RESUMO
The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2-5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.
Assuntos
Microscopia Crioeletrônica , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Prurido/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/química , Agonismo Inverso de Drogas , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/ultraestrutura , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/química , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/ultraestrutura , Humanos , Modelos Moleculares , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/ultraestrutura , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/ultraestrutura , Receptores de Neuropeptídeos/metabolismo , Receptores de Neuropeptídeos/ultraestruturaRESUMO
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
Assuntos
Ritmo Circadiano/fisiologia , Ligantes , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Escuridão , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Feminino , Humanos , Luz , Masculino , Camundongos , Camundongos Knockout , Simulação de Acoplamento Molecular , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/deficiência , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/deficiência , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Receptores de Melatonina/deficiência , Receptores de Melatonina/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato/genéticaRESUMO
Background and Objectives: Despite rapid advances in targeted therapies for renal cell carcinoma (RCC), bone metastases remain a major problem that significantly increases morbidity and reduces patients' quality of life. Conventional fractionated radiotherapy (CF-RT) is known to be an important local treatment option for bone metastases; however, bone metastases from RCC have traditionally been considered resistant to CF-RT. We aimed to investigate the effectiveness of CF-RT for symptomatic bone metastasis from RCC and identify the predictive factors associated with treatment outcomes in the targeted therapy era. Materials and Methods: Between January 2011 and December 2023, a total of 73 lesions in 50 patients treated with a palliative course of CF-RT for symptomatic bone metastasis from RCC were evaluated, and 62 lesions in 41 patients were included in this study. Forty-five lesions (72.6%) were treated using targeted therapy during CF-RT. The most common radiation dose fractionations were 30 gray (Gy) in 10 fractions (50%) and 39 Gy in 13 fractions (16.1%). Results: Pain relief was experienced in 51 of 62 lesions (82.3%), and the 12-month local control (LC) rate was 61.2%. Notably, 72.6% of the treatment course in this study was combined with targeted therapy. The 12-month LC rate was 74.8% in patients who received targeted therapy and only 10.9% in patients without targeted therapy (p < 0.001). Favorable Eastern Cooperative Oncology Group performance status (p = 0.026) and pain response (p < 0.001) were independent predictors of improved LC. Radiation dose escalation improved the LC in radiosensitive patients. A consistent treatment response was confirmed in patients with multiple treatment courses. Conclusions: CF-RT enhances pain relief and LC when combined with targeted therapy. Patients who responded well to initial treatment generally showed consistent responses to subsequent CF-RT for additional painful bone lesions. CF-RT could therefore be an excellent complementary local treatment modality for targeted therapy.
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Neoplasias Ósseas , Carcinoma de Células Renais , Fracionamento da Dose de Radiação , Neoplasias Renais , Humanos , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/secundário , Masculino , Feminino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/radioterapia , Pessoa de Meia-Idade , Idoso , Neoplasias Renais/radioterapia , Neoplasias Renais/patologia , Adulto , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Resultado do Tratamento , Qualidade de VidaRESUMO
The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward ß-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for ß-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.
Assuntos
Neurotensina , Receptores de Neurotensina , Receptores de Neurotensina/química , Receptores de Neurotensina/metabolismo , Neurotensina/metabolismo , Transdução de Sinais , Peptídeos/metabolismo , beta-Arrestinas/metabolismoRESUMO
INTRODUCTION: This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. RESULTS: No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). DISCUSSION: Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).
