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FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers., Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.

Background/Aim: Neutralization of the acidic tumor microenvironment, which is associated with both progression and drug resistance of cancer cells, may be a new treatment option for progressing forms of cancer. We conducted a case-control study to investigate the effects of alkalization therapy, consisting of an alkaline diet with supplementary oral sodium bicarbonate, in patients with metastatic or recurrent pancreatic cancer (study registration no.: UMIN000036126). Patients and Methods: Thirty-six patients in the alkalization group (Karasuma Wada Clinic; alkalization therapy plus chemotherapy) were retrospectively compared to 89 patients in the control group (Kyoto University Hospital; chemotherapy only). Results: The median overall survival (OS) in the alkalization group was significantly longer than that in the control group (15.4 vs. 10.8 months; p7.0 or ΔpH>1.0) in the alkalization group was significantly longer than that of the control group. Conclusion: Alkalization therapy may enhance the effects of chemotherapy in patients with advanced pancreatic cancer.

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti–PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA−CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti–PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1− eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

In this work, we propose an AI-based method that intends to improve the conventional retinal disease treatment procedure and help ophthalmologists increase diagnosis efficiency and accuracy. The proposed method is composed of a deep neural networks-based (DNN-based) module, including a retinal disease identifier and clinical description generator, and a DNN visual explanation module. To train and validate the effectiveness of our DNN-based module, we propose a large-scale retinal disease image dataset. Also, as ground truth, we provide a retinal image dataset manually labeled by ophthalmologists to qualitatively show, the proposed AI-based method is effective. With our experimental results, we show that the proposed method is quantitatively and qualitatively effective. Our method is capable of creating meaningful retinal image descriptions and visual explanations that are clinically relevant., Accepted to IEEE WACV 2021

Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.

As a novel type of anticancer reagent, imatinib inhibits not only BCR-ABL oncogenic protein but also LCK in T cells as an off-target, being able to selectively deplete mature T reg cells and thereby evoke effective immune responses to various cancers., This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not. Imatinib at CML-therapeutic concentrations indeed induced apoptosis specifically in eT reg cells and expanded tumor antigen–specific CD8+ T cells in vitro in healthy individuals and melanoma patients, and suppressed colon tumor growth in vivo in mice. Mechanistically, because of FoxP3-dependent much lower expression of LCK and ZAP-70 in T reg cells compared with other T cells, imatinib inhibition of LCK further reduced their TCR signal intensity, rendering them selectively susceptible to signal-deprived apoptotis. Taken together, eT reg cell depletion by imatinib is instrumental in evoking effective immune responses to various cancers.

Significance PD-1 blockade is a cancer immunotherapy effective in various types of cancer. However, we observed rapid cancer progression, called hyperprogressive disease (HPD), in ∼10% of advanced gastric cancer patients treated with anti–PD-1 monoclonal antibody. Tumors of HPD patients possessed highly proliferating FoxP3+ Treg cells after treatment, contrasting with their reduction in non-HPD tumors. In vitro PD-1 blockade augmented proliferation and suppressive activity of human Treg cells. Likewise, murine Treg cells that were deficient in PD-1 signaling were more proliferative and immunosuppressive. Thus, HPD may occur when PD-1 blockade activates and expands tumor-infiltrating PD-1+ Treg cells to overwhelm tumor-reactive PD-1+ effector T cells. Depletion of the former may therefore help treat and prevent HPD., PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti–PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA−CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti–PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1− eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system with prominent neurodegenerative components. The triggering and progression of MS is associated with transcriptional and epigenetic alterations in several tissues, including peripheral blood. The combined influence of transcriptional and epigenetic changes associated with MS has not been assessed in the same individuals. Here we generated paired transcriptomic (RNA-seq) and DNA methylation (Illumina 450 K array) profiles of CD4+ and CD8+ T cells (CD4, CD8), using clinically accessible blood from healthy donors and MS patients in the initial relapsing-remitting and subsequent secondary-progressive stage. By integrating the output of a differential expression test with a permutation-based non-parametric combination methodology, we identified 149 differentially expressed (DE) genes in both CD4 and CD8 cells collected from MS patients. Moreover, by leveraging the methylation-dependent regulation of gene expression, we identified the gene SH3YL1, which displayed significant correlated expression and methylation changes in MS patients. Importantly, silencing of SH3YL1 in primary human CD4 cells demonstrated its influence on T cell activation. Collectively, our strategy based on paired sampling of several cell-types provides a novel approach to increase sensitivity for identifying shared mechanisms altered in CD4 and CD8 cells of relevance in MS in small sized clinical materials.

