Predictive mutation signature of immunotherapy benefits in NSCLC based on machine learning algorithms.

Background: Developing prediction tools for immunotherapy approaches is a clinically important and rapidly emerging field. The routinely used prediction biomarker is inaccurate and may not adequately utilize large amounts of medical data. Machine learning is a promising way to predict the benefit of immunotherapy from individual data by individuating the most important features from genomic data and clinical characteristics. Methods: Machine learning was applied to identify a list of candidate genes that may predict immunotherapy benefits using data from the published cohort of 853 patients with NSCLC. We used XGBoost to capture nonlinear relations among many mutation genes and ICI benefits. The value of the derived machine learning-based mutation signature (ML-signature) on immunotherapy efficacy was evaluated and compared with the tumor mutational burden (TMB) and other clinical characteristics. The predictive power of ML-signature was also evaluated in independent cohorts of patients with NSCLC treated with ICI. Results: We constructed the ML-signature based on 429 (training/validation = 8/2) patients who received immunotherapy and extracted 88 eligible predictive genes. Additionally, we conducted internal and external validation with the utility of the OAK+POPLAR dataset and independent cohorts, respectively. This ML-signature showed the enrichment in immune-related signaling pathways and compared to TMB, ML-signature was equipped with favorable predictive value and stratification. Conclusion: Previous studies proposed no predictive difference between original TMB and modified TMB, and original TMB contains some genes with no predictive value. To demonstrate that fewer genetic tests are sufficient to predict immunotherapy efficacy, we used machine learning to screen out gene panels, which are used to calculate TMB. Therefore, we obtained the 88-gene panel, which showed the favorable prediction performance and stratification effect compared to the original TMB.

Selection and validation of chemotherapy beneficiaries among elderly nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT): a large real-world study.

PURPOSE: Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy. METHODS AND MATERIALS: 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits. RESULTS: The median follow-up was 59.3 (0.39-170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1-2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3-4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184-0.517; P < 0.001), and validated in the testing set (HR = 0.276, 95% CI 0.113-0.670; P = 0.002). In the poor-prognosis group, a significantly improved OS for chemoradiotherapy (CRT) compared with RT alone was observed (HR = 0.70, 95% CI 0.55-0.88; P = 0.003). Patients who received induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and CCRT had a significantly improved OS compared with RT alone (IC + CCRT vs. RT alone: P = 0.002; CCRT vs. RT alone: P = 0.008) but not in the IC + RT group (P = 0.306). The 5-year OS for CRT versus RT-alone with ACE-27 scores of 0, 1 and 2 were 76.0% versus 70.0% (P = 0.014), 80.5% versus 68.2% (P = 0.150) and 58.5% versus 62.2% (P = 0.490), respectively; for those aged 60-64, 65-70 and ≥ 70 years old they were 80.9% versus 75.9% (P = 0.068), 73.3% versus 63.4% (P = 0.270) and 64.8% versus 67.1% (P = 0.820), respectively. CONCLUSIONS: For elderly NPC patients a simple screening cutoff for chemotherapy beneficiaries might be EBV DNA < 4000 copies/ml & T3-4 and EBV DNA ≥ 4000 copies/ml & any T, but not for those > 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy.

Long-Term Evaluation and Normal Tissue Complication Probability (NTCP) Models for Predicting Radiation-Induced Optic Neuropathy after Intensity-Modulated Radiation Therapy (IMRT) for Nasopharyngeal Carcinoma: A Large Retrospective Study in China.

