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Abstract Polymyalgia rheumatica (PMR) is a chronic inflammatory disease characterized by arthralgia and myalgia of the shoulder and hip girdles, and fever. PMR is linked to autoimmune diseases and autoinflammatory disorders. Exome sequencing has revealed the roles of rare variants in some diseases. Causative genes for monogenic autoinflammatory disorders might be candidate genes for the selective exome analysis of PMR. We investigated rare variants in the coding and boundary regions of candidate genes for PMR. Exome sequencing was performed to analyze deleterious rare variants in candidate genes, and the frequencies of the deleterious rare alleles in PMR were compared with those of Japanese population controls. Deleterious rare alleles in the NLRL12 gene were associated with PMR (P = 0.0069, Pc = 0.0415, odds ratio [OR] 4.49, 95% confidence interval [CI] 1.79–11.27). A multigene analysis demonstrated the deleterious rare allele frequency of the candidate genes for autoinflammatory disorders was also increased in PMR (P = 0.0016, OR 3.69, 95%CI 1.81–7.54). The deleterious rare allele frequencies of the candidate genes including NLRP12 were increased in PMR patients, showing links to autoinflammatory disorders in the pathogenesis of PMR.

Abstract Background This study aimed to compare radiological features and short-term clinical outcomes between open-wedge high tibial osteotomy (OWHTO) and tibial condylar valgus osteotomy (TCVO), to provide information facilitating decision-making regarding those two procedures. Methods Twenty-seven cases involving 30 knees that had undergone OWHTO (HTO group) and eighteen cases involving 19 knees that had undergone TCVO (TCVO group) for medial compartment knee osteoarthritis (OA) were retrospectively evaluated. Patient characteristics, severity of knee OA, lower limb alignment, joint congruity and instability were measured from standing full-length leg and knee radiographs obtained before and 1 year after surgery. Range of motion in the knee joint was measured and Knee Injury and Osteoarthritis Outcome Score (KOOS) was obtained to evaluate clinical results preoperatively and 1 year postoperatively. Results Mean age was significantly higher in the TCVO group than in the HTO group. Radiological features in the TCVO group included greater frequencies of advanced knee OA, varus lower limb malalignment, higher joint line convergence angle, and varus-valgus joint instability compared to the HTO group before surgery. However, alignment of the lower limb and joint instability improved to comparable levels after surgery in both groups. Maximum flexion angles were significantly lower in the TCVO group than in the HTO group both pre- and postoperatively. Mean values in all KOOS subscales recovered similarly after surgery in both groups, although postoperative scores on three subscales (Symptom, Pain, and ADL) were lower in the TCVO group (Symptom: HTO, 79.0; TCVO, 67.5; Pain: HTO, 80.5; TCVO, 71.1; ADL: HTO, 86.9; TCVO, 78.0). Conclusions Both osteotomy procedures improved short-term clinical outcomes postoperatively. TCVO appears preferable in cases of advanced knee OA with incongruity and high varus-valgus joint instability. An appropriate choice of osteotomy procedure is important to obtain favorable clinical outcomes.

Abstract Backgrounds Immune checkpoint inhibitors (ICIs) can significantly prolong the survival of patients with advanced non‐small‐cell lung cancer (NSCLC); however, few studies on the therapeutic effects of ICIs on bone metastases were performed. Methods This retrospective study aimed to investigate the therapeutic effects of ICIs and determine predictors of favorable ICI response and prognosis in 55 advanced NSCLC patients with bone metastases who initiated ICI treatment between 2016 and 2019, with a mean follow‐up period of 23.2 months. Patients were classified into responders (complete or partial response) and non‐responders (stable or progressive disease) according to the MD Anderson Cancer Center (MDA) criteria, and the predictors of therapeutic response were identified using multivariate logistic regression analysis. Furthermore, overall survival from the time of ICI administration to the final follow‐up or death was evaluated, and prognostic predictors were identified using Cox proportional hazards regression analysis. Results ICI response rate was 30.9% (complete in three cases, partial in 14). Median survival time was 9.3 months, with 1‐year and 2‐year survival rates of 40.6% and 19.3%, respectively. Responders survived significantly longer than non‐responders (p = 0.03). Based on the receiver operating characteristic curve, the predictive cutoff value of the pretreatment neutrophil‐to‐lymphocyte ratio (NLR) was 2.1. Multivariate analysis identified female sex (p = 0.03), use of ICIs as first‐line therapy (p

Objective The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen (HLA) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans.Methods Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR.Results DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc=0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10−5, Pc=0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10−6, OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, Pc=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, Pc=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03, but not for DRB1*04:05, SE or DQB1*04:01. Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01.Conclusion This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01, and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR.

Abstract Background Polypharmacy, defined as the concurrent use of over six drugs, is common in the treatment of heart failure (HF); however, unpredictable drug interactions with bepridil may occur. In this study, we have elucidated the influence of polypharmacy on plasma bepridil concentrations in patients with HF. Methods We conducted a multicenter retrospective study involving 359 adult patients with HF who received oral bepridil. Because QT prolongation is an adverse effect following plasma bepridil concentrations ≥800 ng/mL, the risk factors for patients achieving these concentrations at steady state were elucidated via multivariate logistic regression. The correlation between bepridil dose and plasma concentration was examined. The effect of polypharmacy on the value of the concentration-to-dose (C/D) ratio was investigated. Results A significant relationship was observed between bepridil dose and plasma concentration (p

Decreased attentional function causes problems in daily life. However, a quick and easy evaluation method of attentional function has not yet been developed. Therefore, we are searching for a method to evaluate attentional function easily and quickly. This study aimed to collect basic data on the features of electroencephalography (EEG) during attention tasks to develop a new method for evaluating attentional function using EEG. Twenty healthy young adults participated; we examined cerebral activity during a Clinical Assessment for Attention using portable EEG devices. The Mann–Whitney U test was performed to assess differences in power levels of EEG during tasks between the low- and high-attention groups. The findings revealed that the high-attention group showed significantly higher EEG power levels in the δ wave of L-temporal and bilateral parietal lobes, as well as in the β and γ waves of the R-occipital lobe, than did the low-attention group during digit-forward, whereas the high-attention group showed significantly higher EEG power levels in the θ wave of R-frontal and the α wave of bilateral frontal lobes during digit-backward. Notably, lower θ, α, and β bands of the right hemisphere found in the low-attention group may be key elements to detect attentional deficit.

