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1.
J Bone Joint Surg Am ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34788256

RESUMO

BACKGROUND: Subchondral insufficiency fracture of the femoral head (SIFFH) occurs in elderly patients and might be confused with osteonecrosis of the femoral head (ONFH). Subchondral insufficiency fracture of the femoral head is an insufficiency fracture at the dome of the femoral head and has been known to be associated with osteoporosis, hip dysplasia, and posterior pelvic tilt. This study's aims were to evaluate (1) surgical complications, (2) radiological changes, (3) clinical results, and (4) survivorship of THA in patients with SIFFH. METHODS: From November 2010 to June 2017, 21 patients (23 hips); 5 men (5 hips) and 16 women (18 hips) underwent cementless THA due to SIFFH at our institution. Their mean age was 71.9 years (range, 57 to 86) at the time of surgery, and mean T-score was -2.2 (range, -4.2 to 0.2). The mean lateral center-edge angle, abduction, and anteversion of the acetabulum were 29.9° (range, 14.8° to 47.5°), 38.5° (range, 31° to 45°), and 20.0° (range, 12° to 25°), respectively. The mean pelvic incidence, lumbar kyphotic angle and posterior pelvic tilt were 56.4° (range, 39° to 79°), 14.7° (range, -34° to 43°), and 13.0° (range, 3° to 34°), respectively. RESULTS: An intraoperative calcar crack occurred in 1 hip. The mean anteversion and abduction of cup were 29.0° (range, 17° to 43°) and 43.3° (range, 37° to 50°), respectively. One patient sustained a traumatic posterior hip dislocation 2 weeks after the procedure, and was treated with open reduction. At a mean follow-up of 35.4 months (range, 24 to 79 months), no hip had prosthetic loosening or focal osteolysis. At the latest follow-up, the mean modified Harris hip score was 79.1 (range, 60 to 100) points, and mean UCLA activity score was 4.2 (range, 2 to 7) points. The survivorship was 95.7% (95% CI, 94.9% to 100%) at 6 years. CONCLUSIONS: Cementless THA is a favorable treatment option for SIFFH in elderly patients. LEVEL OF EVIDENCE: 3.

2.
Food Sci Biotechnol ; 30(9): 1249-1256, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34603823

RESUMO

This study evaluated the anti-inflammatory effect of ginger-cinnamon mixture using an animal model of dextran sulfate sodium (DSS)-induced intestinal inflammation. The mice were administered either distilled water or ginger extract (GE), cinnamon subcritical water extract (CSWE), low GE + CSWE (GCL), and high GE + CSWE (GCH) for 21 days and drinking water containing 5% DSS for the final 7 days to induce intestinal inflammation. We assessed the change of body weight, disease activity index (DAI), histopathological scores, myeloperoxidase (MPO) activity, and mRNA levels. Compared with the DSS group, the GCH group showed increased body weight, inhibited intestinal shortening, and decreased DAI and histopathological score of intestinal inflammation, which was similar to that for the control group. It inhibited MPO activity as well as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α mRNA levels. Therefore, the ginger-cinnamon complex helps to improve intestine inflammation, which is beneficial for gut health.

3.
Nat Commun ; 12(1): 6071, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663807

RESUMO

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Granzimas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
4.
BMB Rep ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34488928

RESUMO

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, plays pivotal roles in the development and metastasis of HCC. It has been reported that HBx induces liver cancer cell migration and reorganizes actin cytoskeleton, however the molecular basis for actin cytoskeleton reorganization remains obscure. In this study, we for the first time report that HBx promotes actin polymerization and liver cancer cell migration by regulating calcium modulated protein, calmodulin (CaM). HBx physically interacts with CaM to control the level of phosphorylated cofilin, an actin depolymerizing factor. Mechanistically, HBx interacts with CaM, liberates Hsp90 from its inhibitory partner CaM, and increases the activity of Hsp90, thus activating LIMK1/cofilin pathway. Interestingly, the interaction between HBx and CaM is calcium-dependent and requires the CaM binding motif on HBx. These results indicate that HBx modulates CaM which plays a regulatory role in Hsp90/LIMK1/cofilin pathway of actin reorganization, suggesting a new mechanism of HBV-induced HCC metastasis specifically derived by HBx.

