Immune-related lncRNA classification of head and neck squamous cell carcinoma

Background Long noncoding RNAs (lncRNAs) play a critical role in innate and adaptive immune responses. Thus, we aimed to identify ideal subtypes for head and neck squamous cell carcinoma (HNSCC) based on immune-related lncRNAs. Methods TCGA HNSCC cohort was divided into two datasets (training and validation dataset), and 960 previously characterized immune-related lncRNAs were extracted for non-negative matrix factorization analysis. We characterized our HNSCC subtypes based on biological behaviors, immune landscape and response to immunotherapy in both training and validation cohort. A lncRNA-signature was generated to predict our HNSCC subtypes, and essential lncRNAs involved in tumor microenvironment (TME) were identified. Results We developed and validated two HNSCC subtypes (C1 and C2) based on the 70 lncRNAs in the training and validation cohort. C2 subtype displayed good prognosis, high immune cell infiltration, immune-related genes expression and sensitivity to PD-1 blockade. C1 subtype was associated with high activity of mTORC1 signaling and glycolysis as well as high fraction of inactive immune cells. Finally, we generated a 31-lncRNA signature that could predict our above subtypes with high accurate. Additionally, TRG-AS1 was identified as the essential lncRNA involving TME formation. Knockdown of TRG-AS1 inhibited the expression of HLA-A, HLA-B, HLA-C, CXCL9, CXCL10 and CXCL11. High expression of TRG-AS1 indicated a favorable prognosis in HNSCC and anti-PD-L1 cohort (IMvigor210). Conclusions Our study establishes a novel HNSCC classification on the basis of 31-lncRNA, helping to identify beneficiaries for anti-PD-1 treatment. In addition, a critical lncRNA TRG-AS1 is identified as a new potential prognosis biomarker as well as therapeutic target.

Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma

Background Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC). Methods Differentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples. Results Based on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml−1) from high risk population (AUC=0.93; 95% CI 0.892–0.969). Conclusions We have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort. Trial registration The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(#NCT04383353).

Consolidation Tumor Ratio Combined With Pathological Features Could Predict Status of Lymph Nodes of Early-Stage Lung Adenocarcinoma

IntroductionStage IA lung adenocarcinoma manifested as part-solid nodules (PSNs), has attracted immense attention owing to its unique characteristics and the definition of its invasiveness remains unclear. We sought to develop a nomogram for predicting the status of lymph nodes of this kind of nodules.MethodsA total of 2,504 patients between September 2018 to October 2020 with part-solid nodules in our center were reviewed. Their histopathological features were extracted from paraffin sections, whereas frozen sections were reviewed to confirm the consistency of frozen sections and paraffin sections. Univariate and multivariate logistic regression analyses and Akaike information criterion (AIC) variable selection were performed to assess the risk factors of lymph node metastasis and construct the nomogram. The nomogram was subjected to bootstrap internal validation and external validation. The concordance index (C-index) was applied to evaluate the predictive accuracy and discriminative ability.ResultsWe enrolled 215 and 161 eligible patients in the training cohort and validation cohort, respectively. The sensitivity between frozen and paraffin sections on the presence of micropapillary/solid subtype was 78.4%. Multivariable analysis demonstrated that MVI, the presence of micropapillary/solid subtype, and CTR &gt;0.61 were independently associated with lymph node metastasis (p &lt; 0.01). Five risk factors were integrated into the nomogram. The nomogram demonstrated good accuracy in estimating the risk of lymph node metastasis, with a C-index of 0.945 (95% CI: 0.916–0.974) in the training cohort and a C-index of 0.975 (95% CI: 0.954–0.995) in the validation cohort. The model’s calibration was excellent in both cohorts.ConclusionThe nomogram established showed excellent discrimination and calibration and could predict the status of lymph nodes for patients with ≤3 cm PSNs. Also, this prediction model has the prediction potential before the end of surgery.

