194 results found
Harris BHL, McCabe C, Shafique H, et al., 2023, Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK., J Hum Genet
Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.
Han SN, Oza A, Colombo N, et al., 2023, A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer., Gynecol Oncol, Vol: 178, Pages: 110-118
OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.
Krell J, Dolecki PK, Todd A, 2023, School-Based Neurofeedback Training for Sustained Attention, JOURNAL OF ATTENTION DISORDERS, Vol: 27, Pages: 1117-1128, ISSN: 1087-0547
Li Q, Wang R, Lee J, et al., 2023, Thermogels based on biocompatible OEGMA-MEGMA diblock copolymers, European Polymer Journal, Vol: 194, Pages: 1-11, ISSN: 0014-3057
A series of biocompatible thermoresponsive copolymers were successfully synthesised via group transfer polymerisation (GTP) from methoxy ethylene glycol methacrylate (MEGMA) and methoxy oligo (ethylene glycol) methacrylate (OEGMA, Mn=300 g mol -1). Statistical and diblock copolymers with molar mass around 8100 g mol-1 and various compositions were investigated. Specifically, the content in OEGMA and MEGMA was varied from 80-20, 70-30, 60-40, to 50-50 w/w%. The thermoresponsive and self-assembly behaviour of the copolymers was investigated through visual tests, rheology, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Interestingly, the diblock copolymers with higher MEGMA content were able to form gels at relatively low concentrations (as low as 5% w/w) when increasing the temperature, something that is reported for the first time for linear ethylene glycol based copolymers. A transition of spherical micelle to worm-like micelle was observed in these diblock copolymers that promotes gelation. Furthermore, these in-house synthesised polymers were mixed with Pluronic® F127. It was found that the gelation area of Pluronic® F127 was broadened by the addition of the synthesised copolymers with one formulation, specifically a combination of 12.5% w/w Pluronic® F127 and 12.5% w/w of a statistical OEGMA-co-MEGMA, forming a stable gel from 34°C to 48°C that is a desirable temperature range for biological applications. Finally, cell viability experiments were performed for the three most promising diblock copolymers was investigated and they were confirmed to be non-toxic.
Cunnea P, Curry EW, Christie EL, et al., 2023, Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: implications for surgical and clinical outcomes, Cell Reports Medicine, Vol: 4, Pages: 1-20, ISSN: 2666-3791
Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.
Lythgoe M, Dama P, Frampton AE, et al., 2023, Immune modulation and the oral live biotherapeutic product, MRx0518, in treatment-naive patients with cancer: Updated safety data, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Krell J, Frost S, Negroni C, et al., 2023, Evaluation of THEO-260 as a novel oncolytic virus therapy for treating stromal rich tumours., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Samani A, Bennett R, Eremeishvili K, et al., 2023, Corrigendum to 'Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers': [ESMO Open volume 7 (2022) 10.1016/j.esmoop.2022.100401]., ESMO Open, Vol: 8, Pages: 1-1, ISSN: 2059-7029
Salpeter S, Bar V, Neev G, et al., 2023, A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine, 114th Annual Meeting of the American Association for Cancer Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Lythgoe M, Krell J, Bower M, et al., 2023, From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK oncology drug approval following Brexit, The Lancet Oncology, Vol: 24, Pages: e150-e160, ISSN: 1213-9432
The departure of the UK from the European Union (EU) and affiliated European regulatory bodies on the 31st December 2020, including the European Medicines Agency, (EMA), has resulted in the Medicines and Healthcare products Regulatory Agency (MHRA) becoming an independent national regulator. This has required a fundamental transformation of the UK drug regulatory landscape, creating both opportunities and challenges for future oncology drug development. New UK pharmaceutical policy has sought to establish the UK as an attractive market for drug development and regulatory review, by offering expedited review pathways coupled to strong collaborative relations with other leading international medicines regulators, outside of Europe. Oncology is a key global therapy area for both drug development and regulatory approval, and the UK government has been keen to demonstrate regulatory innovation and international collaboration in the approval of new cancer medicines. In this review, we examine the new UK regulatory frameworks, policies, and global collaborations affecting new oncology drug approvals following departure from the EU. We explore some of the challenges which may lie ahead as the UK forges ahead with new and independent regulatory review and approval processes for the next generation of cancer medicines.