Kynurenine pathway (KP) activation by the enzymatic activity of indoleamine 2,3-dioxygenase1 (IDO1) and kynurenine (KYN) production represents an attractive target for reducing tumour progression and improving anti-tumour immunity in multiple cancers. However, immunomodulatory properties of other KP metabolites such as 3-hydroxy kynurenine (3-HK) and kynurenic acid (KYNA) are poorly understood. The association of the kynurenine metabolic pathway with T-cell status in the tumour microenvironment were characterized, using gene expression data of 368 cutaneous skin melanoma (SKCM) patients from the TCGA cohort. Based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived cell lines and primary CD4+ CD25− T-cells. Activation of the CD4+ T-cells produced IFNγ, which yielded increased levels of KYN and KYNA. Concurrently, kynurenine 3-monooxygenase (KMO) expression and proliferation of CD4+ T-cells were reduced, whereas exhaustion markers such as PD-L1, AHR, FOXP3, and CTLA4 were increased. Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity. Our results suggest that, in addition to IDO1, there is an alternative immune regulatory mechanism associated with the lower KMO expression and the higher KYNA production, which contributes to dysfunctional effector CD4+ T-cell response.

Age-Related Macular Degeneration (AMD) is an asymptomatic retinal disease which may result in loss of vision. There is limited access to high-quality relevant retinal images and poor understanding of the features defining sub-classes of this disease. Motivated by recent advances in machine learning we specifically explore the potential of generative modeling, using Generative Adversarial Networks (GANs) and style transferring, to facilitate clinical diagnosis and disease understanding by feature extraction. We design an analytic pipeline which first generates synthetic retinal images from clinical images; a subsequent verification step is applied. In the synthesizing step we merge GANs (DCGANs and WGANs architectures) and style transferring for the image generation, whereas the verified step controls the accuracy of the generated images. We find that the generated images contain sufficient pathological details to facilitate ophthalmologists’ task of disease classification and in discovery of disease relevant features. In particular, our system predicts the drusen and geographic atrophy sub-classes of AMD. Furthermore, the performance using CFP images for GANs outperforms the classification based on using only the original clinical dataset. Our results are evaluated using existing classifier of retinal diseases and class activated maps, supporting the predictive power of the synthetic images and their utility for feature extraction. Our code examples are available online. (https://github.com/huckiyang/EyeNet-GANs).

Automatic clinical diagnosis of retinal diseases has emerged as a promising approach to facilitate discovery in areas with limited access to specialists. Based on the fact that fundus structure and vascular disorders are the main characteristics of retinal diseases, we propose a novel visual-assisted diagnosis hybrid model mixing the support vector machine (SVM) and deep neural networks (DNNs). Furthermore, we present a new clinical retina labels collection sorted by the professional ophthalmologist from the educational project Retina Image Bank, called EyeNet, for ophthalmology incorporating 52 retina diseases classes. Using EyeNet, our model achieves 90.40% diagnosis accuracy, and the model performance is comparable to the professional ophthalmologists (https://github.com/huckiyang/EyeNet2).

Scientific Data, 4, ISSN:2052-4463

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors. Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC). Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression. Results: We observed significant methylation differences in the VMP1/MIR21 locus, with RR-MS displaying higher methylation compared to SP-MS and HC. VMP1/MIR21 methylation did not correlate with a known MS risk variant in VMP1 or smoking but displayed a significant negative correlation with age and the levels of mature miR-21 in CD4+ T cells. Accordingly, RR-MS displayed lower levels of miR-21 compared to SP-MS, which might reflect differences in age between the groups, and healthy individuals and a significant enrichment of up-regulated miR-21 target genes. Conclusion: Disease-related changes in epigenetic marking of MIR21 in RR-MS lead to differences in miR-21 expression with a consequence on miR-21 target genes.

Naturally occurring regulatory T (nTreg) cells, which specifically express the transcription factor Forkhead box protein P3 (FoxP3), are indispensable for the maintenance of immunological self-tolerance and homeostasis. Recent studies have shown that developing nTreg cells in the thymus acquire a Treg-specific and stable hypomethylation pattern in a limited number of genes, which encode key molecules including FoxP3, essential for Treg cell function. This epigenetic change is acquired via T-cell receptor (TCR) stimulation, beginning prior to FoxP3 expression. The Treg-specific DNA hypomethylated regions generally act as gene enhancers in steady state nTreg cells, contributing to the stable expression of Treg function-associated key genes including Ctla4, Il2ra, and Ikzf4 in addition to Foxp3. Upon TCR stimulation of mature nTreg cells, FoxP3 strongly represses many genes including Il2, contributing to Treg suppressive activity. Thus, the Treg-specific epigenome alteration can determine the heritable Treg-specific gene network including Foxp3 regulation. Considering physiological presence of non-suppressive FoxP3(+) T cells in the immune system and loss of FoxP3 in Treg cells under certain immunological conditions, functional nTreg cells can be more accurately defined as a T-cell subpopulation possessing the Treg-type epigenome, rather than FoxP3(+) T cells. This epigenome-based definition of Treg cells would enable better understanding of functional stability, plasticity, and heterogeneity of Treg cells.

Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte-fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB-activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB-induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB-promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis.

With synovial sarcoma (SS) of the thorax, being exceptionally rare, its definite diagnosis is difficult, and the optimal therapy has not yet been established. An examination of our patient, a 64-year-old man with SS using a chest roentgenogram showed a large mass with homogeneous density in the lower two-thirds of the left hemithorax. A computed tomographic image of the chest revealed a large, heterogeneous, enhanced mass in the left hemithorax. Histologic examination of the resected tumor tissues suggested monophasic fibrous SS. A fragment of the SYT-SSX1 fusion transcript, which was smaller than the control, was amplified with reverse transcriptase polymerase chain reaction. Direct sequence analyses revealed the fusion between exon 9 of SYT and exon 5 of SSX1 instead of fusion between exon 10 of SYT and exon 6 of SSX1, which is found in most cases. Although the biological and clinical significance of this rare variant is not yet known, our data present another example of the usefulness of molecular analyses for making a definite diagnosis of SS in unusual sites.

57歳，男性．主訴は発熱．繰り返す肺炎の既往あり．肺炎と診断され抗生物質の投与を受けたが胸部X線上異常陰影は消失しなかった．胸部CT上左肺下葉には最大径6cmの腫瘤影と下行大動脈より分岐し腫瘤影へ注ぐ異常血管が認められた．大動脈造影検査では大動脈より肺底区へ流入する拡張した異常血管がみられたが，還流静脈を同定することは出来なかった．以上の検査結果より肺底動脈体動脈起始症と診断し手術を施行した．手術所見では正常肺と異常肺の境界が不明瞭なため，胸部下行大動脈より左肺下葉へ流入している異常動脈を切離し左肺下葉切除術を行った．切除標本の所見は肺内で約6cmまで拡大し血栓を伴った異常血管が左肺底区へ流入していた．繰り返す肺炎や改善しない胸部異常陰影がある症例では本疾患の可能性も考慮した精査と診断がつけば検査結果を考慮した術式での手術が必要と考えられた．

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33–ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33–ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy., Elevated IL-33 levels have been correlated with metastasis and poor prognosis. Here the authors show in mouse tumour xenograft models that PDGF-BB produced by tumour cells induces IL-33 via Sox7 in tumour pericytes, and IL-33 promotes metastasis through its effects on tumour-associated macrophages.

OBJECTIVE: This retrospective study was designed to examine the acute and long-term outcomes after surgical treatment of patients with pulmonary aspergillomas. PATIENTS AND METHODS: From 1992 to 2006, 24 patients (21 men, mean age 58.4 years) with pulmonary aspergillomas underwent pulmonary resection. Operative indications were massive or repetitive hemoptysis in 6 patients, medically unmanageable localized infection in 14 patients, and undetermined mass in 4 patients. Eighteen patients (75.0 %) had background pulmonary diseases and four patients (16.7 %) were mildly immunocompromised. Eight patients had simple aspergillomas, while sixteen patients had complex aspergillomas. Two patients with pleural empyema had their pleural spaces sterilized before pulmonary resections. Fungus balls and pulmonary cavities along with the surrounding lung were removed in all patients. RESULTS: Surgical procedures consisted of 13 lobectomies, 5 pneumonectomies including one completion penumonectomy, 2 segmentectomies and 4 wedge resections. Postoperative complication occurred in 10 patients (41.6 %) and one patient died from aortic bleeding due to postoperative empyema. Other major complications were prolonged air leaks, bleeding, and chylothorax. In the follow-up period, all but one patient were free from aspergillosis. Hemoptysis was not seen in any patient. Overall survival rates at 2, 5, and 10 years were 86.6 %, 79.4 % and 79.4 %, respectively. Disease-free survival rates from aspergillosis were 86.6 %, 72.6 % and 72.6 % at 2, 5, and 10 years, respectively. CONCLUSION: Pulmonary resection for aspergilloma showed favorable acute and long-term outcomes when surgical treatment was applied in selected patients.

