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Objectives: To elucidate the specific characteristics of fat-containing cells in the pancreas and the mechanism of intrapancreatic fat deposition in humans., Materials and Methods: Fifteen Japanese patients who had undergone pancreatic resection were enrolled, and the normal region from each samples was examined. Immunostaining for adiponectin and perilipin 1 was performed, and the relationships between the pancreatic fat-cell area or clinical parameters and the density or the diameter of the fat cells were analyzed., Results: The expression of adiponectin in the cytoplasm and perilipin 1 along the plasma membrane was observed in fat-containing cells in the pancreas. The fat-containing cell area had a significant positive correlation with cell density. In addition, fat-containing cell density was significantly positively correlated with homeostasis model assessment insulin resistance. The diameter of fat-containing cells had significant positive correlations with BMI, fasting immunoreactive insulin, and homeostasis model assessment insulin resistance. Of all fat-containing cells, 10.4% were intralobular cells, and the diameter of intralobular cells showed a tendency for positive correlation with age., Conclusions: The characteristics of fat-containing cells in the pancreas indicate that some of them may be mature adipocytes, and fat volume may be increased by hyperplasia of fat-containing cells associated with insulin resistance., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Design: This was a multicenter retrospective cohort study., Objective: We investigated the incidence of postoperative shoulder imbalance (PSI) and its risk factors in patients with Lenke types 1 and 2 scoliosis corrected using vertebral coplanar alignment (VCA)., Summary of Background Data: PSI in scoliosis affects patient quality of life. While other correction methods have reported a high correction rate for the main thoracic curve (MTC) in relation to PSI, this correlation has not been confirmed for the VCA technique., Materials and Methods: We studied 176 patients with Lenke types 1 and 2 scoliosis who underwent posterior corrective fusion surgery using the VCA technique at 11 institutions. At 2 years postoperatively, patients were divided into two groups based on radiographic shoulder height (RSH): PSI- (RSH<2 cm) and PSI+ (RSH ≥2 cm) groups. We analyzed the risk factors for PSI., Results: The overall incidence of PSI 2 years postoperatively was 11.4% (20/176), with 9.2% (11/119) and 15.8% (9/57) in patients with Lenke types 1 and 2, respectively. Contrary to a previous study, a high MTC correction rate did not emerge as a risk factor for PSI. Instead, preoperative left shoulder elevation, low postoperative thoracic kyphosis, greater T1 tilt, and high apical vertebral body-to-rib ratio were associated with PSI in patients with Lenke type 1. Preoperative left shoulder elevation and a low postoperative proximal thoracic curve (PTC) correction rate were identified as risk factors for PSI in patients with Lenke type 2., Conclusion: Our results suggest that proper PTC correction, rather than compromising MTC correction, may help prevent PSI in the VCA technique. This method is particularly advantageous for addressing Lenke type 1 scoliosis and yields favorable outcomes in shoulder balance. Patients with preoperative left shoulder elevation, especially Lenke type 2, are at high risk of developing PSI., Level of Evidence: Level 4., Competing Interests: H.T. received a scholarship donation from Medtronic Sophamore Danek Inc. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We investigated the success and complication rates of endoscopic transpapillary gallbladder drainage (ETGBD) and percutaneous transhepatic gallbladder drainage (PTGBD) and the outcomes of subsequent cholecystectomy for acute cholecystitis., Methods: Patients (N=178) who underwent cholecystectomy after ETGBD or PTGBD were retrospectively assessed., Results: ETGBD was successful in 47 (85.5%) of 55 procedures, whereas PTGBD was successful in 123 (100%) of 123 sessions ( P <0.001). Complications related to ETGBD and PTGBD occurred in 6 (12.8%) of 47 and 16 (13.0%) of 123 patients, respectively ( P =0.97). After propensity matching, 43 patients from each group were selected. Median time from drainage to cholecystectomy was 48 (14 to 560) days with ETGBD and 35 (1 to 90) days with PTGBD ( P =0.004). Laparoscopy was selected more often in the ETGBD group (97.7%) than in the PTGBD group (79.1%) ( P =0.007), and conversion from laparoscopy to open cholecystectomy was more common with PTGBD (41.2%) than with ETGBD (7.1%) ( P <0.001). Mean operation time was significantly shorter with ETGBD (135.8±66.7 min) than with PTGBD (195.8±62.2 min) ( P <0.001). The incidence of Clavien-Dindo grade ≥III postoperative complications was 9.3% with ETGBD and 11.6% with PTGBD ( P =0.99)., Conclusions: The success rate is lower but completion of laparoscopic cholecystectomy is more in endoscopic gallbladder drainage than percutaneous gallbladder drainage for acute cholecystitis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection., Summary Background Data: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown., Methods: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated., Results: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways., Conclusion: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs., Competing Interests: Disclosures: All authors disclose no personal and financial conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11 ; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Systematic review and meta-analysis., Objective: Using a network meta-analysis (NMA), this study aimed to compare the risks of C5 palsy after three different procedures of anterior cervical decompression., Summary of Background Data: C5 palsy is a well-known complication affecting the quality of life after anterior procedures. Due to the limited evidence on the various procedures available, we evaluate the basis for selection to prevent palsy and achieve maximal decompression in cases spanning 3-6 levels., Materials and Methods: We conducted a comprehensive search for C5 palsy and complications after 3representative procedures, including anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), and their combination (hybrid), involving 3 to 6 intervertebral levels. The incidence of C5 palsy was compared using a NMA., Results: We identified 1655 patients in 11 studies who met inclusion criteria. Sixty-nine patients (4.2%) developed delayed C5 palsies. The incidences among ACDF, ACCF, and hybrid cases were 2.3% (16/684, 95% CI: 1.4% to 3.8%), 6.4% (39/613, 95% CI: 4.7% to 8.6%), and 3.9% (14/358, 95% CI: 2.3% to 6.5%), respectively ( P < 0.01). A NMA was performed for 15 pairwise comparisons across the 3 procedure arms: ACDF versus hybrid, 7/232 (3.0%) versus 11/234 (4.7%); hybrid versus ACCF, 14/301 (4.3%) versus 18/224 (8.0%); ACCF versus ACDF, 38/523 (7.8%) versus 16/619 (2.6%). Compared with ACDF, the risk of C5 palsy was significantly higher in ACCF (odds ratio: 2.72, 95% CI: 1.47 to 5.01), whereas ACDF versus hybrid did not significantly differ in risk (odds ratio: 1.56, 95% CI: 0.68 to 3.60)., Conclusion: We determined that ACCF was associated with a higher risk of postoperative C5 palsy than ACDF in cases spanning 3 to 6 intervertebral levels. If practicable, ACDF surgery may be an appropriate choice for cases requiring anterior decompression of 3 to 6 levels., Level of Evidence: Level III., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Percutaneous transhepatic gallbladder aspiration (PTGBA) and/or drainage (PTGBD) are useful approaches in the management of acute cholecystitis in patients who cannot tolerate surgery because of poor general condition or severe inflammation. However, reports regarding its effect on the surgical outcomes of subsequent laparoscopic cholecystectomy (LC) are sparse. The aim of this retrospective study was to investigate the influence of PTGBA on surgical outcomes of subsequent LC by comparing the only-PTGBA group, including patients who did not need the additional-PTGBD, versus the additional-PTGBD group, including those who needed the additional-PTGBD after PTGBA., Patients and Methods: We conducted a post hoc analysis of our multi-institutional data. This study included 63 patients who underwent LC after PTGBA, and we compared the surgical outcomes between the only-PTGBA group (n = 56) and the additional-PTGBD group (n = 7)., Results: No postoperative complications occurred among the 63 patients, and the postoperative hospital stay was 11 ± 12 days. Fourteen patients (22.2%) had a recurrence of cholecystitis, of whom 7 patients (11.1%) needed the additional-PTGBD after PTGBA. Significantly longer operative time (245 ± 74 vs 159 ± 65 min, P = 0.0017) and postoperative hospital stay (22 ± 27 vs 10 ± 9 d, P = 0.0118) and greater intraoperative blood loss (279 ± 385 vs 70 ± 208 mL, P = 0.0283) were observed among patients in the additional-PTGBD group compared with the only-PTGBA group, whereas the rates of postoperative complications (Clavien-Dindo grade ≥3: 0% each) and conversion to open surgery (28.6% vs 8.9%, P = 0.1705) were comparable., Conclusion: PTGBA for acute cholecystitis could result in good surgical outcomes of subsequent LC, especially regarding postoperative complications. However, we should keep in mind that the additional-PTGBD after PTGBA failure, which sometimes happened, would be associated with increased operative difficulty and longer recovery., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To analyze 10,000 cases of living donor liver transplantation (LDLT) recipient data to elucidate outcomes with special reference to the graft-versus-recipient weight ratio (GRWR), based on the Japanese Liver Transplantation Society (JLTS) registry., Background: The JLTS registry has been accurate and complete in characterizing and following trends in patient characteristics and survival of all patients with LDLT., Methods: Between November 1989 and August 2021, 10,000 patients underwent LDLT in Japan. The procedures performed during the study period included pediatric liver transplantation (age <18 years, n = 3572) and adult liver transplantation (age ≥18 years, n=6428). Factors related to patient survival (PS) and graft survival (GS) were also analyzed., Results: The GRWR was <0.7, 0.7 to <0.8, 0.8 to <3, 3 to <5, and ≥5 in 0.2%, 2.0%, 61.8%, 31.8%, and 2.6% of pediatric patients and <0.6, 0.6 to <0.7, 0.7 to <0.8, and ≥0.8 in 8.0%, 12.7%, 17.7%, and 61.5% of adult patients, respectively. Among pediatric recipients, the PS rate up to 5 years was significantly better in cases with a GRWR ≤5 than in those with a GRWR >5. When the GRWR and donor age were combined, among adult recipients 50 to 60 years old, the early PS and GS up to 5 years were significantly better in cases with a GRWR ≥0.7, than in those with a GRWR <0.7. (P = 0.02). In adults, a multivariate analysis showed that GRWR <0.6, transplant era (<2011), donor age (>60 years), recipient age (>60 years), model for end-stage liver disease score (≥20), and center volume (<10) were significant prognostic factors for long-term PS., Conclusion: Although a satisfactory long-term PS and GS, especially in the recent era (2011-2021), was achieved in the JLTS series, a GRWR ≥5 in pediatric cases and relatively old donors with a GRWR <0.7 in adult cases should be managed with caution., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the long-term dynamics of recurrence risk and the significance of prognostic variables using conditional recurrence-free survival (C-RFS) analysis in neoadjuvant treatment (NAT) for resectable (R) and borderline resectable (BR) pancreatic cancer (PC)., Background: C-RFS analysis assesses the probability of achieving additional RFS according to the RFS already accrued., Methods: Patients with NAT and subsequent resection for R/BRPC were enrolled. In the C-RFS analysis, the actual 5-year RFS (5yRFS) rate was calculated separately in the subgroup that had already gained a given amount of RFS. The significance levels of prognostic variables associated with 5yRFS were assessed regarding their time-dependent dynamics in a conditional fashion., Results: Among the total 397 patients, 160 survived for more than 5 years without recurrence after surgery (actual 5yRFS rate: 45%). The probability of 5yRFS incrementally increased based on the RFS already accrued. Pathological nodal and vascular involvement were significant influencers of 5yRFS. The patients with nodal involvement consistently remained at significantly higher risk of recurrence than those without, even after 5yRFS, whereas positivity of vascular involvement was significantly associated with the risk of recurrence only during the early postoperative period and lost its significance after 3yRFS accrued., Conclusions: In NAT for R/BRPC, the probability of gaining additional RFS increases as a function of RFS already accrued, and the significance of prognostic variables time-dependently evolves in their own patterns during the long-term postoperative period., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Costimulatory blockade-induced allograft tolerance has been achieved in rodent models, but these strategies do not translate well to nonhuman primate and clinical transplants. One confounder that may underlie this discrepancy is the greater ischemic inflammation imposed on the transplants. In mice, cardiac allografts subjected to prolonged cold ischemic storage (CIS) before transplant have increased ischemia-reperfusion injury, which amplifies infiltrating endogenous memory CD8 T-cell activation within hours after transplantation to mediate acute graft inflammation and cytotoxic lymphocyte-associated molecule-4 immunoglobulin-resistant rejection. This study tested strategies inhibiting memory CD8 T-cell activation within such high ischemic allografts to achieve long-term survival., Methods: A/J (H-2 a ) hearts subjected to 0.5 or 8 h of CIS were transplanted to C57BL/6 (H-2 b ) recipients and treatment with peritransplant costimulatory blockade. At 60 d posttransplant, regulatory T cells (Treg) were depleted in recipients of high ischemic allografts with anti-CD25 monoclonal antibody (mAb) or diphtheria toxin., Results: Whereas peritransplant (days 0 and +1) anti-lymphocyte function-associated antigen-1 mAb and anti-CD154 mAb prolonged survival of >60% allografts subjected to minimal CIS for >100 d, only 20% of allografts subjected to prolonged CIS survived beyond day 80 posttransplant and rejection was accompanied by high titers of donor-specific antibody. Peritransplant anti-lymphocyte function-associated antigen-1, anti-tumor necrosis factor-α, and anti-CD154 mAb plus additional anti-CD154 mAb on days 14 and 16 obviated this donor-specific antibody and promoted Treg-mediated tolerance and survival of 60% of high ischemic allografts beyond day 100 posttransplant, but all allografts failed by day 120., Conclusions: These studies indicate a strategy inducing prolonged high ischemic allograft survival through Treg-mediated tolerance that is not sustained indefinitely., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: No effective therapies have yet been established for liver regeneration in liver failure. Autologous skeletal myoblast cell sheet transplantation has been proven to improve cardiac function in patients with heart failure, and one of the mechanisms has been reported to be a paracrine effect by various growth factors associated with liver regeneration. Therefore, the present study focused on the effect of myoblast cells on liver regeneration in vitro and in vivo., Methods: We assessed the effect of myoblast cells on the cells comprising the liver in vitro in association with liver regeneration. In addition, we examined in vivo effect of skeletal myoblast cell sheet transplantation in C57/BL/6 mouse models of liver failure, such as liver fibrosis induced by thioacetamide and hepatectomy., Results: In vitro, the myoblast cells exhibited a capacity to promote the proliferation of hepatic epithelial cells and the angiogenesis of liver sinusoidal endothelial cells, and suppress the activation of hepatic stellate cells. In vivo, sheet transplantation significantly suppressed liver fibrosis in the induced liver fibrosis model and accelerated liver regeneration in the hepatectomy model., Conclusions: Autologous skeletal myoblast cell sheet transplantation significantly improved the liver failure in the in vitro and in vivo models. Sheet transplantation is expected to have the potential to be a clinically therapeutic option for liver regeneration in liver failure., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This trial evaluated the superiority of intraoperative wound irrigation (IOWI) with aqueous povidone-iodine (PVP-I) compared with that with saline for reducing the incidence of surgical site infection (SSI)., Background: IOWI with aqueous PVP-I is recommended for the prevention of SSI by the World Health Organization and the Centers for Disease Control and Prevention, although the evidence level is low., Methods: This single institute in Japan, prospective, randomized, blinded-endpoint trial was conducted to assess the superiority of IOWI with aqueous PVP-I in comparison with IOWI with saline for reducing the incidence of SSI in clean-contaminated wounds after gastroenterological surgery. Patients 20 years or older were assessed for eligibility, and the eligible participants were randomized at a 1:1 ratio using a computer-generated block randomization. In the study group, IOWI was performed for 1 minute with 40 mL of aqueous 10% PVP-I before skin closure. In the control group, the procedure was performed with 100 mL of saline. Participants, assessors, and analysts were masked to the treatment allocation. The primary outcome was the incidence of incisional SSI in the intention-to-treat set., Results: Between June 2019 and March 2022, 941 patients were randomized to the study group (473 patients) or the control group (468 patients). The incidence of incisional SSI was 7.6% in the study group and 5.1% in the control group (risk difference 0.025, 95% CI -0.006 to 0.056; risk ratio 1.484, 95% CI 0.9 to 2.448; P =0.154)., Conclusion: The current recommendation of IOWI with aqueous PVP-I should be reconsidered., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types., Methods: In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density., Results: In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169)., Conclusions: The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients., Competing Interests: The authors report no conflict of interests., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Wedge thrombus formation around the inflow cannula of a continuous left ventricular assist device (LVAD) is a source of systemic thromboemboli. We previously reported the potential advantages of a new inflow cannula wrapped with titanium mesh (GU30) over the standard smooth surface oblique cut cannula (GU10). The objective of the present study was to clinically validate this new cannula. A retrospective cohort analysis of patients with implanted LVAD (EVAHEART) comparing the GU10 to the GU30 was conducted. Clinical outcomes, including survival, the incidence of thromboembolism, and bleeding events, were compared. Gross and histopathological analyses of explanted GU30 cannula were conducted following transplant or patient death. No significant differences in the survival rate, severe emboli, or cerebral bleeding were observed during the LVAD implantation. However, severe emboli occurred earlier after LVAD implantation when using the GU30 cannula compared with the GU10. In cases of long LVAD support, the neointima fully covered the inflow of the GU30 cannulae without wedge thrombus formation. The titanium mesh-wrapped inflow cannulae did not reduce the overall incidence of neurological events significantly. However, the titanium mesh-wrapped inflow cannula induced autologous neointimal growth over the cannula and prevented wedge thrombus formation in late-phase LVAD implantation., Competing Interests: Disclosure: The authors declare that they have no conflicts of interest., (Copyright © ASAIO 2022.)

