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1.
Am Soc Clin Oncol Educ Book ; 44(3): e100046, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38776483

RESUMO

A community of practice (CoP) is a group of people who share a concern or a passion for something they do and learn how to do it better as they interact regularly. While the field of hematology/oncology has historically prioritized clinical care and biomedical research, medical education has received increasing attention within hematology/oncology in recent years. In 2018, ASCO launched the Education Scholars Program to train hematology/oncology clinicians in the science of teaching and learning. However, the number of hematology/oncology educators nationally and internationally far exceeds the capacity of the Education Scholars Program to train them. In addition, hematology/oncology educators often lack sufficient mentorship and guidance at their own institutions to pursue their chosen career path effectively. To ensure high-quality clinical care and research for generations to come, attention must be paid to improving support for hematology/oncology educators. Therefore, supported by ASCO, we developed an international medical education (Med Ed) CoP for hematology/oncology educators with the purpose of providing them with support, community, mentorship, resources, and scholarly opportunities in medical education. In this article, we describe the development of the Med Ed CoP using a three-stage framework (Establish-Grow-Sustain) including successes, challenges, and reflections. By supporting the needs of hematology/oncology educators, the Med Ed CoP will serve as a home for all who contribute to the field of hematology/oncology.


Assuntos
Educação Médica , Hematologia , Oncologia , Humanos , Oncologia/educação , Hematologia/educação , Mentores , Comunidade de Prática
3.
BMJ Case Rep ; 17(4)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38670566

RESUMO

A woman in her late 60s with severe chronic obstructive pulmonary disease (COPD) and emphysema underwent bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBV) to address hyperinflation. The initial EBV placement has led to partial lobar atelectasis of the left lower lobe and resulted in significant improvement in the patient's symptoms and lung function. However, valve migration occurred later due to pneumothorax unrelated to valves, leading to suboptimal clinical improvement. The patient achieved delayed full lobar atelectasis 21 months after EBV placement, which led to a significant clinical improvement. The patient decided to be delisted from the lung transplant list due to the improvement. This case highlights the importance of considering delayed atelectasis as a possible outcome of EBV placement and suggests the need for further exploration of the long-term implications and associations of this procedure.


Assuntos
Broncoscopia , Pneumonectomia , Atelectasia Pulmonar , Doença Pulmonar Obstrutiva Crônica , Humanos , Atelectasia Pulmonar/etiologia , Atelectasia Pulmonar/diagnóstico por imagem , Feminino , Broncoscopia/métodos , Pneumonectomia/métodos , Doença Pulmonar Obstrutiva Crônica/cirurgia , Doença Pulmonar Obstrutiva Crônica/complicações , Enfisema Pulmonar/cirurgia , Enfisema Pulmonar/diagnóstico por imagem , Pessoa de Meia-Idade , Próteses e Implantes , Resultado do Tratamento
4.
Brain ; 147(7): 2496-2506, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38325327

RESUMO

We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone compared with other leading interictal biomarkers in a multicentre, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centres who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection [International League Against Epilepsy Class 1 outcome (ILAE 1)] and those with persistent seizures (ILAE 2-6) across sites and recording types. We also evaluated available interictal biomarkers: spike, spike-gamma, wideband high frequency oscillation (HFO, 80-500 Hz), ripple (80-250 Hz) and fast ripple (250-500 Hz) rates using previously validated automated detectors. The proportion of resected events was computed and compared across subject outcomes and biomarkers. Overall, 109 subjects were included. Most spike ripples were removed in subjects with ILAE 1 outcome (P < 0.001), and this was qualitatively observed across all sites and for depth and subdural electrodes (P < 0.001 and P < 0.001, respectively). Among ILAE 1 subjects, the mean spike ripple rate was higher in the resected volume (0.66/min) than in the non-removed tissue (0.08/min, P < 0.001). A higher proportion of spike ripples were removed in subjects with ILAE 1 outcomes compared with ILAE 2-6 outcomes (P = 0.06). Among ILAE 1 subjects, the proportion of spike ripples removed was higher than the proportion of spikes (P < 0.001), spike-gamma (P < 0.001), wideband HFOs (P < 0.001), ripples (P = 0.009) and fast ripples (P = 0.009) removed. At the individual level, more subjects with ILAE 1 outcomes had the majority of spike ripples removed (79%, 38/48) than spikes (69%, P = 0.12), spike-gamma (69%, P = 0.12), wideband HFOs (63%, P = 0.03), ripples (45%, P = 0.01) or fast ripples (36%, P < 0.001) removed. Thus, in this large, multicentre cohort, when surgical resection was successful, the majority of spike ripples were removed. Furthermore, automatically detected spike ripples localize the epileptogenic tissue better than spikes, spike-gamma, wideband HFOs, ripples and fast ripples.


Assuntos
Eletrocorticografia , Humanos , Masculino , Feminino , Adulto , Eletrocorticografia/métodos , Adulto Jovem , Adolescente , Eletroencefalografia/métodos , Pessoa de Meia-Idade , Epilepsia/fisiopatologia , Epilepsia/cirurgia , Criança , Ondas Encefálicas/fisiologia , Encéfalo/fisiopatologia
5.
Respir Med Case Rep ; 45: 101889, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457924

RESUMO

Expiratory Central Airway Collapse (ECAC) is a multifactorial, underdiagnosed entity that poses unique challenges. Airway stenting is used as a predictor for successful outcomes after central airway stabilization surgery via tracheobronchoplasty (TBP). This approach may pose suboptimal performance in certain ECAC variants. We hypothesize that Continuous Positive Airway Pressure (CPAP), used as a pneumatic stent, could be a non-invasive alternative to evaluate surgical candidacy in cough-predominant ECAC presentations. We report on a 67-year-old female with a history of chronic cough and confirmed ECAC. After optimization of medical therapy without significant relief and unsuccessful stent trial. We opted to perform CPAP trial during exercise, the patient exercised on a treadmill, and CPAP was applied at two levels (9 cmH2O, 11 cmH2O). The use of CPAP was associated with resolution of cough and a decrease in exercise-related perceived exertion. Applying CPAP during exercise may be a promising alternative to stent trials to determine patients' candidacy for surgical management of cough-predominant ECAC.

6.
Am Soc Clin Oncol Educ Book ; 43: e389392, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37196216

RESUMO

The practice of oncology continues to evolve over time. Educators find themselves in a position where they are no longer able to teach a topic in its entirety. Moreover, the rapid expansion of information available through research and discovery in the field of oncology makes it difficult for learners to process the constant barrage of new content. Lecturers continue to impart knowledge using didactic techniques, often trying to include as much material as possible in the time permitted. The question becomes: In the face of an impossibly large field, how can one assist learners in learning, and retaining, what is most important? The science of learning continues to develop, and we now recognize that there are ways to teach that optimally facilitate the retention and application of knowledge. By using these strategies, educators can make it easier for learners to absorb and retain key information. This article will touch upon several such techniques: cognitive load optimization, analogy, contrasting cases, elaboration, and just-in-time telling. By applying these methods to didactic presentations, educators can ensure that their lessons are heard, understood, and ultimately transformed into something unforgettable.


Assuntos
Educação Médica , Aprendizagem , Humanos
8.
Respirol Case Rep ; 11(2): e01087, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36721846

RESUMO

Pleural effusion is a common condition related to various diseases such as heart failure, malignancies, and pneumonia. Ovarian hemangioma is a rare type of female genital tumour and can rarely cause pleural effusion. In this case, we present a 48-year-old female with repeated episodes of recurrent right-sided pleural effusion over 1 year with no clear aetiology. Abdominal computed tomography revealed a large left ovarian mass. After surgical removal of the mass, the repeated pleural effusion episodes ceased, and histopathology analysis reported a rare ovarian hemangioma. Pseudo Meigs' syndrome is a triad of an ovarian tumour, ascites, and hydrothorax that rarely presents with ovarian hemangioma; both effusions are eradicated after removing the tumour.

9.
Age Ageing ; 51(8)2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35930722

RESUMO

Trauma in older people leads to substantial morbidity and mortality. The National Hip Fracture Database (NHFD) has driven improved practice with units compared to identify outliers. In 2013, our unit was an outlier for mortality post hip fracture (30-day mortality 12.2% vs. 8.3% nationally). This triggered external review. In 2019 the unit was highlighted as an exemplar in the UK. We describe the process that moved us from outlier to outstanding. After the initial review process, we made changes to our healthcare system, with regular reassessment of progress and care quality. Examples include a dedicated hip fracture unit, strong leadership (Nursing, Orthopaedic, Geriatrician, Anaesthetic), consultant-led in-depth monthly mortality reviews, changes to admission pathways and delirium prevention. Improvements were seen in all aspects of hip fracture care in 2019 compared with 2012. Thirty-day case-mixed adjusted mortality halved (12.2-6.1%), with substantial reductions in reoperations and pressure sores. Length of stay reduced by 5.9 days. In 2019 our unit's performance was significantly above the national average for all six indicators assessed by NHFD: prompt orthogeriatric review (97% vs. 91% national average), prompt surgery (85% vs. 68%); NICE compliant surgery (85% vs. 74%); prompt mobilisation (93% vs. 81%); not delirious postoperatively (77% vs. 69%); return to original residence (78% vs. 71%). The NHFD highlighted our Unit as one of nine (from 175 total) highly performing UK trusts. We summarise our service development and improvement work undertaken to achieve 'outstanding' status, which provides a valuable template to units managing trauma in older people.


