RESUMO
BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of chronic disorders of the bone marrow characterised by the overproduction of clonal myeloid stem cells. The most common driver mutation found in MPNs is a point mutation on exon 14 of the JAK2 gene, JAK2V617F. Various studies have suggested that measuring the variable allele frequency (VAF) of JAK2V617F may provide useful insight regarding diagnosis, treatment, risks and outcomes in MPN patients. In particular, JAK2V617F has been associated with increased risk of thrombotic events, a leading cause of mortality in MPNs. AIMS: The aim of this study was to determine if JAK2V617F VAF was associated with clinical outcomes in patients with MPN. METHODS: JAK2V617F VAF was determined by quantitative PCR (qPCR) in a cohort of 159 newly diagnosed MPN patients, and the association of JAK2V617F VAF and risk of thrombosis was examined in this cohort. RESULTS: We observed a significantly higher JAK2V617F VAF in PV and PMF versus ET. A significant association was observed between JAK2V617F VAF and risk of thrombotic events. When patients were stratified by thrombotic events prior to and post diagnosis, an association with JAK2V617F VAF was only observed with post diagnosis thrombotic events. Of note, these associations were not observed when looking at each MPN subtype in isolation. CONCLUSIONS: We have shown that a higher JAK2V617F VAF is associated with thrombotic events post MPN diagnosis. JAK2V617F VAF may therefore provide a valuable prognostic indicator for risk of thrombosis in MPNs.
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Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the in vivo impact of the drug combination on murine blood leukocytes, showing that the leukopenia induced by the free drugs could be significantly mitigated by nanoencapsulation. Taken together, this study demonstrates that formulating these agents within a single nanoparticle delivery platform may provide clinical utility beyond use as nonencapsulated agents.
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Antineoplásicos , Benzamidas , Inibidores de Histona Desacetilases , Piridinas , Pirrolidinas , para-Aminobenzoatos , Humanos , Animais , Camundongos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Combinação de Medicamentos , Proteínas Proto-Oncogênicas c-mdm2RESUMO
BACKGROUND: Calreticulin (CALR) mutations are commonly identified in patients with essential thrombocythaemia or myelofibrosis. CALR type 1 mutations are known to have a higher overall incidence in males but little is known about the risks of mutation subtypes on myelofibrotic change across patient age and sex. AIMS: To identify differences in the incidence of myelofibrotic change within subgroups of patients with CALR type 1 mutations. METHODS: All patients with a positive CALR exon 9 mutation identified within our unit between February 2016 and September 2020 were reviewed with note taken of patient sex, age at diagnosis, initial MPN diagnosis, and subsequent disease transformation. RESULTS: In our cohort, young male patients with CALR type 1 mutations were shown to be at significantly increased risk of myelofibrosis compared to age matched female patients. CONCLUSIONS: Male patients have a worse myeloproliferative neoplasm phenotype than female patients with it occurring at a younger age and being more myelofibrotic in nature. Further investigation is needed into the reasons for this variability.
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Transtornos Mieloproliferativos , Mielofibrose Primária , Feminino , Humanos , Masculino , Calreticulina/genética , Incidência , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/genéticaRESUMO
The aim of this literature review is to examine the significance of the nucleophosmin 1 (NPM1) gene in acute myeloid leukaemia (AML). This will include analysis of the structure and normal cellular function of NPM1, the type of mutations commonly witnessed in NPM1, and the mechanism by which this influences the development and progression of AML. The importance of NPM1 mutation on prognosis and the treatment options available to patients will also be reviewed along with current guidelines recommending the rapid return of NPM1 mutational screening results and the importance of employing a suitable laboratory assay to achieve this. Finally, future developments in the field including research into new therapies targeting NPM1 mutated AML are considered.
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DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , DNA Metiltransferase 3A , Humanos , NucleofosminaRESUMO
Essential thrombocythaemia (ET) is driven by somatic mutations involving the JAK2, CALR and MPL genes. Approximately 10% of patients lack driver mutations and are referred as 'triple-negative' ET (TN-ET). The diagnosis of TN-ET, however, relies on bone marrow examination that is not always performed in routine practice, and thus in the real-world setting, there are a group of cases with suspected TN-myeloproliferativeneoplasm.In this real-world cohort, patients with suspected TN-ET were initially rescreened for JAK2, CALR and MPL and then targeted next-generation sequencing (NGS) was applied.The 35 patients with suspected TN-ET had a median age at diagnosis of 43 years (range 16-79) and a follow-up of 10 years (range 2-28). The median platelet count was 758×109/L (range 479-2903). Thrombosis prior to and following diagnosis was noted in 20% and 17% of patients. Six patients were JAK2V617F and two patients were CALR positive on repeat screening. NGS results showed that 24 of 27 patients harboured no mutations. Four mutations were noted in three patients.There was no evidence of clonality for the majority of patients with suspected TN-ET with targeted NGS analysis. Detection of driver mutations in those who were previously screened suggests that regular rescreening is required. This study also questions the diagnosis of TN-ET without the existence of a clonal marker.
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Calreticulina/genética , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Janus Quinase 2/genética , Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adolescente , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Trombocitemia Essencial/sangue , Trombocitemia Essencial/diagnóstico , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: We wanted to confirm the benefit of mometasone furoate (MF) in preventing acute radiation reactions, as shown in a previous study (Boström et al, Radiother Oncol 2001;59:257-265). METHODS AND MATERIALS: The study was a double-blind comparison of MF with D (Diprobase), administered daily from the start of radiation therapy for 5 weeks in patients receiving breast radiation therapy, 40 Gy in 2.67-Gy fractions daily over 3 weeks. The primary endpoint was mean modified Radiation Therapy Oncology Group (RTOG) score. RESULTS: Mean RTOG scores were significantly less for MF than for D (P=.046). Maximum RTOG and mean erythema scores were significantly less for MF than for D (P=.018 and P=.012, respectively). The Dermatology Life Quality Index (DLQI) score was significantly less for MF than for D at weeks 4 and 5 when corrected for Hospital Anxiety and Depression (HAD) questionnaire scores. CONCLUSIONS: MF cream significantly reduces radiation dermatitis when applied to the breast during and after radiation therapy. For the first time, we have shown a significantly beneficial effect on quality of life using a validated instrument (DLQI), for a topical steroid cream. We believe that application of this cream should be the standard of care where radiation dermatitis is expected.
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Neoplasias da Mama/radioterapia , Fármacos Dermatológicos/administração & dosagem , Pregnadienodiois/administração & dosagem , Radiodermite/prevenção & controle , Administração Tópica , Fracionamento da Dose de Radiação , Método Duplo-Cego , Esquema de Medicação , Emolientes/administração & dosagem , Eritema/patologia , Eritema/prevenção & controle , Feminino , Humanos , Pessoa de Meia-Idade , Furoato de Mometasona , Radiodermite/patologia , Tamanho da Amostra , Creme para a Pele/administração & dosagemRESUMO
OBJECTIVE: To compare traditional hospital follow-up with telephone follow-up by specialist nurses after treatment for breast cancer. DESIGN: A two centre randomised equivalence trial in which women remained in the study for a mean of 24 months. SETTING: Outpatient clinics in two NHS hospital trusts in the north west of England PARTICIPANTS: 374 women treated for breast cancer who were at low to moderate risk of recurrence. INTERVENTIONS: Participants were randomised to traditional hospital follow-up (consultation, clinical examination, and mammography as per hospital policy) or telephone follow-up by specialist nurses (consultation with structured intervention and mammography according to hospital policy). MAIN OUTCOME MEASURES: Psychological morbidity (state-trait anxiety inventory, general health questionnaire (GHQ-12)), participants' needs for information, participants' satisfaction, clinical investigations ordered, and time to detection of recurrent disease. RESULTS: The 95% confidence interval for difference in mean state-trait scores adjusted for treatment received (-3.33 to 2.07) was within the predefined equivalence region (-3.5 to 3.5). The women in the telephone group were no more anxious as a result of foregoing clinic examinations and face-to-face consultations and reported higher levels of satisfaction than those attending hospital clinics (intention to treat P<0.001). The numbers of clinical investigations ordered did not differ between groups. Recurrences were few (4.5%), with no differences between groups for time to detection (median 60.5 (range 37-131) days in hospital group v 39.0 (10-152) days in telephone group; P=0.228). CONCLUSIONS: Telephone follow-up was well received by participants, with no physical or psychological disadvantage. It is suitable for women at low to moderate risk of recurrence and those with long travelling distances or mobility problems and decreases the burden on busy hospital clinics. TRIAL REGISTRATION: National Cancer Research Institute 1477.