Assuntos
Hepatite B Crônica , Linfoma Difuso de Grandes Células B , Humanos , Tenofovir/efeitos adversos , Rituximab/efeitos adversos , Vincristina/efeitos adversos , Prednisona/uso terapêutico , Antígenos de Superfície da Hepatite B , Estudos Prospectivos , Alanina Transaminase , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Vírus da Hepatite B , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/induzido quimicamente , Antivirais/uso terapêutico , DNA ViralRESUMO
PURPOSE: We investigated the characteristics of recurrence pattern and survival of patients with non-endometrioid endometrial cancer (NEEC) and attempted to identify prognostic and treatment factors affecting disease-free survival (DFS) and overall survival (OS) of these patients. METHODS: Fifty-seven patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IA-IVA NEEC from February 2003 to December 2021 were retrospectively analyzed. RESULTS: The 5year DFS and OS rates of the total cohort were 50.6% and 56.1%, respectively. Recurrence occurred in 28 patients (49.1%) during follow-up, and the most common recurrence pattern was distant metastasis (DM; 78.6% of total recurrences). The occurrence of relapse significantly reduced 5year OS (recurrence group vs. non-recurrence group: 12.5% vs. 100%; pâ¯< 0.001). In univariate analysis, adjuvant radiotherapy (RT) group showed significantly higher 5year DFS (56.7% vs. 37.9%; pâ¯= 0.04), local recurrence-free survival (91.6% vs. 50.5%; pâ¯= 0.01), and regional recurrence-free survival (88.2% vs. 56.5%; pâ¯< 0.01) than the non-RT group. In multivariate analysis, advanced FIGO stage was identified as a negative prognostic factor for DFS and OS. Lymphovascular space invasion (LVSI) and adjuvant RT were independent prognostic factors for DFS. CONCLUSION: The most common recurrence pattern observed in patients with NEEC was DM. FIGO stage and LVSI were identified as prognostic factors for survival, and RT was identified as a therapeutic modality that could increase DFS. To improve the OS of patients with NEEC, the addition of effective chemotherapy that can reduce DM may be important.
Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Prognóstico , Estudos Retrospectivos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Carcinoma Endometrioide/patologia , Intervalo Livre de Doença , Neoplasias do Endométrio/radioterapiaRESUMO
The off-label use of racemic ketamine and the FDA approval of (S)-ketamine are promising developments for the treatment of depression. Nevertheless, racemic ketamine and (S)-ketamine are controlled substances with known abuse potential and their use is associated with undesirable side effects. For these reasons, research efforts have focused on identifying alternatives. One candidate is (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a ketamine metabolite that in preclinical models lacks the dissociative and abuse properties of ketamine while retaining its antidepressant-like behavioral efficacy. (2R,6R)-HNK's mechanism of action however is unclear. The main goals of this study were to perform an in-depth pharmacological characterization of (2R,6R)-HNK at known ketamine targets, to use target deconvolution approaches to discover novel proteins that bind to (2R,6R)-HNK, and to characterize the biodistribution and behavioral effects of (2R,6R)-HNK across several procedures related to substance use disorder liability. We found that unlike (S)- or (R)-ketamine, (2R,6R)-HNK did not directly bind to any known or proposed ketamine targets. Extensive screening and target deconvolution experiments at thousands of human proteins did not identify any other direct (2R,6R)-HNK-protein interactions. Biodistribution studies using radiolabeled (2R,6R)-HNK revealed non-selective brain regional enrichment, and no specific binding in any organ other than the liver. (2R,6R)-HNK was inactive in conditioned place preference, open-field locomotor activity, and intravenous self-administration procedures. Despite these negative findings, (2R,6R)-HNK produced a reduction in immobility time in the forced swim test and a small but significant increase in metabolic activity across a network of brain regions, and this metabolic signature differed from the brain metabolic profile induced by ketamine enantiomers. In sum, our results indicate that (2R,6R)-HNK does not share pharmacological or behavioral profile similarities with ketamine or its enantiomers. However, it could still be possible that both ketamine and (2R,6R)-HNK exert antidepressant-like efficacy through a common and previously unidentified mechanism. Given its pharmacological profile, we predict that (2R,6R)-HNK will exhibit a favorable safety profile in clinical trials, and we must wait for clinical studies to determine its antidepressant efficacy.
Assuntos
Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Distribuição Tecidual , Antidepressivos/metabolismoRESUMO
BACKGROUND: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. METHODS: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. RESULTS: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. CONCLUSIONS: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.
