RESUMO
A 69-year-old man presented with lumbago and was diagnosed with multiple myeloma (IgD-λ type, R-ISS stage II) with bone-destructive lesions in the lumbar spine and sacrum. Chromosome analysis showed t (8;14)(q24;q32) and t (11;14)(q13;q32). Treatment with daratumumab, lenalidomide, and dexamethasone resulted in partial response, but the disease relapsed, with a copy number increase in t (11;14) and abnormal amplification of the 1q21 region. The patient was treated for CMV enteritis, and was admitted to the hospital due to sudden abdominal pain. Gastrointestinal perforation was diagnosed by CT scan showing free air and wall thickening in the small intestine. Emergency surgery was performed, and the tumors in the perforated area were positive for CCND1 but negative for MYC on immunostaining. The patient's general condition did not improve after the surgery and he died. Pathological autopsy revealed extramedullary infiltration of multiple organs in addition to the small intestine. Extramedullary infiltration is thought to be caused by clonal evolution, and further research is warranted to clarify its pathogenesis and establish effective therapeutic strategies in high-risk patients.
Assuntos
Mieloma Múltiplo , Humanos , Masculino , Mieloma Múltiplo/patologia , Mieloma Múltiplo/diagnóstico , Idoso , Evolução Fatal , Translocação Genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 11RESUMO
The patient is a 45-year-old man who was diagnosed with severe hemophilia A during childhood and received FVIII replacement therapy, which became ineffective due to inhibitor production (5-225 BU/ml). After initiating emicizumab therapy, bleeding symptoms markedly improved, but he developed an intramuscular hematoma at the right thigh due to a fall. He was hospitalized and maintained on bed rest; however, the size of the hematoma increased, and anemia developed. Since the inhibitor level was markedly decreased at 0.6 BU/ml, a recombinant FVIII preparation was administered, and the size of the hematoma decreased along with an increase in FVIII activity. Levels of the inhibitor increased to 54.2 BU/ml, but tended to decrease during continued emicizumab treatment. Emicizumab therapy seems useful in hemophilia A patients with inhibitor production.
Assuntos
Fator VIII , Hemofilia A , Masculino , Humanos , Pessoa de Meia-Idade , Hemofilia A/diagnóstico , Hemorragia , HematomaRESUMO
Vincristine treatment may cause peripheral neuropathy. In this study, we identified the genes associated with the development of peripheral neuropathy due to vincristine therapy using a genome-wide association study (GWAS) and constructed a predictive model for the development of peripheral neuropathy using genetic information-based machine learning. The study included 72 patients admitted to the Department of Hematology, Tokushima University Hospital, who received vincristine. Of these, 56 were genotyped using the Illumina Asian Screening Array-24 Kit, and a GWAS for the onset of peripheral neuropathy caused by vincristine was conducted. Using Sanger sequencing for 16 validation samples, the top three single nucleotide polymorphisms (SNPs) associated with the onset of peripheral neuropathy were determined. Machine learning was performed using the statistical software R package "caret". The 56 GWAS and 16 validation samples were used as the training and test sets, respectively. Predictive models were constructed using random forest, support vector machine, naive Bayes, and neural network algorithms. According to the GWAS, rs2110179, rs7126100, and rs2076549 were associated with the development of peripheral neuropathy on vincristine administration. Machine learning was performed using these three SNPs to construct a prediction model. A high accuracy of 93.8% was obtained with the support vector machine and neural network using rs2110179 and rs2076549. Thus, peripheral neuropathy development due to vincristine therapy can be effectively predicted by a machine learning prediction model using SNPs associated with it.
Assuntos
Estudo de Associação Genômica Ampla , Doenças do Sistema Nervoso Periférico , Teorema de Bayes , Humanos , Aprendizado de Máquina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Polimorfismo de Nucleotídeo Único/genética , Vincristina/efeitos adversosRESUMO
Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's QOL, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated single nucleotide polymorphisms (SNPs). GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two SNPs associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the retinoic acid receptor beta (RARB) gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.
