Hyperacute experimental model of rat lung transplantation using a coronary shunt cannula.

BACKGROUND: Lung transplantation is a well-established treatment of end-stage lung disease. A rodent model is an inexpensive way to collect biological data from a living model after lung transplantation. However, mastering the surgical technique takes time owing to the small organ size. AIM: To conduct rat lung transplantation using a shunt cannula (SC) or modified cannula (MC) and assess their efficacy. METHODS: Rat lung transplantation was performed in 11 animals in the SC group and 12 in the MC group. We devised a method of rat lung transplantation using a coronary SC for coronary artery bypass surgery as an anastomosis of pulmonary arteriovenous vessels and bronchioles. The same surgeon performed all surgical procedures in the donor and recipient rats without using a magnifying glass. The success rate of lung transplantation, operating time, and PaO2 values were compared after 2-h reperfusion after transplantation. RESULTS: Ten and 12 lungs were successfully transplanted in the SC and MC groups, respectively. In the SC group, one animal had cardiac arrest within 1 h after reperfusion owing to bleeding during pulmonary vein anastomosis. The operating time for the removal of the heart-lung block from the donor and preparation of the left lung graft was 26.8 ± 2.3 and 25.7 ± 1.3 min in the SC and MC groups, respectively (P = 0.21). The time required for left lung transplantation in the recipients was 37.5 ± 2.8 min and 35.9 ± 1.4 min in the SC and MC groups, respectively (P = 0.12). PaO2 values at 2 h after reperfusion were 456.2 ± 25.5 and 461.2 ± 21.5 mmHg in the SC and MC groups, respectively (P = 0.63), without difference between the groups. CONCLUSION: A hyperacute rat lung transplantation model using a coronary SC was created using a simple technique. The MC was inexpensive, easy to prepare, and simple to operate.

Repression of SMAD3 by STAT3 and c-Ski induces conventional dendritic cell differentiation.

A pleiotropic immunoregulatory cytokine, TGF-ß, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115+ common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115+ CDPs, SiglecH- pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH- pre-DCs, and CD115+ CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115+ CDP.

Estimation of threshold thickness of residual normal tissue in lung dysfunction detectable by dynamic chest radiography: A virtual imaging trial.

BACKGROUND: Dynamic chest radiography (DCR) is a recently developed functional x-ray imaging technique that detects pulmonary ventilation impairment as a decrease in changes in lung density during respiration. However, the diagnostic performance of DCR is uncertain owing to an insufficient number of clinical cases. One solution is virtual imaging trials (VITs), which is an emerging alternative method for efficiently evaluating medical imaging technology via computer simulation techniques. PURPOSE: This study aimed to estimate the typical threshold thickness of residual normal tissue below which the presence of emphysema may be detected by DCR via VITs using virtual patients with different physiques and a user-defined ground truth. METHODS: Twenty extended cardiac-torso (XCAT) phantoms that exhibited changes in lung density during respiration were generated to simulate virtual patients. To simulate a locally collapsed lung, an air sphere was inserted into each lung regions in the phantom. The XCAT phantom was virtually projected using an x-ray simulator. The respiratory changes in pixel value (ΔPV) were measured on the projected air spheres (simulated lesions) to calculate the percentage of decrease (ΔPV%) relative to ΔPVexp-ins in the absence of an air sphere. The relationship between the amount of residual normal tissue and ΔPV% was fitted to a cubic approximation curve (hereafter, performance curve), and the threshold at which the ΔPV% began to decrease (normal-tissuethre) was determined. The goodness of fit for each performance curve was evaluated according to the coefficient of determination (R2) and the 95% confidence interval derived from the standard errors between the measured and theoretical values corresponding to each performance curve. The ΔPV% was also visualized as a color scaling to validate the results of the VITs in both virtual and clinical patients. RESULTS: For each lung region in all body sizes, the ΔPV% decreased as the amount of residual normal tissue decreased and could be defined as a function of the amount of residual normal tissue in front of and behind the simulated lesions with high R2 values. Meanwhile, the difference between the measured and theoretical values corresponding to each performance curve was only partially included in the 95% confidence interval. The normal-tissuethre values were 146.0, 179.5, and 170.9 mm for the upper, middle, and lower lungs, respectively, which were demonstrated in virtual patients and one real patient, where the value of the residual normal tissue was less than that of normal-tissuethre; any reduction in the residual normal tissue was reflected as a reduced ΔPV and depicted as a reduced color intensity. CONCLUSIONS: The performance of DCR-based pulmonary impairment assessment depends on the amount of residual normal tissue in front of and behind the lesion rather than on the lesion size. The performance curve can be defined as a function of the amount of residual normal tissue in each lung region with a specific threshold of normal tissue remaining where lesions become detectable, shown as a decrease in ΔPV. The results of VITs are expected to accelerate future clinical trials for DCR-based pulmonary function assessment.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

