Pretreatment malnutrition and quality of life - association with prolonged length of hospital stay among patients with gynecological cancer: A cohort study

Background Length of hospital stay (LOS) is a surrogate marker for patients' well-being during hospital treatment and is associated with health care costs. Identifying pretreatment factors associated with LOS in surgical patients may enable early intervention in order to reduce postoperative LOS. Methods This cohort study enrolled 157 patients with suspected or proven gynecological cancer at a tertiary cancer centre (2004-2006). Before commencing treatment, the scored Patient Generated - Subjective Global Assessment (PG-SGA) measuring nutritional status and the Functional Assessment of Cancer Therapy-General (FACT-G) scale measuring quality of life (QOL) were completed. Clinical and demographic patient characteristics were prospectively obtained. Patients were grouped into those with prolonged LOS if their hospital stay was greater than the median LOS and those with average or below average LOS. Results Patients' mean age was 58 years (SD 14 years). Preoperatively, 81 (52%) patients presented with suspected benign disease/pelvic mass, 23 (15%) with suspected advanced ovarian cancer, 36 (23%) patients with suspected endometrial and 17 (11%) with cervical cancer, respectively. In univariate models prolonged LOS was associated with low serum albumin or hemoglobin, malnutrition (PG-SGA score and PG-SGA group B or C), low pretreatment FACT-G score, and suspected diagnosis of cancer. In multivariable models, PG-SGA group B or C, FACT-G score and suspected diagnosis of advanced ovarian cancer independently predicted LOS. Conclusions Malnutrition, low quality of life scores and being diagnosed with advanced ovarian cancer are the major determinants of prolonged LOS amongst gynecological cancer patients. Interventions addressing malnutrition and poor QOL may decrease LOS in gynecological cancer patients.

Quality of life of women with lower-limb lymphedema following gynecological cancer

Secondary lower-limb lymphedema can develop following treatment for gynecological cancers, and has debilitating effects on quality of life (QoL). Lymphedema can limit mobility and ability to perform daily activities, and have adverse effects on psychological and social wellbeing. When assessing the effect of lymphedema treatment methods, the focus is on change in clinically measured lymphedema status, rather than QoL outcomes. Considering that treatment for lymphedema involves a significant and ongoing commitment from patients, it is essential to determine whether the benefits to patients outweigh the burden associated with treatment. This article summarizes the results of studies assessing the impact of lower-limb lymphedema on QoL in women with gynecological cancer, evaluates their methodologies and discusses limitations and priorities for future research.

Lymphedema after breast or gynecological cancer : use and effectiveness of mainstream and complementary therapies

Objectives: The purpose of this study was to describe the use, as well as perceived effectiveness, of mainstream and complementary and alternative medicine (CAM) therapies in the treatment of lymphedema following breast or gynecological cancer. Further, the study assessed the relationship between the characteristics of lymphedema (including type, severity, stability, and duration), and the use of CAM and/or mainstream treatment. Methods: This was a cross-sectional study using a convenience sample of women with lymphedema following breast and gynecological cancers. A self-administered questionnaire was sent to 247 potentially eligible women. Of those returned (50%), 23 were ineligible and 6 were excluded due to level of missing data. Results: In the previous 12 months, the majority of women (90%) had used mainstream treatments to treat their lymphedema, with massage being the most commonly used (86%). One (1) in 2 women had used CAM to treat their lymphedema, and 98% of those using CAM were also using mainstream treatments. Over 27 types of CAM were reported, with use of a chi machine, vitamin E supplements, yoga, and meditation being the most commonly reported forms. The perceived effectiveness ratings (1–7 with 7 = completely effective) of mainstream(mean – standard deviation (SD): 5.3 – 1.5) and CAM therapies (mean – SD: 5.2 + 1.6) were considered high. Conclusions: These results demonstrate that mainstream and CAM treatment use is common, varied, and considered to be effective among women with lymphedema following breast or gynecological cancer. Furthermore, it highlights the immediate need for larger prospective studies assessing the inter-relationship between the use of mainstream and CAM therapies for treatment success.

