Effective personalized neoantigen vaccine plus anti-PD-1 in a PD-1 blockade-resistant lung cancer patient.

Background: Although significant progress has been made in immune checkpoint inhibitor (ICI) treatment of advanced squamous cell carcinoma (SqCC), most patients still experience acquired drug resistance. Methods: We used a dendritic cell-based neoantigen vaccine combined with ICIs to treat advanced SqCC in a PD-1 blockade-resistant patient. Results: The follow-up of this patient after 12 months revealed significant tumor regression. We also identified a new JAK1 ICI-resistant mutation that could become a potential universal neoantigen target for tumor vaccines. Conclusion: Individualized management of advanced SqCC through a combined neoantigen vaccine and ICI administration could yield beneficial clinical outcomes. Vaccines targeting anti-PD-1-resistant JAK1 mutations might be of particular benefit to a specific group of solid tumor patients.

Immunotherapy based on immune checkpoint inhibitors (ICIs) is very effective in lung cancer treatment. However, many patients with initial response will later develop resistance. There are not many treatment options for patients with drug resistance. Herein, we report a patient with lung cancer who became resistant to ICI, treated with personalized vaccine plus ICI. Based on the patient's own somatic mutational profile, personalized neoantigen vaccines were designed and manufactured unique to the patient. Our report indicated that personalized vaccine plus ICI was safe and might overcome ICI resistance. A new ICI resistance mutation on JAK1 as a potential universal neoantigen target for off-the-shelf vaccine was found, which is promising for the effective treatment of a specific group of patients with JAK1 mutations.

A phase I dose-escalation study of neoantigen-activated haploidentical T cell therapy for the treatment of relapsed or refractory peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a type of highly heterogeneous non-Hodgkin lymphoma with a poor prognosis and lack of effective targeted therapies. Adoptive T-cell therapy has been successfully used in the treatment of B-cell malignancies. We first used adoptive transfer of haploidentical T cells activated by patient-specific neoantigens in vitro to treat an elderly patient with refractory angioimmunoblastic T-cell lymphoma (AITL) in 2017, and the patient achieved long-term complete remission (CR). Here we report on early results from this first-in-human phase 1 clinical trial that aims to assess the safety and tolerability of neoantigen-activated haploidentical T cell therapy (NAHTC) for relapsed/refractory PTCL. Clinical trial registration: http://www.chictr.org.cn/index.aspx, identifier [ChiCTR1800017440].

Effect of Exercise Interventions on Health-Related Quality of Life in Patients with Fibromyalgia Syndrome: A Systematic Review and Network Meta-Analysis.

Objective: Several guidelines highlight the beneficial impact of exercise on the management of symptoms and health-related quality of life (HRQOL) in patients with fibromyalgia syndrome (FMS). However, few analyses have compared different types of exercise. We, therefore, intent to compare the effects of different exercise types on improving the overall HRQOL and typical symptoms in patients with FMS. Methods: Medline, Embase, the Cochrane Register of Clinical Trials, and NIH ClinicalTrials.gov were searched from inception to April 21, 2022. Randomized clinical trials (RCTs) were included to assess the impact of exercise intervention on health parameters in adult FMS patients. Data were extracted independently and a frequentist network meta-analyses (NMA) was performed to rank the effects of interventions according to P-scores. The NMA evidence certainty was assessed using the method recommended by Grading of Recommendations Assessment, Development, and Evaluation Working Group. Results: A total of 57 RCTs were identified, including 3319 participants, involving 9 interventions (7 types of exercise, 2 controls). Of all treatments compared with usual care in efficacy outcomes, Mind-body exercise was associated with the best HRQOL (SMD, -12.12; 95% CI, -15.79 to -8.45). On the other characteristic symptom dimensions, based on moderate quality evidence, sensorimotor training was associated with minimal pain scores compared with usual care (SMD, -1.81; 95% CI, -2.81 to -0.82), whole body vibration therapy was most promising for improving sleep quality (SMD, -6.95; 95% CI, -10.03 to -3.87), pool-based aerobic exercise was most likely to ease anxiety (SMD, -4.83; 95% CI, -7.47 to -2.19), and whole body vibration was most likely to improve depression (SMD, -10.44; 95% CI, -22.00 to 1.12). Conclusion: Mind-body exercise seems to be the most effective exercise to improve the overall HRQOL of patients with FMS. But at the same time, clinicians still need to develop individualized exercise plans for patients according to their symptoms and accessibility.

Evaluation of the reliability of the upper lip bite test and the modified mallampati test in predicting difficult intubation under direct laryngoscopy in apparently normal patients: a prospective observational clinical study.

BACKGROUND AND AIMS: Difficult endotracheal intubation is one of the most challenging operations in anesthesia. How to better predict difficult airway and make corresponding preparations to reduce the occurrence of accidents is a difficult task faced by anesthesiologists every day. This study decide to evaluate the value of the Upper Lip Bite Test (ULBT) and the Modified Mallampati Test (MMT) in predicting difficult intubation under direct laryngoscopy and find out the most intuitive and simple method to predict difficult intubation under direct laryngoscopy in apparently normal patients. PATIENTS AND METHODS: This descriptive-analytical study was performed on 450 patients for elective surgery under general anesthesia requiring endotracheal intubation. The ULBT and MMT grading were evaluated preoperatively and Cormack and Lehane's (CL) classification was recorded on the day of surgery during intubation under direct laryngoscopy. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR), Youden index and area under ROC curve of ULBT and MMT respectively and in combination were calculated and compared. And the consistency between the total scores of ULBT and MMT combined in different ways and CL grading was counted. RESULTS: Of the 450 patients, 69 (15.3%) were classified as difficult cases of direct laryngoscopy. The accuracy, sensitivity, specificity, PPV and NPV of ULBT were 81.33, 11.59, 93.96, 25.81, 85.44%; and those the corresponding values for MMT were 66.22, 62.32, 69.29, 26.88 and 91.03%. A combination of ULBT and MMT did not improve the sensitivity in the sample tested. The combined total scores of ULBT and MMT in both ways were less consistent with CL grading in predicting difficult intubation under direct laryngoscopy. CONCLUSION: Based on findings of current study, we conclude that ULBT and MMT for difficult intubation have only poor to moderate discriminative power when used alone. The combination of the two tests in fractional form is also not a good predictor of difficult intubation under direct laryngoscopy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100052987, Registered 07 November 2021, http://www.chictr.org.cn.

A Novel Computational Framework for Predicting the Survival of Cancer Patients With PD-1/PD-L1 Checkpoint Blockade Therapy.

Background: Immune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies. Methods: Immune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types. Results: A fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz's SKCM, Liu's SKCM, Nathanson's SKCM and Braun's ccRCC, n = 367). IES was also negatively correlated with T cell-inflamed signature and independent of TMB. Conclusions: This novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy.

Morphology changes of maxillary molar distalization by clear aligner therapy / Cambios de la morfología en la distalización de molares maxilares mediante terapia con alineadores transparentes

SUMMARY: To evaluate the skeletal, dento-alveolar and soft tissue morphology changes after maxillary molar distalization by clear aligner therapy and identify the significant efficacy of molar distalization,18 patients in conformity with the inclusion criteria were selected. Pre- and post-treatment Cone Beam Computed Tomography (CBCT) were examined to measure the angular and linear parameters. All subjects were completed non-extraction clear aligner treatment by distalizing molars. A paired-t test and independent-samples t-test were performed to observe the difference between before and after treatment and the difference between the first molar and second molar respectively. P-values <0.05 were considered statistically significant. Predicted movement rate was calculated by the formula: (actual movement(mm)/planned movement(mm)) x100%. Most variables of pre- and post-treatment showed no statistical difference(P<0.05), excepting SNA angle (P<0.05) and Upper lip/E-line linear (P<0.01) due to incisor retraction. The first and second molar revealed a translation movement without significant tipping and vertical movement. Clear aligners provided a high predictability (83.44 %) of distalization the maxillary first molar, and 85.14 % of the maxillary second molar. Clear aligners can effectively achieve distal displacement of molars.

RESUMEN: Se seleccionaron 18 pacientes, de acuerdo con los criterios de inclusión, para evaluar los cambios en la morfología esquelética, dentoalveolar y de los tejidos blandos después de la distalización de los molares maxilares, mediante la terapia con alineadores transparentes e así identificar la significativa eficacia de la distalización de los molares. Se examinó a través de tomografía computarizada de haz cónico (CBCT) antes y después del tratamiento para medir los parámetros angulares y lineales. Todos los sujetos completaron el tratamiento con alineadores transparentes sin extracción mediante la distalización de los molares. Se realizó una prueba t pareada y una prueba t de muestras independientes para observar la diferencia entre antes y después del tratamiento y la diferencia entre el primer molar y el segundo molar, respectivamente. Los valores de p<0,05 se consideraron estadísticamente significativos. La tasa de movimiento prevista se calculó mediante la fórmula: (movimiento real (mm)/movimiento planificado (mm)) x 100 %. La mayoría de las variables de pre y postratamiento no mostraron diferencia estadística (P<0,05), excepto el ángulo SNA (P<0,05) y el labio superior/línea E lineal (P<0,01) debido a la retracción del incisivo. El primer y segundo molar revelaron un movimiento de traslación sin inclinación significativa y movimiento vertical. Los alineadores transparentes proporcionaron una alta previsibilidad (83,44 %) de la distalización del primer molar superior y del 85,14 % del segundo molar superior. Los alineadores transparentes pueden lograr efectivamente el desplazamiento distal de los molares.

Identifying sarcopenia in advanced non-small cell lung cancer patients using skeletal muscle CT radiomics and machine learning.

BACKGROUND: Sarcopenia has been confirmed as a poor prognostic indicator of lung cancer. However, the lack of abdominal computed tomography (CT) hindered the application to assess the status of sarcopenia. The purpose of this study was to assess the ability of chest CT radiomics combined with machine learning classifiers to identify sarcopenia in advanced non-small cell lung cancer (NSCLC) patients. METHODS: This study retrospectively analyzed CT images of 99 patients with NSCLC. Skeletal muscle radiomics were extracted from a single axial slice of the chest CT scan at the 12th thoracic vertebrae level. In total, 854 radiomic and clinical features were obtained from each patient. Feature selection was conducted with FeatureSelector module, optimal key features were fed into the lightGBM classifier for model construction, and Bayesian optimization was adopted to tune hyperparameters. The model's performance was evaluated by specificity, sensitivity, accuracy, precision, F1-score, Matthew's correlation coefficient (MCC), Cohen's kappa coefficient (Kappa), and AUC. RESULTS: A total of 40 patients were found to have sarcopenia. Five optimal features were selected. In the base lightGBM model, the specificity, sensitivity, accuracy, precision, F1-score, AUC, MCC, Kappa of validation set were 0.889, 0.750, 0.833, 0.818, 0.783, 0.819, 0.649, 0.648, respectively. After Bayesian hyperparameter tuning, the optimized lightGBM model achieved better prediction performance, and the corresponding values were 0.944, 0.833, 0.900, 0.909, 0.870, 0.889, 0.791, 0.789, respectively. CONCLUSIONS: Chest CT-based radiomics has the potential to identify sarcopenia in NSCLC patients with the lightGBM classifier, and the optimal lightGBM model via Bayesian hyperparameter tuning demonstrated better performance. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Our study demonstrates that chest CT-based radiomics combined with lightGBM classifier has the ability to identify sarcopenia in NSCLC patients. WHAT THIS STUDY ADDS: Skeletal muscle radiomics would be a potential biomarker for sarcopenia identity in NSCLC patients.

Morphological changes of frankel functional regulator III in mixed dentition with class III malocclusion / Cambios morfológicos del regulador funcional frankel III en dentición mixta con maloclusión clase III

The aim of this study was to evaluate the hard and soft tissue profile changes following treatment of functional and mild skeletal class III malocclusion in mixed dentition by means of the Frankel functional regulator (FR-3) appliance, and to reveal the mechanism and effectiveness of treatment with FR-3 appliance. Twenty-six patients (chronological mean age, 8.7±1.4 years; mean treatment duration, 10.3±1.3 months) with functional and mild skeletal class III malocclusion were selected and treated with FR-3 appliances. Lateral cephalogram was taken pre- and post-treatment, and the data was analyzed by paired-samples t test with SPSS22.0 software package. Differences were considered statistically significant at P < 0.05. The results demonstrated that the FR-3 appliance produced a statistically significant decrease in L1-NB, L1-MP, U1-L1 (P<0.01) and an increase greatly in ANB, MP-FH, Y axis, ANSMe, ANS-Me/N-Me and overjet (P<0.01). SNA, SNB were increased significantly (P<0.05). Meanwhile, N'-Sn-Pog', ULSn-SN, LLSiSN increased, S-N'-Si, LL-EP decreased with significant difference (P<0.01). S-N'-Sn, Cm-Sn-UL, UL-EP, Sn-Mes and Ns-Mes increased with significant difference (P<0.05). Therefore it was concluded that after FR-3 treatment, the position of mandible may rotate clockwise backwards and downwards, with the labioversion of upper incisors and linguoversion of lower incisors. Although point A moved mesially, the length and position of the maxilla did not change significantly. With the protrusion of upper lip and the retrusion of lower lip, the relationship among nose, upper lip, lower lip and chin become harmonious, the profile of soft tissue is more coordinated and attractive.

El objetivo de este estudio fue evaluar los cambios en el perfil de los tejidos duros y blandos después del tratamiento de la maloclusión funcional y leve de la clase III esquelética en la dentición mixta mediante el aparato regulador funcional Frankel (FR-3), y revelar el mecanismo y efectividad del tratamiento con el aparato FR-3. Veintiseis pacientes (edad media 8,7 ± 1,4 años; duración media del tratamiento, 10,3 ± 1,3 meses) con maloclusión funcional y leve de clase esquelética III fueron seleccionados y tratados con aparatos FR-3. El cefalograma lateral se tomó antes y después del tratamiento, y los datos se analizaron mediante la prueba t de muestras con el software SPSS22.0. Las diferencias se consideraron estadísticamente significativas a P <0,05. Los resultados demostraron que el dispositivo FR-3 produjo una disminución estadísticamente significativa en L1-NB, L1MP, U1-L1 (P <0,01) y un gran aumento en ANB, MP-FH, eje Y, ANS-Me, ANS -Me / N-Me y overjet (P <0,01). SNA, SNB se incrementaron significativamente (P <0,05). Mientras tanto, N'Sn-Pog', ULSn-SN, LLSi-SN aumentaron, S-N'-Si, LL-EP disminuyeron con una diferencia significativa (P <0,01). S-N'-Sn, Cm-Sn-UL, UL-EP, Sn-Mes y Ns-Mes aumentaron con una diferencia significativa (P <0,05). Por lo tanto, se concluyó que después del tratamiento con FR-3, la posición de la mandíbula puede girar en sentido reloj hacia atrás y hacia abajo, con labioversión de los incisivos superiores y linguoversión de los incisivos inferiores. Aunque el punto A se movió mesialmente, la longitud y la posición del maxilar no cambiaron significativamente. Con la protuberancia del labio superior y la retrusión del labio inferior, la relación entre la nariz, el labio superior, el labio inferior y el mentón se armoniza, el perfil del tejido blando es más coordinado y atractivo.

Protective Effects of Salidroside against Carbon Tetrachloride (CCl4)-Induced Liver Injury by Initiating Mitochondria to Resist Oxidative Stress in Mice.

The antioxidant effect of salidroside has been proven, but its role in liver injury is poorly understood. In this study, we aimed to evaluate the protective effects and mechanism of salidroside on liver injury induced by carbon tetrachloride (CCl4) in vivo. Mice were pretreated with salidroside (60 mg/kg, intraperitoneally injected, i.p.) once per day for 14 consecutive days and then administered with CCl4 (15.95 g/kg, i.p.) for 24 h to produce a liver injury model. Salidroside attenuated hepatic transaminase elevation in serum and ameliorated liver steatosis and necrosis, thereby suggesting its protective effect on the liver. Salidroside antagonized CCl4-induced toxicity by equilibrating antioxidation system, thereby inhibiting reactive oxygen species accumulation, and restoring mitochondrial structure and function. Salidroside exerts antioxidant and liver-protective effects by selectively inhibiting the activation of genes, including growth arrest and DNA -damage-inducible 45 α (Gadd45a), mitogen-activated protein kinase 7 (Mapk7), and related RAS viral oncogene homolog 2 (Rras2), which induce oxidative stress in the mitogen-activated protein kinase pathway. These results revealed that salidroside can protect the liver from CCl4-induced injury by resisting oxidative stress and protecting mitochondrial function.

Videolaryngoscopy versus direct laryngoscopy for nasotracheal intubation: A systematic review and meta-analysis of randomised controlled trials.

STUDY OBJECTIVE: Nasotracheal intubation (NTI) is a common practice in the oral and maxillofacial surgeries. A systematic review and meta-analysis was performed to determine whether videolaryngoscopy (VL) compared with direct laryngoscopy (DL) can lead to better outcomes for NTI in adult surgical patients. MEASUREMENTS: Only randomised controlled trials comparing VL and DL for NTI were included. The primary outcome was overall success rate and the second outcomes were first-attempt success rate, intubation time, rate of Cormack and Lehane classification 1, rate of Magill Forceps used, rate of postoperative sore throat, and ease of intubation. MAIN RESULTS: Fourteen studies with 20 comparisons (n = 1052) were included in quantitative synthesis. The overall success rate was similar between two groups (RR, 1.03; p = 0.14; moderate-quality evidence). VL was associated with a higher first-attempt success rate (RR 1.09; p = 0.04; low-quality evidence), a shorten intubation time (MD-6.72 s; p = 0.0001; low-quality evidence), a higher rate of Cormack and Lehane classification 1 (RR, 2.11; p < 0.01; high-quality evidence), a less use of the Magill forceps (RR, 0.11; p < 0.01; high-quality evidence) and a lower incidence of postoperative sore throat (RR, 0.50; p = 0.03; high-quality evidence). Subgroup analysis based on whether with a difficult airway showed higher overall success (p < 0.01) and first-attempt success rates with VL (p = 0.04) in patients with difficult airways; however, these benefits was not shown in patients with a normal airway (p > 0.05); Subgroup analysis based on operators' experience showed that success rate did not differ between groups (p > 0.05), but intubation time was shortened by more than 50s by non-experienced operators (p < 0.05). Subgroup analysis based on different devices used showed that only non-integrated VL led to a shorter intubation time (p < 0.05). CONCLUSIONS: The use of VL does not increase the overall success rate of NTI in adult patients with general anesthesia, but it improves the first-attempt success rate and laryngeal visualization, and shortens the intubation time. VL is particularly beneficial for patients with difficult airways.

Prognostic Value of the Combination of Preoperative Hemoglobin, Lymphocyte, Albumin, and Neutrophil in Patients with Locally Advanced Colorectal Cancer.

BACKGROUND Systemic inflammatory response and nutritional status are important to the prognosis of patients with colorectal cancer (CRC). This study aimed to investigate the prognostic value of the combination of preoperative hemoglobin, lymphocyte, albumin, and neutrophil (HLAN) in patients with locally advanced CRC (LACRC). MATERIAL AND METHODS We performed a retrospective analysis in 536 LACRC patients undergoing radical surgery. The value of HLAN was defined as follow: HLAN=Hemoglobin (g/L)×Lymphocyte (/L)×Albumin (g/L)/Neutrophil (/L)/100. The X-tile program was used to determine the optimal cut-point of HLAN, and the prognostic value of HLAN for overall survival (OS) was evaluated with the Cox proportional hazard model. RESULTS The cut-point of HLAN was set at 19.5. Compared with the high-HLAN group, the low-HLAN group had a 1.50-fold (95% confidence interval 1.09-2.05) increased risk of death and a significantly lower OS rate (P<0.001). Furthermore, the risk stratification model based on HLAN (AUC=0.72) displayed better accuracy in OS prediction than the TNM system (AUC=0.61). CONCLUSIONS HLAN is a valuable prognostic marker for patients with LACRC.