BACKGROUND: The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. METHODS: Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. RESULTS: The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. CONCLUSION: Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Clinical importance of anti-Ro52 antibody for polymyositis and dermatomyositis.

OBJECTIVES: To clarify clinical features of anti-Ro52 antibody (Ab)-positive polymyositis (PM)/dermatomyositis (DM). PATIENTS AND METHODS: We retrospectively examined clinical features and status of anti-Ro52 Ab in patients with PM/DM admitted at the University of Tsukuba Hospital between January 2019 and February 2023. We compared anti-Ro52 Ab-positive and -negative groups. RESULTS: A total of 40 patients were selected and analyzed. Median age at diagnosis was 61.5 (48.8-69.3) years and 34 cases were female. Twenty-three cases were PM and 17 cases were DM (including 6 clinically amyopathic dermatomyositis: CADM). Twenty-two cases were positive for anti-Ro52 Ab, 14 for anti-ARS Ab, and 6 for anti-MDA5 Ab. Interstitial lung disease (ILD) was detected in 29 cases, 9 of which were rapidly progressive. Glucocorticoid (GC)-resistant cardiomyopathy was detected in 6 cases, malignancy in 3 cases, and Sjögren's syndrome (SS) in 4 cases. Of the 22 anti-Ro52 Ab positive cases, only 3 were single-positive and the remaining 19 cases simultaneously had other autoantibodies. Comparing the anti-Ro52 Ab-positive and -negative groups, the frequencies of anti-ARS Ab positivity (63.6% vs. 0%), ILD (95.5% vs. 44.4%), GC-resistant cardiomyopathy (27.3% vs. 0%), concomitant use of immunosuppressants (95.5% vs. 55.6%), and levels of C-reactive protein (CRP) were significantly higher in the anti-Ro52 Ab-positive group (p<0.05). The frequencies of PM/DM, positivity of anti-MDA5 Ab, malignancies, and SS were comparable between groups. CONCLUSION: Anti-Ro52 Ab were frequently positive in PM/DM and anti-Ro52 Ab-positive patients showed significantly higher rates of anti-ARS Ab positivity and ILD, GC-resistant cardiomyopathy, concomitant use of immunosuppressants, and higher levels of CRP. Anti-Ro52 Ab may be useful as a severity marker in PM/DM.

Reconstruction of Sjögren's syndrome-like sialadenitis by a defined disease specific gut-reactive single TCR and an autoantibody.

Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2-/- mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2-/- mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.

Combining dynamics of serum inflammatory and nutritional indicators as novel biomarkers in immune checkpoint inhibitor treatment of non-small-cell lung cancer with bone metastases.

OBJECTIVES: We aimed to investigate the association of the dynamics of serum inflammatory and nutritional indicators with immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC) with bone metastases, and to develop a novel predictive scoring system based on these indicators. METHODS: Patients with NSCLC having bone metastases treated with ICIs were categorized as: the development cohort (January 2016 to March 2021, n = 60) and the validation cohort (April 2021 to June 2023, n = 40). Serum indicators of inflammation and nutrition such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), albumin, prognostic nutritional index (PNI) were investigated before and six weeks after ICI initiation. The correlations of these dynamics with bone metastasis response rate (BoMRR) and overall survival (OS) were analyzed. A scoring system consisting of independent predictors was developed (IMMUNO-SCORE) and correlations with clinical outcomes were validated using the validation cohort. RESULTS: In the development cohort, multivariable analysis showed that NLR and PNI dynamics and CRP, NLR, and PNI dynamics were independent predictors of BoMRR and OS, respectively. The IMMUNO-SCORE consisting of NLR and PNI dynamics, which were the common predictors of the clinical outcomes, was significantly correlated with BoMRR (p < 0.01) and OS (p < 0.001) in cross-validation. The area under the curve of the score (0.786) was higher than individual NLR and PNI dynamics (0.72 and 0.684). CONCLUSION: Dynamics in NLR and PNI were demonstrated as biomarkers of treatment response and prognosis in ICI treatment of NSCLC with bone metastases, and the score combining these biomarkers was significantly correlated with clinical outcomes.