背景．Pleomorphic carcinomaは肺原発悪性腫瘍の約0.3％とされている稀な疾患である．今回我々は空洞像を呈したPleomorphic carcinomaの1例を経験したので報告する．症例．62歳，男性．主訴は咳嗽．2ヶ月前より主訴あり，精査することとなった．胸部X線で左上肺野に異常陰影を認め，胸部CTでは左上葉に壁が不整な4 cm大の空洞性病変がみられた．気管支鏡下肺生検で非小細胞肺癌と診断を得たため，左肺上葉切除及び肺門縦隔リンパ節郭清術を施行した．病理組織所見では扁平上皮癌と紡錘細胞，巨細胞が混在して増殖しておりPleomorphic carcinomaと診断された．リンパ節転移は認められず病理病期はpT2N0M0，Stage IBであった．術後8ヶ月再発の兆候はみられていない．結論．本腫瘍は他の組織型と比較して予後不良との報告もあるため厳重な経過観察が必要であると考えられる．

目的．PET検査の肺癌縦隔リンパ節転移診断能を評価した．対象と方法．2003年1月から2005年5月の間に術前にPET検査が施行され，外科手技にて縦隔リンパ節転移の有無が病理組織学的に確定した100例の原発性肺癌患者を対象とした．結果．PET検査による縦隔リンパ節診断能は偽陽性9例，偽陰性13例で，sensitivity 35％，specificity 88.8％，positive predictive value 43.8％，negative predictive value 84.5％，accuracy 78％であった．肺門リンパ節診断能はPET N1 8例は，pN0 3例，pN1 1例，pN2 4例で，N1診断のaccuracyは12.5％と低かった．結語．PET検査による肺癌術前縦隔リンパ節診断能は低かった．

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

Objective: Induction chemoradiotherapy followed by anatomical resection is a current therapeutic strategy for non-small-cell lung cancer with mediastinal node involvement. Dense peritracheal fibrosis and sclerosis after chemoradiotherapy cause difficult mediastinal node dissection. We evaluated a novel technique to make the mediastinal node dissection easier after induction therapy. Methods: At the end of mediastinoscopic node biopsy for staging of lung cancer, cotton-type collagen was inserted anterior and lateral to the trachea in patients with pathologically confirmed mediastinal node involve-ment (n=45). The induction therapy consisted of concurrent use of platinum-based chemotherapy and hyperfractionated radiotherapy. After the chemoradiotherapy all patients underwent a pulmonary resection with complete mediastinal node dissection 7–12 weeks after the collagen insertion. Surgical findings of the mediastinum and the time for node dissection were compared with those without collagen insertion at mediastinoscopy after chemoradiotherapy (n=5). Results: All five patients without collagen insertion showed sclerotic and fibrotic change of mediastinal nodes with severe adhesion to the trachea. In 42 of 45 patients with collagen insertion (93.3%) the collagen remained unabsorbed and separated the mediastinal nodes from the trachea. Mediastinal node dissection was easily accomplished by removing mediastinal tissues lateral and anterior to the collagen. The rate of mediastinal node separation was significantly higher with collagen insertion than without (p< 0.0001). The times for node dissection in patients with and without collagen insertion showed no significant difference. Conclusion: Cotton-type collagen insertion at staging mediastinoscopy for lung cancer separates the mediastinal nodes from the trachea and makes the node dissection easier after induction chemoradiotherapy.

背景．ブラは肺癌発生の危険因子とされている．今回我々は左右のブラ壁に異時性に異なる組織型の肺癌を生じた症例を経験したので報告する．症例．50歳，男性．43歳の時，右上葉ブラ壁に発生した肺扁平上皮癌に対して右上葉切除術（pT1N0M0，Stage IA）を受けた．当時より左上葉のブラを指摘されていた．術後の経過観察中に胸部X線写真で左上肺野に腫瘤がみられた．胸部CTでは左上葉ブラ壁に数珠状に連なる腫瘤影があり，少量の液体貯留がみられた．左肺上葉切除術を施行し，病理診断は肺腺癌（pT2N0M0，Stage IB）だった．結論．ブラが存在する症例では肺癌が発症する可能性が高いことを念頭に入れた定期的な経過観察が必要と考えられた．

膿胸などの良性疾患, 肺癌・胸壁腫瘍などの悪性疾患に対する手術を行う際, 時として骨性胸壁の再建を要することがある. 当科では2001年12月より2003年6月まで6症例に対して自家肋骨を用いた胸壁再建を行った. 原疾患は有瘻性膿胸3例, 肺癌胸壁浸潤1例, 肺癌胸壁転移1例, 原発巣不明胸骨腫瘍1例であった. 肋骨を遊離性に用いた症例が3例, 有茎性に用いた症例が3例であった. 術後肺炎のために死亡した症例を除いた5症例では退院時移植骨の固定は良好で胸壁の安定性は保たれていた. 自家肋骨による再建はおおむね固定良好であり, 異物反応や局所感染は生じなかった.

胸骨骨折は外傷性骨折の中では比較的まれである.当科では最近10年間で18症例の胸骨骨折を経験した.骨折の原因として交通事故が11例, 転落が3例, その他4例だった.合併損傷としては肋骨骨折が6例, 血気胸が5例, 鎖骨骨折が1例, 胸椎骨折が1例, 腰椎骨盤骨折が1例であった.そのうち12症例には保存的治療を行い, 6症例に対して観血的胸骨固定術を施行した.固定方法は (I) ワイヤ3本,(II) ワイヤとバンド,(III) ワイヤ2本,(IV) ワイヤ2本と吸収性胸骨ピンの4通りで行った.術後4症例では再転位はみられなかったが, 2症例では再転位がみられた.手術で十分な固定ができなかったことに加えて, 術後局所安静が維持できなかったことも原因と考えられた.観血的胸骨固定術の適応としては (1) 骨折による転位が大きく疼痛が強い場合,(2) 骨折により他臓器が損傷されている場合が考えられた.

先天性嚢胞性腺腫様奇形 (以下CCAM) の2手術例を経験した.症例1: 5歳の女児.主訴は発熱, 咳噺.胸部X線上右下肺野に鏡面像を伴った複数の嚢胞がみられた.胸部CTでは右下葉に一部鏡面像を伴った多房性嚢胞陰影を認めた.同部位の部分切除術と肺縫縮術を施行した.病理ではCCAM, Stocker分類1型と診断された.術後, 発熱・咳嗽が再び認められ, 遺残嚢胞の拡大による術後再発が確認された.右肺下葉切除を施行し, 以降再発はみられていない.症例2: 8歳の男児.2歳の時に肺炎の既往がある.主訴は発熱.胸部X線上右上肺野に縦隔に接するように腫瘤影を認めた.胸部CTでは右主気管支上縁から縦隔に揺するように肺尖に達する2房性の嚢胞を認めた.右肺上葉切除術を施行し, CCAM Stocker分類1型と診断された.術後再発はみられていない.

背景. 40歳未満の若年者原発性肺癌は稀である. その頻度は全肺癌の3%前後に過ぎないとされている. 今回我々は18歳女性の肺癌症例を経験したので報告する. 症例. 18歳女性. 検診で胸部X線上右肺野に異常陰影を指摘された. 気管支鏡検査で確定診断が得られなかったため, 診断, 治療目的に手術を施行した. 術中迅速診断で肺癌の診断が得られたため右上葉切除術を施行することとなった. 肺胞壁を置換性に進展する高分化型乳頭状腺癌の所見が得られた. 病理病期はpT1N0M0 Stage IAであった. 術後1年経過した現在再発は認められない. 結論. 若年者であっても疑わしい症例では積極的に検査を行い, 診断がつかない場合は開胸生検を施行する必要があると考えられた.

We present a case of intralobar pulmonary sequestration (IPS) and pulmonary aspergillosis (PA) in a 32-year-old Japanese man. Immunological examination indicated an initial diagnosis of PA and an antifungal agent was administered. Since an abnormal chest shadow persisted, another causative lung disease was suspected to exist. Further inspection revealed the presence of IPS and surgical resection was performed. The symptoms of IPS are usually secondary to pyogenic infection; nevertheless, Aspergillus is a possible causative microorganism.

T cells that mediate autoimmune diseases such as rheumatoid arthritis (RA) are difficult to characterize because they are likely to be deleted or inactivated in the thymus if the self antigens they recognize are ubiquitously expressed. One way to obtain and analyze these autoimmune T cells is to alter T cell receptor (TCR) signaling in developing T cells to change their sensitivity to thymic negative selection, thereby allowing their thymic production. From mice thus engineered to generate T cells mediating autoimmune arthritis, we isolated arthritogenic TCRs and characterized the self antigens they recognized. One of them was the ubiquitously expressed 60 S ribosomal protein L23a (RPL23A), with which T cells and autoantibodies from RA patients reacted. This strategy may improve our understanding of the underlying drivers of autoimmunity.