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BACKGROUND: G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells. METHODS: In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 µg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 µg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study. RESULTS: At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 µg per kilogram weekly [30 patients] and 800 µg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-µg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-µg dose level) and 4.2 months (in those who had received it at the 800-µg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively. CONCLUSIONS: Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).
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Anticorpos Biespecíficos , Complexo CD3 , Mieloma Múltiplo , Receptores Acoplados a Proteínas G , Linfócitos T , Humanos , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Síndrome da Liberação de Citocina/induzido quimicamente , Síndrome da Liberação de Citocina/etiologia , Disgeusia/induzido quimicamente , Disgeusia/etiologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Complexo CD3/antagonistas & inibidores , Complexo CD3/imunologia , Administração Intravenosa , Injeções Subcutâneas , Dermatopatias/induzido quimicamente , Dermatopatias/etiologiaRESUMO
WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the results of a phase 1 research study (or clinical trial) called MonumenTAL-1 published in the New England Journal of Medicine in December 2022. A phase 1 study is an early clinical trial where researchers evaluate how safe a medicine is at different doses in a small number of people. In the MonumenTAL-1 study, researchers looked at a new medicine under development called talquetamab, for people living with multiple myeloma (a type of blood cancer) who did not respond (refractory), stopped responding (relapsed), or who had difficulty dealing with their previous treatments. HOW WAS THE STUDY CONDUCTED?: The phase 1 MonumenTAL-1 study was performed in 2 parts. Safety was the main focus of Part 1 in which side effects, and how serious they were, were assessed. The results of Part 1 were used to identify doses of talquetamab that were well tolerated, without a need to stop treatment or reduce the doses, for further study in Part 2. Part 2 of the study examined how well talquetamab worked to decrease signs of the cancer and what side effects, and their severity, people experienced at the doses identified in Part 1. WHAT WERE THE RESULTS?: In Part 1 of the study, researchers identified 2 doses of talquetamab for further study: 405 micrograms for every kilogram of body weight (µg/kg) given weekly and 800 µg/kg every other week. All participants experienced at least one side effect of treatment at these 2 doses. Less than half of participants (43% at 405 µg/kg weekly dose and 34% at the 800 µg/kg every other week dose) experienced serious side effects which are those side effects that led to hospitalization, death, or permanent or life-threatening damage). The most common side effects at both doses were a condition known as cytokine release syndrome (CRS); changes in blood cell levels (where different types of cells in the blood were measured); changes in skin such as itching, dry skin, eczema, ulcers or shedding; changes in nails such as discoloration or ridging (lines or dents); and changes in sense of taste such as food tasting sour or metallic. CRS is caused by the overactivation of the immune system (the body's natural defense system) and can result in fever, feeling sick (nausea), being tired (fatigue), low blood pressure, low blood oxygen levels and body aches. Most cases of CRS, as well as most other side effects, were mild or moderate. Most common serious events were CRS, fever and bone pain. Most people had fewer signs of the cancer after taking talquetamab, and the response was similar between the 2 doses. The median duration of response at the 2 identified doses was 8-10 months. WHAT DO THE RESULTS MEAN?: Most of the side effects people experienced when taking talquetamab were mild or moderate. Most people who took talquetamab responded to the treatment even though they hadn't responded or stopped responding to previous multiple myeloma treatments or stopped taking those treatments because they were unable to tolerate them. These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.
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The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.
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Mieloma Múltiplo , Trombofilia , Tromboembolia Venosa , Humanos , Trombina , Mieloma Múltiplo/tratamento farmacológico , Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Trombofilia/diagnóstico , Trombofilia/etiologia , Trombofilia/tratamento farmacológico , Testes de Coagulação SanguíneaRESUMO
Primary sarcomas of the lung represent less than 0.5% of all primary lung tumors and comprise a heterogeneous group of malignancies including synovial sarcoma (SS). Primary pleuropulmonary SS has non-specific presentations, such as chest pain, shortness of breath and cough, and its associated imaging features resemble those of other intrathoracic malignancies. The diagnosis of these tumors needs to be confirmed by cytogenetic and molecular studies. Here, we describe two rare cases of primary pleuropulmonary SS who were admitted to our hospital. We also provide a concise review of clinical, radiological, and histopathological characteristics of pleuropulmonary SS after exploring 168 studies (415 corresponding patients) that were identified through a literature search.
