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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.
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Mieloma Múltiple , Humanos , Masculino , Mieloma Múltiple/patología , Mieloma Múltiple/diagnóstico , Anciano , Resultado Fatal , Translocación Genética , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 11RESUMEN
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.
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Neoplasias Hematológicas , Músculo Esquelético , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Hematológicas/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Anciano , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Anciano de 80 o más Años , Composición Corporal , SarcopeniaRESUMEN
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.
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Antineoplásicos , Mieloma Múltiple , Humanos , Inhibidores de Proteasoma/farmacología , Factor 2 Relacionado con NF-E2/farmacología , Factor 2 Relacionado con NF-E2/uso terapéutico , Mieloma Múltiple/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/farmacología , Resistencia a Antineoplásicos , Línea Celular Tumoral , Bortezomib/farmacología , Bortezomib/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas , Proteínas Serina-Treonina QuinasasRESUMEN
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.
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Factor VIII , Hemofilia A , Masculino , Humanos , Persona de Mediana Edad , Hemofilia A/diagnóstico , Hemorragia , HematomaRESUMEN
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.
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Mieloma Múltiple , Humanos , Anciano , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Estudios Retrospectivos , Relevancia Clínica , Recurrencia Local de Neoplasia , Aberraciones Cromosómicas , Pronóstico , Estadificación de NeoplasiasRESUMEN
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.
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Supervivientes de Cáncer , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios de Cohortes , Reinserción al Trabajo , Ausencia por Enfermedad , Incidencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Empleo , SobrevivientesRESUMEN
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.
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Histona Desacetilasa 1 , Interleucina-6 , Benzamidas , PiridinasRESUMEN
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.
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Deficiencia del Factor V , Anciano , Pruebas de Coagulación Sanguínea/efectos adversos , Factor V/genética , Deficiencia del Factor V/complicaciones , Deficiencia del Factor V/diagnóstico , Hemorragia/etiología , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Tiempo de ProtrombinaRESUMEN
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.
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Linfoma Anaplásico de Células Grandes , Linfoma Anaplásico Cutáneo Primario de Células Grandes , Papulosis Linfomatoide , Neoplasias Cutáneas , Anciano , Humanos , Inmunoterapia , Linfoma Anaplásico Cutáneo Primario de Células Grandes/tratamiento farmacológico , Papulosis Linfomatoide/diagnóstico , Papulosis Linfomatoide/tratamiento farmacológico , Papulosis Linfomatoide/patología , Masculino , Metotrexato/uso terapéutico , Neoplasias Cutáneas/patologíaRESUMEN
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.
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Estudio de Asociación del Genoma Completo , Enfermedades del Sistema Nervioso Periférico , Teorema de Bayes , Humanos , Aprendizaje Automático , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/genética , Polimorfismo de Nucleótido Simple/genética , Vincristina/efectos adversosRESUMEN
OBJECTIVES: Patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) have a higher risk of falls than those receiving other therapies for haematological disorders. This study aimed to investigate the impact of pretransplant lower extremity muscle strength (LEMS) on post-transplant falls. METHODS: In this retrospective cohort study, patients aged ≥18 years who underwent allo-HSCT were included. All data were extracted from medical records. LEMS was defined as the knee extension force measured by a handheld dynamometer divided by the patient's weight. The receiver operating characteristic (ROC) curve was used to calculate the optimal LEMS cut-off value for prediction of falls. Patients were categorised into low and normal LEMS groups based on the cut-off value. The impact of pretransplant LEMS on post-transplant falls was analysed using a Cox proportional hazards model. RESULTS: In total, 101 patients were analysed. During the observation period, falls occurred in 32 patients (31.7%). The ROC curve analysis results showed that the optimal LEMS cut-off value for prediction of falls was 45.4% per body weight. In multivariate analysis, pretransplant low LEMS was a significant predictor of falls in model 1 with patient characteristics as a confounding factor and model 2 with medications-inducing falls as a confounding factor, respectively (model 1: HR 3.23, 95% CI 1.37 to 7.64; model 2: HR 2.82, 95% CI 1.20 to 6.59). CONCLUSIONS: Pretransplant LEMS was a significant predictor of post-transplant falls. The results of this study may help to prevent falls in patients undergoing allo-HSCT.
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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.
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Antineoplásicos , Estudio de Asociación del Genoma Completo , Antineoplásicos/efectos adversos , Disgeusia/inducido químicamente , Disgeusia/genética , Predisposición Genética a la Enfermedad , Humanos , Preparaciones Farmacéuticas , Polimorfismo de Nucleótido Simple , Calidad de VidaRESUMEN
OBJECTIVES: Muscle strength decline is reported to predict mortality in many cancers. However, there is little knowledge of the relation between muscle strength decline and clinical outcomes of allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study aimed to determine the impact of pre-transplant lower extremity muscle strength (LEMS) on post-transplant overall survival (OS) and non-relapse mortality (NRM). METHODS: In this retrospective cohort study, 97 adult patients underwent allo-HSCT during 2012-2020. LEMS was defined as knee extension force divided by patient's body weight. The patients were divided into low and high LEMS groups based on pre-transplant LEMS. OS was measured using the Kaplan-Meier method and the Cox proportional hazards model. The cumulative incidence of NRM was evaluated using the Fine and Gray method, with relapse considered as a competing risk event. RESULTS: Probability of OS was significantly lower in the low LEMS groups (HR 2.48, 95% CI 1.20 to 5.12, p=0.014) than in the high LEMS group on multivariate analysis. Five-year OS was 25.8% and 66.4% in the low and high LEMS groups, respectively. Risk of NRM was significantly higher in the low LEMS group (HR 4.49, 95% CI 1.28 to 15.68, p=0.019) than in the high LEMS group. The cumulative incidence of NRM was 41.4% and 11.1% in the low and high LEMS groups, respectively. CONCLUSIONS: Pre-transplant LEMS was a significant factor in predicting OS and NRM.