The Lymphedema Evaluation in Gynecological cancer Study (LEGS): Design of a prospective, longitudinal, cohort study

Background The Lymphoedema Evaluation in Gynecological cancer Study (LEGS) was a longitudinal, observational, cohort study prospectively evaluating the incidence and risk factors of lower-limb lymphedema after treatment for gynecological cancer. Here we describe the study protocol and characteristics of the sample. Methods Women with a newly diagnosed gynecological cancer between June 1, 2008 and February 28, 2011, aged 18 years or older, and treated at one of six hospitals in Queensland, Australia, were eligible. Lymphedema was assessed by circumference measurements, bioimpedance spectroscopy, and self-reported swelling. LEGS incorporated a cohort of patients requiring surgery for benign gynecological conditions for comparison purposes. Data were collected prior to surgery and at regular intervals thereafter up to 2-years post-diagnosis. Results 546 women participated (408 cancer, 138 benign), with a 24-month retention rate of 78%. Clinical and treatment characteristics of participants were similar to the Queensland gynecological cancer population, except for a higher proportion of early-stage cervical cancers recruited to LEGS compared with Queensland proportions (89% versus 55%, respectively). Discussion Few imbalances were observed between participants with complete and incomplete follow-up data. The prospective design and collection of objective and patient-reported outcome data will allow comprehensive assessment of incidence and risk factors of lower-limb lymphedema.

Fatigue in gynecological cancer patients during and after anticancer treatment

Research has indicated that individuals with gynecological cancer experience severe fatigue.

Fibroblast growth factor receptor inhibition synergizes with paclitaxel and doxorubicin in endometrial cancer cells

OBJECTIVE: The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines. METHODS: Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis. RESULTS: FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in the 3 FGFR2 mutant cell lines evaluated. In addition, although nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of paclitaxel and doxorubicin in a subset of FGFR2 wild-type endometrial cancer cell lines. CONCLUSIONS: Together these data suggest a potential therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors.

Prevalence, predictors, and correlates of supportive care needs among women 3–5 years after a diagnosis of endometrial cancer

Purpose The purpose of this study is to examine the prevalence, sociodemographic and clinical predictors, and physical and psychosocial correlates of unmet needs among women 3–5 years following treatment for endometrial cancer. Methods Women with endometrial cancer completed a survey around the time of diagnosis and again 3–5 years later. The follow-up survey asked women about their physical and psychosocial functioning and supportive care needs (CaSUN). Multivariable-adjusted logistic regression identified the predictors and correlates of women’s unmet needs 3–5 years after diagnosis. Results Of the 629 women who completed the cancer survivors’ unmet needs measure (CaSUN), 24 % (n = 153) women reported one or more unmet supportive care needs in the last month. Unmet needs at 3–5 years post-diagnosis were predicted by younger age (OR = 4.47; 95 % CI: 2.09–9.56) and advanced disease stage at diagnosis (OR = 2.47; 95 % CI: 1.38–4.45) and correlated with greater cancer symptoms (OR = 1.78; 95 % CI: 1.05–3.02), lower limb swelling (OR = 2.50; 95 % CI: 1.51–4.15), symptoms of anxiety (OR = 2.21; 95 % CI: 1.31–3.72), and less availability of social support (OR = 3.42; 95 % CI: 1.92–6.11). Women with a history of comorbidities (OR = 0.47; 95 % CI: 0.27–0.82) and those living in a rural area at the time of diagnosis (OR = 0.56; 95 % CI: 0.34–0.92) were less likely to report unmet needs. Conclusions Sociodemographic, health, and psychosocial factors seem important for identifying women who will or will not have unmet needs several years following endometrial cancer. Longitudinal assessments of people’s needs over the course of their cancer trajectory may be an effective way to identify areas that should receive further attention by health providers.