PURPOSE: To quantify the long-term evaluation of optic chiasma (OC) and/or optic nerve(s) (ONs) and to develop predictive models for radiation-induced optic neuropathy (RION) in nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 3,662 patients' OC/ONs with full visual acuity and dosimetry data between 2010 and 2015 were identified. Critical dosimetry predictors of RION were chosen by machine learning and penalized regression for survival. A nomogram containing dosimetry and clinical variables was generated for predicting RION-free survival. RESULTS: The median follow-up was 71.79 (2.63-120.9) months. Sixty-six eyes in 51 patients (1.39%) developed RION. Two patients were visual field deficient, and 49 patients had visual acuity of less than 0.1 (20/200). The median latency time was 36 (3-90) months. The 3-, 5-, and 8-year cumulative incidence of RION was 0.78%, 1.19%, and 1.97%, respectively. Dmax was the most critical dosimetry variable for RION (AUC: 0.9434, the optimal cutoff: 64.48 Gy). Patients with a Dmax ≥64.48 Gy had a significantly higher risk of RION (HR = 102.25; 95%CI, 24.86-420.59; P < 0.001). Age (>44 years) (HR = 2.234, 95% CI = 1.233-4.051, p = 0.008), advanced T stage (T3 vs. T1-2: HR = 7.516, 95% CI = 1.725-32.767, p=0.007; T4 vs. T1-2: HR = 37.189, 95% CI = 8.796-157.266, P < 0.001), and tumor infiltration/compression of the OC/ONs (HR = 4.572, 95% CI = 1.316-15.874, p=0.017) were significant clinical risk factors of RION. A nomogram comprising age, T stage, tumor infiltration/compression of the OC/ON, and Dmax significantly outperformed the model, with only Dmax predicting RION (C-index: 0.916 vs. 0.880, P < 0.001 in the training set; 0.899 vs. 0.874, P=0.038 in the test set). The nomogram-defined high-risk group had a worse 8-year RION-free survival. CONCLUSIONS: In the IMRT era, Dmax <60 Gy is safe and represents an acceptable dose constraint for most NPC patients receiving IMRT. A reasonable trade-off for selected patients with unsatisfactory tumor coverage due to proximity to the optic apparatus would be Dmax <65 Gy. Caution should be exercised when treating elderly and advanced T-stage patients or those with tumor infiltration/compression of the OC/ON. Our nomogram shows strong efficacy in predicting RION.

Perioperative Albumin Supplementation is Associated With Decreased Risk of Complications Following Microvascular Head and Neck Reconstruction.

PURPOSE: Studies have demonstrated that low serum albumin levels are associated with a high postoperative complication rate after microvascular free flap reconstruction. The aim of this study was to investigate whether perioperative albumin supplementation reduced the postoperative complications of microvascular free flap reconstruction in oral and maxillofacial tumor resections. PATIENTS AND METHODS: Patients who underwent microvascular free flap reconstruction during oral and maxillofacial tumor resections from January 2012 to December 2017 were enrolled in this retrospective study. The predictor variable was perioperative albumin supplementation. The primary outcome variables were surgery-associated postoperative complications, including local and systemic complications. The secondary outcome variables were the total duration of hospital stay, postoperative ICU admission rate, duration of ICU stay, and mortality during hospitalization. RESULTS: In total, 315 patients met the criteria. Patients with serum albumin supplementation showed a lower rate of surgery-associated local complications (6.5 vs 21.6%) with an adjusted odds ratio (OR) of 0.24 (95% confidence interval (CI), 0.12 to 0.49, P < .001). The average postoperative hospital stay was significantly shortened for patients with albumin supplementation (12.56 ± 4.23 vs 15.34 ± 5.24 days, P < .001). However, albumin supplementation had no effect on systemic complications. CONCLUSIONS: The results of this study suggest that perioperative albumin supplementation is associated with a decreased risk of local complications, shortened hospital stay, and decreased need for crystalloid infusion in patients who underwent oral and maxillofacial tumor resections with microvascular free flap reconstruction.

Intra-abdominal Pressure Has a Good Predictive Power for 28-Day Mortality: A Prospective Observational Study Conducted in Critically Ill Children.