Assuntos
Antineoplásicos , Estudo de Associação Genômica Ampla , Antineoplásicos/efeitos adversos , Disgeusia/induzido quimicamente , Disgeusia/genética , Predisposição Genética para Doença , Humanos , Preparações Farmacêuticas , Polimorfismo de Nucleotídeo Único , Qualidade de VidaRESUMO
Acquired factor V deficiency is a rare disease that presents with various bleeding symptoms because of the acquired production of factor V inhibitors and decrease in factor V activity. We have experienced five cases of acquired factor V deficiency diagnosed on the basis of abnormalities in coagulation tests in the last 10 years. All five patients were older men, of whom one had no bleeding symptoms, and three had a history of renal failure and malignant tumors. In the cross-mixing test, two of three cases demonstrated an inhibitor pattern, but one case showed a deficient pattern. In all cases, steroid treatment improved factor V activity as well as prothrombin time and activated partial thromboplastin time. However, patients with intracranial hemorrhage had a poor prognosis. Although this disease is rare, careful management is necessary, especially in the absence of bleeding symptoms and where cross-mixing test does not show an inhibitor pattern.
Assuntos
Deficiência do Fator V , Idoso , Testes de Coagulação Sanguínea/efeitos adversos , Fator V/genética , Deficiência do Fator V/complicações , Deficiência do Fator V/diagnóstico , Hemorragia/etiologia , Humanos , Masculino , Tempo de Tromboplastina Parcial , Tempo de ProtrombinaRESUMO
The standard therapies for primary cutaneous anaplastic large cell lymphoma (pcALCL) in an advanced stage remain undefined. A 71-year-old man presented with multiple erythema and nodules. He was diagnosed with lymphomatoid papulosis (LyP) through a skin biopsy from the left postauricular area. All skin lesions achieved complete response by electron beam irradiation. However, nodular lesions appeared in both inner canthi 5 months later. Histopathological evaluation of the lesional biopsy revealed dominant infiltration of CD30-positive large cells. Positron emission tomography/computed tomography revealed fluorodeoxyglucose-positive cervical and inguinal lymph node swelling and right tonsillitis, followed by the diagnosis of pcALCL and TNM classification T3bN3M0. Since the patient had severe chronic obstructive pulmonary disease and recurrent pneumonia, he received low-dose methotrexate (MTX) (15 mg/week) therapy. Low-dose MTX effectively debulked the lymphadenopathies over time without particular adverse effects. Although the standard therapies for pcALCL are not established, low-dose MTX was effective and considered safe for patients with frailty and compromised respiratory function. Further study is warranted on the pathophysiology of pcALCL after the development of LyP and mechanisms of action of low-dose MTX against LyP and pcALCL.
Assuntos
Linfoma Anaplásico de Células Grandes , Linfoma Anaplásico Cutâneo Primário de Células Grandes , Papulose Linfomatoide , Neoplasias Cutâneas , Idoso , Humanos , Imunoterapia , Linfoma Anaplásico Cutâneo Primário de Células Grandes/tratamento farmacológico , Papulose Linfomatoide/diagnóstico , Papulose Linfomatoide/tratamento farmacológico , Papulose Linfomatoide/patologia , Masculino , Metotrexato/uso terapêutico , Neoplasias Cutâneas/patologiaRESUMO
Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-ß-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.
Assuntos
MAP Quinase Quinase Quinases , Mieloma Múltiplo , Osteólise , Animais , Células da Medula Óssea , Camundongos , Mieloma Múltiplo/tratamento farmacológico , NF-kappa B , Osteoclastos , Ligante RANK/genética , Microambiente TumoralRESUMO
Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.
Assuntos
Antineoplásicos/farmacologia , Mieloma Múltiplo/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Proteínas Proto-Oncogênicas/metabolismoRESUMO
Disseminated Cryptosporidium infection results in manifestations similar to those of graft-versus-host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Criptosporidiose/parasitologia , Cryptosporidium/isolamento & purificação , Diarreia/parasitologia , Oocistos/isolamento & purificação , Biópsia , Criptosporidiose/patologia , Feminino , Humanos , Intestinos/parasitologia , Pessoa de Meia-Idade , TransplantadosRESUMO
Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.