Quantifying physical activity and the associated barriers for women with ovarian cancer

Objective The purpose of this study was to quantify physical activity levels and determine the barriers to physical activity for women with ovarian cancer. Materials and Methods Women with ovarian cancer from 3 oncology clinics enrolled in the cross-sectional study. Physical activity and barriers to physical activity were measured using the International Physical Activity Questionnaire and Perceived Physical Activity Barriers scale, respectively. Demographic, medical, and anthropometric data were obtained from medical records. Results Ninety-five women (response rate, 41%), with a mean (SD) age of 61 (10.6) years, a body mass index of 26.5 (6.8) kg/m2, and 36.6 (28.2) months since diagnosis, participated in the study. The majority of the participants had stage III (32%) or IV (32%) ovarian cancer, were undergoing chemotherapy (41%), and had a history of chemotherapy (93%). The majority of the participants reduced their physical activity after diagnosis, with 19% meeting recommended physical activity guidelines. The participants undergoing treatment reported lower moderate-vigorous physical activity compared with those not undergoing active treatment (mean [SD], 42 [57] vs 104 [119] min/wk; P < 0.001) and less total physical activity barriers (mean [SD], 49 vs 47; P > 0.4). The greatest barriers to physical activity included fatigue (37.8%), exercise not in routine (34.7%), lack of self-discipline (32.6%), and procrastination (27.4%). Conclusions Women with ovarian cancer have low levels of physical activity. There are disease-specific general barriers to physical activity participation. The majority of the participants reduced their physical activity after diagnosis, with these patients reporting a higher number of total barriers. Behavioral strategies are required to increase physical activity adherence in this population to ensure that recommended guidelines are met to achieve the emerging known benefits of exercise oncology.

An exercise intervention during chemotherapy for women with recurrent ovarian cancer: A feasibility study

Objective: The aim of this study was to determine the feasibility of a combined supervised and home-based exercise intervention during chemotherapy for women with recurrent ovarian cancer. Secondary aims were to determine the impact of physical activity on physical and psychological outcomes and on chemotherapy completion rates. Methods: Women with recurrent ovarian cancer were recruited from 3 oncology outpatient clinics in Sydney and Canberra, Australia. All participants received an individualized exercise program that consisted of 90 minutes or more of low to moderate aerobic, resistance, core stability, and balance exercise per week, for 12 weeks. Feasibility was determined by recruitment rate, retention rate, intervention adherence, and adverse events. Aerobic capacity, muscular strength, fatigue, sleep quality, quality of life, depression, and chemotherapy completion rates were assessed at weeks 0, 12, and 24. Results: Thirty participants were recruited (recruitment rate, 63%), with a retention rate of 70%. Participants averaged 196 ± 138 min · wk of low to moderate physical activity throughout the intervention, with adherence to the program at 81%. There were no adverse events resulting from the exercise intervention. Participants who completed the study displayed significant improvements in quality of life (P = 0.017), fatigue (P = 0.004), mental health (P = 0.007), muscular strength (P = 0.001), and balance (P = 0.003) after the intervention. Participants completing the intervention had a higher relative dose intensity than noncompleters (P = 0.03). Conclusions: A program consisting of low to moderate exercise of 90 min · wk was achieved by two-thirds of women with recurrent ovarian cancer in this study, with no adverse events reported. Randomized control studies are required to confirm the benefits of exercise reported in this study.

