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Background Not every elderly person is frail, and whether it would be beneficial to perform endovascular aneurysm repair (EVAR) solely because a patient is older is unclear. This study aimed to compare the results of EVAR and open surgical repair (OSR) in elderly individuals.Methods and Results:From May 1998 to March 2021, 828 EVAR patients and 886 OSR patients with abdominal aortic aneurysm (AAA) were reviewed. Patients aged ≥80 years were included among them. After propensity score matching by age, sex, and American Society of Anesthesiologists (ASA) classification, the outcomes were compared between patients who underwent EVAR and OSR. The study cohort was composed of 351 EVAR patients and 90 OSR patients. The groups had similar comorbidities, except that EVAR patients were significantly older and had higher ASA classifications. After propensity score matching, 79 pairs of patients were selected. The 30-day mortality (0 vs. 1.2%) and aneurysm-related death (ARD) rates during follow up (2.3% vs. 2.3%, respectively) were similar between the groups. Kaplan-Meier curves revealed that estimated overall survival and freedom from ARD were also similar. Conclusions This study suggests that EVAR cannot improve survival outcomes compared with OSR if applied solely because a patient is aged ≥80 years. Not only age but also other risk factors and quality of life after surgery need to be further studied.

Adoptive immunotherapy has emerged as a powerful approach to cure cancer and chronic infections. Currently, the generation of a massive number of T cells that provide long-lasting immunity is challenged by exhaustion and differentiation-associated senescence, which inevitably arise during in vitro cloning and expansion. To circumvent these problems, several studies have proposed an induced pluripotent stem cell (iPSC)-mediated rejuvenation strategy to revitalize the exhausted/senescent T cell clones. Because iPSC-derived cytotoxic T lymphocytes (iPSC-CTLs) generated via commonly used monolayer systems have unfavorable, innate-like features such as aberrant natural killer (NK) activity and limited replication potential, we modified the redifferentiation culture to generate CD8αβ(+)CD5(+)CCR7(+)CD45RA(+)CD56(−)-adaptive iPSC-CTLs. The modified iPSC-CTLs exhibited early memory phenotype, including high replicative capacity and the ability to give rise to potent effector cells. In expansion culture with an optimized cytokine cocktail, iPSC-CTLs proliferated more than 10(15)-fold in a feeder-free condition. Our redifferentiation and expansion package of early memory iPSC-CTLs could supply memory and effector T cells for both autologous and allogeneic immunotherapies.

Sarcopenia and malnutrition are often used as surrogates for frailty, which is predictive of poor prognosis after surgery. We investigated the effects of sarcopenia and malnutrition on mortality after endovascular aneurysm repair (EVAR). The subjects of this study were patients who underwent EVAR at our hospital between June 2007 and December 2013, excluding those who underwent reintervention. The psoas muscle area at the L4 level was used as an indicator of sarcopenia. The Geriatric Nutritional Risk Index was used as an indicator of malnutrition. There were 324 patients included in the study, with a mean age of 78.1 years and a median follow-up period of 56.7 months. Multivariate analysis revealed that sarcopenia (HR, 1.79; p = .042) and malnutrition (HR, 1.78; p = .043) were independent prognostic factors. Patients with both factors were classified as the high-risk group and others were classified as the low-risk group. The survival rate was significantly lower in the high-risk group than in the low-risk groups (p

Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology., 動物由来の成分を含まないより安全な製法でiPS細胞から大量の再生T細胞を培養する方法の開発 --T細胞を使ったがん免疫療法での利用も--. 京都大学プレスリリース. 2021-01-18.

Background: Several reports have indicated that suprarenal (SR) fixation may impair renal function after endovascular abdominal aortic aneurysm repair (EVAR). However, most were short-term or at most, 1-year observational studies; therefore, the midterm effects on renal function remain unclear. This study aimed to identify predictors of midterm renal dysfunction after EVAR and compare renal outcomes in patients after EVAR with SR and infrarenal (IR) fixation. Methods: A total of 467 patients who underwent EVAR of nonruptured IR abdominal aortic aneurysm between 2007 and 2014 were reviewed in a prospectively collected database. Patients on hemodialysis at baseline were excluded. Among the remaining patients, those with 3-year laboratory testing were included in this study. Patients who developed acute kidney injury were excluded from the late renal function estimation. Predictors of 3-year renal function decline were estimated using logistic regression analysis. In addition, patients undergoing EVAR with IR (IR group) and SR fixation devices (SR group) were propensity matched by age, sex, baseline renal function, baseline aneurysm diameter, comorbidities, smoking habits, and regular use of medicines that may act on kidney function. Changes in renal function after surgery were compared between the IR group and the SR group. Results: During the study period, 237 patients (102 IRs and 135 SRs) were followed up with laboratory testing 3 years after surgery. Logistic regression analysis revealed that the use of a SR fixation device was independently predictive of a more than 20% decrease in the estimated glomerular filtration rate at 3 years after EVAR (odds ratio, 2.06; 95% confidence interval, 1.18-3.58; P = .011). Eleven patients who developed acute kidney injury (1 IR and 10 SRs) were excluded from the subsequent analysis. After propensity score matching, 87 pairs were selected (mean age, 77.2 ± 6.3 years; 151 males [86.8%]). The mean follow-up duration was 5.5 ± 1.8 years. In the SR group, estimated glomerular filtration rate at 3 years after surgery decreased significantly more than that in the IR group (mean of 17.8% vs 11.6%, respectively; P = .034). Conclusions: This study suggests that, compared with EVAR with IR endograft fixation, EVAR with SR endograft fixation is associated with worse outcomes for midterm renal function., ファイル公開：2021-02-01

Background : Although we have witnessed several cases of late proximal type I endoleak (T1AEL) after endovascular aneurysm repair (EVAR), most patients did not have “hostile neck” preoperatively. We hypothesized that the distance between the lowest renal artery and the neck angulation point and neck length are the two most important factors for maintaining long-term proximal sealing. This study evaluated “neck hostility”, which is the product of the distance to the angulation point and the neck length, as a preoperative morphological risk factor for the development of late T1AEL after EVAR. Methods : A retrospective review of a prospectively assembled database was performed for all patients who had undergone EVAR at a single institution from June 2007 to May 2017. Patient demographics and preoperative imaging data were collected, and Cox regression analysis was performed to identify the risk factors for late T1AEL. Results : Of the 655 patients who underwent EVAR during the study period, 115 were excluded due to complex EVAR (n=14), primary indications for iliac aneurysms (n=86), primary T1AEL (n = 3), or other reasons (n=15). Of the remaining 537 patients, twelve patients (2.2%) developed late T1AEL a median of 3.2 (interquartile range [IQR]; 3.0, 5.4) years after EVAR. Receiver operating characteristic (ROC) curve analysis revealed a neck hostility cutoff value of 8. Cox regression analysis revealed that a neck hostility value ≤8 and conical neck anatomy were risk factors for the development of late T1AEL after EVAR. Well-known hostile neck factors such as short neck, severe angulated neck, and severe calcification/thrombus in the proximal neck were not significantly different. Conclusions : The present study demonstrated a correlation between late T1AEL and the product of the angulation distance and the neck length. This factor may be useful for predicting poor late proximal outcomes after EVAR.

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, PμM vs 755 μM, P Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

Endovenous laser ablation (EVLA) with concomitant phlebectomy is commonly performed in many institutions. However, phlebectomy is associated with cosmetic complications such as surgical scarring, hemorrhage, and hematoma. This study aims to compare the need for additional sclerotherapy during follow-up after EVLA with and without concomitant phlebectomy.Between November 2013 and December 2018, we performed EVLA on 1,363 limbs in 1,009 patients with symptomatic primary varicose veins, of which 954 limbs in 771 patients with great saphenous vein (GSV) or small saphenous vein (SSV) insufficiency were included in this study. Data were collected prospectively and supplemented with retrospective medical record review. Demographic and clinical characteristic profiles were collected. The outcomes of EVLA with or without concomitant phlebectomy were compared. Logistic regression was used to assess predictors for additional sclerotherapy after EVLA.CEAP classification (P 0.001), operative time (P 0.001), laser device type (P 0.001), length of the treated vein (P 0.001), linear endovenous energy density (P 0.001), and tumescent local anesthesia volume (P 0.001) differed significantly. Pain after EVLA was significantly more frequent in the nonphlebectomy group than in the phlebectomy group (P = 0.005). During follow-up, 34 of 954 limbs (3.6%) underwent additional sclerotherapy for residual visible varicose veins after EVLA. No statistical difference was found in the rate of additional sclerotherapy between the groups (P = 0.849). Logistic regression showed that female sex (odds ratio [OR], 6.18; 95% confidence interval [CI], 1.86-20.6; P = 0.003) is significantly associated with additional sclerotherapy, and concomitant phlebectomy is not a significant predictor of additional sclerotherapy (OR, 0.844; 95% CI, 0.375-1.90; P = 0.682).Patient preference for additional sclerotherapy was comparable between those who underwent EVLA with and without concomitant phlebectomy. This result supports our present strategy of avoiding simultaneous phlebectomy at the time of primary EVLA.

Background In thoracic endovascular aortic repair (TEVAR), covering the celiac artery (CA) is sometimes necessary to secure the distal seal. We report the outcomes of planned CA coverage in our experience with TEVAR. Methods Cases requiring CA coverage during TEVAR from October 2008 to September 2018 were retrospectively reviewed. Patient demographics, indications for CA coverage, communication between the CA and the superior mesenteric artery (SMA), concomitant CA embolization, and perioperative and late results were collected in a prospective database and analyzed. Results During the study decade, 357 patients underwent TEVAR at our institution. Of these patients, 15 (4.2%) required CA coverage. All 15 patients were male, and the mean age was 72.8 years (range, 44-80 years). The mean aneurysm size was 67.5 mm (range, 50-82 mm). The etiologies included 10 degenerative aneurysms (66.7%; 2 ruptures [13.3%], 4 dissecting aneurysms [26.7%], and 1 case of type IB endoleak [6.7%]) after TEVAR. Communicating collaterals between the CA and the SMA were confirmed by preoperative computed tomography angiography in eight patients (53.3%) and by intraoperative angiography in four patients (26.7%). Seven patients (46.7%) underwent concomitant embolization of the CA. CA coverage offered a mean extension of 20.3 mm (range, 12-22 mm) in the length of the distal seal. Postoperative computed tomography angiography revealed a type IB endoleak that resolved spontaneously in one patient (6.7%). Postoperative complications included splenic infarction/pancreatitis in one patient (6.7%) and spinal cord ischemia in two patients (13.3%). There were no cases of postoperative in-hospital mortality. During the follow-up period (mean, 3.6 years; range, 0.9-8.0 years), two patients developed a new type IB endoleak. One patient underwent distal extension of the stent graft with ilio-SMA bypass, and one patient was observed conservatively in accordance with the patient's decision. There were no cases of type II endoleak via the CA. Most aneurysms (86.7%) were stable or reduced in size at the most recent follow-up. There were no cases of targeted aneurysm-related death during the follow-up period. Conclusions Our study demonstrates the safety and efficacy of CA coverage in facilitating adequate distal sealing in selected patients undergoing TEVAR. Because the distal sealing length is not completely sufficient in most cases requiring CA coverage, the long-term efficacy of CA coverage during TEVAR should be determined in a large prospective study.

Summary CD4+ T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into original TCR-expressing T-lineage cells (iPS-T cells) with gene expression patterns resembling those of group 1 innate lymphoid cells. CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR. iPS-T cells upregulated CD40 ligand (CD40L) expression in response to interleukin-2 and interleukin-15. In the presence of Wilms tumor 1 (WT1) peptide, antigen-specific dendritic cells (DCs) conditioned by CD4-modified CD40Lhigh iPS-T cells stimulated WT1-specific CTL priming, which eliminated WT1 peptide-expressing CML cells in vitro and in vivo. Thus, CD4 modification of CD40Lhigh iPS-T cells generates innate lymphoid helper-like cells inducing bcr-abl-specific TCR signaling that mediates effectiveanti-leukemic CTL responses via DC maturation, showing potential for adjuvant immunotherapy against leukemia., Graphical Abstract, Highlights • iPSC-derived T cells have molecular similarity to group 1 innate lymphoid cells • iPSC-derived CD40Lhigh T cell-adjuvants induce leukemia-specific CTLs via DCs, Kaneko and colleagues describe the generation of CD4+ T helper clone-derived iPSCs and differentiation of the cells into T-lineage cells, which had molecular signatures and functional properties more consistent with group 1 innate lymphoid cells. CD4 transduction and CD40 ligand high population purification of the regenerated cells enhanced the antigen-specific adjuvant responses via dendritic cells in an antigen-specific manner.

Summary Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of “rejuvenated” induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.

Chimeric antigen receptor (CAR) is an artificial protein that provides HLA-independent antigen specificity to T cells. CAR-T therapy has shown remarkable clinical responses especially in hematologic malignancies. But this therapy needs cell preparation for each patient. That limits its applicability. We have reported regeneration of T cells from iPSCs (Cell Stem Cell 2013). This technology provides unlimited number of T cells, so CAR-T therapy using iPSCs can broadens its applicability. Regenerated T cells previously described in some reports including ours have some different characters from peripheral T cells. In particular, they express only CD8α, and do not express CD8β. We successfully generate CAR-iPS-T cells expressing CD8β with some modification of differentiation protocols. We assayed the function of CAR-iPS-T cells in view of the difference between CD8β positive and negative iPS-T cells. We found CD8β positive CAR-iPS-T cells showed enhanced function to suppress tumor progression compared with CD8β negative CAR-iPS-T cells in subcutaneous xenograft model. In vivo kinetics study revealed that CD8β positive CAR-iPS-T cells have superior function to traffic to target expressing tumor site and enhanced sustainability in vivo compared with CD8β negative CAR-iPS-T cells. These findings indicate that CD8β positive CAR-iPS-T cells may be a potent cell source for iPSC-based cancer immunotherapy. Citation Format: Tatsuki Ueda, Shoichi Iriguchi, Yohei Kawai, Atsutaka Minagawa, Hiroyuki Miyoshi, Seitaro Terakura, Yasushi Uemura, Knut Woltjen, Yuzo Kodama, Hiroshi Seno, Yasumichi Hitoshi, Tetsuya Nakatsura, Koji Tamada, Shin Kaneko. Generation of CAR-iPS-T cells expressing CD8β [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2550.

The use of antigen-specific T cell derived induced iPSCs as a cell source for regeneration of cytotoxic T lymphocytes (CTLs) have advantages in rejuvenation profile, and reproducible number of CTLs. However for the safe and efficient regenerated T cell immunotherapy, strict antigen specificity is essential. Here we report CD8αβ T cells differentiated from T cell-derived iPSCs underwent additional rearrangement of the T cell receptor (TCR) α-chain gene at the CD4/CD8 double positive stage during in vitro differentiation and lost antigen specificity. CRISPR knockout of a recombinase gene in the T-iPSCs successfully prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from non-T cell-derived but antigen-specific TCR-transduced iPSCs, they showed monoclonal expression of the transduced TCR. TCR stabilized regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies. Citation Format: Atsutaka Minagawa, Akitsu Hotta, Yohei Kawai, Yutaka Yasui, Yasushi Uemura, Masaki Yasukawa, Tetsuya Nakatsura, Shin Kaneko. T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3585.