Assuntos
Anti-Inflamatórios/administração & dosagem , Encefalopatias/tratamento farmacológico , Infecções por Bunyaviridae/tratamento farmacológico , Febre/tratamento farmacológico , Metilprednisolona/administração & dosagem , Phlebovirus/isolamento & purificação , Trombocitopenia/tratamento farmacológico , Doenças Transmitidas por Carrapatos/tratamento farmacológico , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Encefalopatias/líquido cefalorraquidiano , Encefalopatias/etiologia , Encefalopatias/virologia , Infecções por Bunyaviridae/líquido cefalorraquidiano , Infecções por Bunyaviridae/complicações , Infecções por Bunyaviridae/virologia , Feminino , Febre/líquido cefalorraquidiano , Febre/etiologia , Febre/virologia , Hospitais Universitários , Humanos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Phlebovirus/efeitos dos fármacos , Phlebovirus/genética , Pulsoterapia , Síndrome , Trombocitopenia/líquido cefalorraquidiano , Trombocitopenia/virologia , Doenças Transmitidas por Carrapatos/líquido cefalorraquidiano , Doenças Transmitidas por Carrapatos/virologiaRESUMO
Cardiac AL amyloidosis (CA) is generally known as a severe disease with very poor prognosis. Here we retrospectively examined seven patients with CA in our cohort who achieved long-term survival. All six patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT) survived for >3 years, whereas four patients survived for >5 years. Patients who underwent ASCT had prompt hematological responses, and five patients showed organ responses. ASCT helps to achieve a quick and deep hematological response required for long-term survival in patients with CA. New agents have been implemented for the treatment of CA. However, the risks and benefits of each treatment modality should be considered according to patient condition, thus making the best use of ASCT in combination with new agents for the treatment of CA.
Assuntos
Cardiopatias/diagnóstico , Cardiopatias/tratamento farmacológico , Adulto , Idoso , Amiloidose , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sobreviventes , Fatores de Tempo , Resultado do TratamentoAssuntos
Fosfatase Alcalina/sangue , Denosumab , Hipocalcemia , Mieloma Múltiplo , Idoso , Denosumab/administração & dosagem , Denosumab/efeitos adversos , Feminino , Humanos , Hipocalcemia/sangue , Hipocalcemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Estudos RetrospectivosAssuntos
ADP-Ribosil Ciclase 1/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Glicoproteínas de Membrana/biossíntese , Mieloma Múltiplo/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Interferon-alfa/administração & dosagem , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/metabolismo , Tretinoína/administração & dosagemRESUMO
OBJECTIVE: This study investigated whether baseline or alteration in muscle mass affects complications during chemotherapy or overall survival (OS) in haematological malignancies. METHODS: Skeletal Muscle Index (SMI) was evaluated by bioimpedance analysis before and after chemotherapy in patients with haematological malignancies, and the association between muscle mass and clinical data was retrospectively analysed. RESULTS: Exactly 104 patients were enrolled, with a mean age of 62.2 years. SMI was 7.85 and 6.08 in male and female patients under 65 years and 7.10 and 5.92 over 65 years, before chemotherapy, respectively. Lower baseline SMI was not correlated with worse OS in total patients (p=0.915). After a median measurement interval of 30 days after chemotherapy (n=67), body weight and SMI decreased by 2.73% and 2.87% (mean), respectively. The decrease in body weight correlated with the loss of trunk muscle mass (R2=0.2107) but was more strongly associated with the loss of lower limbs muscle mass (R2=0.3985). The muscle mass of lower limbs significantly decreased in lymphoma patients who experienced febrile neutropenia (-0.42% vs -6.04%, p=0.040). OS significantly decreased in lymphoma patients with loss of lower limbs muscle ≥2.8% (p=0.0327). CONCLUSIONS: Muscle loss occurred following anticancer treatments, significantly contributing to worse outcomes. Body composition assessment and relevant multimodal prevention of muscle loss may be vital for patients receiving chemotherapy for haematological malignancies.
Assuntos
Neoplasias Hematológicas , Músculo Esquelético , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Hematológicas/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Idoso , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Idoso de 80 Anos ou mais , Composição Corporal , SarcopeniaRESUMO
Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of ß5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of ß5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.
