[Surgical Stabilization of Traumatic Multiple Rib Fractures Using Absorbable Osteosynthesis Agent(u-HA/PLLA Composite Material)].

In case that met several indication criteria with 4 or more rib fractures, we performed surgical stabilization of multiple fractured ribs using a plate and screw system( Super FIXORB MX) that was made of uncalcined hydroxyapatite (u-HA)/poly-L-lactic acid (PLLA) composite material with excellent bioactivity and absorbability. We report our clinical experience of 7 cases in which this device was used. Although there is still room for further consideration of the technique and the strength of the device itself, computed tomography( CT) images taken 9 months after surgery showed that the fixative device was almost assimilated with the bone at the fracture repair site in cases where fixation was successful.

Baricitinib for anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis-associated interstitial lung disease: a case series and literature review on Janus kinase inhibitors for the disease.

Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-DM) is frequently complicated by progressive interstitial lung disease (ILD), the prognosis of which is poor, and management is a major challenge. We treated three patients with anti-MDA5-DM-associated ILD (anti-MDA5-DM-ILD) using the Janus kinase (JAK) inhibitor, baricitinib, which improved lung opacities and saved two patients. We reviewed 6 patients with anti-MDA5-DM-ILD who had been treated with tofacitinib at our institution. Five of the patients survived, although discontinuation of tofacitinib due to complications was frequently observed. In addition, a literature search of patients with anti-MDA5-DM-ILD who were treated with JAK inhibitors yielded 21 articles involving 79 cases. All patients except one were treated with tofacitinib, and the survival rate was 75.9%. Although not statistically confirmed, the deceased patients tended to be older and had higher ferritin levels. A total of 92 complications were observed, 11 of which resulted in JAK inhibitor discontinuation. Cytomegalovirus reactivation comprised a substantial percentage of all complications and of those patients who required JAK inhibitor discontinuation. Five cases with fatal infective complications were also observed. While tofacitinib has been proposed to be a therapeutic option for anti-MDA5-DM-ILD, other JAK inhibitors, including baricitinib, are a treatment option. Further investigation is warranted to optimize treatment of anti-MDA5-DM-ILD.

Age-associated CD4+ T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity.

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4+ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3midCD4+ effector memory T cell subset that expands with age, which we designated "age-associated T helper (THA) cells." THA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of THA cells, gene expression in THA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that THA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of THA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.

[Cavernostomy for Extensive Intrapulmonary Cavitary Abscesses That Turned into Destroyed Lungs].

Surgical resection of the infected lung with curative intent is the treatment of choice for lung abscesses that are difficult to control with medical treatment alone. However, lung resection is considered difficult in some cases. Herein, we report two cases of destroyed lungs with severe symptoms, for which palliative cavernostomy was performed instead of infected lung resection. Case 1 was a 45-year-old man who had granulomatosis with polyangiitis in both lungs. Steroid pulse and immunosuppression therapies were repeated, resulting in a huge, destroyed lung on the right side with chronic necrotizing bilateral aspergillosis, causing severe symptoms. Considering the bilateral spread and extension of the cavity lesions, cavernostomy was performed for the destroyed right lung. Case 2 was a 73-year-old woman who had undergone a left lower lobectomy for a metastatic lung tumor and developed a destroyed lung with severe symptoms in the residual left upper lobe caused by a non-tuberculous mycobacterial infection. Since a completion pneumonectomy with curative intent was considered too invasive for her poor general condition, cavernostomy was performed for the destroyed lung. Palliative operations significantly relieved the severe symptoms and improved the general conditions of these patients, enabling outpatient follow up.

Efficacy and safety of plasma exchange in interstitial lung diseases with anti-melanoma differentiation-associated 5 gene antibody positive clinically amyopathic dermatomyositis.

OBJECTIVE: Clinically amyopathic dermatomyositis (CADM) patients frequently develop refractory interstitial lung disease (ILD), with a poor prognosis. We aimed to verify the efficacy and safety of plasma exchange (PE) treatment for ILD in CADM. METHOD: A retrospective case-control study was conducted to compare clinical outcomes with and without PE treatment in CADM-ILD patients refractory to combination therapy of high-dose glucocorticoids, calcineurin inhibitors, and cyclophosphamide. Among 19 enrolled patients, 11 were further treated with PE. We compared survival rates and other clinical characteristics. PE consisted of either fresh-frozen plasma or albumin as a replacement solution. RESULTS: Basal clinical characteristics at diagnosis, including age, gender, serum ferritin, Krebs von den Lungen-6 (KL-6), C-reactive protein, and respiratory function tests, did not differ between the two groups. The survival rate for treatment with PE was higher than for treatment without PE (91% and 50%, respectively, p < 0.05). Among PE-treated patients, anti-melanoma differentiation-associated gene-5 (anti-MDA-5) antibody titre, ferritin, and KL-6 as serological activity markers were sustainably reduced only after initiating PE. Therapeutic intervention with PE reduced the frequency of exacerbation of ILD requiring methylprednisolone pulse therapy. The occurrence of bacterial, fungal, and cytomegalovirus infection did not differ between the groups with and without PE, and adverse events associated with PE resolved with appropriate intervention. CONCLUSION: Combination therapy with PE was associated with an improved survival rate, and may be effective for the management of refractory ILD in CADM patients. A personalized therapeutic strategy including PE could be introduced for fatal rapidly progressive ILD.