Abstract: Pancreatic mucinous cystic neoplasm (MCN) rarely ruptures because of their surrounding fibrotic capsules and has never been reported with detailed information regarding prerupture and postrupture states. We report a case of MCN rupture where performed emergency surgery was performed while waiting for elective surgery. A 54-year-old woman was referred to our department for a pancreatic cystic tumor with slight abdominal pain. A cystic tumor with a nodular lesion was found, with a contrast effect measuring 78 mm in diameter. On day 21, the patient visited our hospital complaining of increased abdominal pain, but few signs of peritonitis were observed. Tests conducted revealed moderate ascites, marginal shrinkage of the cyst diameter, and a slight elevation of inflammatory markers. We suspected an MCN rupture and immediately performed distal pancreatectomy. Brown turbid ascites and rupture of the anterior wall of the cyst were observed. In the ascites, amylase levels were not elevated, and bacterial cultures were negative. The histopathological diagnosis was noninvasive mucinous cystadenocarcinoma. At 9 months after surgery, she started chemotherapy because of a recurrence of the peritoneal dissemination. This case provided valuable insight into the rupture of MCNs using thorough imaging techniques, laboratory, and physical findings before and after rupturing., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Prophylaxis of antibody-mediated rejection (AMR) caused by donor-specific antibodies remains challenging. Given the critical roles of complement activity in antibody-mediated graft injury, we developed a lipid nanoparticle (LNP) formulation of small-interfering RNA against complement C5 (C5 siRNA-LNP) and investigated whether C5 siRNA-LNP could downregulate the complement activity and act as an effective treatment for AMR., Methods: Lewis recipient rats were sensitized by skin grafting from Brown Norway donor rats. Kidney transplantation was performed at 4 wk post-skin grafting.C5 siRNA- or control siRNA-LNP was administered intravenously, and the weekly injections were continued until the study's conclusion. Cyclosporin (CsA) and/or deoxyspergualin (DSG) were used as adjunctive immunosuppressants. Complement activity was evaluated using hemolysis assays. The deposition of C5b9 in the grafts was evaluated using immunohistochemical analysis on day 7 posttransplantation., Results: C5 siRNA-LNP completely suppressed C5 expression and complement activity (hemolytic activity ≤ 20%) 7 d postadministration. C5 siRNA-LNP in combination with CsA and DSG (median survival time: 56.0 d) prolonged graft survival compared with control siRNA-LNP in combination with CsA and DSG (median survival time: 21.0 d; P = 0.0012; log-rank test). Immunohistochemical analysis of the grafts revealed that downregulation of C5 expression was associated with a reduction in C5b9-positive area ( P = 0.0141, Steel-Dwass test)., Conclusions: C5 siRNA-LNP combined with immunosuppressants CsA and DSG downregulated C5 activity and significantly prolonged graft survival compared with control siRNA-LNP with CsA and DSG. Downregulation of C5 expression using C5 siRNA-LNP may be an effective therapeutic approach for AMR., Competing Interests: S.M., C.M., A.T., T.N., Y.K., and T.I. are employees of KAN Research Institute, Inc, Japan; Y.S. is an employee of Eisai, Co, Ltd, Japan; the other authors declare no conflicts of interest. KAN Research Institute, Inc is a subsidiary of Eisai Co, Ltd., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Older people with chronic pain are at higher risk of developing sarcopenia. Central sensitization (CS) has been implicated in chronic pain among community-dwelling older adults. However, a relationship between CS and chronic pain with sarcopenia has not been established. This cross-sectional study aimed to clarify the relationship between chronic pain with sarcopenia or presarcopenia and CS among community-dwelling older adults. We assessed chronic pain and sarcopenia in 104 older adults participating in community health checks. We defined sarcopenia using the Asian Working Group for Sarcopenia (AWGS) consensus recommendations based on the following outcomes: low muscle mass, low muscle strength, and slow gait speed. Pain-related assessments included pain intensity, the Pain Catastrophizing Scale, the CS Inventory-9, the pressure pain threshold, the Tampa Scale of Kinesiophobia-11, and the EuroQol 5-dimension 5-level (EQ5D-5L). Chronic pain was defined by related symptoms within the month prior to the health check that had continued for ≥ 3 months and corresponded to a numerical rating scale score of ≥ 1 at the site of maximum pain. The prevalence of chronic pain was 43.3%. In addition, the prevalence of chronic pain with sarcopenia or presarcopenia was 29.8%. A logistic regression analysis revealed that the pressure pain threshold (odds ratio: 0.82, 95% CI: 0.95-1.02) and the EQ5D-5L (odds ratio: 0.58, 95% CI: 0.36-0.76) were significantly associated with the presence of chronic pain with sarcopenia or presarcopenia. Chronic pain with sarcopenia or presarcopenia was affected by central sensitization. Therefore, CS should be evaluated in the elderly., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC., Summary of Background Data: The pathological response to preoperative treatment is commonly evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery., Methods: We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III, <10%; and IV, 0%. We analyzed the correlation of grade with clinico-pathological parameters., Results: Among 319 patients with clinically positive LNs, pathological LN regression grades were I/II/III/IV in 115/51/58/95 patients, and 191 patients (59.9%) showed discordance between the PT and LN pathological regression grades. LN regression grade significantly correlated with cN positive number, ypTNM, lymphovascular invasion, and clinical/pathological PT response. Multivariate analysis for recurrence-free survival revealed that LN regression grade [hazard ratio (HR) = 2.25, P < 0.001], ypT (HR = 1.65, P = 0.005), and ypT (HR = 1.62, P = 0.004) were independent prognostic factors, but not pathological PT regression grade (P = 0.67)., Conclusions: Compared to PT response, pathological LN response better predicted long-term survival in EC patients who received NAC plus curative surgery., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Pancreatic fistula is a severe complication after laparoscopic distal gastrectomy (LDG). We previously evaluated the pancreas-left gastric artery angle (PLA) as a risk indicator for developing a pancreatic fistula after LDG. This study evaluated the incidence of pancreatic fistula with robotic distal gastrectomy (RDG) in comparison to LDG from the view of the PLA., Materials and Methods: An association between the PLA and the incidence of pancreatic fistula in 165 patients who underwent either RDG (n=45) or LDG (n=120) was investigated retrospectively., Results: RDG patients had significantly lower drain amylase values (postoperative day 2) than LDG patients. As opposed to LDG patients, drain amylase values were similar for patients with small (PLA <62 degrees) and large (PLA ≥62 degrees) PLA in RDG patients., Conclusion: Robotic surgery may reduce the risk of postoperative pancreatic fistula in patients with a small PLA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors declare no conflicts of interest.

