RESUMO
Background Electrical activity underlying the T-wave is less well understood than the QRS-complex. This study investigated the relationship between normal T-wave morphology and the underlying ventricular repolarization gradients using the equivalent dipole layer (EDL). Methods Body-surface-potential-maps (BSPM, 67leads) were obtained in nine normal cases. Subject specific MRI-based anatomical heart/torso-models with electrode positions were created. The boundary element method was used to account for the volume conductor effects. To simulate the measured T-waves, the EDL was used to apply different ventricular repolarization gradients: a) transmural, b) interventricular c) apico-basal and d) all three gradients (a-c) combined. The combined gradient (d) was optimized using an inverse procedure (Levenberg-Marquardt). Correspondence between simulated and measured T-waves was assessed using correlation coefficient (CC) and relative difference (RD). Results Realistic T-waves were simulated if repolarization times of: (a) the epicardium were smaller than the endocardium; (b) the left ventricle were smaller than the right ventricle and (c) the apex increased towards the base. The apico-basal gradient resulted in the highest correspondence between measured and simulated T-waves (CC = 0.84(0.81-0.91);RD = 0.68(0.60-0.71)) compared to a transmural gradient (CC = 0.77(0.71-0.80);RD = 1.46(0.82-1.75)) and an interventricular gradient (CC = 0.71(0.67-0.80);RD = 0.85(0.75-0.87)). All three gradients combined further improved the correspondence between measured and simulated T-waves (CC = 0.83(0.82-0.89);RD = 0.60(0.51-0.63)), especially after optimization (CC = 0.96(0.94-0.98);RD = 0.27(0.22-0.34)). Conclusion The application of all repolarization gradients combined resulted in the largest agreement between simulated and measured T-waves, followed by the apico-basal repolarization gradient. With these findings, we will optimize our EDL-based inverse procedure to assess repolarization abnormalities.
Assuntos
Eletrocardiografia , Sistema de Condução Cardíaco , Humanos , Eletrocardiografia/métodos , Potenciais de Ação , Pericárdio , Endocárdio , Arritmias CardíacasRESUMO
BACKGROUND: CineECG offers a visual representation of the location and direction of the average ventricular electrical activity throughout a single cardiac cycle, based on the 12lead ECG. Currently, CineECG has not been used to visualize ventricular activation patterns during ischemia. PURPOSE: To determine the changes in ventricular activity during acute ischemia with the use of CineECG, and relating this to changes in the ECG. METHODS: Continuous ECG's during percutaneous coronary intervention with prolonged balloon inflation from the STAFF III database were analyzed with CineECG at baseline and every 10 s throughout the first 150 s of balloon inflation. The CineECG direction was determined for the initial QRS-complex, terminal QRS-complex, ST-segment and T-wave. Changes in the CineECG were quantified by calculating the Δangle between the direction at baseline and the direction at every 10 s of inflation. Additionally, the root mean square amplitude (rmsA) of the ST-segment was computed. RESULTS: 94 patients were included. At start inflation, the median Δangle was 14.7° [7.5-33.4], 21.8° [11.4-34.2], 20.6° [8.0-43.9], and 23.5° [11.8-48.0] for the initial QRS-complex, terminal QRS-complex, ST-segment and T-wave, respectively. Meanwhile, the median rmsA increased from 0.039 mV [0.027-0.058] at baseline to 0.045 mV [0.033-0.075] at start of inflation. CONCLUSIONS: CineECG was able to detect immediate changes in ventricular electrical activity during induced ischemia, while changes in the ST-segment of the ECG were still subtle. Therefore, CineECG might support the early detection of acute ischemia, even before distinct ECG changes become visible.
Assuntos
Isquemia Miocárdica , Intervenção Coronária Percutânea , Humanos , Eletrocardiografia , Isquemia Miocárdica/diagnóstico , Isquemia , Arritmias CardíacasRESUMO
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 XRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is a rare and rapidly progressive form of invasive breast cancer. The aim of this study was to explore the clinical evolution, stromal tumour-infiltrating lymphocytes (sTIL) infiltration and programmed death-ligand 1 (PD-L1) expression in a large IBC cohort. PATIENTS AND METHODS: Data were collected prospectively from patients with IBC as part of an international collaborative effort since 1996. In total, 143 patients with IBC starting treatment between June 1996 and December 2016 were included. Clinicopathological variables were collected, and sTIL were scored by two pathologists on standard H&E stained sections. PD-L1 expression was assessed using a validated PD-L1 (SP142) assay. A validation cohort of 64 patients with IBC was used to test our findings. RESULTS: Survival outcomes of IBC remained poor with a 5-year overall survival (OS) of 45.6%. OS was significantly better in patients with primary non-metastatic disease who received taxane-containing (neo)adjuvant therapy (P = 0.01), had a hormone receptor-positive tumour (P = 0.001) and had lower cN stage at diagnosis (P = 0.001). PD-L1 positivity on immune cells (42.9%) was higher in IBC than in non-IBC in both our patient samples and the validation cohort. Furthermore, PD-L1 expression predicted pCR (P = 0.002) and correlated with sTIL infiltration (P < 0.001). sTIL infiltration of more than 10% of the stroma was a significant predictor of improved OS (HR 0.47, 95% CI 0.27-0.81, P = 0.006) in a multivariate model. CONCLUSIONS: IBC is characterised by poor survival and high PD-L1 immunoreactivity on sTIL. This suggests a role for PD1/PD-L1 inhibitors in the treatment of IBC. Furthermore, we showed that PD-L1 expression predicts response to neo-adjuvant therapy and that sTIL have prognostic significance in IBC.
Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Inflamatórias Mamárias/imunologia , Linfócitos do Interstício Tumoral/imunologia , Células Estromais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/mortalidade , Neoplasias Inflamatórias Mamárias/patologia , Neoplasias Inflamatórias Mamárias/terapia , Linfócitos do Interstício Tumoral/metabolismo , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Células Estromais/metabolismo , Análise de SobrevidaRESUMO
BACKGROUND: The enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer. METHODS: CellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ≥5 CTCs per 7.5 ml blood. RESULTS: No significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ≥1 and ≥5 CTCs per 7.5 ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ≥80 CTCs per 7.5 ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ≥5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B-HER2-negative and TN disease. CONCLUSION: The detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.
Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Contagem de Células/métodos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise Multivariada , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Receptor ErbB-2/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive disease. To date, no molecular feature reliably predicts either the response to chemotherapy (CT) or the survival. Using DNA microarrays, we searched for multigene predictors. PATIENTS AND METHODS: The World IBC Consortium generated whole-genome expression profiles of 137 IBC and 252 non-IBC (nIBC) samples. We searched for transcriptional profiles associated with pathological complete response (pCR) to neoadjuvant anthracycline-based CT and distant metastasis-free survival (DMFS) in respective subsets of 87 and 106 informative IBC samples. Correlations were investigated with predictive and prognostic gene expression signatures published in nIBC (nIBC-GES). Supervised analyses tested genes and activation signatures of 19 biological pathways and 234 transcription factors. RESULTS: Three of five tested prognostic nIBC-GES and the two tested predictive nIBC-GES discriminated between IBC with and without pCR, as well as two interferon activation signatures. We identified a 107-gene signature enriched for immunity-related genes that distinguished between responders and nonresponders in IBC. Its robustness was demonstrated by external validation in three independent sets including two IBC sets and one nIBC set, with independent significant predictive value in IBC and nIBC validation sets in multivariate analysis. We found no robust signature associated with DMFS in patients with IBC, and neither of the tested prognostic GES, nor the molecular subtypes were informative, whereas they were in our nIBC series (220 stage I-III informative samples). CONCLUSION: Despite the relatively small sample size, we show that response to neoadjuvant CT in IBC is, as in nIBC, associated with immunity-related processes, suggesting that similar mechanisms responsible for pCR exist. Analysis of a larger IBC series is warranted regarding the correlation of gene expression profiles and DMFS.
