282 results found
Cortés-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
BACKGROUND: A human chorionic gonadotropin (hCG) cut-off of ≤300 IU/l for starting actinomycin D (ActD) in post-molar gestational trophoblastic neoplasia (GTN) patients developing methotrexate resistance (MTX-R) reduced the number of women needing toxic multi-agent chemotherapy (etoposide, MTX and ActD alternating weekly with cyclophosphamide and vincristine; EMA/CO) without affecting survival. Here we assess whether an increased hCG cut-off of ≤1000 IU/l spares more women EMA/CO. PATIENTS AND METHODS: All post-molar GTN patients treated with first-line methotrexate and folinic acid (MTX/FA) were identified in a national cohort between 2009 and 2016. Data collected included age, FIGO score, the hCG levels at MTX-R, and treatment outcomes. RESULTS: In total, 609 GTN patients commenced treatment with MTX/FA achieving a complete response in 57% (348/609). Resistance developed in 25.1% (153/609) at an hCG ≤ 1000 IU/l and switching to ActD achieved remission in 92.8% without any major toxicity with the remaining 7.2% remitting on EMA/CO. Comparative analysis of patients switching at an hCG <100 versus 100-300 versus 300-1000 IU/l revealed a significant fall in the cure rate with second-line ActD from 97% (93/96) to 87% (34/39) to 78% (14/18), respectively, P = 0.009. However, by increasing the hCG cut-off from ≤300 to ≤1000 IU/l, 14 patients were spared EMA/CO chemotherapy. Moreover, in the present series, all post-molar GTN remain in remission. CONCLUSION: This study demonstrates that increasing the hCG cut-off from ≤300 to ≤1000 IU/l for choosing patients for ActD following MTX-R spares more women with GTN from the greater toxicity of EMA/CO without compromising 100% survival outcomes.
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
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
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.
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al., 2016, 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC), European Journal of Heart Failure, Vol: 19, Pages: 9-42, ISSN: 1879-0844
Zhao S, Sebire NJ, Kaur B, et al., 2016, Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance., Gynecologic Oncology, ISSN: 1095-6859
OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p<0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles.
Ghorani E, Ramaswami R, Smith RJ, et al., 2016, Anti-Mullerian hormone in patients treated with chemotherapy for gestational trophoblastic neoplasia does not predict short-term fertility, Journal of Reproductive Medicine, Vol: 61, Pages: 205-209, ISSN: 0024-7758
OBJECTIVE: Serum anti-Müllerian hormone (AMH) is an emerging indicator of ovarian reserve which may be predictive of reproductive capacity. Although AMH levels decline with chemotherapy, little is known about the relevance of this to subsequent fertility, and we set out to evaluate this association in patients with gestational trophoblastic neoplasia (GTN).STUDY DESIGN: The GTN database of our national referral center was screened from 2008–2012 for patients undergoing AMH testing, and subsequent fertility outcomes were reviewed.RESULTS: Of 470 treated patients, 3 underwent AMH testing for evaluation of potential subfertility 4–13 months following multiagent chemotherapy, with levels ranging from 0.07–4.62 pmol/L. All 3 were counseled by independent fertility specialists of the low probability of subsequent conception but went on to initiate spontaneously conceived pregnancies within 2–9 months, resulting in healthy infants.CONCLUSION: Low serum AMH is not a reliable predictor of reduced short-term fertility postchemotherapy for GTN and should be interpreted with caution when counseling patients in this setting.
Eagles N, Sebire NJ, Short D, et al., 2016, Correction to: "Risk of recurrent molar pregnancies following complete and partial hydatidiform moles", Human Reproduction, Vol: 31, Pages: 1379-1379, ISSN: 1460-2350
Ke H, Masoumi KC, Ahlqvist K, et al., 2016, Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) lein alveolar epithelial cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Jiao L, Ghorani E, Sebire NJ, et al., 2016, Intraplacental choriocarcinoma: Systematic review and management guidance, Gynecologic Oncology, ISSN: 1095-6859
Pardo OE, Munro CE, Castellano L, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.