Muscle Quality Predicts Outcomes after Surgery for Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: This study investigated the impact of skeletal muscle quality on the outcomes of patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC). METHODS: A total of 98 patients with pathological stage I-II NSCLC who underwent lobectomy or segmentectomy were retrospectively analyzed. Along with skeletal muscle quantity, muscle quality was evaluated by intramuscular adipose tissue content (IMAC) at the first lumbar vertebral level; a higher IMAC indicates lower skeletal muscle quality. Patients were divided into two groups according to the gender-specific quartiles of IMAC, and the prognostic impact of IMAC was investigated. RESULTS: No significant differences in the body and skeletal mass indices, which indicate skeletal muscle quantity, were observed between patients with high and those with normal IMAC. Patients with high IMAC (n = 23) showed a significantly poorer prognosis in overall and disease-specific survivals than those with normal IMAC (n = 75; P <0.001 and P = 0.048, respectively). In a bivariate analysis that included other clinicopathological factors, a high IMAC was independently associated with worse overall survival. CONCLUSION: The skeletal muscle quality evaluated by IMAC could be used to predict survival risk after surgery for early-stage NSCLC.

Mediastinal Ancient Schwannoma Causing Intrathoracic Bleeding.

Spontaneous hemothorax caused by the rupture of a benign schwannoma has rarely been reported. Herein, we present the successful excision of an extremely rare case of mediastinal ancient schwannoma causing intrathoracic bleeding. A 27-year-old man was admitted to our emergency department because of back pain and dyspnea. Computed tomography revealed massive pleural effusion with a posterior mediastinal tumor. We performed a resection of the tumor which had ruptured, and the tumor was diagnosed as an ancient schwannoma.

Predominant mesangial IgM, C3, and λ light chain depositions and interstitial nephritis in a patient with overlap syndrome and positivity for anti-mitochondrial M2 antibody: a case report.

Overlap syndrome refers to a group of conditions that have clinical features of more than one well-characterised rheumatic disease and meet the respective classification criteria. There are no typical renal histological findings in overlap syndrome. When patients with overlap syndrome develop renal dysfunction, various potential causes, including lupus nephritis (LN), renal crisis by systemic sclerosis, interstitial nephritis, and so on, need to be distinguished. Here, we report a 44-year-old woman with overlap syndrome involving systemic lupus erythematosus (SLE), diffuse cutaneous systemic scleroderma, and Sjogren's syndrome, who was also positive for anti-mitochondrial M2 antibody. She developed glomerular haematuria, proteinuria, and increase in creatinine appeared gradually. Suspecting LN, renal biopsy was performed. However, in the interstitium, mild infiltration of lymphocytes and plasma cells and very partial fibrosis were observed. Immunofluorescence microscopy revealed predominant mesangial immunoglobulin M, C3, and λ light chain staining. Overall, LN was not diagnosed based on these findings. Renal dysfunction was normalised by glucocorticoid treatment for 3 months. This case suggests the importance of a renal diagnosis based on renal pathological findings, especially in a case of overlap syndrome including SLE.

Intestinal ulcers induced by intravesical bacillus Calmette-Guérin therapy.

Intravesical bacillus Calmette-Guérin (iBCG) therapy, one of the established treatments for bladder carcinoma, is known for its association with adverse events, including rheumatic manifestations. We describe the case of a 72-year-old man with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome who developed inflammatory bowel disease unclassified after iBCG therapy for bladder carcinoma. The critical role of the IL-23/IL-17 axis in the pathogenesis IBD and all the domains of SAPHO syndrome has been reported previously. In the present case, the activation of the IL-23/IL-17 axis, probably due to the disease, could have been exacerbated by iBCG therapy, as observed in mice that received BCG immunotherapy. We suggest that patients with rheumatic diseases on iBCG therapy should be observed carefully since iBCG could be a contributing factor for autoimmune pathology including IBD.

Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: a case-control study.

