Molecular mechanisms of action and chemosensitization of tumor cells in ovarian cancer by phytochemicals: A narrative review on pre-clinical and clinical studies.

Ovarian cancer is the second-leading cause of death among women with cancer of the genital tract. Currently, drugs derived from platinum and taxanes constitute the majority of ovarian cancer treatments. Patients undergoing this chemotherapy are susceptible to cumulative toxic effects and resistance to chemotherapy. Therefore, it is crucial to identify treatment options that are both more effective and better tolerated by patients. Phytochemicals in this context are plant-derived chemicals with antitumor activity that can be used as therapeutic or adjuvant agents in the treatment of ovarian cancer. Consequently, the purpose of this literature review is to demonstrate through existing pre-clinical and clinical trials the potential of phytochemicals in the treatment of ovarian cancer, the mechanisms of action involved, and to contribute to the development of new therapeutic options for ovarian cancer. For this review, the databases PubMed, Scopus, Science Direct, and ClinicalTrials.gov were queried between 2010 and 2022 using terms such as "ovarian cancer," "phytochemicals," "phenolic compounds," "terpenes," and "alkaloids." The present review summarized the possible molecular mechanisms of action by which phytochemicals, such as phenolic acids, flavonoids, diterpenes, triterpenes, saponins, and alkaloids, inhibit this type of cancer, specifically the ability of phytochemicals to induce cell growth regulation, apoptosis, oxidative stress reduction, anti-angiogenesis, and chemosensitization of tumors in ovarian cancer. As their action and cellular mechanism have already been demonstrated in several pre-clinical trials, the phytochemicals identified in our study have the potential to be investigated for the treatment of ovarian cancer. Through pre-clinical and clinical trials, our study demonstrates the potential of phytochemicals in the treatment of ovarian cancer, contributing to the development of novel therapeutic options for ovarian cancer.

Interdigitated Electrode for Electrical Characterization of Commercial Pseudo-Binary Biodiesel-Diesel Blends.

Non-standard diesel blends can be harmful to the environment and human health. In this context, a simple analytical method to estimate the biodiesel mixture ratio in diesel was developed based on impedance spectroscopy (IS) associated with interdigitated sensors. In this article, four different interdigitated sensors with varied comb spacing (G) were simulated using the COMSOL Multiphysics software. Based on finite element simulations, four interdigitated electrode architectures were manufactured and evaluated. The best geometry was chosen according to theoretical data simulations, and its interdigitated electrodes were manufactured for the compositional evaluation of pseudo-binary biodiesel-diesel mixtures. According to the X-ray powder diffraction technique, the deposition of the conductive layer (Au0) over the surface of the dielectric substrate (SiO2) did not alter its phase composition. In the analysis of AFM and SEM, it was possible to observe irregular edges on the electrodes, possibly related to the manufacturing process of the thin layers and mechanical stability. Another characteristic observed in the AFM images was the height of the step of the gold layer of the sensor. Several cross sections were obtained, and the mean step value was 225.71 ± 0.0032 nm. Although there were differences in the roughness, the whole sensor had nanometric roughness. Based on the finite element method simulation performed, it can be assumed that the geometric parameters more suitable for the manufacturing of the electrode are W = 20 µm, L = 1000 µm, G = 50 µm, and N = 40 digits. The electrical characterization performed by impedance spectroscopy showed that we could differentiate between biodiesel and diesel fuels and their pseudo-binary mixtures in the low-frequency region.

Arrabidaea chica Verlot fractions reduce MIA-induced osteoarthritis progression in rat knees.