Assuntos
Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Gástricas , Humanos , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgiaRESUMO
Background and Objectives: Treatment options for most patients with recurrent cervical cancer within the previously irradiated field are limited. This study aimed to investigate the feasibility and safety of re-irradiation using intensity-modulated radiation therapy (IMRT) for patients with cervical cancer who experienced intrapelvic recurrence. Materials and Methods: We retrospectively analyzed 22 patients with recurrent cervical cancer who were treated with re-irradiation for intrapelvic recurrence using IMRT between July 2006 and July 2020. The irradiation dose and volume were determined based on the range considered safe for the tumor size, location, and previous irradiation dose. Results: The median follow-up period was 15 months (range: 3-120) and the overall response rate was 63.6%. Of the symptomatic patients, 90% experienced symptom relief after treatment. The 1- and 2-year local progression-free survival (LPFS) rates were 36.8% and 30.7%, respectively, whereas the 1- and 2-year overall survival (OS) rates were 68.2% and 25.0%, respectively. Multivariate analysis revealed that the interval between irradiations and gross tumor volume (GTV) were significant prognostic factors for LPFS. The response to re-irradiation showed borderline statistical significance for LPFS. The GTV and response to re-irradiation were also independent prognostic factors for OS. Grade 3 late toxicities were observed in 4 (18.2%) of the 22 patients. Recto- or vesico-vaginal fistula occurred in four patients. The irradiation dose was associated with fistula formation with borderline significance. Conclusions: Re-irradiation using IMRT is a safe and effective treatment strategy for patients with recurrent cervical cancer who previously received RT. Interval between irradiations, tumor size, response to re-irradiation, and radiation dose were the main factors affecting efficacy and safety.
Assuntos
Radioterapia de Intensidade Modulada , Reirradiação , Neoplasias do Colo do Útero , Feminino , Humanos , Radioterapia de Intensidade Modulada/efeitos adversos , Reirradiação/efeitos adversos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/etiologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/patologia , Pelve/patologiaRESUMO
We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/terapia , Linfócitos T/imunologia , Adulto , Idoso , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Feminino , Humanos , Imunoterapia Adotiva , Linfoma Extranodal de Células T-NK/complicações , Masculino , Pessoa de Meia-Idade , Linfócitos T/transplante , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To identify the morphological characteristics of the acromion and subacromial bursal space after arthroscopic acromioplasty using magnetic resonance imaging (MRI). MATERIALS AND METHODS: One hundred patients who received arthroscopic rotator cuff repair and acromioplasty each received at least three MRI examinations (preoperative, first immediate postoperative, and second follow-up imaging between 8 months and 1 year postoperatively). Changes over time in the thickness and morphology of the postoperative acromion as well as the subacromial bursal space were assessed. Clinical and radiological parameters were also analyzed to identify any association with changes in acromial morphology. RESULTS: Despite minimal acromial thinning observed at the first immediate postoperative state, the acromions showed significant thinning at the second postoperative MRI, with a mean reduction of 32%. Along with acromial thinning, an exaggerated concave contour of the acromial undersurface was observed in some patients. In the subacromial space, a loculated fluid collection developed in 91% of the patients at the second postoperative follow-up. No statistically significant association was noted between postoperative acromial thickness change and clinical or radiological factors (P value > 0.05). CONCLUSION: A significant delayed reduction in acromial thickness within approximately 1 year of arthroscopic acromioplasty is thought to be a normal postoperative feature. The simultaneous collection of a loculated, cyst-like fluid in the subacromial bursal space may be an important associated factor of postoperative acromial thinning.
Assuntos
Acrômio , Lesões do Manguito Rotador , Acrômio/diagnóstico por imagem , Acrômio/cirurgia , Artroplastia , Artroscopia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
AIMS AND OBJECTIVES: To investigate the incidence of urinary tract infection and analyse its risk factors among hospitalised patients with spinal cord injury. BACKGROUND: While the incidence of urinary tract infection varies widely according to the healthcare setting and patients' clinical characteristics, formal reports are limited in quantity. There has been no consensus regarding the risk factors for urinary tract infection. DESIGN: A retrospective descriptive study. METHODS: Electronic medical records of 964 subjects between 2010-2017 were reviewed. Urinary tract infection status was examined to identify newly occurred cases. Data included demographic and clinical characteristics, hydration status and length of hospitalisation. The reporting of the study followed the EQUATOR Network's STROBE checklist. RESULTS: Of the sample, 31.7% had urinary tract infection (95% confidence interval: 1.288 to 1.347, p < .001). Sex, completeness of injury, type of bladder emptying, detrusor function and urethral pressure were significant factors affecting urinary tract infection. Patients who were male and those with injury classifications A, B and C had higher risk of urinary tract infection. Patients with urinary or suprapubic indwelling catheters, as well as those with areflexic detrusor combined with normotonic urethral pressure or overactive detrusor combined with normotonic urethral pressure, showed higher risk. Length of hospitalisation in patients with urinary tract infection was greater than that in uninfected patients, which implies the importance of prevention of urinary tract infection. CONCLUSIONS: Nurses should carefully assess risk factors to prevent urinary tract infection in patients with spinal cord injury in the acute and sub-acute stages of the disease trajectory and provide individualised nursing care. RELEVANCE TO CLINICAL PRACTICE: This study contributes evidence for up-to-date clinical nursing practice for the comprehensive management of urinary tract infection. This can lead to improvements in nursing care quality and patient outcomes, including length of hospitalisation.