Objective: To evaluate the Eustachian tube (ET) dimensions in patulous ET (PET) patients compared with that by aging using sitting 3D computed tomography (CT)., Study Design: Retrospective study., Setting: Tertiary referral center., Subjects and Methods: A retrospective survey of medical records in Sen-En Rifu Hospital identified 105 ears of 76 PET patients and 65 ears of 34 patients without ET dysfunction findings (non-PET). Subjects in both PET and non-PET groups were then divided into two age groups. Groups A and C defined as non-PET and PET subjects respectively, who were under the age of 60 years, while Groups B and D defined of non-PET and PET subjects respectively, who were 60 years and above. 3D CT (Accuitomo; Morita, Kyoto, Japan) was performed on all subjects in the sitting position. The ET lumen from the ET pharyngeal orifice to 15 mm was analyzed., Results: No significant difference in the ET lumen near the pharyngeal orifice was found between Group A and C; however, there was a significant difference in the ET at points lateral to the pharyngeal orifice. The ET lumen was significantly larger at the site close to the pharyngeal orifice in Group B as compared to that of Group A. For the two groups of PET classified according to the size of the pharyngeal orifice and area close to the isthmus, age was only significantly different between two groups of pharyngeal orifice. On the contrary, sonotumometry and Ohta method were significantly different between the two groups of the area close to the isthmus., Conclusion: The lumen of the ET is enlarged in both PET and aging. However, the responsible site was found to be different. While the enlargement of the ET lumen in 60 years and above subjects without PET mainly occurred near the pharyngeal orifice of the ET, it was near the isthmus in under 60 years PET patients. Further study of possible clinical implications of these findings as well as treatment strategy are required., Competing Interests: Compliance with Ethical Standards: The authors declare no financial relationships or conflict of interest. The authors disclose no financial relationships or conflict of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