OBJECTIVES: Interstitial lung disease sometimes occurs in rheumatoid arthritis patients. Although the underlying immunological mechanisms responsible for interstitial lung disease associated with rheumatoid arthritis have not yet been clarified, some reports have suggested possible roles of B cells. To examine the role of B-cell subsets in interstitial lung disease in rheumatoid arthritis patients, we analyzed peripheral blood B-cell subsets. METHODS: We analyzed the frequencies of the peripheral blood B-cell subsets by flow cytometry in rheumatoid arthritis patients with and without interstitial lung disease (n = 16 and 81, respectively) and in healthy donors (n = 110) by high-resolution computed tomography. RESULTS: Compared with healthy donors, rheumatoid arthritis patients showed statistically higher frequencies of naive B cells and lower frequencies of memory B cells. Moreover, the frequencies of memory B cells were lower in rheumatoid arthritis patients with interstitial lung disease than in those without. Multivariate analysis showed that the frequency of memory B cells, particularly switched memory B cells, was significantly decreased in rheumatoid arthritis patients with interstitial lung disease, even after adjusting for prednisolone dose. CONCLUSIONS: We suspect memory B cells play important roles in interstitial lung disease associated with rheumatoid arthritis.

ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma.

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.

Efficacy of complete video-assisted thoracoscopic surgery lobectomy using the three-dimensional endoscopic system for lung cancer.

OBJECTIVE: We aimed to investigate the efficacy of complete video-assisted thoracoscopic surgery (cVATS) lobectomy using the three-dimensional (3D) endoscopic system in patients with lung cancer and compare it with that of cVATS lobectomy using the conventional two-dimensional (2D) endoscopic system in former consecutive cases. METHODS: We retrospectively analyzed the prospectively collected database of patients with clinical stage I lung cancer who underwent cVATS lobectomy using the 3D endoscopic system; the patients who underwent surgery using the 2D endoscopic system were considered the historical control group. The operative and perioperative data were compared, and propensity-score matched comparisons were used to assess the potential impact of selection bias. RESULTS: We performed 189 cVATS lobectomies. Of these, 105 were performed using the 3D endoscopic system, while 84 were performed using the 2D endoscopic system. After matching, there was no significant difference in the preoperative factors between the two groups. The operation time was significantly shortened (P = 0.003), and the intraoperative blood loss was significantly reduced in the 3D group (P < 0.001). In particular, there was only one case of intraoperative hemorrhage of 201 mL or more in the 3D group, compared to 12 cases in the 2D group (P < 0.001). After matching, the intraoperative blood loss and operation time were significantly reduced in the 3D group. CONCLUSIONS: Our results showed that the 3D endoscopic system for cVATS lobectomy may be a useful surgical tool and switching to it from the 2D endoscopic system can be performed safely.

The RNA-binding protein Mex-3B plays critical roles in the development of steroid-resistant neutrophilic airway inflammation.

While most asthma can be treated with steroids, about 10%, called severe asthma, is refractory to steroids. It has recently been shown that in a subgroup of severe asthma cases, neutrophils that infiltrate into the airways play an important role in inflammation. However, the mechanisms underlying this increased neutrophil infiltration are not well understood. Here, using a mouse model of steroid-resistant neutrophilic inflammation, we show that mice deficient for the RNA-binding protein Mex-3B have significantly less neutrophil infiltration in the airways than wild-type mice. We further demonstrate that Mex-3B post-transcriptionally upregulates CXCL2, a chemokine that induces neutrophil chemotaxis and migration. Moreover, we show that treatment with either anti-CXCL2 antibody or anti-Mex-3B antisense oligonucleotide suppresses neutrophilic allergic airway inflammation. These results suggest that Mex-3B-mediated induction of CXCL2 is crucial for steroid-resistant neutrophilic allergic airway inflammation. Our findings suggest new strategies for therapeutic intervention in steroid-resistant severe asthma.

Lung cancer risk stratification using methylation profile in the oral epithelium.

BACKGROUND: Assuming that the entire airway is affected by the same inhaled carcinogen, similar molecular alterations may occur in the lung and oral cavity. Thus, we hypothesized that DNA methylation profiles in the oral epithelium may be a promising biomarker for lung cancer risk stratification. METHODS: A methylation-specific polymerase chain reaction was performed on oral epithelium from 16 patients with lung cancer and 32 controls without lung cancer. Genes showing aberrant methylation profiles in the oral epithelium were compared between patients and controls. RESULTS: The analysis revealed that HOXD11 and PCDHGB6 were methylated more frequently in patients than in controls ( p = 0.0055 and p = 0.0247, respectively). Combined analyses indicated that 8 of 16 (50%) patients and 3 of 32 (9.4%) controls showed DNA methylation in both genes ( p = 0.0016). Among the population limited to current and former smokers, 6 of 11 (54.5%) patients showed methylation in both genes, compared to 1 of 17 (5.9%) controls ( p = 0.0037). In a subgroup analysis limited to the population above 50-years old, 8 of 16 (50%) patients and 2 of 16 (12.5%) controls showed methylation in both genes ( p = 0.0221). CONCLUSIONS: The results of this study indicate that specific gene methylation in the oral epithelium might be a promising biomarker for lung cancer risk assessment, especially among smokers. Risk stratification through the analysis of DNA methylation profiles in the oral epithelium may be a useful and less invasive first-step approach in an efficient two-step lung cancer screening strategy.