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Genomic evolutional analysis of surgical resected specimen to assess osimertinib as a first-line therapy in two patients with lung cancer harboring EGFR mutation: Case series.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is crucial for patients with lung cancer harboring EGFR mutations. However, almost all patients experience disease progression, regardless of their response to the targeted therapy, necessitating the development of additional treatment options. Two patients with lung cancer harboring EGFR-L858R mutations in exon 21 were treated by surgical resection during successful osimertinib treatment. Because the pathological diagnosis was suspected to be pleural metastasis, osimertinib treatment was continued until disease progression. We analyzed the evolution of genomic alterations and the levels of AXL using tumor specimens obtained by repeated biopsies during the course of treatment: initial diagnosis, operation, and disease progression. Genetic alterations detected at the three time points were dramatically changed and showed reductions in numbers, while EGFR-L858R mutations were detected in all samples tested in both patients. Immunohistochemical expression of AXL remained positive from the beginning of analysis to disease progression. Clonal evolution under oncogenesis is related to gradual accumulation of genomic alterations during tumor growth. However, our case series revealed that volume reduction procedures may cause this phenomenon. Therefore, identification of intrinsic drug-resistant cells in tumors may be as important as detection of acquired genetic alterations.

Role of inter-alpha-trypsin inhibitor heavy chain 4 and its citrullinated form in experimental arthritis murine models.

Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) is a major protein in serum and reported to be upregulated at the onset of rheumatoid arthritis (RA). Its citrullinated form, cit-ITIH4, is specifically found in the serum and synovial fluid of patients with RA. However, the detailed function of ITIH4 in arthritis remains unknown. The aim of this study was to clarify the role of ITIH4 and cit-ITIH4 using experimental arthritis models. ITIH4 and cit-ITIH4 expression was examined in steady-state mice and two different arthritis models, and their pathological effects were examined in Itih4-deficient mice. In naïve C57BL/6 (WT) mice, ITIH4 was expressed as mRNA in the liver and the lung and was expressed as protein in serum and hepatocytes. In K/BxN serum transferred arthritis (K/BxN-STA) and collagen-induced arthritis (CIA), ITIH4 and cit-ITIH4 in sera were increased before the onset of arthritis, and cit-ITIH4 was further increased at the peak of arthritis. In Itih4-deficient mice, citrullinated proteins in serum and joints, especially 120 kDa protein, were clearly diminished; however, there was no significant difference in arthritis severity between WT and itih-/- mice either in the K/BxN-STA or CIA model. CIA mice also exhibited pulmonary lesions and itih4-/- mice tended to show enhanced inflammatory cell aggregation compared to WT mice. Neutrophils in the lungs of itih4-/- mice were significantly increased compared to WT mice. In summary, ITIH4 itself did not alter the severity of arthritis but may inhibit autoimmune inflammation via suppression of neutrophil recruitment.

An overlapping case of IgG4-related disease and systemic lupus erythematosus treated with belimumab: a case-based review.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4+ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Multidrug-resistant IgA Vasculitis with Gastrointestinal Symptoms Successfully Treated with Intravenous Cyclophosphamide and Maintained with Mycophenolate Mofetil.

We present the case of a 17-year-old woman with IgA vasculitis (IgAV) who presented with relapsing gastrointestinal (GI) symptoms that were refractory to glucocorticoid and combination therapy with cyclosporine A, azathioprine or mycophenolate mofetil (MMF). The patient responded well to remission induction with intravenous cyclophosphamide (IVCY) and was successfully maintained with MMF. Remission induction with IVCY followed by maintenance therapy with MMF was effective in a patient with multidrug-resistant IgAV with GI lesions.

Benign endobronchial lipoma causing repeated pneumonia.