5.
Cell Tissue Bank ; 22(4): 575-585, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34581914

RESUMO

The use of processed nerve allografts as an alternative to autologous nerve grafts, the gold standard treatment for peripheral nerve defects, is increasing. However, it is not widely used in Korea due to cost and insurance issues. Moreover, the main detergent used in the conventional Hudson method is unavailable. Therefore, a new nerve allograft decellularization process is needed. We aimed to compare the traditional Hudson method with a novel decellularization process that may remove cellular content more efficiently while preserving the extracellular matrix (ECM) structure using low concentration sodium dodecyl sulfate (SDS) and nuclease. After each decellularization process, DNA content was measured in nerve tissue. Masson's trichrome staining and scanning electron microscopy were performed to determine the state of preservation of the ECM. A significantly greater amount of DNA content was removed in the novel method, and the ECM structure was preserved in both methods. For the in vivo study, a 15-mm long sciatic nerve defect was created in two groups of Sprague-Dawley rats, and processed nerve allografts decellularized using the Hudson or novel method were transplanted. Functional and histological recovery results were measured 12 weeks post-transplantation. Ankle contracture angle, maximal isometric tetanic force of the tibialis anterior (TA), and the TA mass were compared between the groups, as well as the percent neural tissue (100 × neural area/intrafascicular area). There was no significant difference in functional and histological nerve recovery between the methods. The novel method is appropriate for developing a processed nerve allograft.


Assuntos
Tecido Nervoso , Nervo Isquiático , Aloenxertos , Animais , Matriz Extracelular , Ratos , Ratos Sprague-Dawley
6.
Transplant Cell Ther ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34537419

RESUMO

In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

8.
Clin Cancer Res ; 27(21): 5847-5856, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380640

RESUMO

PURPOSE: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT). PATIENTS AND METHODS: We evaluated 194 patients with follicular lymphoma who received an alloSCT (n = 98) or autoSCT (n = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). RESULTS: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; P = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT (P < 0.001), and the 8-year relapse rates were 11% and 43%, respectively (P < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; P = 0.27). CONCLUSIONS: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma.

9.
Transplant Cell Ther ; 27(11): 913.e1-913.e12, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34329753

RESUMO

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m2 busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m2 and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% µmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

10.
Transplant Cell Ther ; 27(8): 689-695, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34023569

RESUMO

Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched-unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI <2 at HCT2.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Adulto Jovem
12.
J Mov Disord ; 14(3): 221-225, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34030433

RESUMO

OBJECTIVE: To assess nocturnal hypokinesia using the Korean version of the Nocturnal Hypokinesia Questionnaire (NHQ-K) in Parkinson's disease (PD) patients across disease stages. METHODS: We developed the NHQ-K and performed questionnaire-based interviews with 108 PD patients from three referral hospitals. Clinical associations of nocturnal hypokinesia and its impact on health-related quality of life (HRQoL) were also analyzed. RESULTS: The NHQ-K showed acceptable internal consistency (0.83) and interrater reliability (0.95). Nocturnal hypokinesia significantly affected HRQoL in PD patients at both the early and advanced stages (adjusted p < 0.001). Increased severity of nocturnal hypokinesia was associated with dyskinesias, off-period disability, apathy, and anxious mood in PD patients (adjusted p < 0.01) after controlling for disease severity and medication dose. CONCLUSION: The NHQ-K is useful for screening nocturnal hypokinesia in PD patients. Given the high impact of nocturnal hypokinesia on HRQoL, comprehensive management of nocturnal disability is needed for PD patients.