Polymorphic lymphoproliferative disorders in patients with rheumatoid arthritis are associated with a better clinical outcome.

OBJECTIVES: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department. METHODS: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed. RESULTS: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively). CONCLUSION: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

Prostaglandin D2 metabolite in urine is an index of food allergy.

Food allergy is immediate hypersensitive reactions to ingested foods. Since early diagnosis is effective for disease control, development of an objective diagnostic index is required. Using mediator-lipidomics, we found that levels of the urinary prostaglandin D2 (PGD2) metabolite, tetranor-PGDM, reflected the severity of the allergic symptoms and intestinal mast cell hyperplasia in mice. Repeated oral challenges with ovalbumin promoted allergic symptoms in sensitized mice. Particularly, the allergic mice presented with increased numbers of intestinal mast cells, which strongly expressed hematopoietic PGD synthase (H-PGDS). The levels of urinary tetranor-PGDM increased as the disease progressed. Treatment with a mast cell inactivator or an anti-inflammatory steroid attenuated these symptoms and decreased the tetranor-PGDM urinary levels. The levels of urinary tetranor-PGDM did not correlate with the disease severity in murine models of colitis, asthma, or allergic dermatitis. Furthermore, we have shown that urinary levels of tetranor-PGDM were significantly higher in patients with food allergy than those in healthy volunteers and patients with other types of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. These findings suggest that urinary tetranor-PGDM is a useful diagnostic index of food allergy in both mice and humans.

Clinical benefit of neoadjuvant chemoradiotherapy for the avoidance of pneumonectomy; assessment in 12 consecutive centrally located non-small cell lung cancers.

BACKGROUND: Considering that pneumonectomy itself is a disease, avoidance of pneumonectomy needs to be deliberated. Herein, we evaluated the role of neoadjuvant chemoradiotherapy for avoidance of pneumonectomy in patients with centrally located locally advanced non-small cell lung cancer. METHODS: Patients who underwent neoadjuvant chemoradiotherapy after being judged to require pneumonectomy by cancer board between 1997 and 2011 were retrospectively evaluated. RESULTS: Twelve patients, including 10 males and 2 females with median age 63.5 years, were referred. Clinical stage was IB (1 patient), IIB (2 patients), IIIA (8 patients), and IIIB (1 patient). There were no disease progression after neoadjuvant chemoradiotherapy, and all patients underwent curative resection. For 8 patients, pneumonectomy was avoided, with 3 bronchoplasties and 3 pulmonary arterial angioplasties. We had 4 pneumonectomies: three cases of metastatic enlarged lymph nodes invading either the carina or a more central portion of the pulmonary artery than the left A3 branch or vein which needs incision of the inner pericardium and 1 case with a tumor involving the upper lobe bronchus to the inferior lobe bronchus. There were no postoperative deaths and 1 case of bronchopleural fistula. The 5-year disease-free and overall survival rates were 55.6 and 72.7% without stump or anastomotic recurrence. CONCLUSIONS: Neoadjuvant chemoradiotherapy for centrally located NSCLC appeared to be a useful treatment option for avoiding pneumonectomy without impairing curability and safety, especially in highly selected cases without invasion to carina or right-or-left main trunk of pulmonary artery or vein at pretreatment.

Efficacy of intensive immunosuppression in exacerbated rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Acute or subacute exacerbations are recognized as a severe complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Nevertheless, the role of intensive immunosuppression in RA-ILD remains elusive. We attempted to evaluate the clinical characteristics and efficacy of immunosuppressive treatment in exacerbated RA-ILD. METHODS: Clinical data, including respiratory function, imaging, treatment, and prognosis, were retrospectively collected for 17 patients with RA-ILD who required hospitalization at the University of Tokyo Hospital due to an acute exacerbation (12 patients) or subacute exacerbation (5 patients). RESULTS: Patients with RA-ILD demonstrated a significantly higher titers of anticyclic citrullinated peptide antibodies compared with RA patients in Japanese Ninja registry, suggesting the role of adaptive immunity. Immunosuppressive treatment suppressed the deterioration of pulmonary functions with improved ground grass opacity and consolidation. In particular, in patients with less fibrosis on computed tomography (CT) images showed a better response to treatment. Although five patients treated with combination therapy, including cyclophosphamide, showed a severely decreased lung volume, these intensive therapies provided a good prognosis without fatalities for the average observation period of 474 days. CONCLUSIONS: Immunosuppressive therapy is effective for exacerbations of RA-ILD. For severe cases with low respiratory function, intensive therapy, including cyclophosphamide, has a potential to improve the prognosis.