Oncolytic Adenoviruses for Gynecologic Cancer

Gene therapy is a promising novel approach for treating cancers resistant to or escaping currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development with adenoviruses as the most popular vehicle. Recent developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters or infectivity enhancement. A rapidly developing field is as well replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and therefore synergistic effects are possible. This study focused on development of adenoviral vectors suitable for treatment of various gynecologic cancer types, describing the development of the field from non-replicating adenoviral vectors to multiple-modified conditional replicating viruses. Transcriptional targeting of gynecologic cancer cells by the use of the promoter of vascular endothelial growth factor receptor type 1 (flt-1) was evaluated. Flt-1 is not expressed in the liver and thus an ideal promoter for transcriptional targeting of adenoviruses. Our studies implied that the flt-1 promoter is active in teratocarcinomas.and therefore a good candidate for development of oncolytic adenoviruses for treatment of this often problematic disease with then poor outcome. A tropism modified conditionally replicating adenovirus (CRAd), Ad5-Δ24RGD, was studied in gynecologic cancers. Ad5-Δ24RGD is an adenovirus selectively replication competent in cells defective in the p16/Rb pathway, including many or most tumor cells. The fiber of Ad5-Δ24RGD contains an integrin binding arginine-glycine-aspartic acid motif (RGD-4C), allowing coxackie-adenovirus receptor independent infection of cancer cells. This approach is attractive because expression levels of CAR are highly variable and often low on primary gynecological cancer cells. Oncolysis could be shown for a wide variety of ovarian and cervical cancer cell lines as well as primary ovarian cancer cell spheroids, a novel system developed for in vitro analysis of CRAds on primary tumor substrates. Biodistribution was evaluated and preclinical safety data was obtained by demonstrating lack of replication in human peripheral blood mononuclear cells. The efficicacy of Ad5-Δ24RGD was shown in different orthotopic murine models including a highly aggressive intraperitoneal model of disseminated ovarian cancer cells, where Ad5-Δ24RGD resulted in complete eradication of intraperitoneal disease in half of the mice. To further improve the selectivity and specificity of CRAds, triple-targeted oncolytic adenoviruses were cloned, featuring the cyclo-oxygenase-2 (cox-2) promoter, E1A transcomplementation and serotype chimerism. Those viruses were evaluated on ovarian cancer cells for specificity and oncolytic potency with regard to two different cox2 versions and three different variants of E1A (wild type, delta24 and delta2delta24). Ad5/3cox2Ld24 emerged as the best combination due to enhanced selectivity without potency lost in vitro or in an aggressive intraperitoneal orthotopic ovarian tumor model. In summary, the preclinical therapeutic efficacy of the CRAds tested in this study, taken together with promising biodistribution and safety data, suggest that these CRAds are interesting candidates for translation into clinical trials for gynecologic cancer.

Women’s Wellness after Cancer Program Study (WWACP)– A multi centre randomised controlled trial examining the benefits and cost effectiveness of an Evidenced Based, e-health intervention

Background Advances in cancer diagnosis and treatment have significantly improved survival rates, through their subsequent health needs are often not adequately addressed by current health services. National Health and Medical Research Council (NHMRC) Partnerships Project awarded a national collaborative project to develop, trial and evaluate clinical benefits and cost effectiveness of an e-health enabled structured health promotion intervention - The Women’s Wellness after Cancer Program (WWACP). The aim of this e-health enabled multimodal intervention is to improve health related quality of life in women previously treated for target cancers. Aim The WWACP is a 12-week web based, interactive, holistic program. Primary outcomes for this project are to promote a positive change in health-related quality of life (HRQoL) and reduction in Body Mass Index (BMI) in the women undertaking WWACP compared to women who receive usual care. Secondary outcomes include managing other side effects of cancer treatment through evidence-based nutrition and exercise practices, dealing with stress, sleep, menopause and sexuality issues. Methods The single-blinded multi-center randomized controlled trial recruited a toatl of 330 women within 24 months of completion of chemotherapy and /or radiotherapy. Women were randomly assigned to either a usual care or intervention group. Women provided with the intervention were provided with an interactive iBook and journal, web interface, and three virtual consultations by experienced cancer nurses. A variety of methods were utilized, to enable positive self- efficacy and lifestyle changes. These include online coaching with a registered nurse trained in the intervention, plus written educational and health promotional information. The program has been delivered through the e-health enabled interfaces, which enables virtual delivery via desktop and mobile computing devices. Importantly this enables accessibility for rural and regional women in Australia who are frequently geographically disadvantaged in terms of health care provision. Results Research focusing on alternative methods of delivering post treatment / or survivorship care in cancer utilizing web based interfaces is limited, but emerging evidence suggests that Internet interventions can increase psychological and physical wellbeing in cancer patients. The WWACP trial aims to establish the effectiveness of delivery of the program in terms of positive patient outcomes and cost effective, flexibility. The trial will be completed in September and results will be presented at the conference. Conclusions Women after acute hematological, breast and gynecological cancer treatments demonstrate good cancer survival rates and face residual health problems which are amenable to behavioral interventions. The conclusion of active treatment is a key 'teachable moment' in which sustainable positive lifestyle change can be achieved if patients receive education and psychological support which targets key treatment related health problems and known chronic disease risk factors.