Background: Islet transplantation is an effective replacement therapy for type 1 diabetes (T1D) patients. However, shortage of donor organ for allograft is obstacle for further development of the treatment. Subcutaneous transplantation with stem cell-derived β-cells might overcome this, but poor vascularity in the site is burden for success in the transplantation. We investigated the effect of subcutaneous transplantation of vascularized β-cell spheroid tissue constructed 3-dimensionally using a layer-by-layer (LbL) cell-coating technique in a T1D model mouse., Methods: We used MIN6 cells to determine optimal conditions for the coculture of β-cell spheroids, normal human dermal fibroblasts, and human umbilical vein endothelial cells, and then, under those conditions, we constructed vascularized spheroid tissue using human induced pluripotent stem cell-derived β-cells (hiPS β cells). The function of insulin secretion of the vascularized hiPS β-cell spheroid tissue was evaluated in vitro. Furthermore, the function was investigated in T1D model NOD/SCID mice subcutaneously transplanted with the tissue., Results: In vitro, the vascularized hiPS β-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS β-cell spheroid tissue also significantly decreased blood glucose levels in diabetic immunodeficient mice when transplanted subcutaneously. Furthermore, host mouse vessels were observed in the explanted vascularized hiPS β-cell spheroid tissue., Conclusions: Vascularized hiPS β-cell spheroid tissue decreased blood glucose levels in the diabetic mice. This therapeutic effect was suggested due to host angiogenesis in the graft. This method could lead to a promising regenerative treatment for T1D patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We conducted a multicenter randomized prospective phase 2 trial of chemoradiotherapy (CRT) versus chemotherapy (CT) as initial induction therapy for conversion surgery (CS) in clinical T4b esophageal cancer. We compared treatment effects and adverse events (AEs)., Summary Background Data: Although induction followed by CS is potentially curative for T4b esophageal cancer, the optimal initial induction treatment is unclear., Methods: Ninety-nine patients with T4b esophageal cancer were randomly allocated to chemoradiotherapy (Group A, n = 49) or CT (Group B, n = 50) as initial induction treatment. CRT consisted of radiation (50.4 Gy) with cisplatin and 5-fluorouracil. CT consisted of 2 cycles of docetaxel plus cisplatin and 5-fluorouracil (DCF). CRT or CT was followed by CS if resectable. If unresectable, the patient received the other treatment as secondary treatment. CS was performed if resectable after secondary treatment. The primary end point was 2-year overall survival., Results: In Group A, CS was performed in 34 (69%) and 7 patients (14%) after initial and secondary treatment. In Group B, CS was performed in 25 (50%) and 17 patients (34%) after initial and secondary treatment. The R0 resection rate after initial and secondary treatment was similar (78% vs 76%, P = 1.000). AEs including leukopenia, neutropenia, febrile neutropenia, and diarrhea were significantly more frequent in Group B. Group A had better histological complete response of the primary tumor (40% vs 17%, P = 0.028) and histological nodal status (P = 0.038)., Conclusion: Upfront CRT was superior to upfront CT in terms of pathological effects and AEs. The Japan Registry of Clinical Trials (s051180164)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Japanese Liver Transplantation Society (JLTS), a cooperative research consortium, was established in 1980 to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed factors that may affect the current outcomes of pediatric patients who undergo liver transplantation (LT) by evaluating one of the largest pediatric LT cohorts in the world., Methods: Between November 1989 and December 2018, 3347 pediatric patients underwent LT in Japan. The survival outcomes of each donor and recipient variant were evaluated., Results: The procedures performed during the study period included living donor LT (LDLT; n = 3271), deceased donor LT (DDLT; n = 69), and domino LT (n = 7). There were 1510 male (45.1%) and 1837 female (54.9%) recipients with a median age of 1.7 y (range: 9 d to 17.9 y). The graft survival rates at 1, 10, 20, and 30 y were 88.9%, 82.2%, 77.1%, and 75.4%, respectively. Donor age, donor BMI, blood type incompatibility, recipient age, etiology of liver disease, transplant type, center experience, and transplant era were found to be significant predictors of overall graft survival. LDLT is a major treatment modality for the end-stage liver disease in children; DDLT and domino LT were applied as alternative treatments for LDLT in patients with specific pediatric liver diseases that are considered to have a poor prognosis following LDLT., Conclusions: Satisfactory long-term pediatric patient survival outcomes were achieved in the JLTS series, and we should continue to promote the deceased donor organ transplantation program in Japan., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pediatric brain tumor survivors who received proton beam therapy at the University of Tsukuba Hospital from 2004 to 2011 were retrospectively evaluated for cognitive function. Five patients were included. The median age of diagnosis was 5.4 years (range: 1.5 to 12.5 y) and the median follow-up time was 5.8 years (range: 3.1 to 8.1 y). IQ scores at follow-up were decreased in 2 of 5 patients; 1 underwent whole-brain irradiation and the other was examined just after surgical removal of recurrent tumors. Local proton beam therapy may preserve cognitive function in survivors of pediatric brain tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim is to report four cases of patulous Eustachian tube (PET) patients with respiratory fluctuation of the tympanic membrane (TM) even in the supine position, and to examine the frequency and characteristics of such patients., Patients: There were 195 ears (99 right ears and 96 left ears) from 146 cases (56 male and 90 female subjects aged 8-88, average 48.0 ± 18.9 yrs) diagnosed with definite PET by diagnostic criteria proposed by Japan Otologic Society (JOS) between January 2017 and December 2019 at Sen-En Rifu Hospital. Patients who presented with respiratory fluctuation of the TM in both the sitting and supine positions were examined., Main Outcome Measures: Clinical patient records, the severity of subjective symptoms (PET handicap inventory-10 [PHI-10]), objective ET function tests (tubo-tympano-aerodynamic graphy [TTAG] and sonotubometry), and sitting three-dimensional computed tomography (3-D CT) were analyzed., Results: Six ears (3.1%) of four cases (2.7%) exhibited respiratory fluctuation of the TM, even in the supine position. In these six ears (four cases), the PHI-10 score ranged from 16 to 36 with three ears exhibiting PHI-10 score equal to or exceeding 26 (in the category of severe handicap). Sitting CT indicated the findings of completely open ET in only two ears. All ears but one were managed by conservative treatment., Conclusion: Respiratory fluctuation of the TM in both the sitting and supine positions was observed in 2.7% of the definite PET patients. Surprisingly, such findings can be an indication of neither the subjective nor objective severity of the disease. Therefore, even for PET patients with such findings, surgery should not be immediately proposed, but rather, conservative management should be undertaken first., Competing Interests: Compliance with Ethical Standards: The authors declare no financial relationships or conflict of interest. The authors disclose no financial relationships or conflicts of interest., (Copyright © 2021, Otology & Neurotology, Inc.)

