Primary treatments for solitary hepatocellular carcinoma ≤ 3 cm: A systematic review and network meta-analysis.

Various treatment modalities are available for small solitary hepatocellular carcinoma (HCC), yet the optimal primary treatment strategy for tumors ≤ 3 cm remains unclear. This network meta-analysis investigates the comparative efficacy of various interventions on the long-term outcomes of patients with solitary HCC ≤ 3 cm. A systematic search of electronic databases from January 2000 to December 2023 was conducted to identify studies that compared at least two of the following treatments: surgical resection (SR), radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE). Survival data were extracted, and pooled hazard ratios with 95% confidence intervals were calculated using a frequentist network meta-analysis. A total of 30 studies, comprising 2 randomized controlled trials and 28 retrospective studies, involving 8,053 patients were analyzed. Surgical resection showed the highest overall survival benefit with a p-score of 0.95, followed by RFA at 0.59, MWA at 0.23, and TACE, also at 0.23. Moreover, SR provided the most significant recurrence-free survival advantage, with a p-score of 0.95, followed by RFA at 0.31 and MWA at 0.19. Sensitivity analyses, excluding low-quality or retrospective non-matched studies, corroborated these findings. This network meta-analysis demonstrates that SR is the most effective first-line curative treatment for single HCC ≤ 3 cm, followed by RFA in patients with preserved liver function. The limited data on MWA and TACE underscore the need for further studies.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex.

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUSpMHC and VACINUSTCR: VACINUSpMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUSTCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUSpMHC and VACINUSTCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUSpMHC, 48 peptides were ultimately selected using VACINUSTCR. In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUSTCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex.

Determining the vertebra for pedicle subtraction osteotomy in surgical correction for ankylosing spondylitis with thoracolumbar kyphosis.

OBJECTIVE: This study aimed to provide a method for determining the apical vertebra for pedicle subtraction osteotomy (PSO) in corrective surgery for patients with ankylosing spondylitis (AS) with thoracolumbar kyphosis (TLK). METHODS: The medical records of AS patients with TLK who underwent PSO between May 2009 and August 2022 were retrospectively reviewed, and 235 patients were included in the study. Using the proposed method, choosing the vertebra based on Kim's apex (KA), which is defined as the farthest vertebra from a line drawn from the center of the T10 vertebral body to the midpoint of the S1 upper endplate, the authors analyzed 229 patients with apices at T12, L1, or L2 (excluding L3 because of the small sample size, n = 6). They divided all patients into two groups. Group A (n = 144) underwent PSO at the KA vertebra, while group B (n = 85) underwent PSO at a different level. Demographic and radiological data, including sagittal spinopelvic parameters of the entire spine, were collected. An additional analysis was performed on patients with the same KA vertebra. RESULTS: The vertebra distributions of patients based on KA were T12 (28 [12.2%]), L1 (119 [52.0%]), and L2 (82 [35.8%]). The corrections of sagittal vertical axis (SVA; 101.0 ± 48.5 mm vs 82.0 ± 53.8 mm, p = 0.010), global kyphosis (GK; 31.6° ± 10.0° vs 26.4° ± 10.5°, p = 0.005), and TLK (29.4° ± 10.2° vs 24.2° ± 12.9°, p = 0.012) in group A were significantly greater than those in group B, and there was no difference in the corrections of thoracic kyphosis (TK), lumbar lordosis, and pelvic incidence between the two groups. On further analysis, group A showed greater correction in TK (26.2° ± 13.7° vs 0.1° ± 8.1°, p = 0.013) for patients with T12 as the KA; greater improvements in SVA (101.5 ± 44.2 mm vs 73.4 ± 48.7 mm, p = 0.020), GK (30.6° ± 11.0° vs 25.0° ± 10.4°, p = 0.046), and TLK (32.6° ± 7.8° vs 26.7° ± 9.9°, p = 0.012) for those with L1 as the KA; and significant correction in TLK (30.0° ± 6.3° vs 4.3° ± 19.5°, p = 0.008) for patients with L2 as the KA, compared with group B. CONCLUSIONS: PSO at the apical vertebra provides a greater degree of correction of sagittal imbalance. The proposed method, selecting the vertebra based on KA, is easily reproducible for determining the apex level in AS patients with TLK.

Association of parental depression with adolescent children's psychological well-being and health behaviors.

BACKGROUND: Parental depression is a significant problem that negatively affects parents' welfare and influences family dynamics, children's academic and health behaviors, and mental health. However, there is limited evidence regarding the impact of the parental depression into the children's' psychological and physical wellbeing on Asian cultures. This study examined the psychological burdens and health behaviors of adolescent children with parents with depression in the Republic of Korea. METHODS: We conducted a cross-sectional study using data from the Korean National Health and Nutrition Examination Survey (KNHANES) spanning 2013 to 2021 to compare health behaviors and mental health outcomes between 203 adolescent children with parents diagnosed with depression and 3,856 control adolescents aged 12-19 years. RESULTS: Following multivariate adjustments, the risk of depressive mood for more than two weeks was significantly increased in boys with parental depression (adjusted Odds Ratio [aOR] = 2.05, 95% Confidence Interval [CI] = 1.91-3.52) and adolescents with parents with moderate-to-severe depression (aOR = 2.60, 95% CI = 1.17-5.77). Adolescents with parental depression reported significantly worse subjective health status (aOR = 1.88, 95% CI = 1.05-3.36) and higher stress levels (aOR = 1.91, 95% CI = 1.33-2.76). Additionally, when parental depression was present and the time since depression diagnosis was more than five years, adolescents with parental depression exhibited even poorer subjective health status and higher stress levels. CONCLUSIONS: The study found that adolescents whose parents experienced depression had poorer mental health than those whose parents did not have mental health issues. These findings emphasize the importance of providing support for the mental health of adolescents in families affected by parental depression.

Association between body composition and subsequent cardiovascular diseases among 5-year breast cancer survivors.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) remain one of the leading causes of mortality in breast cancer survivors. This study aimed to investigate the association between body composition and subsequent CVD in breast cancer survivors. METHODS AND RESULTS: A retrospective cohort study of more than 70 thousand 5-year breast cancer survivors aged 40 years or older was conducted using data from the National Health Insurance Service of South Korea. Based on the percentage of predicted lean body mass (pLBMP), appendicular skeletal muscle mass (pASMP), and body fat mass (pBFMP), which were calculated using prediction equations with anthropometric data and health habits, groups were equally divided into quartiles. The risk of CVD was evaluated using multivariate Cox proportional hazards regression. Compared to those with the lowest pLBMP and pASMP, those with the highest pLBMP and pASMP had a 38% and 42% lower risk of CVD, respectively. In contrast, those with the highest pBFMP had a 57% higher risk of CVD compared to those with the lowest pBFMP. Each 1 % increase in pLBMP and pASMP was associated with a decreased risk of CVD [pLBMP, adjusted hazard ratio (aHR): 0.96, 95% CI 0.94-0.98, p < 0.05; pASMP, aHR: 0.91, 95% CI 0.87-0.95, p < 0.05] while each 1 % increase in pBFMP was associated with the increased risk of CVD (aHR: 1.05, 95% CI 1.03-1.07, p < 0.01). CONCLUSION: In this cohort study, a high pLBMP, a high pASMP, and a low pBFMP were associated with a lower risk of CVD.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Surgical Correction of Left Ventricular Assist Device Outflow Graft Obstruction Caused by a Wrapped Expanded Polytetrafluoroethylene Graft: A Case Report.

A 70-year-old man with dilated cardiomyopathy underwent left ventricular assist device (LVAD) implantation, using a HeartWare ventricular assist device, as a bridge to candidacy. After 26 months, computed tomography (CT) angiography indicated stenosis in the LVAD outflow graft; however, the patient was asymptomatic, prompting a decision to manage his condition with close monitoring. Ten months later, the patient presented with dizziness and low-flow alerts. Subsequent CT angiography revealed a critical obstruction involving the entire LVAD outflow graft. The patient underwent emergency surgery, during which an organized seroma causing the graft obstruction was found between a wrapped expanded polytetrafluoroethylene (ePTFE) graft and a Dacron outflow graft. The covering of the outflow graft was removed, along with the organized seroma. Following removal of the ePTFE wrap and decompression of the outflow graft, normal LVAD flow was reestablished. The practice of wrapping the outflow graft with synthetic material, commonly done to facilitate later redo sternotomy, may pose a risk for outflow graft obstruction.

Associations of cholecystectomy with metabolic health changes and incident cardiovascular disease: a retrospective cohort study.

Although some studies conducted about the risk of cholecystectomy and cardiovascular disease, there was a limit to explaining the relationship. We investigated the short-term and long-term relationship between cholecystectomy and cardiovascular disease, and evidence using the elements of the metabolic index as an intermediate step. It was a retrospective cohort study and we used the National Health Insurance Service database of South Korea between 2002 and 2015. Finally, 5,210 patients who underwent cholecystectomy and 49,457 at 1:10 age and gender-matched controls of subjects were collected. The main results was estimated by Multivariate Cox proportional hazard regression to calculate the hazard ratio (HR) with 95% confidence interval (CI) for risk of cardiovascular disease after cholecystectomy. Regarding short-term effects of cholecystectomy, increased risk of cardiovascular disease (aHR 1.35, 95% CI 1.15-1.58) and coronary heart disease (aHR 1.77, 95% CI 1.44-2.16) were similarly seen within 2 years of surgery. When analyzing the change in metabolic risk factors, cholecystectomy was associated with a change in systolic blood pressure (adjusted mean [aMean]: 1.51, 95% CI: [- 1.50 to - 4.51]), total cholesterol (aMean - 14.14, [- 20.33 to 7.95]) and body mass index (aMean - 0.13, [- 0.37 to 0.11]). Cholecystectomy patients had elevated risk of cardiovascular disease in the short-term, possibly due to the characteristics of the patient before surgery. The association of cholecystectomy and cardiovascular disease has decreased after 2 years in patients who underwent cholecystectomy, suggesting that because of improvement of metabolic health, cholecystectomy-associated elevation of cardiovascular disease risk may be ameliorated 2 years after cholecystectomy.

Achieving 400 Living Donor Liver Transplantations Annually During the COVID-19 Pandemic: A Single-Center Experience.

BACKGROUND: The COVID-19 pandemic has had a major impact on liver transplantation (LT) and living donor programs globally. PURPOSE: In this study, we aimed to present the principles and strategies of our LT program during the pandemic period and describe its achievements. BASIC PROCEDURES: We retrospectively reviewed the outcomes of 1417 LTs performed at Asan Medical Center, Seoul, Korea, from 2020 to 2022. Of these, 216 recipients who received transplants from deceased donors were excluded, and 1201 recipients who received transplants from 1268 live donors were included in the study, including 38 children <18 years old. MAIN FINDINGS: Among the 1201 living donor LT (LDLT) recipients, the most common indication for LT was unresectable hepatocellular carcinoma (315/1163, 27.1%) in adults and biliary atresia (29/38, 76.3%) in pediatric recipients. Emergency LDLT was performed in 40 patients (3.3%). The median model of end-stage liver disease and pediatric end-stage liver disease scores were 13.9 ± 7.2 and 13.8 ± 7.1, respectively. In-hospital mortality of recipients was higher than usual at 2.2%, but the cause of death was not related to COVID-19 infection. Of the 1268 live donors who underwent hepatectomy for liver donation, 660 (52.1%) underwent hepatectomy using a minimally invasive approach. Although 17 (1.3%) live donors experienced major complications, there were no serious life-threatening complications and no mortality. CONCLUSION: Even in a pandemic era, a team with well-established infection control protocols, patient-tailored surgical strategies, and thorough perioperative care can maintain LDLT at a similar quantitative and qualitative level as in a non-pandemic era.

Characteristics and standards of severe sagittal imbalance in adult patients with spinal deformities: a retrospective analysis.