Abstract Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease characterized by the production of anti-U1 ribonucleoprotein antibodies and systemic symptoms similar to those of some other autoimmune diseases. HLA-DRB1 polymorphisms are important genetic risk factors for MCTD, but precise associations of DRB1 genotypes with MCTD have not been reported in Japanese people. Genotyping of HLA-DRB1 and -DQB1 was performed in Japanese MCTD patients (n = 116) and controls (n = 413). Associations of specific allele carriers and genotype frequencies with MCTD were analyzed.The following alleles were found to be associated with predisposition to MCTD: HLA-DRB1*04:01 (P = 8.66 × 10–6, Pc = 0.0003, odds ratio [OR] 7.96, 95% confidence interval [CI] 3.13‒20.24) and DRB1*09:01 (P = 0.0189, Pc = 0.5468, OR 1.73, 95% CI 1.12‒2.67). In contrast, the carrier frequency of the DRB1*13:02 allele (P = 0.0032, Pc = 0.0929, OR 0.28, 95% CI 0.11‒0.72) was lower in MCTD patients than in controls. The frequencies of heterozygosity for HLA-DRB1*04:01/*15 (P = 1.88 × 10–7, OR 81.54, 95% CI 4.74‒1402.63) and DRB1*09:01/*15 (P = 0.0061, OR 2.94, 95% CI 1.38‒6.25) were also higher in MCTD patients. Haplotype and logistic regression analyses suggested a predisposing role for HLA-DRB1*04:01, DQB1*03:03, and a protective role for DRB1*13:02. Increased frequencies of HLA-DRB1*04:01/*15 and DRB1*09:01/*15 heterozygous genotypes were found in Japanese MCTD patients.

GM1-gangliosidosis is a progressive neurodegenerative glycosphingolipidosis resulting from a GLB1 gene mutation causing a deficiency of the lysosomal enzyme β-galactosidase, which leads to the abnormal accumulation of GM1 ganglioside in the central nervous system. In the most severe early infantile phenotype, excessive ganglioside accumulation results in a rapid decline in neurological and psychomotor functions, and death occurs within 2 years of age. Currently, there is no effective therapy for GM1-gangliosidosis. In this study, we evaluated the therapeutic efficacy of ex vivo gene therapy targeting hematopoietic stem cells using a lentiviral vector to increase enzyme activity, reduce substrate accumulation, and improve astrocytosis and motor function. Transplanting GLB1-transduced hematopoietic stem cells in mice increased β-galactosidase enzyme activity in the central nervous system and visceral organs. Specifically, this gene therapy significantly decreased GM1 ganglioside levels in the brain, especially in the cerebrum. More important, this gene therapy rectified astrocytosis in the cerebrum and improved motor function deficits. Furthermore, the elevation of serum β-galactosidase activity in secondary-transplanted mice suggested the ability of transduced hematopoietic stem cells to repopulate long term. These data indicate that ex vivo gene therapy with lentiviral vectors is a promising approach for the treatment of brain deficits in GM1 gangliosidosis.

More than 50 lysosomal storage diseases (LSDs) are associated with lysosomal dysfunctions with the frequency of 1:5,000 live births. As a result of missing enzyme activity, the lysosome dysfunction accumulates undegraded or partially degraded molecules, affecting the entire body. Most of them are life-threatening diseases where patients could die within the first or second decade of life. Approximately 20 LSDs have the approved treatments, which do not provide the cure for the disorder. Therefore, the delivery of missing genes through gene therapy is a promising approach for LSDs. Over the years, ex vivo lentiviral-mediated gene therapy for LSDs has been approached using different strategies. Several clinical trials for LSDs are under investigation.Ex vivo lentiviral-mediated gene therapy needs optimization in dose, time of delivery, and promoter-driven expression. Choosing suitable promoters seems to be one of the important factors for the effective expression of the dysfunctional enzyme. This review summarizes the research on therapy for LSDs that has used different lentiviral vectors, emphasizing gene promoters.

Abstract Background Giant cell tumor of bone (GCTB) is an intermediate tumor commonly arising from the epiphysis of the distal femur and proximal tibia. Standard GCTB treatment is joint-preserving surgery performed using thorough curettage and the filling of the cavity with allo-, auto-, polymethyl methacrylate (PMMA), or synthetic bone graft. Calcium phosphate cement (CPC) is an artificial bone substitute, which has the benefit of being able to adjust defects, consequently inducing immediate mechanical strength, and promoting biological healing. Secondary osteoarthritis may occur following GCTB treatment and may need additional surgery if severe. However, details regarding surgery for secondary osteoarthritis have not been fully elucidated. There are no reports on the use of total knee arthroplasty (TKA) for the treatment of secondary osteoarthritis following CPC packing. The insertion of an alignment rod is a standard procedure in TKA; however, it was difficult to perform in this case due to CPC. Therefore, we used a computed tomography (CT)-free navigation system to assist the distal femur cut. This study presents a knee joint secondary osteoarthritis case following CPC packing for GCTB curettage that was treated with standard TKA. Case presentation A 67-year-old Japanese woman, who was previously diagnosed with left distal femur GCTB and was treated by curettage and CPC packing 7 years ago, complained of severe knee pain. Left knee joint plain radiography revealed Kellgren and Lawrence (K-L) grade 4 osteoarthritis without evidence of tumor recurrence. Therefore, she was scheduled for TKA. There are no reports on the cutting of a femoral condyle surface with massive CPC with accurate alignment. Because it is difficult to insert the alignment rod intramedullary and cut the femoral condyle with CPC, we planned CT-free navigation-guided surgery for accurate bone cutting using an oscillating tip saw system to prevent CPC cracks. We performed standard TKA without complications, as planned. Postoperative X-ray showed normal alignment. Knee Society Knee Score (KSKS) and Knee Society Function Score (KSFS) ameliorated from 27 and 29 to 64 and 68, respectively The patient can walk without a cane postoperatively. Conclusion There was no report about the surface TKA guided by CT-free navigation after primary GCT surgery with CPC. We believe that this case report will help in planning salvage surgery for secondary osteoarthritis after CPC packing.

