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BACKGROUND: Multiple myeloma (MM) is the second most common hematological malignancy with its prevalence increasing. Patients with symptomatic MM can show numerous comorbidities, affecting their quality of life (QoL). Physical activity (PA) may improve QoL but is not a standardized intervention of comprehensive cancer centers (CCCs). Since data on the PA of patients with MM are scarce, we aimed to prospectively assess fitness levels and patients' motivation to join PA-interventions at our CCC. METHODS: We generated an exercise questionnaire to interview consecutive patients MM. We prospectively collected data on (a) past and current PA, defined by the World Health Organization (WHO) recommendations, (b) knowledge on exercise effects, (c) exercise motivation, and (d) willingness to participate in PA-interventions. Demographics, comorbidities, response, progression-free survival (PFS), and overall survival (OS) were assessed in 211 symptomatic patients MM. RESULTS: While our patients were elderly and most showed bone involvement, their PA was similar to healthy individuals. Aerobic PA (≥â 60 minutes/week) was performed by 65%, and 25% exercisedâ ≥â 150 minutes/week. WHO PA recommendations were fulfilled by 17% of patients. No sport activities or complete physical inactivity were observed in 35% and 16%, respectively. Notably, 38% were motivated to join MM-specific sport interventions. Self-reported knowledge of PA-induced benefits for patients cancer was high (82%), but only 27% knew which exercises were safe to perform. CONCLUSION: This study provides an overview of the PA of patients MM. Our results suggest that the PA of patients MM might not be much lower than in the age-matched general population.
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The established standard to ensure state-of-the-art cancer treatment is through multidisciplinary tumor boards (TBs), although resource- and time-intensive. In this validation study, the multiple myeloma (MM)-TB was reexamined, aiming to validate our previous (2012-2014) results, now using the TB data from March 2020 to February 2021. We assessed MM-TB protocols, physicians' documentation, patient, disease, remission status, progression-free survival (PFS), and overall survival (OS) as left-truncated survival times. Moreover, TB-adherence, level of evidence according to grade criteria, time requirements, study inclusion rates, and referral satisfaction were determined. Within a 1-year period, 312 discussed patients were documented in 439 TB protocols. Patient and disease characteristics were typical for comprehensive cancer centers. The percentages of patients discussed at initial diagnosis (ID), with disease recurrence or in need of interdisciplinary advice, were 39%, 28%, and 33%, respectively. Reasons for the MM-TB presentation were therapeutic challenges in 80% or staging/ID-defining questions in 20%. The numbers of presentations were mostly one in 73%, two in 20%, and three or more in 7%. The TB adherence rate was 93%. Reasons for non-adherence were related to patients' decisions or challenging inclusion criteria for clinical trials. Additionally, we demonstrate that with the initiation of TBs, that the number of interdisciplinarily discussed patients increased, that TB-questions involve advice on the best treatment, and that levels of compliance and evidence can be as high as ≥ 90%. Advantages of TBs are that they may also improve patients', referrers', and physicians' satisfaction, inclusion into clinical trials, and advance interdisciplinary projects, thereby encouraging cancer specialists to engage in them.
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Mieloma Múltiplo , Recidiva Local de Neoplasia , HumanosRESUMO
PURPOSE OF REVIEW: Multiple myeloma is a disease of elderly adults. Improvement in survival has occurred because of biological insights and novel agents. Therapeutic options involve choices today, thus have become more complex. Demographics have led to an increased number of elderly patients and age may be associated with a poorer outcome but is not the only prognostic predictor today. RECENT FINDINGS: To evaluate patients' health status rather than their chronological age alone, frailty scores and functional geriatric assessments are used to identify prognostic groups, avoid adverse events, compare clinical trials and tailor treatment. As most clinical trials exclude frail elderly patients, those enrolled therein are often younger and healthier than the typical multiple myeloma patient. This represents a challenge for frail cohorts because of their increased risk of adverse events, overtreatment and undertreatment and/or therapy discontinuation, which may lead to poorer survival and quality of life (QoL). Reassessing patients' status via geriatric assessments is also relevant during treatment to adjust interventions appropriately. SUMMARY: Integrating geriatric assessments may lead to individual treatment decisions, dose adjustments, better clinical outcome and QoL. Prospective clinical trials that enroll elderly multiple myeloma patients with comorbidities, incorporate frailty scores/geriatric assessments and help with prognostication, adverse event avoidance and QoL maintenance, remain warranted.
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Avaliação Geriátrica , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Idoso , Idoso de 80 Anos ou mais , Fragilidade/diagnóstico , Humanos , Medicina de Precisão , Prognóstico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Despite significantly improved survival and response rates in patients diagnosed with multiple myeloma, it still remains an incurable disease with a poor outcome, especially in high-risk groups. Allogeneic stem cell transplantation offers a potentially curative option but remains controversial due to considerable treatment-related toxicity. We analyzed 109 consecutive myeloma patients who had received reduced-intensity conditioning allogeneic transplantation at the Freiburg University Medical Center between 2000 and 2016. Although most patients were heavily pre-treated in high-risk constellations, the overall response rate was high with 70%, the median overall survival (OS) 39.2%, and the median progression-free survival (PFS) 14.2 months, with a median follow up of 71.5 months. Survival was significantly better in patients with response to previous therapies than in those with progressive disease (median OS 65 vs. 11.5 months, P=0.003; median PFS 18.4 vs. 5.1 months, P=0.001). Moreover, survival of patients transplanted in first-line was significantly prolonged compared to relapsed/refractory disease (median OS not reached vs. 21.6 months, P<0.001; median PFS 47.7 vs. 9.6 months, P<0.001). The non-relapse mortality was relatively low with a cumulative incidence of 12.4% at ten years. Acute graft-versus-host disease (GvHD) grade II-IV was observed in 25%, and moderate or severe chronic GvHD in 24%. Quality of life (QoL) assessed with the revised Myeloma Comorbidity Index before and after transplantation remained unchanged. Our data suggest that allogeneic transplantation in the context of novel immunotherapeutic approaches may enable long-term survival and even a potential cure in a carefully selected subgroup of high-risk multiple myeloma patients with acceptable toxicity and preserved QoL.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Qualidade de Vida , Adulto , Idoso , Terapia Combinada , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Seleção de Pacientes , Recidiva , Retratamento , Estudos Retrospectivos , Transplante Homólogo , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is the second most common hematologic malignancy and represents approximately 10% of all hematological neoplasms. Standard therapy consists of induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) or, if ASCT cannot be performed, standard doublet, triplet, or quadruplet, novel agent-containing induction treatment until progression. Although MM is still regarded as mostly incurable by current standards, the development of several novel compounds, combination therapies, and immunotherapy approaches has raised great hopes about transforming MM into an indolent, chronic disease and possibly achieving a cure for individual patients. Several new inhibitory and immunological agents have been approved or are under intensive investigation and may lead to new therapeutic options for patients with relapsed/refractory MM, for patients ineligible for ASCT, and for patients after ASCT. Especially in the field of immunotherapy, including monoclonal antibodies, checkpoint inhibition, and chimeric antigen receptor T cells, current advances are rapid and highly promising. This review aims to summarize the newest and most promising immunotherapeutic agents for MM, their clinical efficacy, their adverse event (AE) profiles, and the ways in which these AEs can best be overcome or avoided. Cancer 2018;124:2075-85. © 2018 American Cancer Society.
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Antineoplásicos Imunológicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia/métodos , Mieloma Múltiplo/terapia , Linfócitos T/transplante , Antineoplásicos Imunológicos/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoterapia/efeitos adversos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão/métodos , Linfócitos T/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
This open-label, multicentre phase I/II study determined the maximum tolerated dose (MTD), safety and efficacy of clofarabine administered with cytarabine and idarubicin in newly diagnosed acute myeloid leukaemia (AML) patients lacking favourable genetic aberrations. The MTD was 30 mg/m2 clofarabine for patients below and above 60 years. The most frequently reported grade 3-4 non-haematological adverse events were infectious and gastrointestinal toxicities. Complete remission (CR)/CR with incomplete recovery rate was 67%. Allogeneic haematopoietic cell transplantation in first remission was feasible in a high proportion of younger AML patients and probably contributed to the favourable outcome compared to historical controls.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Clofarabina/administração & dosagem , Clofarabina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Quimioterapia de Indução/métodos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
OBJECTIVE: The heavy/light chain (HLC)-immunoassay quantifies light chain types of each immunoglobulin class in patients with monoclonal gammopathies. METHODS: We assessed 147 consecutive patients with different forms and stages of plasma cell dyscrasias (PCD) who received standard tests (serum and urine protein electrophoresis [SPEP, UPEP], immunofixation [IFE], serum-free light chain [SFLC]), and HLC-immunoassay. Patients with multiple myeloma (MM, n = 102), smoldering MM (SMM, n = 5), monoclonal gammopathy of undetermined significance (MGUS, n = 28), and Waldenström's macroglobulinemia (WM, n = 12) were included. RESULTS: We verified a significant correlation between HLC- and standard monoclonal protein (mp)-parameters, and HLC-increases with higher disease stage and unfavorable remission status. In patients with difficult to quantify mp, more abnormal HLC- than SPEP-, immunoglobulin-, or SFLC-results were found. In WM, a pathological HLC κ/λ-ratio and M-component were observed in 95% and 58%, respectively. In 21/28 MGUS and 5/5 SMM patients, HLC κ/λ-ratios were abnormal. Testing different HLC cutoffs, patients with extreme HLC values showed impaired progression-free survival (PFS). CONCLUSIONS: Despite the fact that different PCD patients were included, the assessment of the HLC-immunoassay in MGUS, SMM, MM, and WM, our comparison with standard mp-assays, and relevant PFS differences may excite future applications, which should be confirmed in prospective multicenter trials.
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Imunoensaio , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paraproteinemias/mortalidade , Paraproteínas , Sensibilidade e Especificidade , Avaliação de SintomasRESUMO
We describe the development of acute myeloid leukemia (AML) in an adult with CBL syndrome caused by a heterozygous de novo germline mutation in CBL codon D390. In the AML bone marrow, the mutated CBL allele was homozygous after copy number-neutral loss-of-heterozygosity and amplified through a chromosomal gain; moreover, an inv(16)(p13q22) and, as assessed by whole-exome sequencing, 12 gene mutations (eg, in CAND1, NID2, PTPRT, DOCK6) were additionally acquired. During complete remission of the AML, in the presence of normal blood counts, the hematopoiesis stably maintained the homozygous CBL mutation, which is reminiscent of the situation in children with CBL syndrome and transient juvenile myelomonocytic leukemia. No additional mutations were identified by whole-exome sequencing in granulocytes during complete remission. The study highlights the development of AML in an adult with CBL syndrome and, more generally, in genetically aberrant but clinically inconspicuous hematopoiesis.
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Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Amplificação de Genes , Mutação em Linhagem Germinativa , Doenças Hematológicas/complicações , Doenças Hematológicas/genética , Hematopoese/genética , Homozigoto , Humanos , Leucemia Mieloide Aguda/etiologia , Perda de Heterozigosidade , Masculino , Esferocitose Hereditária/complicações , Esferocitose Hereditária/genética , SíndromeRESUMO
AIM: The current work aimed to investigate the clinical benefit of radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC) developing acquired resistance to immune checkpoint inhibitors. METHOD: We report on a pooled, two-institution, phase II single-arm prospective cohort study. The study included patients with stage IV NSCLC who showed progression of one or more measurable lesions under anti-PD-(L)1 inhibition alone, after initially having achieved at least stable disease. Hypofractionated radiotherapy (hRT) of one to four metastases was performed, while one or more lesions were kept untreated. Following hRT, treatment with immune checkpoint inhibitors was continued unchanged until further evidence of tumor progression or unacceptable toxicity. Primary endpoint of the pooled analysis was progression-free survival (PFS), secondary endpoints included overall survival (OS) and toxicity. RESULTS: A total of 48 patients were enrolled: mean age was 67.1 ± 9.3 years, 50 % were male and 72.9 % were PD-L1 positive. Immunotherapy was in 95.8 % of patients the first or second line therapy at time of enrollment. hRT was performed to one (93.8 % of cases) or more lesions (median total dose: 27.5 Gy, median 6.5 Gy/fraction). Forty-five patients (93.8 %) were able to continue immunotherapy for a median of 6.2 months following hRT. Median PFS was 4.4 months, with 62.5 % disease control at three months and 37.5 % at six months. Median OS was 14.9 months. Severe adverse events (grade ≥ 2) were reported in 12 cases (25 %), of which none were radiotherapy-related and four were immunotherapy-related. Salvage therapy consisted of chemotherapy (48.8 %) or repeated irradiation (21.9 %). No further tumor treatment was performed in 29.3 % of patients. CONCLUSIONS: The current pooled analysis is a prospective evaluation of the role of radiation therapy for metastatic NSCLC in the setting of newly acquired immunotherapy resistance. Hypofractionated radiotherapy can support the outcome of immune checkpoint inhibitors and thus allow continuation of treatment for a relevant amount of time despite initial tumor progression.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Prospectivos , Imunoterapia/efeitos adversos , Antígeno B7-H1/metabolismo , Ensaios Clínicos Fase II como AssuntoRESUMO
There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.
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Apetite , Neoplasias , Humanos , Caquexia/terapia , Caquexia/tratamento farmacológico , Ingestão de Alimentos , Neoplasias/complicações , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Ensaios Clínicos como AssuntoRESUMO
Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.
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Composição Corporal , Peso Corporal , Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Caquexia/terapia , Neoplasias/complicações , Ensaios Clínicos como AssuntoRESUMO
The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990-2023). Seven thousand four hundred thirty-five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full-text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty-four (48%) were double-blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty-nine trials (78%) included multiple cancer types. Twenty-seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4-96). The most frequent QOL measure was the EORTC QLQ-C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well-validated QOL measures, including cachexia-specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co-primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific-based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.
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Caquexia , Neoplasias , Qualidade de Vida , Humanos , Caquexia/etiologia , Caquexia/terapia , Neoplasias/complicações , Neoplasias/psicologia , Ensaios Clínicos como Assunto , Medidas de Resultados Relatados pelo PacienteRESUMO
Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.
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COVID-19 , Neoplasias Hematológicas , Linfoma de Células B , Mieloma Múltiplo , Humanos , Vacinas contra COVID-19 , Vacina BNT162 , COVID-19/prevenção & controle , SARS-CoV-2 , Linfócitos T , Anticorpos Neutralizantes , VacinaçãoAssuntos
Abatacepte/uso terapêutico , Antígeno CTLA-4/metabolismo , Citocinas/metabolismo , Hemodiafiltração/métodos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Animais , Antígeno CTLA-4/genética , Febre , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , LinhagemRESUMO
To sustain genomic stability by correct DNA replication and mitosis, cell cycle progression is tightly controlled by the cyclic activity of cyclin-dependent kinases, their binding to cyclins in the respective phase and the regulation of cyclin levels by ubiquitin-dependent proteolysis. The spindle assembly checkpoint plays an important role at the metaphase-anaphase transition to ensure a correct separation of sister chromatids before cytokinesis and to initiate mitotic exit, as an incorrect chromosome distribution may lead to genetically unstable cells and tumorigenesis. The ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C) is essential for these processes by mediating the proteasomal destruction of cyclins and other important cell cycle regulators. To this end, it interacts with the two regulatory subunits Cdh1 and Cdc20. Both play a role in tumorigenesis with Cdh1 being a tumor suppressor and Cdc20 an oncogene. In this review, we summarize the current knowledge about the APC/C-regulators Cdh1 and Cdc20 in tumorigenesis and potential targeted therapeutic approaches.
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Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1-2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL-1 , respectively). Four patients (19%) remained ctDNA-positive at 1-2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.
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Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches.