The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up.

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

Case report: Mononeuropathy multiplex of extranodal natural killer/T-cell lymphoma misdiagnosed as systemic vasculitis.

Background: Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma that typically develops in the upper aerodigestive tract. Case presentation: We encountered an ENKTL patient who presented with purpura-like rashes and foot drops as initial symptoms and later developed other peripheral nerve involvement. The nerve conduction study of both the motor nerve and the sensory nerve showed axonal damage resembling mononeuropathy multiplex. Although the initial response to steroids was encouraging, the patient's symptoms reappeared and aggravated. A biopsy of the abdominal subcutaneous fat tissue with additional immunohistochemistry revealed neoplastic NK/T lymphocytes. Conclusion: We reported the first case presented as mononeuropathy multiplex as the initial clinical manifestation in ENKTL patients. Lymphoma should be considered in the diagnosis of atypical mononeuropathy in multiplex patients.

Treatment of insomnia in myasthenia gravis-A prospective study on non-benzodiazepine hypnotics in the treatment of myasthenia gravis patients with insomnia.

Objectives: This study aimed to evaluate the efficacy and safety of non-benzodiazepine hypnotics in the treatment of myasthenia gravis (MG) patients with insomnia. Methods: This is a prospective longitudinal study. Outpatients who met the criteria for stable MG and insomnia diagnosis according to the International Classification of Sleep Disorders (third edition) were included in the study. They took a regular dose of non-benzodiazepine hypnotics (zolpidem 10 mg per night or zopiclone 7.5 mg per night) based on their own preferences. Patients received psychotherapy (including sleep health education) and were followed up for 4-5 weeks. Cases with lung diseases, respiratory disorders, or inappropriate use of hypnotic medications were excluded. The primary outcome is the difference in total Pittsburgh Sleep Quality Index (PSQI) score between baseline and the end of follow-up period. Secondary outcomes include the difference in Myasthenia Gravis Activities of Daily Living (MG-ADL) score, 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire-9 (PHQ-9) between baseline and the end of follow-up period and the safety of medication. Results: A total of 75 MG patients with insomnia were included in this study. After 4-5 weeks of treatment, the total PSQI score and MG-ADL score were lower than baseline (p < 0.01). No patients had an increased MG-ADL score. The incidence rate of adverse events was 16.0% (12 cases), including dizziness (6 cases, 8.0%), drowsiness (3 cases, 4.0%), fatigue (2 cases, 2.7%), and nausea (1 case, 1.3%), all of which were mild. No patients had new onset breathing disorders. Conclusion: Non-benzodiazepine hypnotics are safe and effective for stable MG patients who need insomnia treatment.

Risk profiles and a concise prediction model for lymph node metastasis in patients with lung adenocarcinoma.

BACKGROUND: Lung cancer is the second most commonly diagnosed cancer and ranks the first in mortality. Pathological lymph node status(pN) of lung cancer affects the treatment strategy after surgery while systematic lymph node dissection(SLND) is always unsatisfied. METHODS: We reviewed the clinicopathological features of 2,696 patients with LUAD and one single lesion ≤ 5 cm who underwent SLND in addition to lung resection at the Sun Yat-Sen University Cancer Center. The relationship between the pN status and all other clinicopathological features was assessed. All participants were stochastically divided into development and validation cohorts; the former was used to establish a logistic regression model based on selected factors from stepwise backward algorithm to predict pN status. C-statistics, accuracy, sensitivity, and specificity were calculated for both cohorts to test the model performance. RESULTS: Nerve tract infiltration (NTI), visceral pleural infiltration (PI), lymphovascular infiltration (LVI), right upper lobe (RUL), low differentiated component, tumor size, micropapillary component, lepidic component, and micropapillary predominance were included in the final model. Model performance in the development and validation cohorts was as follows: 0.861 (95% CI: 0.842-0.883) and 0.840 (95% CI: 0.804-0.876) for the C-statistics and 0.803 (95% CI: 0.784-0.821) and 0.785 (95% CI: 0.755-0.814) for accuracy, and 0.754 (95% CI: 0.706-0.798) and 0.686 (95% CI: 0.607-0.757) for sensitivity and 0.814 (95% CI: 0.794-0.833) and 0.811 (95% CI: 0.778-0.841) for specificity, respectively. CONCLUSION: Our study showed an easy and credible tool with good performance in predicting pN in patients with LUAD with a single tumor ≤ 5.0 cm without SLND and it is valuable to adjust the treatment strategy.

AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research.

BACKGROUND: The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. METHODS: Patients' data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect. RESULTS: The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group. CONCLUSIONS: The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.

Establishment and validation of a prognostic risk classification for patients with stage T1-3N0M0 esophageal squamous cell carcinoma.

INTRODUCTION: At present, clinical factors and hematological indicators have been proved to have great potential in predicting the prognosis of cancer patients, and no one has combined these two valuable indicators to establish a prognostic model for esophageal squamous cell carcinoma (ESCC) patients with stage T1-3N0M0 after R0 resection. To verify, we aimed to combine these potential indicators to establish a prognostic model. METHODS: Stage T1-3N0M0 ESCC patients from two cancer centers (including training cohort: N = 819, and an external validation cohort: N = 177)-who had undergone esophagectomy in 1995-2015 were included. We integrated significant risk factors for death events by multivariable logistic regression methods and applied them to the training cohort to build Esorisk. The parsimonious aggregate Esorisk score was calculated for each patient; the training set was divided into three prognostic risk classes according to the 33rd and 66th percentiles of the Esorisk score. The association of Esorisk with cancer-specific survival (CSS) was assessed using Cox regression analyses. RESULTS: The Esorisk model was: [10 + 0.023 × age + 0.517 × drinking history - 0.012 × hemoglobin-0.042 × albumin - 0.032 × lymph nodes]. Patients were grouped into three classes-Class A (5.14-7.26, low risk), Class B (7.27-7.70, middle risk), and Class C (7.71-9.29, high risk). In the training group, five-year CSS decreased across the categories (A: 63%; B: 52%; C: 30%, Log-rank P < 0.001). Similar findings were observed in the validation group. Additionally, Cox regression analysis showed that Esorisk aggregate score remained significantly associated with CSS in the training cohort and validation cohort after adjusting for other confounders. CONCLUSIONS: We combined the data of two large clinical centers, and comprehensively considered their valuable clinical factors and hematological indicators, established and verified a new prognostic risk classification that can predict CSS of stage T1-3N0M0 ESCC patients.

ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome.

The quantitative profiling of residue reactivity in proteins promotes the discovery of covalent druggable targets for precise therapy. Histidine (His) residues, accounting for more than 20% of the active sites in enzymes, have not been systematically characterized for their reactivity, due to lack of labeling probes. Herein, we report a chemical proteomics platform for the site-specific quantitative analysis of His reactivity by combination of acrolein (ACR) labeling and reversible hydrazine chemistry enrichment. Based on this platform, in-depth characterization of His residues was conducted for the human proteome, in which the rich content of His residues (>8200) was quantified, including 317 His hyper-reactive residues. Intriguingly, it was observed that the hyper-reactive residues were less likely to be the sites for phosphorylation, and the possible mechanism of this antagonistic effect still needs to be evaluated in further research. Based on the first comprehensive map of His residue reactivity, many more residues could be adopted as the bindable sites to disrupt the activities of a diverse number of proteins; meanwhile, ACR derivatives could also be used as a novel reactive warhead in the development of covalent inhibitors.

Iron metabolism in non-anemic myasthenia gravis patients: A cohort study.

