Professor Agnieszka Michael

Inoperable maliganant bowel obstruction (IBO) is very common in ovarian cancer patients. A lack of guidelines and research in this area means that nutrition support for patients with IBO is challenging. Parenteral nutrition (PN) is the recommended route for patients with a prognosis of > 2 months1, otherwise patients are encouraged to drink sips of clear fluids only. An elemental diet (ED) is licensed for strictures in Crohn’s disease and been used in one case report of a pregnant woman in bowel obstruction2. The aim of the EDMONd study was to evaluate ED as an alternative to PN in patients with IBO and to provide a ‘Proof of Concept’ of ED as an acceptable feeding option.

Introduction/Background: Inoperable bowel obstruction (IBO) occurs in up to 50% of patients diagnosed with ovarian cancer. Nutrition support for patients with IBO is challenging. Parenteral feeding (PN) is the recommended route for patients with a prognosis of > 2 months, however there is little evidence that it improves quality of life and the cost of it is very high. If PN is not available patients are frequently discharged home from hospital with sips of clear fluids only. Management of inoperable bowel obstruction remains a major challenge and clear guidelines are needed. Elemental diet (ED) is a liquid diet that contains proteins in the form of amino acids, fats in the form of medium chain triglycerides, vitamins and trace minerals. ED is almost completely absorbed in the upper small intestine. Methodology The primary objective of the study was to establish if ED can be used as an alternative to home PN in patients with IBO. The secondary aim was to examine the impact of ED on quality of life. The primary endpoints of the study were acceptability and tolerability of ED with respect to taste, and incidence of vomiting and pain. The secondary endpoints included the number of patients alive at the end of the study, quality of life, nutritional intake, and the number of women who can tolerate ED and subsequently be treated with palliative chemotherapy (as per standard of care).Results29 women with IBO caused by metastatic ovarian cancer were recruited into the EDMONd study. Of those 8 could not complete the trial due to disease progression, and 2 had missing data that was deemed irretrievable, leaving 19 patients who contributed data to the primary endpoint analysis. The mean age of the patients who continued the trial was 68 (SD 12.5). Preliminary analysis shows that 68.4% of patients met the primary endpoint and tolerated ED; the ED did not worsen the vomiting or pain as measured by Memorial Symptoms Assessment Scale. At baseline 72% of patients experienced vomiting and this number reduced to 28% by the end of week1 of the study and to 23.5% by the end of week 2. 96% of patients reported pain at baseline and this proportion reduced to 72% and 76% by the end of week 1 and 2 respectively. Conclusion ED is well tolerated by patients with IBO and can provide an acceptable feeding option for this group of patients.

TPS1614 Background: Cancer is the leading contributor of disease burden worldwide, and incidence rates are estimated to rise 47% by 2040. With increasing numbers of people living with cancer, alongside healthcare workforce shortages, current models for cancer monitoring and surveillance are unsustainable. Within the UK’s National Health Service (NHS), this is exacerbated by a rising backlog following the COVID-19 pandemic. Furthermore, a 2020 Macmillan Cancer Support survey showed that current patient information and support is scattered, inaccessible, and poorly personalized. There is an urgent need for effective personalized tools to support cancer patient self-management and data collection to enable healthcare professional (HCP) monitoring and remote follow-up. Methods: A multi-site randomized controlled trial is underway within the NHS to evaluate the implementation of a novel digital oncology platform (Vinehealth) for personalized support. Vinehealth consists of a mobile patient application, integrated wearables data, and a clinician dashboard. The study aims to recruit 180 patients across 8 NHS Trusts diagnosed with (i) colorectal, breast, or lung cancer undergoing adjuvant systemic treatment (chemotherapy +/- targeted therapies) post surgery, or (ii) asymptomatic breast cancer undergoing neoadjuvant treatment. A power calculation was conducted relating to the primary objective demonstrating the efficacy in improvement of QoL in the interventional arm, providing 80% power and at a significance level of 0.05. Enrolled patients will be randomized (1:1) between standard of care (SoC) and interventional arms (SoC plus Vinehealth platform). The main objective is to assess if implementation of Vinehealth improves patients’ quality of life (QoL) compared to SoC based on EQ-5D-5L, EORTC QLQ-C30, and FACT-G (PWB) questionnaires. Secondary objectives include assessing patient compliance with electronic patient-reported outcome (ePRO) data collection and patient self-management of symptoms. The study will further evaluate whether Vinehealth improves the process of care (assessed through medication adherence) and reduces emergency healthcare utilization (including ED/GP visits/admissions and acute oncology hotline use). Questionnaires are completed by all patients at baseline, 6, 12, 18 and 24 weeks. Qualitative interviews will be conducted with a subset of interventional arm patients and HCPs from each NHS Trust to understand engagement with the Vinehealth platform. To our knowledge, this is the first multi-site RCT within the NHS to evaluate the impact of a digital oncology platform on cancer patients’ QoL, ePRO compliance, process of care, and healthcare utilization. The trial is expected to end by September 2023 with results being reported in January 2024. Clinical trial information: ISRCTN44293246 .

Simple Summary Ovarian cancer survival in the UK is poorer than other similar countries. Results from the National Ovarian Cancer Audit Feasibility Pilot (OCAFP) showed that approximately 1 in 4 women with advanced stage ovarian cancer (greater than Stage 2) do not receive any anti-cancer treatment and that only 51% will receive both surgery and chemotherapy in England. The audit also showed that the proportions of women receiving treatment varies a lot across different areas in England. In response, a multidisciplinary team from the British Gynaecological cancer society has established Quality performance indicators that can be evaluated regularly using routinely collected data and will help improve cancer outcomes. Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.

There is an unmet need for improved diagnostic testing and risk prediction for cases of prostate cancer (PCa) to improve care and reduce overtreatment of indolent disease. Here we have analysed the serum proteome and lipidome of 262 study participants by liquid chromatography-mass spectrometry, including participants diagnosed with PCa, benign prostatic hyperplasia (BPH), or otherwise healthy volunteers, with the aim of improving biomarker specificity. Although a two class machine learning model separated PCa from controls with sensitivity of 0.82 and specificity of 0.95, adding BPH resulted in a statistically significant decline in specificity for prostate cancer to 0.76, with half of BPH cases being misclassified by the model as PCa. A small number of biomarkers differentiating between BPH and prostate cancer were identified, including proteins in MAP Kinase pathways, as well as in lipids containing oleic acid; these may offer a route to greater specificity. These results highlight, however, that whilst there are opportunities for machine learning, these will only be achieved by use of appropriate training sets that include confounding comorbidities, especially when calculating the specificity of a test.

12009 Background: Older and frail patients with cancer (Ca) often receive less aggressive treatment and as a result have worse survival. Current methods of assessing fitness (performance status) for intensive treatment such as chemotherapy are inadequate. The complexity of geriatric assessments, lack of training and time pressures in busy clinics, mean that better solutions are needed. A UK initiative - the electronic frailty index (eFI) - is derived from a cumulative deficit frailty model and provides a measure of frailty alongside pre-existing conditions such as issues with mobility, fractures, falls, memory, sight, hearing , anaemia, tremor, diabetes, heart, thyroid, skin, respiratory, cerebrovascular, circulation, social vulnerability, and polypharmacy (36 fields) (Clegg et al). Patients are classified into the following groups: no frailty, mild, moderate or severe frailty. We used the same methodology to investigate whether eFI predicts adverse outcomes of chemotherapy in frail patients with Ca. Methods: The study conducted retrospective data analysis of Ca patients treated with chemotherapy from Public Health England (PHE) Systemic Chemotherapy Dataset (SACT) years 2015-2018. Eligible patients had stage II - III breast Ca, stage III colon Ca or stage IIIB–IV non-small-cell lung Ca (NSCLC). The data from SACT was linked with hospital episodes' statistics (obtained from NHS-Digital) to calculate 30-day SACT mortality, overall survival and hospital admissions. EFI was calculated from the above 35 fields; polypharmacy was not available from NHS-Digital data. Results: The eFI was calculated for 78799 patients: colorectal 17951, lung 22052, and breast 38796. 20388 patients were ≥ 70y. o. and 58411 were < 70y.o. Most patients were fit with an eFI score of 0-69% (54563), 19% (15,295) had mild frailty, 7.7% (6104)- moderate, and 3.6% (2837) had severe frailty. 4.2% (3356) of patients died within 30 days of SACT. For colorectal Ca patients the risk of dying within 30 days of SACT in patients ≥70y.o was twice that of the < 70y.o (OR 2.04 -CI 1.58 - 2.64); patients with mild eFI did not differ- OR: 1.07 (CI 0.78-1.45), moderate frailty: 1.6 (CI 1.1-2.33) and severe frailty: 2.13 (CI 1.34-3.39). In breast Ca patients, 30-day mortality for ≥70y.o. was 6.38 times higher than for < 70y.o (95% CI 4.29-9.49); eFI for mild frailty- OR of 1.45 (95% CI 0.78-2.71), moderate frailty-OR of 3.5 (95%CI 1.82-6.75) and severe frailty 5.73 (95% CI 2.66-12.3). The 30-day mortality in lung cancer in ≥70y.o and < 70y.o did not differ with OR 0.95 (95% CI 0.88-1.03) for ≥70y.o. Patients with mild frailty had OR for 30-day mortality of 1.17 (95% CI 1.07-1.28), moderate frailty-OR of 1.28 (95%CI 1.15-1.44) and severe frailty 1.48 (95% CI 1.28-1.77). Conclusions: The eFI closely predicts poor outcomes from SACT, particularly in early breast and colon cancer, and requires further evaluation in a prospective study.

Correction to: Nature Genetics https://doi.org/10.1038/s41588-020-00748-0, published online 4 January 2021. In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

Purpose: The scope of radiation therapy is limited in melanoma. Using in vitro melanoma models, we investigated a Notch signaling inhibitor as a radiosensitizer to explore its potential to improve the efficacy of radiation therapy to widen the clinical application of radiation therapy in melanoma. Methods and Materials: Melanoma cell lines A375, SKMEL28, and G361 were grown using standard tissue culture methods. Radiation was delivered with a clinical x-ray unit, and a gamma secretase inhibitor RO4929097 was used to inhibit Notch signaling. Cell viability signal was used to calculate Loewe's combination index to assess the interaction between radiation and RO4929097 and also the effect of scheduling of radiation and RO4929097 on synergy. Clonogenic assays were used to assess the clonogenic potential. An in vitro 3-dimensional culture model, gamma-H2AX, and notch intracellular domain assays were used to interrogate potential underlying biological mechanisms of this approach. Scratch and transwell migration assays were used to assess cell migration. Results: A375 and SKMEL28 cell lines showed consistent synergy for most single radiation doses examined, with a tendency for better synergy with the radiation -first schedule (irradiation performed 24 hours before RO4929097 exposure). Clonogenic assays showed dose-dependent reduction in colony numbers. Both radiation and RO4929097 reduced the size of melanospheres grown in 3-dimensional culture in vitro, where RO4929097 demonstrated a significant effect on the size of A375 and SKMEL28 melanospheres, indicating potential modulation of stem cell phenotype. Radiation induced gamma-H2AX foci signal levels were reduced after exposure to RO4929097 with a tendency toward reduction in notch intracellular domain levels for all 3 cell lines. RO4929097 impaired both de novo and radiation-enhanced cell migration. Conclusions: We demonstrate Notch signaling inhibition with RO4929097 as a promising strategy to potentially improve the efficacy of radiation therapy in melanoma. This strategy warrants further validation in vivo. (C) 2020 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

The objective of the study was to document the effect of adipocytokines on endometrial cancer progression. A search of the databases CINAHL, Medline, PubMed, Cochrane, Web of Science, Embase and Google Scholar was performed for English language articles from January 2000 to December 2020 using the keywords: (Endometrial cancer) AND (progression OR metastasis) AND (adipocytokine OR adiponectin OR leptin OR visfatin OR IL-6 OR TNF-alpha OR adipokine OR cytokine). Forty-nine studies on adipocytokines have been included in this review. Adiponectin has been linked with anti-proliferative and anti-metastatic effects on endometrial cancer cells and is associated with a better prognosis. Leptin, visfatin and resistin are linked to the stimulation of endometrial cancer growth, proliferation, invasion and metastasis and are associated with worse prognosis or with a higher grade/stage of endometrial cancer. IL-6, Il-11, IL-31, IL-33, TNF-alpha, TGF-beta 1, SDF-1 and CXCR are involved in endometrial cancer cell growth and metastasis or involved in epithelial mesenchymal transformation (EMT) or associated with advanced disease. Adipocytokines have been found to directly impact endometrial cancer cell proliferation, invasion and migration. These molecules and their signalling pathways may be used to determine prognosis and course of the disease and may also be exploited as potential targets for cancer treatment and prevention of progression.

