RESUMO
BACKGROUND: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. METHODS: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% conï¬dence intervals were also calculated along with 2-year probabilities. RESULTS: The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. CONCLUSIONS: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Transplante de Células-Tronco de Sangue Periférico , Terapia de Salvação , Humanos , Terapia de Salvação/métodos , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Masculino , Adulto , Neoplasias do Mediastino/terapia , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/patologia , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Indiana , Transplante de Células-Tronco de Sangue Periférico/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Feminino , Neoplasias Testiculares/terapia , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).
Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fosfato de Sitagliptina/uso terapêutico , Adulto , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Sirolimo/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos , Análise de Sobrevida , Tacrolimo/uso terapêutico , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: High-dose chemotherapy (HDCT) plus peripheral blood stem cell transplantation (PBSCT) is effective salvage therapy for relapsed metastatic germ cell tumors (GCTs) but has potential toxicity. Historically, an age of ≥40 years has been associated with greater toxicity and worse outcomes. METHODS: This is a retrospective analysis of 445 consecutive patients with relapsed GCT treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen. Kaplan-Meier methods and log-rank tests were used for progression-free survival (PFS) and overall survival (OS) analysis. RESULTS: A total of 329 patients were <40 years of age, whereas 116 patients were ≥40 years of age; HDCT was used as second-line therapy in 85% and 79%, respectively. Median follow-up time was 42.5 months (range, 0.3-173.4 months). Grade ≥3 toxicities were similar between either group, except for greater pulmonary (P = .02) and renal toxicity (P = .01) in the ≥40-years-of-age group. Treatment-related mortality was similar between both age groups: 10 patients (3%) in the <40-years-of-age group and 4 patients (3.5%) in ≥40-years-of-age group died from complications of HDCT. Two-year PFS for <40 years of age versus ≥40 years of age was 58.7% versus 59.6% (P = .76) and 2-year OS was 63.9% versus 61.5% (P = .93). Factors predicting worse PFS included Eastern Cooperative Oncology Group performance status ≥1, platinum refractory disease, nonseminoma histology, and not completing 2 cycles of HDCT. Age was not an independent predictor of worse outcomes. CONCLUSIONS: HDCT plus PBSCT is effective salvage therapy in patients ≥40 years of age with relapsed metastatic GCT. Patients ≥40 years of age experience similar rates of toxicity and treatment-related mortality as those <40 years of age.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Transplante de Células-Tronco de Sangue Periférico , Neoplasias Testiculares , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Etoposídeo , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/etiologia , Estudos Retrospectivos , Terapia de Salvação , Transplante de Células-Tronco , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/etiologiaRESUMO
A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P = .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.
Assuntos
Biomarcadores Tumorais/sangue , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Aloenxertos , Área Sob a Curva , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Curva ROC , Sensibilidade e Especificidade , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. PATIENTS AND METHODS: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. RESULTS: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. CONCLUSIONS: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobreviventes de Câncer , Hipogonadismo/epidemiologia , Hipogonadismo/etiologia , Neoplasias Testiculares/complicações , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Variação Genética , Humanos , Hipogonadismo/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Avaliação de Resultados da Assistência ao Paciente , Medidas de Resultados Relatados pelo Paciente , Fatores de Risco , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/mortalidade , Adulto JovemRESUMO
Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Leucemia Mieloide Aguda , Microambiente Tumoral , Animais , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Purpose The purpose of this paper is to study the effect of the implementation of Lean bundles on hospital performance in private hospitals in Jordan and evaluate how much the size of organization can affect the relationship between Lean bundles implementation and hospital performance. Design/methodology/approach The research is considered as quantitative method (descriptive and hypothesis testing). Three statistical techniques were adopted to analyse the data. Structural equation modeling techniques and multi-group analysis were used to examine the research's hypothesis, and to perform the required statistical analysis of the data from the survey. Reliability analysis and confirmatory factor analysis were used to test the construct validity, reliability and measurement loadings that were performed. Findings Lean bundles have been identified as an effective approach that can dramatically improve the organizational performance of private hospitals in Jordan. Main Lean bundles - just in time, human resource management, and total quality management are applicable to large, small and medium hospitals without significant differences in advantages that depend on size. Originality/value According to the researchers' best knowledge, this is the first research that studies the impact of Lean bundles implementation in healthcare sector in Jordan. This research also makes a significant contribution for decision makers in healthcare to increase their awareness of Lean bundles.
Assuntos
Eficiência Organizacional , Hospitais/normas , Garantia da Qualidade dos Cuidados de Saúde , Gestão da Qualidade Total/métodos , Grupos Focais , Humanos , Melhoria de Qualidade/organização & administraçãoRESUMO
Despite the fact that colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world, the development of improved and robust biomarkers to enable screening, surveillance, and therapy monitoring of CRC continues to be evasive. In particular, patients with colon polyps are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients suffer from poor performance. In consideration of the challenges involved in identifying metabolite biomarkers in individuals with high risk for colon cancer, we have investigated NMR-based metabolite profiling in combination with numerous demographic parameters to investigate the ability of serum metabolites to differentiate polyp patients from healthy subjects. We also investigated the effect of disease risk on different groups of biologically related metabolites. A powerful statistical approach, seemingly unrelated regression (SUR), was used to model the correlated levels of metabolites in the same biological group. The metabolites were found to be significantly affected by demographic covariates such as gender, BMI, BMI(2), and smoking status. After accounting for the effects of the confounding factors, we then investigated potential of metabolites from serum to differentiate patients with polyps and age matched healthy controls. Our results showed that while only valine was slightly associated, individually, with polyp patients, a number of biologically related groups of metabolites were significantly associated with polyps. These results may explain some of the challenges and promise a novel avenue for future metabolite profiling methodologies.
Assuntos
Pólipos do Colo/metabolismo , Doenças Retais/metabolismo , Estudos de Casos e Controles , Pólipos do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retais/patologiaRESUMO
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and a major cause of human morbidity and mortality. In addition to early detection, close monitoring of disease progression in CRC can be critical for patient prognosis and treatment decisions. Efforts have been made to develop new methods for improved early detection and patient monitoring; however, research focused on CRC surveillance for treatment response and disease recurrence using metabolomics has yet to be reported. In this proof of concept study, we applied a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) metabolic profiling approach focused on sequential metabolite ratio analysis of serial serum samples to monitor disease progression from 20 CRC patients. The use of serial samples reduces patient to patient metabolic variability. A partial least squares-discriminant analysis (PLS-DA) model using a panel of five metabolites (succinate, N2, N2-dimethylguanosine, adenine, citraconic acid, and 1-methylguanosine) was established, and excellent model performance (sensitivity = 0.83, specificity = 0.94, area under the receiver operator characteristic curve (AUROC) = 0.91 was obtained, which is superior to the traditional CRC monitoring marker carcinoembryonic antigen (sensitivity = 0.75, specificity = 0.76, AUROC = 0.80). Monte Carlo cross validation was applied, and the robustness of our model was clearly observed by the separation of true classification models from the random permutation models. Our results suggest the potential utility of metabolic profiling for CRC disease monitoring.
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Colo/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Metaboloma , Metabolômica/métodos , Reto/patologia , Espectrometria de Massas em Tandem/métodos , Colo/metabolismo , Neoplasias Colorretais/diagnóstico , Progressão da Doença , Humanos , Reto/metabolismoRESUMO
Relapsed testicular germ cell tumours (GCTs) might be cured with salvage chemotherapy. Accepted salvage treatment is conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT). HDCT with peripheral blood stem cell transplant might produce a higher number of durable responses than CDCT. We discuss studies reporting on outcomes of salvage HDCT in relapsed GCTs. The most reproducible results were achieved with HDCT with two cycles of etoposide and carboplatin or three cycles of the paclitaxel, ifosfamide, carboplatin and etoposide regime. Using these two regimens, sustained cure rates of 50-66% were reported in phase I, phase II and retrospective studies published in the past two decades. Cure rates in patients with cisplatin-resistant disease are between 30% and 45%. Two phase III randomized studies were conducted with certain limitations and were unsuccessful in showing a survival benefit of HDCT. Thus, salvage treatment remains a controversial topic. Salvage HDCT with peripheral blood stem cell transplant and CDCT are two recommended treatment options for relapsed GCTs. Consistently reported cure rates from phase I, phase II and large retrospective studies support the use of HDCT in the hands of an experienced team of oncologists.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Estudos Retrospectivos , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação/métodosRESUMO
BACKGROUND: Disparities in academia are increasingly recognized, but what has historically been underrecognized is the cancer institutional disparities in the distribution of grants. We sought to characterize grants awarded by the American Society of Clinical Oncology (ASCO) ove the last 38 year with focus on grants awarded for career development and professional growth. METHODS: We used ASCO online database that contains grant and award recipients (1984-December 2021). We included all grants that were awarded for more than one year with $10,000 or more in annual funds. RESULTS: More than a third (38%) of all the individual grants were awarded for researchers from four institutions. Career development awards and young investigator awards were awarded for investigators of whom two-thirds were affiliated with a university in one of five states. CONCLUSION: There is a significant concentration of grants awarded to oncology investigators from a few institutions including grant focused on professional growth (Career development awards and young investigator awards) POLICY STATEMENT: Institutions such as ASCO may need to facilitate awarding grants and/or providing external mentorship for institutions with low number of previous grants, especially for career development and young investigator grants to help in resolving the current institutional disparities.
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Distinções e Prêmios , Neoplasias , Humanos , Estados Unidos , Organização do Financiamento , Oncologia , Instalações de SaúdeRESUMO
Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Alelos , Mutação , Fatores de Processamento de RNA , Algoritmo Florestas Aleatórias , Proteína Supressora de Tumor p53/genética , Fatores de TranscriçãoRESUMO
PURPOSE: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.
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Síndrome de Bronquiolite Obliterante , Humanos , Criança , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Piperidinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-CegoRESUMO
BACKGROUND: Finding effective ways to increase physical activity immediately following high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) for treatment of multiple myeloma (MM) is challenging. OBJECTIVE: This pilot randomized clinical trial tested the acceptability, feasibility, and preliminary effects of a free-living physical activity intervention (STEPS) compared with usual care (UC) on physical activity, fatigue, muscle strength, functional ability, sleep, and quality of life following treatment for MM with HCT. METHODS: Using a 2-group pretest/posttest design (N = 32), this study compared the 6-week STEPS intervention to UC. Data were collected using self-report questionnaires, functional performance tests, and wrist actigraphy before HCT and 7 weeks following hospital discharge. RESULTS: The STEPS group achieved their physical activity goals on 53% of intervention days. The STEPS group experienced greater appetite loss, more diarrhea, and slept more than UC regardless of time point. Both groups reported improvements in mental fatigue, emotional functioning, pain, sleep disturbance, anger, anxiety, and depression but climbed stairs slower and had weaker hand grips after intervention. Both groups subjectively reported fewer sleep disturbances but objectively experienced more wakefulness after sleep onset and an increased number of awakenings postintervention. CONCLUSIONS: The STEPS intervention is acceptable and feasible for people with MM treated with HCT. Both groups reported some improved symptoms but experienced some declines in physical performance postintervention. IMPLICATIONS FOR PRACTICE: Nurses strive to optimize health and promote well-being. Helping people increase their physical activity after treatment for MM with HCT may improve symptoms, but additional studies are needed.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Transtornos do Sono-Vigília , Exercício Físico , Humanos , Mieloma Múltiplo/terapia , Força Muscular , Qualidade de VidaRESUMO
Purpose: To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods: This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results: Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23-74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2-33). At a median follow up of 16.6m (2.4-31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 - 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7-31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion: Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted. (clinicaltrials.gov ID: NCT02220855). Clinical trial registration: clinicaltrials.gov, identifier (NCT02220855).
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PURPOSE: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies.
Assuntos
Mieloma Múltiplo , Variações do Número de Cópias de DNA , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Mutação , Translocação Genética , Sequenciamento Completo do GenomaRESUMO
Single-cell RNA sequencing reveals gene expression differences between individual cells and also identifies different cell populations that are present in the bulk starting material. To obtain an accurate assessment of patient samples, single-cell suspensions need to be generated as soon as possible once the tissue or sample has been collected. However, this requirement poses logistical challenges for experimental designs involving multiple samples from the same subject since these samples would ideally be processed at the same time to minimize technical variation in data analysis. Although cryopreservation has been shown to largely preserve the transcriptome, it is unclear whether the freeze-thaw process might alter gene expression profiles in a cell-type specific manner or whether changes in cell-type proportions might also occur. To address these questions in the context of multiple myeloma clinical studies, we performed single-cell RNA sequencing (scRNA-seq) to compare fresh and frozen cells isolated from bone marrow aspirates of six multiple myeloma patients, analyzing both myeloma cells (CD138+) and cells constituting the microenvironment (CD138-). We found that cryopreservation using 90% fetal calf serum and 10% dimethyl sulfoxide resulted in highly consistent gene expression profiles when comparing fresh and frozen samples from the same patient for both CD138+ myeloma cells (R ≥ 0.96) and for CD138- cells (R ≥ 0.9). We also demonstrate that CD138- cell-type proportions showed minimal alterations, which were mainly related to small differences in immune cell subtype sensitivity to the freeze-thaw procedures. Therefore, when processing fresh multiple myeloma samples is not feasible, cryopreservation is a useful option in single-cell profiling studies.
RESUMO
PURPOSE: Poor prognosis of metastatic melanoma mandates the development of novel strategies for its treatment and prevention. In this study, the effect of lupeol, a diet-based triterpene, was determined on the growth and tumorigenicity of human melanoma cells in vitro and in vivo. EXPERIMENTAL DESIGN: Normal human melanocytes, and human metastatic (451Lu) and nonmetastatic (WM35) cells were treated with lupeol; its effect on growth, proliferation, and apoptosis were evaluated. Further athymic nude mice bearing 451Lu cell-originated tumors were administered with lupeol thrice a week, and its effect on tumor growth and surrogate biomarkers was evaluated. RESULTS: Lupeol significantly decreased the viability of 451Lu and WM35 melanoma cells but had only a marginal effect on normal human melanocyte cells at similar doses. Lupeol treatment of 451Lu cells caused (a) G(1)-S phase cell cycle arrest and apoptosis; (b) down-regulation of Bcl2 and up-regulation of Bax; (c) activation of caspase-3 and induction of poly(ADP)ribose polymerase cleavage; (d) decreased expression of cyclin D1, cyclin D2, and cdk2; and (e) increased expression of p21 protein. Next, lupeol significantly reduced 451Lu tumor growth in athymic nude mice and modulated the expression of proliferation markers, apoptotic markers, and cell cycle regulatory molecules in tumor xenografts. CONCLUSION: Our findings showed the anticancer efficacy of lupeol with mechanistic rationale against metastatic human melanoma cells. We suggest that lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human melanoma.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Triterpenos/farmacologia , Animais , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Triterpenos Pentacíclicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multiple myeloma (MM) has two clinical precursor stages of disease: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the mechanism of progression is not well understood. Because gene co-expression network analysis is a well-known method for discovering new gene functions and regulatory relationships, we utilized this framework to conduct differential co-expression analysis to identify interesting transcription factors (TFs) in two publicly available datasets. We then used copy number variation (CNV) data from a third public dataset to validate these TFs. First, we identified co-expressed gene modules in two publicly available datasets each containing three conditions: normal, MGUS, and SMM. These modules were assessed for condition-specific gene expression, and then enrichment analysis was conducted on condition-specific modules to identify their biological function and upstream TFs. TFs were assessed for differential gene expression between normal and MM precursors, then validated with CNV analysis to identify candidate genes. Functional enrichment analysis reaffirmed known functional categories in MM pathology, the main one relating to immune function. Enrichment analysis revealed a handful of differentially expressed TFs between normal and either MGUS or SMM in gene expression and/or CNV. Overall, we identified four genes of interest (MAX, TCF4, ZNF148, and ZNF281) that aid in our understanding of MM initiation and progression.