Assuntos
Carcinoma Ductal de Mama/metabolismo , Neoplasias Inflamatórias Mamárias/metabolismo , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/secundário , Quimioterapia Adjuvante , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/mortalidade , Neoplasias Inflamatórias Mamárias/patologia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Citocromo P-450 CYP2C9/genética , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Glucuronosiltransferase/genética , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Polimorfismo de Nucleotídeo Único , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Molecular characterisation of single circulating tumour cells (CTCs) holds considerable promise for predictive biomarker assessment and to explore CTC heterogeneity. We evaluate a new method, the DEPArray system, that allows the dielectrophoretic manipulation and isolation of single and 100% purified groups of CTCs from pre-enriched blood samples and explore the feasibility of their molecular characterisation. METHODS: Samples containing known numbers of two cell populations were used to assess cell loss during sample loading. Cultured breast cancer cells were isolated from spiked blood samples using CellSearch CTC and Profile kits. Single tumour cells and groups of up to 10 tumour cells were recovered with the DEPArray system and subjected to transcriptional and mutation analysis. RESULTS: On average, 40% cell loss was observed when loading samples to the DEPArray system. Expected mutations in clinically relevant markers could be obtained for 60% of single recovered tumour cells and all groups of tumour cells. Reliable gene expression profiles were obtained from single cells and groups of up to 10 cells for 2 out of 3 spiked breast cancer cell lines. CONCLUSION: We describe a semiautomated workflow for the isolation of small groups of 1 to 10 tumour cells from whole blood samples and provide proof of principle for the feasibility of their comprehensive molecular characterisation.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Separação Celular/métodos , Perfilação da Expressão Gênica , Células Neoplásicas Circulantes/patologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Separação Celular/instrumentação , Feminino , Humanos , Mutação/genéticaRESUMO
OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count. METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70. RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL). CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.
Assuntos
COVID-19 , Esclerose Múltipla , Anticorpos Monoclonais Humanizados , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
BACKGROUND: The enumeration of circulating tumour cells (CTC) has prognostic significance in patients with metastatic breast cancer (MBC) and monitoring of CTC levels over time has considerable potential to guide treatment decisions. However, little is known on CTC kinetics in the human bloodstream. METHODS: In this study, we compared the number of CTC in both 7.5 ml central venous blood (CVB) and 7.5 ml peripheral venous blood (PVB) from 30 patients with MBC starting with a new line of chemotherapy. RESULTS: The number of CTC was found to be significantly higher in CVB (median: 43.5; range: 0-4036) than in PVB (median: 33; range: 0-4013) (P=0.001). When analysing samples pairwise, CTC counts were found to be significantly higher in CVB than in PVB in 12 out of 26 patients with detectable CTC. In contrast, only 2 out of 26 patients had higher CTC counts in PVB as compared with CVB, whereas in 12 remaining patients no significant difference was seen. The pattern of CTC distribution was independent of the sites of metastatic involvement. CONCLUSION: A substantial difference in the number of CTC was observed between CVB and PVB of patients with MBC. Registration of the site of blood collection is warranted in studies evaluating the role of CTC assessment in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Cateterismo Venoso Central , Cateterismo Periférico , Células Neoplásicas Circulantes , Veias , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , PrognósticoRESUMO
AIMS: The impact of depression on patients with chronic medical illnesses such as diabetes is well documented. Depression is relatively common in diabetes patients with diabetes-related complications and they are more likely to be referred to specialized outpatient facilities. Only a few studies have addressed the association between depression and multiple diabetes-related complications at these specialized outpatient facilities. The aim of this study was to determine the association between diabetes with multiple complications and depression in patients with Type 2 diabetes at a specialized outpatient clinic. METHODS: After giving informed consent, 1194 patients were screened for depression using the Patient Health Questionnaire (PHQ-9). Additional data on the type of diabetes and complications were taken from the medical records. Logistic regression analysis was conducted, with complications as the predictor variable and the probability of depression as the dependent variable. RESULTS: A total of 596 (63%) patients with Type 2 diabetes participated in the study. The presence of two or more complications (OR 2.23, 95% CI 1.022.94) was significantly associated with depression. Neuropathy (OR 1.7, 95% CI 1.102.77) and nephropathy (OR 1.68, 95% CI 1.002.48) were especially related to depression. CONCLUSIONS: Patients with Type 2 diabetes with two or more complications, especially neuropathy or nephropathy, are at high risk of depression. Knowing this can help clinicians identify patients at risk for depression and facilitate timely and adequate treatment.
