorreducción quirúrgica / Nutritional assessment and support in patients with peritoneal carcinomatosis of ovarian cancer with cytoreductive surgery

Introducción: El tratamiento multidisciplinar de la carcinomatosis peritoneal, también conocido como procedimiento Sugarbaker, pretende erradicar el tumor microscópico residual a la cirugía. Esta técnica de alta complejidad está asociada a morbilidad y mortalidad elevada por lo que es relevante la selección de los pacientes. Existe una relación directa entre el estado nutricional, la calidad de vida, la supervivencia y la capacidad de tolerancia al tratamiento. Por tanto, es importante evaluar previamente el estado nutricional para detectar si existe riesgo de malnutrición. Objetivos: El objetivo principal es evaluar los resultados de la valoración nutricional completa previa a to das las pacientes intervenidas por el procedimiento Sugarbaker. Los objetivos secundarios son: conocer las composición promedio de la fórmula de nutrición parenteral más utilizada y comparar los resultados obtenidos de dichas pacientes con una cohorte histórica a la que no se realizó la valoración nutricional previa. Métodos: Estudio prospectivo donde se incluyeron todas las pacientes adultas que se iban a someter al procedimiento Sugarbaker a las que se les realizó la valoración nutricional previa. Se compararon los datos clínicos del seguimiento postoperatorio de las pacientes con una cohorte histórica retrospectiva de pa cientes sometidas al mismo procedimiento (a las que no se les realizó la valoración nutricional previa). Los parámetros que se utilizaron para el diagnóstico de malnutrición fueron antropométricos y analíticos. Los parámetros de estudio fueron los siguientes: edad, albúmina previa a la intervención, índice de carcinomatosis peritoneal, la administración o no de quimioterapia previa a la intervención y el estadiaje del tumor. En el seguimiento postoperatorio se establecieron como parámetros a valorar: días en unidad de cuidados intensivos, días en planta, días totales de hospitalización y complicaciones postoperatorias. Resultados: Se incluyeron un total de 32 pacientes: veinte pacientes sin valoración nutricional previa y doce pacientes con valoración nutricional previa con una edad media de 58,9±14 años. No se observan diferencias estadísticamente significativas entre ambos grupos en índice de carcinomatosis peritoneal, estadio tumoral, quimioterapia previa a la intervención y albúmina previa a la intervención. Requirieron nutrición parenteral 30 pacientes durante el postoperatorio. La composición media de la fórmula de nutrición parenteral fue 1,2±0,1 g de proteína por kg peso y día, 2,8±0,4g de hidratos de carbono por kg peso y día y 1±0,1g de lípidos por kg peso y día. De las doce valoraciones nutricionales previas realizadas, en nueve de ellas se observó algún tipo de desnutrición. En los parámetros evaluados durante el seguimiento de las pacientes no se obtuvieron diferencias estadísticamente significativas, aunque se observó una tendencia a una menor estancia en la unidad de cuidados intensivos y un menor número de complicaciones en las pacientes a las que se les ha realizado valoración nutricional previa. Discusión: Se observa que el índice de masa corporal y el porcentaje de pérdida de peso en estas pacientes no es representativo de la desnutrición que presentan. Las necesidades elevadas de nutrición parenteral en este estudio pueden ser debidas las complicaciones derivadas de la resección gastrointestinal. Posiblemente no se observen diferencias en los parámetros de estudio debido al tamaño muestral del mismo, pero si existe una tendencia a disminuir la estancia y complicaciones como muestra la bibliografía. La intervención nutricional aporta la energía y proteínas necesarias para disminuir la pérdida de peso y de masa muscular derivada del proceso patológico del cáncer y la cirugía. Conclusiones: Los resultados de la valoración nutricional previa indican que la desnutrición es una patología que tiene elevada prevalencia en las pacientes con carcinomatosis peritoneal de origen ovárico. Se observa una tendencia de que la mejora del estado nutricional aumentará la calidad de vida reduciendo estos parámetros. La composición en macronutrientes de la nutrición parenteral es similar a los requierimientos nutricionales en un paciente crítico. Consideramos que la selección de pacientes que van a ser sometidos a un procedimiento Sugarbaker debe incluir la evaluación del estado nutricional previo

