Showing papers by "Donal J. Brennan published in 2020"

Primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for FIGO stage III epithelial ovarian cancer: OVHIPEC-2, a phase III randomized clinical trial

Abstract: Background The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery improves recurrence-free and overall survival in patients with FIGO stage III ovarian cancer who are ineligible for primary cytoreductive surgery. The effect of HIPEC remains undetermined in patients who are candidates for primary cytoreductive surgery. Primary objective The primary objective is to evaluate the effect of HIPEC on overall survival in patients with FIGO stage III epithelial ovarian cancer who are treated with primary cytoreductive surgery resulting in no residual disease, or residual disease up to 2.5 mm in maximum dimension. Study hypothesis We hypothesize that the addition of HIPEC to primary cytoreductive surgery improves overall survival in patients with primary FIGO stage III epithelial ovarian cancer. Trial design This international, randomized, open-label, phase III trial will enroll 538 patients with newly diagnosed FIGO stage III epithelial ovarian cancer. Following complete or near-complete (residual disease ≤2.5 mm) primary cytoreduction, patients are randomly allocated (1:1) to receive HIPEC or no HIPEC. All patients will receive six courses of platinum-paclitaxel chemotherapy, and maintenance PARP-inhibitor or bevacizumab according to current guidelines. Major eligibility criteria Patients with FIGO stage III primary epithelial ovarian, fallopian tube, or primary peritoneal cancer are eligible after complete or near-complete primary cytoreductive surgery. Patients with resectable umbilical, spleen, or local bowel lesions may be included. Enlarged extra-abdominal lymph nodes should be negative on FDG-PET or fine-needle aspiration/biopsy. Primary endpoint The primary endpoint is overall survival. Sample size To detect a HR of 0.67 in favor of HIPEC, 200 overall survival events are required. With an expected accrual period of 60 months and 12 months additional follow-up, 538 patients need to be randomized. Estimated dates for completing accrual and presenting results The OVHIPEC-2 trial started in January 2020 and primary analyses are anticipated in 2026. Trial registration ClinicalTrials.gov:NCT03772028

Fertility-sparing treatment in early endometrial cancer: current state and future strategies

Abstract: Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14-25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status associated with nulliparity, obesity, and metabolic syndrome. Standard treatment for EC, which involves total hysterectomy and bilateral salpingo-oophorectomy, has excellent survival outcomes, particularly for low-grade endometrioid tumors. However, it leads to permanent loss of fertility among women who wish to preserve their reproductive potential. With current trends of reproductive-age women delaying childbearing, rising EC incidence rates, and a growing epidemic of obesity, particularly in developed countries, research on conservative non-surgical treatment approaches remains a top priority. Fertility-sparing treatment predominantly involves the use of oral progestins and levonorgestrel-releasing intrauterine devices, which have been shown to be feasible and safe in women with early stage EC and minimal or no myometrial invasion. However, data on the efficacy and safety of conservative management strategies are primarily based on retrospective studies. Randomized clinical trials in younger women and high-risk obese patients are currently underway. Here, we have presented a comprehensive review of the current literature on conservative, fertility-sparing approaches, defining the optimal candidates and evaluating tumor characteristics, reproductive and oncologic outcomes, and ongoing clinical trials. We have also summarized current guidelines and recommendations based on the published literature.

Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer.

Abstract: Obesity is a major public health concern worldwide. The increased risk of certain types of cancer is now an established deleterious consequence of obesity, although the molecular mechanisms of this are not completely understood. In this review, we aim to explore the links between MAPK signalling and obesity-related cancer. We focus mostly on p38 and JNK MAPK, as the role of ERK remains unclear. These links are seen through the implication of MAPK in obesity-related immune paralysis as well as through effects on the endoplasmic reticulum stress response and activation of aromatase. By way of example, we highlight areas of interest and possibilities for future research in endometrioid endometrial cancer and hepatocellular carcinoma associated with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and MAPK.