Assuntos
Nefropatias Diabéticas/psicologia , Neuropatias Diabéticas/psicologia , Comorbidade , Transtorno Depressivo/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.
Assuntos
Antineoplásicos , COVID-19 , Neoplasias , Vacina BNT162 , Vacinas contra COVID-19 , Humanos , Imunidade Humoral , Estudos Prospectivos , RNA Mensageiro , SARS-CoV-2 , VacinaçãoRESUMO
BACKGROUND: MicroRNAs (miRNAs) are key regulators of gene expression. In this study, we explored whether altered miRNA expression has a prominent role in defining the inflammatory breast cancer (IBC) phenotype. METHODS: We used quantitative PCR technology to evaluate the expression of 384 miRNAs in 20 IBC and 50 non-IBC samples. To gain understanding on the biological functions deregulated by aberrant miRNA expression, we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of 10 962 messenger RNAs (mRNAs) and by comparing these results with predicted miRNA targets from TargetScan5.1. RESULTS: We identified 13 miRNAs for which expression levels were able to correctly predict the nature of the sample analysed (IBC vs non-IBC). For these miRNAs, we detected a total of 17,295 correlated miRNA-mRNA pairs, of which 7012 and 10 283 pairs showed negative and positive correlations, respectively. For four miRNAs (miR-29a, miR-30b, miR-342-3p and miR-520a-5p), correlated genes were concordant with predicted targets. A gene set enrichment analysis on these genes demonstrated significant enrichment in biological processes related to cell proliferation and signal transduction. CONCLUSIONS: This study represents, to the best of our knowledge, the first integrated analysis of miRNA and mRNA expression in IBC. We identified a set of 13 miRNAs of which expression differed between IBC and non-IBC, making these miRNAs candidate markers for the IBC subtype.
Assuntos
Neoplasias da Mama/genética , MicroRNAs/genética , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Inflamação , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: The detection, enumeration and isolation of circulating tumour cells (CTCs) have considerable potential to influence the clinical management of patients with breast cancer. There is, however, substantial variability in the rates of positive samples using existing detection techniques. The lack of standardisation of technology hampers the implementation of CTC measurement in clinical routine practice. METHODS: This study was designed to directly compare three techniques for detecting CTCs in blood samples taken from 76 patients with metastatic breast cancer (MBC) and from 20 healthy controls: the CellSearch CTC System, the AdnaTest Breast Cancer Select/Detect and a previously developed real-time qRT-PCR assay for the detection of CK-19 and mammaglobin transcripts. RESULTS: As a result, 36% of patients with MBC were positive by the CellSearch System, 22% by the AdnaTest, 26% using RT-PCR for CK-19 and 54% using RT-PCR for mammaglobin. Samples were significantly more likely to be positive for at least one mRNA marker using RT-PCR than using the CellSearch System (P=0.001) or the AdnaTest (P<0.001). CONCLUSION: We observed a substantial variation in the detection rates of CTCs in blood from breast cancer patients using three different techniques. A higher rate of positive samples was observed using a combined qRT-PCR approach for CK-19 and mammaglobin, which suggests that this is currently the most sensitive technique for detecting CTCs.
Assuntos
Neoplasias da Mama/diagnóstico , Células Neoplásicas Circulantes , Biomarcadores Tumorais/sangue , Neoplasias da Mama/secundário , Técnicas e Procedimentos Diagnósticos , Feminino , HumanosRESUMO
INTRODUCTION: Inflammatory breast cancer (IBC) is an uncommon, but aggressive form of breast cancer that accounts for a disproportionally high fraction of breast cancer related mortality. The aim of this study was to explore the peripheral immune response and the prognostic value of blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), in a large IBC cohort. PATIENTS & METHODS: We retrospectively identified 127 IBC patients and collected lab results from in-hospital medical records. The differential count of leukocytes was determined at the moment of diagnosis, before any therapeutic intervention. A cohort of early stage (n = 108), locally advanced (n = 74) and metastatic breast cancer patients (n = 41) served as a control population. RESULTS: The NLR was significantly higher in IBC compared to an early stage breast cancer cohort, but no difference between IBC patients and locally advanced breast cancer patients was noted. In the metastatic setting, there was also no significant difference between IBC and nIBC. However, a high NLR (>4.0) remained a significant predictor of worse outcome in IBC patients (HR: 0.49; 95% CI: 0.24-1.00; P = .05) and a lower platelet-lymphocyte ratio (PLR) (≤210) correlated with a better disease-free survival (DFS) (HR: 0.51; 95% CI: 0.28-0.93; P = .03). CONCLUSION: Patients with a high NLR (>4.0) have a worse overall prognosis in IBC, while the PLR correlated with relapse free survival (RFS). Since NLR and PLR were not specifically associated with IBC disease, they can be seen as markers of more extensive disease.
