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1.
Cardiovasc Diabetol ; 22(1): 234, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37658327

RESUMO

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Acetilcolina , Estudos Transversais , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Estudos Prospectivos , Volume Sistólico , Insulina
2.
J Cardiovasc Transl Res ; 16(6): 1267-1275, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37278928

RESUMO

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.


Assuntos
Cardiomiopatia Hipertrófica , Humanos , Estudos Transversais , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Fenótipo , Biomarcadores , Mutação
3.
Trials ; 24(1): 307, 2023 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-37143158

RESUMO

BACKGROUND: Spinal metastases can lead to unremitting pain and neurological deficits, which substantially impair daily functioning and quality of life. Patients with unstable spinal metastases receive surgical stabilization followed by palliative radiotherapy as soon as wound healing allows. The time between surgery and radiotherapy delays improvement of mobility, radiotherapy-induced pain relief, local tumor control, and restart of systemic oncological therapy. Stereotactic body radiotherapy (SBRT) enables delivery of preoperative high-dose radiotherapy while dose-sparing the surgical field, allowing stabilizing surgery within only hours. Patients may experience earlier recovery of mobility, regression of pain, and return to systemic oncological therapy. The BLEND RCT evaluates the effectiveness of SBRT followed by surgery within 24 h for the treatment of symptomatic, unstable spinal metastases. METHODS: This phase III randomized controlled trial is embedded within the PRospective Evaluation of interventional StudiEs on boNe meTastases (PRESENT) cohort. Patients with symptomatic, unstable spinal metastases requiring stabilizing surgery and radiotherapy will be randomized (1:1). The intervention group (n = 50) will be offered same-day SBRT and surgery, which they can accept or refuse. According to the Trial within Cohorts (TwiCs) design, the control group (n = 50) will not be informed and receive standard treatment (surgery followed by conventional radiotherapy after 1-2 weeks when wound healing allows). Baseline characteristics and outcome measures will be captured within PRESENT. The primary outcome is physical functioning (EORTC-QLQ-C15-PAL) 4 weeks after start of treatment. Secondary endpoints include pain response, time until return to systemic oncological therapy, quality of life, local tumor control, and adverse events up to 3 months post-treatment. DISCUSSION: The BLEND RCT evaluates the effect of same-day SBRT and stabilizing surgery for the treatment of symptomatic, unstable spinal metastases compared with standard of care. We expect better functional outcomes, faster pain relief, and continuation of systemic oncological therapy. The TwiCs design enables efficient recruitment within an ongoing cohort, as well as prevention of disappointment bias and drop-out as control patients will not be informed about the trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05575323. Registered on October 11, 2022.


Assuntos
Parafusos Pediculares , Radiocirurgia , Neoplasias da Coluna Vertebral , Humanos , Radiocirurgia/efeitos adversos , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/cirurgia , Qualidade de Vida , Dor/etiologia , Hospitais
4.
Gynecol Oncol ; 167(1): 3-10, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36085090

RESUMO

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.


Assuntos
Carcinoma de Células Escamosas , Linfadenopatia , Linfonodo Sentinela , Neoplasias Vulvares , Carcinoma de Células Escamosas/patologia , Feminino , Virilha , Humanos , Excisão de Linfonodo/efeitos adversos , Linfonodos/patologia , Linfonodos/cirurgia , Linfadenopatia/patologia , Metástase Linfática/patologia , Recidiva Local de Neoplasia/patologia , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Vulvares/patologia
5.
Neth Heart J ; 30(7-8): 388-389, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35731468
6.
Biophys Rev ; 14(1): 369-379, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35340597

RESUMO

In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resources of international human heart tissue biobanks have assembled 30 ventricular tissue samples from PPCM patients, and we are actively seeking to enlarge this patient base by collaborating with human heart tissue banks and research laboratories who would like to join this endeavour.

7.
Neth Heart J ; 30(2): 63-64, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35060106
8.
Clin Epigenetics ; 13(1): 61, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757590

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts. RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations. CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.


Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Metilação de DNA , Expressão Gênica , Genes Homeobox , Histonas/genética , Humanos , Mutação , Transcriptoma
9.
Ann Oncol ; 32(6): 710-725, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675937

RESUMO

Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
10.
Clin Exp Metastasis ; 38(2): 209-217, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33634347

RESUMO

Implementation of COVID-19 measures may have induced concerns about access and quality of health care for cancer patients with bone metastases, and it may have affected their quality of life. In this study, we evaluated the effect of the first COVID-19 lockdown on quality of life and emotional functioning of patients with stage IV cancer treated for painful bone metastases in the UMC Utrecht, the Netherlands. A COVID-19 specific questionnaire was sent to active participants in the Prospective Evaluation of interventional StudiEs on boNe meTastases (PRESENT) cohort, consisting of patients irradiated for metastatic bone disease. Patient reported outcomes (PROs) were compared with the last two PROs collected within the PRESENT cohort before the COVID-19 lockdown in the Netherlands on the 16th of March. For the 169 (53%) responders, median age at start of lockdown was 68 years (range 38-92) and 62% were male. Patients reported a statistically significant decrease in emotional functioning (83.6 to 79.2, P = 0.004) and in general quality of life score during the COVID-19 lockdown (72.4 to 68.7, P = 0.007). A steep increase in feeling isolated was reported (18% before and 67% during lockdown). This study has shown a strong increase in the experience of isolation and a decrease of emotional functioning and general quality of life during the COVID-19 lockdown in cancer patients with bone metastases. Due to the nature of the treatment of this patient population, efforts should be made to minimize these changes during future lockdowns.


Assuntos
Neoplasias Ósseas/radioterapia , COVID-19/prevenção & controle , Emoções , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/psicologia , Neoplasias Ósseas/secundário , COVID-19/transmissão , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Países Baixos , Medidas de Resultados Relatados pelo Paciente , Distanciamento Físico , Estudos Prospectivos , Isolamento Social , Inquéritos e Questionários , Resultado do Tratamento
11.
Neth Heart J ; 29(6): 318-329, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33532905

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. AIM: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. METHODS: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). RESULTS: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. CONCLUSION: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.

12.
PLoS One ; 16(2): e0247130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606805

RESUMO

OBJECTIVES: Although ethnic minority clients (EMs) from STI endemic countries have a higher risk for STI, little is known about their STI clinic consultation rate proportionality. The aim of this study was to assess consultation and chlamydia positivity rates among different EMs visiting STI clinics in the Netherlands. METHODS: We calculated consultation rates in EM groups by dividing the number of STI consultations by the total number of inhabitants in the region belonging to an EM, then compared the EM rates to native Dutch rates. Factors associated with chlamydia positivity were analysed using multivariate regression analysis. RESULTS: A total of 23,841 clients visiting an eastern Netherlands STI clinic between 2011 and 2013 were included in the analysis, of which 7% were EMs. The consultation rate of native Dutch clients was 22.5 per 1000, compared to 8.5 per 1000 among EMs. Consultation rates in all EMs were lower than in Dutch clients, except for Antillean or Aruban EMs and Latin American EMs. The chlamydia positivity rate among all clients was 15.5%, and Antillean or Aruban ethnicity (27.1%) EMs had the highest rates. Multivariate analysis identified the following factors associated with chlamydia positivity: Eastern or Northern European EM, African EM, Antillean or Aruban EM, STI related symptoms, heterosexual preference, partner in a risk group, receiving a partner notification, and having had three or more partners in the past six months. CONCLUSION: On a population level, most EMs visit STI clinics less often than native Dutch clients, but they have a higher rate of positive chlamydia diagnoses. STI clinics should increase outreach activities for EM clients because they are insufficiently reached by current practices, but contribute substantially to chlamydia incidence rates.