Derivation and External Validation of a Simple Prediction Rule for the Development of Respiratory Failure in Hospitalized Patients With Influenza

BACKGROUND: Influenza viruses cause seasonal epidemics worldwide with a significant morbimortality burden. Clinical spectrum of Influenza is wide, being respiratory failure (RF) one of its most severe complications. This study aims to elaborate a clinical prediction rule of RF in hospitalized Influenza patients.METHODS: a prospective cohort study was conducted during two consecutive Influenza seasons (December 2016 - March 2017 and December 2017 - April 2018) including hospitalized adults with confirmed A or B Influenza infection. A prediction rule was derived using logistic regression and recursive partitioning, followed by internal cross-validation. External validation was performed on a retrospective cohort in a different hospital between December 2018 - May 2019. RESULTS: Overall, 707 patients were included in the derivation cohort and 285 in the validation cohort. RF rate was 6.8% and 11.6%, respectively. Chronic obstructive pulmonary disease, immunosuppression, radiological abnormalities, respiratory rate, lymphopenia, lactate dehydrogenase and C-reactive protein at admission were associated with RF. A four category-grouped seven point-score was derived including radiological abnormalities, lymphopenia, respiratory rate and lactate dehydrogenase. Final model area under the curve was 0.796 (0.714-0.877) in the derivation cohort and 0.773 (0.687-0.859) in the validation cohort (p<0.001 in both cases). The predicted model showed an adequate fit with the observed results (Fisher’s test p>0.43). CONCLUSION: we present a simple, discriminating, well-calibrated rule for an early prediction of the development of RF in hospitalized Influenza patients, with proper performance in an external validation cohort. This tool can be helpful in patient´s stratification during seasonal Influenza epidemics.

Simple risk scores to predict hospitalization or death in outpatients with COVID-19

Importance Outpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them. Objective To develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging. Design Derivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules. Setting Primary and Express care clinics in a Pennsylvania health system. Participants Patients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19. Main outcomes and measures Classification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC). Results Overall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%). Conclusions and relevance Simple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/.

Prediction of distant metastasis of spinal and pelvic osteosarcoma by constructing and validating nomogram:a retrospective study based on SEER database

Background:Spinal and pelvic osteosarcoma is a rare type of all osteosarcomas,and distant metastasis is an important factor for poor prognosis of this disease. There are no similar studies on prediction of distant metastasis of spinal and pelvic osteosarcoma. We aim to construct and validate a nomogram to predict the risk of distant metastasis of spinal and pelvic osteosarcoma.Methods:We collected the data on patients with spinal and pelvic osteosarcoma from the Surveillance, Epidemiology, and End Results(SEER) database retrospectively. The Kaplan-Meier curve was used to compare differences in survival time between patients with metastasis and non-metastasis. Total patients were randomly divided into training cohort and validation cohort. The risk factor of distant metastasis were identified via the least absolute shrinkage and selection operator(LASSO) regression and multivariate logistic analysis. The nomogram we constructed were validated internally and externally by C-index, calibration curves,receiver operating characteristic(ROC) curve and Decision curve analysis (DCA).Results:The Kaplan-Meier curve showed that the survival time of non-metastatic patients was longer than that of metastatic patients(P＜0.001).All patients(n=358) were divided into training cohort(n=269) and validation cohort(n=89).The LASSO regression selected five meaningful variables in the training cohort. The multivariate logistic regression analysis demonstrated that surgery(yes,OR=0.175, 95%CI=0.095-0.321,p=0.000) was the independent risk factors for distant metastasis of patients with spinal and pelvic osteosarcoma. The C-index and calibration curves showed the good agreement between the predicted results and the actual results. The area under the receiver operating characteristic curve(AUC) values were 0.748(95%CI=0.687-0.817) and 0.758(95%CI=0.631-0.868) in the training and validation cohorts respectively. The DCA showed that the nomogram has a good clinical usefulness and net benefit.Conclusion:No surgery is the independent risk factor of distant metastasis of spinal and pelvic osteosarcoma. The nomogram we constructed to predict the probability of distant metastasis of patients with spinal and pelvic osteosarcoma is reliable and effective by internal and external verification.