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

Abstract: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

The Impact of Sarcopenia and Low Muscle Attenuation on Overall Survival in Epithelial Ovarian Cancer: A Systematic Review and Meta-analysis

Abstract: Sarcopenia is defined as a progressive loss of skeletal muscle mass, strength and physical performance. Myosteatosis is an increase of intra- and intermuscular fat and can be measured radiologically by muscle attenuation. The study aim was to perform a systematic review and meta-analysis on the prognostic potential of sarcopenia and low muscle attenuation in relation to 3-year survival rates (3YSR) and 5YSR in epithelial ovarian cancer (EOC). A systematic literature search was conducted using the databases Ovid Medline, EMBASE, and Scopus, using PRISMA guidelines, from inception to 10th of May 2019. Studies evaluated the prognostic potential of sarcopenia and low muscle attenuation on 3YSR and 5YSR in EOC. Quality assessment of included studies was performed using the Methodological Index for Non-Randomised Studies criteria. A comprehensive search of databases resulted in the identification of 2194 studies, resulting in 1695 citations meeting the inclusion criteria. Six studies were included for systematic review. Sarcopenia was not significantly associated with improved 3YSR (OR 1.7, 95% CI 0.8–3.5, p = 0.15) or 5YSR (OR 1.8, 95% CI 1.0–3.2, p = 0.07) in meta-analysis. Normal muscle attenuation was associated with a favourable 3YSR (OR 3.0, 95% CI 2.0–4.5, p < 0.001) and 5YSR (OR 2.3, 95% CI 1.6–3.4, p < 0.001) compared to low muscle attenuation. Our meta-analysis indicated normal muscle attenuation was significantly associated with improved 3YSR and 5YSR in patients with EOC. Sarcopenia was not significantly associated with 3YSR or 5YSR in patients with EOC.

Prophylactic human papillomavirus vaccination to prevent recurrence of cervical intraepithelial neoplasia: a meta-analysis.

Abstract: Objective The aim of this systematic review and meta-analysis was to review evidence supporting the use of prophylactic human papillomavirus (HPV) vaccines to influence the risk of recurrence of cervical intraepithelial neoplasia after surgical treatment. Methods A systematic literature search was performed for publications reporting risk of recurrence of cervical intraepithelial neoplasia after surgical treatment in patients receiving HPV vaccination (either in the prophylactic or adjuvant setting). Comprehensive searches of six electronic databases (MEDLINE, Embase, Web of Science, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and references of identified studies) from their inceptions were performed (English language only), and hand search reference lists were performed. Two independent reviewers applied inclusion and exclusion criteria to select manuscripts, with differences discussed and agreed by consensus. The literature search was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Results A total of 5744 citations were reviewed; 5 studies comprising 2912 patients were selected for the analysis. There were 1338 patients in the vaccinated group and 1574 in the placebo or unvaccinated group. The incidence of histologically confirmed cervical intraepithelial neoplasia 2+ was reduced in the vaccinated compared to the unvaccinated group (OR 0.34, 95% CI 0.21–0.54, p= Conclusion Prophylactic or adjuvant HPV vaccination reduces the risk of recurrent cervical intraepithelial neoplasia 2+. These data support further investigation of its role as an adjuvant to surgical treatment.

Improving response to progestin treatment of low-grade endometrial cancer

Abstract: Objectives This review examines how response rates to progestin treatment of low-grade endometrial cancer can be improved. In addition to providing a brief overview of the pathogenesis of low-grade endometrial cancer, we discuss limitations in the current classification of endometrial cancer and how stratification may be refined using molecular markers to reproducibly identify 'low-risk' cancers which may represent the best candidates for progestin therapy. We also discuss constraints in current approaches to progestin treatment of low-grade endometrial cancer and perform a systematic review of predictive biomarkers. Methods PubMed, ClinicalTrials.gov, and Cochrane Library were searched for studies reporting pre-treatment biomarkers associated with outcome in women with low-grade endometrial cancer or endometrial hyperplasia with an intact uterus who received progestin treatment. Studies of fewer than 50 women were excluded. The study protocol was registered in PROSPERO (ID 152374). A descriptive synthesis of pre-treatment predictive biomarkers reported in the included studies was conducted. Results Of 1908 records reviewed, 19 studies were included. Clinical features such as age or body mass index cannot predict progestin response. Lesions defined as 'low-risk' by FIGO criteria (stage 1A, grade 1) can respond well; however, the reproducibility and prognostic ability of the current histopathological classification system is suboptimal. Molecular markers can be reproducibly assessed, have been validated as prognostic biomarkers, and may inform patient selection for progestin treatment. DNA polymerase epsilon (POLE)-ultramutated tumors and a subset of p53 wild-type or DNA mismatch repair (MMR)-deficient tumors with 'low-risk' features (eg, progesterone and estrogen receptor-positive) may have improved response rates, though this needs to be validated. Discussion Molecular markers can identify cases which may be candidates for progestin treatment. More work is needed to validate these biomarkers and potentially identify new ones. Predictive biomarkers are anticipated to inform future research into progestin treatment of low-grade endometrial cancer and ultimately improve patient outcomes.