BACKGROUNDMalignant bowel obstruction is a common cause of morbidity and mortality in patients with advanced ovarian cancer. Many patients aren't suitable for, or decline, surgical decompression. The outcomes for this frail group of patients are not well characterized. AIMTo evaluate survival outcomes of ovarian cancer patients who undergo non-surgical management of malignant bowel obstruction. DESIGNSystematic review and meta-analysis. DATA SOURCESOnline literature search of Pubmed, Embase and Medline libraries up until December 2020. Searching abstracts of scientific meetings, reference lists of included studies and contacting experts in the field. SELECTION CRITERIAStudies that investigated non-surgical management of confirmed bowel obstruction in advanced ovarian cancer patients were included. All levels of evidence including RCTs, cohort studies and case-series if they included greater than 5 patients. DATA COLLECTION AND ANALYSISThe studies were independently chosen by two reviewers who extracted and analyzed the data separately through OpenMeta Analyst software. Study quality was assessed using the JADAD score and the Newcastle Ottawa Score. RESULTS24 studies met the eligibility criteria for the systematic review and 9 for the meta-analysis. Median survival of patients managed non-surgically for bowel obstruction was 44 days (95% CI 38-49 days, I 2 = 0%, P = 0.128). CONCLUSIONThe quality of studies was relatively low, however the evidence shows that non-surgical management of bowel obstruction results in a short life expectancy but with controlled symptoms. Where quality of life is the main concern, this may be a feasible and effective strategy.

Royal Surrey NHS Foundation Trust introduced robotic surgery for uterine corpus cancer in 2010 to support increased access to minimally invasive surgery, a central element of an enhanced recovery after surgery (ERAS) pathway. More than 1750 gynaecological oncology robotic procedures have now been performed at Royal Surrey NHS Foundation Trust. A retrospective cohort study was performed of patients undergoing surgery for uterine corpus cancer between the 1 January 2010 and the 31 December 2019 to evaluate its success. Data was extracted from the dedicated gynaecological oncology database and a detailed notes review performed. During this time; 952 patients received primary surgery for uterine corpus cancer; robotic: n = 734; open: n = 164; other minimally invasive surgery: n = 54. The introduction of the Da Vinci (TM) robot to Royal Surrey NHS Foundation Trust was associated with an increase in the minimally invasive surgery rate. Prior to the introduction of robotic surgery in 2008 the minimally invasive surgery (MIS) rate was 33% for women with uterine corpus cancer undergoing full surgical staging. In 2019, 10 years after the start of the robotic surgery program 91.3% of women with uterine corpus cancer received robotic surgery. Overall the MIS rate increased from 33% in 2008 to 92.9% in 2019. Robotic surgery is associated with a low 30-day mortality (0.1%), low return to theatre (0.5%), a low use of blood transfusion and intensive care (1.8% & 7.2% respectively), low conversion to open surgery (0.5%) and a reduction in median length of stay from 6 days (in 2008) to 1 day, regardless of age/BMI. Robotic survival is consistent with published data. Introduction of the robotic program for the treatment of uterine cancer increased productivity and was associated with a highly predicable patient pathway of care, for high-risk patients, with reduced demands on health services. Future health care commissioning should further expand access to robotic surgery nationally for women with uterine corpus cancer.

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66–84; placebo, 77 mo, IQR 69–85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80–1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m2 compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC. In the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. This trial is registered at Clinicaltrials.gov as NCT01235962. Adjuvant pazopanib does not extend overall survival compared to placebo in patients with locally advanced or metastatic renal cell carcinoma.

On March 11, 2020 the COVID-19 outbreak was declared a 'pandemic' by the World Health Organization. COVID-19 is associated with higher surgical morbidity and mortality. An array of guidelines on the management of cancer during this pandemic have been published since the first reports of the outbreak. This narrative review brings all the relevant information from the guidelines together into one document, to support patient care. We present a detailed review of published guidelines, statements, comments from peer-reviewed journals, and nationally/internationally recognized professional bodies and societies' web pages (in English or with English translation available) between December 1, 2019 and May 27, 2020. Search terms included combinations of COVID, SARS-COV-2, guideline, gynecology, oncology, gynecological, cancer. Recommendations for surgical and oncological prioritization of gynecological cancers are discussed and summarized. The role of minimally invasive surgery, patient perspectives, medico-legal aspects, and clinical trials during the pandemic are also discussed. The consensus is that elective benign surgery should cease and cancer surgery, chemotherapy, and radiotherapy should continue based on prioritization. Patient and staff face-to-face interactions should be limited, and health resources used efficiently using prioritization strategies. This review and the guidelines on which it is based support the difficult decisions currently facing us in gynecological cancer. It is a balancing act: limited resources and a hostile environment pitted against the time-sensitive nature of cancer treatment. We can only hope to do our best for our patients with the resources available to us.

Prostate cancer is the most common malignant tumour in men. Improved testing for di- agnosis, risk prediction, and response to treatment would improve care. Here, we identified a pro- teomic signature of prostate cancer in peripheral blood using data-independent acquisition mass spectrometry combined with machine learning. A highly predictive signature was derived, which was associated with relevant pathways, including the coagulation, complement, and clotting cas- cades, as well as plasma lipoprotein particle remodeling. We further validated the identified bi- omarkers against a second cohort, identifying a panel of five key markers (GP5, SERPINA5, ECM1, IGHG1, and THBS1) which retained most of the diagnostic power of the overall dataset, achieving an AUC of 0.91. Taken together, this study provides a proteomic signature complementary to PSA for the diagnosis of patients with localised prostate cancer, with the further potential for assessing risk of future development of prostate cancer. Data are available via ProteomeXchange with identi- fier PXD025484.

Chronic inflammation has been closely linked to the development and progression of various cancers. The epithelial-mesenchymal transition (EMT) is a process involving the acquisition of mesenchymal features by carcinoma cells and is an important link between inflammation and cancer development. Inflammatory mediators in the tumour micro-environment, such as cytokines and chemokines, can promote EMT changes in cancer cells. The aim of this systematic review is to analyse the effect of cytokines on EMT in gynaecological cancers and discuss their possible therapeutic implications. A search of the databases CINAHL, Cochrane, Embase, Medline, PubMed, TRIP, and Web of Science was performed using the keywords: "cytokines" AND "epithelial mesenchymal transition OR transformation" AND "gynaecological cancer". Seventy-one articles reported that various cytokines, such as TGF-β, TNF-α, IL-6, etc., promoted EMT changes in ovarian, cervical, and endometrial cancers. The EMT changes included from epithelial to mesenchymal morphological change, downregulation of the epithelial markers E-cadherin/β-catenin, upregulation of the mesenchymal markers N-cadherin/vimentin/fibronectin, and upregulation of the EMT-transformation factors (EMT-TF) / . Cytokine-induced EMT can lead to gynaecological cancer development and metastasis and hence novel therapies targeting the cytokines or their EMT signalling pathways could possibly prevent cancer progression, reduce cancer recurrence, and prevent drug-resistance.