Single HER2-positive tumor cells are detected in initially HER2-negative breast carcinomas using the DEPArray™–HER2-FISH workflow

Background In breast cancer (BC), overexpression of HER2 on the primary tumor (PT) is determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to stratify samples as negative, equivocal and positive to identify patients (pts) for anti-HER2 therapy. CAP/ASCO guidelines recommend FISH for analyzing HER2/neu (ERBB2) gene amplification and for resolving equivocal HER2 IHC results. However, pre-analytical and analytical aspects are often confounded by sample related limitations and tumor heterogeneity and HER2 expression may differ between the PT and circulating tumor cells (CTCs), the precursors of metastasis. We used a validation cohort of BC patients to establish a new DEPArray™-PT-HER2-FISH workflow for further application in a development cohort, characterized as PT-HER2-negative but CTC-HER2/neu-positive, to identify patients with PT-HER2 amplified cells not detected by routine pathology. Methods 50 µm FFPE tumor curls from the validation cohort (n = 49) and the development cohort (n = 25) underwent cutting, deparaffinization and antigen retrieval followed by dissociation into a single-cell suspension. After staining for cytokeratin, vimentin, DAPI and separation via DEPArray™, single cells were processed for HER2-FISH analysis to assess the number of chromosome 17 and HER2 loci signals for comparison, either with available IHC or conventional tissue section FISH. CTC-HER2/neu status was determined using the AdnaTest BreastCancer (QIAGEN, Hilden, Germany). Results Applying CAP/ASCO guidelines for HER2 evaluation of single PT cells, the comparison of routine pathology and DEPArray™-HER2-FISH analysis resulted in a concordance rate of 81.6% (40/49 pts) in the validation cohort and 84% (21/25 pts) in the development cohort, respectively. In the latter one, 4/25 patients had single HER2-positive tumor cells with 2/25 BC patients proven to be HER2-positive, despite being HER2-negative in routine pathology. The two other patients showed an equivocal HER2 status in the DEPArray™-HER2-FISH workflow but a negative result in routine pathology. Whereas all four patients with discordant HER2 results had already died, 17/21 patients with concordant HER2 results are still alive. Conclusions The DEPArray™ system allows pure tumor cell recovery for subsequent HER2/neu FISH analysis and is highly concordant with conventional pathology. For PT-HER2-negative patients, harboring HER2/neu-positive CTCs, this approach might allow caregivers to more effectively offer anti-HER2 treatment.

A Web-Based Prediction Model for Cancer-Specific Survival of Elderly Patients With Early Hepatocellular Carcinoma: A Study Based on SEER Database

Background: Primary liver cancer is a common malignant tumor primarily represented by hepatocellular carcinoma (HCC). The number of elderly patients with early HCC is increasing, and older age is related to a worse prognosis. However, an accurate predictive model for the prognosis of these patients is still lacking.Methods: Data of eligible elderly patients with early HCC in Surveillance, Epidemiology, and End Results database from 2010 to 2016 were downloaded. Patients from 2010 to 2015 were randomly assigned to the training cohort (n = 1093) and validation cohort (n = 461). Patients' data in 2016 (n = 431) was used for external validation. Independent prognostic factors were obtained using univariate and multivariate analyses. Based on these factors, a cancer-specific survival (CSS) nomogram was constructed. The predictive performance and clinical practicability of our nomogram were validated. According to the risk scores of our nomogram, patients were divided into low-, intermediate-, and high-risk groups. A survival analysis was performed using Kaplan–Meier curves and log-rank tests.Results: Age, race, T stage, histological grade, surgery, radiotherapy, and chemotherapy were independent predictors for CSS and thus were included in our nomogram. In the training cohort and validation cohort, the concordance indices (C-indices) of our nomogram were 0.739 (95% CI: 0.714–0.764) and 0.756 (95% CI: 0.719–0.793), respectively. The 1-, 3-, and 5-year areas under receiver operating characteristic curves (AUCs) showed similar results. Calibration curves revealed high consistency between observations and predictions. In external validation cohort, C-index (0.802, 95%CI: 0.778–0.826) and calibration curves also revealed high consistency between observations and predictions. Compared with the TNM stage, nomogram-related decision curve analysis (DCA) curves indicated better clinical practicability. Kaplan–Meier curves revealed that CSS significantly differed among the three different risk groups. In addition, an online prediction tool for CSS was developed.Conclusions: A web-based prediction model for CSS of elderly patients with early HCC was constructed and validated, and it may be helpful for the prognostic evaluation, therapeutic strategy selection, and follow-up management of these patients.