Evaluating liquid biopsies for methylomic profiling of prostate cancer.

Abstract: Background: Liquid biopsies offer significant potential for informing on cancer progression and therapeutic resistance via minimally invasive serial monitoring of genetic alterations. Although the ...

Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment.

Abstract: STUDY QUESTION Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1β, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S) Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER NA.

Patient perceptions and understanding of obesity related endometrial cancer.

Abstract: Obesity is the greatest risk factor for endometrial cancer. There is often a lack of recognition amongst patients about this risk. Evidence for weight-loss in the management of endometrial cancer is emerging. This was questionnaire-based study, that examined opinions and attitudes of patients with endometrial cancer and obesity towards obesity as a risk factor for cancer as well as examining their willingness to engage in weight loss interventions as an alternative treatment to endometrial cancer. This survey was conducted in a gynaeoncology out-patient department in Ireland. A total of 45/50 (90%) of questionnaires were completed. The majority of the patients questioned (86.7%; 39/45) agreed that obesity is a disease. Just over half of the cohort (53.3%; 24/45) believed that obesity can cause cancer. Over one-third, 39.9% (18/45) either disagreed or strongly disagreed that obesity is a risk factor for endometrial cancer while 35.5% (16/45) agreed or strongly agreed. Two-thirds (66.6%; 30/45) knew that the greatest amount of weight could be lost through metabolic surgery. Over three-quarters (82.1%; 37/45) of patients surveyed would be willing to engage in a combination of treatments in order to achieve weight-loss should it be proven to have a role in the management of endometrial cancer. This study demonstrates a need for patient education regarding the strong relationship between obesity and endometrial cancer risk. Patients are willing to consider weight loss interventions if they were proven to be as safe and effective as pelvic surgery in the management of endometrial cancer.

The Molecular Effects of a High Fat Diet on Endometrial Tumour Biology

Abstract: We sought to validate the BDII/Han rat model as a model for diet-induced obesity in endometrial cancer (EC) and determine if transcriptomic changes induced by a high fat diet (HFD) in an EC rat model can be used to identify novel biomarkers in human EC. Nineteen BDII/Han rats were included. Group A (n = 7) were given ad lib access to a normal calorie, normal chow diet (NCD) while Group B (n = 12) were given ad lib access to a calorie rich HFD for 15 months. RNAseq was performed on endometrial tumours from both groups. The top-ranking differentially expressed genes (DEGs) were examined in the human EC using The Cancer Genome Atlas (TCGA) to assess if the BDII/Han rat model is an appropriate model for human obesity-induced carcinogenesis. Weight gain in HFD rats was double the weight gain of NCD rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7-57% vs. 4/12-33%; p = 0.37). All tumours were equivalent to a Stage 1A, Grade 2 human endometrioid carcinoma. A total of 368 DEGs were identified between the tumours in the HFD group compared to the NCD group. We identified two upstream regulators of the DEGs, mir-33 and Brd4, and a pathway analysis identified downstream enrichment of the colorectal cancer metastasis and ovarian cancer metastasis pathways. Top-ranking DEGs included Tex14, A2M, Hmgcs2, Adamts5, Pdk4, Crabp2, Capn12, Npw, Idi1 and Gpt. A2M expression was decreased in HFD tumours. Consistent with these findings, we found a significant negative correlation between A2M mRNA expression levels and BMI in the TCGA cohort (Spearman's Rho = -0.263, p < 0.001). A2M expression was associated with improved overall survival (HR = 0.45, 95% CI 0.23-0.9, p = 0.024). Crabp2 expression was increased in HFD tumours. In human EC, CRABP2 expression was associated with reduced overall survival (HR = 3.554, 95% CI 1.875-6.753, p < 0.001). Diet-induced obesity can alter EC transcriptomic profiles. The BDII/Han rat model is a suitable model of diet-induced obesity in endometrial cancer and can be used to identify clinically relevant biomarkers in human EC.