Objectives: In this study we wished to determine the rank order of risk factors for endometrial cancer and calculate a pooled risk and percentage risk for each factor using a statistical meta-analysis approach. The next step was to design a neural network computer model to predict the overall increase or decreased risk of cancer for individual patients. This would help to determine whether this prediction could be used as a tool to decide if a patient should be considered for testing and to predict diagnosis, as well as to suggest prevention measures to patients. Design: A meta-analysis of existing data was carried out to calculate relative risk, followed by design and implementation of a risk prediction computational model based on a neural network algorithm. Setting: Meta-analysis data were collated from various settings from around the world. Primary data to test the model were collected from a hospital clinic setting. Participants: Data from 40 patients notes currently suspected of having endometrial cancer and undergoing investigations and treatment were collected to test the software with their cancer diagnosis not revealed to the software developers. Main outcome measures: The forest plots allowed an overall relative risk and percentage risk to be calculated from all the risk data gathered from the studies. A neural network computational model to determine percentage risk for individual patients was developed, implemented, and evaluated. Results: The results show that the greatest percentage increased risk was due to BMI being above 25, with the risk increasing as BMI increases. A BMI of 25 or over gave an increased risk of 2.01%, a BMI of 30 or over gave an increase of 5.24%, and a BMI of 40 or over led to an increase of 6.9%. PCOS was the second highest increased risk at 4.2%. Diabetes, which is incidentally also linked to an increased BMI, gave a significant increased risk along with null parity and noncontinuous HRT of 1.54%, 1.2%, and 0.56% respectively. Decreased risk due to contraception was greatest with IUD (intrauterine device) and IUPD (intrauterine progesterone device) at −1.34% compared to −0.9% with oral. Continuous HRT at −0.75% and parity at −0.9% also decreased the risk. Using open-source patient data to test our computational model to determine risk, our results showed that the model is 98.6% accurate with an algorithm sensitivity 75% on average. Conclusions: In this study, we successfully determined the rank order of risk factors for endometrial cancer and calculated a pooled risk and risk percentage for each factor using a statistical meta-analysis approach. Then, using a computer neural network model system, we were able to model the overall increase or decreased risk of cancer and predict the cancer diagnosis for particular patients to an accuracy of over 98%. The neural network model developed in this study was shown to be a potentially useful tool in determining the percentage risk and predicting the possibility of a given patient developing endometrial cancer. As such, it could be a useful tool for clinicians to use in conjunction with other biomarkers in determining which patients warrant further preventative interventions to avert progressing to endometrial cancer. This result would allow for a reduction in the number of unnecessary invasive tests on patients. The model may also be used to suggest interventions to decrease the risk for a particular patient. The sensitivity of the model limits it at this stage due to the small percentage of positive cases in the datasets; however, since this model utilizes a neural network machine learning algorithm, it can be further improved by providing the system with more and larger datasets to allow further refinement of the neural network.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR 98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69–1.77] to 2.41 [2.40–2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR 98/50 of the Discovery-SNP model increased from 1.05 [0.93–1.18] to 2.19 [2.16–2.23]. HR 98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70–1.85] and 1.73 [1.71–1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential ‘salvage’ measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.

Objectives: To evaluate current first-line treatment strategies in advanced or metastatic renal cell carcinoma (RCC), and to review other promising treatments under investigations. Materials and methods: We reviewed all relevant pivotal first-line systemic therapy trials, and studies investigating the role of cytoreductive nephrectomy, metastectomy, and ablative radiotherapy in advanced or metastatic RCC. Results: In total we identified 21 relevant studies, investigating both systemic and non-systemic therapies, including treatments under investigations. Conclusion: Metastatic RCC (mRCC) is a highly heterogeneous disease that is notoriously difficult to treat, however, the discovery of novel targeted therapies over the past decade have revolutionised its management. The International mRCC Database Consortium (IMDC) is a prognostic model that is commonly used in both clinical trials and routine clinical care to risk-stratify patients with mRCC, which has helped with therapy selection for mRCC patients over the past decade. However, with an improved understanding of tumour biology and genetics, this has prompted a shift from cytokine therapy to receptor tyrosine kinase inhibitors, and now to Immune Checkpoint Inhibitors (ICIs). Recent promising results from clinical studies with ICI combination treatments have transformed the treatment landscape for the management of intermediate- and poor- risk clear cell RCC, however, further research is still needed for favourable-risk, and non-clear cell patients. Level of evidence: Not applicable

Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. UK National Institute for Health and Care Research.

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72–1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P 

Recent advances in the treatment of metastatic renal cell carcinoma expose a gap in the treatment of less advanced, localized disease. Tyrosine kinase inhibitors, which revolutionized the treatment of metastatic disease, have not provided a similar survival benefit in the adjuvant setting and currently only sunitinib is approved by the Food and Drug Administration for adjuvant treatment in patients with high-risk of recurrence based on S-TRAC disease-free survival data. The advent of immune checkpoint inhibitors has offered a fresh hope in the field of adjuvant treatment after encouraging results are seen with combination of immune checkpoint inhibitors as well as with targeted therapy in the metastatic setting. Several studies are investigating these combinations in the adjuvant setting, and it is hoped that they will bring about a better outcome for a largely unmet need in kidney cancer treatment.

Featured Application Preliminary in vitro screening of radiation-drug combinations within a clinical set-up. We designed and developed a multiwell tissue culture plate irradiation setup, and intensity modulated radiotherapy plans were generated for 96-, 24-, and 6-well tissue culture plates. We demonstrated concordance between planned and measured/imaged radiation dose profiles using radiochromic film, a 2D ion chamber array, and an electronic portal-imaging device. Cell viability, clonogenic potential, and gamma-H2AX foci analyses showed no significant differences between intensity-modulated radiotherapy and open-field, homogeneous irradiations. This novel platform may help to expedite radiobiology experiments within a clinical environment and may be used for wide-ranging ex vivo radiobiology applications.

Metastatic Renal Cell Carcinoma (mRCC) is a highly heterogeneous disease that is notoriously difficult to treat successfully. However, the discovery of novel, targeted therapies over the last decade has revolutionized its management. As the therapeutic options continue to evolve, developing a more individualized treatment strategy is of paramount importance. The International mRCC Database Consortium (IMDC) is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients. This allows for optimal therapy selection on a more individual basis. However, the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response. An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase Inhibitors, immune checkpoint inhibitors or combination strategies. Studies have identified some putative markers and genetic mutations as potential predictors of therapy response. Early results are promising, and there are many ongoing trials further assessing their suitability for clinical use. This review will evaluate the current treatment landscape and molecular biology of mRCC, with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.

Aims: Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma. Materials and methods: Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1e14 for six cycles. The end points included the objective response rate and median survival. Results: Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44e79 years) and the median Karnofsky performance status was 80% (range 60e100%). The median followup was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6e21.6 months). Conclusions: The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer - sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.