Endobronchial lipomas are rare; nonetheless, physicians should consider them as a differential diagnosis in patients with repeated pneumonia. Computed tomography and bronchoscopy are recommended for diagnosis. In this case, the patient's cough was ameliorated after undergoing a right basal segmentectomy.

Long-term outcome of patients with peripheral ground-glass opacity-dominant lung cancer after sublobar resections.

OBJECTIVE: This study aimed to evaluate the long-term prognosis of patients with peripheral small ground-glass opacity-dominant lung cancer after sublobar resection. We have already reported the 5-year safety and efficacy of sublobar resection and report the long-term outcomes after a 10-year follow-up period. METHODS: Between May 2009 and April 2011, 333 patients with radiologically noninvasive peripheral lung cancer were enrolled from 51 institutions (median age, 62 years at registration) and followed up until May 6, 2021. Of these patients, sublobar resections with wedge resection as the first choice were performed in 314 patients (258 wedge resections and 56 segmentectomies), conversion lobectomies were performed in 11 patients, and 8 patients were ineligible. RESULTS: The 10-year relapse-free survival and overall survival for the 314 patients with sublobar resections were 98.6% (95% confidence interval, 96.2-99.5) and 98.5% (95% confidence interval, 96.1-99.4), respectively. There was 1 local recurrence at the resection margin. Among the patients, second cancers were observed in 43 patients (13.4%; 95% confidence interval, 9.8-17.6), of which 18 were second lung cancers (5.8%; 95% confidence interval, 3.5-8.9). CONCLUSIONS: Peripheral ground-glass opacity-dominant lung cancer is cured by sublobar resection, with wedge resection as the first choice, and the indications for other treatment options should be further investigated. The incidence of second cancer is similar to that in the general Japanese population.

[Left Metastatic Lung Tumor for a Patient with Scimitar Syndrome:Report of a Case].

Scimitar syndrome is a subtype of partial anomalous pulmonary venous connection, a rare congenital disorder associated with hypoplasia of the right lung. In addition to the difficulty of isolated lung ventilation, resection of the left lung is associated with the risk of developing right heart failure due to increased right-to-left shunts. We report a case of a left lung metastasis of a patient with scimitar syndrome. The patient, a 58-year-old male, was diagnosed with scimitar syndrome at the age of 26 but had never experienced any symptoms. He underwent chemoradiotherapy for mid-pharynx carcinoma and achieved complete response. During follow-up, a nodule appeared in the lower lobe of the left lung. Since right heart catheterization revealed a pulmonary blood flow/systemic blood flow ratio (Qp/Qs) ratio of 2.6, intra-cardiac blood flow was diverted prior to pulmonary resection. Stanford type A acute aortic dissection occurred intra-operatively, and total aortic arch replacement was performed. Three months later, partial pulmonary resection was performed with extracorporeal membrane oxygenation (ECMO) on standby. As oxygenation was maintained by placing a blocker in the left lower lobe bronchus and ventilating the left upper lobe with high frequency jet ventilation, the operation was completed without using ECMO. The nodule was pathologically diagnosed as metastasis of mid-pharynx carcinoma. He did not develop heart failure and was discharged on post operated day 15.

Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01.

OBJECTIVE: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01. With respect to DRB1*15:01, strong linkage disequilibrium with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. METHODS: Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese Genome-Wide Association Study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants was performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by PCR-reverse sequence-specific oligonucleotide probes. RESULTS: Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01. In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. CONCLUSION: In the Japanese population, HLA-DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region.

Preoperative assessment of pleural adhesions in patients with lung cancer based on quantitative motion analysis with dynamic chest radiography: A retrospective study.