Challenges of False Positive and Negative Results in Cervical Cancer Screening

Abstract: Objective To quantify the impact and accuracy of different screening approaches for cervical cancer, including liquid based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and their combinations via parallel co-testing and sequential triage. The secondary goal was to predict the effect of differing coverage rates of HPV vaccination on the performance of screening tests and in the interpretation of their results. Design Modelling study. Main outcomes measured Different screening modalities were compared in terms of number of cases of Cervical intra-epithelial neoplasia (CIN) grade 2 and 3 detected and missed, as well as the number of false positives leading to excess colposcopy, and number of tests required to achieve a given level of accuracy. The positive predictive value (PPV) and negative predictive value (NPV) of different modalities were simulated under varying levels of HPV vaccination. Results The model predicted that in a typical population, primary LBC screening misses 4.9 (95% Confidence Interval (CI) 3.5-CIN 2 / 3 cases per 1000 women, and results in 95 (95% CI: 93-97%) false positives leading to excess colposcopy. For primary HPV testing, 2.0 (95% CI: 1.9-2.1) cases were missed per 1000 women, with 99 (95% CI: 98-101) excess colposcopies undertaken. Co-testing markedly reduced missed cases to 0.5 (95% CI: 0.3-0.7) per 1000 women, but at the cost of dramatically increasing excess colposcopy referral to 184 per 1000 women (95% CI: 182-188). Conversely, triage testing with reflex screening substantially reduced excess colposcopy to 9.6 cases per 1000 women (95% CI: 9.3 - 10) but at the cost of missing more cases (6.4 per 1000 women, 95% CI: 5.1 - 8.0). Over a life-time of screening, women who always attend annual and 3-year co-testing were predicted to have a virtually 100% chance of falsely detecting a CIN 2 / 3 case, while 5 year co-testing has a 93.8% chance of a false positive over screening life-time. For annual, 3 year, and 5 year triage testing (either LBC with HPV reflex or vice versa), lifetime risk of a false positive is 35.1%, 13.4%, and 8.3% respectively. HPV vaccination rates adversely impact the PPV, while increasing the NPV of various screening modalities. Results of this work indicate that as HPV vaccination rates increase, HPV based screening approaches result in fewer unnecessary colposcopies than LBC approaches. Conclusion The clinical relevance of cervical cancer screening is crucially dependent upon the prevalence of cervical dysplasia and/or HPV infection or vaccination in a given population, as well as the sensitivity and specificity of various modalities. Although screening is life-saving, false negatives and positives will occur, and over-testing may cause significant harm, including potential over-treatment.

Surgical morbidity during covid-19 pandemic - a gynaecology oncology persective

Abstract: Introduction COVID-19 has had significant repercussions on the provision of oncological surgical services worldwide Within any Gynaecological Oncology service, careful consideration needs to be given when weighing up peri-operative risks & potential inpatient exposure to COVID-19 versus the risk of delaying surgery Often, for these patients, deferral of surgery may result in disease progression Since March 2020, we identified 118 Gynaecological Oncology patients referred to the Ireland East Gynaecological Group between the Mater Misericordiae University Hospital (MMUH) & St Vincent's University Hospital (SVUH) for whom major oncological surgery was deemed clinically urgent To minimise peri-operative morbidity and the risk of onward hospital transmission of COVID-19, screening questionnaires were administered before hospital admission These screened for epidemiological risk, symptoms, recent travel & contacts If asymptomatic, testing for SARS-CoV-2 was not performed Methods We analysed the clinical data of the above 118 patients to determine their baseline characteristics/risk factors for COVID-19, suspected diagnoses, surgical procedures & 7- day morbidity Results This cohort consisted of ovarian (n=57), endometrial (n=41), cervical (n=6) and vulvo-vaginal (n=14) cancer patients 44% of cases were laparoscopic and 18% were major cytoreductive surgeries All patients screened were deemed asymptomatic & low risk- therefore proceeded to surgery 49 (41 5%) patients had a defined risk factor for COVID-19 7- day post-operative morbidity was 13% (N=16) 3 patients met symptomatic criteria for COVID-19 testing post-operatively, however none tested positive Conclusion Careful patient selection based on risk factors and symptoms allows units to continue to perform safe oncological surgery during a pandemic