Abstract Objective Rheumatoid arthritis (RA) is often complicated with chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway disease, which occur as extra-articular manifestations. CLD in RA have been associated with the production of rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), or anti-carbamylated protein (CarP) antibody. However, few validation studies have been performed thus far. In the present study, we investigated the association of RF, ACPA, and anti-CarP antibodies with RA complicated with CLD. Methods Sera from RA patients with or without CLD were collected. The levels of serum RF, RF immunoglobulin A (IgA), ACPA IgG, ACPA IgA, and ACPA secretory component (SC) were measured using enzyme-linked immunosorbent assay. Results The comparison of RA patients with and without CLD showed that RF IgA was associated with ILD (mean ± standard deviation: 206.6 ± 400.5 vs. 95.0 ± 523.1 U/ml, respectively, P = 1.13 × 10− 8), particularly usual interstitial pneumonia (UIP) (263.5 ± 502.0 U/ml, P = 1.00 × 10− 7). ACPA SC was associated with RA complicated with ILD (mean ± standard deviation: 8.6 ± 25.1 vs. 2.3 ± 3.4 U/ml, respectively, P = 0.0003), particularly nonspecific interstitial pneumonia (NSIP) (10.7 ± 31.5 U/ml, P = 0.0017). Anti-CarP antibodies were associated with RA complicated with ILD (0.042 ± 0.285 vs. 0.003 ± 0.011 U/ml, respectively, P = 1.04X10− 11). Conclusion RF IgA and ACPA SC in RA were associated with UIP and NSIP, respectively, suggesting different specificities in patients with RA. Anti-CarP antibodies were associated with ILD in RA. These results may help elucidate the different pathogeneses of UIP and NSIP in RA.

Background Interstitial lung disease (ILD) occasionally occurs in rheumatoid arthritis (RA) and confers a dismal prognosis. We previously reported that a single-nucleotide variant (SNV) of MUC5B was associated with ILD in RA. However, the pathogenesis of ILD in Japanese patients with RA could not be explained solely by this SNV because its frequency is extremely low in the Japanese population. Here, we examined whether a different idiopathic pulmonary fibrosis susceptibility SNV might be associated with ILD in Japanese patients with RA.Methods Genotyping of rs2609255 (G/T) in FAM13A was conducted in 208 patients with RA with ILD and 420 without chronic lung disease using TaqMan assays.Results A significant association with usual interstitial pneumonia (UIP) in RA was detected for rs2609255 under the allele model (p=0.0092, Pc=0.0276, OR 1.53, 95% CI 1.12 to 2.11) and recessive model for the G allele (p=0.0003, Pc=0.0009, OR 2.63, 95% CI 1.59 to 4.32). FAM13A rs2609255 was significantly associated with UIP in male patients with RA (p=0.0043, OR 3.65, 95% CI 1.52 to 8.73) under the recessive model.Conclusions This study is the first to document an association of rs2609255 with ILD in Japanese patients with RA, implicating it in the pathogenesis of UIP, though studies on the function of rs2609255 are warranted.

Background: Pectoralis minor tightness has been thought to affect the scapular position. Despite the wide implementation of doorway stretch in clinical practice owing to its apparent effectiveness in stretching the pectoralis minor, limited studies have investigated its influence on the glenohumeral rotational range of motion (ROM). This study aimed to examine the acute effects of doorway stretch on the glenohumeral rotational ROM and the correlation between the scapular position and ROM. Materials and Methods: In total, 34 male high-school baseball players participated in this study. Outcomes included the pectoralis minor muscle length, glenohumeral rotational ROM, and scapular position. The distance between the sternocostal joint of rib 4 and the coracoid process was measured as the pectoralis minor length. Internal and external rotation ROM with the shoulder abducted at 90° were measured. The scapular position was defined by the following two measurements: the distance between the surface and the posterolateral corner of the acromion as well as the scapular index. The participants performed doorway stretch by abducting and externally rotating the shoulder at 90° and flexing the elbow at 90°. The outcomes were compared before and after stretching. Furthermore, the correlation between these changes was investigated. Results: Pectoralis minor muscle length and glenohumeral internal rotation ROM was significantly higher after stretching than before, and the scapular position also significantly changed (P

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular neoplasm that requires long-term management. Several reports describe disseminated intravascular coagulation (DIC) associated with angiosarcoma, but no association with EHE has been reported. We encountered a patient with DIC complicated by multifocal EHE. The patient was an 83-year-old woman with spinal lesions, small lung nodules, and a soft tissue mass in the right buttock. The tumor was biopsied and diagnosed as EHE. The patient received pain control therapy without antitumor therapy. One month later, DIC developed with tumor progression. DIC subsided with nafamostat mesylate infusion, and oral apixaban was administered. DIC was managed for 5 months until the patient died of brain metastases. This is the first report of a patient with DIC complicated by EHE. It should be noted that progression of EHE can cause DIC. We were able to manage DIC using anticoagulant agents.

Recently, the prognosis of metastatic renal cell carcinoma (mRCC) has improved owing to the development of immunotherapy using immune checkpoint inhibitors (ICIs). However, there have been few studies on the therapeutic effect of ICIs in bone metastases from renal cell carcinoma (RCC). We report a case in which pulmonary and humeral metastases from RCC were significantly ameliorated using ICIs, while surgery for a pathological fracture of the humerus significantly improved the patient’s quality of life (QoL). A 70-year-old man who underwent a left nephrectomy for RCC developed multiple pulmonary metastases and humeral metastasis with a pathological fracture one year after surgery, and combined treatment with nivolumab and ipilimumab was initiated. After four courses of ICI treatment, multiple pulmonary metastases had almost disappeared, and the tumor at the fracture site had shrunk remarkably. However, the shoulder joint function had decreased due to the fracture, worsening his QoL. Therefore, he underwent surgery and returned to normal daily life one month after. Postoperative histopathological examination of bone and soft tissue at the fracture site revealed no malignancy. To our knowledge, this is the first case report of complete remission of bone metastasis of RCC based on histopathological examination with ICI treatment.

Aging affects several tissues in the body, including skeletal muscle. Multiple types of collagens are localized in the skeletal muscle and contribute to the maintenance of normal muscle structure and function. Since the effects of aging on muscle fibers vary by muscle fiber type, it is expected that the effects of aging on intramuscular collagen might be influenced by muscle fiber type. In this study, we examined the effect of aging on collagen levels in the soleus (slow-twitch muscle) and gastrocnemius (fast-twitch muscle) muscles of 3-, 10-, 24-, and 28-month-old male C57BL/6J mice using molecular and morphological analysis. It was found that aging increased collagen I, III, and VI gene expression and immunoreactivity in both slow- and fast-twitch muscles and collagen IV expression in slow-twitch muscles. However, collagen IV gene expression and immunoreactivity in fast-twitch muscle were unaffected by aging. In contrast, the expression of the collagen synthesis marker heat shock protein 47 in both slow- and fast-twitch muscles decreased with aging, while the expression of collagen degradation markers increased with aging. Overall, these results suggest that collagen gene expression and immunoreactivity are influenced by muscle fiber type and collagen type and that the balance between collagen synthesis and degradation tends to tilt toward degradation with aging.