OBJECTIVE: To analyze the characteristics of "severe" dynamic sagittal imbalance (DSI) in patients with adult spinal deformity (ASD) and establish criteria for them. METHODS: We retrospectively analyzed 102 patients with ASD presenting four cardinal signs of lumbar degenerative kyphosis. All patients underwent deformity corrective surgery and were divided into three groups according to the diagnostic criteria based on the Oswestry disability index and dynamic features (△Timewalk: time until C7 sagittal vertical axis [C7SVA] reaches ≥ 20 cm after the start of walking) of sagittal imbalance. The paravertebral back muscles were analyzed and compared using T2-weighted axial imaging. We performed a statistically time-dependent spinopelvic sagittal parameter analysis of full standing lateral lumbar radiographs. Lumbar flexibility was analyzed using dynamic lateral lumbar radiography. RESULTS: The patients were classified into the mild (△Timewalk ≥ 180 s, 35 patients), moderate (180 s > △Timewalk ≥ 30 s, 38 patients), and severe (△Timewalk < 30 s, 29 patients) groups. The back muscles in the severe group exhibited a significantly higher signal intensity (533.4 ± 237.5, p < 0.05) and larger area of fat infiltration (35.2 ± 5.4, p < 0.05) than those in the mild (223.8 ± 67.6/22.9 ± 11.9) and moderate groups (294.4 ± 214.7/21.6 ± 10.6). The analysis of lumbar flexibility revealed significantly lower values in the severe group (5.8° ± 2.5°, p < 0.05) than in the mild and moderate groups (14.2° ± 12.4° and 11.4° ± 8.7°, respectively). The severe group had significantly lower lumbar lordosis (LL, 25.1° ± 22.7°, p < 0.05) and Pelvic incidence-LL mismatch (PI-LL, 81.5° ± 26.6°, p < 0.001) than those of the mild (8.2° ± 16.3°/58.7° ± 18.8°) and moderate (14.3° ± 28.6°/66.8° ± 13.4°) groups. On receiver operating characteristic curve analysis, PI-LL was statistically significant, with an area under the curve of 0.810 (95% confidence interval) when the baseline was set at 75.3°. The severe group had more postoperative complications than the other groups. CONCLUSIONS: Our results suggest the following criteria for severe DSI: C7SVA > 20 cm within 30 s of walking or standing, a rigid lumbar curve < 10° on dynamic lateral radiographs, and a PI-LL mismatch > 75.3°.

Anterior Column Realignment Through Open Pre-posterior Release-Anterior-Posterior Fusion Versus Hybrid Minimally Invasive-Anterior-Posterior Fusion for Dynamic Sagittal Imbalance of the Spine.

STUDY DESIGN: Retrospective comparative study. OBJECTIVES: To investigate the clinical and radiological outcomes after anterior column realignment (ACR) through pre-posterior release-anterior-posterior surgery (PAP) and minimally invasive surgery -lateral lumbar interbody fusion (MIS-LLIF) using hybrid anterior-posterior surgery (AP). METHODS: A total of 91 patients who underwent ACR with long fusions from T10 vertebra to the sacropelvis with a follow-up period of at least 2 years after corrective surgery for adult spinal deformity were included and divided into two groups by surgical method: AP and PAP. AP was performed in 26 and PAP in 65 patients. Clinical outcomes and radiological parameters were investigated and compared. A further comparison was conducted after propensity score matching between the groups. RESULTS: The more increase of LL and decrease of PI-LL mismatch were observed in the PAP group than in the AP group postoperatively. After propensity score matching, total operation time and intraoperative bleeding were greater, and intensive care unit care and rod fracture were more frequent in the PAP group than in the AP group with statistical significance. Reoperation rate was higher in PAP (29.2%) than in AP (16.7%) without statistical significance. CONCLUSIONS: PAP provides a more powerful correction for severe sagittal malalignment than AP procedures. AP results in less intraoperative bleeding, operation time, and postoperative complications. Therefore, this study does not suggest that one treatment is superior to the other. LEVEL OF EVIDENCE: III.

Tailored radiation dose according to margin width for patients with ductal carcinoma in situ after breast-conserving surgery.

A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins < 2 mm and the appropriate margin width for high-risk DCIS. We retrospectively evaluated 137 patients who received adjuvant radiotherapy after breast-conserving surgery for DCIS between 2013 and 2019. The patients were divided into three- positive, close (< 2 mm), and negative (≥ 2 mm) margin groups. Radiation dose to the tumor bed in equivalent dose in 2 Gy fractions were a median of 66.25 Gy, 61.81 Gy, and 59.75 Gy for positive, close, and negative margin groups, respectively. During a median follow-up of 58 months, the crude rates of local recurrence were 15.0%, 6.7%, and 4.6% in the positive, close, and negative margin groups, respectively. The positive margin group had a significantly lower 5-year local recurrence-free survival (LRFS) rate compared to the close and negative margin groups in propensity-weighted log-rank analysis (84.82%, 93.27%, and 93.20%, respectively; p = 0.008). The difference in 5-year LRFS between patients with the high- and non-high-grade tumors decreased as the margin width increased (80.4% vs. 100.0% for margin ≥ 2 mm, p < 0.001; 92.3% vs. 100.0% for margin ≥ 6 mm, p = 0.123). With the radiation dose tailored for margin widths, positive margins were associated with poorer local control than negative margins, whereas close margins were not. Widely clear margins (≥ 2 mm) were related to favorable local control for high-grade DCIS.

Unexpected Restart Failure of Durable Left Ventricular Assist Devices: A Report of Two Cases.

The HeartWare Ventricular Assist Device (HVAD) was widely used for mechanical circulatory support in patients with end-stage heart failure. However, there have been reports of a critical issue with HVAD pumps failing to restart, or experiencing delays in restarting, after being stopped. This case report describes 2 instances of HVAD failure-to-restart during heart transplantation surgery and routine outpatient care. Despite multiple attempts to restart the pump using various controllers and extensions, the HVAD failed to restart, triggering a hazard alarm for pump stoppage. In one case, the patient survived after receiving a heart transplantation, while in the other, the patient died immediately following the controller exchange. These cases highlight the rare but life-threatening complication of HVAD failure-to-restart, underscoring the importance of awareness among clinicians, patients, and caregivers, and adherence to the manufacturer's guidelines and recommendations for HVAD management.

Pericardial Window Operation in Oncology Patients: Analysis of Long-Term Survival and Prognostic Factors.

Background: Pericardial effusion (PE) is a serious condition in cancer patients, primarily arising from malignant dissemination. Pericardial window formation is a surgical intervention for refractory PE. However, the long-term outcomes and factors associated with postoperative survival remain unclear. Methods: We retrospectively analyzed data from 166 oncology patients who underwent pericardial window formation at Samsung Medical Center between 2011 and 2023. We analyzed survival and PE recurrence regarding surgical approach, cancer type, and cytopathological findings. To identify factors associated with survival, we utilized Cox proportional-hazards regression. Results: All patients had tumors documented in accordance with the American Joint Committee on Cancer staging manual, including lung (61.4%), breast (9.6%), gastrointestinal (9.0%), hematologic (3.6%), and other cancers (16.4%). Surgical approaches included mini-thoracotomy (67.5%) and thoracoscopy (32.5%). Postsurgical cytopathology confirmed malignancy in 94 cases (56.6%). Over a median follow-up duration of 50.0 months, 142 deaths and 16 PE recurrences occurred. The 1-year overall and PE recurrence-free survival rates were 31.4% and 28.6%, respectively. One-year survival rates were significantly higher for thoracoscopy recipients (43.7% vs. 25.6%, p=0.031) and patients with negative cytopathology results (45.1% vs. 20.6%, p<0.001). No significant survival difference was observed between lung cancer and other types (p=0.129). Multivariate analysis identified New York Heart Association class, cancer stage, and cytopathology as independent prognostic factors. Conclusion: This series is the largest to date concerning window formation among cancer patients with PE. Patients' long-term survival after surgery was generally unfavorable. However, cases with negative cytopathology or earlier tumor stage demonstrated comparatively high survival rates.

Different cutoff value of motor evoked potentials for the postoperative outcome in the ossification of the posterior longitudinal ligament surgery in the cervical and thoracic spine.