Assuntos
Serviços Médicos de Emergência , Fraturas do Quadril , Ortopedia , Idoso , Geriatras , Fraturas do Quadril/cirurgia , Humanos , Tempo de Internação , Qualidade da Assistência à Saúde
10.
Surg Endosc ; 36(10): 7656-7663, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35182218

RESUMO

INTRODUCTION: Measures of mood and effective coping strategies have notable correlations with quality of life and treatment responses. There is evidence that patients with previously diagnosed anxiety disorders have less improvement in patient-reported outcome measures (PROMs) after laparoscopic anti-reflux surgery (LARS) and that objective pathology does not correlate well with symptom severity. We were interested in investigating whether anxiety and hypervigilance, as measured preoperatively with the esophageal hypervigilance anxiety scale (EHAS), is associated with the improvement in GERD-specific PROMs and EHAS scores 6 months after LARS. METHODS: We performed a retrospective cohort study of 102 adult patients (31% men, average age 64) who underwent LARS. In the preoperative evaluation, baseline gastroesophageal reflux disease-health-related quality of life (GERD-HRQL), laryngopharyngeal reflux symptom index (LPR-RSI) and EHAS scores were collected in addition to the standard reflux workup, including endoscopy, manometry, barium swallow, and pH study. For all three surveys, a higher score represents worse symptom severity. At 6 months postoperatively, 70 patients completed repeat GERD-HRQL, LPR-RSI, and EHAS surveys. We then analyzed for surgical and patient-related factors associated with improvement in the 6-month postoperative GERD-HRQL and LPR-RSI scores. RESULTS: There was a statistically significant decrease in the GERD-HRQL (25 vs. 2, p < 0.001), LPR-RSI (17 vs. 3, p < 0.001) and EHAS (34 vs. 15, p < 0.001) 6 months after LARS. On multivariable linear regression, a higher baseline EHAS score was independently associated with a greater improvement in GERD-HRQL (ß 0.35, p < 0.001) and LPR-RSI (ß 0.19, p = 0.03) 6-months after LARS. Additionally, the degree of improvement in EHAS, GERD-HRQL, and LPR-RSI was not influenced by the type of LARS performed or by the severity of disease. CONCLUSION: These findings are consistent with literature suggesting that measures of psychoemotional health correlate better with symptom intensity than objective pathology. We found that patients with a higher EHAS score have greater symptom severity and lower quality of life at baseline. Novel findings to this study are that patients with a higher preoperative EHAS, a measure of psychoemotional health, actually benefitted more from surgery and not less, which has been the traditional view in the literature. Future studies are warranted to establish directionality and explore the role of preoperative cognitive behavioral therapy with LARS for patients with significant symptoms of hypervigilance and anxiety.


Assuntos
Laparoscopia , Refluxo Laringofaríngeo , Adulto , Ansiedade/diagnóstico , Ansiedade/etiologia , Bário , Feminino , Humanos , Refluxo Laringofaríngeo/diagnóstico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
11.
Cell Rep ; 35(13): 109291, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34192548

RESUMO

To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-ß-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the ßIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.


Assuntos
Proteína Substrato Associada a Crk/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Microtúbulos/metabolismo , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Acetamidas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Calpaína/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Microtúbulos/efeitos dos fármacos , Morfolinas/farmacologia , Mutação/genética , Organoides/efeitos dos fármacos , Organoides/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/farmacologia , Transcrição Gênica/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
12.
J Natl Compr Canc Netw ; 18(9): 1248-1269, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886902

RESUMO

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.


Assuntos
Eosinofilia , Transtornos Mieloproliferativos , Neoplasias , Eosinofilia/diagnóstico , Eosinofilia/genética , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Proteínas de Fusão Oncogênica/genética
13.
Am J Hematol ; 95(12): 1457-1465, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32777116

RESUMO

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Taxa de Sobrevida
14.
Leuk Lymphoma ; 61(6): 1484-1492, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32037935

RESUMO

This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m2 on d6-15 of each induction cycle and 20 mg/m2 on d6-10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina/efeitos adversos , Decitabina/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Resultado do Tratamento
15.
Australas J Ageing ; 39(3): 287-291, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31769178

RESUMO

OBJECTIVE: To describe the use of medications that interact with alcohol or for which alcohol reduces the medication's efficacy in older adults consuming alcohol at hazardous levels. METHOD: Retrospective file audit of patients discharged from Australia's only older adult-specific alcohol and other drug treatment service. RESULTS: Seventy-two patients aged between 58 years and 87 years (M = 65.88; SD = 5.67) drinking alcohol at hazardous or harmful levels were taking between 1 and 12 pharmaceutical drugs (M = 4.03; SD = 2.42). The majority (92%) of patients were taking at least one medication that placed them at high risk of serious adverse side effects when consumed with alcohol. The efficacy of most patients' (97%) medication was deemed to be significantly reduced when consumed with alcohol. CONCLUSIONS: Among older adults who consume alcohol at hazardous levels, many take prescribed medications that adversely interact with alcohol or have reduced efficacy when consumed alongside alcohol. Targeted education is required for patients and health-care workers to mitigate these risks.


Assuntos
Consumo de Bebidas Alcoólicas , Preparações Farmacêuticas , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Austrália/epidemiologia , Humanos , Estudos Retrospectivos , Inquéritos e Questionários
16.
Cell Rep ; 29(1): 118-134.e8, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577942

RESUMO

The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/metabolismo , Proteínas ras/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células HCT116 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Pelados , Camundongos SCID , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
17.
Lancet Haematol ; 6(6): e317-e327, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060979

RESUMO

BACKGROUND: Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes. METHODS: This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m2 on days 1-5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m2 (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m2 (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8-3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27-54] with 60 mg/m2 and 27 of 49 [55%, 95% CI 40-69] with 90 mg/m2; p=0·16). 25 of 49 (51%, 95% CI 36-66) patients who were treatment-naive and 23 of 53 (43%, 30-58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m2 group and 28 [57%] of 49 in the 90 mg/m2 group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m2 and four with 60 mg/m2), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m2; pneumonia with 90 mg/m2). INTERPRETATION: Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m2 on a 5-day schedule for these patients. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer.


Assuntos
Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Síndromes Mielodisplásicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Neutropenia/etiologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento , Adulto Jovem
18.
Cancer Res ; 79(9): 2404-2414, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30755442

RESUMO

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a 5-day idasanutlin pulse causing marked regression of all xenografts, including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene TP53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides preclinical evidence that compounds inhibiting these proteins have therapeutic potential.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Sistemas CRISPR-Cas , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Geriatr Orthop Surg Rehabil ; 10: 2151459318818972, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729062

RESUMO

INTRODUCTION: Despite awareness of overall poor survival rates following cardiopulmonary resuscitation (CPR), some orthopedic patients with significant comorbidities continue to have inappropriate resuscitation plans. Furthermore, in certain injury groups such as patients with hip fractures, survival outcome data are very limited; current discussions regarding resuscitation plans may be inaccurate. This study assesses survival in orthopedic patients following CPR, to inform decision-making between physicians, surgeons, and patients. METHODS: A dual center, retrospective cohort study was performed analyzing all orthopedic admissions that received CPR over a 25-month period, with a minimum of 1 year follow-up. National Cardiac Arrest Audit data, "mortality and morbidity" meeting records, National Hip Fracture Databases, and electronic notes were analyzed. Survival duration was measured, alongside reason for admission, location CPR occurred, and initial rhythm encountered. RESULTS: Thirty-two patients received CPR over the 25-month period (median age: 83; range: 30-96). Three (9%) of 32 patients survived to discharge. Only 1 of the 26 patients older than 65 years survived to discharge. Fifteen (47%) of 32 had hip fractures, where 4 (27%) of 15 of this group survived 24 hours; none survived to discharge. When recorded, 22 (92%) of 24 initially had a nonshockable rhythm. DISCUSSION: Cardiopulmonary resuscitation was conceptualized as a treatment for reversible cardiopulmonary causes. When used in trauma and orthopedic patients, especially older and/or hip fracture patients, it seldom led to hospital discharge. Different admission practices such as "front door" orthogeriatric reviews may explain the contrast in usage of CPR between the hospitals. CONCLUSION: Survival rates following CPR were very low, with it proving specifically ineffective in hip fracture patients. Although every decision about resuscitation should be patient centered and individualized, this study will allow clinicians to be more realistic about outcomes from CPR, particularly in the hip fracture group.

20.
J Natl Compr Canc Netw ; 16(12): 1500-1537, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545997

RESUMO

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.


Assuntos
Anafilaxia/terapia , Mastocitose Sistêmica/terapia , Oncologia/normas , Equipe de Assistência ao Paciente/normas , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biópsia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Imunofenotipagem/métodos , Imunofenotipagem/normas , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/imunologia , Oncologia/métodos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/normas , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Sociedades Médicas/normas , Transplante Homólogo/métodos , Transplante Homólogo/normas , Resultado do Tratamento , Fatores de Poliadenilação e Clivagem de mRNA/genética
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