Banerjee S, Giannone G, Clamp AR, et al., 2023, Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma: the octopus multicenter, phase 2, randomized clinical trial., JAMA Oncology, Vol: 9, Pages: 675-682, ISSN: 2374-2437
IMPORTANCE: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. OBJECTIVE: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. INTERVENTIONS: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. RESULTS: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (wee
Correia JS, Miron Barroso S, Hutchings C, et al., 2023, How does the polymer architecture and position of cationic charges affect cell viability?, Polymer Chemistry, Vol: 14, Pages: 303-317, ISSN: 1759-9954
Polymer chemistry, composition and molar mass are factors that are known to affect cytotoxicity however the influence of polymer architecture has not been investigated systematically. In this study the influence of the position of the cationic charges along the polymer chain on cytotoxicity was investigated while keeping constant the other polymer characteristics. Specifically, copolymers of various architectures, based on a cationic pH responsive monomer, 2-(dimethylamino)ethyl methacrylate (DMAEMA) and a non-ionic hydrophilic monomer, oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were engineered and their toxicity towards a panel of cell lines investigated. Of the seven different polymer architectures examined, the block-like structures were less cytotoxic than statistical or gradient/tapered architectures. These findings will assist in developing future vectors for nucleic acid delivery.
Lythgoe MP, Mullish BH, Frampton A, et al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, Vol: 30, Pages: 1131-1134, ISSN: 0966-842X
Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and key effectors in determining anti-cancer therapy efficacy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
Rizwan N, Khaki AR, Desai A, et al., 2022, 427 Approval timings and review speed of immune checkpoint inhibitors (ICIs) in cancer therapy between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) from 2010-2022, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
Lythgoe M, Mullish B, Frampton A, et al., 2022, ORAL ADMINISTRATION OF MRX0518 IN TREATMENTNAIVE CANCER PATIENTS IS ASSOCIATED WITH COMPOSITIONAL TAXONOMIC AND METABOLOMIC CHANGES INDICATIVE OF ANTI-TUMORIGENIC EFFICACY, Publisher: BMJ PUBLISHING GROUP, Pages: A659-A659
Mirón-Barroso S, Correia JS, Frampton AE, et al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X
As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.
Montero-Macias R, Rigolet P, Mikhael E, et al., 2022, Traditional systemic treatment options in advanced low-grade serous ovarian cancer after successful cytoreduction: a systematic review and meta-analysis, Cancers, Vol: 14, Pages: 1-13, ISSN: 2072-6694
Objective: We performed a systematic literature review and a subsequent meta-analysis to compare traditional treatment options, i.e., antihormonal and cytotoxic, in LGSOC. Methods: We conducted a systematic literature review in MEDBASE and MEDLINE between September 2000 and June 2021 for women who received cytotoxic chemotherapy and/or antihormonal treatment after primary cytoreduction due to stage II–IV LGSOC and also at relapse. PFS and OS were calculated depending on the type of their adjuvant treatment. For each endpoint in the meta-analysis, pooled HR was calculated using the random effect model with the inverse variance weighted method. Only primary patients were included in the subsequent meta-analysis due to the small number of studies in the relapsed setting. Results: Five eligible first-line studies were included. Systemic chemotherapy failed to provide a significant OS benefit when compared to no systemic treatment (pooled HR = 1.01, 95% CI [0.79, 1.29]) after successful cytoreduction. Moreover, systemic chemotherapy followed by antihormonal treatment also did not result to a significant PFS or OS benefit when compared to systemic chemotherapy alone (for PSF: pooled HR = 0.59, 95% CI [0.33, 1.04]; for OS: pooled HR = 0.83, 95% CI [0.50, 1.39]). There were insufficient data from studies in the recurrent setting to allow their inclusion in the meta-analysis. Conclusions: In this meta-analysis, we failed to identify a traditional cytotoxic or antihormonal systemic treatment option that was associated with a significant OS or PFS benefit when administered following successful cytoreduction for advanced LGSOC. Prospective randomized studies are urgently warranted to define optimal adjuvant options in this challenging disease.
Samani A, Krell J, McNeish I, et al., 2022, Response to the letter entitled "Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers", ESMO Open, Vol: 7, Pages: 1-1, ISSN: 2059-7029
Cheng Z, Mirza HB, Ennis DP, et al., 2022, The copy number landscape of early stage ovarian high grade serous carcinoma, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Lythgoe M, Desai A, Gyawali B, et al., 2022, Cancer therapy approval timings, review speed and publication of pivotal registration trials in the US and Europe from 2010-2019, Jama Network Open, Vol: 5, ISSN: 2574-3805
Importance: Ensuring patients have access to safe and efficacious medicines in a timely manner is an essential goal for regulatory agencies, which has particular significance in oncology due to the significant unmet need for new therapies. The two largest regulatory agencies, the FDA and EMA have pivotal global roles, and their recommendations and approvals are frequently followed by other national regulators.Objective: To compare market authorization dates for new oncology therapies approved in the US and Europe over the past decade and to examine and contrast the regulatory activities of the FDA and EMA in the approval of new cancer medicines.Design, Setting and Participants: A review of the FDA and EMA regulatory databases to identify new oncology therapies approved in both the US and Europe from 2010 to 2019, and characterization of the timings of regulatory activities. Main Outcome Measures: Regulatory approval date, review time, submission of market authorization application, accelerated approval or conditional marketing authorisation status and proportion of approvals prior to peer-reviewed publication of pivotal trial results. Results: In total, 89 new concomitant oncology therapies were approved in the US and Europe from 2010 to 2019. The FDA approved 85 (95%) oncology therapies before European authorization and 4 (5%) therapies after. The median delay in market authorization for new oncology therapies in Europe was 241 days compared to the US. The median review time was 200 days and 426 days for the FDA and EMA, respectively. 60 (67%) new licensing applications were submitted to the FDA first, compared to 25 (28%) to the EMA. 35 (39%) oncology therapies were approved by the FDA prior to pivotal study publication, whereas only 8 (9%) by the EMA.Conclusion and Relevance: In this study we demonstrate that new oncology therapies are approved earlier in the US than Europe. The FDA receives licensing applications sooner and has shorter review times. However, mor
Giannone G, Ennis D, Mirza HB, et al., 2022, Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial, ESMO, Publisher: ELSEVIER, Pages: S384-S384, ISSN: 0923-7534
Samani A, Bennett R, Eremeishvili K, et al., 2022, Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers (vol 7, 100401, 2022), ESMO OPEN, Vol: 8
Cheng Z, Mirza H, Ennis DP, et al., 2022, The genomic landscape of early-stage ovarian high grade serous carcinoma, Clinical Cancer Research, Vol: 28, Pages: 2911-2922, ISSN: 1078-0432
Purpose: Ovarian high grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of volutionary advantage compared to early-stage tumours.Experimental Design: We performed targeted next generation sequencing and shallow whole genome sequencing (sWGS) on pre-treatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy number alterations (SCNA). We comparedresults to pre-treatment samples from 52 stage IIIC/IV HGSC patients from the BriTROC-1 study.Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs 62.3 years respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behaviour. However, ploidy was higher in late-stage (median 3.0) than early-stage (median 1.9) samples. Copy number (CN) signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clustersthat were prognostic.Conclusions: Early stage and late stage HGSC have highly similar patterns of mutation and focal SCNA. However, copy number signature analysis showed that late-stage disease has distinct signature exposures consistent with whole genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early and late-stage or simply time-related markers of evolutionary fitness.
Fiorentino F, Krell J, de la Rosa CN, et al., 2022, DICE: Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian cancer resistant to standard treatment-a study protocol for a randomised trial investigating a novel therapy called TAK228, Trials, Vol: 23, Pages: 1-15, ISSN: 1745-6215
BackgroundThe standard initial treatment for ovarian cancer is surgery and platinum-based chemotherapy and potentially maintenance therapy with avastin or inhibitors of poly-ADP ribose polymerase (PARP). While a proportion of women are cured by this approach, the vast majority will relapse and become resistant to platinum chemotherapy either initially or on subsequent treatment. There is an unmet need to improve response to treatment and quality of life in these women. TAK228 is a novel therapy that can be added to standard treatment in the participant population and the aim of the DICE trial is to assess its effectiveness. Laboratory and clinical research has shown that these ovarian cancers may respond to the molecular target of a drug such as TAK228, and there have been studies using it in other advanced solid tumours including endometrial cancer.MethodsOne hundred twenty-four eligible women will be recruited from participating research sites in the United Kingdom (UK) and Germany. Randomised participants will receive either weekly paclitaxel alone (standard treatment, n = 62) or TAK228 plus weekly paclitaxel (n = 62) until the cancer significantly worsens; there are significant adverse events or any other protocol-defined stopping criteria. Participants will be monitored for response to treatment (using radiological imaging), adverse events and quality of life during both randomised treatment and subsequent follow-up.DiscussionThe primary objective/endpoint of the study is to compare the two treatments in terms of progression-free survival, or the length of time that each participant is alive without the cancer significantly worsening according to defined assessment criteria. If the addition of TAK228 to weekly paclitaxel chemotherapy is shown to significantly improve this statistically, and adverse events and quality of life are not significantly worse than standard treatment, then TAK228 plus weekly paclitaxel could potentially be taken forward within the cont
Liu D, Yang QZC, Asim M, et al., 2022, The clinical significance of transfer RNAs present in extracellular vesicles, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067
Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organ-isms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs pre-sent within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1st January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included the most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging be-tween 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.
Clark J, Fotopoulou C, Cunnea P, et al., 2022, Novel ex vivo models of epithelial ovarian cancer: the future of biomarker and therapeutic research, Frontiers in Oncology, Vol: 12, Pages: 1-17, ISSN: 2234-943X
Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel ex vivo systems to model different cancer types including ovarian cancer. PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive
Ma C, Pai RK, Schaeffer DF, et al., 2022, Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 10
Samani A, Bennett R, Eremeishvili K, et al., 2022, Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers, ESMO Open, Vol: 7, ISSN: 2059-7029
Background:Carboplatin remains integral for treatment of gynaecological malignancies and dosing is based on glomerular filtration rate (GFR). Measurement via radiotracer decay (nmGFR) is ideal. However, this may be unavailable. Therefore, GFR is often estimated using formulae that have not been validated in patients with cancer and/or specifically for gynaecological malignancies, leading to debate over optimal estimation. Suboptimal GFR estimation may affect efficacy or toxicity. Methods:We surveyed several UK National Health Service Trusts to assess carboplatin dosing practise. We then explored single-centre accuracy, bias and precision of various formulae for GFR estimation, relative to nmGFR, before validating our findings in an external cohort. Results:Across 18 Trusts, there was considerable heterogeneity in GFR estimation, including the formulae used (Cockcroft-Gault (CG) vs Wright), weight-adjustment and area under the curve (5 vs 6). We analysed 274 and 192 patients in two centres. Overall, CamGFR v2 (a novel formula for GFR estimation developed at Cambridge University Hospitals NHS Foundation Trust) excelled, showing the highest accuracy and precision. This translated into accuracy of hypothetical carboplatin dosing; nmGFR-derived carboplatin dose fell within 20% of the Cam GFR v2-derived dose in 86.5% and 87% of patients across the cohorts. Amongst the CG formula and its derivatives, using adjusted body weight in those with BMI ≥25 kg/m2 (CG-AdBW) was optimal. The Wright and unadjusted CG estimators performed most poorly. Conclusions:When compared with nmGFR assessment, accuracy, bias and precision varied widely between GFR estimators, with the newly developed Cam GFR v2 and CG-AdBW perfoming best. In general, weight (or body surface area)-adjusted formulae performed best, while the unadjusted CG and Wright formulae or the use of AUC6 (vs. nmGFR AUC5) produced risk of significant overdose. Thus, individual centres should validate their GFR estimation me
Merali N, Chouari T, Kayani K, et al., 2022, A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma, Cancers, Vol: 14, Pages: 1-34, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.
Constantinou AP, Nele V, Doutch JJ, et al., 2022, Investigation of the thermogelation of a promising biocompatible ABC triblock terpolymer and its comparison with pluronic F127, Macromolecules, Vol: 55, Pages: 1783-1799, ISSN: 0024-9297
Thermoresponsive polymers with the appropriate structure form physical networks upon changes in temperature, and they find utility in formulation science, tissue engineering, and drug delivery. Here, we report a cost-effective biocompatible alternative, namely OEGMA30015-b-BuMA26-b-DEGMA13, which forms gels at low concentrations (as low as 2% w/w); OEGMA300, BuMA, and DEGMA stand for oligo(ethylene glycol) methyl ether methacrylate (MM = 300 g mol–1), n-butyl methacrylate, and di(ethylene glycol) methyl ether methacrylate, respectively. This polymer is investigated in depth and is compared to its commercially available counterpart, Poloxamer P407 (Pluronic F127). To elucidate the differences in their macroscale gelling behavior, we investigate their nanoscale self-assembly by means of small-angle neutron scattering and simultaneously recording their rheological properties. Two different gelation mechanisms are revealed. The triblock copolymer inherently forms elongated micelles, whose length increases by temperature to form worm-like micelles, thus promoting gelation. In contrast, Pluronic F127’s micellization is temperature-driven, and its gelation is attributed to the close packing of the micelles. The gel structure is analyzed through cryogenic scanning and transmission electron microscopy. Ex vivo gelation study upon intracameral injections demonstrates excellent potential for its application to improve drug residence in the eye.
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