BACKGROUND CONTEXT: Transcranial muscle motor evoked potentials (Tc-mMEPs), a key component of intraoperative neurophysiologic monitoring (IONM), effectively reflect the changes in corticospinal tract integrity and are closely related to the occurrence of the postoperative motor deficit (PMD). Most institutions have applied a specified (fixed) alarm criterion for the heterogeneous groups in terms of etiologies or lesion location. However, given the high risk of PMD in ossification of the posterior longitudinal ligament (OPLL) surgery, it is essential to determine a tailored cutoff value for IONM. PURPOSE: We aimed to establish the intraoperative cutoff value of Tc-mMEPs reduction for predicting PMD in OPLL according to lesion levels. DESIGN: Retrospective analysis using a review of electrical medical records. PATIENT SAMPLE: In this study, we included 126 patients diagnosed with OPLL, who underwent surgery and IONM. OUTCOME MEASURES: The occurrence of PMD immediately and 1 year after operation, as well as the decrement of intraoperative Tc-mMEPs amplitude. METHODS: We analyzed OPLL surgery outcomes using Tc-mMEPs monitoring. Limbs with acceptable baseline Tc-mMEPs in the tibialis anterior or abductor hallucis were included in the final set. PMD was defined as a ≥1 decrease in Medical Research Council score in the legs, and it was evaluated immediately and 1year after operation. The reduction ratios of Tc-mMEPs amplitude compared with baseline value were calculated at the two time points: the maximal decrement during surgery and at the end of surgery. Receiver operating characteristic curve analysis was used to determine the cutoff value of Tc-mMEPs amplitude decrement for predicting PMDs. RESULTS: In total, 203 limbs from 102 patients with cervical OPLL and 42 limbs from 24 patients with thoracic OPLL were included. PMD developed more frequently in thoracic lesions than in cervical lesions (immediate, 9.52% vs 2.46%; 1 year, 4.76% vs 0.99%). The Tc-mMEPs amplitude cutoff point at the end of surgery for PMD (both immediate and 1-year) was a decrease of 93% in cervical and 50% in thoracic OPLL surgeries. Similarly, the Tc-mMEPs amplitude cutoff point at the maximal decrement during surgery for PMD (both immediate and 1 year) was a reduction of 97% in cervical and 85% in thoracic OPLL surgeries. CONCLUSIONS: The thoracic lesion exhibited a lower cutoff value than the cervical lesion for both immediate and long-term persistent PMD in OPLL surgery (Tc-mMEPs at the end of surgery measuring 93% vs 50%; and Tc-mMEPs at the maximal decrement measuring 97% vs 85% for cervical and thoracic lesions, respectively). To enhance the reliability of monitoring, considering the application of tailored alarm criteria for Tc-mMEPs changes based on lesion location in OPLL could be beneficial.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Serum neurofilament and glial fibrillary acidic protein in idiopathic and seropositive transverse myelitis.

BACKGROUND: Serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) reflect the disease activity and disability in central nervous system (CNS) demyelinating diseases. However, the clinical significance of NfL and GFAP in idiopathic transverse myelitis (iTM), an inflammatory spinal cord disease with unknown underlying causes, remains unclear. This study aimed to investigate NfL and GFAP levels in iTM and their association with the clinical parameters compared with those in TM with disease-specific antibodies such as anti-aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies (sTM). METHODS: We collected serum and clinical data of 365 patients with CNS inflammatory diseases from 12 hospitals. The serum NfL and GFAP levels were measured in patients with iTM (n = 37) and sTM (n = 39) using ultrasensitive single-molecule array assays. Regression analysis was performed to investigate the associations between serum levels of NfL and GFAP and the clinical parameters such as higher EDSS scores (EDSS ≥ 4.0). RESULTS: Mean NfL levels were not significantly different between iTM (50.29 pg/ml) and sTM (63.18 pg/ml) (p = 0.824). GFAP levels were significantly lower in iTM (112.34 pg/ml) than in sTM (3814.20 pg/ml) (p = 0.006). NfL levels correlated with expanded disability status scale (EDSS) scores in sTM (p = 0.001) but not in iTM (p = 0.824). Disease duration also correlated with higher EDSS scores in sTM (p = 0.017). CONCLUSION: NfL levels and disease duration correlated with EDSS scores in sTM, and GFAP levels could be a promising biomarker to differentiate iTM from sTM.