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1.
Anticancer Res ; 40(11): 6327-6335, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109570

RESUMO

BACKGROUND/AIM: Despite numerous studies, the etiology of chronic lymphocytic leukemia (CLL) remains unknown. A hypothesis of autoantigen stimulation in leukemic clone selection might explain 'stereotypy' of B-cell receptors. In healthy cells, cofilin-1 (CFL1) has multiple functions. Its role was described in several malignancies. The aim of this study was characterization of the role of CFL1 in CLL. Materialas and Methods: Cells from peripheral blood of 180 patients and 42 healthy volunteers (HVs) were isolated. Gene expression was assessed with reverse transcription polymerase chain reaction (RT-qPCR); western blot was performed for determination of protein level and activity. After silencing of CFL1 gene, cell ability for migration and chemotaxis was investigated with Transwell method. Post-silencing, apoptosis and cell cycle was determined by flow cytometry. RESULTS: In RT-qPCR, we observed significantly higher expression of CFL1. Higher activity of protein in CLL cells when compared to HVs was detected. Knock-down of CFL1 led to decreased chemotaxis and migration of CLL cells versus cells from HVs. Apoptosis was increased amongst cells with silenced CFL1 and correlated with higher proportion of cells in the G2/M phase. CONCLUSION: Significantly higher expression of CFL1 mRNA in CLL and higher protein activity might indicate high utilization of CFL1 in malignant cells, maintaining their viability, as its inhibition affected viability, cell-cycle progression and motility of leukemia cells.


Assuntos
Cofilina 1/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Quimiotaxia/genética , Cofilina 1/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Frações Subcelulares/metabolismo
3.
Lancet Oncol ; 21(9): 1188-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888452

RESUMO

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos , Resultado do Tratamento
4.
Int J Hematol ; 112(4): 459-465, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32889697

RESUMO

Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disease characterized by the accumulation of immature monoclonal B lymphocytes in blood cells, bone marrow, spleen and lymph nodes. This is the most common type of leukemia among the Caucasoid race. When CLL skin lesions occur in about 25% of patients, they are extremely diverse. These lesions can be divided into specific, including infiltration of the skin by leukemic cells and the skin form of Richter's syndrome, secondary skin tumors, nonspecific lesions and associated skin diseases.Leukemic infiltration of the skin in patients with leukemia is called specific skin lesions (SSL). Many authors associate the unfavorable prognosis with the transformation of CLL with specific infiltration of the skin into Richter syndrome, as well as the appearance of SSL before the diagnosis of CLL. The risk of developing various cancer pathologies in patients with CLL is three times higher than in healthy people identical in sex and age. It was found that the risk of skin cancer in these patients is eight times higher than in the healthy population. The most common secondary skin tumors in CLL are basal-cell carcinoma, squamous-cell carcinoma, melanoma, and Merkel tumor.Nonspecific skin changes are extremely diverse and occur in patients with CLL in 30-50% of cases. The most common secondary changes in the skin in CLL are those of infectious nature. There are also increased reactions to insect bites, generalized itching, exfoliative erythroderma, nodular erythema, paraneoplastic pemphigoid, bullous pemphigoid, drug eruption. Concomitant dermatoses in these patients are more severe and often torpid to the previously conducted therapy. There is no doubt that together with the clarification of the etiology and pathogenesis of CLL, particular issues related to the study of clinical and morphological changes in individual organs and systems, in particular the skin, formed at various stages of the development of this disease should be studied in detail. This can not only expand and clarify our understanding of this pathology, but also can help to clarify the essence of the disease.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Infiltração Leucêmica/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Neoplasias Cutâneas/etiologia , Síndrome
6.
Cochrane Database Syst Rev ; 7: CD012022, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32735048

RESUMO

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long-term outcome in people newly-diagnosed with CLL. OBJECTIVES: To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression-free survival (PFS) or treatment-free survival (TFS) in newly-diagnosed (previously untreated) adults with CLL, and meta-analyse their predictive performances. SEARCH METHODS: We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies. SELECTION CRITERIA: We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B-cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design. DATA COLLECTION AND ANALYSIS: We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta-analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random-effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models. MAIN RESULTS: From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL-IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2-microglobulin and TP53 status. Calibration: for the low-, intermediate- and high-risk groups, the pooled five-year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high-risk group, predicted survival from CLL-IPI was lower than observed from external validation studies. Discrimination: the pooled c-statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c-statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona-Brno score Aimed at simplifying the CLL-IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low- and intermediate-risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2-microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low- and intermediate-risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77. AUTHORS' CONCLUSIONS: Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly-diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta-analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL-IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.


Assuntos
Leucemia Linfocítica Crônica de Células B/mortalidade , Modelos Teóricos , Adulto , Fatores Etários , Viés , Biomarcadores Tumorais , Calibragem , Intervalos de Confiança , Análise Discriminante , Intervalo Livre de Doença , Feminino , Genes p53/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Receptores de Antígenos de Linfócitos B/genética , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/genética
8.
Leukemia ; 34(8): 2225-2229, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601378
10.
Nature ; 584(7819): 130-135, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581364

RESUMO

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.


Assuntos
Envelhecimento/genética , Aberrações Cromossômicas , Cromossomos Humanos/genética , Células Clonais/metabolismo , Genoma Humano/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Idoso de 80 Anos ou mais , Alelos , Linhagem da Célula , Células Clonais/citologia , Células Clonais/patologia , Estudos de Coortes , Feminino , Loci Gênicos/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia de Células T/genética , Leucemia de Células T/patologia , Masculino , Mosaicismo , Reino Unido
11.
Hautarzt ; 71(7): 553-556, 2020 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-32394077

RESUMO

We report the case of an 85-year-old chronic lymphocytic leukemia patient with a local metastatic MCVPyV-negative Merkel cell carcinoma at initial diagnosis. Therapy comprised surgical excision and radiotherapy but without lymphadenectomy. Six months after the primary diagnosis, liver metastases were detected. They responded to the PD-L1 inhibitor avelumab for more than 15 months. Thus, we postulate a synergistic effect of combined therapy with chlorambucil and avelumab through a mutual improvement of immune function, from which both diseases benefit.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Clorambucila/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/secundário , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Resultado do Tratamento
12.
Medicine (Baltimore) ; 99(19): e20115, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384487

RESUMO

B lymphocytic leukemia (B-ALL) is a hematopoietic malignant disease characterized by an accumulation of early B cells. This study aimed to construct a children B-ALL Nomogram prediction model based on Therapeutically Applicable Research to Generate Effective Treatments database, so as to further guide clinical diagnose and treatment.Clinical data related to children B-ALL were collected from the TARGET database, among which, the stage II clinical data were used as the prediction model, while the stage I clinical data were utilized as the external verification model. The stage II clinical factors were analyzed through Lasso regression analysis to screen the risk factors for the construction of Nomogram prediction model. In addition, the model prediction capacity and accuracy were verified internally and externally using the ROC curve, C-index and calibration curve, respectively.A total of 1316 B-ALL children were enrolled in this study. Lasso regression analysis revealed that, Age, Gender, WBC, CNSL, MRD29, BMR, CNS R, BCR-ABL1, BMA29, DS, and DI were the important prognostic risk factors. The C-index values of internal and external verification models were 0.870 and 0.827, respectively, revealing the ideal model discriminating capacity. Besides, the calibration curve had high contact ratio, which suggested favorable consistency between the incidence predicted by the model and the actual incidence. Moreover, the AUC values of the ROC curve were 0.858, 0.787, 0.898, and 0.867, respectively, indicating high model prediction accuracy in predicting the 3- and 5-year survival rates of children with B-ALL.The Nomogram prediction model plotted in this study exhibits favorable prediction capacity and clinical practicability for the survival rate of B-ALL children, which contributes to patients screening and clinical intervention.


Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Nomogramas , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Análise de Regressão , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida
13.
Hematol Oncol ; 38(4): 509-516, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32400885

RESUMO

Until recently, a combination of anti-CD20 antibody plus less intensive chemotherapy was a standard of care in elderly population with previously untreated chronic lymphocytic leukemia (CLL). The aim of this observational study was to retrospectively assess efficacy and safety of obinutuzumab + chlorambucil (G-Clb), rituximab + chlorambucil (R-Clb), and bendamustine + rituximab (BR) given as the frontline therapy within routine practice. The final analyzed dataset included 398 consecutive CLL patients from 10 hematology centers cooperating within the Czech CLL Study Group: 63 treated with G-Clb, 78 with R-Clb, and 257 with BR. There were no significant differences in prognostic and predictive markers among the groups. On the contrary, median age at the start of therapy and cumulative illness rating scale (CIRS) score was significantly higher in R-Clb group. Obinutuzumab plus chlorambucil regimen was preferably offered to elderly patients (compared to BR) with less severe comorbidities and lower CIRS score (compared to R-Clb). A time period when a treatment was indicated had also a strong impact on the choice of the regimen. The overall response rate reached 76% (30% complete remissions, CRs) in G-Clb, 75% (22% CRs) in R-Clb, and 85% (47% CRs) in BR group. Median event-free survival was 49.0 months for G-Clb, 20.3 months for R-Clb, and 37.0 months for BR group. Neutropenia grade ≥ 3 developed in 43% of G-Clb, 31% of R-Clb and in 49% of BR patients, grade ≥ 3 infections were recorded in 17% of G-Clb, 6.4% of R-Clb, and 17% of BR patients. In conclusion, real-world therapeutic activity of G-Clb appears to be at least comparable to prospective clinical trial data. R-Clb yields relatively good results in very old and severely comorbid patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Clorambucila/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de Sobrevida
14.
J Cancer Res Ther ; 16(1): 180-182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362634

RESUMO

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is one of the common lymphoproliferative disorders with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of secondary malignancy. Breast, brain, skin and prostate tumors have been reported as usual coincident malignancies of CLL, while in occasional cases CLL may occur with malignancies of other solid organs, such as skin, lung, heart, and prostate. Synchronous CLL with urothelial carcinoma (UC) is an infrequent occurrence. We report this case because of its rarity in Indian literature and interesting hematological, immunophenotypic, histopathological, and cytopathological features of metastatic high-grade UC in a 61-year-old male with CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Hepáticas/secundário , Neoplasias Primárias Múltiplas/patologia , Neoplasias da Bexiga Urinária/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
15.
Mod Pathol ; 33(6): 1007-1014, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-67631

RESUMO

Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients' ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.


Assuntos
Infecções por Coronavirus/patologia , Fígado/patologia , Pulmão/patologia , Miocárdio/patologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Biópsia com Agulha de Grande Calibre , China , Infecções por Coronavirus/complicações , Feminino , Fibrose , Humanos , Hipertrofia , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/patologia , Contagem de Leucócitos , Pulmão/diagnóstico por imagem , Linfopenia/patologia , Linfopenia/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Radiografia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X
16.
Medicine (Baltimore) ; 99(15): e19806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282746

RESUMO

RATIONALE: Acute lymphoblastic leukemia (ALL) has acute and severe onset characterized by fever, moderate to severe anemia, bone and joint pain, and sternal tenderness. It is easy to be misdiagnosed as rheumatic disease when joint pain is the first symptom. PATIENT CONCERNS: A male Han, 18 years of age was admitted on July 15th, 2016 for multi-joint swelling and pain with intermittent fever for half a year which had aggravated in the last 10 days. DIAGNOSIS: Based on symptoms, imaging, family history, and blood tests, he was first diagnosed with ankylosing spondylitis, but he was refractory to treatment. Bone marrow biopsy then revealed acute B-lymphoblastic leukemia (possibility Pro-B-ALL). INTERVENTIONS: The patient was transferred to the hematology department on July 23rd, 2016 for chemotherapy. OUTCOMES: No joint pain occurred during follow-up, which ended on November 4th, 2018. LESSONS: ALL may present with symptoms suggestive of rheumatic diseases like ankylosing spondylitis. Physicians should be aware of this possibility, especially in young patients.


Assuntos
Artralgia/etiologia , Leucemia Linfocítica Crônica de Células B/patologia , Espondilite Anquilosante/diagnóstico , Adolescente , Antineoplásicos/uso terapêutico , Artralgia/diagnóstico , Biópsia , Medula Óssea/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Febre/diagnóstico , Febre/etiologia , Humanos , Artropatias/diagnóstico por imagem , Artropatias/patologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Espondilite Anquilosante/sangue , Espondilite Anquilosante/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
17.
Toxicol Appl Pharmacol ; 398: 115016, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32325063

RESUMO

Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia, possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells from nine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA), vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrial biogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to force hypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2 levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that we denoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two non-supervised classification algorithms discriminated CLL patients with active disease (ADT) and stable disease (NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, the potency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towards antagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role of mitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response of drugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked the metabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinical features of individual patients, therefore providing new sources of data on disease progression, drug response and risk prognosis.


Assuntos
Antineoplásicos/farmacologia , Hipóxia/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Transdução de Sinais/efeitos dos fármacos
18.
Am J Hematol ; 95(8): 906-917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32279347

RESUMO

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10-8 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Linfocítica Crônica de Células B/genética , Linfocitose/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
19.
Mod Pathol ; 33(6): 1007-1014, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32291399

RESUMO

Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients' ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.


Assuntos
Infecções por Coronavirus/patologia , Fígado/patologia , Pulmão/patologia , Miocárdio/patologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Biópsia com Agulha de Grande Calibre , China , Infecções por Coronavirus/complicações , Feminino , Fibrose , Humanos , Hipertrofia , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/patologia , Contagem de Leucócitos , Pulmão/diagnóstico por imagem , Linfopenia/patologia , Linfopenia/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Radiografia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X
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