Objective: Elevated intra-abdominal pressure (IAP) is associated with organ dysfunction in critically ill children. Thus far, the predictive value of IAP for mortality remains unknown. Moreover, only few studies determined normal IAP values in pediatric intensive care unit (PICU) children. This study aimed to determine the predictive value of IAP for mortality and calculate normal IAP values in PICU patients. Methods: This prospective observational study was conducted in two PICUs of two tertiary care university teaching hospitals. Patients admitted to the PICU between December 2013 and November 2015 were included. IAP was determined by bladder pressure measurements performed every 8 h until 48 h or until PICU discharge. All patients (except neonatal patients) aged ≤ 14 years who were admitted to the PICUs and had no history of chemical neuromuscular blockade use, neurogenic bladder, or bladder surgery were enrolled. Binary logistic regression was used to analyze the predictive value of IAP for 28-day mortality. Receiver operating characteristic curves were generated to evaluate the prediction effect of IAP. Results: Overall, 229 patients were enrolled. IAP (hazard ratio 1.09, 95% confidence interval [CI] 1.029-1.161, P = 0.004) and lactic acid (hazard ratio 3.04, 95% CI 1.769-5.21, P < 0.001) were independent predictors of 28-day mortality. Additionally, IAP had good predictive power for 28-day mortality, with an area under the curve of 0.74. The optimal cutoff point was 12.13 mmHg (sensitivity 0.58, specificity 0.80). The Youden index was 0.38.Furthermore, 111 (48.47%) patients without high-risk factors or clinical manifestations of IAH were analyzed to determine normal IAP values, which were 7.57 ± 2.85 mmHg (range, 1.98-13.16 mmHg). There were no significant differences in normal IAP values according to different diseases, sex, age, weight, or body mass index (BMI). Conclusions: IAP has good predictive power for 28-day mortality. The optimal IAP cutoff point is 12.13 mmHg. The IAP reference range is 2.0-13.2 mmHg, which was not associated with factors such as sex, age, weight, and BMI in PICU children. We recommend that IAP be included in critical illness scoring systems in the future. IAP >12.13 mmHg may be more suitable for IAH definition in PICU patients.

Evaluation of the effectiveness of a WHO-5A model based comprehensive tobacco control program among migrant workers in Guangdong, China: a pilot study.

BACKGROUND: As a vulnerable population in China, migrant workers have a higher smoking rate than the general population. This study aims to assess the effectiveness of a WHO-5A based comprehensive tobacco control program in workplaces aggregated with migrants. METHODS: Using a controlled before and after design, four purposely selected manufacturing factories were assigned to either intervention or control groups. Participants in the intervention arm received adapted 5A group counseling regularly supported by social-media and traditional health education approaches. The primary outcome was the change of smoking rate based on salivary cotinine concentration at three-month follow-up as compared to the control arm. Secondary outcomes were changes in smoking-related knowledge and attitudes assessed using questionnaires. Difference-in-differences approach (DID) and generalized estimating equations (GEE) models were used to conduct the effectiveness analysis. RESULTS: 149 and 166 workers were enrolled in the intervention and control arm respectively. The multiple imputed and adjusted GEE models demonstrated that, compared to those in the control arm, participants in the intervention arm had nearly 2.4 times odds of improving smoking-related knowledge (OR = 2.40, 95% CI = 1.32-4.36, P = 0.02) and three times the odds of improving smoking-related attitude (OR = 3.07, 95% CI = 1.28-7.41, P = 0.03). However, no significant difference was found regarding the change of smoking rate between the two arms (P > 0.05). The regression analysis showed that attendance at the 5A group counseling sections was an important determinant of stopping smoking or improving smoking-related knowledge and attitudes in the intervention group. CONCLUSIONS: This WHO-5A comprehensive intervention was effective in improving migrant workers' knowledge of smoking and anti-smoking attitudes. A large-scale, long-term trial is recommended to determine the effectiveness of this intervention. TRIAL REGISTRATION: ChiCTR-OPC-17011637 at Chinese Clinical Trial Registry. Retrospectively registered on 12th June 2017.