296 results found
Ghorani E, Quartagno M, Blackhall F, et al., 2023, REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment., Lancet Oncol, Vol: 24, Pages: e219-e227
Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.
Hennah L, Seckl M, Ghorani E, 2023, Novel approaches to managing gestational trophoblastic tumors in the age of immunotherapy., Int J Gynecol Cancer, Vol: 33, Pages: 414-419
The discovery that anti-programmed death-1 antibody (anti-PD-1) immunotherapy can cure patients with multidrug-resistant gestational trophoblastic neoplasia provides a new powerful and low toxicity treatment. This heralds an era within which the majority of patients, including those with previously difficult to treat disease, can expect to achieve long-term remission. This development should prompt a rethink of how patients with this rare disease are managed, focusing on maximizing cure rate with minimal exposure to toxic chemotherapy.
Coombes RC, Badman PD, Lozano-Kuehne JP, et al., 2023, Author Correction: Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer., Nature Communications, Vol: 14, Pages: 1-1, ISSN: 2041-1723
Georgiou M, Ntavelou P, Stokes W, et al., 2022, Correction: ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma, Oncogene, Vol: 41, Pages: 3510-3510, ISSN: 0950-9232
Coombes R, Badman P, Lozano-Kuehne JP, et al., 2022, Results of the Phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer, Nature Communications, Vol: 13, ISSN: 2041-1723
We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients’ samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.
Ghorani E, Seckl MJ, 2022, Emergency craniotomy: a life-saving procedure as part of multi-modal therapy of GTN, JOURNAL OF GYNECOLOGIC ONCOLOGY, Vol: 33, ISSN: 2005-0380
Georgiou M, Ntavelou P, Stokes W, et al., 2022, ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma, ONCOGENE, Vol: 41, Pages: 2540-2554, ISSN: 0950-9232
Braga A, Berkowitz RS, Seckl MJ, 2021, Gestational trophoblastic neoplasia: one size does not fit all, LANCET ONCOLOGY, Vol: 22, Pages: E421-E421, ISSN: 1470-2045
Blay J-Y, Casali P, Bouvier C, et al., 2021, European Reference Network for rare adult solid cancers, statement and integration to health care systems of member states: a position paper of the ERN EURACAN, ESMO Open, Vol: 6, ISSN: 2059-7029
Braga A, Paiva G, Ghorani E, et al., 2021, Predictors for single-agent resistance in FIGO score 5 or 6 gestational trophoblastic neoplasia: a multicentre, retrospective, cohort study, LANCET ONCOLOGY, Vol: 22, Pages: 1188-1198, ISSN: 1470-2045
Bergamini A, Sarwar N, Ferrandina G, et al., 2021, Response to letter entitled: Re: Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? An international multicenter analysis, EUROPEAN JOURNAL OF CANCER, Vol: 152, Pages: 257-258, ISSN: 0959-8049
Pardo O, Chrysostomou S, Roy R, et al., 2021, Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, Science Translational Medicine, Vol: 13, ISSN: 1946-6234
Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
Seckl MJ, Ghorani E, 2021, Progress to international harmonisation of care and future developments, BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY, Vol: 74, Pages: 159-167, ISSN: 1521-6934
Cortes-Charry R, Hennah L, Froeling FEM, et al., 2021, Increasing the human chorionic gonadotrophin cut-off to <= 1000 IU/l for starting actinomycin D in post-molar gestational trophoblastic neoplasia developing resistance to methotrexate spares more women multi-agent chemotherapy, ESMO OPEN, Vol: 6
Bouchard-Fortier G, Ghorani E, Short D, et al., 2020, Following chemotherapy for gestational trophoblastic neoplasia, do residual lung lesions increase the risk of relapse?, GYNECOLOGIC ONCOLOGY, Vol: 158, Pages: 698-701, ISSN: 0090-8258
Bergamini A, Sarwar N, Ferrandina G, et al., 2020, Can we replace adjuvant chemotherapy with surveillance for stage IA-C immature ovarian teratomas of any grade? an international multicenter analysis, EUROPEAN JOURNAL OF CANCER, Vol: 137, Pages: 136-143, ISSN: 0959-8049
Lok C, van Tromme N, Massuger L, et al., 2020, Practical clinical guidelines of the EOTTD for treatment and referral of gestational trophoblastic disease, EUROPEAN JOURNAL OF CANCER, Vol: 130, Pages: 228-240, ISSN: 0959-8049
Balachandran K, Salawu A, Ghorani E, et al., 2019, When to stop human chorionic gonadotrophin (hCG) surveillance after treatment with chemotherapy for gestational trophoblastic neoplasia (GTN): A national analysis on over 4,000 patients, GYNECOLOGIC ONCOLOGY, Vol: 155, Pages: 8-12, ISSN: 0090-8258
Froeling FEM, Ramaswami R, Papanastasopoulos P, et al., 2019, Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours, BRITISH JOURNAL OF CANCER, Vol: 120, Pages: 587-594, ISSN: 0007-0920
Frijstein MM, Lok CAR, Short D, et al., 2019, The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia, EUROPEAN JOURNAL OF CANCER, Vol: 109, Pages: 162-171, ISSN: 0959-8049
Ngan HYS, Seckl MJ, Berkowitz RS, et al., 2018, Update on the diagnosis and management of gestational trophoblastic disease, INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS, Vol: 143, Pages: 79-85, ISSN: 0020-7292
