Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4+ T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

[Video-assisted Thoracoscopic Surgery for Mediastinal Tumor and Thoracic Wall Tumor].

"A final conceptual change concerns the appreciation that all major thymoma subtypes can behave in a clinically aggressive fashion and, therefore, should no longer be called benign tumors, irrespective tumor stage. Accordingly, their International Classification of Disease for Oncology( ICD)-O codes now have a /3 suffix, thymomas, for as malignant.1)" This manuscript indicated that almost all mediastinal tumors, which could not be easy to diagnose per-operatively, should be removed. There were two large problems for mediastinal tumors resection with video-assisted thoracoscopic surgery (VATS). First is management or approach for the thymic vein, which have a short distance but large diameter relatively, and individual variation about the position and the number. Some solutions were 1) performance of pre-operative enhanced computed tomograpy( CT) or magnetic resonance imaging( MRI), 2) transcervical approach with Kent retractor, 3) sternal-L shape approach. Second is for the patients, which have thymoma or thymic tumor with myasthenia gravis, to what extent should be removed anterior fatty tissue. For the moment including beneath the innominate vein it should be removed as extent as possible. Liga Sure Impact was useful to remove a large thoracic wall tumor with VATS for resection of thick muscle.

＜Editors' Choice＞ Myelodysplastic syndrome with trisomy 8 presenting periodic fever and multiple MEFV gene variants outside exon 10: a case report.

Myelodysplastic syndrome is associated with the development of autoinflammatory conditions, such as recurrent fever, polymyalgia, arthralgia, and erythema. Trisomy 8 is a common chromosomal abnormality in patients with myelodysplastic syndrome. Myelodysplastic syndrome with trisomy 8 involves autoinflammatory conditions, especially Behçet's disease-like symptoms with intestinal mucosal damage. MEFV variants, particularly those in exon 10, are pathogenic in familial Mediterranean fever, the most common autoinflammatory disease, presenting typical symptoms such as periodic fever and pleuritis/pericarditis/peritonitis. MEFV variants outside exon 10 are common in Japanese patients with familial Mediterranean fever and are associated with atypical symptoms, including myalgia and erythema. MEFV variants in myelodysplastic syndrome with trisomy 8 have rarely been investigated, although myelodysplastic syndrome with trisomy 8 might develop autoinflammatory conditions similar to those in familial Mediterranean fever. We encountered a 67-year-old man who had myelodysplastic syndrome with trisomy 8 and multiple MEFV variants outside exon 10. He presented with periodic fever, as well as chest/abdominal pain, myalgia, and erythema, although the symptoms did not fulfill the diagnostic criteria of familial Mediterranean fever. We discussed the possibility that these symptoms are modified by MEFV variants outside exon 10 in myelodysplastic syndrome with trisomy 8.

Students' perception of a hybrid interprofessional education course in a clinical diabetes setting: a qualitative study.

OBJECTIVES: To explore what the student participants learned and how they felt about the use of three educational settings, namely, face-to-face workshop setting, asynchronous and synchronous online learning environments and interactions with outpatients in a real-world clinical setting in a hybrid interprofessional education course. METHODS: This qualitative study used semi-structured in-depth interviews with healthcare undergraduate student participants in a course comprising workshops in three educational settings. A total of 15 healthcare undergraduate students, which included four medical, three pharmacy, five nursing and three nutrition students, completed this IPE course. All students agreed to participate in the study. We conducted four focus groups selected using convenient sampling. Focus group transcripts were analysed using the 'Steps for Coding and Theorization' qualitative data analysis method. We investigated the students' perception through the experience of three educational settings in the hybrid interprofessional education course. RESULTS: The students recognised that this course had three types of educational spaces, namely, real, semi-real and unreal. Then, the positive changes in the awareness of students are trained in recognition of the patient perspective, the recognition of the roles discharged by the other professions and the recognition of the functions of their own profession after experiencing the educational spaces designated for this course. CONCLUSIONS: The repeated experience of participants to real, semi-real and unreal educational spaces promoted changes over time in the students' awareness of interprofessional competencies with respect to patient-centred care and ameliorated their readiness to undertake interprofessional tasks.

[Contrivance for Video-assisted Thoracic Surgery Lung Operation Especially Lobectomy with Adhesive and Fissureless Complications].