This study aims to investigate the activity of n-hexane, ethyl acetate and butanol fractions obtained from Arrabidaea chica Verlot against MIA-induced osteoarthritis (OA). The antinociceptive potentials of each fraction were evaluated through a cyclooxygenase (COX) 1 and 2 inhibition test and an in vivo OA-model. In addition, toxicity assessments in the liver, spleen and kidney, as well as radiographic and histopathological knee analyses, were performed. The chemical composition of the n-hexane fraction was elucidated, and a molecular docking protocol was carried out to identify which compounds are associated with the detected bioactivity. The n-hexane A. chica fraction preferentially inhibits COX-2, with 90% inhibition observed at 10 µg/mL. The fractions also produced significant improvements in OA incapacity, motor activity and hyperalgesia parameters and in radiological knee conditions. However, concerning the histopathological evaluations, these improvements were only significant in the hexane and ethyl acetate fraction treatments, which resulted in better average scores, suggesting that these fractions slow OA-promoted joint injury progression. Histopathological organ analyses indicate that the fractions are not toxic to animals. Twenty compounds were identified in the n-hexane fraction, comprising fatty acids, terpenes and phytosterols. In silico analyses indicate the presence of favourable interactions between some of the identified compounds and the COX-2 enzyme, mainly concerning alpha-tocopherol (Vitamin E), squalene and beta-sitosterol. The findings indicate that A. chica fractions display analgesic, anti-inflammatory properties, are non-toxic and are able to slow OA progression, and may, therefore, be prioritized as natural products in OA human clinical trials.

Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection.

BACKGROUND: Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from ß-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES: In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS: in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS: Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION: N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

Effects of Extract of Arrabidaea chica Verlot on an Experimental Model of Osteoarthritis.

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.

Anti-Inflammatory and Antinociceptive Activity of Pollen Extract Collected by Stingless Bee Melipona fasciculata.

The stingless bee, Melipona fasciculata Smith (Apidae, Meliponini), is a native species from Brazil. Their products have high biotechnological potential, however there are no studies about the biological activities of pollen collected by M. fasciculata. In this context, the present study investigated the chemical composition, anti-oxidant, anti-inflammatory, and analgesic activities of hydroethanolic pollen extracts collected by M. fasciculata in three cities in Maranhão State, Brazil. We verified the antioxidant activity of the extracts and inhibitory activity against the cyclooxygenase enzyme using in vitro assays and in allowed to select the extract with higher efficiency to be used on in vivo assays. In these trials, the selected extract showed high anti-inflammatory activity as well as nociceptive effects at central and peripheral level, suggesting that this extract acts on inhibition of histamine release and decreased synthesis of prostaglandins and the in-silico study suggested that polyphenols and acids fatty acids in the extract may be associated with these activities. The results of the present study report the high biological potential of pollen extract and we conclude that the pollen collected by M. fasciculata can be considered as the object of research for new pharmacological alternatives.

Therapeutic Use of Scoparia dulcis Reduces the Progression of Experimental Osteoarthritis.

Pain is recognized as one of the main symptoms in knee osteoarthritis and is the main reason why patients seek medical attention. Scoparia dulcis has been popularly used to relieve discomfort caused by various painful conditions. The objective of the study is to evaluate the analgesic and anti-inflammatory effect of the crude extract of S. dulcis, in an experimental model of osteoarthritis. The experiment was performed with Wistar rats divided into 4 groups with 5 animals each: healthy, saline, crude extract, and meloxicam groups. Knee osteoarthritis was induced by intra-articular injection of sodium mono-iodoacetate. First, clinical parameters of pain were assessed at days 0, 5, 10, 15, and 20 after induction. Second, the potential cyclooxygenase inhibition was evaluated, and the cytokines of the synovial fluid were quantified. An in silico test and Molecular Docking tests were performed. A histopathological evaluation was made on articular cartilage with safranin O staining. The results showed that a 15-day treatment with crude extract reduced edema, spontaneous pain, peripheral nociceptive activity, and proinflammatory cytokines in the synovial fluid. The highest inhibition of cyclooxygenase 2 in the crude extract occurred at 50 µg/mL. The crude extract of S. dulcis presents therapeutic potential for the treatment of osteoarthritis due to its anti-inflammatory and anti-nociceptive action.

Laparoscopy versus laparotomy for the management of early stage endometrial cancer.