© 2013 Springer-Verlag London. All rights are reserved.Prostate cancer can present at any stage of the disease and very frequently does not cause any symptoms at all. Most cancers arise in the periphery of the prostate gland and cause symptoms only when they have grown to compress the urethra or invade the sphincter [1]. In recent years, more and more of prostate cancer patients from the western hemisphere are diagnosed at an earlier stage due to rising prevalence of prostate-specific antigen (PSA) testing [2]. A study by Cooperberg et al. analyzed trends in clinical presentation in 2,078 men diagnosed between 1989 and 2001. The proportion of patients with low-risk tumor characteristics rose from 29.8 % in 1989-1992 to 45.3 % in 1999-2001 [3]. Studies based on the Department of Defense Center for Prostate Disease (CPDR) found downward migration at higher stage [3]. The percentage of patients presenting with locally advanced (T3 to T4) disease fell from 19.2 % in 1988 to 4.4 % in 1998; rates of metastatic disease at diagnosis likewise declined from 14.1 % in 1988 to 3.3 % in 1998.

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region

OBJECTIVE: HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. METHODS: HOX gene expression was determined in ovarian cancer cell lines and primary EOCs, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one way ANOVA and t-tests, using statistical software R and GraphPad. RESULTS: 30 of the 39 HOX genes were overexpressed in high grade serous EOC compared to normal tissue, most significant being HOXA3, A9, B13 and C10. We detected a molecular HOX gene-signature that predicted poor outcome: overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer.CONCLUSIONS: HOX genes are highly dysregulated in ovarian cancer. High expression of HOXA13, B6, C13, D1 and D13 is predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum–resistant cancer represents a new therapeutic option that should be further developed and tested in clinical trials.

Despite extensive efforts to identify a clinically useful diagnostic biomarker in prostate cancer, no new test has been approved by regulatory authorities. As a result, this unmet need has shifted to biomarkers that additionally indicate presence or absence of "significant" disease. EN2 is a homeodomain-containing transcription factor secreted by prostate cancer into the urine and can be detected by enzyme-linked immunoassay. EN2 may be an ideal biomarker because normal prostate tissue and benign prostatic hypertrophic cells do not secrete EN2. This review discusses the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, inexpensive, and reliable prostate cancer biomarker.

Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.

Background Checkpoint immunotherapy has revolutionised the way that melanoma is treated and has also shown significant effectiveness in lung, bladder, renal and head and neck cancers. At the present time, trials of checkpoint immunotherapy are at early phases in cervical cancer but there is very good rationale for pursuing this as a treatment option especially as cervical cancer is a virally driven cancer and therefore should be recognised by the immune system as being foreign. This review explores the biomarkers for the selection of patients for immunotherapy in other cancers such as PD-L1 expression, tumour infiltrating lymphocytes and total mutational burden and relates these biomarkers to cervical cancer. Design A PubMed search for publications published in English with the terms “immunotherapy” OR “cervical cancer” OR “checkpoint blockade” OR “tumour infiltrating lymphocytes” OR ‘total mutational burden”. Articles that met these criteria and were available on PubMed before October 8, 2018, were included. Results PD-L1 is positive in up to 90% of cervical cancers and the total mutational burden is moderately high with 5-6 mutations per megabase. In addition, the tumour microenvironment in cervical cancer has an impact on prognosis with higher ratios of CD8+ tumour infiltrating lymphocytes (TILs) to CD4+ T regulatory cells being associated with improved survival. Clinical studies to date have shown the response rate of cervical cancer to checkpoint immunotherapy to be in the region to 10-25%. Conclusion Cervical cancer exhibits many of the features that have been shown to be correlated with response to checkpoint immunotherapy in other tumour sites. However, response rates to date are in the region of 10-25%. Therefore, combinations of immunotherapeutic agents or checkpoint inhibitors with radiotherapy may be required to maximise the therapeutic benefit of harnessing the host immune system to fight cancer.

Anti-angiogenic agents targeting tumour vasculature have an established place in clinical practice, and new data are constantly emerging. However, despite rapid clinical uptake, a very large number of questions regarding these agents remain unanswered. One of the main hurdles in clinical practice is lack of accurate and feasible ways of assessing response to drug beyond tumour reduction on conventional imaging. This review summarises recent developments in the field of biomarkers of response to anti-VEGF drugs.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P ˂ 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10−9; G˃C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T˃G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.

Extensive efforts to identify a clinically useful biomarker for the diagnosis of prostate cancer have resulted in important insights into the biology of the disease, but no new test has been approved by regulatory authorities. The unmet need has also shifted to identifying biomarkers that not only diagnose prostate cancer but also indicate whether the patient has 'significant' disease. EN2 is a homeobox-containing transcription factor secreted specifically by prostate cancers into urine, where it can be detected by a simple ELISA assay. A number of studies have demonstrated the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, cheap and efficient prostate cancer biomarker.

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

BACKGROUND: Epithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker. METHODS We evaluated 8 Epithelial ovarian cancer cell lines, along with >100 surgical specimens from the Royal Surrey County Hospital (2009-2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/-resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in >150 tumours (immunohistochemistry). RESULTS En2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.

Objectives: Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to many false positives and overdiagnosis of indolent disease, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient’s risk. We sought to develop and validate a genetic tool to predict age of aggressive PCa onset and to guide decisions of whom to screen and at what age. Design: Genotype, PCa status, and age were analyzed to select single-nucleotide polymorphisms (SNPs) associated with PCa diagnosis. These SNPs were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (i.e., not eligible for surveillance per NCCN Guidelines; any of: Gleason score ≥7, stage T3-T4, PSA ≥10, nodal metastasis, distant metastasis). The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and screening PSA data. PHS was calculated for these men to test prediction of PCa-free survival. Setting: Multiple, international PRACTICAL consortium member institutions. Participants: All PRACTICAL consortium participants of European ancestry with known age, PCa status, and quality-assured iCOGS array genotype data. Development dataset comprised 31,747 men. Validation dataset comprised 6,411 men. Main outcome measures: PHS prediction of age of onset of aggressive PCa in validation set. Results: In the independent validation set, PHS calculated from 54 SNPs was a highly significant predictor of age at diagnosis of aggressive PCa (z=11.2, p98th percentile) were compared to those with average PHS (30th-70th percentile), the hazard ratio for aggressive PCa was 2.9. Conclusions:Polygenic hazard scores give personalized genetic risk estimates that predict for age of onset of aggressive PCa.

Introduction/Background MIRRORS is a UK based prospective feasibility study opened June 2020, following ethics approval. Its purpose is to establish the feasibility of launching a randomised control trial (RCT) of Robotic interval debulking surgery for ovarian cancer (including cancer of the fallopian tube & peritoneum) MIRRORS-RCT in the future. MIRRORS will focus on the feasibility of obtaining consent from women and the acceptability of Robotic interval debulking surgery for advanced ovarian cancer. Methodology Women will be identified through the Gynaecological Oncology multi-disciplinary team meeting. Inclusion Criteria adult women ≥18 years with stage IIIc–IVb ovarian cancer (including cancer of the fallopian tube & peritoneum) undergoing neo–adjuvant chemotherapy considered suitable for interval debulking surgery (IDS). ≤8 cm pelvic mass on CT Exclusion Criteria Pelvic Mass >8 cm open surgical approach considered necessary following MDT review. Women lacking capacity to the extent they are unable to understand or complete trial documentation/questionnaires will be excluded from the trial. MIRRORS inclusion criteria are intentionally wide, not restricting by Body Mass Index (BMI), patient comorbidity or Ca125 values. Surgery will commence with an initial laparoscopic assessment followed by a decision to proceed to robotic or open interval debulking surgery. The aim of surgery is to remove all visible disease safely by whichever route. If conversion to open surgery is required to complete this, then it will be done. Results All women recruited to MIRRORS, whether eventually undergoing robotic or open surgery, will be followed up to assess recovery, complication rate, pain and quality of life. If the following Success Criteria are met, we will progress to MIRRORS-RCT: ≥20% of women eligible for the study accept inclusion in MIRRORS. Robotic IDS Complication rate is not higher than for open interval debulking surgery Conversion to open surgery rate not greater than 50% in patient group deemed suitable for Robotic IDS following initial diagnostic laparoscopy.Abstract 255 Figure 1 Conclusion Robotic surgery is unlikely to be suitable in all cases of ovarian cancer, particularly those with large pelvic masses or extensive disease around the upper part of the abdomen, however, it has the potential to provide significant recovery and quality of life benefits. Ultimately we would like to determine whether, in selected women, robotic surgery offers improved quality of life and recovery with equivalent overall and progression free survival. Disclosures Anil Tailor: Proctor for Intuitive Surgical Jayanta Chatterjee: paid-lectures on behalf of pharmaceutical companies Agnieszka Michael: Educational-grants: Clovis, GSK, Ipsen, Novartis, Pfizer, and Tesaro Simon Butler-Manuel: Proctor for Intuitive Surgical, Plasma Surgical & Ethicon

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC). Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with intravenous paclitaxel (175 mg/m ) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II). Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9-52.4] by RECIST 1.1 and 52% (95% CI, 31.3-72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3-9.0 months). Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT ), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT ) and safety. Results The primary analysis results of DFS ITT favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.

This retrospective study. CERES (NCT03696407), describes early clinical experience with cabozantinib in patients with advanced renal cell carcinoma (aRCC) enrolled in the UK managed access programme (MAP). Cabozantinib demonstrated clinically meaningful activity in all patients across multiple lines of therapy. Charlson Comorbidity Index score warrants further investigation as a prognostic/predictive marker. Our results provide a benchmark for future real-world studies in aRCC. Background: Cabozantinib monotherapy is approved in the UK for patients with treatment-naive intermediate-or poor-risk advanced renal cell carcinoma (aRCC), or patients who received prior vascular endothelial growth factor-targeted therapy. Data are limited on the real-world use of cabozantinib for aRCC. Patients and Methods: CERES (NCT03696407) was a retrospective study of patients with aRCC who received cabozantinib through he UK managed access programme (MAP; August 2016-July 2017), at which time cabozantinib had European regulatory approval for second- or later-line use only. The study objectives were to characterize aRCC treatment patterns and evaluate cabozantinib effectiveness. Outcomes were stratified by cabozantinib treatment line, MAP treatment date (months 0-7 vs. 8-12) and (post hoc) Charlson Comorbidity Index (CCI; >= 6 vs. < 6). Results: Of 100 patients included, 99% had stage IV disease, 63% had a CCI >= 6 and 81% had an Eastern Cooperative Oncology Group Performance Status 0-1. Median (range) duration of follow-up was 10.8 (0.4-33.5) months. Cabozantinib was administered as second-line, third-line and fourth- or later-line in 41%. 31% and 28% of patients, respectively. Most patients (84%) initiated cabozantinib at 60 mg. Average (range) cabozantinib dose was 45.5 (19.6-59.8) mg/day; 66% of patients had >= 1 dose reduction. Disease progression was the most common reason for discontinuation (65.1%). Median (95% confidence interval) progression-free survival (PFS) and overall survival (OS) were 6.01 (5.16-785) and 10.84 (7.92-16.85) months, respectively. Overall response rate was 34.5%; disease control rate 70.1% and duration of response 6.9 (1.8-26.9) months. No significant differences M survival estimates were observed between treatment line or treatment date subgroups. Total CCI score 6) was associated with prolonged median PFS and OS. Conclusion: Cabozantinib demonstrated clinical activity in this UK real-world aRCC population. The results provide a benchmark tor future real-world studies in aRCC. (C) 2021 The Authors. Published by Elsevier Inc.

Aims: Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma. Materials and methods: Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1e14 for six cycles. The end points included the objective response rate and median survival. Results: Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44e79 years) and the median Karnofsky performance status was 80% (range 60e100%). The median followup was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6e21.6 months). Conclusions: The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

Advanced renal-cell carcinoma is a very difficult tumour to treat, and response rates to biological therapies are less than 20%. The identification of various molecular and cellular markers has led to the development of novel therapies. Despite evaluation of their association with histological subtype, immune infiltration, molecular markers of cell proliferation, p53 mutation, and growth-factor-receptor expression, none of these markers has proved better predictive factors than tumour stage and histological grade. The identification of tumour-associated antigens and the specificity of cellular immune responses have led to the development of targeted immunotherapy with monoclonal antibodies, radioimmunotherapy, and T-cell therapies. In this review, we evaluate a range of markers associated with renal-cell carcinoma and new treatment approaches based on tumour-associated antigens and, in particular, T-cell epitopes.

DNA vaccines are known to induce long-term antigen specific cellular responses. We tested two new strains of Salmonella typhimurium, one carrying a mutation in a SPI-2 gene and the aroC-gene and another carrying mutations in the s ifA- and aroC-genes, as potential DNA vaccine delivery vehicles. We compared them with the SL7207 strain and found that the new strains were more invasive, and that they were efficient mediators of gene transfer in vitro using EGFP as reporter gene. We tested the ability of the new strains to survive within the spleen, liver and mesenteric lymph nodes and evaluated their safety in C57/BL/6J mice.

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [

Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody that may prolong survival in ovarian and cervical cancer when given in combination with chemotherapy. It works by blocking the signalling pathways that are required for tumour angiogenesis, potentially limiting the cancer's ability to grow and spread. Hypertension is a known side effect of all angiogenesis inhibitors and could lead to interruption or premature discontinuation of effective anti-cancer treatment. Hypertension may also act as a barrier to the initiation of such treatment. In this review, we aim to present clear and practical recommendations on the management of blood pressure in ovarian and cervical cancer patients before, during and after bevacizumab treatment. This guidance covers considerations before initiating bevacizumab therapy and recommendations on the management of patients who develop hypertension, or who experience worsening of pre-existing hypertension, during bevacizumab treatment, and once the course of bevacizumab has been completed. These recommendations were developed collaboratively by a group of clinicians, comprising cardiologists, oncologists, a general practitioner and specialist oncology nurses, with expertise and practical experience in either oncology or hypertension. The aim of these recommendations is to support oncologists with hypertension assessment and management to facilitate starting or continuing bevacizumab.

Background Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. Methods We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. Results Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. Conclusions Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer.

HOX genes are highly conserved members of the homeobox superfamily that have a crucial role in determining cellular identity. High grade ovarian cancer is the most lethal gynaecological malignancy. Our understanding of the role of HOX genes in the oncogenesis of ovarian cancer is evolving, and here we review their dysregulated expression patterns, their function in cell survival and invasion, their potential uses as biomarkers, and ways in which HOX genes are being targeted with new and existing drugs.

Introduction/Background MIRRORS is a UK based prospective feasibility study opened June 2020, following ethics approval. Its purpose is to establish the feasibility of launching a randomised control trial (RCT) of Robotic interval debulking surgery for ovarian cancer (including cancer of the fallopian tube & peritoneum) MIRRORS-RCT in the future. MIRRORS will focus on the feasibility of obtaining consent from women and the acceptability of Robotic interval debulking surgery for advanced ovarian cancer. Methodology Women will be identified through the Gynaecological Oncology multi-disciplinary team meeting. Inclusion Criteria adult women ≥18 years with stage IIIc–IVb ovarian cancer (including cancer of the fallopian tube & peritoneum) undergoing neo–adjuvant chemotherapy considered suitable for interval debulking surgery (IDS). ≤8 cm pelvic mass on CT Exclusion Criteria Pelvic Mass >8 cm open surgical approach considered necessary following MDT review. Women lacking capacity to the extent they are unable to understand or complete trial documentation/questionnaires will be excluded from the trial. Exclusion CriteriaMIRRORS inclusion criteria are intentionally wide, not restricting by Body Mass Index (BMI), patient comorbidity or Ca125 values. Surgery will commence with an initial laparoscopic assessment followed by a decision to proceed to robotic or open interval debulking surgery. The aim of surgery is to remove all visible disease safely by whichever route. If conversion to open surgery is required to complete this, then it will be done. Results All women recruited to MIRRORS, whether eventually undergoing robotic or open surgery, will be followed up to assess recovery, complication rate, pain and quality of life. If the following Success Criteria are met, we will progress to MIRRORS-RCT: ≥20% of women eligible for the study accept inclusion in MIRRORS. Robotic IDS Complication rate is not higher than for open interval debulking surgery Conversion to open surgery rate not greater than 50% in patient group deemed suitable for Robotic IDS following initial diagnostic laparoscopy.

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-κB, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-α and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guerin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Background: Prostate cancer is a leading cause of cancer related death in men but its diagnosis is still complicated by the lack of a highly predictive biochemical marker. Here we show that the transcription factor Engrailed-2 is secreted from prostate tumours in a highly specific manner and is present in the urine of men with prostate cancer. Methods: Urine was collected under standardised conditions from men with prostate cancer, or with non-cancerous conditions of the prostate such as benign prostatic hypertrophy, or men who were found to have no prostate abnormalities after saturation biopsy. Results: Engrailed-2 protein was detected in the untreated, unconcentrated urine of 62% of men with prostate cancer, but only 3% of men with no prostatic abnormalities (n=258, p

Background: Standard treatment for epithelial ovarian (EOC) and primary peritoneal (PP) cancer is combination of surgery and chemotherapy. Most commonly used first-line drugs are carboplatin and paclitaxel (C/P). Treatment decisions involving elderly patients are complex and single agent carboplatin (C) is often preferred. To help the decision process we analysed the toxicity profile and outcome for elderly patients treated first line with both: C/P and C alone. Methods: A retrospective analysis of 82 elderly patients (> 75 years) treated for EOC and PP cancer between April 1996 and October 2009 was performed. Age, comorbidities, CA-125 at diagnosis, histology, stage, outcome of cytoreductive surgery (CRS), chemotherapy regimen, toxicity and clinical response were recorded. Results: The majority, 76% (63/82) of patients had serous ovarian cancer with 58.5% presenting as FIGO stage 3c, median CA-125 of 340.2 U/mL (range: 5-5702). 67.1% (55/82) had CRS with 61.9% (34) optimally debulked. 84.2% of patients (69/82) received chemotherapy and were therefore evaluable for the purpose of this analysis. 94.2% (65/69) completed treatment (mean number of cycles = 5.1). 35.4% (23/65) received C/P and 63.1% (41/65) received single agent C. The commonest complication was peripheral neuropathy- 56.5% (13/23) in combination arm. Treatment was deferred mainly due to haematological toxicity: neutropaenia - 13.9% (6/43) in the C arm and 11.1% (3/27) in C/P; grade 3/4 thrombocytopaenia-4 (3-C, 1-P/C); grade 3-anaemia-1 (C). Dose reduction was required for 46.1% (12/26) in the combination arm and 25.5% (11/43) in the C arm. There were 35 dose delays-34.6% (9/26) C/P and 60.4% (26/43) C. Median survival for this group of patients was 21.3months. Median PFS was 8.8 months in C/P arm and 7 months in the C arm (95% CI-0.71 to1.8-not statistically significant). Conclusions: The toxicity of combination treatment with C/P is comparable to single agent C in elderly population with frequent dose delays and dose reductions. Initial assessment of comorbidities and performance status is essential however effort should be made to offer patients optimal treatment with the combination regimen.