Braga A, Biscaro A, do Amaral Giordani JM, et al., 2018, Does a human chorionic gonadotropin level of over 20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole constitute an indication for chemotherapy for gestational trophoblastic neoplasia?, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 223, Pages: 50-55, ISSN: 0301-2115
Cormio G, Seckl MJ, Loizzi V, et al., 2018, Increased human Chorionic Gonadotropin levels five years before diagnosis of an ovarian dysgerminoma, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 220, Pages: 138-139, ISSN: 0301-2115
Coyle C, Short D, Jackson L, et al., 2017, What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients., Gynecologic Oncology, Vol: 148, Pages: 254-257, ISSN: 0090-8258
OBJECTIVE: To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. METHODS: The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. RESULTS: We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. CONCLUSIONS: Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged.
Ghorani E, Kaur B, Fisher RA, et al., 2017, Pembrolizumab is effective for drugresistant gestational trophoblastic neoplasia, Lancet, Vol: 390, Pages: 2343-2345, ISSN: 0140-6736
Roy R, Pardo O, Seckl M, et al., 2017, Emerging roles of hnRNPA1 inmodulating malignanttransformation, Wiley Interdisciplinary Reviews: RNA, Vol: 8, ISSN: 1757-7004
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes such as processing of heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, RNA splicing, transactivation of gene expression, and modulation of protein translation. hnRNPA1 is the most abundant and ubiquitously expressed member of this protein family and has been shown to be involved in multiple molecular events driving malignant transformation. In addition to selective mRNA splicing events promoting expression of specific protein variants, hnRNPA1 regulates the gene expression and translation of several key players associated with tumorigenesis and cancer progression. Here, we will summarize our current knowledge of the involvement of hnRNPA1 in cancer, including its roles in regulating cell proliferation, invasiveness, metabolism, adaptation to stress and immortalization.
Singh K, Warnock C, Ireson J, et al., 2017, Experiences of Women With Gestational Trophoblastic Neoplasia Treated With High-Dose Chemotherapy and Stem Cell Transplantation: A Qualitative Study, ONCOLOGY NURSING FORUM, Vol: 44, Pages: 375-383, ISSN: 0190-535X
Eysbouts YK, Ottevanger PB, Massuger LFAG, et al., 2017, Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset, Annals of Oncology, Vol: 28, Pages: 1856-1861, ISSN: 0923-7534
BackgroundWorldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible.Patients and methodsBetween January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified.ResultsOf the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5–10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7–44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0–16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3–3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9–12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4–30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system.ConclusionOur s
Seckl MJ, Ottensmeier CH, Cullen M, et al., 2017, Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR), Journal of Clinical Oncology, Vol: 35, Pages: 1506-1514, ISSN: 0732-183X
PurposeTreating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies showthat statins exert additive effects with agents, such as cisplatin, to impair tumor growth, andobservational studies suggest that statins combined with anticancer therapies delay relapse andprolong life in several cancer types. To our knowledge, we report the first large, randomized,placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer,specifically SCLC.Patients and MethodsPatients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 wererandomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles ofetoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerabletoxicity. Primary end point was overall survival (OS), and secondary end points were progressionfreesurvival (PFS), response rate, and toxicity.ResultsEight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median ageof recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease.There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in allpatients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2%(95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01(95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. Themedian PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, forextensive disease. Adverse events were similar between groups.ConclusionPravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients.Our conclusions are the same as those found in all four much smaller, randomized, placebocontrolledtr
Li H, Stokes W, Chater E, et al., 2016, Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer, Cell Discovery, Vol: 2, ISSN: 2056-5968
Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
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