BACKGROUND: This is an update of a previous Cochrane Review published in 2012, Issue 9.Surgery for endometrial cancer (hysterectomy with removal of both fallopian tubes and ovaries) is performed through laparotomy. It has been suggested that the laparoscopic approach is associated with a reduction in operative morbidity. Over the last two decades there has been a steady increase of the use of laparoscopy for endometrial cancer. This review investigated the evidence of benefits and harms of laparoscopic surgery compared with laparotomy for presumed early stage endometrial cancer. OBJECTIVES: To compare overall survival (OS) and disease free survival (DFS) for laparoscopic surgery versus laparotomy in women with presumed early stage endometrial cancer. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5) in the Cochrane Library, MEDLINE via Ovid (April 2012 to June 2018) and Embase via Ovid (April 2012 to June 2018). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. The trial registers included NHMRC Clinical Trials Register, UKCCCR Register of Cancer Trials, Meta-Register and Physician Data Query Protocol. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing laparoscopy and laparotomy for early stage endometrial cancer. DATA COLLECTION AND ANALYSIS: We independently abstracted data and assessed risk of bias. We used hazard ratios (HRs) for OS and recurrence free survival (RFS), risk ratios (RR) for severe adverse events and mean differences (MD) for continuous outcomes in women who received laparoscopy or laparotomy with 9% confidence intervals (CI). These were pooled in random-effects meta-analyses. MAIN RESULTS: We identified one new study in this update of the review. The review contains nine RCTs comparing laparoscopy with laparotomy for the surgical management of early stage endometrial cancer.All nine studies met the inclusion criteria and assessed 4389 women at the end of the studies. Six studies assessing 3993 participants with early stage endometrial cancer found no significant difference in the risk of death between women who underwent laparoscopy and women who underwent laparotomy (HR 1.04, 95% 0.86 to 1.25; moderate-certainty evidence) and five studies assessing 3710 participants found no significant difference in the risk of recurrence between the laparoscopy and laparotomy groups (HR 1.14, 95% CI 0.90 to 1.43; moderate-certainty evidence). There was no significant difference in the rate of perioperative death; women requiring a blood transfusion; and bladder, ureteric, bowel and vascular injury. However, one meta-analysis of three studies found that women in the laparoscopy group lost significantly less blood than women in the laparotomy group (MD -106.82 mL, 95% CI -141.59 to -72.06; low-certainty evidence). A further meta-analysis of two studies, which assessed 3344 women and included one very large trial of over 2500 participants, found that there was no clinical difference in the risk of severe postoperative complications in women in the laparoscopy and laparotomy groups (RR 0.78, 95% CI 0.44 to 1.38). Most studies were at moderate risk of bias. All nine studies reported hospital stay and results showed that on average, laparoscopy was associated with a significantly shorter hospital stay. AUTHORS' CONCLUSIONS: This review found low to moderate-certainty evidence to support the role of laparoscopy for the management of early endometrial cancer. For presumed early stage primary endometrioid adenocarcinoma of the endometrium, laparoscopy is associated with similar OS and DFS. Furthermore, laparoscopy is associated with reduced operative morbidity and hospital stay. There is no significant difference in severe postoperative morbidity between the two modalities.The certainty of evidence for OS and RFS was moderate and was downgraded for unclear risk of bias profiles and imprecision in effect estimates. However, most studies used adequate methods of sequence generation and concealment of allocation so studies were not prone to selection bias. Adverse event outcomes were downgraded for the same reasons and additionally for low event rates and low power thus these outcomes provided low-certainty evidence.

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

Body mass index and the quality of life of endometrial cancer survivors--a systematic review and meta-analysis.