Introduction: The multidisciplinary treatment of peritoneal carcinomatosis, also known as Sugarbaker´s procedure, aims to eradicate microscopic residual tumor after surgery. This technique is highly complex and it´s associated with high mortality and morbidity, so the patient selection is relevant. There is a direct relationship between nutritional status, quality of life, survival and ability to tolerate treatment. It is therefore important to assess nutritional status prior to detect if there is risk or malnutrition. Objectives: The main objective is to evaluate the results of the nutritional assessment after all patients operated by Sugarbaker´s procedure. Secondary objectives are to know the parenteral nutrition composition formula most commonly used and to compare the results of those patients with a historical cohort to which the previous nutritional assessment wasn´t performed.. Methods: Prospective study where all adult patients who were undergoing Sugarbaker procedure and who underwent previous nutritional assessment were included. Postoperative clinical and patient follow-up data were compared with a historical cohort of patients undergoing the same procedure (which will not be made prior nutritional assessment). For the diagnosis of malnutrition were used anthropometric and laboratory parameters. Study parameters were: age, albumin prior to the intervention, peritoneal carcinomatosis index, quimiotherapy administration and tumor staging. In the postoperative follow-up, the study parameters were: days in intensive care unit, hospitalization days, total days of hospitalization and postoperative complications. Results: A total of 32 patients were included: twenty patients without nutritional assessment and twelve patients with previous nutritional assessment with a mean age of 59 ± 14 years. No statistically significant differences are observed between groups in peritoneal carcinomatosis index, tumor stage, chemotherapy and albumin before the intervention. A total of 30 patients were required parenteral nutrition. The average composition formula of parenteral nutrition was 1.2 ± 0.1 g proteins per kg body weight and per day, 2.8 ± 0.4 g of carbohydrates per kg body weight and per day and 1 ± 0.1 g of lipid per kg body weight and per day. Of the twelve previous nutritional assessment conducted in nine of them some form of malnutrition was observed. In the parameters evaluated during follow-up of patients, no statistically significant differences were found, although was observed a trend to a shorter in the intensive care unit stay and fewer complications in patients who have undergone nutritional assessment. Discussion: It should be noted that body mass index and the percentage weight loss in these patients is not representative of the observed malnutrition. The high needs of parenteral nutrition in this study may be due the complications of gastrointestinal resection. Possibly no differences are observed in study parameters due to sample size, but if there is a tendency to increase the stay and complications as shown in the literature. Nutritional intervention provides energy and protein needed to reduce the loss of weight and muscle mass from the pathological process of cancer and surgery. Conclusions: The results of the previous nutritional assessment indicate that malnutrition is a pathology that has high prevalence in patients with peritoneal carcinomatosis of ovarian origin. A trend that improve nutritional status will increase the quality of life by reducing these parameters is observed. The macronutrient composition of parenteral nutrition is similar to nutritional requirement in critically ill patients. We believe that the selection of patients who are going to undergo a Sugarbaker procedure should include assessment of prior nutritional status

Does vitamin D mediate inhibition of epithelial ovarian cancer by modulating cytokines?

Objective. Vitamin D deficiency is reported to be involved in pathogenesis of ovarian cancer. But the mechanism is yet to be explored. An imbalance between Th1 and Th2 activity play a crucial role in pathogenesis of many cancers. The purpose of the study is to find out the Th1/Th2 status by estimating TNF-α (Th1 marker) and IL-4 (Th2 marker) in ovarian cancer cases and controls and to correlate these with serum vitamin D levels. Materials and methods. A case–control study with 50 ovarian cancer cases and 50 healthy controls was conducted. The cytokines TNF-α and IL-4 were estimated by ELISA. Serum vitamin D was measured by electro-chemiluminescence immunoassay method. Results. Median TNF-α levels (12.2 vs 6.2 pg/ml; p value <0.001) were significantly higher in ovarian cancer patients and mean IL-4 levels (2.22 ± 0.51 vs 2.99 ± 0.68 pg/ml; p value <0.05) were significantly lower as compared to those of controls. Levels of TNF-α and IL-4 did not vary significantly with clinical staging, and histological grading. Vitamin D levels were negatively correlated with TNF-α and positively correlated with IL-4. Conclusions. Low vitamin D levels promotes Th1 activity increasing TNF-α levels and inhibits Th2 activity decreasing IL-4 levels in ovarian cancer. These low levels of vitamin D may induce pro-inflammatory micro ambience which might contribute to pathogenesis of ovarian cancer (AU)

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Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins.

Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15 KDa cytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodelling processes. In the last years, the role of CRBP-1-related retinoid signalling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers. Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cells in vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients' screening for a more personalized and efficacy retinoid therapy.

p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers.

Mitochondria are highly dynamic organelles, and mitochondrial fission is a crucial step of apoptosis. Although Oma1 is believed to be responsible for long form Opa1 (L-Opa1) processing during mitochondrial fragmentation, whether and how Oma1 is involved in L-Opa1 processing and participates in the regulation of chemoresistance is unknown. Chemosensitive and chemoresistant ovarian (OVCA) and cervical (CECA) cancer cells were treated with cisplatin (CDDP). Mitochondrial dynamics and protein contents were assessed by immunofluorescence and Western blot, respectively. The requirements of Oma1 and p53 for CDDP-induced L-Opa1 processing, mitochondrial fragmentation, and apoptosis were examined by siRNA or cDNA. CDDP induces L-Opa1 processing and mitochondrial fragmentation in chemosensitive but not in chemoresistant cells. CDDP induced Oma1 40-kDa form increases in OV2008 cells, not in C13* cells. Oma1 knockdown inhibited L-Opa1 processing, mitochondrial fragmentation, and apoptosis. Silencing p53 expression attenuated the effects of CDDP in Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis in chemosensitive OVCA cells, whereas reconstitution of p53 in p53 mutant or null chemoresistant OVCA cells induced Oma1 (40 kDa) increase, L-Opa1 processing, mitochondrial fragmentation, and apoptosis irrespective of the presence of CDDP. Prohibitin 1 (Phb1) dissociates from Opa1-Phb1 complex and binds phosphorylated p53 (serine 15) in response to CDDP in chemosensitive but not chemoresistant CECA cells. These findings demonstrate that (a) p53 and Oma1 mediate L-Opa1 processing, (b) mitochondrial fragmentation is involved in CDDP-induced apoptosis in OVCA and CECA cells, and (c) dysregulated mitochondrial dynamics may in part be involved in the pathophysiology of CDDP resistance.

Dietary energy balance modulates ovarian cancer progression and metastasis.

A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

Dietary supplementation of Ashwagandha (Withania somnifera, Dunal) enhances NK cell function in ovarian tumors in the laying hen model of spontaneous ovarian cancer.

PROBLEM: Ovarian cancer (OVCA) disseminates in a distinct pattern through peritoneal metastasis and little is known about the immunosuppression in the tumor microenvironment. Our goal was to determine changes in NK cell population during OVCA development and the effects of Ashwagandha (Withania somnifera, Dunal) supplementation on NK cell localization in laying hens with OVCA. METHODS: Frequency of NK cells in ovarian tumors at early and late stages in 3- to 4-year-old hens (exploratory study) as well as in hens supplemented with dietary Ashwagandha root powder for 90 days (prospective study) was examined. RESULTS: The population of stromal NK cells but not the intratumoral NK cells increased with OVCA development and progression. Ashwagandha supplementation decreased the incidence and progression of OVCA. Both the stromal and intratumoral NK cell population increased significantly (P < 0.0001) in Ashwagandha supplementated hens. CONCLUSION: The results of this study suggest that the population of stromal and tumorinfiltrating NK cells is increased by dietary Ashwagandha supplementation. Thus, Ashwagandha may enhance antitumor function of NK cells. This study may be useful for a clinical study to determine the effects of dietary Ashwagandha on NK cell immune function in patients with ovarian cancer.

A randomized parallel-group dietary study for stages II-IV ovarian cancer survivors.

OBJECTIVE: Few studies have examined the dietary habits of ovarian cancer survivors. Therefore, we conducted a study to assess the feasibility and impact of two dietary interventions for ovarian cancer survivors. METHODS: In this randomized, parallel-group study, 51 women (mean age, 53 years) diagnosed with stages II-IV ovarian cancer were recruited and randomly assigned to a low fat, high fiber (LFHF) diet or a modified National Cancer Institute diet supplemented with a soy-based beverage and encapsulated fruit and vegetable juice concentrates (FVJCs). Changes in clinical measures, serum carotenoid and tocopherol levels, dietary intake, anthropometry, and health-related quality of life (HRQOL) were assessed with paired t-tests. RESULTS: The recruitment rate was 25%, and the retention rate was 75% at 6 months. At baseline, 28% and 45% of women met guidelines for intake of fiber and of fruits and vegetables, respectively. After 6 months, total serum carotenoid levels and α- and ß-carotene concentrations were significantly increased in both groups (P<0.01); however, ß-carotene concentrations were increased more in the FVJC group. Serum ß-cryptoxanthin levels, fiber intake (+5.2g/day), and daily servings of juice (+0.9 servings/day) and vegetables (+1.3 servings/day) were all significantly increased in the LFHF group (all P<0.05). Serum levels of albumin, lutein and zeaxanthin, retinol, and retinyl palmitate were significantly increased in the FVJC group (all P<0.05). No changes in cancer antigen-125, anthropometry, or HRQOL were observed. CONCLUSION: Overall, this study supports the feasibility of designing dietary interventions for stages II-IV ovarian cancer survivors and provides preliminary evidence that a low fat high fiber diet and a diet supplemented with encapsulated FVJC may increase phytonutrients in ovarian cancer survivors.

Reduction of ovarian and oviductal cancers in calorie-restricted laying chickens.

Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie-restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie-restricted group. On the basis of histopathology, 45 (26.3%) birds in the full-fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie-restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC.

Dietary phytoestrogens and the risk of ovarian cancer in the women's lifestyle and health cohort study.

BACKGROUND: Dietary intake of phytoestrogens has been inversely associated to hormone-dependent cancers, such as prostate and breast cancers. Few studies have investigated the association between ovarian cancer and intake of phytoestrogens. We evaluated the associations between intake of phytoestrogens (isoflavonoids/lignans/coumestrol) and fiber (vegetable/cereal) and risk of ovarian cancer. METHODS: In 1991-1992 a prospective population-based cohort study among Swedish women was conducted, including 47,140 women with complete dietary questionnaire data. During follow-up until December 2007, 163 women developed invasive (n = 117) and borderline (n = 46) ovarian cancers. The median follow-up time was 16 years and total person year was 747,178. Cox proportional hazards models were conducted to estimate multivariate risk ratios, 95% CI for associations with risk of ovarian cancer. RESULTS: We found no association between intake of phytoestrogens or fiber and overall ovarian cancer risk. In addition, we found no statistically significant association between intake of specific food items rich in phytoestrogens (berries, nuts, beans/soy, and crisp or whole-grain bread) and ovarian cancer risk overall. Fiber and coumestrol was inversely associated with borderline ovarian cancer, but not with invasive ovarian cancer. CONCLUSIONS: We found no association between intake of phytoestrogens or fiber and overall ovarian cancer risk. IMPACT: Phytoestrogens do not play a major etiologic role in ovarian cancer, at least among women in this Swedish cohort with low bean/soy intake. However, our results of a difference in the effect of fiber or coumestrol between invasive and borderline ovarian cancer need to be evaluated in larger studies.

Decreased severity of ovarian cancer and increased survival in hens fed a flaxseed-enriched diet for 1 year.

OBJECTIVE: With the exception of the laying hen, no other animal model of spontaneous ovarian surface epithelial cancer replicates the human disease. Flaxseed is the richest vegetable source of omega-3 fatty acids, which are chemopreventive in breast cancer and may be important in other cancers. The objective of this study was to determine if a flaxseed-enriched diet had a chemopreventive effect on ovarian cancer in the laying hen. METHODS: White Leghorn hens were fed with 10% flaxseed-enriched or standard diet for 1 year. The incidence and severity of ovarian cancer were determined by gross pathology and histology in the two groups. General health markers were also measured. Eggs were collected and analyzed by gas chromatography to determine omega-3 fatty acid levels. RESULTS: A significant reduction in late stage ovarian tumors was detected in the flaxseed-fed hens. Incidence rates of ovarian cancer were not significantly different between the two groups. The results indicate that a flaxseed diet increases overall survival in the laying hen. Flaxseed-fed hens' eggs incorporated significantly more omega-3 fatty acids compared to control hens. CONCLUSIONS: These findings show that 10% flaxseed supplementation for 1 year in the laying hen results in a significant reduction in the severity of ovarian cancer, but no change in the incidence of the disease. Hens fed flaxseed had overall better health and reduced mortality. These findings may provide the basis for a clinical trial that evaluates the efficacy of flaxseed as a chemosuppressant of ovarian cancer in women.

Effects of omega-3 fatty acids on components of the transforming growth factor beta-1 pathway: implication for dietary modification and prevention in ovarian cancer.

OBJECTIVE: We previously demonstrated that omega-3 fatty acids (OM-3FAs) have definitive inhibitory effects on ovarian cancer cell lines. We sought to determine whether the inhibitory effects of OM-3FAs were mediated by the transforming growth factor (TGF)-beta1 signaling pathway. STUDY DESIGN: Ovarian cancer cell lines were grown at 37 degrees C in 5% CO(2) and treated with OM-3FAs, omega-6 fatty acids, and control at different concentrations for 24-72 hours. Enzyme-linked immunosorbent assay (ELISA) assay and Western blot analysis were used to measure TGF-beta1, phosphorylated mothers against decapentaplegic (Smad)-3 and p21 protein levels. RESULTS: An ELISA assay demonstrated that OM-3FA treatment increased TGF-beta1 in all 3 Hey cell lines (P < .05). In both SKOV-3 and OVCAR-3 cells, TGF-beta1 levels were not significantly increased. Western blots confirmed increases in TGF-beta1, Smad-3 and p21 protein levels in Hey and HeyC2 but not SKOV-3 and OVCAR-3 cells. CONCLUSION: OM-3FAs increased the level of TGF-beta1, Smad-3, and p21 protein in ovarian cancer cells known to be more sensitive to their inhibitory effect.