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.

[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.

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.

[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.

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.

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.

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.

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.

[Clinical Study of Nine Surgical Cases of Thymic Carcinoma].

Several reports are available on the effectiveness of multimodal therapies, such as chemotherapy and radiotherapy before and after surgery, in addition to surgical resection, as the treatment for thymic carcinoma. However, the sensitivity of each treatment modality varies according to the histological subtype of the carcinoma. Nine patients with thymic carcinoma treated at our hospital were reviewed retrospectively for staging( based on Masaoka's classification), histological findings, surgical method, preoperative and postoperative adjuvant therapy, and prognosis. Differences in the prognosis and treatment response of same-stage thymic carcinomas may be attributable to a difference in histological subtype. The choice of treatment may depend on the histological subtype.

[Anomalous Systemic Arterialization of a Normal Basal Lung Segment with Aneurysm of the Aberrant Artery].

A 40-year-old woman was noted to have clubbing of the nails during an outpatient service for smoking cessation. Chest computed tomography showed an aneurysm of an aberrant artery running from the descending aorta to the left lower lobe. Hence, we diagnosed anomalous systemic arterialization of the lung. The proximal part of the aberrant artery measured 13 mm in diameter;moreover, it had developed an aneurysm(17 mm in diameter) in the lung parenchyma. The aberrant artery was ligated with a covering material (absorbable felt) and cut via a small access thoracotomy by a cardiovascular surgeon;subsequently, left lower lobectomy was performed. Pathological examination revealed significant atherosclerosis in the aberrant artery, demonstrating its severe fragility. To apply appropriate safety procedures and approaches are recommended when treating an aberrant artery to the lung, especially in the presence of an aneurysm.

[Tracheal Resection and Primary Anastomosis for Adenoid Cystic Carcinoma Using an Extracorporeal Membrane Oxygenation].

We report a case of tracheal resection and primary anastomosis for adenoid cystic carcinoma using an extracorporeal membrane oxygenation (ECMO). A 45-year-old female was referred to our hospital because of a tracheal tumor that occupied most of the tracheal lumen. In case of airway obstruction by the tracheal tumor during anesthesia and operation, we decided to use ECMO before induction of general anesthesia. Under secure respiratory control using ECMO, tracheal resection and primary anastomosis was performed. Since histopathological examination revealed microscopically positive results at the surgical margin, postoperative adjuvant radiation therapy( 60 Gy/30 Fr) was conducted. Although a tracheal tumor is a relatively rare neoplasm, careful planning and a treatment strategy are necessary with special emphasis on the location and size of tumor. In this case, ECMO made a substantial contribution to secure respiratory control during surgery.

Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2.

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.

Comparison of Postoperative Pain after Different Thoracic Surgery Approaches as Measured by Electrical Stimulation.

BACKGROUND: Postoperative pain is commonly evaluated using the numerous rating scale (NRS), visual analogue scale, or pain scale; however, these assessments are easily affected by various subjective factors. We measured the degree of postoperative chest pain among different thoracic surgery approaches using NRS and electrical stimulation measurements. METHODS: Seventy patients who underwent lobectomy or segmentectomy were enrolled. Concomitant with NRS, pain scores were quantitatively measured on postoperative day 2 using an electrical neurostimulator to compare the degree of pain among three different surgical approaches: pure video-assisted thoracic surgery (VATS), hybrid VATS, and conventional thoracotomy. The risk factors associated with postoperative pain were also analyzed. RESULTS: Thirty patients underwent lung resection with pure VATS, while 30 had hybrid VATS, and 10 had conventional thoracotomy. Among the three surgical approaches, analyzing the pain score indicated statistically significant differences (pure, 159.50 ± 26.22; hybrid, 269.36 ± 30.49; thoracotomy, 589.40 ± 141.11; p = 0.003); however, NRS did not obtain a statistically significant difference between the three approaches (pure, 4.26 ± 0.27; hybrid, 4.96 ± 0.30; thoracotomy, 5.50 ± 0.68; p = 0.105). A multivariate analysis showed that the surgical approach was an independent risk factor for postoperative pain as determined by the pain score (pure vs. hybrid, p = 0.076; pure vs. thoracotomy, p < 0.001). CONCLUSION: For lung surgery, the differences in surgical approach were an independent risk factor for postoperative pain. In the early postoperative period, pure VATS was shown to be the least painful of the three surgical approaches.

[A Resected Case Whose Poor Pulmonary Function was Improved through Preoperative Comprehensive Respiratory Rehabilitation].

A 70-years-old man was diagnosed as having primary lung adenocarcinoma (cT1aN0M0, cStage I A) in the left lingula. Because of poor pulmonary function [vital capacity (VC):1,840 ml, forced expiratory volume (FEV)1.0:790 ml],we thought he could not tolerate the surgery and should be treated by chemoradiation therapy. However,by his strong hope for surgical treatment,comprehensive pulmonary rehabilitation by nutritional therapy and physiotherapy of breathing was started and was continued for about 1 month. As the value of pulmonary function test was improved (VC:2,010 ml,FEV1.0:1,040 ml), we did left lingulectomy. Postoperative complications did not occur and the patient shows a favorable condition without respiratory failure 18 months postoperation.

[Assessment of Feasibility of Early Ambulation and Food-intake on the Operative Day after Lung Resection].

To decrease the risk of morbidity, we have started an early ambulation and food-intake program conducted on the same day as pulmonary resection. This protocol was developed with consideration of the characteristics of lung surgery and conducted through an interdisciplinary team-approach. The assessment of feasibility and clinical effectiveness of this protocol was evaluated in 64 consecutive patients. No apparent adverse effect relating to this protocol was recorded. Fifty-five of 64 patients( 80%) were able to accomplish ambulation to the up-right standing position. Thirty-four of 64 patients( 53%) were able to consume more than half the amount of their hospital supper. No patients, including 5 patients who had had a past-history of postoperative delirium after their previous surgery, developed postoperative delirium after conducting this protocol. This protocol, which consisted of extraordinary early ambulation and food-intake on the operative day, was done safely and is expected to have some benefit as a postoperative management protocol for lung surgery.

Perillyl alcohol suppresses antigen-induced immune responses in the lung.

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

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.

Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non-small cell lung cancer.

BACKGROUND: Even after early detection and curative resection of early stage non-small cell lung cancer (NSCLC), a significant fraction of patients develop recurrent disease. Molecular biomarkers that can predict the risk of recurrence thus need to be identified to improve clinical outcomes. METHODS: Using the methylation-specific polymerase chain reaction assay, promoter methylation of the breast cancer susceptibility gene 1 (BRCA1) was assessed in cancer tissues from 70 patients with curatively resected stage I NSCLC. The clinical relevance of BRCA1 methylation status was evaluated in terms of outcome of the disease. RESULTS: Methylation of the BRCA1 promoter was detected in 13 of 70 patients (18.6%). Multiple logistic regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence (P = .0197) and that patients with BRCA1 methylation demonstrated significantly poorer recurrence-free survival compared to those without (P = .0139). Cox's proportional hazard regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence-free survival (P = .0155). CONCLUSIONS: Methylated BRCA1 can be a potential biomarker that predicts the prognosis after curative resection of stage I NSCLC. Considering that BRCA1 plays a role in chemotherapy-induced apoptosis, it is plausible that identification of methylated BRCA1 could provide information that is clinically relevant to tailored adjuvant therapy.