Background: Ovarian cancer remains the most lethal gynaecologic tumour in the Western world. Stimulation of the immune system to consolidate response to chemotherapy can potentially be beneficial however so far none of the vaccination strategies have offered survival advantage. Thus identifying and targeting clinically relevant antigens for immunotherapy continues to be an important research strategy. We have evaluated Engrailed-2 (EN2) as a potential target for vaccine strategy. EN2 is a homeodomain-containing transcription factor with a multifunctional role in neural development. There is evidence that over-expression of EN2 protein maybe linked to tumour development. Methods: Ovarian cancer cell lines were analysed by FACS for EN2 cell surface expression. EN2 expression in ovarian cancer tissue arrays were done by immunohistochemistry. A serum analysis (ELISA) was done to evaluate the presence of antibodies to EN2 in ovarian cancer patients and age-matched controls. A set of potentially immunogenic HLA-A2 restricted epitopes from the EN2 protein was identified using a computer algorithm SYFPEITHI. These peptides have been tested on HLA-A2 positive ovarian cancer patients’ PBMC using an in vitro culture method. The specificity of these T cell lines was analysed against T2 target cells loaded with or without EN2 peptides Results: Cell surface expression of EN2 was observed in ovarian cancer cell lines OVCAR3, OV90, CaOV-3, ES-2 and SKOV-3 of which ES-2 and SKOV3 showed strong expression. EN2 was also present in approximately 80% of ovarian cancer tissues whereas EN-2 expression was very low (

Introduction/Background: Ovarian cancer is the most lethal gynaecological malignancy and the 6th most common cancer among women globally. The incidence of malignant bowel obstruction (MBO) in patients with advanced disease is up to 51%. It presents a very distressing scenario for patients, their families and clinicians. Management of MBO can be divided into surgical and medical management. Surgical management can involve direct resection, bypass surgery or stoma formation. Medical management includes endoscopic procedures, nasogastric tubes for decompression, bowel rest, parenteral feeding and symptom control such as chemotherapy, steroids, antisecretory drugs, analgesia and anti-emetics. The rationale in choosing between surgical or medical management strategies is not well defined. High perioperative morbidity (up to 90%) and mortality (up to 40%) can make surgery a risky choice and there is increasing evidence that non-surgical management can significantly improve symptoms and quality of life. The objective of this study was to evaluate the outcomes of patients with advanced ovarian cancer who undergo non-surgical management of malignant bowel obstruction and conduct a meta-analysis to estimate median survival. Methodology: A literature search was carried out using the Pubmed, Embase and Medline online libraries up until November 2019. We also searched abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Relevant studies that met the inclusion criteria were independently selected by two of the co-authors and the data extracted and analysed separately. Results: In total 24 studies were found to be relevant for the systematic review and 9 met the eligibility criteria for the meta-analysis, a total of 2236 patients were included. Median survival for patients managed medically for bowel obstruction was 44 days (95% CI 38–49 days, I2 = 0%, P = 0.128).Abstract 296 Figure 1ConclusionThe quality of the included studies was relatively low, however the evidence shows that non-surgical management of bowel obstruction in advanced ovarian cancer patients results in a short survival period, but with controlled symptoms. Where quality of life is the main concern, this may be a feasible and effective strategy.

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.

Background: GSK795 is a potent, ATP-competitive, pan AKT inhibitor. The purpose of this study was to characterize the relationship between AKT inhibition by GSK795 and downstream effects in platinum resistant ovarian cancer pts. Methods: Pts with recurrent platinum-resistant ovarian cancer received 25, 50 or 75mg of oral GSK795 daily. Dynamic FDG-PET scans and paired tumor biopsies (PTB) were performed prior to first dose and at 2 and/or 4 weeks post treatment. Semi-quantitative (SUV) and quantitative (Ki, MRglu) PET PD parameters were derived. PTB were analyzed by immunohistochemistry (IHC) for PD marker expression. PK samples were obtained in parallel. Response was monitored by RECIST and CA125 criteria. Results: 12 pts have been treated on study: 4 at 25mg, 4 at 50mg and 4 at 75mg. After completion of the 2 or 4 week post-treatment PD assessment, all eligible pts underwent intra-subject dose escalation to 75mg. The most common drug-related adverse events (≥ 10%) were decreased appetite (18%) and vomiting (18%), all G1/2. Mean Cmax and AUC24 increased with increasing doses and increased 1.2-fold from Week 2 to Week 4 where 2 and 4 week doses were the same. Median Tmax was 4 h. Overall tumor FDG metabolism decreased in 71% of tumors with treatment, although inter- and intra-patient variability in tumor uptake measurements following therapy was seen. There was no clear temporal or dose-response effect in FDG uptake. IHC analysis of PTB from 5 pts dosed at either 50 or75mg indicated that pAKT levels increased in 2/2 pts dosed at 75mg, pPRAS40 levels decreased in 4/5 pts, and Ki67 levels decreased in 4/5 pts after treatment with GSK795. 8/12 pts had stable disease and 4/12 had progressive disease by RECIST criteria at week 4. Currently 4 pts are still on the study, 2 > 24 weeks, with tumor regressions of 26% and 11% and CA125 decreases of 70% and 58% respectively. Conclusions: A dose response relationship between changes in FDG-PET and GSK795 was not observed in pts dosed from 25 to 75mg daily. Evidence of AKT pathway inhibition was observed in PTB from pts dosed with 50 or 75mg GSK795. Clinical activity evidenced by tumor regressions and CA125 decreases was also observed.

Background: Sunitinib is a first line treatment for majority of patients with metastatic RCC. The recommended dose of 50mg often results in a spectrum of serious side effects which subsequently lead to dose reduction and may have an impact on response rates. Methods: We conducted a retrospective analysis of 62 RCC patients from single institution treated with sunitinib between September 2007-May 2010. Patients were stratified according to age groups, into ≤ 70 year old (y.o.) and > 70 y.o. to compare tolerability, response rates and median survival. Results: All patients were evaluable for toxicity, 55 patients were evaluable for response. 38 (61.2%) were ≤ 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of ≤70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in ≤70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% ≤70 y.o. vs 47% in the older age group and progressive disease PD:22% vs 31.5% respectively. 24 (38.7%) of patients required dose reductions after the first or second cycle- 12 (33%) in ≤70 vs 11 (59%) in >70 yrs old. A small number of patients presented with PS 2 and these were started on a reduced dose of 37.5mg: 3 (8%) in ≤70y.o. and 11 (58%) > 70y.o. Toxcities were comparable in both groups however grade 3 palmar-plantar erythema (PPE) and mucositis (18% vs 1.6% and 18 vs 8% respectively) were more prevalent in the younger cohort. Grade 3 diarrhoea and fatigue were more common in older patients (10% in >70y.o vs 1.6% in ≤70y.o. and 16% vs 9.6% respectively). Median survival was 23 months for both age groups. Conclusions: Elderly patients more commonly require dose reduction due to poor performance status and toxicity profile. The objective response rate is lower with the lower dose intensity however the rate of disease stabilisation is comparable in both groups. The lower dose of Sunitinib is well tolerated in the elderly and this regimen should be considered for older patients with poor performance status.

PURPOSE: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies. EXPERIMENTAL DESIGN: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7), and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens. RESULTS: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed. CONCLUSIONS: Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.