Abstract Age affects the clinical outcomes of cancer treatment, including those for bone sarcoma. Successful reconstruction using frozen autograft after excision of bone sarcoma has been reported; however, little is known about the clinical outcomes of frozen autograft reconstruction according to age. The purpose was to evaluate the clinical outcomes of the frozen autograft reconstruction focusing on skeletally mature adolescents and young adults (AYAs) that was 15 to 39 years of age. A total of 37 AYA patients with primary bone sarcoma on the appendicular skeleton were enrolled in this study. The mean follow-up period was 89 months. The graft survival (GS), overall survival (OS), recurrence-free survival (RFS), complications and the function were retrospectively evaluated using medical records. The 10-year GS, OS, and RFS rates were 76%, 84%, and 79%, respectively. Bone union was achieved with a rate of 94% within 1 year after surgery, and nonunion (n = 1) and fracture (n = 2) were infrequently observed. Graft removal was performed in 7 cases, and the most common reason for the removal was infection (n = 5). The Musculoskeletal Tumor Society score was excellent in 23 cases of the available 29 cases. Frozen autograft reconstruction for AYAs showed excellent clinical outcomes, although the long-term follow-up is required.

Abstract Background Synovial sarcoma is an aggressive but chemosensitive soft-tissue tumor. We retrospectively analyzed the efficacy of perioperative chemotherapy for synovial sarcoma with data from the nationwide database, Bone and Soft Tissue Tumor Registry in Japan. Methods This study included 316 patients diagnosed with synovial sarcoma between 2006 and 2012. Oncologic outcomes were analyzed using a Cox-hazard regression model. Moreover, the effects of perioperative chemotherapy on outcomes were evaluated using a matched-pair analysis. The oncologic outcomes of patients who did or did not receive chemotherapy were compared (cx + and cx-). Results Multivariate analysis revealed significant correlations of age (over 40, hazard ratio [HR] = 0.61, p = 0.043), margin status (marginal resection, HR = 0.18, p

IntroductionSarcomas are rare heterogeneous malignant tumors that originate and develop in soft tissue or bone. Effective treatment for sarcomas is still limited to traditional chemotherapy and surgery that are often ineffective for recurrent disease. Cyclin-dependent kinases (CDKs) promote abnormal cell cycling and cell division in many cancers including sarcomas. Therefore, our hypothesis was that CDK inhibitors may be useful candidates for sarcoma treatment. Patient-derived orthotopic xenograft (PDOX) mouse models mimic the clinical disease for all major cancer types and have identified effective treatments that hold much clinical promise. The present report reviews sarcoma PDOX models that we have established for their potential to discover effective combination treatments based on CDK inhibitors for recalcitrant sarcoma.MethodsWe have previously reported six sarcoma PDOX studies evaluating the CDK inhibitor palbociclib on sarcoma, including osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma.ResultsPalbociclib monotherapy significantly inhibited, but not regressed, the PDOX growth of osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma. A combination of palbociclib and a mammalian target of rapamycin (mTOR) inhibitor, everolimus, significantly inhibited, but did not regress, the PDOX growth of osteosarcoma. Combinations of palbociclib with a multikinase inhibitor, sorafenib, and palbociclib combined with recombinant methioninase were effective and regressed the osteosarcoma and de-differentiated liposarcoma PDOX models, respectively.ConclusionsNovel effective drug combinations using the CDK inhibitor palbociclib were identified in PDOX models of the major types of sarcomas. Methionine restriction effected by methioninase increased the efficacy of palbociclib. Combination therapy with palbociclib is a promising future strategy for improved sarcoma therapy in the clinic.

Abstract In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p

Abstract Background Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously. Case presentation We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free. Conclusions An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.

Abstract Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

Abstract Background Atypical fractures may occur due to the combined effect of severely suppressed bone turnover (SSBT) caused by long-term bisphosphonate treatment and chronic repetitive bone microdamage. Atypical fracture of the ulna due to SSBT is a rare entity; there is no standardized treatment strategy for this condition. We successfully treated a patient with atypical fracture of the ulna. Herein, we present this patient, review the relevant literature, and discuss the treatment strategy. Case presentation An 84-year-old woman presented with atypical fracture of the left ulnar shaft due to SSBT. She had a history of bisphosphonate therapy (ibandronate and alendronate) since more than 10 years; her bone turnover was severely suppressed. We performed open reduction and internal fixation (ORIF) using dual plate with some additional treatments. These included drilling and decortication, use of autogenous bone graft, low-intensity pulsed ultrasound (LIPUS) treatment, and administration of teriparatide. Finally, bone union was observed at 11 months after surgery. Conclusions Based on the literature review and our experience with this case, ORIF alone may not be adequate to achieve bone union; drilling, decortication, and use of cancellus bone graft is important to achieve favorable outcomes. Administration of teriparatide and LIPUS may facilitate early bone union, although further studies are required to provide more definitive evidence. Furthermore, ORIF using dual plate may help avoid implant failure owing to the long time required for bone union.

Background: Rheumatoid arthritis (RA) is occasionally complicated with interstitial lung disease (ILD). A recent genome-wide association study of ILD in RA reported an association with the polymorphism rs12702634 in RPA3-UMAD1 . We conducted an association study of this variant with ILD in Japanese RA patients to replicate this association. Methods: Genotyping of rs12702634 was performed in 175 RA with ILD and 411 RA without chronic lung disease. Results: No association was detected for rs12702634 with ILD in RA ( P = .6369, odds ratio [OR] 1.13, 95% confidence interval [CI] 0.72-1.78). Meta-analysis of these data combined with the data from the recent report showed no significant association ( P = .0996, OR 1.52, 95% CI 0.92–2.49). Conclusions: The present study demonstrated no association of RPA3-UMAD1 rs12702634 with ILD in RA, suggesting the heterogeneity of the disease.