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The prognosis of relapsed or refractory lymphoma with central nervous system (CNS) involvement remains poor because of the lack of anticancer drugs with sufficient CNS penetration. [Case 1] A 65-year-old man was diagnosed with Stage IV mantle cell lymphoma. After two courses of chemotherapy and autologous hematopoietic stem cell (HSC) collection, urinary retention with fever developed. Cerebrospinal fluid analysis revealed leptomeningeal involvement, which was refractory to high-dose methotrexate therapy. Autologous peripheral blood stem cell transplantation (ASCT) was performed, followed by intravenous busulfan (ivBU), cyclophosphamide, and etoposideâ ;â thereafter, no relapse has been detected for over six years. [Case 2] A 40-year-old woman with right lower hemiplegia was diagnosed with primary CNS lymphoma. Although four courses of high-dose methotrexate therapy were administered, the cerebral tumor increased in size. HSCs were collected after methotrexate therapy, and ASCT was performed in addition to conditioning using ivBU, cyclophosphamide, and etoposide, followed by whole-brain and local boost irradiation. She achieved complete remission, but relapsed two years after ASCT. High-dose ivBU-containing conditioning regimens with ASCT may be useful for refractory B-cell lymphoma with CNS involvement. J. Med. Invest. 68 : 196-201, February, 2021.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Busulfano , Sistema Nervioso Central , Terapia Combinada , Femenino , Humanos , Linfoma de Células B/terapia , Masculino , Recurrencia Local de Neoplasia , Tiotepa , Trasplante AutólogoRESUMEN
A 33-year-old man was admitted to our hospital for fever and abdominal pain. A blood analysis revealed pancytopenia and increased serum pancreatic enzymes with disseminated intravascular coagulation. A detailed examination revealed acute pancreatitis, with diffuse swelling of the pancreas and diffuse beaded dilatation of the main pancreatic duct, which mimicked autoimmune pancreatitis complicated by acute myeloid leukemia. Systemic cytotoxic chemotherapy led to the remission of leukemia and pancreatitis. We hypothesized that the etiology of acute pancreatitis was invasion of leukemia cells. Acute pancreatitis is rare as a symptom of leukemia; however, we should consider the possibility of leukemia during the differential diagnosis of acute pancreatitis.
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Enfermedades Autoinmunes , Pancreatitis Autoinmune , Leucemia Mieloide Aguda , Pancreatitis , Enfermedad Aguda , Adulto , Enfermedades Autoinmunes/diagnóstico , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pancreatitis/diagnósticoRESUMEN
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.
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Quinasas Quinasa Quinasa PAM , Mieloma Múltiple , Osteólisis , Animales , Células de la Médula Ósea , Ratones , Mieloma Múltiple/tratamiento farmacológico , FN-kappa B , Osteoclastos , Ligando RANK/genética , Microambiente TumoralRESUMEN
Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.
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We retrospectively analyzed multiple myeloma (MM) patients who underwent autologous stem cell transplantation (ASCT) without maintenance therapy to assess the impact of recovery of normal immunoglobulin (Ig) on clinical outcomes. The recovery of polyclonal Ig was defined as normalization of all values of serum IgG, IgA, and IgM 1 year after ASCT. Among 50 patients, 26 patients showed polyclonal Ig recovery; 14 patients were in ≥complete response (CR) and 12 remained in non-CR after ASCT. The patients with Ig recovery exhibited a significantly better progression-free survival (PFS, median, 46.8 vs 26.7 months, p = 0.0071) and overall survival (OS, median, not reached vs 65.3 months, p < 0.00001) compared with those without Ig recovery. The survival benefits of Ig recovery were similarly observed in ≥CR patients (median OS, not reached vs 80.5 months, p = 0.061) and non-CR patients (median OS, not reached vs 53.2 months, p = 0.00016). Multivariate analysis revealed that non-CR and not all Ig recovery were independent prognostic factors for PFS (HR, 4.284, 95%CI (1.868-9.826), p = 0.00059; and HR, 2.804, 95%CI (1.334-5.896), p = 0.0065, respectively) and also for OS (HR, 8.245, 95%CI (1.528-44.47), p = 0.014; and HR, 36.55, 95%CI (3.942-338.8), p = 0.0015, respectively). Therefore, in addition to the depth of response, the recovery of polyclonal Ig after ASCT is a useful indicator especially for long-term outcome and might be considered to prevent overtreatment with maintenance therapy in transplanted patients with MM.