Assuntos
Infecções por Chlamydia/diagnóstico , Encaminhamento e Consulta/estatística & dados numéricos , Adolescente , Adulto , Instituições de Assistência Ambulatorial , Infecções por Chlamydia/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Grupos Minoritários , Países Baixos/epidemiologia , Fatores de Risco , Parceiros Sexuais , Adulto Jovem
13.
Eur J Surg Oncol ; 47(1): 101-107, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128948

RESUMO

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Ovarianas/terapia , Qualidade de Vida , Idoso , Bélgica , Carboplatina/administração & dosagem , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Inquéritos e Questionários
14.
Neth J Med ; 78(6): 349-356, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33380532

RESUMO

BACKGROUND: Combined administration of intravenous (iv) and intraperitoneal (ip) (iv/ip) chemotherapy is an effective adjuvant treatment option after primary debulking surgery (PDS) for advanced ovarian cancer (OC). Increased toxicityand patient burden limit its use in daily practice. OBJECTIVE: To assess toxicity and survival outcomes of iv/ip chemotherapy in daily practice in the Netherlands. METHODS: This retrospective cohort study included 81 women who underwent at least an optimal PDS for FIGO stage III OC followed by iv/ip chemotherapy according to the Armstrong regimen, in four hospitals in the Netherlands between January 2007 and May 2016. We collected information on surgical procedure, abdominal port implantation, toxicity, and recurrence-free and overall survival. RESULTS: All participants underwent PDS, of whom 60 (74%) had their ip catheter implanted during PDS. Most frequently reported all grade toxicity was haematological n = 44 (54%). Forty-four patients (54%) completed all six cycles of iv/ip chemotherapy. The most frequent causes of discontinuation of iv/ip administration were renal dysfunction (12/37 = 32%) and catheter problems (7/37 = 19%). Median recurrence-free survival and overall survival were 24 months (range 0 - 108) and 80 months (range 4-115), respectively. Surgical outcome, completion of more than three courses of treatment and intra-abdominal localisation of recurrent disease were associated with better survival outcomes. CONCLUSION: In daily practice, 54% of patients with advanced OC could complete all scheduled cycles of iv/ ip chemotherapy with acceptable morbidity and toxicity, leading to outcomes comparable with the results of published trials on iv/ip chemotherapy.


Assuntos
Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Feminino , Humanos , Infusões Parenterais , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos
15.
Gynecol Oncol ; 159(3): 706-711, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33019981

RESUMO

OBJECTIVE: Decrease in skeletal muscle index (SMI) during neoadjuvant chemotherapy (NACT) has been associated with worse outcome in patients with advanced ovarian cancer. To validate these findings, we tested if a decrease in SMI was a prognostic factor for a homogenous cohort of patients who received NACT in the randomized phase 3 OVHIPEC-trial. METHODS: CT-scans were performed at baseline and after two cycles of neoadjuvant chemotherapy in stage III ovarian cancer patients. The SMI (skeletal muscle area in cm2 divided by body surface area in m2) was calculated using SliceOMatic software. The difference in SMI between both CT-scans (ΔSMI) was calculated. Cox-regression analyses were performed to analyze the independent effect of a difference in SMI (ΔSMI) on outcome. Log-rank tests were performed to plot recurrence-free (RFS) and overall survival (OS). The mean number of adverse events per patient were compared between groups using t-tests. RESULTS: Paired CT-scans were available for 212 out of 245 patients (87%). Thirty-four of 74 patients (58%) in the group with a decrease in ΔSMI and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median RFS and OS did not differ significantly (p = 0.297 and p = 0.764) between groups. Patients with a decrease in SMI experienced more pre-operative adverse events, and more grade 3-4 adverse events. CONCLUSION: Decreased SMI during neoadjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer included in the OVHIPEC-trial. However, a strong association between decreasing SMI and adverse events was found.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/terapia , Sarcopenia/epidemiologia , Idoso , Índice de Massa Corporal , Ensaios Clínicos Fase III como Assunto , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Músculo Esquelético/diagnóstico por imagem , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Período Pré-Operatório , Prognóstico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Tomografia Computadorizada por Raios X
16.
Neth Heart J ; 28(Suppl 1): 50-56, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32780332

RESUMO

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.

17.
Sci Rep ; 10(1): 7687, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376900

RESUMO

RNA-binding proteins are key regulators of post-transcriptional processes such as alternative splicing and mRNA stabilization. Rbm24 acts as a regulator of alternative splicing in heart and skeletal muscle, and is essential for sarcomere assembly. Homozygous inactivation of Rbm24 in mice disrupts cardiac development and results in embryonic lethality around E12.5. In the present study, we generated somatic Rbm24 knockout (KO) mice and investigated the effects of reduced levels of Rbm24 in the adult heart. Due to the embryonic lethality of Rbm24 KO mice, we examined cardiac structure and function in adult Rbm24 heterozygotes (HETs). Rbm24 protein expression was 40% downregulated in HET hearts compared to WT hearts. Force measurements on isolated membrane-permeabilized myocytes showed increased sarcomere slack length and lower myofilament passive stiffness in adult Rbm24 HET compared to wildtype cardiomyocytes. As a result of the differences in sarcomere slack length, the relations between force development and sarcomere length differed between WT and Rbm24 HET hearts. No differences in sarcomere structure and titin isoform composition were observed. Likewise, in vivo cardiac function and myocardial structure was unaltered in Rbm24 HET mice compared to WT, at baseline and upon pressure overload after transverse aortic constriction. In conclusion, we generated a somatic Rbm24 KO model and recapitulated the previously reported embryonic phenotype. In adult Rbm24 HET cardiomyocytes we observed increased sarcomere slack length, but no difference in sarcomere structure and cardiac function.


Assuntos
Perda de Heterozigosidade , Miocárdio/metabolismo , Proteínas de Ligação a RNA/genética , Sarcômeros/metabolismo , Animais , Biomarcadores , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Modelos Animais de Doenças , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Cardiopatias/genética , Cardiopatias/metabolismo , Imuno-Histoquímica , Contração Isométrica , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sarcômeros/ultraestrutura
18.
Neth Heart J ; 28(6): 299-300, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378128
19.
Acta Oncol ; 59(3): 291-297, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31760850

RESUMO

Introduction: An increasing number of patients is diagnosed with spinal metastases due to elevated cancer incidence and improved overall survival. Patients with symptomatic spinal bone metastases often receive radiotherapy with or without surgical stabilisation. Patients with a life expectancy of less than 3 months are generally deemed unfit for surgery, therefore adequate pre-treatment assessment of life expectancy is necessary. The aim of this study was to assess new factors associated with overall survival for this category of patients.Patients and methods: Patients who received radiotherapy for thoracic or lumbar spinal metastases from June 2013 to December 2016 were included in this study. The pre-treatment planning CT for radiotherapy treatment was used to assess the patient's visceral fat area, subcutaneous fat area, total muscle area and skeletal muscle density on a single transverse slice at the L3 level. The total muscle area was used to assess sarcopenia. Furthermore, data were collected on age, sex, primary tumour, Karnofsky performance score, medical history, number of bone metastases, non-bone metastases and neurological symptoms. Univariable and multivariable cox regressions were performed to determine the association between our variables of interest and the survival at 90 and 365 days.Results: A total of 310 patients was included. The median age was 67 years. Overall survival rates for 90 and 365 days were 71% and 36% respectively. For 90- and 365-day survival, the Karnofsky performance score, muscle density and primary tumour were independently significantly associated. The visceral or subcutaneous fat area and their ratio and sarcopenia were not independently associated with overall survival.Conclusions: Of the body morphology, only muscle density was statistically significant associated with overall survival after 90 and 365 days in patients with spinal bone metastases. Body fat distribution was not significantly associated with overall survival.


Assuntos
Distribuição da Gordura Corporal/efeitos adversos , Radioterapia , Sarcopenia , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/secundário , Idoso , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias da Coluna Vertebral/fisiopatologia , Taxa de Sobrevida
20.
Neth Heart J ; 27(6): 287-288, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049837
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