IntroductionIn advanced non-small-cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) have been reported a better treatment outcome on primary lesions, however, the therapeutic effect on bone metastases has not been clarified. This study investigates the therapeutic effect of ICIs on bone metastases in advanced NSCLC.MethodsThe data of patients with advanced NSCLC, treated with ICIs from 2016 to 2019 at our hospital, were analyzed. The therapeutic effects of ICIs on primary lung and metastatic bone lesions, concomitant use of bone modifying agents (BMA), treatment outcomes, and frequency of immune-related adverse events (irAEs) and skeletal-related events (SREs) were investigated.ResultsA total of 29 patients were included (19 men and 10 women; mean age, 64.2 years). Among the ICIs, pembrolizumab was the most used (55.2%), and concomitant use of BMA was prevalent in 21 patients (zoledronic acid=1, denosumab=20). The therapeutic effect was partial response (PR) in 10.3% (n=3) on primary lung lesions by RECIST 1.1, complete response (CR) in 6.9% (n=2) and PR in 17.2% (n=5) on bone metastatic lesions by MDA criteria. ICIs suppressed the progression of bone metastasis in 21 cases (72.4%). All patients in CR and PR were treated with pembrolizumab and denosumab. SREs and irAEs were developed in 3.4% (n=1) and 20.7% (n=6), respectively. The median survival time after treatment with ICIs was 11.0 months. Concomitant therapy with ICIs and denosumab significantly prolonged the overall survival compared to ICI-only therapy (16.0 months vs. 2.5 months, p

OBJECTIVES Coronavirus Disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Serological testing for anti-SARS-CoV-2 nucleocapsid (N) antibodies (Abs) and anti-SARS-CoV-2 spike (S) Abs is performed to detect prior COVID-19 infection. It is still controversial which antibodies are the most sensitive and specific, and which can be detected earliest after infection. Here, we evaluated the results of serological tests of anti-SARS-CoV-2 N and S Abs in Japan. METHODS Symptomatic COVID-19 patients (n = 84) and control patients with rheumatoid arthritis (n = 93) were recruited at Tokyo National Hospital. Anti-SARS-CoV-2 N and S Abs were measured by commercial electrochemiluminescence immunoassays. RESULTS The fraction of patients positive for anti-SARS-CoV-2 N and S Abs was highest >14 days after symptom onset. The frequency of anti-SARS-CoV-2 S Ab positivity at this time (80.4%) tended to be slightly but not significantly lower than anti-SARS-CoV-2 N Ab positivity (84.8%). Optimized cut-off levels for anti-SARS-CoV-2 N and S Ab positivity were lower than the manufacturer's recommended cut-off levels. Using multiple linear regression analyzes with anti-SARS-CoV-2 N and S Abs, we created an Ab-index with high sensitivity. CONCLUSION To increase the sensitivity of serological diagnostic tests for COVID-19, it is suggested that both anti-SARS-CoV-2 N and S Abs should be measured and cut-off levels decreased.

Objectives: The severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019. A serological test is conducted to determine prior infection by severe acute respiratory syndrome coronavirus 2. We investigated whether the results of anti-severe acute respiratory syndrome coronavirus 2 antibody tests are modified in patients with rheumatoid arthritis. Methods: Patients in Japan with rheumatoid arthritis were recruited at Sagamihara Hospital from July 2014 to October 2015 ( n = 38; 2014 cohort) and at Tokyo Hospital from June to October 2020 ( n = 93; 2020 cohort). Anti-severe acute respiratory syndrome coronavirus 2 antibodies were measured by electrochemiluminescence immunoassay or immunochromatographic assay. Results: Anti-severe acute respiratory syndrome coronavirus 2 antibodies were not detected in any of the samples from rheumatoid arthritis patients tested by electrochemiluminescence immunoassay. Anti-severe acute respiratory syndrome coronavirus 2 antibodies were detected by immunochromatographic assay in the 3 (7.9%) serum samples in the 2014 cohort and 15 (16.1%) serum samples in the 2020 cohort. The IgM rheumatoid factor levels were increased in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (mean ± standard deviation (IU/ml), 1223.0 ± 1308.7 versus 503.6 ± 1947.2; P = 0.0101). The levels of IgG rheumatoid factor were also upregulated in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (4.0 ± 0.7 versus 2.4 ± 0.9; P = 0.0013). Conclusion: The results of IgM anti-severe acute respiratory syndrome coronavirus 2 antibody testing by immunochromatographic assay are modified by IgM or IgG rheumatoid factors in rheumatoid arthritis patients.

Abstract Background Intramedullary osteosclerosis (IMOS) is a rare condition without specific radiological findings except for the osteosclerotic lesion and is not associated with family history and infection, trauma, or systemic illness. Although the diagnosis of IMOS is confirmed after excluding other osteosclerotic lesions, IMOS is not well known because of its rarity and no specific feature. Therefore, these situations might result in delayed diagnosis. Hence, this case report aimed to investigate three cases of IMOS and discuss imaging findings and clinical outcomes. Case presentation All three cases were examined between 2015 and 2019. The location of osteosclerotic lesions were femoral diaphyses in the 60-year-old man (Case 1) and 41-year-old woman (Case 2) and tibial diaphysis in the 44-year-old woman (Case 3). All cases complained of severe pain and showed massive diaphyseal osteosclerotic lesions in plain radiograms and computed tomography (CT) scans. Cases 2 and 3 were examined using the triphasic bone scan, and a fusiform-shaped intense area of the tracer uptake on delayed bone image was detected in both cases without (Case 2) or slightly increased vascularity (Case 3) on the blood pool image, which was reported as a specific finding of IMOS. Open biopsy was performed in all cases, and histologic section showed trabecular bone sclerosis with hypocellular fibrous tissues, finally diagnosed as IMOS. The pain was sharply improved after biopsy and kept at the latest follow-up periods (34, 33, and 6 months in Cases 1, 2, and 3, respectively). Conclusions Massive sclerotic lesions with severe pain in the diaphyseal region of long bones should be considered as IMOS to avoid the delayed diagnosis, although other sclerotic bony lesions should be carefully excluded. Triphasic bone scan with a fusiform-shaped intense area of tracer uptake on delayed bone image and without or slightly increased vascularity on the blood pool image will help confirm IMOS. The role of open biopsy was to confirm the diagnosis of IMOS and to give the severe pain relief immediately in the three cases, although more cases and long-term follow-up are necessary.

Abstract Background Limb salvage surgery is becoming increasingly popular after tumor resection in the lower extremity. Biological reconstruction and use of megaprosthesis are main methods for malignant bone tumors of the proximal femur, which remain controversial due to short- and long-term complication in the proximal femur. Tumor-bearing bone treated by liquid nitrogen is one of biological reconstruction. This study aimed to evaluate the mid- and long-term functional outcomes and complications in patients treated with frozen autograft–prosthesis composite (FAPC) reconstructions in the proximal femur. Methods This retrospective study included 19 patients (10 women, 9 men) with malignant tumors of the proximal femur who underwent tumor-wide resection and FAPC reconstruction (mean age, 46 years; range, 9–77 years). The mean follow-up period of 69 months (range, 9–179 months). Functional outcomes, oncological outcome and complications were evaluated by Musculoskeletal Tumor Society score, clinical and radiological examinations. Results The overall survival rate was 68.4%, and the mean Musculoskeletal Tumor Society functional score was 26.4 points (88%). FAPC survival rates were 100 and 50% at 5 and 10 years, respectively. Five of the 19 patients (26%) had complications: 2 required prosthesis removal and 2 developed a deep infection around acetabular. Wear of the acetabulum occurred in 2 cases, while disease recurrence was occurred in 1 case. There were no cases of greater trochanter avulsion, obvious absorption around frozen bone, prosthesis loosening or leg length discrepancy. Conclusions Due to without femoral osteotomy, this technique features satisfactory functional outcome and provide biomechanical stability that is comparable to those of other methods of biological reconstruction or megaprosthesis.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

Background. We report a retrospective case series analysis of clinical outcomes of patients with soft tissue sarcoma around the elbow. Methods. Twenty-two patients underwent surgical tumor excision between January 1999 and May 2017, with a mean follow-up of 85.2 months. Results. Six tumors were localized in the upper arm, nine in the elbow, and seven in the forearm. Sixteen tumors were deep-seated, and six were superficially located. Fifteen patients underwent wide excision, including one amputation, and 18 achieved (81.8%) negative margins histologically. Two local recurrences and four distant metastases developed. The mean Musculoskeletal Tumor Society score was 92.0% (range, 33.3–100). The 5-year local recurrence-free survival rate, metastasis-free survival rate, and overall survival rate were 90.0%, 77.0%, and 79.7%, respectively. Conclusions. Local control and limb function can have favorable outcomes when the tumor excised has a histologically negative margin without sacrificing the major structure.

Chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway diseases (ADs), are common complications of rheumatoid arthritis (RA). Rheumatoid factor (RF) and anti-citrullinated peptide antibodies are reported to be associated with CLD in RA patients. The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (Abs) is associated with clinically amyopathic dermatomyositis developing into rapidly progressive ILD. However, few studies on anti-MDA5 Abs in RA have been published. Here, we analyzed the association of anti-MDA5 Abs with CLD complications in RA. Anti-MDA5 Abs were quantified in sera from RA patients with or without CLD. Anti-MDA5 Ab levels were higher in RA patients with ADs than without (mean ± SDM, 4.4 ± 2.4 vs. 4.0 ± 4.2, p = 0.0001). AUC values of anti-MDA5 Ab and RF ROC curves were similar in RA patients with or without CLD (0.578, 95%CI 0.530–0.627 and 0.579, 95%CI 0.530–0.627, respectively, p = 0.9411). Multiple logistic regression analysis of anti-MDA5 Abs and clinical characteristics yielded an MDA5-index with a higher AUC value than anti-MDA5 Ab alone (0.694, 95%CI 0.648–0.740, p = 5.08 × 10−5). Anti-MDA5 Abs were associated with ADs in RA patients and could represent a biomarker for CLD, similar to RF. The involvement of anti-MDA5 Abs in the pathogenesis of ADs in RA is proposed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019. Anti-SARS-CoV-2 spike (S) and neutralizing antibodies (Abs) are measured to evaluate the efficacy of vaccines. Human leukocyte antigen (HLA) may be associated with vaccine efficacy. Here, we investigated the association of HLA polymorphisms with the production of anti-SARS-CoV-2 S or neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Genotyping of DRB1 and DQB1 was conducted in 87 Japanese RA patients vaccinated with BNT162b2. Associations of allele or haplotype carrier frequencies with anti-SARS-CoV-2 S or neutralizing Abs were examined. DRB1*12:01 was significantly positively associated with the production of S Ab (p = 0.0225, odds ratio [OR] 6.08, 95% confidence interval [CI] 1.32–28.03). The DQB1*03:01 allele carrier frequency tended to be higher in high responders of S Ab. Allele carrier frequencies of DRB1*15:01 (p = 0.0102, OR 9.26, 95% CI 1.65–52.01) and DQB1*06:02 (p = 0.0373, OR 7.00, 95% CI 1.18–41.36) were higher in responders of neutralizing Ab. Haplotype and two-locus analyses of DRB1 and DQB1 suggested that DRB1 alleles were the primary drivers of these associations. Logistic regression analysis showed associations of these alleles independent of clinical characteristics. Independent associations were found between HLA alleles and anti-SARS-CoV-2 Ab production by vaccinated RA patients.

Interstitial lung disease (ILD) is frequently a complication of rheumatoid arthritis (RA) as an extra-articular manifestation which has a poor prognosis. Acute-onset diffuse ILD (AoDILD) occasionally occurs in RA and includes acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia. AoDILD also confers a poor prognosis in RA. Previously-established biomarkers for ILD include Krebs von den lungen-6 and surfactant protein-D originally defined in patients with idiopathic pulmonary fibrosis; the sensitivity of these markers for RA-associated ILD (RA-ILD) is low. Although many studies on ILD markers have been performed in idiopathic pulmonary fibrosis, only a few validation studies in RA-ILD or AoDILD have been reported. Biomarkers for RA-ILD and AoDILD are thus still required. Recently, genomic, cytokine, antibody, and metabolomic profiles of RA-ILD or AoDILD have been investigated with the aim of improving biomarkers. In this review, we summarize current preliminary data on these potential biomarkers for RA-ILD or AoDILD. The development of biomarkers on RA-ILD has only just begun. When validated, such candidate biomarkers will provide valuable information on pathogenesis, prognosis, and drug responses in RA-ILD in future.

Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.

Abstract Background The purpose of this study was to compare radiological features between high tibial osteotomy (HTO) and tibial condylar valgus osteotomy (TCVO), in order to define the radiological indication criteria for TCVO. Methods Thirty-two cases involving 35 knees that had undergone HTO and the same number that had undergone TCVO for knee osteoarthritis were retrospectively evaluated. Characteristics of both groups did not differ significantly. Lower limb alignment, bone morphology, joint congruity, and joint instability were measured in standing full-length leg and knee radiographs obtained before and after surgery. Results Radiological features in the TCVO group included greater frequencies of advanced knee OA grade, varus lower limb malalignment, depression of the medial tibial plateau, and varus-valgus joint instability compared to the HTO group before surgery. However, tibial morphology, alignment of the lower limb, and joint instability improved to comparable levels after surgery in both groups. Conclusions TCVO appears preferable in cases with advanced knee OA, destroyed or inclined medial tibial plateau, widened and subluxated lateral joint, and high varus-valgus joint instability.

The goal of the present study was to determine the efficacy of osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor for the treatment of aggressive EGFR-mutant non-small cell lung cancer (NSCLC), compared to cisplatinum (CDDP) + pemetrexed (PEM). The NSCLC cell line PC-9 expressing green fluorescence protein (PC-9-GFP) was implanted in the brain of nude mice and was treated with CDDP + PEM or AZD9291. Tumors were observed by non-invasive fluorescence imaging. AZD9291 treatment caused tumor regression in contrast to CDDP + PEM which had only a slight inhibitory effect. These results suggest that AZD9291 is a promising clinical option for NSCLC patients with brain metastasis.

Undifferentiated/unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as first-line therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM). The major goal of the present study was to determine the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or first-line drug DOX on a USTS not-otherwise specified (USTS/NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. USTS PDOX models were randomized into six groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX. Tumor size and body weight were measured. Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX. Tumors treated with GEM combined with nab-PTX had the most necrosis. Body weight of the treated mice was not significantly different from the untreated controls. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas. These results suggest that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS.

Abstract Background Use of an implant is one of the risk factors for surgical site infection (SSI) after malignant bone tumor resection. We developed a new technique of coating titanium implant surfaces with iodine to prevent infection. In this retrospective study, we investigated the risk factors for SSI after malignant bone tumor resection and to evaluate the efficacy of iodine-coated implants for preventing SSI. Methods Data from 302 patients with malignant bone tumors who underwent malignant bone tumor resection and reconstruction were reviewed. Univariate analyses were performed, followed by multivariate analysis to identify risk factors for SSI based on the treatment and clinical characteristics. Results The frequency of SSI was 10.9% (33/302 tumors). Pelvic bone tumor (OR: 4.8, 95% CI: 1.8–13.4) and an operative time ≥ 5 h (OR: 3.4, 95% CI: 1.2–9.6) were independent risk factors for SSI. An iodine-coated implant significantly decreased the risk of SSI (OR: 0.3, 95% CI: 0.1–0.9). Conclusion The present data indicate that pelvic bone tumor and long operative time are risk factors for SSI after malignant bone tumor resection and reconstruction, and that iodine coating may be a promising technique for preventing SSI.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A serological test is used to assess the efficacy of vaccination. It has been reported that anti-SARS-CoV-2 spike (S) and neutralizing antibody (Ab) levels are lower following vaccination in patients with rheumatic disease. Here, we investigated anti-SARS-CoV-2 S and neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Anti-SARS-CoV-2 S and neutralizing Abs were quantified in 101 RA patients and 117 controls. Anti-SARS-CoV-2 S Ab levels were lower in RA patients than both earlier after vaccination in controls (mean RA 324.1 ± 591.8 SDM vs. control 1216.6 ± 854.4 [U/mL], p < 0.0001) and later after vaccination (324.1 ± 591.8 vs. 582.0 ± 415.6 [U/mL], p = 0.0002). The interval between vaccination of the RA patients and serum collection was longer than for controls early after vaccination (142.1 ± 31.6 vs. 98.3 ± 11.2 [days], p < 0.0001), but shorter than the later sample from the controls (142.1 ± 31.6 vs. 257.3 ± 11.2 [days], p < 0.0001). Importantly, anti-SARS-CoV-2 neutralizing Ab titers in RA patients were higher than in either early or later control samples (10.7 ± 4.9 vs. 8.6 ± 6.6 [%], p = 0.0072, and 10.7 ± 4.9 vs. 3.1 ± 3.7 [%], p < 0.0001, respectively). Anti-SARS-CoV-2 S Ab titers in vaccinated RA patients were lower than in controls, but they were influenced by other clinical manifestations. Anti-SARS-CoV-2 neutralizing Ab levels were independently increased in RA.

Serological detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N), spike (S), and neutralizing antibodies (Abs) is commonly undertaken to evaluate the efficacy of vaccination. However, the relative efficiency of different SARS-CoV-2 Ab detection systems has not been extensively investigated. Here, we evaluated serological test systems in vaccinated Japanese. SARS-CoV-2 N, S, and neutralizing Abs in sera of 375 healthy subjects a mean 253 days after vaccination were assessed. The sensitivity of Elecsys Anti-SARS-CoV-2 S (Roche S) and Anti-SARS-CoV-2 S IgG (Fujirebio S) was 100% and 98.9%, respectively, with a specificity of 100% for both. The sensitivity of Anti-SARS-CoV-2 neutralizing Ab (MBL Neu) was 2.7%, and the specificity was 100%. Fujirebio S correlated with Roche S (rho = 0.9182, p = 3.97 × 10−152). Fujirebio S (rho = 0.1295, p = 0.0121) and Roche S (rho = 0.1232, p = 0.0170) correlated weakly with MBL Neu. However, Roche S did correlate with MBL Neu in patients with COVID-19 (rho = 0.8299, p = 1.01 × 10−12) and in healthy subjects more recently after vaccination (mean of 90 days, rho = 0.5306, p = 0.0003). Thus, the Fujirebio S and Roche S results were very similar, but neither correlated with neutralizing antibody titers by MBL Neu at a later time after vaccination.

There are several options for biological reconstruction after bone tumor resection. If the tumor invades an epiphysis, the reconstruction is far more complicated because there is no option to restore large joint cartilage using currently available medical techniques. Frozen autograft with liquid nitrogen has been used as recycled autologous bone graft and the purpose of the present study was to assess the outcome of grafted cartilage in osteoarticular frozen autografts used in the treatment of patients with bone and soft-tissue sarcoma. We have treated 27 patients with cases of bone tumor resection involving an epiphysis where frozen autografts were used for reconstruction. If the tumor was located in a limited part of the epiphysis, partial resection of the epiphysis was performed to preserve the healthy part of the cartilage in 4 cases. The survival of grafted frozen cartilage was assessed by X-ray imaging. The end point was defined as grade IV of the Kellgren and Lawrence osteoarthritis grading system and was recorded using the Kaplan–Meier method. In case of removal of grafted bone after the surgery, pathological findings were assessed by hematoxylin and eosin staining of sections of resected cartilage in available cases to observe the fate of grafted cartilage over time. The postoperative mean follow-up period was 94.0 months. Grade IV osteoarthritis occurred in 12 patients. All patients in the partial epiphyseal freezing group survived compared with only 1 patient in the total epiphyseal freezing group who had survived to the final follow up (p

Bone is one of the most frequent metastatic sites in non-small cell lung cancer (NSCLC). Osimertinib, with and without bevacizumab (BV), has been investigated on advanced NSCLC patients. However, the efficacy of those drugs on bone metastasis of NSCLC has not been investigated. The human NSCLC cell line H1975, expressing red fluorescent protein (H1975-RFP), was orthotopically injected to the tibia of nude mice. The established mouse models were randomized into four treatment groups of nine mice: Control; BV alone; osimertinib alone; osimertinib and BV combination. The tumors were observed by non-invasive fluorescence imaging. Osimertinib, with or without BV, caused tumor regression, increased mouse survival, and bone remodeling in the bone metastasis models. These results suggest that osimertinib is a promising clinical option for NSCLS patients with bone metastasis.

Abstract Background Difficult resection of tumors from regions with complex local anatomy, such as the pelvis and sacrum, is likely to result in inadequate surgical margins (intralesional or marginal); this is because three-dimensional osteotomy is difficult particularly around the acetabulum. Additionally, removal of the joint makes reconstruction very difficult; thus, retention of good function also becomes difficult. In musculoskeletal oncology, computer navigation systems are still not widely used to prevent tumor-positive margins. We performed wide excision with guidance from a computer navigation system and reconstruction using frozen bone autografts for malignant pelvic bone tumors in two patients, and we obtained excellent functional and oncological outcomes. Here we present these patients and discuss our approach. Case presentation Case 1: A 12-year-old girl presented with Ewing sarcoma of the left pelvis (PI-II). We performed wide excision assisted by a computer navigation system with the osteotomy of the load surface of acetabulum and reconstruction using a frozen bone autograft. At the final follow-up, she showed excellent function and was alive without the disease. Moreover, she did not have osteoarthritis of the left hip joint. Case 2: A 71-year-old woman presented with dedifferentiated chondrosarcoma of the right pelvis (PII-III). We performed wide excision assisted by a computer navigation system with osteotomy avoiding load surface of the acetabulum and reconstruction using a frozen bone autograft; there was no tumor at the load surface. At the final follow-up, she showed good function, was alive without the disease, and did not have osteoarthritis of the left hip joint. Conclusions Wide excision assisted by a computer navigation system and reconstruction using a frozen bone autograft are very useful for the management/treatment of extremely difficult cases such as malignant pelvic bone tumors, particularly those including the acetabulum.

Objective To analyze patient characteristics of cancer rehabilitation and outcomes at our hospital. Methods This retrospective study analyzed 580 patients, who underwent cancer rehabilitation at our hospital and rehabilitation outcome after therapy were investigated. The relationship between the initial Barthel index and discharge outcomes was investigated, with a special focus on cancer patients with bone metastasis. The Barthel index and performance status (Eastern Cooperative Oncology Group) before and after rehabilitation were analyzed, and threshold value of home discharge was calculated from a receiver operating characteristic curve (ROC). General criteria for home discharge from our hospital included independence in performing basic activities of daily living such as bathing, feeding, and toileting or availability of home support from a family member/caregiver. Results The outcomes after rehabilitation among all the patients were as follows: discharge home 59%, death 13%, and others 27%. Statistical differences were observed between the initial and final values of the Barthel index in patients with bone metastasis, who could be discharged home (p=0.012). ROC analysis of the initial Barthel index for predicting home discharge revealed a threshold value of 60, sensitivity of 0.76, and specificity of 0.72. Conclusion The patients with bone metastasis had a lower rate of home discharge and a higher rate of mortality than all the study patients who underwent cancer rehabilitation at our hospital. It is proposed that at the time of initiation of rehabilitation for patients with bone metastasis, an initial Barthel index lower than 60 might predict a worse outcome than home discharge.

Abstract Background Epiphyseal-preservation surgery for osteosarcoma is an alternative method which has been indicated carefully to selected patients. The tumor-devitalised autograft treated with liquid nitrogen procedure is one of the biological reconstruction method to reconstruct the defect after tumor excision. The limb length discrepancy is usually appeared in children with their growth after limb-sparing surgery. This study was aimed to investigated the growth of residual epiphysis following epiphyseal-preservation surgery for childhood osteosarcoma around the knee joint. Methods We retrospectively reviewed 12 patients with osteosarcoma who underwent epiphysis preserving tumor excision (8 in distal femur and 4 in proximal tibia) and reconstructed by using tumor-devitalized autograft treated with liquid nitrogen. The mean patient age was 11 (range, 6 to 14) years. The mean follow-up period were 63 (range, 41 to 90) months. Epiphysis transverse growth rate, epiphysis-width discrepancy (EWD) and collapse of epiphysis were evaluated by using pre- and post-operative whole standing leg radiographs. A retrospective chart review was performed to investigate functional outcome, complications and oncological status. Results The mean growth of epiphysis rate was 12.6% (range, 3.3 to 28.0%) of affected side and 12.7% (range, 3.8 to 28.9%) of contralateral side, mean EWD was 0.1 mm (range, − 1.0 to 1.7 mm), mean LLD was + 26.1 mm (range, + 1 to + 48 mm) and two patients with distal femoral reconstruction underwent limb lengthening of tibia. There was no collapse of the residual epiphysis. The mean MSTS score was 27.7 (range, 18 to 30). Conclusions Epiphysis transverse growth was not diminished, and there was absence of epiphyseal collapse even after epiphyseal-preservation surgery in this small series of childhood osteosarcoma around the knee. With careful assessment for epiphyseal tumor involvement, epiphyseal-preservation surgery shall be possible, and could be an alternative method worth considering.

Abstract Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemotherapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti‐inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti‐tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ‐responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase‐2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity.

Abstract Background The wrist joint is an extremely rare site for osteosarcoma. Joint structure preservation to maintain good limb function is well described in case of knee osteosarcoma, whereas it is not described in case of wrist joint osteosarcoma. In this report, we present the first case of joint preservation surgery to treat distal radius osteosarcoma using a tumor bearing autograft treated with liquid nitrogen. Case presentation A 46-year-old male presented with swelling and pain in the right wrist and was diagnosed with conventional osteosarcoma of the distal radius. The patient responded well to neoadjuvant chemotherapy and the tumor shrank remarkably. Wide tumor excision to preserve the radiocarpal joint and reconstruction with a tumor bearing frozen autograft were performed. Partial bone union was detected 3 months postoperatively and complete bone union was detected 9 months postoperatively. Following the surgery, there was immediate commencement of the range of motion (ROM) training in both the wrist and fingers. At the final postoperative follow-up of 41 months, the patient had normal ROM in the wrist, fingers, and forearms, with a score of 100% in the Musculoskeletal Tumor Society (MSTS) score and was disease free. Conclusion We present the first case in which en bloc tumor excision with joint preservation of the wrist and reconstruction using a tumor bearing frozen autograft were performed. The surgery yielded excellent hand, wrist, and forearm function at the final follow-up.

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