13.
Orthop J Sports Med ; 9(5): 23259671211007734, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34036114

RESUMO

Background: Metabolic factors have been linked to tendinopathies, yet few studies have investigated the association between metabolic factors and lateral epicondylitis. Purpose: To evaluate risk factors for lateral epicondylitis, including several metabolic factors. Study Design: Case-control study; Level of evidence, 3. Methods: We evaluated 1 elbow in each of 937 volunteers from a rural region that employs many agricultural laborers. Each participant received a questionnaire, physical examinations, blood tests, simple radiographic evaluations of both elbows, magnetic resonance imaging of bilateral shoulders, and an electrophysiological study of bilateral upper extremities. Lateral epicondylitis was diagnosed using 3 criteria: (1) pain at the lateral aspect of the elbow, (2) point tenderness over the lateral epicondyle, and (3) pain during resistive wrist dorsiflexion with the elbow in full extension. Multivariable logistic regression analysis was used to calculate the odds ratios (ORs) and 95% CIs for various demographic, physical, and social factors, including age, sex, waist circumference, dominant-side involvement, smoking habit, alcohol intake, and participation in manual labor; the comorbidities of diabetes, hypertension, thyroid dysfunction, metabolic syndrome, ipsilateral biceps tendon injury, ipsilateral rotator cuff tear, and ipsilateral carpal tunnel syndrome; and the serologic parameters of serum lipid profile, glycosylated hemoglobin A1c, level of thyroid hormone, and high-sensitivity C-reactive protein. Results: The prevalence of lateral epicondylitis was 26.1% (245/937 participants). According to the multivariable logistic regression analysis, female sex (OR, 2.47; 95% CI, 1.78-3.43), dominant-side involvement (OR, 3.21; 95% CI, 2.24-4.60), manual labor (OR, 2.25; 95% CI, 1.48-3.43), and ipsilateral rotator cuff tear (OR, 2.77; 95% CI, 1.96-3.91) were significantly associated with lateral epicondylitis (P < .001 for all). No metabolic factors were significantly associated with lateral epicondylitis. Conclusion: Female sex, dominant-side involvement, manual labor, and ipsilateral rotator cuff tear were found to be risk factors for lateral epicondylitis. The study results suggest that overuse activity is more strongly associated with lateral epicondylitis than are metabolic factors.

14.
J Hand Surg Am ; 46(9): 822.e1-822.e7, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33820657

RESUMO

Ulnar impaction syndrome (UIS) and triangular fibrocartilage complex (TFCC) tear are common causes of ulnar-sided wrist pain. As a standard surgical treatment, ulnar-shortening osteotomy (USO) and TFCC repair are used respectively. Patient spectrums of UIS accompanied by distal radioulnar joint instability or traumatic TFCC foveal tear with UIS symptoms exist, and both USO and TFCC repair are necessary for treating some of these patients. However, there have been few reports on the procedure for performing these 2 operations concurrently. We introduce a combined procedure to concurrently perform USO and TFCC repair. We performed a USO in the ulnar metaphysis using a locking plate and open TFCC knotless repair using a suture anchor at the ulnar fovea. In this technique, USO is conducted in the metaphysis, which is favorable to union, using a small plate that is easy to handle, and knotless TFCC repair can be performed simultaneously through a single small incision.


Assuntos
Instabilidade Articular , Fibrocartilagem Triangular , Traumatismos do Punho , Artroscopia , Humanos , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/cirurgia , Osteotomia , Fibrocartilagem Triangular/diagnóstico por imagem , Fibrocartilagem Triangular/cirurgia , Ulna/diagnóstico por imagem , Ulna/cirurgia , Traumatismos do Punho/diagnóstico por imagem , Traumatismos do Punho/cirurgia , Articulação do Punho
15.
Front Immunol ; 12: 659625, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912187

RESUMO

Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS). Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients; however these studies that leverage mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRß chains in bone marrows of 11 MDS patients prior to treatment (n=11 bone marrows prior to treatment), and in at least 2 timepoints for each patient following treatment (n=26 bone marrow aspirates post-treatment) with (HMA), alongside analyzing bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed in responders or non-responders following treatment with HMAs. However, we found an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH2 for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.


Assuntos
Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Idoso , Idoso de 80 Anos ou mais , Células Clonais/efeitos dos fármacos , Células Clonais/imunologia , Células Clonais/metabolismo , Estudos de Coortes , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia , Reação em Cadeia da Polimerase/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Análise de Sequência de DNA/métodos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
16.
J Clin Oncol ; 39(24): 2710-2719, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-33929874

RESUMO

PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.