Objective: To establish a preoperative risk assessment method for loss of independence after hepatic resection., Summary Background Data: Hepatic resection often results in loss of independence in preoperatively self-sufficient elderly people. Elderly patients should therefore be carefully selected for surgery., Methods: In this prospective, multicenter study, 347 independently-living patients aged ≥65 years, scheduled for hepatic resection, were divided into study (n = 232) and validation (n = 115) cohorts. We investigated the risk factors for postoperative loss of independence in the study cohort and verified our findings with the validation cohort. Loss of independence was defined as transfer to a rehabilitation facility, discharge to residence with home-based healthcare, 30-day readmission for poor functionality, and 90-day mortality (except for cancer-related deaths)., Results: In the study cohort, univariate and multivariate analyses indicated that frailty, age ≥ 76 years, and open surgery were independent risk factors for postoperative loss of independence. Proportions of patients with postoperative loss of independence in the study and validation cohorts were respectively 3.0% and 0% among those with no applicable risk factors, 8.1% and 12.5% among those with 1 applicable risk factor, 25.5% and 25.0% among those with 2 applicable risk factors, and 56.3% and 50.0% among those with all 3 factors applicable (P < 0.001 for both cohorts). Areas under the receiver operating characteristic curves for the study and validation groups were 0.777 and 0.783, respectively., Conclusions: Preoperative risk assessments using these 3 factors may be effective in predicting and planning for postoperative loss of independence after hepatic resection in elderly patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Mini: Most patients with neurogenic thoracic outlet syndrome (NTOS) have a history of trauma. Scar tissue formation within the scalene muscle and around the nerves after injury cause arm and hand symptoms. We report that supraclavicular scalenotomy followed by external neurolysis without rib resection is very effective as the surgical treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: A cross-sectional analysis using T1 slope (T1S) and C7 slope (C7S) in asymptomatic individuals., Objective: The aim of this study was to identify normative values, ranges of motion (ROMs), age-related changes in T1S and C7S, and correlation between the two slopes., Summary of Background Data: Few studies have reported age-related changes in the T1S and C7S angles. Additionally, studies investigating the effects of cervical position on these slopes are limited., Methods: A total of 388 asymptomatic subjects (162 males and 226 females) for whom T1S measurement was performed on radiographs were enrolled in the study. The T1S and C7S angles were measured using neutral radiography of the cervical spine. ROMs were assessed by measuring the difference in alignment in the neutral position, flexion, and extension., Results: The mean C7S and T1S angles were 19.6° (22.2° in males, 17.9° in females) and 24.0° (26.7° in men and 22.1° in women), respectively. The T1S angle was significantly greater than the C7S angle. Both the C7S and T1S angles significantly increased with age. The flexion ROM of C7S was higher than that of T1S, whereas no significant difference was detected between the extension ROMs of the two slopes. The flexion ROMs of the two slopes did not change, whereas the extension ROMs significantly increased with age. A significant positive correlation was observed between the C7S and T1S angles (r2 = 0.75)., Conclusion: The normative values and age-related changes in C7S and T1S were analyzed. Both the C7S and T1S angles increased with age. The C7S angle was strongly correlated with the T1S angle, suggesting that C7S can substitute T1S on radiographic images.Level of Evidence: 3., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Outcome study to determine the construct validity and reliability of the Japanese version of the Lumbar Stiffness Disability Index., Objective: The aim of this study was to evaluate the psychometric measurement properties of the Japanese version of the Lumbar Stiffness Disability Index (J-LSDI) following lumbar spinal surgery in order to assess its construct validity and reliability., Summary of Background Data: The LSDI was designed and validated as a tool to assess functional impacts of lumbar spine stiffness and diminished spinal flexibility. A Japanese version has been developed, but its construct validity and reliability have not been evaluated., Methods: A Pearson correlation coefficient was calculated using flexion and extension range of motion, Oswestry Disability Index (ODI) and Tampa Scale for Kinesiophobia (TSK) as external standards to evaluate construct validity. An intraclass correlation coefficient (ICC) and a Bland-Altman analysis were used to evaluate test-retest reliability., Results: A total of 244 patients following lumbar spinal surgery participated in the study. Fifty one of the 244 patients participated in the reliability study. The ICC of the J-LSDI for test-retest reliability was 0.89 (95% confidence interval, 0.79-0.93). There was no systematic error found in the results of the Bland-Altman analysis. One hundred ninety-three of the 244 patients participated in the validity study. There were significant correlations between the J-LSDI and trunk flexion range of motion (r = -0.66), extension (r = -0.51), ODI (r = 0.62), and TSK (r = 0.38)., Conclusion: The construct validity and reliability of the Japanese version of the LSDI were confirmed. The J-LSDI can be used to evaluate lumbar stiffness and associated disability in Japanese patients following lumbar spinal surgery.Level of Evidence: 2., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To propose a simple grading of inner ear malformation (IEM) and investigate intracochlear electrical auditory brainstem response (EABR) and outcomes for hearing in terms of the novel grading system., Study Design: Retrospective case review., Setting: Tertiary referral center., Patients: Sixty patients with IEMs who received cochlear implants., Intervention: Grading according to observation of modiolus deficiency and/or internal auditory canal (IAC) cochlear nerve deficiency (CND)., Main Outcome Measure: Intracochlear EABR and categories of auditory performance (CAP) scores were assessed; children in school were categorized according to the type of school attended., Results: Among 60 patients, 38% were classified as Grade I (modiolus present + normal cochlear nerve), 22% as grade II (modiolus deficiency + normal cochlear nerve), 33% as grade III (modiolus present + IAC CND), and 7% as grade IV (modiolus deficiency + IAC CND). During the operation, 93% of Grade I, 36% of Grade II, 23% of Grade III, and 50% of Grade IV patients showed typical EABR waves. CAP scores of 4 or more were obtained from 91% of Grade I, 62% of Grade II, 35% of Grade III, and 25% of Grade IV. Whereas none of children in Grades III and IV entered main stream school, 55% of Grade I and 25% of Grade II entered mainstream schools., Conclusions: Outcomes of hearing with cochlear implantations in IEM children depend on the severity of IEM and IAC CND. Our novel grading of IEM is simple and can be useful for understanding the severity of IEM., Competing Interests: Conflicts of Interest and Source of Funding: Minami is currently receiving a grant (19K09881) from JSPS KAKENHI. For the remaining authors none were declared., (Copyright © 2020, Otology & Neurotology, Inc.)

Study Design: A retrospective analysis of magnetic resonance imaging (MRI) was conducted., Objective: This study aims to develop an automated system for the detection of spinal schwannoma, by employing deep learning based on object detection from MRI. The performance of the proposed system was verified to compare the performances of spine surgeons., Summary of Background Data: Several MRI scans were conducted for the diagnoses of patients suspected to suffer from spinal diseases. Typically, spinal diseases do not involve tumors on the spinal cord, although a few tumors may exist at the unexpectable level or without symptom by chance. It is difficult to recognize these tumors; in some cases, these tumors may be overlooked. Hence, a deep learning approach based on object detection can minimize the probability of overlooking these tumors., Methods: Data from 50 patients with spinal schwannoma who had undergone MRI were retrospectively reviewed. Sagittal T1- and T2-weighted magnetic resonance imaging (T1WI and T2WI) were used in the object detection training and for validation. You Only Look Once version3 was used to develop the object detection system, and its accuracy was calculated. The performance of the proposed system was compared to that of two doctors., Results: The accuracies of the proposed object detection based on T1W1, T2W1, and both T1W1 and T2W1 were 80.3%, 91.0%, and 93.5%, respectively. The accuracies of the doctors were 90.2% and 89.3%., Conclusion: Automated object detection of spinal schwannoma was achieved. The proposed system yielded a high accuracy that was comparable to that of the doctors.Level of Evidence: 4., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Design: A systematic review and meta-analysis were performed with the literature including the case of C5 palsy following anterior cervical decompression surgery., Objective: The aim of this study was to compare three reconstructive procedures of anterior cervical decompression, the incidences of delayed C5 palsy and other complications were assessed., Summary of Background Data: Delayed C5 palsy is now a well-known complication after cervical decompression surgery. The etiology of C5 palsy has been studied, especially after posterior surgery. However, in anterior surgery there has been a lack of investigation due to procedure variation. Additionally, limited evidence exists regarding the risk of C5 palsy in surgical procedures., Methods: We performed an extensive literature search for C5 palsy and other complications with ACDF, ACCF, and their combination (Hybrid). Gross incidences of C5 palsy after these three procedures were compared, and specific superiorities (or inferiorities) were investigated via comparison of binary outcomes between two of three groups using odds ratios (OR)., Results: Twenty-six studies met the inclusion criteria. A total of 3098 patients were included and 5.8% of those developed C5 palsy. Meta-analyses demonstrated that ACDF had a lower risk of palsy than ACCF (OR 0.36, 95% confidence interval [CI] 0.16-0.78), whereas ACDF versus Hybrid (OR 0.60, 95% CI 0.24-1.51) and Hybrid versus ACCF (OR 1.11, 95% CI 0.29-4.32) were not significantly different. Although these differences were not observed in shorter lesion subgroups, there were significant differences between the three procedures in longer lesion subgroups (P = 0.0005). Meta-analyses revealed that in longer lesions, ACDF had a significantly lower incidence than ACCF (OR 0.42, 95% CI 0.22-0.82). Additionally, Hybrid surgery was noninferior for palsy occurrence compared to ACCF, and suggested a trend for reduced rates of other complications compared to ACCF., Conclusion: ACDF may yield better outcomes than Hybrid and ACCF. Furthermore, Hybrid may have advantages over ACCF in terms of surgical complications., Level of Evidence: 3.