BACKGROUND: Obesity is a risk factor for developing endometrial cancer and known to negatively affect outcomes and survival. However, the association between obesity and quality of life of endometrial cancer survivors (ECS) remains unclear. OBJECTIVES: To assess the association between body mass index (BMI) and the quality of life of endometrial cancer survivors. In addition we assessed the associations between BMI and anxiety, depression and sexual function of endometrial cancer survivors. METHODS: The review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the Cochrane Handbook for Systematic Reviews of Interventions. We performed a search of Medline (1946-2014), Embase (1980-2014), Cinahl (1981-2014), and PsycInfo (1806-2014) to identify studies that reported on the association between BMI and quality of life outcomes in endometrial cancer survivors. RESULTS: Seven studies fulfilled the inclusion criteria, of which four studies could be included in the analysis. The four studies which included 1362 patients, showed that obese survivors had a significantly poorer physical functioning (P=0.001, MD: -11.61, 95% CI: -18.66 to -4.55), social functioning (P=0.01, MD: -4.37, 95% CI: -7.75 to -1.00) and role functioning (P=0.002, MD: -5.44 95% CI: -8.90 to -1.98) when compared to non-obese women. Emotional functioning and cognitive functioning did not show significant differences (P=0.18, P=0.21). AUTHORS' CONCLUSIONS: Obesity is associated with poorer quality of life outcomes in endometrial cancer survivors, including poorer physical, role and social functioning. Future research should be directed at lifestyle interventions aiming to enhance the quality of life of this group of survivors.

The effect of lifestyle interventions on the quality of life of gynaecological cancer survivors: A systematic review and meta-analysis.

OBJECTIVE: We aimed to evaluate the effectiveness of lifestyle interventions in improving the quality of life (QoL) of endometrial and ovarian cancer survivors. METHODS: The review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the Cochrane Handbook for Systematic Reviews of Interventions. We performed a search of MEDLINE (1946-2015), EMBASE (1980-2015), CINAHL (1981-2015), PsycINFO (1806-2015) and the Cochrane Trial Register to identify studies evaluating the effect of lifestyle interventions on the QoL of endometrial and ovarian cancer survivors. RESULTS: Eight studies fulfilled the inclusion criteria and comprised a total of 413 patients. Three studies were randomised controlled trials (RCTs), which showed that lifestyle interventions may improve physical functioning and significantly reduce fatigue in endometrial cancer survivors. In addition, lifestyle interventions in endometrial cancer survivors resulted in significant weight loss and improved physical activity levels, but did not show improvements in global QoL in the meta-analysis (P=0.75, P=0.49). Non-randomised trials in ovarian cancer survivors support the feasibility of lifestyle interventions and suggest they may result in QoL improvements. CONCLUSIONS: Lifestyle interventions have the potential to improve the QoL of endometrial cancer and ovarian cancer survivors, and may significantly reduce fatigue. However, the current evidence is limited and there is a need for future studies to further evaluate lifestyle interventions and their effect on QoL outcomes.

The impact of BMI on surgical complications and outcomes in endometrial cancer surgery--an institutional study and systematic review of the literature.

OBJECTIVES: We aimed to evaluate the association between body mass index (BMI), perioperative complications and outcomes in endometrial cancer (EC) patients at our institution. In addition, we performed a systematic review to compare our results to the literature. METHODS: This was a retrospective study of surgically managed EC patients between January 2006 and January 2015. Patient characteristics, surgical complications and intra- and postoperative outcomes were evaluated across BMI groups; BMI <30kg/m(2), BMI ≥30kg/m(2) and BMI ≥40kg/m(2). The systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: In total, we identified 627 women of which 514 were included; 249 women had a BMI of <30kg/m(2), 195 women had a BMI of 30-39.9kg/m(2), and 70 women were morbidly obese (BMI ≥40kg/m(2)). Obese women (BMI ≥30kg/m(2)) had significantly more postoperative surgical complications, including wound complications and antibiotics use, which was confirmed by the systematic review. The increase in complications mainly occurred in open surgery and morbidly obese patients were at highest risk. Obesity did not impact other outcomes including 30-day mortality. CONCLUSION: Obesity is associated with an increased risk of surgical morbidity in EC patients, and is most profound in open surgery and among the morbidly obese. Laparoscopic surgery may well prevent the majority of postoperative complications in this group of patients, and should therefore be the favoured approach.

Body mass index, physical activity and quality of life of ovarian cancer survivors: time to get moving?