Assuntos
Contagem de Células Sanguíneas/estatística & dados numéricos , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Neoplasias Inflamatórias Mamárias/sangue , Neoplasias Inflamatórias Mamárias/mortalidade , Adulto , Biomarcadores Tumorais/sangue , Plaquetas/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Circulating tumour cells (CTC) and tumour-related methylated DNA in blood have been separately assessed for their utility as a marker for subclinical metastasis in breast cancer. However, no studies have looked into the relation between the both molecular markers in this type of cancer. In this study, we investigated the correlations between total/methylated DNA and CTC in the blood from metastatic breast cancer patients. We simultaneously obtained whole blood, plasma and serum samples from 80 patients and 20 controls. The CellSearch System was used to enumerate CTC in blood samples. Plasma total DNA levels were determined by a QPCR method. Sera were analysed by methylation-specific QPCR for three markers: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A) and oestrogen receptor 1 (ESR1). Total DNA levels in patients were significantly increased when compared with controls (P<0.001) and correlated with the number of CTC (r=0.418, P<0.001). Hypermethylation of one or more genes was detected in 42 (53%) serum samples from breast cancer patients and in three (16%) serum samples from controls (P=0.003). APC was hypermethylated in 29%, RASSF1A in 35% and ESR1 in 20% of breast cancer cases. Detection of a methylated gene in serum was associated with the detection of CTC in blood (P=0.03). The detection of large amounts of circulating total/methylated DNA correlated with the presence of CTC in the blood from patients with breast cancer. This can be interpreted in two ways: (a) CTC are a potential source of circulating tumour-specific DNA; (b) high numbers of CTC and circulating methylated DNA are both a phenotypic feature of more aggressive tumour biology.
Assuntos
Neoplasias da Mama/genética , Metilação de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Polipose Adenomatosa do Colo/genética , Neoplasias da Mama/sangue , DNA/sangue , Metilação de DNA/genética , Receptor alfa de Estrogênio/genética , Feminino , Genes p53 , Humanos , Reação em Cadeia da Polimerase , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Valores de Referência , Proteínas Supressoras de Tumor/genéticaRESUMO
Vascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue microarray of clinical samples (N=86), tumour cell immunohistochemical staining of AKT/mTOR downstream targets, pS6 and p4E-BP1, together with tumour cell staining of VEGF-A and pVEGFR2 were semi-quantified. A correlation was found between the marker for VEGFR2 activation (pVEGFR2) and a downstream target of AKT/mTOR signalling (pS6) (R=0.29; P=0.002). Additional gene expression analysis in an independent cDNA microarray dataset (N=24) showed a negative correlation (R=-0.73, P<0.0001) between the RPS6 and the VEGFR2 gene, which is consistent as the gene expression and phosphorylation of S6 is inversely regulated. An activated tumour cell VEGFR2/AKT/mTOR pathway was associated with increased incidence of ascites (chi(2), P=0.002) and reduced overall survival of cisplatin-taxane-based patients with serous histology (N=32, log-rank test, P=0.04). These data propose that VEGF-A signalling acts on tumour cells as a stimulator of the AKT/mTOR pathway. Although VEGF-A inhibitors are classified as anti-angiogenic drugs, these data suggest that the working mechanism has an important additional modality of targeting the tumour cells directly.
Assuntos
Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/fisiologia , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/fisiopatologia , Neoplasias Ovarianas/fisiopatologia , Proteínas Quinases S6 Ribossômicas 70-kDa/análise , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Serina-Treonina Quinases TOR , Análise Serial de Tecidos , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologiaRESUMO
CONTEXT: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range. PARTICIPANTS: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years. CONCLUSIONS: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions.