A culture method with berbamine, a plant alkaloid, enhances CAR-T cell efficacy through modulating cellular metabolism.

Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells.

Endovascular Treatment as an Alternative to Bypass Surgery for Juxtarenal Aortic Occlusion: Results from the CHAOS (CHronic Abdominal Aortic Occlusion, ASian Multicenter) Registry.

BACKGROUND: Juxtarenal aortic occlusion (JRAO), in which the occlusion of the aorta extends to just below the renal artery, is often treated by bypass surgery because of concerns about the risk of procedural failure and fatal embolization to abdominal organs when treated with endovascular treatment (EVT). This study assessed the outcome of EVT for JRAO compared with aorto-biiliac /aorto-bifemoral (AOB) or axillo-bifemoral (AXB) bypass. METHODS: A retrospective review of an international database created by 30 centers in Asia (CHronic Abdominal Aortic Occlusion, ASian Multicenter registry) was performed for patients who underwent revascularization for chronic total occlusion of the infrarenal aorta from 2007 to 2017. Of the 436 patients, 130 with JRAO (Forty-seven AOBs, 32 AXBs, and 51 EVTs) from 25 institutions were included in this study. RESULTS: Patients were significantly older in the AXB and EVT groups and more malnourished in the EVT group than the AOB group. EVT was attempted but failed in 1 patient. Seven patients (1 [2.1%] in the AOB group, 1 [3.1%] in the AXB group, and 5 [9.8%] in the EVT group) died during hospitalization, but most of the causes in the EVT group were not related to the revascularization procedure. No visceral embolism was observed, which had been concerned, even though protection was performed only in 2 cases of the EVT group. At the latest follow-up (median duration 3.0 years), the ankle-brachial pressure index was significantly higher in the order of AOB, EVT, and AXB. At 4 years, the estimated primary and secondary patency rates of the AOB group (87.5% and 90.3%, respectively) were significantly higher than the AXB group (66.7% and 68.6%, respectively). CONCLUSIONS: AOB remains the gold standard and should be the first choice for acceptable risk patients. For frail patients, EVT is a good option and likely preferable as a first-line treatment compared to AXB.

＜Editors' Choice＞ Thoracic endovascular aortic repair and spinal cord injury.

We previously reported that spinal cord injury following thoracic endovascular aortic repair for a thoracic aortic aneurysm is a micro embolism caused by a vulnerable mural thrombus. Conversely, patients who underwent thoracic endovascular aortic repair for aortic dissection develop spinal cord injury less frequently due to fewer mural thrombi. Paying attention to preserving blood flow toward the spinal cord, namely collateral circulation and steal phenomenon, prevents spinal cord injury following thoracic endovascular aortic repair for aortic dissection.

Optimal D-Dimer Cutoff Values for Diagnosing Deep Vein Thrombosis in Patients with Comorbid Malignancies.

BACKGROUND: Patients with malignancy are at high risk of venous thromboembolism, and early diagnosis is important. The Khorana score is known as a risk assessment for cancer-related thrombosis during chemotherapy, but there are still few reports on its diagnostic potential, the optimal D-dimer cutoff values for indications other than chemotherapy and the use of the Khorana score in combination with D-dimers. In this study, we examined the clinical appropriateness of increasing the D-dimer cutoff value. METHODS: We retrospectively studied 208 malignancies out of 556 patients who underwent lower extremity venous ultrasonography at our hospital over a 2-year period from January 2018 to December 2019. The optimal D-dimer cutoff value for predicting deep vein thrombosis (DVT) in patients with malignancy was calculated by the Youden index. The usefulness of the Khorana score alone and the model combining the Khorana score with D-dimer for predicting DVT diagnosis was compared using receiver operating characteristic analysis. RESULTS: Of 208 eligible patients, 59 (28.4%) had confirmed DVT. The optimal D-dimer cutoff value for predicting DVT comorbidity in patients with malignancy was 3.96 µg/mL. When the new D-dimer cutoff value was set at 4.0 µg/mL, the odds ratio (OR) for DVT diagnosis was 4.23 (95% confidence interval (CI) 2.10-8.55, P < 0.001), which was higher than the OR of 1.33 (95% CI: 0.98-1.81, P = 0.064) for the Khorana score. The area under the curve for the Khorana score and D-dimer was 0.714, which was significantly higher than the 0.611 for the Khorana score alone, with the difference being significantly higher at 0.103 (P = 0.004, 95% CI: 0.033-0.173). CONCLUSIONS: The optimal D-dimer cutoff value for the diagnosis of DVT in patients with malignancy was 4.0 µg/mL. It was also suggested that the combination of the Khorana score with the D-dimer level was more accurate in diagnosing DVT than the Khorana score alone.

The Association Between the D-dimer Level at 1 Year After EVAR and Sac Diameter Change in Patients With Persistent Type 2 Endoleak.

PURPOSE: Recent studies suggested that continuous clotting renewal in thrombi plays a central role in sac enlargement after endovascular aneurysm repair (EVAR). We reviewed patients with persistent type 2 endoleak (T2EL) to estimate the impact of D-dimer level on sac enlargement. METHODS: A retrospective review of elective EVAR for infrarenal abdominal aortic aneurysm performed between June 2007 and February 2020. Persistent T2EL was defined as T2EL confirmed at both the 6 and 12 month contrast-enhanced computed tomography (CECT) follow-ups. "Isolated" T2EL was defined as T2EL without other types of endoleak within 12 months. Patients with >2 year follow-up, persistent isolated T2ELs, and D-dimer level data at 1 year (DD1Y) were included. Patients with any reintervention within 12 months were excluded. The association between DD1Y and aneurysm enlargement (AnE), defined as a ≥5 mm diameter increase, within 5 years was analyzed. Among 761 conventional EVAR, 515 patients had >2 years of follow-up. Thirty-three patients with any reintervention within 12 months and 127 patients without CECT at either 6 or 12 months were excluded. Among 131 patients with persistent isolated T2ELs, 74 patients with DD1Y data were enrolled. During a 37 month median follow-up [25-60, IQR], 24 AnEs were observed. In the AnE patients, the median DD1Y was significantly higher than that in the other patients (12.30 [6.88-21.90] vs 7.62 [4.41-13.00], P=0.024). ROC curve analysis indicated that the optimal cutoff point of DD1Y for AnE was 5.5 µg/mL (AUC=0.681). In univariate analysis, angulated neck, occlusion of the inferior mesenteric artery, and DD1Y≥5.5 µg/mL were significantly associated with AnE (P= 0.037, 0.038, and 0.010). Cox regression analysis revealed that DD1Y≥5.5 µg/mL was correlated with AnE (P=0.042, HR [95% CI] 4.520 [1.056-19.349]). CONCLUSION: A 1 year higher D-dimer level can potentially predict AnE within 5 years in persistent T2EL patients. AnE was considered improbable when the D-dimer level was low enough. CLINICAL IMPACT: The present study suggests that a 1-year higher D-dimer level could potentially predict aneurysm expansion within 5 years in patients with persistent type 2 endoleak (T2EL). On the other hand, aneurysm expansion was considered unlikely if the D-dimer level was low enough.As there are many patients with T2EL who require regular follow-up, any predictor of future aneurysm expansion could be of great help in conserving medical resources. In patients with a low likelihood of future expansion, we might consider delaying follow-up, similar to patients with sac shrinkage.

Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells.

The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αß cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours.

Factors Associated With Spontaneous Sac Shrinkage in Patients With Persistent Type 2 Endoleaks After EVAR.

PURPOSE: Despite controversy surrounding the management of type 2 endoleaks (T2ELs) after endovascular aortic aneurysm repair (EVAR), the current European guidelines recommend reintervention for T2ELs when the aneurysm expands by ≥10 mm. Meanwhile, sac shrinkage ≥10 mm can be considered low risk for failure even with T2ELs, and the guidelines suggest less frequent follow-up delayed until 5 years after EVAR. This study reviewed patients with persistent T2ELs to identify predictors of spontaneous sac shrinkage (SpS) within 5 years. METHODS: A retrospective review of elective EVAR for infrarenal aortic aneurysms between June 2007 and December 2017. Patients with >1 year follow-up and persistent T2ELs, defined as T2ELs confirmed at both the 6 and 12 month follow-up with contrast-enhanced computed tomography (CT), were included. Any reintervention or type 1 or 3 endoleaks within 12 months were excluded. SpS was defined as a ≥10 mm reduction in diameter without any reintervention. Aneurysm enlargement (AnE) was defined as a ≥5 mm increase in diameter. Factors associated with SpS within 5 years were analyzed. The clinical outcomes were reviewed. RESULTS: Among 726 patients, 162 patients had persistent isolated T2ELs. After excluding 21 patients, 141 patients were enrolled. During a median follow-up of 43 months (interquartile range [IQR], 26-60), 28 SpS and 39 AnE were observed, and 31 reinterventions were performed. The cumulative rates of SpS were 14.2%±2.9% and 25.6%±5.1% at 1 and 5 years. Cox regression analysis revealed that the presence of ≥6 patent lumbar arteries had a significant negative correlation with SpS (p=0.036). During further follow-up after SpS, 2 reinterventions for type 1a and 3b endoleaks were required at 49 and 45 months. CONCLUSIONS: Patients with fewer patent lumbar arteries were likely to experience SpS within 5 years, even in the presence of persistent T2ELs. Follow-up imaging studies were advisable earlier than 5 years, even after SpS.

One-year sac regression is associated with freedom from fatal adverse events after endovascular aneurysm repair.

OBJECTIVE: Although the predictors of long-term prognosis after endovascular aneurysm repair (EVAR) have been investigated, several reports have suggested that early sac shrinkage (ESS) is associated with superior long-term prognosis. However, it was not clear whether ESS was associated with aneurysm-related mortality. The aim of this study was to define fatal adverse events and to examine their association with ESS. METHODS: All consecutive patients who underwent EVAR for an abdominal aortic aneurysm at Nagoya University Hospital between June 2007 and August 2018 were identified. We defined ESS as an aneurysm diameter decrease of 10 mm or more at 1 year after EVAR, and we defined fatal adverse events as aneurysm-related death, aneurysm sac rupture, open conversion, secondary type Ia endoleak, or secondary type IIIa/b endoleak. Then, we evaluated the association between ESS and fatal adverse events and identified predictors of ESS. RESULTS: During the study period, 553 patients were identified and included. Fatal adverse events occurred in 42 patients (7.6%), and the details of the fatal adverse events were as follows: 13 aneurysm-related deaths, 17 aneurysm sac ruptures, 14 open conversions, 13 type Ia endoleaks, and 6 type III endoleaks. ESS occurred in 146 patients (26.4%). Kaplan-Meier curves showed that the ESS group had a significantly lower incidence of fatal adverse events (P < .001). Multivariate analysis showed that there were significant differences in terms of 5 or more preoperatively patent lumbar arteries (odds ratio [OR], 0.67; P = .049; 95% confidence interval [CI], 0.45-1.00), chronic kidney disease (OR, 0.49; P < .01; 95% CI, 0.29-0.84), and Zenith endograft use (OR, 1.76; P < .01; 95% CI, 1.16-2.67). Furthermore, the percentage of cases that achieved an aneurysm diameter of less than 40 mm was significantly higher in the ESS group (76.0% vs 15.5%; P < .01). The use of Zenith endografts showed a significantly higher rate of aneurysm disappearance than the use of Endurant endografts (P < .01) and Excluder endografts (P < .01). In addition, it was found that ESS was more likely to occur with the use of Zenith endografts, even when propensity score matching was performed for the neck morphology. CONCLUSIONS: ESS was associated with a lower rate of life-threatening adverse events after EVAR. The use of Zenith endografts was a predictor of ESS and was associated with increased rates of long-term sac shrinkage and aneurysm disappearance compared with the Endurant and Excluder endografts. Using the predictors of ESS identified in this study, we may be able to expand the indications for EVAR to patients with a longer life expectancy.

Severe Tortuosity of the Distal Descending Thoracic Aorta Affects the Accuracy of Distal Deployment During a Thoracic Endovascular Aortic Repair.

PURPOSE: An accurate distal deployment is essential for successful thoracic endovascular aortic repair (TEVAR) of a paradiaphragmatic aortic aneurysm. This study aimed to investigate the anatomical and intraoperative factors that affect the accuracy of distal deployment during TEVAR. METHODS: We conducted a retrospective review of preoperative and postoperative computed tomography scans of 426 patients undergoing TEVAR at our institution between October 2008 and May 2021, of which the stent-graft was attempted to be deployed just above the celiac axis or the superior mesenteric artery in 56 patients. Based on the anatomical factors related to the malposition (deployed >10 mm away from the target vessel) and the greater curve to the straight-line ratio (G/S ratio), the patients were categorized as severe tortuosity (n=21) and mild tortuosity (n=35) groups to compare the operative and clinical outcomes. RESULT: Stent-graft malpositioning occurred in 21 cases. Among all anatomical variables, only the G/S ratio was significantly larger in the malpositioned cases (p=0.049). A cutoff G/S ratio value of 1.15 was determined using the receiver operating curve analysis. In the severe tortuosity group, the distal end of the stent-graft was significantly farther (median: 10.0 [interquartile range (IQR): 2.5-19.5] mm vs 3.0 [0-8.0] mm; p=0.015) from the target vessel, and the tilt angle of the stent-graft's distal edge was larger (median: 21.4 [IQR: 15.8-24.5] vs 9.5 [5.5-12.5] degree; p<0.01) than that in the mild tortuosity group. Both groups were comparable for the incidence of a primary type Ib endoleak (p=0.454), a secondary type Ib endoleak (p=1.0), and the rate of distal reintervention (p=0.276). CONCLUSION: Severe tortuosity in the distal descending thoracic aorta is associated with a malpositioned and tilted distal end of the stent-graft. CLINICAL IMPACT: Thoracic endovascular aortic repair (TEVAR) for paradiaphragmatic thoracic aortic aneurysms requires accurate distal landing. In this paper, a retrospective CT analysis revealed that the greater curve to the straight-line ratio (G/S ratio) was associated to affects the malposition of the stent graft, defined as being deployed more than 10 mm away from the target vessel. Further, a comparative analysis based on the G/S ratio demonstrated that severe aortic tortuosity was associated with a more distal and tilted deployment of the stent graft.

Predictors of infrapopliteal vein bypass graft revision in patients with chronic limb-threatening ischemia.

PURPOSE: Surgical revascularization is the standard treatment for chronic limb-threatening ischemia (CLTI). However, some patients may require reintervention. The Global Anatomic Staging System (GLASS), which evaluates the complexity of infrainguinal lesions, was proposed. This study aimed to identify predictors for graft revision and evaluate whether GLASS impacts vein graft revision. METHODS: Between 2011 and 2018, CLTI patients who underwent de novo infrapopliteal bypass using autogenous veins were retrospectively analyzed. To assess anatomic complexity with GLASS, femoropopliteal, infrapopliteal, and inframalleolar/pedal (IM) disease grades were determined. The outcomes of patients with or without graft revision were compared. Cox regression analysis was performed. RESULTS: Thirty-six of the 80 patients underwent reintervention for graft revision. Compared to the non-graft revision group, the graft revision group exhibited significantly higher rates of GLASS stage III (66% vs 81%, p = 0.046) and grade P2 IM disease (25% vs 58%, p = 0.009). Multivariate analysis revealed that IM grade P2 (hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.66-6.75; p = 0.001) and spliced vein grafts (HR, 3.18; 95% CI, 1.43-7.06; p = 0.005) were significantly associated with graft revision. CONCLUSIONS: This study demonstrated that IM grade P2 and spliced vein grafts were predictors of graft revision. The GLASS stratification of IM disease grade may be useful in optimizing treatment for CLTI.

Epicardial adipose tissue volume is associated with abdominal aortic aneurysm expansion.

BACKGROUND: The epicardial adipose tissue volume (EATV) is associated with cardiovascular diseases such as coronary artery disease. However, no information is available regarding the relationship between the EATV and abdominal aortic aneurysm (AAA) expansion. In the present study, we evaluated the association between the EATV and AAA growth and sought to identify the predictors of AAA expansion. METHODS: Between June 2009 and December 2019, 906 patients had undergone endovascular or open repair of AAAs at our institution. Patients with previous cardiac surgery, previous ascending thoracic aortic surgery, a ruptured AAA, an infected AAA, an inflammatory AAA, a saccular aneurysm, a solitary iliac aneurysm, or reintervention after treatment of the AAA were excluded. A total of 237 patients with at least two preoperative computed tomography (CT) scans performed >180 days apart were included in the present study. The EATV within the pericardium was retrospectively quantified from the preoperative non-contrast-enhanced CT images using a three-dimensional workstation. The EATV index was defined as the EATV divided by the body surface area. The AAA expansion rate was defined as an increase in the AAA diameter annually, and the patients were divided into the slow-expansion group (expansion rate, <5 mm/y) and the fast-expansion group (expansion rate, ≥5 mm/y). The correlation between the expansion rate and the EATV index was analyzed, and the cutoff value for the EATV index was determined using a receiver operating characteristics curve. Multivariate analysis was used to assess the predictors of the AAA expansion rate. RESULTS: The expansion rate of AAA correlated positively with the EATV index (R = 0.237; P < .001). The initial aneurysm diameter (P < .001) and EATV index (P = .009) differed significantly between the two groups. The cutoff for the EATV index was 60.3 cm3/m2 (area under the curve, 0.658; 95% confidence interval [CI], 0.568-0.749; sensitivity, 1.000; specificity, 0.309). Multivariate analysis revealed that the initial aneurysm diameter and an EATV index of >60.3 cm3/m2 were significantly associated with the AAA expansion rate. CONCLUSIONS: The results of the present study have demonstrated that the EATV index is associated with AAA expansion.

Impact of Serum Zinc Level and Oral Zinc Supplementation on Clinical Outcomes in Patients Undergoing Infrainguinal Bypass for Chronic Limb-Threatening Ischemia.

BACKGROUND: Zinc (Zn) has been reported to play an important role in wound healing (WH). Nevertheless, the effect of Zn in chronic limb-threatening ischemia (CLTI) patients is unclear. This study investigated the effect of Zn on the clinical outcomes of CLTI patients undergoing bypass surgery.Methods and Results: This study reviewed 111 consecutive patients who underwent an infrainguinal bypass from 2012 to 2020. Patients with Zn deficiency (serum Zn level <60 µg/dL) received oral Zn supplementation and maintained a normal level until WH. This study aimed to explore: (1) the effect of Zn deficiency; and (2) Zn supplementation in Zn-deficient patients on the clinical outcomes of this cohort. Patients with Zn deficiency, Zn supplementation, and no Zn supplementation despite Zn deficiency accounted for 48, 21, and 42 patients, respectively. (1) Zn deficiency was associated with WH (HR, 0.47; 95% CI, 0.29-0.78: P=0.003), major adverse limb events (MALE) (HR, 2.53; 95% CI, 1.26-5.09: P=0.009), and major amputation or death (HR, 3.17; 95% CI, 1.51-6.63: P=0.002). (2) Zn supplementation was positively related to WH (HR, 2.30; 95% CI, 1.21-4.34: P=0.011). This result was confirmed using propensity score matching (HR, 2.24; 95% CI, 1.02-4.87: P=0.043). CONCLUSIONS: The current study revealed that Zn level was associated with clinical outcomes in CLTI patients after bypass surgery. Oral Zn supplementation could improve WH in these patients.

Sustainable Antiviral Efficacy of Rejuvenated HIV-Specific Cytotoxic T Lymphocytes Generated from Induced Pluripotent Stem Cells.

Persistence of HIV latently infected cells is a barrier to HIV cure. The "kick and kill" strategy for a cure includes clearance of the viral reservoir by HIV-specific cytotoxic T lymphocytes (CTLs). However, exhaustion and senescence of T cells accelerates during HIV infection, and does not fully recover, despite complete viral suppression under antiretroviral therapy. We previously established an induced pluripotent stem cell (iPSC) from a parental HIV-specific CTL clone and generated an iPSC-derived rejuvenated HIV-specific CTL clone (iPSC-CTL), which exhibited an early memory phenotype, high proliferation capacity and effector functions in vitro. Here, we assessed the antiviral efficacy of the HIV-specific iPSC-CTL by single- and multiple-round viral suppression assays (VSAs). The HIV-specific iPSC-CTL suppressed viral replication in an HLA-dependent manner with equivalent efficacy to the parental CTL clone in single-round VSA. In multiple-round VSA, however, the ability of the iPSC-CTL to suppress viral replication was longer than that of the parental CTL clone. These results indicate that HIV-specific iPSC-CTL can sustainably exert suppressive pressure on viral replication, suggesting a novel approach to facilitate clearance of the HIV reservoir via adoptive transfer of rejuvenated CTLs. IMPORTANCE Elimination of latently HIV-infected cells is required for HIV cure. In the "kick and kill" strategy proposed for a cure to HIV, the host immune system, including HIV-specific cytotoxic T lymphocytes (CTLs), play a central role in eliminating HIV antigen-expressing cells following reactivation by latency-reversing agents (LRAs). However, CTL dysfunction due to exhaustion and senescence in chronic HIV infection can be an obstacle to this strategy. Adoptive transfer with effective HIV-specific CTLs may be a solution of this problem. We previously generated an induced pluripotent stem cell (iPSC)-derived rejuvenated HIV-specific CTL clone (iPSC-CTL) with high functional and proliferative capacity. The present study demonstrates that iPSC-CTL can survive and suppress HIV replication in vitro longer than the parental CTL clone, indicating the potential of iPSC-CTL to sustainably exert suppressive pressure on viral replication. Adoptive transfer with rejuvenated HIV-specific CTLs in combination with LRAs may be a new intervention strategy for HIV cure/remission.

Preoperative sarcopenia and malnutrition are correlated with poor long-term survival after endovascular abdominal aortic aneurysm repair.

PURPOSE: 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). METHODS: 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. RESULTS: 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 < .001). Even after propensity score matching, the high-risk group had a significantly lower survival rate (p < .001). CONCLUSION: Both sarcopenia and malnutrition were associated with long-term mortality after EVAR. Patients with both indicators had a poor mid-term survival.

New Morphological Factor for Predicting Late Proximal Type I Endoleak after Endovascular Aneurysm Repair.

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 2 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.

Endovascular Aneurysm Repair Compared With Open Repair Does Not Improve Survival in Octogenarians.

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.

The therapeutic potential of multiclonal tumoricidal T cells derived from tumor infiltrating lymphocyte-1derived iPS cells.

Tumor-infiltrating lymphocytes (TIL), which include tumor-specific T lymphocytes with frequency, are used for adoptive cell transfer therapy (ACT) in clinical practice. The optimization of TIL preparation has been investigated to reduce the senescence and increase the abundance of TIL, as both the quality and quantity of the transferred cells have great influence on the outcome of TIL-based ACT (TIL-ACT). Considering the effects of cell reprogramming on senescence, we expected that the anti-tumor effect could be enhanced by TIL regeneration. To confirm this hypothesis, we established tumor-specific TIL-derived iPS cells (TIL-iPSC) with human colorectal cancer specimens. T cells differentiated from TIL-iPSC (TIL-iPS-T) retained not only intrinsic T cell functions and tumor specificity, but also exhibited improved proliferation capacity and additional killing activity. Moreover, less differentiated profiles and prolonged persistency were seen in TIL-iPS-T compared with primary cells. Our findings imply that iPSC technology has great potential for TIL-ACT.

Generation of highly proliferative, rejuvenated cytotoxic T cell clones through pluripotency reprogramming for adoptive immunotherapy.

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 CD8αß+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 1015-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.