A Predictive Model of Live Birth Based on Obesity and Metabolic Parameters in Patients With PCOS Undergoing Frozen-Thawed Embryo Transfer

AimsTo determine the clinical predictors of live birth in women with polycystic ovary syndrome (PCOS) undergoing frozen-thawed embryo transfer (F-ET), and to determine whether these parameters can be used to develop a clinical nomogram model capable of predicting live birth outcomes for these women.MethodsIn total, 1158 PCOS patients that were clinically pregnant following F-ET treatment were retrospectively enrolled in this study and randomly divided into the training cohort (n = 928) and the validation cohort (n = 230) at an 8:2 ratio. Relevant risk factors were selected via a logistic regression analysis approach based on the data from patients in the training cohort, and odds ratios (ORs) were calculated. A nomogram was constructed based on relevant risk factors, and its performance was assessed based on its calibration and discriminative ability.ResultsIn total, 20 variables were analyzed in the present study, of which five were found to be independently associated with the odds of live birth in univariate and multivariate logistic regression analyses, including advanced age, obesity, total cholesterol (TC), triglycerides (TG), and insulin resistance (IR). Having advanced age (OR:0.499, 95% confidence interval [CI]: 0.257 – 967), being obese (OR:0.506, 95% CI: 0.306 - 0.837), having higher TC levels (OR: 0.528, 95% CI: 0.423 - 0.660), having higher TG levels (OR: 0.585, 95% CI: 0.465 - 737), and exhibiting IR (OR:0.611, 95% CI: 0.416 - 0.896) were all independently associated with a reduced chance of achieving a live birth. A predictive nomogram incorporating these five variables was found to be well-calibrated and to exhibit good discriminatory capabilities, with an area under the curve (AUC) for the training group of 0.750 (95% CI, 0.709 - 0.788). In the independent validation cohort, this model also exhibited satisfactory goodness-of-fit and discriminative capabilities, with an AUC of 0.708 (95% CI, 0.615 - 0.781).ConclusionsThe nomogram developed in this study may be of value as a tool for predicting the odds of live birth for PCOS patients undergoing F-ET, and has the potential to improve the efficiency of pre-transfer management.

MR-based radiomics-clinical nomogram in epithelial ovarian tumor prognosis prediction: tumor body texture analysis across various acquisition protocols

Background Epithelial ovarian cancer (EOC) is the most malignant gynecological tumor in women. This study aimed to construct and compare radiomics-clinical nomograms based on MR images in EOC prognosis prediction. Methods A total of 186 patients with pathologically proven EOC were enrolled and randomly divided into a training cohort (n = 130) and a validation cohort (n = 56). Clinical characteristics of each patient were retrieved from the hospital information system. A total of 1116 radiomics features were extracted from tumor body on T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), diffusion weighted imaging (DWI) and contrast-enhanced T1-weighted imaging (CE-T1WI). Paired sequence signatures were constructed, selected and trained to build a prognosis prediction model. Radiomic-clinical nomogram was constructed based on multivariate logistic regression analysis with radiomics score and clinical features. The predictive performance was evaluated by receiver operating characteristic curve (ROC) analysis, decision curve analysis (DCA) and calibration curve. Results The T2WI radiomic-clinical nomogram achieved a favorable prediction performance in the training and validation cohort with an area under ROC curve (AUC) of 0.866 and 0.818, respectively. The DCA showed that the T2WI radiomic-clinical nomogram was better than other models with a greater clinical net benefit. Conclusion MR-based radiomics analysis showed the high accuracy in prognostic estimation of EOC patients and could help to predict therapeutic outcome before treatment.