Sebire NJ, May PC, Kaur B, et al., 2016, Abnormal Villous Morphology Mimicking a Hydatidiform Mole Associated with Paternal Trisomy of Chromosomes 3,7,8 and Unipaternal Disomy of Chromosome 11., Diagnostic Pathology, Vol: 11, ISSN: 1746-1596
BackgroundPregnancies affected by non-molar chromosomal abnormality may sometimes demonstrate abnormal chorionic villous morphology that is similar to partial hydatidiform mole. Determination of the underlying aetiology may be difficult in such cases.Case PresentationThis report describes a case referred to the regional trophoblastic disease unit as a possible hydatidiform mole that demonstrated both villous dysmorphology and abnormal p57KIP2 expression. Molecular genotyping revealed that while most chromosomes in the villous tissue were diploid and biparental, chromosomes 3, 7 and 8 were trisomic with an additional paternally derived chromosome. In contrast chromosome 11 showed uniparental disomy of paternal origin a situation more usually associated with complete hydatidiform moles. This unusual case highlights that exceptions may occur to the general rules of both histological morphology and immunoprofile, and that these can be resolved by detailed molecular genetic investigations.ConclusionThe findings confirm that trisomic pregnancies may demonstrate morphological villous features similar to hydatidiform mole, and that loss of p57KIP2 expression occurs due to an absence of maternally transcribed genes on chromosome 11 and can therefore be independent of androgenetic complete hydatidiform mole.
Taylor F, Short D, Harvey R, et al., 2016, Late spontaneous resolution of persistent molar pregnancy, BJOG-An International Journal of Obstetrics and Gynaecology, Vol: 123, Pages: 1175-1181, ISSN: 1471-0528
Fisher RA, Openshaw M, Harvey R, et al., 2015, Circulating cell free DNA in the diagnosis of trophoblastic tumors, EBioMedicine, Vol: 4, Pages: 146-152, ISSN: 2352-3964
Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of humanchorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosisis important for appropriate clinical management. However, a histopathological diagnosis is not alwaysavailable. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma ofwomen with GTN for use as a “liquid biopsy” in patients without histopathological diagnosis. cfDNA was preparedfrom the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknownorigin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from thetumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patientswith GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molarconception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instabilityand loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTNand can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases withouthistopathological diagnosis
Braga A, Maestá I, Short D, et al., 2015, Hormonal contraceptive use before hCG remission does not increase the risk of gestational trophoblastic neoplasia following complete hydatidiform mole: a historical database review, BJOG - An International Journal of Obstetrics and Gynaecology, Vol: 123, Pages: 1330-1335, ISSN: 1470-0328
OBJECTIVE: To re-evaluate the safety of hormonal contraceptives (HC) after uterine evacuation of complete hydatidiform mole (CHM). DESIGN: Historical database review. SETTING: Charing Cross Hospital Gestational Trophoblastic Disease Centre, London, United Kingdom. POPULATION: Two thousand four hundred and twenty-three women with CHM of whom 154 commenced HC while their human chorionic gonadotropin (hCG) was still elevated, followed between 2003 and 2012. METHODS: We compared time to hCG remission between HC users and nonusers. The relationship between HC use and gestational trophoblastic neoplasia (GTN) development was assessed. The relationship between HC use and a high International Federation of Gynecology and Obstetrics (FIGO) risk score was determined. MAIN OUTCOME MEASURES: Time to hCG remission, risk of developing postmolar GTN and proportion of women with high FIGO risk score. RESULTS: No relationship was observed between HC use with mean time to hCG remission (HC users versus non-users: 12 weeks in both, P = 0.19), GTN development (HC users versus non-users: 20.1 and 16.7%, P = 0.26) or high-risk FIGO score (HC users versus nonusers: 0% and 8%, P = 0.15). Moreover, no association between HC and GTN development was found, even when an age-adjusted model was used (OR = 1.37, 95% CI 0.91-2.08, P = 0.13). CONCLUSIONS: The use of current HC is not associated with development of postmolar GTN or delayed time to hCG remission. Therefore, HC can be safely used to prevent a new conception following CHM regardless of hCG level. TWEETABLE ABSTRACT: Non-concurrent cohort study to re-evaluate the safety of low dose HCs after uterine evacuation of CHM.
Eysbouts YK, Massuger LFAG, Thomas CM, et al., 2015, A RETROSPECTIVE COMPARISON OF THE DUTCH RISK CLASSIFICATION SYSTEM AND FIGO 2000 FOR GESTATIONAL TROPHOBLASTIC NEOPLASIA, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 25, Pages: 657-658, ISSN: 1048-891X
Ngan HY, Seckl MJ, Berkowitz RS, et al., 2015, Update on the diagnosis and management of gestational trophoblastic disease., International Journal of Gynecology and Obstetrics, Vol: 131, Pages: S123-S126, ISSN: 1879-3479
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