OBJECTIVE: To evaluate the association between body mass index (BMI), physical activity (PA) and the quality of life (QoL) of ovarian cancer survivors. METHODS: We performed a two-centre cross-sectional study of women who had been treated for ovarian cancer between January 2007 and December 2014 at the Royal Cornwall Hospital Trust and the Plymouth Hospitals NHS Trust. QoL was assessed using the EORTC QLQ-C30 and QLQ-OV28 questionnaires, and PA using the Godin Leisure Time Exercise questionnaire. RESULTS: In total, 293 ovarian cancer survivors were invited to participate, of which 209 women (71.3%) responded. Thirty-five percent of women were overweight and 18% were obese, whilst only 21% met recommendations for PA. Obesity was associated with significantly poorer global QoL, physical, cognitive and social functioning, a poorer body image and more symptomatology. Sedentary behaviour was associated with poorer QoL scores including global QoL, physical, role, social and sexual functioning. After adjustment, BMI and PA both remained independently associated with QoL scores. CONCLUSION: Obesity and inactivity are associated with poorer QoL among ovarian cancer survivors. Future interventions promoting PA and weight loss should be evaluated as possible means to improve the QoL of this population.

Quality of life in ovarian cancer survivors: the influence of obesity.

OBJECTIVE: In this study, we evaluated the effect of body mass index (BMI) on the quality of life of ovarian cancer survivors. METHODS: Women diagnosed with ovarian cancer at the Royal Cornwall Hospital Trust between January 2008 and May 2013 were identified. Ovarian cancer survivors were invited to participate by completing the European Organization for Research and Treatment of Cancer QLQ-C30 (quality of life) questionnaire. Univariate and multiple regression analyses were used to determine associations between BMI and quality-of-life outcomes. RESULTS: A total of 176 ovarian cancer survivors were invited to participate, of which 133 were eligible for this study. In total, 81 ovarian cancer survivors (60.4%) completed the questionnaire, of which 26 responders (32.1%) were overweight (BMI, 25-29.9 kg/m²) and 27 (33.3%) were obese (BMI, ≥30 kg/m²). Increasing BMI was significantly associated with poorer quality-of-life outcomes in terms of physical functioning and emotional functioning, and this effect persisted for physical functioning after multiple regression analysis. CONCLUSIONS: Increasing BMI is associated with poorer quality-of-life outcomes in terms of physical and emotional functioning in ovarian cancer survivors. Further research is needed to evaluate the association between BMI and quality of life from diagnosis to survivorship to develop novel interventions.

Follow-up strategies after treatment (large loop excision of the transformation zone (LLETZ)) for cervical intraepithelial neoplasia (CIN): Impact of human papillomavirus (HPV) test.

BACKGROUND: Development of cancer of the cervix is a multi-step process as before cervical cancer develops, cervical cells undergo changes and become abnormal. These abnormalities are called cervical intraepithelial neoplasia (CIN) and are associated with increased risk of subsequent invasive cancer of the cervix. Oncogenic high-risk human papillomavirus (hrHPV), the causative agent of cervical cancer and its precursor lesions, is present in up to one-third of women following large loop excision of the transformation zone (LLETZ) treatment and is associated with increased risk of residual disease and disease recurrence. HPV testing may serve as a surveillance tool for identifying women at higher risk of recurrence. High-risk human papillomavirus testing will enable us to identify women at increased risk of residual or recurrent CIN and therefore will allow us to offer closer surveillance and early treatment, when indicated. OBJECTIVES: • To evaluate the effectiveness and safety of hrHPV testing after large loop excision of the transformation zone (LLETZ) treatment• To determine optimal follow-up management strategies following LLETZ treatment according to hrHPV status SEARCH METHODS: We searched the Cochrane Gynacological Cancer Review Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed and PsycINFO up to August 2013. We searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and we contacted experts in the field. SELECTION CRITERIA: We searched for randomised control trials (RCTs) that compared follow-up management strategies following LLETZ treatment for CIN. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found; therefore no data were analysed. MAIN RESULTS: The search identified 813 references on MEDLINE, 418 on EMBASE, 22 on CINAHL, 666 on PubMed, 291 on PsycINFO and 145 on CENTRAL. When all references were imported into EndNote and duplications were removed, 1348 references remained. Initial screening of titles and abstracts of these references revealed that 42 references were potentially eligible for this review. After reading the full-text versions, we identified no relevant trials comparing hrHPV and cytology testing versus cytology testing alone for detecting residual or recurrent disease during follow-up to LLETZ treatment of adult women with CIN.We found no evidence on the effects of hrHPV and cytology testing on residual or recurrent CIN2 or higher lesions, anxiety and psychosexual morbidity outcomes in women undergoing colposcopy and treatment for CIN. AUTHORS' CONCLUSIONS: We found no evidence from RCTs to inform decisions about the best surveillance strategy for women following treatment for CIN. A prognostic systematic review is needed to investigate the risk of developing recurrent cervical intraepithelial neoplasia 2+ (CIN2+) in women with a positive hrHPV test after large loop excision of the transformation zone (LLETZ) treatment.