There were 74 cases (29.5%) with adhesive and fissureless complications in comparison with all 251 cases who had undergone video-assisted thoracic surgery (VATS) lung operations in author's hospital. On lobectomy and segmentectomy adhesive and fissureless effective factors were old age( p=0.012), the difference between %DLco to %DLco/VA( p<0.05), Brinkman index( p=0.043) compared with non-ad- hesive cases, therefore operation times of fissureless group prolonged (p=0.009). The point at issue was in what manner we should perform appropriate division of the bronchus, the pulmonary arteries and the veins on the fissureless lobectomy. Especially it is very important which the apicoposterior artery( rA2b:Asc) on right upper lobectomy and the lingular segmental artery( lA4+5) on left upper lobectomy branch from the major fissure or not. For that purpose the management procedure had been done pulmonary artery (primary upper division: A1+2+A3)→ pulmonary vein → bronchus → residual pulmonary artery (rA2b or lA4+5). On the very severe fissureless cases the management procedure had been done pulmonary vein → bronchus → pulmonary artery. Mobilization of "fissure first, hilum last" and/or "hilum first, fissure last" techniques should be performed for VATS fissureless lobectomy.

Prediction of an oxygen extraction fraction map by convolutional neural network: validation of input data among MR and PET images.

PURPOSE: Oxygen extraction fraction (OEF) is a biomarker for the viability of brain tissue in ischemic stroke. However, acquisition of the OEF map using positron emission tomography (PET) with oxygen-15 gas is uncomfortable for patients because of the long fixation time, invasive arterial sampling, and radiation exposure. We aimed to predict the OEF map from magnetic resonance (MR) and PET images using a deep convolutional neural network (CNN) and to demonstrate which PET and MR images are optimal as inputs for the prediction of OEF maps. METHODS: Cerebral blood flow at rest (CBF) and during stress (sCBF), cerebral blood volume (CBV) maps acquired from oxygen-15 PET, and routine MR images (T1-, T2-, and T2*-weighted images) for 113 patients with steno-occlusive disease were learned with U-Net. MR and PET images acquired from the other 25 patients were used as test data. We compared the predicted OEF maps and intraclass correlation (ICC) with the real OEF values among combinations of MRI, CBF, CBV, and sCBF. RESULTS: Among the combinations of input images, OEF maps predicted by the model learned with MRI, CBF, CBV, and sCBF maps were the most similar to the real OEF maps (ICC: 0.597 ± 0.082). However, the contrast of predicted OEF maps was lower than that of real OEF maps. CONCLUSION: These results suggest that the deep CNN learned useful features from CBF, sCBF, CBV, and MR images and predict qualitatively realistic OEF maps. These findings suggest that the deep CNN model can shorten the fixation time for 15O PET by skipping 15O2 scans. Further training with a larger data set is required to predict accurate OEF maps quantitatively.

PARP1 V762A polymorphism affects the prognosis of myelodysplastic syndromes.

OBJECTIVE: Myelodysplastic syndromes (MDS), caused by various genetic mutations in hematopoietic stem cells, are associated with highly variable outcomes. Poly (ADP-ribose) polymerase-1 (PARP1) plays an important role in DNA damage repair and contributes to the progression of several types of cancer. Here, we investigated the impact of PARP1 V762A polymorphism on the susceptibility to and prognosis of MDS. METHODS: Samples collected from 105 MDS patients and 202 race-matched healthy controls were subjected to polymerase chain reaction-restriction fragment length polymorphism for genotyping. RESULTS: The allele and genotype frequencies of PARP1 V762A did not differ between MDS patients and the control group. However, MDS patients with the PARP1 V762A non-AA genotype, which is associated with high gene activity, had shorter overall survival rates (P = .01) than those with the AA genotype. Multivariate analysis of overall survival also revealed PARP1 V762A non-AA genotype as a poor prognostic factor (P = .02). When patients were analyzed according to treatment history, the PARP1 V762A non-AA genotype was only associated with poor survival in patients who had received treatment (P = .02). CONCLUSION: PARP1 V762A polymorphism may be an independent prognostic factor for MDS, and a predictive biomarker for MDS treatment.

Three Consecutive Cases of Familial Hemophagocytic Lymphohistiocytosis, Including a Case Due to Maternal Uniparental Disomy.

We have experienced 3 consecutive cases of familial hemophagocytic lymphohistiocytosis (FHL). All affected infants had mutations in exon 3 of the perforin gene. The first had a homozygous mutation, c.1168C>T (p.R390*), caused by maternal uniparental isodisomy. The second and third had compound heterozygous mutations: c.781G>A (p.E261K) and c.1491T>A (p.C497*); c.1724G>T (p.C242G) and p.R390*, respectively. FHL is very rare in Northern Japan but should be suspected if infants exhibit prolonged fever. This is the first report of a relationship of p.R390* with FHL caused by uniparental isodisomy, and the second reported case of FHL type 2 with this form of inheritance.

Fatal case of TAFRO syndrome associated with over-immunosuppression: a case report and review of the literature.

TAFRO syndrome is a novel disease concept characterized by Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly, multiple lymphadenopathy and a histopathological pattern of atypical Castleman's disease. A 58-year-old man was diagnosed as TAFRO syndrome by clinical and histopathological findings. After receiving intensive immunosuppressive therapy, his thrombocytopenia and anasarca had not improved. He developed complications such as methicillin-resistant Staphylococcus aureus sepsis, gastrointestinal bleeding, peritonitis caused by Stenotrophomonas maltophilia, gastrointestinal perforation, and disseminated candidiasis resulting in death. Autopsy revealed disseminated candidiasis and hemophagocytic lymphohistiocytosis, with no evidence of TAFRO syndrome. During treatment, we regarded his lasting thrombocytopenia and anasarca as insufficient control of TAFRO syndrome. However, the autopsy revealed that thrombocytopenia was caused by secondary hemophagocytic lymphohistiocytosis caused by over-immunosuppression. We reviewed the published literature to identify indicators of adequate treatment, which suggested improvement of platelet count and anasarca several weeks after initial therapy. This indicated that we could not depend on the platelet count and anasarca in acute medical care after initial treatment. We should treat TAFRO syndrome based on patients' clinical status and obviate the risk of treatment-related complications caused by over-immunosuppression.

Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response.

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.

A Scottish and Japanese experience of patient-centred diabetic care: descriptive study of interprofessional education on live webinar.

To minimise the global burden of diabetes, the awareness of appropriate intervention methods for diabetes education and practice is essential. This project is the first international interprofessional education (IIPE) for the awareness of diabetes, with a focus on patient-centred care wherein three medical and four pharmacy students from Japan and one medical, two pharmacy, two nutrition and one occupational therapy (OT) student from Scotland participated. We described IIPE effects using interdisciplinary education perception scale (IEPS) before and after the programme among Scottish and Japanese students. University of Aberdeen/ Robert Gordon University and Nagoya University developed and established a shared online platform that provided knowledge to students on diabetes in both languages. We developed a case-based scenario that reflected diabetes care in each country using a standardised patient (SP). Lastly, a student-led live webinar was conducted on 14 November 2014 (the World Diabetes Day) to discuss and exchange care methods for SP. Each participating national team presented their care plan and all students discussed the diabetic care plan online. Both Japanese and Scottish teams were able to accurately assess the patient's condition and empathise with the SP. In conclusion, all participants learned that interprofessional collaboration was clearly required for diabetes management focused on patient-centred care. All participants appreciated the differences in the approach of the two countries involved because of the cultural- and health related differences. This programme was significant in raising awareness regarding the need for international interprofessional intervention on diabetes towards developing a model for live webinar IIPE.

Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia.

Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35-12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.

[One-stage Operation through the Same Skin Incision for Synchronous Double Primary Breast and Lung Cancer;Report of a Case].

A 75-year-old woman noticed a small mass in the right side breast and consulted our hospital. The results of the detailed examination indicated the synchronous double primary right breast cancer and the same side lung cancer (rS5). One-stage operation from the same skin incision was scheduled. Volume rendering (VR) of computed tomography (CT)-scan was very useful in deciding the position and the length of the skin incision. The breast tumor resection and the right middle lobe resection were successfully performed through 6.5 cm skin incision.

IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma.

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.

[Treatment Policy for Avoiding Pneumonectomy Regarding the Locally Advanced Lung Cancers].

The problem of pneumonectomy may result from an elimination of the extensive pulmonary vascular bed as a unit. Therefore this paper has indicated that 10 cases with the locally advanced lung cancers had been treated with some parenchymal sparing procedures including chemotherapy in order to avoid pneumonectomy. Six cases with preoperative chemotherapy were performed sleeve lobectomy in 3 cases, tangential pulmonary artery(PA) resection in 2, and left atrium partial resection in 1. One case with irradiation in vain was done sleeve LLL+lS4+5segmentectomy. Three cases without pre-treatment were done tangential PA resection in 2 cases, sleeve lobectomy in 1. Outcome was that there were no perioperative mortality and 7 cases achieved long-term survival, however, 2 cases died of relapse, and one died of pneumonia. On surgical technique U-shape mattress interrupted suture for bronchoplasty and tangential PA resection were proved very useful procedures.

[Reconstructive method after resection of chest wall, diaphragm and pericardium, mainly using Composix-mesh].

This study examined utility and question about the reconstructive prostheses in 11 cases which were resected chest wall and/or diaphragm and/or pericardium. One of 3 patients, who were used metal plates after chest wall resection, was prevented from post-operative irradiation therapy by limitation and diffuse reflection of beam by the metal plates. Gore-Tex( ePTFE) sheets, which were used for coverage of diaphragm defect and pericardium defect, occurred no problems. Composix-meshes (Composix-Kugel, Hernia-patch) were used for 7 cases which had large defects due to resection of chest wall and diaphragm. These kinds of meshes (or patches) consist of double layer mesh and memory recoil ring and then have airtightness and rigidity. After reconstruction of chest wall and diaphragm there were no problems without any flail chest.

[Cutaneous metastasis from lung adenocarcinoma resected 34 months before surviving 5-year after skin tumor resection without relapse].

A 79-year-old man complained incurable skin ulcer that was treated in the neighborhood hospital during 2 months. He had been undergone right upper lobectomy for the lung adenocarcinoma in our hospital 34 months ago. The skin lesion in the right axilla was an elastic hard tumor about 2 cm large in thesubcutaneous tissue with ulceration, and was diagnosed as adenocarcinoma by cytology. Fluorodeoxy glucose-positron emission tomography (FDG-PET) /computed tomography (CT) showed no metastatic lesion other than the skin tumor, and the tumor was resected with a margin. Immunohistochemistry [cytokeratin (CK)-7(+++), CK-20(-), thyroid transcription factor (TTF)-1(-)] indicated the skin tumor to be metastasis from lung adenocarcinoma. He is alive over 8 years after right upper lobectomy(RUL)and 5 years after skin tumor resection without relapse.

Identification of novel ALK rearrangement A2M-ALK in a neonate with fetal lung interstitial tumor.

Fetal lung interstitial tumor (FLIT) is a recently reported type of congenital lung lesion comprising solid and cystic components. The pathological features include unique interstitial mesenchyme-based cell proliferation, and differ from other neoplasms represented by pleuropulmonary blastoma or congenital peribronchial myofibroblastic tumor. FLIT is extremely rare and its gene expression profile has not yet been reported. We provide the first report of a novel chromosomal rearrangement resulting in α-2-macroglobulin (A2M) and anaplastic lymphoma kinase (ALK) gene fusion in a patient with FLIT. The tumor cells contained a t(2;12)(p23;p13) and were mesenchymal in origin (e.g., inflammatory myofibroblastic tumors), suggesting the involvement of ALK in this case of FLIT. Break apart fluorescence in situ hybridization demonstrated chromosomal rearrangement at ALK 2p23. Using 5'-rapid amplification of cDNA ends, we further identified a novel transcript fusing exon 22 of A2M to exon 19 of ALK, which was confirmed by reverse-transcription polymerase chain reaction. The corresponding chimeric gene was subsequently confirmed by sequencing, including the genomic break point between intron 22 and 18 of A2M and ALK, respectively. Discovery of A2M as a novel ALK fusion partner, together with the involvement of ALK, provides new insights into the pathogenesis of FLIT, and suggests the potential for new therapeutic strategies based on ALK inhibitors.