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Assistência Ambulatorial/normas , Neoplasias da Mama/enfermagem , Consulta Remota/métodos , Telefone , Adulto , Idoso , Assistência Ambulatorial/estatística & dados numéricos , Ansiedade/prevenção & controle , Neoplasias da Mama/psicologia , Inglaterra , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enfermagem , Recidiva Local de Neoplasia/prevenção & controle , Relações Enfermeiro-Paciente , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Educação de Pacientes como Assunto , Satisfação do Paciente , Resultado do TratamentoRESUMO
The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients with platinum-resistant recurrent ovarian cancer, who had been treated according to an ATP-based tumour chemosensitivity assay in comparison with physician's choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physician's-choice chemotherapy (n=86). Median follow-up at analysis was 18 months. Response was assessable in 147 patients: 31.5% achieved a partial or complete response in the physician's-choice group compared with 40.5% in the assay-directed group (26 versus 31% by intention-to-treat analysis respectively). Intention-to-treat analysis showed a median progression-free survival of 93 days in the physician's-choice group and 104 days in the assay-directed group (hazard ratio 0.8, 95% confidence interval 0.59-1.10, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physician's-choice arm obtained a response. Increased use of combination therapy was seen in the physician's-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. Patients entering the physician's-choice arm of the study during the first year did significantly worse than those who entered in the subsequent years (hazard ratio 0.44, 95% confidence interval 0.2-0.9, P<0.03). This small randomized clinical trial has documented a trend towards improved response and progression-free survival for assay-directed treatment. Chemosensitivity testing might provide useful information in some patients with ovarian cancer, although a larger trial is required to confirm this. The ATP-based tumour chemosensitivity assay remains an investigational method in this condition.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Padrões de Prática Médica , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Células Tumorais CultivadasRESUMO
The prostate gland is conventionally divided into zones or regions. This morphology is of clinical significance as prostate cancer (CaP) occurs mainly in the peripheral zone (PZ). We obtained tissue sets consisting of paraffin-embedded blocks of cancer-free transition zone (TZ) and PZ and adjacent CaP from patients (n = 6) who had undergone radical retropubic prostatectomy; a seventh tissue set of snap-frozen PZ and TZ was obtained from a CaP-free gland removed after radical cystoprostatectomy. Paraffin-embedded tissue slices were sectioned (10-mum thick) and mounted on suitable windows to facilitate infrared (IR) spectra acquisition before being dewaxed and air dried; cryosections were dessicated on BaF(2) windows. Spectra were collected employing synchrotron Fourier-transform infrared (FTIR) microspectroscopy in transmission mode or attenuated total reflection-FTIR (ATR) spectroscopy. Epithelial cell and stromal IR spectra were subjected to principal component analysis to determine whether wavenumber-absorbance relationships expressed as single points in "hyperspace" might on the basis of multivariate distance reveal biophysical differences between cells in situ in different tissue regions. After spectroscopic analysis, plotted clusters and their loadings curves highlighted marked variation in the spectral region containing DNA/RNA bands ( approximately 1490-1000 cm(-1)). By interrogating the intrinsic dimensionality of IR spectra in this small cohort sample, we found that TZ epithelial cells appeared to align more closely with those of CaP while exhibiting marked structural differences compared to PZ epithelium. IR spectra of PZ stroma also suggested that these cells are structurally more different to CaP than those located in the TZ. Because the PZ exhibits a higher occurrence of CaP, other factors (e.g., hormone exposure) may modulate the growth kinetics of initiated epithelial cells in this region. The results of this pilot study surprisingly indicate that TZ epithelial cells are more likely to exhibit what may be a susceptibility-to-adenocarcinoma spectral signature. Thus, IR spectroscopy on its own may not be sufficient to identify premalignant prostate epithelial cells most likely to progress to CaP.