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Neoplasias Pulmonares/patologia , Sarcoma Sinovial/patologia , Adulto , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Prognóstico , Sarcoma Sinovial/diagnóstico por imagem , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/terapia , Adulto JovemRESUMO
A crucial component of the immune system are chemokiness. Chemokine's dysregulation has been linked to a number of pathological diseases. Recently, CXCL17, a chemokine belonging to the CXC subfamily, was identified. With regard to a number of physiological conditions and disorders, CXCL17 either has homeostatic or pathogenic effects. Some research suggests that CXCL17 is an orphan ligand, despite the fact that G protein-coupled receptor (GPR) 35 has been suggested as a possible receptor for CXCL17. Since CXCL17 is primarily secreted by mucosal epithelia, such as those in the digestive and respiratory tracts, under physiological circumstances, this chemokine is referred to as a mucosal chemokine. Macrophages and monocytes are the cells that express GPR35 and hence react to CXCL17. In homeostatic conditions, this chemokine has anti-inflammatory, antibacterial, and chemotactic properties. CXCL17 promotes angiogenesis, metastasis, and cell proliferation in pathologic circumstances like malignancies. However, other studies suggest that CXCL17 may have anti-tumor properties. Additionally, studies have shown that CXCL17 may have a role in conditions such as idiopathic pulmonary fibrosis, multiple sclerosis, asthma, and systemic sclerosis. Additionally, deregulation of CXCL17 in some diseases may serve as a biomarker for diagnosis and prognosis. Clarifying the underlying mechanism of CXCL17's activity in homeostatic and pathological situations may thus increase our understanding of its role and hold promise for the development of novel treatment strategies.
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Quimiocinas CXC , Infecções , Inflamação , Neoplasias , Quimiocinas , Quimiocinas CXC/fisiologia , Humanos , Infecções/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Receptores Acoplados a Proteínas GRESUMO
Since Dec. 2019 the new coronavirus (SARS-CoV-2) has infected millions and claimed life of several hundred thousand worldwide. However, so far no approved vaccine or drug therapy is available for treatment of virus infection. Convalescent plasma has been considered a potential modality for COVID-19 infection. One hundred eighty-nine COVID-19 positive patients including 115 patients in plasma therapy group and 74 patients in control group, registered in the hospitals with confirmed COVID-19 infection, entered this multi-center clinical study. Comparison of outcomes including all-cause mortality, total hospitalization days and patients' need for intubation between the two patient groups shows that total of 98 (98.2 %) of patients who received convalescent plasma were discharged from hospital which is substantially higher compared to 56 (78.7 %) patients in control group. Length of hospitalization days was significantly lower (9.54 days) in convalescent plasma group compared with that of control group (12.88 days). Only 8 patients (7%) in convalescent plasma group required intubation while that was 20 % in control group. This clinical study provides strong evidence to support the efficacy of convalescent plasma therapy in COVID-19 patients and recommends this treatment for management of these patients. Clinical efficacy, immediate availability and potential cost effectiveness could be considered as main advantages of convalescent plasma therapy.
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COVID-19/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Feminino , Humanos , Imunização Passiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Resultado do Tratamento , Adulto Jovem , Soroterapia para COVID-19RESUMO
BACKGROUND: Endometriosis is seen in 0.5%-5% of fertile and 25%-40% of infertile women. To investigate this conflict between gynecologists that ovarian endometriomas should be removed or not before making any decision about pregnancy among infertile women, the authors decided to carry out a systematic review and meta-analysis to compare the effect of various available therapeutic methods and notice the impact of these options on women's pregnancy rate. METHODS: This review is based on PRISMA recommendations with an electronic search using the following databases: PubMed, Scopus, Google scholar, etc, from 2000 to 2018, in the English language. The studies compare pregnancy rate based on four different treatment types of OMAs between infertile women: (surgery + ART, surgery + spontaneous pregnancy, aspiration ± sclerotherapy + ART, and ART alone). MAIN FINDINGS: At least eight prospective studies were included, in which 553 infertile women were compared in terms of treatment methods of OMAs before trying to become pregnant. CONCLUSION: Treatments are usually based on the patient's clinical condition and must be individual, with the purpose of relieving pain, improving fertility, or both. The authors do not have not any significant difference between our four groups of study; however, the success of surgical procedure compared to other methods was higher and the success of ART alone was the least.
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In neuropsychological disorders, the significant abnormalities in the brain connections in some regions are observed. This paper presents a novel model to demonstrate the connections between different regions in children with autism. The proposed model first conducts the wavelet decomposition of electroencephalography signals by wavelet transform then the features are extracted, such as relative energy and entropy. These features are fed to the 3D-cellular neural network model as inputs to indicate the brain connections. The results showed that there are significant differences and abnormalities in the left hemisphere, (p<0.05) at the electrodes AF3, F3, P7, T7 and O1 in alpha band, AF3, F7, T7 and O1 in beta band, T7 and P7 in gamma band for children with autism compared with the control children. Also, the evaluation of the obtained connections values between brain regions indicated that there are more abnormalities in the connectivity of frontal and parietal lobes and the relations of the neighboring regions in all three bands especially in gamma band for autistic children. Evaluation of the analysis demonstrated that alpha frequency band had the best distinction level of 96.6% based on the obtained values of the cellular neural network using support vector machine method.
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Transtorno Autístico/diagnóstico , Transtorno Autístico/fisiopatologia , Encéfalo/fisiopatologia , Diagnóstico por Computador/métodos , Eletroencefalografia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Redes Neurais de Computação , Vias Neurais/fisiopatologia , Máquina de Vetores de Suporte , Análise de OndaletasRESUMO
BACKGROUND: There is evidence suggesting that most thromboembolic complications could be prevented with adequate pharmacological anticoagulation. We estimated the direct health care costs of anticoagulant treatment with oral vitamin K antagonists in patients diagnosed with non-valvular atrial fibrillation. METHODS: This observational study examined the clinical records of patients diagnosed with non-valvular atrial fibrillation who received anticoagulant treatment with oral vitamin K antagonists. Data from clinical records were used in the study: international normalized ratio, number of monitoring visits, type of anticoagulant, hospital admissions from complications, and concomitant medication. Drug cost was calculated based on the official Spanish Ministry of Health price list. Monitoring expenses were included the cost of the medical supplies used in the procedures. Hospitalization costs were calculated using the Diagnosis Related Group price for each case. Hospital visits costs were calculated by one of four different scenarios, using either the invoice rates for the regional health care authority or cost per visit as established by analytical accounting methods. RESULTS: We collected data from 1,257 patients diagnosed with non-valvular atrial fibrillation who were receiving oral anticoagulant therapy. Depending on the scheme used, the direct health care costs for these patients ranged from 423,695 - 1,436,038 per annum. The average cost per patient varied between 392 - 1,341, depending on the approach used. Patients with international normalized ratio values within the therapeutic range on 25% of their visits represented an average cost between 441.70 - 1,592. Those within the therapeutic range on 25%-50% of visits had associated costs of 512.37 - 1,703.91. When international normalized ratio values were within the therapeutic range on 50% - 75% of the visits, the costs ranged between 400.80- 1,375.74. The average cost was 305.23 - 1,049.84 when the values were within the therapeutic range for over 75% of visits. CONCLUSIONS: Most direct health care costs associated with the sampled patients arise from the specialist-care monitoring required for the treatment. Good monitoring is inversely related to direct health care costs.
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Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Custos de Cuidados de Saúde/estatística & dados numéricos , Vitamina K/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/economia , Fibrilação Atrial/complicações , Custos de Medicamentos/estatística & dados numéricos , Feminino , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha , Adulto JovemRESUMO
Lipofibroadenoma (LFA) is an epithelial tumor. It has been seen rarely in the thymus, and only a handful of cases have been reported. LFA is usually seen in the anterior mediastinum and is defined as a coalescence of epithelial thymic, adipose, and fibrotic tissue. We present a 30-year-old female who presented due to an unrelated traffic accident. An incidental mass was found in her left anterior superior mediastinum. After performing a complete excision, a histologic examination of the excised mass revealed it to be LFA of the thymus, which is extremely rare. The follow-up period was uneventful. LFA is a slow-growing benign tumor and is very similar to fibroadenoma of the breast. The etiology and clinical findings are yet to be well-defined. It was only seen in men in the prior cases. But recent cases, including this one, have also reported female patients. The tumor is mainly observed in the anterior mediastinum, which was also the case in our patient. The gold standard of diagnosis is pathologic examination. Our examination showed strands and nests of thymic parenchyma, including Hassall corpuscles, which separated fibro adipose tissue. Thymectomy is the treatment of choice. It can be performed by either video-assisted thoracic surgery or open surgery. We performed open surgery. The most important prognostic factor for this tumor is staging.
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Mucoid impaction of the bronchi (MIB) is a specific form of proximal bronchiectasis characterized by obstruction and dilation of bronchi usually presented with thick mucoid plug. MIB mostly occurs as the manifestation of a hypersensitivity state in patients with bronchial asthma or in association with allergic bronchopulmonary aspergillosis (ABPA) and clinical overlap between MIB and ABPA can occur. MIB with no history of allergic background is not common and is less reported in the literature. In the following report we discuss a 39-year-old man with no previous history of allergy and atopy who initially presented with fever and shortness of breath. Further assessments demonstrated that the patient had a chronic endobronchial lesion and consolidation of the left lower lobe of the lung. A tissue biopsy reveals no malignant cells. Despite antibiotic therapy, the patient's symptoms persisted, and lobectomy was performed due to no clinical improvement. Even though gross pathology suggested endoluminal impaction, the patient didn't meet the ABPA diagnostic criteria.
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The COVID-19 pandemic has caused significant disruptions in TB services across the globe. Like many other countries, TB case notifications decreased during the pandemic in Iran. In this paper, we describe two cases of concomitant COVID-19 and TB infection whose diagnosis of pulmonary TB was delayed amid the pandemic. We depict how atypical imaging findings may guide physicians to pulmonary TB diagnosis and discuss strategies to maximize TB case detection.
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BACKGROUND: On March 14, 2020, a state of alarm was declared in Spain due to the spread of SARS-CoV-2. Beyond this date, COVID-19 in the country changed the practice of oncologic care. OBJECTIVE: Since recurrent hospital visits were a potential risk factor for contagion, the aim of this prospective observational study was to analyze the consequences of the COVID-19 pandemic in the health care of patients with lymphoma. METHODS: All data were obtained from the electronic medical record. Variables such as age, sex, reason of the visit, use of the patient portal, changes in management, enrollment in clinical trials, and COVID-19 infection were recorded. RESULTS: In all, 290 patients visited the lymphoma clinic, totaling 437 appointments. The median age was 66 (range 18-94) years, and 157 (54.1%) patients were male. Of them, 214 (73.8%) patients had only 1 visit to the clinic. Only 23 (7.9%) patients did not have access to the patient portal. Amid the COVID-19 pandemic, 78 (26.9%) patients remained in active treatment, 35 (12.1%) experienced delays in their treatments, and 6 (2.1%) experienced treatment discontinuation. During the follow-up, only 7 (2.4%) patients had a COVID-19 infection (6 cases with confirmed polymerase chain reaction test and 1 case with clinical suspicion). Despite the implementation of telemedicine strategies to avoid visits to the hospital, 66 (22.8%) patients had in-person visits at the lymphoma clinic. Patients who attended in-person consultations were younger than those who preferred telemedicine consultations (62 vs 66 years; P=.10) and had less use of the patient portal (17/224, 7.6% vs 6/66, 9%; P=.10), although these differences did not reach statistical significance. Patients who attended in-person visits were more likely to have had only 1 visit to the hospital (29/66, 43.9% vs 185/224, 82.6%; P<.001). Regarding the reason of in-person consultations, more patients were on active treatment in comparison to those using telemedicine resources (37/66, 56.1% vs 42/224, 18.3%; P<.001). Patients with a preference for telemedicine strategies had more surveillance visits (147/224, 65.6% vs 24/66, 36.4%; P<.001). Regarding treatment modifications, more treatment delays (29/224, 12.9% vs 6/66, 9.1%; P=.10) and more definite treatment discontinuations (6/224, 2.7% vs 0/66, 0%; P=.10) were seen in patients using telemedicine resources when compared to patients attending in-person visits, although these differences did not reach statistical significance. Regarding the type of therapy, patients attending in-person visits were more likely to receive an intravenous treatment rather than those using telemedicine (23/66, 62.2% vs 17/224, 40.5%; P<.001). CONCLUSIONS: Telemedicine such as patient portals are feasible strategies in the management of patients with lymphoma during the COVID-19 pandemic, with a reduction of in-person visits to the hospital and a very low contagion rate.
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PURPOSE: A study analyzing the application of a protocol of comprehensive geriatric assessment (CGA) in older patients with lymphoma was carried out to allow frailty-based patient classification and individualized treatment. METHODS: Lymphoma patients older than 70 years referred to the Geriatric Clinic at a tertiary hospital between May 2016 and March 2021 were included. The assessment protocol included comorbidity, polypharmacy, nutritional, functional, and mental status, geriatric syndromes, and life expectancy. CGA enabled patient classification into four groups (Type I to Type IV) based on frailty assessment instrument scoring and clinical, functional, and mental status. Variables were compared using parametric and non-parametric statistical tests and Kaplan-Meier survival curves. RESULTS: Ninety-three patients (55.9% women) were included. Median age was 81.1 years (± 5.7). 23 patients (24.7%) were classified as robust (type I), 30 (32.3%) as pre-frail (type II) with potentially reversable deficits, 38 (40.9%) as frail (type III), and 2 (2.2%) as requiring palliative care (type IV). Patients received oncospecific treatment with modifications carried out in 64.5% of cases based on CGA results. Differences in overall survival (p = 0.002), response to treatment (p < 0.001) and likelihood of increased frailty (p = 0.024) were observed, with type III-IV patients showing significantly worse outcomes. CONCLUSION: Performance of standardized, systematic CGA by geriatricians permits older lymphoma patients to be classified according to frailty, with significant differences in terms of clinical outcomes across groups. We propose incorporating CGA performed by geriatricians as part of the multidisciplinary care team to optimize therapeutic strategy for these patients.
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Fragilidade , Linfoma , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Comorbidade , Linfoma/terapia , Atividades Cotidianas , Avaliação Geriátrica/métodosRESUMO
Waldenström macroglobulinemia (WM) is a slowly progressive hematologic malignancy that usually responds rapidly to treatment. Being a lymphoplasmacytoid neoplasm, it is associated with a monoclonal IgM component, which may be associated with multiple manifestations and symptoms. We report the case of a 77-year-old woman diagnosed with WM following the development of severe and sudden pancytopenia associated with a cold agglutinin syndrome. In order to treat the WM and the underlying hemolysis, treatment with rituximab, corticosteroids and cyclophosphamide was started. Despite the improvement in hemolysis parameters, pancytopenia persisted, and we started a second line with ibrutinib. During treatment the patient developed an uncommon invasive fungal infection (IFI) with bone marrow granulomatosis and myelofibrosis. This case shows an unusual clinical course with a poor hematopoietic response to treatment and a large number of intercurrent complications.
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To provide insight into the subclonal architecture and co-dependency patterns of the alterations in Waldenström's macroglobulinemia (WM), we performed single-cell mutational and protein profiling of eight patients. A custom panel was designed to screen for mutations and copy number alterations at the single-cell level in samples taken from patients at diagnosis (n=5) or at disease progression (n=3). Results showed that in asymptomatic WM at diagnosis, MYD88L265P was the predominant clonal alteration; other events, if present, were secondary and subclonal to MYD88L265P. In symptomatic WM, clonal diversity was more evident, uncovering combinations of alterations that synergized to promote clonal expansion and dominance. At disease progression, a dominant clone was observed, sometimes accompanied by other less complex minor clones, which could be consistent with a clonal selection process. Clonal diversity was also reduced, probably due to the effect of treatment. Finally, we combined protein expression with mutational analysis to map somatic genotype with the immunophenotype. Our findings provide a comprehensive view of the clonality of tumor populations in WM and how clonal complexity can evolve and impact disease progression.
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Evolução Clonal , Variações do Número de Cópias de DNA , Mutação , Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Humanos , Análise de Célula Única , Análise Serial de Proteínas , Fator 88 de Diferenciação Mieloide/genética , Análise Mutacional de DNARESUMO
Belantamab-mafodotin (belamaf) is a novel antibody-drug conjugate targeting B-cell maturation antigen that showed anti-myeloma activity in patients with relapsed and refractory multiple myeloma (RRMM). We performed an observational, retrospective, and multicenter study aimed to assess the efficacy and safety of single-agent belamaf in 156 Spanish patients with RRMM. The median number of prior therapy lines was 5 (range, 1-10), and 88% of patients were triple-class refractory. Median follow-up was 10.9 months (range, 1-28.6). The overall response rate was 41.8% (≥CR 13.5%, VGPR 9%, PR 17.3%, MR 2%). The median progression-free survival was 3.61 months (95% CI, 2.1-5.1) and 14.47 months (95% CI, 7.91-21.04) in patients achieving at least MR (p < 0.001). Median overall survival in the entire cohort and in patients with MR or better was 11.05 months (95% CI, 8.7-13.3) and 23.35 (NA-NA) months, respectively (p < 0.001). Corneal events (87.9%; grade ≥ 3, 33.7%) were the most commonly adverse events, while thrombocytopenia and infections occurred in 15.4% and 15% of patients, respectively. Two (1.3%) patients discontinued treatment permanently due to ocular toxicity. Belamaf showed a noticeably anti-myeloma activity in this real-life series of patients, particularly among those achieving MR or better. The safety profile was manageable and consistent with prior studies.
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INTRODUCTION: Belantamab mafodotin (BM) is a new anti-BCMA antibody-drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP). METHODS: We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Thirty-three patients were included with a median of 70 years of age (range, 46-79 years). Median time from diagnosis was 71 months (range, 10-858 months). Median prior lines was 5 (range, 3-8 lines); 90% of patients were triple-/quad-/penta-refractory; 48% showed high-risk cytogenetics. Median BM doses was 3 (range 1-16 doses), with a median follow-up of 11 months (6-15 months). ORR was 42.2% (≥ VGPR, 18.2%). Median PFS was 3 months (95% CI 0.92-5.08) in the overall population, and 11 months (HR 0.26; 95% CI 0.10-0.68) for patients who achieved ≥ PR. PFS was not significantly different according to age, cytogenetic risk, and prior therapy lines. OS was 424 days (95% CI 107-740). Non-hematological TEAEs (57.6% of patients; 30.3% ≥ G3) included keratopathy (51.5%; 21.2% ≥ G3) and patient-reported vision-related symptoms (45.5%). Keratopathy was resolved in 70.6% of patients. G3 hematological TEAEs was 18.2%, thrombocytopenia (21.2%). Dose reductions due to TEAEs: 30.3%; delays: 36.4%. Treatment discontinuation causes: progression (54.5%), toxicity (non-ocular; 6%/ocular; 6% /ocular + non-ocular toxicity; 3%), death (6%), and patient's decision (3%). CONCLUSIONS: BM showed relevant anti-myeloma activity in RRMM with a manageable safety profile. These results corroborate those observed in the BM pivotal trial.
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Primary pulmonary lymphoma (PPL) is a rare entity with the most common presentation as mediastinal lymphadenopathy. The most common form of PPL is Mucosa-Associated Lymphoid Tissue Lymphoma (MALToma) which is an extranodal B-cell lymphoma originating from the mucosal layers involving different organs such as the gastrointestinal tract as well as the lung. Herein, we present a case of a 51-year-old woman with progressive dyspnea for 6 months and no prior medical history. The computed tomography (CT scan) revealed bilateral multifocal consolidation and ground-glass opacities as well as interlobular septal thickening. Bronchoscopy was normal and CT-guided biopsy of lung consolidations was conclusive of MALToma. Complete extrapulmonary evaluations inducing bone marrow aspiration were unremarkable. The primary pulmonary MALToma is an extremely rare entity that presents with non-specific symptoms and a wide variety of CT findings such as mediastinal, hilar lymphadenopathy, and single or multiple lung nodules ranging from 2 to 8 cm. the disease has a favorable prognosis, so prompt diagnosis is essential.
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Neutrophil extracellular trap (NETosis), the web-like structures induced by neutrophil death, is an important inflammatory mechanism of the immune system leading to reactive oxygen species production/coagulopathy, endothelial dysfunction, atherosclerosis, and ischemia. NETosis exerts its role through different mechanisms such as triggering Toll-like receptors, inflammatory cytokines, platelet aggregation, neutrophil activation/infiltration, and vascular impairment. NETosis plays a key role in the prognosis of coronary artery disease, ischemic injury of kidney, lung, gastrointestinal tract and skeletal muscles. In this review, we explored the molecular mechanisms involved in NETosis, and ischemic/reperfusion injuries in body organs.