Assuntos
Traumatismos da Medula Espinal , Infecções Urinárias , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/epidemiologia , Cateterismo Urinário/efeitos adversos , Infecções Urinárias/complicações , Infecções Urinárias/epidemiologiaRESUMO
An additional affiliation for the first author was not indicated. Hyewon Lee is also affiliated with: Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea.
RESUMO
Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.
Assuntos
Linfoma de Célula do Manto , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Radioterapia , Estudos Retrospectivos , Fatores de Risco , Rituximab/administração & dosagem , Taxa de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagemRESUMO
We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m2 on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m2 on day 5, and i.v. oxaliplatin 130 mg/m2 on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin , Proteínas de Neoplasias/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína C-Reativa/metabolismo , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Recidiva , Taxa de Sobrevida , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Neutropenia Febril/epidemiologia , Neutropenia Febril/etiologia , Feminino , Idoso Fragilizado , Fragilidade/complicações , Fragilidade/diagnóstico , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Incidência , Infecções/epidemiologia , Estimativa de Kaplan-Meier , Lenalidomida/administração & dosagem , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Proteínas do Mieloma/análise , Prednisona/administração & dosagem , Intervalo Livre de Progressão , Recidiva , República da Coreia/epidemiologia , Talidomida/administração & dosagem , Talidomida/análogos & derivadosRESUMO
Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Linfoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Etoposídeo/uso terapêutico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Melfalan/uso terapêutico , República da Coreia , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
BACKGROUND: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. METHODS: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). RESULTS: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. CONCLUSIONS: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. TRIAL REGISTRATION: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).
Assuntos
Doença de Hodgkin/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Feminino , Amplificação de Genes , Doença de Hodgkin/enzimologia , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/enzimologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nitrilas , Projetos Piloto , Estudos Prospectivos , Pirimidinas , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
This prospective study evaluated the efficacy and toxicity of intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A total of 99 patients with MM, enrolled between January 2013 and March 2016, received intravenous busulfan (9.6 mg/kg) and melphalan (140 mg/m2) before ASCT. The median time to transplant was 6.2 months, and 90 (90.9%) patients underwent ASCT within 12 months of the diagnosis. The overall response rate after ASCT was 94.0%, including 43.5% with a stringent complete response/complete response, 27.3% with very good partial response, and 23.2% with partial response. The most common severe nonhematologic toxicity (grade 3 to 4) was infection (26.3%) and stomatitis (15.2%). Three (3.2%) patients developed veno-occlusive disease. No treatment-related mortality was observed. After a median follow-up of 26.1 months, the median progression-free survival was 27.2 months (range, 13.0 to 41.4 months) and median overall survival was not reached. In conclusion, a conditioning regimen of intravenous busulfan and melphalan was effective and tolerable. ClinicalTrials.gov. number: NCT01923935.
Assuntos
Bussulfano/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Administração Intravenosa , Adulto , Idoso , Bussulfano/uso terapêutico , Bussulfano/toxicidade , Feminino , Humanos , Infecções/etiologia , Masculino , Melfalan/uso terapêutico , Melfalan/toxicidade , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estomatite/etiologia , Transplante Autólogo/métodos , Insuficiência Venosa/etiologia , Adulto JovemRESUMO
BACKGROUND: The FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined. METHODS: BV2 microglial cells were treated with ibrutinib (1 µM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 µg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry. RESULTS: Ibrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1ß proinflammatory cytokine levels. CONCLUSIONS: Our data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.