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1.
Expert Rev Gastroenterol Hepatol ; : 1-14, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39435480

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. AREAS COVERED: This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. EXPERT OPINION: Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC.While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice.

2.
Lancet Oncol ; 2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39437804

RESUMO

BACKGROUND: Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival. METHODS: In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival. FINDINGS: At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival. INTERPRETATION: The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials. FUNDING: None.

3.
JCO Glob Oncol ; 10: e2400254, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39173079

RESUMO

PURPOSE: The study assesses the current state of global oncology (GO)/hematology training opportunities in US fellowship programs. METHODS: We developed a comprehensive survey of 64-Likert multiple-choice and open-ended questions. The survey was electronically distributed to fellowship program leaders at Accreditation Council for Graduate Medical Education-accredited adult hematology/oncology fellowships. Program directors received three reminders after which survey was sent to assistant program directors or division heads for programs not represented. RESULTS: A total of 171 programs were eligible for the survey. We received 42 (24.6%) responses; 40 were included in the analysis, and two were excluded for declined consent and incomplete responses. The programs include large academic (81.6%) and community hospitals (10.5%). Of the respondents, 18 (48.6%) reported offering some opportunities for global health training, and half reported interest among current fellows. Most programs (29, 82.9%) had three or fewer faculty engaged in GO research. Institutional training grants were available in 15 (39.5%) programs, of which six (40%) allowed for global health research. Of the 18 programs offering global health training activities, most (15, 83.3%) report less than a quarter of their trainees currently participate in GO experiences. The most commonly perceived barriers to GO opportunities include competing priorities (85.3%) and lack of faculty mentors with GO-related experience (82.4%). Conversely, the most commonly perceived facilitators include established partnerships outside the United States (97.0%) and dedicated institutional funding (93.9%). CONCLUSION: Our survey demonstrates that although there is significant interest among fellowship trainees, a minority of the fellowship programs offer GO opportunities. Providing GO opportunities would require programs to establish partnerships with institutions outside the United States and to have systematic approaches of addressing other barriers, including enhancing funding and mentorship.


Assuntos
Bolsas de Estudo , Saúde Global , Hematologia , Oncologia , Humanos , Oncologia/educação , Inquéritos e Questionários , Hematologia/educação , Estados Unidos , Educação de Pós-Graduação em Medicina , Liderança , Equidade em Saúde
4.
ESC Heart Fail ; 11(5): 3041-3051, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38845140

RESUMO

AIMS: Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine-associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. METHODS AND RESULTS: Single-centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3 months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety-eight patients were included (45% male; median age 64 years), with median follow up 24.5 (11.5-48.3 months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)-most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11-4.93, P = 0.03). On multivariable analysis, beta-blocker use (HR 1.04, 95% CI 1.00-1.08, P = 0.04) and higher BMI (HR 2.33, 95% CI 1.04-5.19, P = 0.04) were independently associated with incident CV events. Thirty-two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P = 0.50). CONCLUSIONS: High BMI and use of beta-blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re-challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.


Assuntos
Doenças Cardiovasculares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco/métodos , Doenças Cardiovasculares/epidemiologia , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Idoso , Seguimentos , Cardiotoxicidade/epidemiologia , Incidência , Fatores de Risco de Doenças Cardíacas , Fatores de Risco , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico
5.
J Immunother Cancer ; 11(6)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37344102

RESUMO

BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. METHODS: Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. RESULTS: Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. CONCLUSIONS: Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia , Neoplasias Pancreáticas , Animais , Feminino , Humanos , Camundongos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Gencitabina , Fator Estimulador de Colônias de Granulócitos/farmacologia , Terapia de Imunossupressão , Leucócitos Mononucleares , Camundongos Endogâmicos C57BL , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Recombinantes , Microambiente Tumoral
6.
J Pain Symptom Manage ; 66(2): 146-159, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37088114

RESUMO

CONTEXT: Palliative care remains largely inaccessible in low- and middle-income countries (LMICs), and efforts to increase access are impeded by lack of training of proven effectiveness for physicians. OBJECTIVES: To measure the effectiveness of palliative care training for Vietnamese physicians. METHODS: The palliative care-related knowledge, attitudes, and self-assessment of Vietnamese physicians were studied prior to a basic course in palliative care (baseline), just after the physicians completed the course (post), and 6-18 months later (follow-up). RESULTS: The self-assessment scores and knowledge scores increased significantly from baseline to post and decreased significantly from post to follow-up, but the follow-up scores remained significantly higher than baseline. There were significant interactions between changes over time of the knowledge scores and baseline age, degree, years of graduation, training, type of work, and whether participants had ever prescribed morphine for pain. Medically appropriate attitudes increased significantly from baseline to post and did not decrease significantly from post to follow-up. CONCLUSION: Our basic palliative care course in Vietnam resulted in significant and enduring improvements among physicians in palliative care-related knowledge, attitudes, and self-assessed competence. To respond to the enormous unmet need for palliative care in LMICs, primary care providers and physician-specialists in many fields, among others, should receive palliative care training of proven effectiveness, receive ongoing mentoring or refresher training, and be given the responsibility and opportunity to practice what they learn.


Assuntos
Cuidados Paliativos , Médicos , Humanos , Cuidados Paliativos/métodos , Vietnã , Conhecimentos, Atitudes e Prática em Saúde , Dor , Atitude do Pessoal de Saúde , Inquéritos e Questionários
8.
Breast Cancer Res Treat ; 193(3): 625-635, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35420316

RESUMO

BACKGROUND: There are limited data on breast surgery completion rates and prevalence of care-continuum delays in breast cancer treatment programs in low-income countries. METHODS: This study analyzes treatment data in a retrospective cohort of 312 female patients with non-metastatic breast cancer in Haiti. Descriptive statistics were used to summarize patient characteristics; treatments received; and treatment delays of > 12 weeks. Multivariate logistic regressions were performed to identify factors associated with receiving surgery and with treatment delays. Exploratory multivariate survival analysis examined the association between surgery delays and disease-free survival (DFS). RESULTS: Of 312 patients, 249 (80%) completed breast surgery. The odds ratio (OR) for surgery completion for urban vs. rural dwellers was 2.15 (95% confidence interval [CI]: 1.19-3.88) and for those with locally advanced vs. early-stage disease was 0.34 (95%CI: 0.16-0.73). Among the 223 patients with evaluable surgery completion timelines, 96 (43%) experienced delays. Of the 221 patients eligible for adjuvant chemotherapy, 141 (64%) received adjuvant chemotherapy, 66 of whom (47%) experienced delays in chemotherapy initiation. Presentation in the later years of the cohort (2015-2016) was associated with lower rates of surgery completion (75% vs. 85%) and with delays in adjuvant chemotherapy initiation (OR [95%CI]: 3.25 [1.50-7.06]). Exploratory analysis revealed no association between surgical delays and DFS. CONCLUSION: While majority of patients obtained curative-intent surgery, nearly half experienced delays in surgery and adjuvant chemotherapy initiation. Although our study was not powered to identify an association between surgical delays and DFS, these delays may negatively impact long-term outcomes.


Assuntos
Neoplasias da Mama , Quimioterapia Adjuvante , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Feminino , Haiti/epidemiologia , Humanos , Mastectomia , Estudos Retrospectivos
9.
BMJ Case Rep ; 14(3)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722912

RESUMO

A 40-year-old man presented to a local hospital with a 2-day history of dyspnoea having been started on adjuvant chemotherapy consisting of oxaliplatin and capecitabine for mucinous adenocarcinoma of the colon. During his admission, he develops chest pain, worsening shortness of breath, and intermittent dysarthria and disorientation. Investigations reveal severely impaired left ventricular function on echocardiogram, bilateral acute pulmonary embolisms on CT pulmonary angiogragraphy, and diffused subcortical and callosal white matter signal change and restricted diffusion consistent with a toxic leukoencephalopathy on MRI of brain. This case highlights the pivotal role of the multidisciplinary cardio-oncology approach which enabled these challenging diagnoses to be made and ensured optimal patient outcome.


Assuntos
Antineoplásicos , Meios de Contraste , Adulto , Antineoplásicos/efeitos adversos , Gadolínio , Humanos , Masculino , Volume Sistólico , Função Ventricular Esquerda
10.
BMC Cancer ; 21(1): 301, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757459

RESUMO

BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. METHODS: The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. DISCUSSION: The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. TRIAL REGISTRATION: EudraCT Number: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Hepatectomia , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Terapia Neoadjuvante , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde
11.
Nat Commun ; 11(1): 4841, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973176

RESUMO

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tretinoína/uso terapêutico , Biomarcadores Tumorais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Dose Máxima Tolerável , Neoplasias Pancreáticas/diagnóstico por imagem , Receptores do Ácido Retinoico/metabolismo , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/farmacocinética , Neoplasias Pancreáticas
12.
Br J Cancer ; 123(9): 1360-1369, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32741975

RESUMO

BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.


Assuntos
Benzimidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oxidiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Fuso Acromático/efeitos dos fármacos , Reino Unido
13.
Oncogene ; 39(8): 1797-1806, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31740786

RESUMO

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (PtenΔ/Δ BRF1Tg) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In PtenΔ/Δ BRF1Tg tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.


Assuntos
Carcinogênese , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Idoso , Linfócitos T CD4-Positivos/imunologia , Ciclo Celular , Proliferação de Células , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo
15.
Curr Treat Options Oncol ; 20(9): 73, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396720

RESUMO

OPINION STATEMENT: Early detection and treatment of cardiotoxicity from cancer therapies is key to preventing a rise in adverse cardiovascular outcomes in cancer patients. Over-diagnosis of cardiotoxicity in this context is however equally hazardous, leading to patients receiving suboptimal cancer treatment, thereby impacting cancer outcomes. Accurate screening therefore depends on the widespread availability of sensitive and reproducible biomarkers of cardiotoxicity, which can clearly discriminate early disease. Blood biomarkers are limited in cardiovascular disease and clinicians generally still use generic screening with ejection fraction, based on historical local expertise and resources. Recently, however, there has been growing recognition that simple measurement of left ventricular ejection fraction using 2D echocardiography may not be optimal for screening: diagnostic accuracy, reproducibility and feasibility are limited. Modern cancer therapies affect many myocardial pathways: inflammatory, fibrotic, metabolic, vascular and myocyte function, meaning that multiple biomarkers may be needed to track myocardial cardiotoxicity. Advanced imaging modalities including cardiovascular magnetic resonance (CMR), computed tomography (CT) and positron emission tomography (PET) add improved sensitivity and insights into the underlying pathophysiology, as well as the ability to screen for other cardiotoxicities including coronary artery, valve and pericardial diseases resulting from cancer treatment. Delivering screening for cardiotoxicity using advanced imaging modalities will however require a significant change in current clinical pathways, with incorporation of machine learning algorithms into imaging analysis fundamental to improving efficiency and precision. In the future, we should aspire to personalized rather than generic screening, based on a patient's individual risk factors and the pathophysiological mechanisms of the cancer treatment they are receiving. We should aspire that progress in cardiooncology is able to track progress in oncology, and to ensure that the current 'one size fits all' approach to screening be obsolete in the very near future.


Assuntos
Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Diagnóstico por Imagem , Neoplasias/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Cardiotoxicidade/fisiopatologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Diagnóstico por Imagem/efeitos adversos , Diagnóstico por Imagem/métodos , Humanos , Imagem Multimodal/métodos , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/etiologia , Neoplasias/tratamento farmacológico , Disfunção Ventricular
16.
J Pain Symptom Manage ; 58(6): 1015-1022.e10, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31425821

RESUMO

CONTEXT: Palliative care is rarely accessible in low- and middle-income countries, and lack of adequate training for health care providers is a key reason. In Vietnam, the Ministry of Health, major hospitals and medical universities, and foreign physician-educators have partnered to initiate palliative care training for physicians. OBJECTIVES: To measure the baseline palliative care-related knowledge, attitudes, and self-assessment of Vietnamese physicians as a basis for curriculum development and to enable evaluation of training courses. METHODS: Before palliative care training courses in Vietnam from 2007 to 2014, we collected data on the participating physicians' demographics, self-assessed competence in palliative care, and palliative care-related knowledge and attitudes. Scores were calculated in three outcome categories-knowledge, attitudes, and self-assessment-and in two subcategories related to physical and psychological symptoms. Associations between the demographic, education, and practice factors and these scores were assessed using linear regression. RESULTS: Among the 392 physicians surveyed, concern about untreated suffering was highly prevalent. 85% felt that most patients with cancer in Vietnam die in pain. On self-assessment, only 8% felt adequately trained in palliative care and the mean knowledge assessment score was 44%. Although 77% had prescribed an opioid in the past year and most had appropriate attitudes toward the use of morphine for pain, the majority reported explicit or implicit restrictions on prescribing morphine. CONCLUSION: There is a great need among Vietnam's physicians for training in palliative care and especially in nonpain and psychological symptom control. Rational, balanced, and clear opioid-prescribing policies are needed to enable physicians to treat pain without fear of repercussions.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Cuidados Paliativos , Médicos , Adulto , Analgésicos Opioides/uso terapêutico , Atitude do Pessoal de Saúde , Prescrições de Medicamentos , Educação Médica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Manejo da Dor , Autoavaliação (Psicologia) , Estresse Psicológico , Inquéritos e Questionários , Vietnã , Adulto Jovem
17.
BMC Public Health ; 19(1): 574, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092219

RESUMO

BACKGROUND: Adherence to smoking, alcohol consumption, diet and physical activity (PA) guidelines may improve outcomes for people with a stoma. A better understanding of these behaviours following stoma formation surgery and their experiences and attitudes towards receiving lifestyle advice, could help identify specific gaps and inform interventions going forward. The aim of this study was to describe changes in current lifestyle following stoma formation and to explore concerns, desire for lifestyle information, advice and support among people who have or have had a stoma. METHODS: A sample of adults who currently had or in the past had a stoma for treatment for any medical condition was recruited online through relevant charities and companies, and invited to complete a cross-sectional, online survey. Consenting participants (n = 425) provided demographic information and completed brief, validated questionnaires about their lifestyle, alongside questions around their concerns regarding permanent stoma and experiences of lifestyle information and advice. Responses were summarised using descriptive statistics, and associations between reported concerns about stoma and changes in health behaviours were explored. RESULTS: Most respondents (93%) still had a stoma at the time of completing the survey. The majority (80%) had not consumed at least 5 portions of fruit and vegetables on the previous day and 20% reported they had not participated in at least 30 min of physical activity on any day in the previous week. Most respondents were non-smokers (84%) and did not exceed recommendations for alcohol intake (60%). Most (56%) felt their PA had decreased following stoma formation. Frequencies of concerns about a permanent stoma were high, and appeared to be associated with reported decreases in PA. Of those reporting nausea, 40% felt their diet had worsened since having their stoma. A large proportion of respondents had not received PA (42%) or dietary (30%) advice, and of these > 90% would have liked guidance. CONCLUSIONS: Few respondents to this survey were eating the recommended amount of fruit and vegetables, and most reported a decrease in their PA following stoma surgery. Lifestyle advice would be welcomed by this population, which professionals should take into account when addressing stoma- related concerns.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Dieta , Exercício Físico , Fumar/epidemiologia , Estomas Cirúrgicos , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Comportamentos Relacionados com a Saúde , Inquéritos Epidemiológicos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto Jovem
19.
Physiotherapy ; 105(1): 53-64, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30316547

RESUMO

OBJECTIVES: To determine whether individualised manual therapy plus guideline-based advice results in superior outcomes to advice alone in participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. DESIGN: Multi centre parallel group randomised controlled trial. SETTING: 14 physiotherapy clinics in Melbourne, Australia. PARTICIPANTS: Sixty-four participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. INTERVENTIONS: 10-weeks of physiotherapy comprising individualised manual therapy based on pathoanatomical, psychosocial and neurophysiological barriers to recovery plus guideline-based advice (10 sessions) or advice alone (two sessions). MAIN OUTCOME MEASURES: Primary outcomes were activity limitation (Oswestry Disability Index), and separate 0 to 10 numerical rating scales for leg pain and back pain. Measures were taken at baseline and 5, 10, 26 and 52-week. RESULTS: Between-group differences for back pain favoured individualised manual therapy over advice for back pain at 5 (1.0; 95% CI 0.6 to 2.0), 10 (1.5; 95% CI 0.5 to 2.4) and 26-weeks (1.4; 95% CI 0.4 to 2.3) as well as for activity limitation at 26 (8.3; 95% CI 2.6 to 14.2) and 52-weeks (8.2; 95% CI 2.3 to 14.2). There were no significant between-group differences for leg pain. Secondary outcomes and responder analyses also favoured individualised manual therapy at almost all time-points. CONCLUSIONS: In participants with clinical features potentially indicative of lumbar zygapophyseal joint pain, individualised manual therapy led to greater reduction in back pain at 5, 10 and 26-week follow-up as well as activity limitation at 26 and 52-weeks. Between-group differences were likely to be clinically important. TRIAL REGISTRATION: ACTRN12609000334202.


Assuntos
Aconselhamento/métodos , Dor Lombar/reabilitação , Vértebras Lombares/fisiopatologia , Manipulações Musculoesqueléticas/métodos , Articulação Zigapofisária/fisiopatologia , Adulto , Austrália , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Método Simples-Cego
20.
Chiropr Man Therap ; 26: 42, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364333

RESUMO

Background: Chronic pain is a substantial burden on the Australian healthcare system with an estimated 19.2% of Australians experiencing chronic pain. Knowledge of the neurophysiology and multidimensional aspects of pain is imperative to ensure health professionals apply a biopsychosocial approach to pain. Questionnaires may be used to assess learner changes in neurophysiology knowledge and beliefs and attitudes towards pain after education interventions.The aim of this study was to evaluate changes in pain neurophysiology knowledge, beliefs and attitudes following a 12 week clinically-focused pain module in year 3 osteopathy students as measured by the Neurophysiology of Pain (NPQ) Questionnaire and Health Care Providers Pain and Impairment Relationship scale (HC-PAIRS). Methods: A pre-post design was utilised. Learners completed a demographic information survey pre-module, and completed the NPQ & HC-PAIRS prior to undertaking, and after completing, a twelve week clinically-focused pain module. Results: Learners (n = 55) completed the NPQ & HC-PAIRS at both time points. The median NPQ score was significantly increased with a large effect size (p < 0.001, z = - 5.71, r = 0.78) following the completion of the module. In contrast, the HC-PAIRS total score was significantly increased after the completion of the module (p < 0.01, z = - 6.95, r = 0.91) suggesting an increase in negative pain attitudes and beliefs. Results indicate that a clinically-focused pain module can increase pain neurophysiology knowledge. However the HC-PAIRS results suggest an increase in negative pain attitudes and beliefs. The HC-PAIRS questionnaire was developed for use with chronic low back pain attitudes & beliefs in practitioners, rather than pre-clinical students. Students were provided with general principles of pain management, rather than condition specific pain management. This study is the first comparing pain neurophysiology knowledge and changes in attitudes and beliefs towards pain pre-post a clinically-focused pain module using the NPQ & HC-PAIRS. Conclusions: There was a significant improvement in NPQ score after the 12 week clinically-focused pain module. The HC-PAIRS result was paradoxical and may reflect issues with the module design or the measurement tool. The module duration is longer than that reported in the literature and demonstrates effectiveness in increasing pain neurophysiology knowledge.


Assuntos
Medicina Osteopática/educação , Manejo da Dor/psicologia , Estudantes de Medicina/psicologia , Adulto , Atitude , Cultura , Feminino , Humanos , Conhecimento , Masculino , Medição da Dor/psicologia , Adulto Jovem
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