Assuntos
Antineoplásicos , Mieloma Múltiplo , Humanos , Inibidores de Proteassoma/farmacologia , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Mieloma Múltiplo/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/farmacologia , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas , Proteínas Serina-Treonina QuinasesAssuntos
Reabsorção Óssea/etiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Osteogênese/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Expressão Gênica , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNARESUMO
High-risk cytogenetic abnormalities (HRCAs) are the most critical factor affecting prognosis in multiple myeloma (MM). However, the clinical significance of HRCAs in routine practice has not been fully elucidated. We retrospectively analyzed clinical features and outcome in 60 newly diagnosed MM patients with or without HRCAs including t(4;14), t(14;16), del(17p), and 1q gain/amplification. The median age was 71 years (range, 35-90). Abnormalities with t(4;14), t(14;16), del(17p), and 1q gain/amplification were found in 10, 1, 6, and 21/14 patients, respectively, and 10 patients had ≥ 2 HRCAs. Patients with HRCAs exhibited progressive clinical features such as anemia, high ß2-microglobulin, and high LDH. Symptomatic relapse was more common in patients with HRCAs. The median progression-free survival (PFS) by number of HRCAs (0, 1, and ≥ 2) was 51.7, 21.4, and 26.1 months (p = 0.011), and the median overall survival (OS) was not reached, 60.7, and 46.8 months (p = 0.045), respectively. Multivariate analysis revealed that HRCAs were an independent factor for PFS. Accordingly, the second revision of International Staging System (R2-ISS), which incorporates HRCA scores, was more useful for prognostic stratification (p = 0.0023). These results suggest that presence of multiple HRCAs including 1q gain/amplification is associated with advanced stage and poor prognosis in clinical practice as well.
Assuntos
Mieloma Múltiplo , Humanos , Idoso , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Relevância Clínica , Recidiva Local de Neoplasia , Aberrações Cromossômicas , Prognóstico , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Although rather favorable probabilities of return to work have been reported after allogeneic hematopoietic cell transplantation (allo-HCT), survivors often have difficulty continuing to work because of their immunocompromised status and diverse late effects after allo-HCT. We evaluated the incidence of and risk factors for recurrent sick leave in allo-HCT survivors after they initially returned to work. METHODS: We targeted allo-HCT survivors who were employed at diagnosis, aged 20-64 at survey, and survived for ≥ 2 years without relapse. Of the 1904 survivors who were informed of the study, 1148 returned the questionnaire (60%), and 1048 eligible participants were included in the overall analysis. In the present study that considered recurrent sick leave after return to work, we targeted 896 participants who returned to work at least once after allo-HCT. Participants stated if they had recurrent sick leave after returning to work and its reasons, as well as associated patient-, HCT/HCT center-, and work-related factors and clinical events after allo-HCT. A logistic regression analysis was conducted to explore correlated factors for recurrent sick leave. RESULTS: In survivors who returned to work, 30% required recurrent sick leave. The most frequent causes of recurrent leave were physical issues (72%), and analysis of free descriptions demonstrated that these were mainly associated with graft-versus-host disease, infection, or readmission. Other reasons included work-related issues such as gap between physical and working conditions. Multivariate analysis showed that cord blood transplantation, longer employment duration, and counseling from healthcare professionals were associated with a lower risk of recurrent leave. Readmission, immunosuppressant use, and symptoms involving the respiratory system, gut, and joints and muscles were associated with a higher risk. CONCLUSIONS: Our results drawn from a large cohort study should help healthcare professionals identify and assist at-risk patients. Multi-professional teams that provide continuous support and effective communication with the workplace are necessary to improve long-term outcomes after allo-HCT. IMPLICATIONS FOR CANCER SURVIVORS: In order to continue working after the initial return to work, it is important to receive counseling from healthcare professionals and obtain reasonable accommodation from workplace.
Assuntos
Sobreviventes de Câncer , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos de Coortes , Retorno ao Trabalho , Licença Médica , Incidência , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Emprego , SobreviventesRESUMO
Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.