Toll-Like Receptors 7, 8, and 9 Expression and Function in Primary Human Cervical Cancer Langerhans Cells Evidence of Anergy

Objective: Human papillomavirus oncoproteins E6 and E7 down modulate Toll-like receptor (TLR) 9 expression in infected keratinocytes. We explored the status of expression and function of TLR7, TLR8, and TLR9 in primary human Langerhans cells (LCs) isolated from cervical tumors. Methodology: Single-cell suspensions were made from fresh tissues of squamous cell carcinoma (International Federation of Gynecology and Obstetrics stage IB2); myeloid dendritic cells were purified using CD1c magnetic activated cell separation kits. Langerhans cells were further flow sorted into CD1a(+)CD207(+) cells. Acute monocytic leukemia cell line THP-1-derived LCs (moLCs) formed the controls. mRNA from flow-sorted LCs was reverse transcribed to cDNA and TLR7, TLR8, and TLR9 amplified. Monocyte-derived Langerhans cells and cervical tumor LCs were stimulated with TLR7, TLR8, and TLR9 ligands. Culture supernatants were assayed for interleukin (IL) 1 beta, IL-6, IL-10, IL-12p70, interferon (IFN) alpha, interferon gamma, and tumor necrosis factor (TNF) alpha by Luminex multiplex bead array. Human papillomavirus was genotyped. Results: We have for the first time demonstrated that the acute monocytic leukemia cell line THP-1 can be differentiated into LCs in vitro. Although these moLCs. expressed all the 3 TLRs, tumor LCs expressed TLR7 and TLR8, but uniformly lacked TLR9. Also, moLCs secreted IL-6, IL-1 beta, and tumor necrosis factor alpha to TLR8 ligand and interferon alpha in response to TLR9 ligand; in contrast, tumor LCs did not express any cytokine to any of the 3 TLR ligands. Human papillomavirus type 16 was one of the common human papillomavirus types in all cases. Conclusions: Cervical tumor LCs lacked TLR9 expression and were functionally anergic to all the 3: TLR7, TLR8, and TLR9 ligands, which may play a crucial role in immune tolerance. The exact location of block(s) in TLR7 and TLR8 signaling needs to be investigated, which would have important immunotherapeutic implications.

Mutations du gène HFE dans le cancer épithélial de l'ovaire

Le cancer épithélial de l’ovaire est le cancer gynécologique le plus agressif avec le plus haut taux de mortalité. La croissance des cellules cancéreuses de l’ovaire est limitée par les nutriments de l’environnement, le fer étant un des éléments indispensables à leur prolifération. L’hémochromatose héréditaire est une maladie associée à une accumulation corporelle de fer. Cette maladie est liée à deux mutations majeures du gène HFE soit H63D et C282Y. Étant donnée l’influence de la protéine HFE sur l’entrée du fer dans la cellule, des mutations du gène HFE pourraient être associées à une croissance rapide des cellules cancéreuses. Des études de génotypage du gène HFE effectuées chez 526 patientes avec cancer épithélial de l’ovaire, ont révélées une fréquence allélique de la mutation C282Y significativement plus élevées chez les patientes avec tumeur ovarienne comparativement aux patientes du groupe contrôle (5.9% versus 1.3%, p = 0.02). De plus, le taux de survie des patientes avec mutations C282Y et tumeur ovarienne de G3, après 2 ans, est faible (20%) lorsque comparé à celui des patientes sans mutations (60%, p = 0.005). Une analyse de régression multivariée de Cox a démontrée un risque relatif de 3.1, suggérant que les patientes avec mutations C282Y ont 3 fois plus de chance d’avoir une faible survie (p=0.001). Également, des études de corrélation ont démontrées que les niveaux de ferritine du sérum étaient plus élevés chez les patientes avec grade avancé du cancer épithélial de l’ovaire (r = 0.445 et p= 0.00001), suggérant que ce paramètre pourrait servir comme marqueur tumoral. Afin de comprendre ces résultats, nous avons tout d’abord étudiés l’influence des mutations HFE sur les cellules cancéreuses. Pour ce faire, la lignée du cancer de l’ovaire TOV-112D, homozygote pour la mutation C282Y, a été transfectée avec les vecteurs HFEwt et HFEC282Y. Bien qu’aucune différence significative n’ait été trouvée en termes de TfR totaux, des analyses par FACS ont démontrées un phénotype de déficience de fer pour les clones stables HFEwt. In vitro, la restauration de la protéine HFE, dans la lignée TOV-112D du cancer de l’ovaire, n’influence pas la croissance cellulaire. Ensuite, nous avons étudiés l’influence des niveaux de fer sur la progression tumorale. Une expérience in vivo préliminaire a démontré une tendance à un volume tumoral supérieur dans un modèle de souris de surcharge de fer,HfeRag1-/-. De plus, les souris HfeRag1-/-, injectées avec la lignée du cancer de l’ovaire TOV-21G, ont montrées des niveaux significativement plus faibles de fer sérique comparativement à leur contrôle (fer sérique 40±7μM versus 27±6μM, p = 0.001). En conclusion, des études supplémentaires sont nécessaires afin de comprendre davantage le rôle des mutations HFE sur la progression tumorale. Notamment, les niveaux élevés de fer pourraient rendre les cellules tumorales résistantes aux traitements ou encore, augmenter la toxicité et ainsi, contribuer à un mauvais prognostique.

Caractérisation fonctionnelle de la GTPase Ran dans le cancer épithélial de l'ovaire

Le cancer épithélial de l’ovaire est le plus létal des cancers gynécologiques. Les tumeurs de l’ovaire se divisent en différentes classes reflétant l’étendue de la maladie. Les tumeurs à faible potentiel de malignité présentent une survie relative à 5 ans de 90%, alors que pour les tumeurs invasives, la survie à 5 ans chute drastiquement à 35-40%. Au laboratoire, nous avons précédemment identifié la protéine Ran, un membre de la superfamille des GTPases Ras, comme marqueur fortement exprimé dans les cancers épithéliaux de l’ovaire de haut grade et de haut stade dont la surexpression est associée à un mauvais pronostic. Ran est déjà connue pour contribuer au transport nucléocytoplasmique et à la progression du cycle cellulaire, mais son rôle dans le cancer ovarien n’est pas bien défini. En utilisant une approche de shRNA inductibles à la tétracycline basée sur les lentivirus, nous avons montré que la diminution de l’expression de Ran dans des lignées cellulaires agressives du cancer de l’ovaire affecte drastiquement la prolifération cellulaire par l’induction d’une apoptose caspase-3 dépendante. Par un essai de tumeurs en xénogreffes, nous avons démontré que la déplétion de Ran résulte en une diminution de la tumorigenèse et que la formation éventuelle de tumeurs est associée à une sélection des cellules tumorales ayant la capacité de ré-exprimer la protéine Ran. Ces résultats suggèrent un rôle critique pour Ran dans la survie et la tumorigénicité des cellules du cancer ovarien, indiquant que Ran pourrait être une cible thérapeutique intéressante.