Astigmatism causes deterioration of the retinal image and affects vision quality. Maintenance and improvement of visual function requires an understanding of the prevalence, age-related changes, and mechanisms of astigmatism. In this article, we discuss the findings of studies that investigated astigmatism. Some of these studies showed that the prevalence of high degrees of astigmatism in childhood typically decreases with emmetropization. With-the-rule astigmatism occurs most commonly in young adults. With age, the prevalence of astigmatism increases, and the axis shifts from a predominance of with-the-rule astigmatism to a predominance of against-the-rule astigmatism. This age-related change is caused by alterations in corneal curvature. Although the cause of this change is not fully understood, alterations in the position and tension of the eyelid, corneal stromal collagen fibrils, Descemet membrane, and extraocular muscles may influence the shape of the cornea. Furthermore, genetic factors may contribute to the development of astigmatism. Technological advances in ophthalmology are expected to improve our understanding of the etiology of astigmatism and enable the maintenance of quality of vision.

Objectives: The objective of this study was to clarify the role of pancreatectomy for patients with resectable and borderline resectable pancreatic ductal adenocarcinoma aged 80 years or older using a nationwide audit by the Japan Pancreas Society., Methods: Data were collected from 39 institutions from 2007 to 2014. The primary endpoint was overall survival, and secondary endpoints were surgical outcomes and predictive factors for prognosis., Results: Data were obtained from 556 octogenarians who underwent pancreatectomy (n = 369, 66%), chemo(radio)therapy (n = 99, 18%), and palliative therapy (n = 88, 16%). Median survival times were 20.6, 18.6, and 8.8 months in each group, respectively. Even after propensity score matching, median survival time in the surgery group (22.8 months) was significantly higher than that in the chemotherapy group (18.5 months; hazard ratio, 0.64 [95% confidence interval, 0.44-0.93]; P = 0.020). Significant independent prognostic factors were body mass index, lymph node metastasis, and tumor diameter in the surgery group, and serum albumin level, American Society of Anesthesiologists classification, body mass index, modified Glasgow prognostic score, second-line chemotherapy, and tumor diameter in the chemotherapy group., Conclusions: Octogenarians with resectable/borderline resectable pancreatic ductal adenocarcinoma can be recommended for pancreatectomy according to mental and physical fitness for surgical procedures.

Introduction: Corynebacterium striatum is common contaminant in clinical specimens. Here, we report a rare case of pyogenic tenosynovitis of the wrist caused by C striatum in a dermatomyositis patient taking oral immunosuppressants., Patient Concerns: A 67-year-old Japanese woman with dermatomyositis had a history of multiple intraarticular injections of corticosteroids to the right wrist joint for the treatment of osteoarthritis. She was admitted to our hospital with a painful lump on the right dorsal wrist lasting for three months. MRI revealed cellulitis of the dorsum of the right wrist and hand and fluid collection in the extensor tendon sheath. C striatum was detected in the cultures of three samples of synovial fluid taken from the dorsal hand., Diagnosis: Pyogenic tenosynovitis of the wrist due to C striatum., Interventions: The infection was successfully controlled with synovectomy and adjuvant antibiotic therapy., Outcomes: There has been no sign of recurrence for 12-months after the surgical treatment., Lessons: This is the first reported case of pyogenic tenosynovitis due to C striatum in a patient with dermatomyositis. Clinicians should be aware that patients undergoing immunosuppressive therapy have a risk of C striatum infection.

A number of cases have been reported in recent years regarding the use of proton beam therapy to mitigate adverse events affecting important cranial organs in cases of rhabdomyosarcoma at parameningeal sites. However, few reports have described the use of proton beam therapy as urgent radiotherapy for parameningeal rhabdomyosarcoma with intracranial extension. We treated 3 patients diagnosed with parameningeal rhabdomyosarcoma extending into the cranium who were assessed at other hospitals as suitable for urgent radiotherapy and transferred to our hospital for proton beam therapy. These patients comprised 2 boys and 1 girl 6 to 12 years of age at diagnosis, and proton beam therapy was started on days 5, 11, and 23 after diagnosis, respectively. Patients with parameningeal rhabdomyosarcoma extending into the cranium can be transferred to institutions equipped to perform proton beam therapy. To minimize the interval to starting therapy, medical information should be shared with institutions capable of providing such therapy as soon as the possibility of intracranial soft-tissue sarcoma is recognized. Proton beam therapy is 1 option for radiotherapy in cases of intracranial rhabdomyosarcoma.

Neuroblastoma (NB) predominantly presents as high-risk disease, requiring intensive multimodal therapy. Proton beam therpy (PBT) is a promising option for many childhood cancers, but is not widely available. Patients with NB hoping to receive PBT may therefore need to be transferred between institutions during intensive multimodal therapy, risking undesirable effects. We evaluated patients with high-risk NB who received PBT at our institute as part of first-line therapy, mainly focusing on the safety and feasibility of mid-treatment patient transfer. Eighteen patients with newly diagnosed high-risk NB who received PBT between April 2010 and June 2016 were retrospectively analyzed for local control, outcomes, and toxicity. Survival (3-y overall survival 71%±11%; 3-y event-free survival 44%±12%) and local control rate (100%) were comparable with previous studies. Few acute adverse events were recorded, and all patients completed PBT without treatment delay. PBT for high-risk NB was safe and feasible for patients requiring mid-treatment interinstitutional transfer.