BACKGROUND: The association of iron metabolism parameters with disease severity and outcome in myasthenia gravis (MG) patients has not been reported. This study was conducted to determined clinical factors including iron metabolism parameters correlated with disease severity and future outcome in non-anemic immunotherapy-naïve MG patients first receiving immunotherapy. MATERIAL AND METHODS: One hundred and ten patients were included at baseline to explore predictor variables associated with disease severity represented by variables derived from MG activities of daily living (MG-ADL) score using multivariate logistic regression, after which 103 and 98 patients were included respectively in multivariate survival analyses at 6-month and 12-month follow-up to identify predictors for minimal manifestation status (MMS) after starting immunotherapy. RESULTS: Higher ferritin level was independently associated with higher risk of severe generalized disease in non-anemic immunotherapy-naïve MG patients. Total iron binding capacity <250 µg/dL and the interval between onset and immunotherapy <1 year were independent predictors for MMS at 6-month and 12-month follow-up after initiating immunotherapy. Transferrin <2.00 g/L was an independent predictor for MMS at 12-month follow-up. CONCLUSION: Iron metabolism parameters might be promising biomarkers for evaluating disease severity and guiding therapeutic decision in MG patients.

The postoperative prognosis of skip-N2 metastasis is favorable in small-cell lung carcinoma patients with pathological N2 classification: a propensity-score-adjusted retrospective multicenter study.

Background: The study on skip-N2 metastasis in small-cell lung cancer (SCLC) is lacking. Therefore, this study aimed to explore the prognostic significance of skip-N2 metastasis based on a multicenter cohort. Methods: We collected 176 SCLC patients with pathological categories T1-4N1-2M0 from four hospitals in China. Survival curves were drawn through the Kaplan-Meier method and compared by the log-rank test. The Cox regression method was used to calculate the hazard ratio (HR) and 95% confidence interval of the characteristics for cancer-specific survival (CSS). Two propensity-score methods were used to reduce the bias, including the inverse probability of treatment weighting (IPTW) and propensity-score matching (PSM). Results: This multicenter database included 64 pN1 patients, 63 non-skip-N2 cases, and 49 skip-N2 cases. Skip-N2 and the non-skip-N2 patients had gap CSS rates (skip-N2 no versus yes: 41.0% versus 62.0% for 1-year CSS, 32.0% versus 46.0% for 2-year CSS, and 20.0% versus 32.0% for 3-year CSS). After PSM, there were 32 pairs of patients to compare survival differences between N2 and skip-N2 diseases, and 34 pairs of patients to compare prognostic gaps between N1 and skip-N2 diseases, respectively. The results of IPTW and PSM both suggested that skip-N2 cases had better survival outcomes than the non-skip-N2 cases (IPTW-adjusted HR = 0.578; PSM-adjusted HR = 0.510; all log-rank p < 0.05). Besides, the above two analytic methods showed no difference in prognoses between pN1 and skip-N2 diseases (all log-rank p > 0.05). Conclusions: Skip-N2 patients were confirmed to have a better prognosis than non-skip-N2 patients. Besides, there was no survival difference between pN1 and skip-N2 cases. Therefore, we propose that the next tumor-node-metastasis staging system needs to consider the situation of skip metastasis with lymph nodes in SCLC.

Treatment of primary progressive aphasia by repetitive transcranial magnetic stimulation: a randomized, double-blind, placebo-controlled study.

To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with primary progressive aphasia (PPA). In this randomized, double-blind trial in a single center, patients who were diagnosed with PPA were randomly assigned to receive either real rTMS or sham rTMS treatment. High-frequency rTMS was delivered to the dorsolateral prefrontal cortex (DLPFC). The primary outcome was the change in Boston Naming Test (BNT) score at each follow-up compared to the baseline. The secondary outcomes included change in CAL (Communicative Activity Log) and WAB (Western Aphasia Battery) compared to baseline and neuropsychological assessments. Forty patients (16 with nonfluent, 12 with semantic and 12 with logopenic variant PPA) were enrolled and randomly assigned to the rTMS or sham rTMS group, with 20 patients in each group. Thirty-five patients (87.5%) completed a 6-month follow-up. Compared to the sham rTMS group, the BNT improvement and WAB improvement in the real rTMS group were significantly higher. These significant improvements could be observed throughout the entire 6-month follow-up. At 1 month and 3 months after treatment, CAL improvements of real rTMS were significantly higher than sham rTMS. The improvements in BNT, CAL and WAB did not significantly differ among PPA variants. No significant improvement in neuropsychological assessments was observed. High-frequency rTMS delivered to DLPFC improved language functions in patients with different PPA variants. The efficacy was still observed after 6 months of treatment. Trial registration: NCT04431401 ( https://clinicaltrials.gov/ct2/show/NCT04431401 ).

Nomogram predicts the prognosis of patients with thymic carcinoma: A population-based study using SEER data.

BACKGROUND: Thymic carcinoma (TC) is a rare malignant tumor that can have a poor prognosis, and accurate prognostication prediction remains difficult. We aimed to develop a nomogram to predict overall survival (OS) and cancer-specific survival (CSS) based on a large cohort of patients. METHODS: The Surveillance Epidemiology and End Results (SEER) database was searched to identify TC patients (1975-2016). Univariate and multivariable Cox regression analyses were used to identify predictors of OS and CSS, which were used to construct nomograms. The nomograms were evaluated using the concordance index (C-index), calibration curve, receiver operating characteristic curve, and decision curve analysis (DCA). Subgroup analysis was performed to identify high-risk patients. RESULTS: The analysis identified six predictors of OS (Masaoka stage, surgical method, lymph node metastasis, liver metastasis, bone metastasis, and radiotherapy) and five predictors of CSS (Masaoka stage, surgical method, lymph node metastasis, tumor size, and brain metastasis), which were used to create nomograms for predicting three-year and five-year OS and CSS. The nomograms had reasonable C-index values (OS: 0.687 [training] and 0.674 [validation], CSS: 0.712 [training] and 0.739 [validation]). The DCA curve revealed that the nomograms were better for predicting OS and CSS, relative to the Masaoka staging system. CONCLUSION: We developed nomograms using eight clinicopathological factors that predicted OS and CSS among TC patients. The nomograms performed better than the traditional Masaoka staging system and could identify high-risk patients. Based on the nomograms' performance, we believe they will be useful prognostication tools for TC patients.

Iron metabolism patterns in non-anemic patients with myasthenia gravis: A cross-sectional and follow-up study.

Background and purpose: Iron metabolism in myasthenia gravis (MG) and factors associated with it are explored by few published studies. Therefore, this study aimed to compare iron metabolism patterns between patients with MG and healthy individuals as well as between the same group of patients before and after immunotherapy, and to identify predictors of iron metabolism disorders in MG. Materials and methods: For this study, 105 patients and healthy individuals were included at baseline, after which paired parametric and non-parametric tests were adopted to compare their iron metabolism patterns, and multivariate binary logistic regression was used to identify predictors of iron metabolism disorders. Patients with MG were then followed up for 12 ± 3 months to explore alterations in their iron metabolism patterns after starting immunotherapy with the help of paired tests. Results: Non-anemic immunotherapy-naive patients with MG had significantly lower serum iron (SI) and transferrin saturation (TS) levels than healthy individuals. Premenopausal female was significantly associated with SI < 65 µg/dL and iron deficiency in these patients. However, iron metabolism parameters did not significantly alter after around 12 months of immunotherapy in patients with MG. Conclusion: Iron inadequacy was present in patients with MG, particularly premenopausal female patients, and it would hardly improve after immunotherapy. Given the significant role of iron in human body, it should be given more attention in patients with MG.

Prognostic value of preoperative C-reactive protein to albumin ratio in patients with thymic epithelial tumors: a retrospective study.