The impact of BMI on quality of life in obese endometrial cancer survivors: does size matter?

BACKGROUND: Survivorship and quality of life issues are becoming increasingly relevant in endometrial cancer as a result of the marked increase in incidence of the disease combined with excellent and improving long term survival. OBJECTIVE: The purpose of this study was to evaluate the effect of obesity on quality of life (QoL) in endometrial cancer survivors. METHODS: Participants were endometrioid endometrial cancer survivors diagnosed between 2008 and 2013. Quality of life was measured through the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30, version 3.0). Associations between BMI and quality of life were determined by means of multivariate analyses. RESULTS: 322 women diagnosed with endometrioid endometrial cancer were invited to participate. Excluded were 15 women with unknown BMI, 40 with non-endometrioid histology and 10 with concurrent cancer. The QLQ-C30 questionnaire was completed by 158 (61.5%) women, of which 63 women (40%) were obese (BMI ≥ 30-39.9), and 30 women (19%) were morbidly obese (BMI ≥ 40). Morbidly obese women reported worse physical, role and social functioning and more somatic complaints. CONCLUSION: Morbid obesity is associated with poorer quality of life in endometrial cancer survivors. Life style interventions such as exercise programs and diet interventions could be viable means to improve the quality of life of obese endometrial cancer survivors. Future research should focus on means to improve quality of life in obese endometrial cancer survivors.

Adjuvant chemotherapy for advanced endometrial cancer.

BACKGROUND: Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random-effects model in Review Manager (RevMan) software. MAIN RESULTS: We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data.Overall survival (OS) and progression-free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment-related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00).There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD.We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison. AUTHORS' CONCLUSIONS: There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long-term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.

Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects.

Surgical cytoreduction for recurrent epithelial ovarian cancer.