MINI: On magnetic resonance imaging, indirect decompression using lateral lumbar interbody fusion and posterior fixation was confirmed immediately after surgery and also continuously progressed after surgery, particularly during the first 6 months. Thecal sac enlargement was also confirmed, and is suspected to be caused by the atrophy of the ligamentum flavum and the disc., Study Design: A prospective cohort study., Objective: The aim of this study was to investigate radiographical changes related to indirect decompression using lateral lumbar interbody fusion (LLIF) with posterior fixation., Summary of Background Data: Indirect lumbar decompression via LLIF is used to treat degenerative lumbar diseases requiring neural decompression. Although evidence suggests that thecal sac enlargement follows shortly after surgery, few studies have described the postoperative changes on MRIs., Methods: This study involved 102 patients who underwent indirect decompression at 136 levels, with LLIF and posterior fixation. Magnetic resonance imaging (MRIs) were collected preoperatively and several times postoperatively (over a 2-year period starting immediately after surgery). We then quantified the cross-sectional areas of the thecal sac and ligamentum flavum, as well as the anteroposterior diameter of disc bulging, and qualitatively assessed lumbar spinal stenosis according to a modified version of Schizas' classification [Grades A (mild) to C (severe)]. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was used for the assessment of the clinical symptoms., Results: All changes were observable immediately after surgery, progressed over time, and were significantly different statistically at 2 years after surgery. The thecal sac was significantly larger (189% of preoperative; P < 0.0001), while the ligamentum flavum and disc bulge were significantly smaller [58.9% and 67.3% of preoperative (P < 0.001), respectively]. The number of patients with grade C (severe) lumbar stenosis also dropped significantly (preoperative, 17.6%; 2 years postoperative, 0%). There were no significant differences in JOABPEQ results at 6 months, 1 year, and 2 years postsurgery., Conclusion: Indirect decompression produces immediate positive results that continue to improve over time. The cross-sectional area of the thecal sac doubled by 2 years after surgery, and the ligamentum flavum cross-sectional area and disc bulging both shrank significantly. At the same time, however, postoperative radiographical improvements do not appear to correlate with clinical symptoms., Level of Evidence: 3.

Objective: Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions., Conclusions: Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.

Objectives: To characterize the real size and morphology of tracheas in childhood for the optimal selection of endotracheal tube., Design: A retrospective cohort study of pediatric patients who received CT scan of the cervical spine from July 2011 to March 2018. Cross-sectional CT images vertical to trachea were reconstructed and the accurate tracheal diameters were measured. The validity of the traditional age-based formula for predicting the endotracheal tube size was assessed for the best fit to trachea., Setting: Tertiary Emergency and Critical Care Center of Kyushu University Hospital., Patients: Children, who are 1 month to 15 years old, received CT scan of the cervical spine., Interventions: None., Measurements and Main Results: We enrolled 86 children with median age of 53 months. The cross-sectional shape of pediatric trachea was circular at the cricoid level and elliptical at the infraglottic level. The narrowest part of pediatric trachea was the transverse diameter at the infraglottic level at any age. Significant positive correlation between age and the narrowest diameter was observed. When compared the transverse diameter at the infraglottic level with the outer diameter of endotracheal tubes, uncuffed endotracheal tubes selection based on the traditional age-based formula ran a significant risk of oversized endotracheal intubation until 10 years old compared with cuffed endotracheal tubes selection (60.0% vs 23.8%; p < 0.05)., Conclusions: These findings indicate the safety and efficacy of cuffed endotracheal tubes in infants and children and the reconsideration for the airway management in pediatric anesthesia and intensive care.

Purpose: To investigate factors associated with cystoid macular edema (CME) after Descemet membrane endothelial keratoplasty (DMEK) in Asian eyes., Methods: In this retrospective, interventional, consecutive case series, 77 eyes of 65 patients who underwent DMEK were evaluated; in 53 eyes, cataract surgery was performed 1 month before DMEK (staged DMEK), and 24 eyes underwent DMEK alone (simple DMEK). Central retinal thickness, incidence of CME, postoperative best-corrected visual acuity, central corneal thickness, and corneal endothelial cell density were assessed at 1, 3, and 6 months after surgery. Multiple regression analysis and stepwise variable selection were performed for parameters such as type of surgery, iris damage scores, age, sex, axial length, preoperative visual acuity, rebubbling, air volume in the anterior chamber on postoperative day 1, history of diabetes, and endothelial cell density loss rates at 6 months after surgery., Results: CME occurred in 12 (15.6%) of 77 eyes. There was no significant difference in best-corrected visual acuity between eyes with and without CME (P = 0.27). Multivariable analysis revealed that the difference in iris damage scores between before and after DMEK (P < 0.001), air volume in the anterior chamber (P = 0.012), simple DMEK (P = 0.020), and rebubbling (P = 0.036) were significantly associated with CME. Stepwise variable selection indicated that iris damage (P < 0.001) was the most important risk factor for CME., Conclusions: Iris damage due to DMEK might be a possible risk and aggravating factor for the development of CME after DMEK. Surgeons should attempt to minimize damage to the iris.

While it is important to treat lifestyle-related diseases for the primary and secondary prevention of cardiovascular diseases, medication adherence is still poor. Although various causes of poor adherence have been reported, the differences between physicians and their patients regarding the recognition of medication adherence have not been well-investigated.We administered a questionnaire about medication adherence to 300 outpatients and their 23 cardiologists at the Department of Cardiology, Fukuoka University Hospital. The questionnaires for patients and physicians included acceptable total number of drug doses and dosing schedule, forgetting to take the medicine, and dose-reduction or -increase based on self-judgement. The patients were 70.6 ± 12.3 years old and 61.0% (n = 183) were male. Patients reported that it was acceptable to receive 0-5 doses twice daily. The patients were divided into two groups: an agreement group, in which physicians and their patients had the same answer to the question regarding forgetting medication (203 cases; 67.7%), and a disagreement group (97 cases; 32.3%). Overall, the inter-rater agreement between physicians and patients with regard to forgetting medication was significant, but slight (κ coefficient = 0.12). In a multivariate analysis, absence of hypertension [odds ratio (OR): 0.21, 95% confidence interval (CI): 0.09-0.50, P < .001), β-blocker usage (OR: 1.86, 95% CI: 1.11-3.12, P = .02), and biguanide usage (OR: 4.04, 95% CI: 1.43-11.41, P = .01) were independent predictors of disagreement with regard to forgetting medication.The inter-rater agreement between physicians and patients with regard to medication adherence was slight. An increase in inter-rater agreement should improve medication adherence.

Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5 -/- mice and delineate the role of SREBP-1c in vivo by generating Apoa5 -/- ;Srebp-1c -/- mice. The Apoa5 -/- mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in the Apoa5 -/- ;Srebp-1c -/- mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance. Conclusions- Severe hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.