BACKGROUND: The C-reactive protein to albumin ratio (CAR) is associated with poor prognosis in various cancers. However, its value in thymic epithelial tumors remains to be elucidated, we aimed to evaluate the prognostic significance of preoperative CAR in patients with surgically resected thymic epithelial tumors (TETs). METHODS: We retrospectively collected data from 125 patients with TETs who underwent thymoma resection at our center. The best cutoff values ​​for the continuous variable, CAR, were obtained using X-tile software. Univariate and multivariate Cox regression analyses were used to evaluate CAR as an independent predictor of overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier analysis and log-rank tests were used to present risk stratification of patients based on CAR and the Glasgow-prognostic-score (GPS). The prognostic effect of CAR was assessed using a receiver operating characteristic curve. RESULTS: Patients were categorized into high (≥ 0.17) and low (< 0.17) CAR groups according to the optimal cutoff value of 0.17. Univariate and multivariate analyses showed that CAR was an independent predictor of prognosis. World health organization stage, CAR level, GPS score, and drinking history were important independent prognostic factors for OS (p < 0.05). T stage, CAR level, and drinking history were important independent prognostic factors for RFS (p < 0.05). The area under the curve value of CAR to predict prognosis was 0.734 for OS and 0.680 for RFS. CONCLUSIONS: Elevated preoperative CAR was independently associated with poor OS and RFS after thymectomy. Therefore, CAR may be a valuable biomarker for the postoperative prognosis of TETs.

The Prognostic Value of Preoperative Serum D-dimer Levels After Surgical Resection of Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors are the most common mediastinal tumors. Despite the high survival rate after surgery, some patients still require postoperative adjuvant therapy and closer follow-up. Hematological indicators such as biochemical routines and coagulation indicators have been reported to be independently associated with the prognosis of various malignancies. Therefore, we included hematological indicators in the analysis. METHODS: The data of 105 patients with thymic epithelial tumors were retrospectively collected from Sun Yat-sen University Cancer Center, and the patients with missing preoperative hematological indicators were excluded. X-tile software was used to obtain the best cutoff value of each preoperative hematological indicator, and COX regression analysis and Kaplan-Meier survival curves were used to demonstrate statistically significant results. RESULTS: COX univariate regression analysis of all patients showed that Masaoka stage, T stage, WHO histologic types, D-dimer, albumin-fibrinogen ratio (AFR), Fibrinogen (Fbg) were associated with postoperative overall survival (P < .05). T stage, WHO histologic types, D-dimer, and AFR were associated with postoperative recurrence-free survival (P < .05). Finally, multivariate regression analysis showed that T stage, D-dimer levels were independently associated with postoperative overall survival (OS) and recurrence-free survival (RFS) in patients with thymic epithelial tumors. CONCLUSIONS: For thymic epithelial tumors, higher preoperative D-dimer levels predict poorer survival and shorter recurrence-free survival. This may help guide postoperative adjuvant therapy and follow-up patterns in patients with thymic epithelial tumors.

Prognostic Value of Preoperative Serum Carcinoembryonic Antigen for Overall Survival and Recurrence-Free Survival in Resectable Thymic Epithelial Tumors.

Introduction: Tumor markers have been shown to be closely related to the long-term survival of patients with cancer and the recurrence of various malignant tumors. However, their role in thymic epithelial tumors (TETs) remains to be elucidated. We aimed to investigate whether the preoperative tumor biomarkers carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) could serve as independent predictors of postoperative prognosis in patients with TETs. Materials and Methods: We retrospectively included a total of 111 patients with TETs who underwent thymectomy at our hospital. Cox regression analysis was used to evaluate the statistical significance of CEA and NSE as independent predictors of overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier curves were used to present the results of our survival analyses. Results: Cox regression analysis showed that T stage, World Health Organization (WHO) histologic type, tumor size, and CEA levels served as independent prognostic factors for OS (P < .05). Whereas for RFS, multivariate analysis showed that only T stage, WHO histologic type, and drinking history were independently associated with it (P < .05). Conclusion: Our study found that preoperative serum CEA levels and tumor size may be strong predictors of postoperative OS in patients with TETs.

Prognostic Value of Preoperative Nutritional Assessment and Neutrophil-to-Lymphocyte Ratio in Patients With Thymic Epithelial Tumors.

Introduction: Systemic nutrition and immune inflammation are the key factors in cancer development and metastasis. This study aimed to compare and assess four nutritional status and immune indicators: prognostic nutritional index (PNI), nutritional risk index (NRI), neutrophil-to-lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII) as prognostic indicators for patients with thymic epithelial tumors. Materials: We retrospectively reviewed 154 patients who underwent thymic epithelial tumor resection at our hospital between 2004 and 2015. The optimal cutoff value for each nutritional and immune index was obtained using the X-tile software. Kaplan-Meier curves and Cox proportional hazards models were used for survival analysis. Results: Univariate analysis showed that PNI, NRI, NLR, SII, albumin (ALB), the albumin/globulin ratio (A/G), WHO stage, T stage, and drinking history were associated with the overall survival (OS) of patients (P < 0.05). The NRI, NLR, A/G, ALB, T stage, and WHO stage were significant independent prognostic factors of OS in multivariate analysis (P < 0.05). Finally, we constructed a coNRI-NLR model to predict OS and recurrence-free survival (RFS). Conclusions: This study suggests that the preoperative NRI, NLR, and coNRI-NLR model may be important prognostic factors for patients with thymic epithelial tumors who undergo surgical resection.

Long-Term Efficacy of Non-steroid Immunosuppressive Agents in Anti-Muscle-Specific Kinase Positive Myasthenia Gravis Patients: A Prospective Study.

Background and Purpose: Anti-muscle-specific kinase (MuSK) positive myasthenia gravis (MG) is characterized by a high relapsing rate, thus, choosing the appropriate oral drug regimen is a challenge. This study aimed to evaluate the efficacy of oral immunosuppressants (IS) in preventing relapse in MuSK-MG. Methods: This prospective cohort observational study included patients with MuSK-MG at Peking Union Medical College Hospital between January 1, 2018, and November 15, 2021. The patients were divided into 2 groups: those with (IS+) or without (IS-) non-steroid immunosuppressive agents. The primary outcome was relapsed at follow-up, and the log-rank test was used to compare the proportion of maintenance-free relapse between the groups; hazard ratio (HR) was calculated using the Cox proportional hazards models. Results: Fifty-three of 59 patients with MuSK-MG were included in the cohort, 14 were in the IS+ group, and 39 were in the IS- group. Twenty-four cases in the cohort experienced relapse at least once; the relapse rate was 2/14 (14.3%) in the IS+ group and 22/39 (56.4%) in the IS- group. At the end of follow-up, the proportion of maintenance-free relapse was significantly different between the two groups (log-rank χ2 = 4.94, P = 0.02). Of all the potential confounders, only the use of IS was associated with a reduced risk of relapse. The HR for relapse among patients in the IS+ group was 0.21 (95%CI 0.05-0.58) and was 0.23 (95%CI 0.05-0.93) in a model adjusted for age, sex, relapse history, highest Myasthenia Gravis Foundation of America (MGFA), and accumulated time of steroid therapy. Conclusions: This study provides evidence that oral non-steroid immunosuppressive agents may be beneficial in reducing relapse in patients with MuSK-MG.

Association Between Clinical Factors and Result of Immune Checkpoint Inhibitor Related Myasthenia Gravis: A Single Center Experience and Systematic Review.

Background: Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase use of ICIs, incidence of nirAEs is growing, among which ICI related MG (irMG) is causing high fatality rate. Given the limited evidence, data from a large cohort of patients with irMG is needed to aid in recognition and management of this fatal complication. Objective: This study aimed to summarize clinical characteristics of irMG and explore predictors of irMG clinical outcome. Methods: We summarized our institution's patients who were diagnosed as irMG between Sep 2019 and Oct 2021. We systematically reviewed the literature through Oct 2021 to identify all similar reported patients who met inclusion criteria. As the control group, patients with idiopathic MG were used. We collected data on clinical features, management, and outcomes of both irMG and idioMG cases. Further statistical analysis was conducted. Results: Sixty three irMG patients and 380 idioMG patients were included in the final analysis. For irMG patients, six were from our institution while the rest 57 were from reported cases. The average age of irMG patients is 70.16 years old. Forty three were male. Average time from first ICI injection to symptom onset was 5.500 weeks. Eleven patients had a past history of MG. Higher MGFA classification and higher QMGS rates were observed in irMG patients compared to idioMG patients. For complication, more irMG patients had myositis or myocarditis overlapping compared to idioMG patients. The most commonly used treatment was corticosteroids for both idioMG and irMG. Twenty one patients (35%) with irMG had unfavorable disease outcome. Single variate and multivariate binary logistic regression proved that association with myocarditis, high MGFA classification or QMGS rates at first visit were negatively related to disease outcome in irMG patients. Conclusion: irMG is a life-threatening adverse event. irMG has unique clinical manifestations and clinical outcome compared to idioMG. When suspicious, early evaluation of MGFA classification, QMGS rates and myositis/myocarditis evaluation are recommended.

Structural Insights into the Mechanism of High-Affinity Binding of Ochratoxin A by a DNA Aptamer.

A 36-mer guanine (G)-rich DNA aptamer (OBA36) is able to distinguish one atomic difference between ochratoxin analogues A (OTA) and B (OTB), showing prominent recognition specificity and affinity among hundreds of aptamers for small molecules. Why OBA36 has >100-fold higher binding affinity to OTA than OTB remains a long-standing question due to the lack of high-resolution structure. Here we report the solution NMR structure of the aptamer-OTA complex. It was found that OTA binding induces the aptamer to fold into a well-defined unique duplex-quadruplex structural scaffold stabilized by Mg2+ and Na+ ions. OTA does not directly interact with the G-quadruplex, but specifically binds at the junction between the double helix and G-quadruplex through π-π stacking, halogen bonding (X-bond), and hydrophobic interaction. OTB has the same binding site as OTA but lacks the X-bond. The strong X-bond formed between the chlorine atom of OTA and the aromatic ring of C5 is the key to discriminating the strong binding toward OTA. The present research contributes to a deeper insight of aptamer molecular recognition, reveals structural basis of the high-affinity binding of aptamers, and provides a foundation for further aptamer engineering and applications.

Postoperative survival effect of the number of examined lymph nodes on esophageal squamous cell carcinoma with pathological stage T1-3N0M0.

BACKGROUND: The postoperative survival effect of the number of examined lymph nodes on patients of R0-resected esophageal squamous cell carcinoma with pathological stage T1-3N0M0 is still unclear. METHODS: Patients diagnosed with pathological stage T1-3N0M0 esophageal squamous cell carcinoma from two cancer databases-our cancer center (N = 707), and Surveillance Epidemiology and End Results (N = 151). The primary clinical endpoint was overall survival. The X-tile software was used to determine the optimal cutoff value of the number of examined lymph nodes, and propensity score matching was conducted to reduce selection bias according to the results of X-tile software. The cohort of 151 patients from another database was used for validation. RESULTS: X-tile software provided an optimal cutoff value of 15 examined lymph nodes based on 707 patients, and 231 pairs of matched patients were included. In the unmatched cohort, Cox proportional hazard regression analysis revealed better overall survival in patients with more than 15 examined lymph nodes (adjusted hazard ratio, 0.566, 95% confidence interval, 0.445-0.720; p < 0.001) compared with patients with 15 or fewer examined lymph nodes. In the validation cohort, patients with more than 15 examined lymph nodes also had better overall survival (adjusted hazard ratio 0.665, p = 0.047). CONCLUSIONS: The number of examined lymph nodes is a significant prognostic factor in esophageal squamous cell carcinoma patients with pathological stage T1-3N0M0, and more than 15 examined lymph nodes are associated with better overall survival. Although the difference is not significant, the survival curve of patients with examined lymph nodes > 30 is better than those with examined lymph nodes 15-30. We believe that the number of examined lymph nodes can provide prognostic guidance for those patients, and the more examined lymph nodes cause lesser occult lymph nodes metastasis and lead to a better prognosis. Therefore, surgeons and pathologists should try to examine as many lymph nodes as possible to evaluate the pathological stage precisely. However, we need more validation from other studies.