BACKGROUND: The standard management of primary ovarian cancer is optimal cytoreductive surgery followed by platinum-based chemotherapy. Most women with primary ovarian cancer achieve remission on this combination therapy. For women achieving clinical remission after completion of initial treatment, most (60%) with advanced epithelial ovarian cancer will ultimately develop recurrent disease. However, the standard treatment of women with recurrent ovarian cancer remains poorly defined. Surgery for recurrent ovarian cancer has been suggested to be associated with increased overall survival. OBJECTIVES: To evaluate the effectiveness and safety of optimal secondary cytoreductive surgery for women with recurrent epithelial ovarian cancer. To assess the impact of various residual tumour sizes, over a range between 0 cm and 2 cm, on overall survival. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. For databases other than MEDLINE, the search strategy has been adapted accordingly. SELECTION CRITERIA: Retrospective data on residual disease, or data from randomised controlled trials (RCTs) or prospective/retrospective observational studies that included a multivariate analysis of 50 or more adult women with recurrent epithelial ovarian cancer, who underwent secondary cytoreductive surgery with adjuvant chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm. DATA COLLECTION AND ANALYSIS: Two review authors (KG, TA) independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis. MAIN RESULTS: There were no RCTs; however, we found nine non-randomised studies that reported on 1194 women with comparison of residual disease after secondary cytoreduction using a multivariate analysis that met our inclusion criteria. These retrospective and prospective studies assessed survival after secondary cytoreductive surgery in women with recurrent epithelial ovarian cancer.Meta- and single-study analyses show the prognostic importance of complete cytoreduction to microscopic disease, since overall survival was significantly prolonged in these groups of women (most studies showed a large statistically significant greater risk of death in all residual disease groups compared to microscopic disease).Recurrence-free survival was not reported in any of the studies. All of the studies included at least 50 women and used statistical adjustment for important prognostic factors. One study compared sub-optimal (> 1 cm) versus optimal (< 1 cm) cytoreduction and demonstrated benefit to achieving cytoreduction to less than 1 cm, if microscopic disease could not be achieved (hazard ratio (HR) 3.51, 95% CI 1.84 to 6.70). Similarly, one study found that women whose tumour had been cytoreduced to less than 0.5 cm had less risk of death compared to those with residual disease greater than 0.5 cm after surgery (HR not reported; P value < 0.001).There is high risk of bias due to the non-randomised nature of these studies, where, despite statistical adjustment for important prognostic factors, selection is based on retrospective achievability of cytoreduction, not an intention to treat, and so a degree of bias is inevitable.Adverse events, quality of life and cost-effectiveness were not reported in any of the studies. AUTHORS' CONCLUSIONS: In women with platinum-sensitive recurrent ovarian cancer, ability to achieve surgery with complete cytoreduction (no visible residual disease) is associated with significant improvement in overall survival. However, in the absence of RCT evidence, it is not clear whether this is solely due to surgical effect or due to tumour biology. Indirect evidence would support surgery to achieve complete cytoreduction in selected women. The risks of major surgery need to be carefully balanced against potential benefits on a case-by-case basis.

Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma.

BACKGROUND: Uterine carcinosarcomas are uncommon with about 35% not confined to the uterus at diagnosis. The survival of women with advanced uterine carcinosarcoma is poor with a pattern of failure indicating greater likelihood of upper abdominal and distant metastatic recurrence. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant radiotherapy and/or systemic chemotherapy in the management of uterine carcinosarcoma. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), 2012, Issue 10, MEDLINE and EMBASE up to November 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant radiotherapy and/or chemotherapy in women with uterine carcinosarcoma. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) comparing adverse events in women who received radiotherapy and/or chemotherapy were pooled in random-effects meta-analyses. MAIN RESULTS: Three trials met the inclusion criteria and these randomised 579 women, of whom all were assessed at the end of the trials. Two trials assessing 373 participants with stage III to IV persistent or recurrent disease, found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide, after adjustment for performance status (HR = 0.75, 95% confidence interval (CI): 0.60 to 0.94 and HR = 0.72, 95% CI: 0.58 to 0.90 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, where significantly more women experienced these ailments in the combination therapy group than the Ifosamide group (RR = 3.53, 95% CI: 1.33 to 9.37).In one trial there was no statistically significant difference in the risk of death and disease progression in women who received whole body irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI: 0.48 to 1.05 and HR = 0.79, 95% CI: 0.53 to 1.18 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, where significantly less women experienced these morbidities in the whole body irradiation group than the chemotherapy group (RR= 0.02, 95% CI: 0.00 to 0.16) for haematological morbidity and all nine women in the trial experiencing neuropathy morbidity were in the chemotherapy group). AUTHORS' CONCLUSIONS: In advanced stage metastatic uterine carcinosarcoma as well as recurrent disease adjuvant combination, chemotherapy with ifosfamide should be considered. Combination chemotherapy with ifosfamide and paclitaxel is associated with lower risk of death compared with ifosfamide alone. In addition, radiotherapy to the abdomen is not associated with improved survival.