PURPOSE: Preoperative assessment of pleural adhesion is crucial for appropriate surgical planning. This study aimed to quantitatively evaluate the usefulness of motion analysis using dynamic chest radiography (DCR) for assessing pleural adhesions. METHODS: Sequential chest radiographs of 146 lung cancer patients with or without pleural adhesions (n = 25/121) were obtained using a DCR system during respiration (registration number: 1729). The local motion vector was measured, and the percentage of poor motion area to the maximum expiration lung area (%lung area with poor motion) was calculated. Subsequently, percentage values ≥49.0% were considered to indicate pleural adhesions. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the prediction performance. The percentage of lung area with poor motion was compared between patients with and without pleural adhesions (p < 0.05). RESULTS: DCR-based motion analysis correctly predicted pleural adhesions in 21 out of 25 patients, with 47 false-positive results (sensitivity, 84.0%; specificity, 61.2%; PPV, 30.9%; NPV, 94.9%). The lung with pleural adhesions showed a significantly greater %lung area with poor motion than the opposite lung in the same patient, similar to the cancerous lung in patients without pleural adhesions. CONCLUSION: On DCR-based motion analysis, pleural adhesions could be indicated by an increase in the percentage of lung area with poor motion. Although the proposed method cannot identify the exact location of pleural adhesions, information regarding the presence or absence of pleural adhesions provided by DCR would help surgeons prepare for challenging surgeries and obtain informed consent from patients.

Investigation of time profile of FEV1 across the onset of potential COPD: a retrospective cohort study using medical checkup data in Japan.

This study compared the time profile of FEV1 after COPD diagnosis among rapid decliners, slow decliners, and sustainers in the year of COPD diagnosis. COPD subjects were identified from the annual medical checkup records of Hitachi, Ltd., employees in Japan (April 1998-March 2019). Subjects were categorized into 3 groups (rapid decliner [decrease of FEV1 ≥ 63 mL/year], slow decliner [< 63 and ≥ 31 mL/year], and sustainer [< 31 mL/year]) for 5 years. The time profile of FEV1 was compared using mixed-effects model for 5 years after diagnosis; risk factors of rapid decliner were detected using logistic model/gradient boosting decision tree. Of 1294 eligible subjects, 18.6%, 25.7%, and 55.7% were classified as rapid decliners, slow decliners, and sustainers, respectively. The annual rates of FEV1 decline were similar 3 years before and until COPD diagnosis. The mean FEV1 in rapid decliners was 2.82 ± 0.04 L in year 0 and 2.41 ± 0.05 L in year 5, and in sustainers, it was 2.67 ± 0.02 L and 2.72 ± 0.02 L (year 0, p = 0.0004). In conclusion, FEV1 declined yearly before diagnosis and the time profiles of FEV1 were different in the 3 groups after COPD diagnosis. Therefore, appropriate treatment of the 3 groups with regular lung function tests is necessary to follow FEV1 decline after COPD onset.

Novel predictors of immune checkpoint inhibitor response and prognosis in advanced non-small-cell lung cancer with bone metastasis.

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 < 0.01), and NLR <2.1 (p = 0.03) as significant predictors of therapeutic response, whereas concomitant use of a bone-modifying agent (p < 0.01), Katagiri score ≤6 points (p < 0.01), and NLR <2.1 (p = 0.02) were identified as significant predictors of good prognosis. CONCLUSIONS: This study identified some novel predictors for favorable therapeutic response and prognosis in advanced NSCLC patients with bone metastases undergoing ICI treatment. Pretreatment NLR less than 2.1 can be considered the most important predictor.

Diagnostic approach for mediastinal masses with radiopathological correlation.

PURPOSE: Mediastinal masses have various histopathological and radiological findings. Although lymphoma is the most common type of tumor, thymic epithelial and neurogenic tumors are common in adults and children, respectively, but several other types are difficult to distinguish. No previous review has simply and clearly shown how to differentiate mediastinal masses. METHOD: We conducted a review of the latest mediastinal classifications and mass differentiation methods, with a focus on neoplastic lesions. Both older and recent studies were searched, and imaging and histopathological findings of mediastinal masses were reviewed. Original simple-to-use differentiation flowcharts are presented. RESULTS: Assessing localizations and internal characteristics is very important for mediastinal mass differentiation. The mass location and affected organ/tissue should be accurately assessed first, followed by more qualitative diagnosis, and optimization of the treatment strategy. In 2014, the International Thymic Malignancy Interest Group presented a new mediastinal clinical classification. In this classification, mediastinal masses are categorized into three groups according to location: prevascular (anterior)-, visceral (middle)-, and paravertebral (posterior)-compartment masses. Then, the internal characteristics and functional images are evaluated. CONCLUSIONS: Differentiation of mediastinal masses is very difficult. However, if typical imaging findings and clinical characteristics are combined, reasonable differentiation is possible. In each patient, proper differential diagnosis may contribute to better treatment selection.