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Biomarcadores Tumorais/análise , Lesões Pré-Cancerosas/patologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Espectrofotometria Infravermelho/métodos , Algoritmos , Células Cultivadas , Diagnóstico por Computador/métodos , Estudos de Viabilidade , Humanos , Masculino , Análise Multivariada , Projetos Piloto , Lesões Pré-Cancerosas/química , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Epidemiological studies suggest that environment plays an important role in the aetiology of cancer. Thus, if a cancer (e.g. prostate cancer (CaP)) arises in males, one could hypothesize that risk in co-habiting partners might be elevated. We conducted an observational-questionnaire study in NorthWest England evaluating the medical histories of CaP males and their female partners. Details regarding previous partners (>10y) were also sought. Self-filled questionnaires were obtained from 548 males, 81 of whom provided information on previous female partners (PFPs) and 448 current female partners (CFPs). Observed rates over a 30-y period (1971-2001) of common cancers (breast, colorectal or lung) in female partners and colorectal cancer in males were compared to the cumulative expected probability (estimated using crude incidence rates for England provided by the Office of National Statistics, UK) using a Chi-Square Goodness-of-Fit test. Colorectal cancers in males were similar to national estimates. Rates for breast, colorectal or lung cancer among CFPs and the total female cohort (CFPs plus PFPs) were also similar to estimates. However, observed rates for breast or lung cancers among PFPs were significantly (P< or =0.001) elevated. Our results suggest no evidence of elevated risk among female partners of CaP males.
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Saúde da Família , Neoplasias/epidemiologia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Exposição Ambiental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Neoplasias/etiologia , Neoplasias da Próstata/etiologia , Fumar , Inquéritos e Questionários , Reino UnidoRESUMO
Prostate cancer (CaP) mostly occurs in the peripheral zone whereas benign prostatic hypertrophy (BPH) occurs in the transition zone. Human prostates (n = 12) were obtained, with ethical approval, from radical retropubic prostatectomies. Following resection, tissue sets consisting of peripheral zone and transition zone were isolated from a lobe pre-operatively identified as negative for CaP. Real-time RT-PCR was employed to quantitatively examine CYP1A1, CYP1A2 and CYP1B1. Quantifiable CYP1A1 expression was observed (in nine out of twelve tissue sets) whilst CYP1A2 mRNA transcripts, although detectable (in six out of twelve tissue sets), were unquantifiable. In ten tissue sets, 2- to 6-fold higher CYP1B1 expression in peripheral zone as compared to transition zone was observed. In the other two, equal CYP1B1 expression levels were observed; retrospective examination identified malignancy in one of the zones. Inter-individual variations (up to 10-fold) in CYP1B1 were also noted. Immunohistochemistry for CYP1B1 showed epithelial and stromal nuclear staining. Since CYP1B1 metabolises hormones and carcinogens our results, if confirmed, suggest that this enzyme may influence susceptibility to CaP.
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Hidrocarboneto de Aril Hidroxilases/metabolismo , Próstata/enzimologia , Neoplasias da Próstata/enzimologia , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Núcleo Celular/enzimologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1B1 , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Próstata/ultraestrutura , Prostatectomia , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/ultraestrutura , RNA Mensageiro , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/enzimologia , Células Estromais/patologiaRESUMO
BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centres.