Assuntos
Cistite/tratamento farmacológico , Transtornos Hemorrágicos/tratamento farmacológico , Linfócitos T Citotóxicos/metabolismo , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
17.
Transplant Cell Ther ; 27(3): 272.e1-272.e5, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781539

RESUMO

Steroid-refractory (SR) lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD) has poor prognosis, and novel drugs are needed. We describe outcomes of patients with SR-LGI aGVHD treated with vedolizumab. The primary objective was to determine overall response rate (ORR) at days 14, 28, and 56. Secondary outcomes included overall survival (OS), non-relapse mortality and toxicities. Twenty patients, median age 46 years (range, 23-71), were included. All but 2 patients (90%) had grade 3 to 4 aGVHD (45% stage 4, 40% stage 3 LGI). Median time to vedolizumab was 21 days (range, 5-1031) and 13 days (range, 0-533) after diagnosis of LGI aGVHD and SR-LGI aGVHD, respectively. It was given as ≥3rd line (median 3; range 2-6) in 75% after failure of steroids, and additional treatments including ruxolitinib (n = 12) and others. Median follow-up was 17 months (range, 10-34). The days 14, 28 and 56 ORRs were 45% (9/20; complete response [CR] 25%), 35% (7/20; CR 20%), and 25% (5/20; CR 20%), respectively. Among ruxolitinib failures, it was 50% (6/12; CR 25%), 50% (6/12; CR 25%) and 25% (3/12; CR 16.7%), respectively. Fifteen patients died (14 GVHD, 1 leukemia relapse). The actuarial 6-month OS was 35% (95% confidence interval 16-55). No progressive multifocal leukoencephalopathy or infusion reaction occurred. Forty-four infection events (22 viral, 18 bacterial, and 4 fungal) were noted in 16 patients. Vedolizumab was well tolerated and demonstrated potential efficacy even after ruxolitinib failure for SR-LGI aGVHD. Yet the responses were suboptimal, and its use requires further investigation.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Anticorpos Monoclonais Humanizados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Trato Gastrointestinal Inferior , Pessoa de Meia-Idade , Esteroides/uso terapêutico
18.
Acta Haematol ; 144(1): 74-81, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32604096

RESUMO

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.


Assuntos
Medula Óssea/patologia , Aberrações Cromossômicas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Análise Citogenética , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
20.
Arch Orthop Trauma Surg ; 141(7): 1189-1195, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32852594

RESUMO

INTRODUCTION: Radial nerve palsy (RNP) associated with humeral shaft fracture (HSF) is the most common nerve complication in long bone fractures. There is still controversy over the need for immediate exploration of the radial nerve (RN) in HSF with RNP. The purpose of the current study was to determine which situations of HSF with RNP require early exploration of the RN. MATERIALS AND METHODS: This is a retrospective study that included 55 patients who had visited the emergency department of the current authors' hospital and had been diagnosed with HSF between March of 2005 and September of 2015. Of these 55 patients, 14 (25.4%) had been diagnosed with HSF with RNP. We reviewed the medical records of those 14 patients and their radiographs to evaluate each fracture's type, location, pattern, energy of trauma, status of RN injury, and time until recovery from RNP. RESULT: All the 14 RNP patients had suffered high-energy trauma. Three had fractures in the proximal third (21.4%), six in the middle third (42.9%), and five in the distal third (35.7%). The three patients (21.4%) with incomplete recovery of RNP all had proximal third fractures; two of these three patients had RN transection. CONCLUSION: Early exploration of the radial nerve should be considered in patients with radial nerve palsy associated with proximal third humeral shaft fracture, regardless of the fracture patterns caused by the high-energy trauma.


Assuntos
Fraturas do Úmero , Nervo Radial/fisiologia , Neuropatia Radial , Humanos , Fraturas do Úmero/complicações , Fraturas do Úmero/cirurgia , Neuropatia Radial/etiologia , Neuropatia Radial/cirurgia , Estudos Retrospectivos
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