Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use.

Introduction: Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods: The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2-ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results: In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67-0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion: The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.

MicroRNAs predict early complications of autologous hematopoietic stem cell transplantation.

Autologous hematopoietic stem cell transplantation (AHSCT) remains the most prevalent type of stem cell transplantation. In our study, we investigated the changes in circulating miRNAs in AHSCT recipients and their potential to predict early procedure-related complications. We collected serum samples from 77 patients, including 54 with multiple myeloma, at four key time points: before AHSCT, on the day of transplantation (day 0), and at days + 7 and + 14 post-transplantation. Through serum miRNA-seq analysis, we identified altered expression patterns and miRNAs associated with the AHSCT procedure. Validation using qPCR confirmed deviations in the levels of miRNAs at the beginning of the procedure in patients who subsequently developed bacteremia: hsa-miR-223-3p and hsa-miR-15b-5p exhibited decreased expression, while hsa-miR-126-5p had increased level. Then, a neural network model was constructed to use miRNA levels for the prediction of bacteremia. The model achieved an accuracy of 93.33% (95%CI: 68.05-99.83%), with a sensitivity of 100% (95%CI: 67.81-100.00%) and specificity of 90.91% (95%CI: 58.72-99.77%) in predicting bacteremia with mean of 6.5 ± 3.2 days before occurrence. In addition, we showed unique patterns of miRNA expression in patients experiencing platelet engraftment delay which involved the downregulation of hsa-let-7f-5p and upregulation of hsa-miR-96-5p; and neutrophil engraftment delay which was associated with decreased levels of hsa-miR-125a-5p and hsa-miR-15b-5p. Our findings highlight the significant alterations in serum miRNA levels during AHSCT and suggest the clinical utility of miRNA expression patterns as potential biomarkers that could be harnessed to improve patient outcomes, particularly by predicting the risk of bacteremia during AHSCT.

Circulating serum microRNAs as biomarkers of drug resistance in multiple myeloma patients treated with bortezomib-based regimens - pilot study.

Despite advances in multiple myeloma (MM) treatment, drug resistance remains a clinical challenge. We aimed to develop a prognostic model for bortezomib resistance based on miRNA expression profiling. The study included 40 previously untreated MM patients receiving bortezomib-based regimens (20 treatment-sensitive, 20 resistant). Pretreatment venous blood samples were analyzed for miRNA expression. Differential expression analysis revealed upregulated miR-27b-3p (FC 1.45, p = 0.017) and let-7b-5p (FC 1.44, p = 0.025) in the resistant group. Univariate analysis identified let-7b-5p (OR 3.17, 95%CI: 1.19-11.4, p = 0.04) and miR-27b-3p (OR 4.73, 95%CI: 1.4-26.6, p = 0.036) as risk factors for resistance. The final multivariate model included miR-27b-3p (OR 23.1, 95% CI: 2.8-452, p = 0.015), let-7b-5p (OR 4.38, 95% CI: 1.28-22.2, p = 0.038), and miR-103a-3p (OR 15.3, 95% CI: 1.33-351, p = 0.049). These miRNAs may serve as biomarkers of treatment response in MM. However, external validation is necessary to confirm the clinical utility of our model.

Extreme acute radiation-induced toxicity in a patient with polymorphous low-grade adenocarcinoma of the nasopharynx and rare variants in DNA repair genes.

BACKGROUND: Polymorphous low-grade adenocarcinoma (PLGA) is an extremely rare finding in the nasopharynx. There are no guidelines for the treatment of PLGA in this localization. Radiotherapy may be administered to treat this malignancy; however, in radiosensitive individuals, it is associated with a risk of severe radiotherapy-induced toxicity. METHODS: We present a case of a 73-year-old woman with locally advanced polymorphous low-grade adenocarcinoma of the nasopharynx who developed a severe adverse acute reaction to radiotherapy leading to treatment discontinuation. Despite intensive treatment, the patient died 40 days after RT initiation. Whole genome sequencing was performed using DNA from peripheral blood mononuclear cells in the search for variants that could explain such extreme toxicity. RESULTS: We identified a combination of pathogenic variants that may have contributed to the patient's reaction to radiation therapy, including predisposing variants in XRCC1, XRCC3, and LIG4. We also identified candidate variants, not previously described in this context, which could be associated with radiation toxicity based on plausible mechanisms. We discuss previous reports of this rare tumor from the literature and known contributors to radiation-induced toxicity. CONCLUSIONS: Genetic causes should be considered in cases of extreme radiosensitivity, especially when is not explained by clinical factors.

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer.

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.

High-Speed Videoendoscopy Enhances the Objective Assessment of Glottic Organic Lesions: A Case-Control Study with Multivariable Data-Mining Model Development.

The aim of the study was to utilize a quantitative assessment of the vibratory characteristics of vocal folds in diagnosing benign and malignant lesions of the glottis using high-speed videolaryngoscopy (HSV). METHODS: Case-control study including 100 patients with unilateral vocal fold lesions in comparison to 38 normophonic subjects. Quantitative assessment with the determination of vocal fold oscillation parameters was performed based on HSV kymography. Machine-learning predictive models were developed and validated. RESULTS: All calculated parameters differed significantly between healthy subjects and patients with organic lesions. The first predictive model distinguishing any organic lesion patients from healthy subjects reached an area under the curve (AUC) equal to 0.983 and presented with 89.3% accuracy, 97.0% sensitivity, and 71.4% specificity on the testing set. The second model identifying malignancy among organic lesions reached an AUC equal to 0.85 and presented with 80.6% accuracy, 100% sensitivity, and 71.1% specificity on the training set. Important predictive factors for the models were frequency perturbation measures. CONCLUSIONS: The standard protocol for distinguishing between benign and malignant lesions continues to be clinical evaluation by an experienced ENT specialist and confirmed by histopathological examination. Our findings did suggest that advanced machine learning models, which consider the complex interactions present in HSV data, could potentially indicate a heightened risk of malignancy. Therefore, this technology could prove pivotal in aiding in early cancer detection, thereby emphasizing the need for further investigation and validation.

Serum miRNA-based signature indicates radiation exposure and dose in humans: A multicenter diagnostic biomarker study.

PURPOSE: Mouse and non-human primate models showed that serum miRNAs may be used to predict the biological impact of radiation doses. We hypothesized that these results can be translated to humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters. METHODS: To test this hypothesis, serial serum samples were obtained from 25 patients (pediatric and adults) who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. miRNAs with diagnostic potential were quantified with qPCR and used to build logistic regression models with lasso penalty to reduce overfitting, identifying samples drawn from patients who underwent total body irradiation to a potentially lethal dose. RESULTS: Differential expression results were consistent with previous studies in mice and non-human primates. miRNAs with detectable expression in this and two prior animal sets allowed for distinction of the irradiated from non-irradiated samples in mice, macaques and humans, validating the miRNAs as radiation-responsive through evolutionarily conserved transcriptional regulation mechanisms. Finally, we created a model based on the expression of miR-150-5p, miR-30b-5p and miR-320c normalized to two references and adjusted for patient age with an AUC of 0.9 (95%CI:0.83-0.97) for identifying samples drawn after irradiation; a separate model differentiating between high and low radiation dose achieved AUC of 0.85 (95%CI: 0.74-0.96). CONCLUSIONS: We conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.

Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles.

Identifying germline BRCA1/2 mutation carriers is vital for reducing their risk of breast and ovarian cancer. To derive a serum miRNA-based diagnostic test we used samples from 653 healthy women from six international cohorts, including 350 (53.6%) with BRCA1/2 mutations and 303 (46.4%) BRCA1/2 wild-type. All individuals were cancer-free before and at least 12 months after sampling. RNA-sequencing followed by differential expression analysis identified 19 miRNAs significantly associated with BRCA mutations, 10 of which were ultimately used for classification: hsa-miR-20b-5p, hsa-miR-19b-3p, hsa-let-7b-5p, hsa-miR-320b, hsa-miR-139-3p, hsa-miR-30d-5p, hsa-miR-17-5p, hsa-miR-182-5p, hsa-miR-421, hsa-miR-375-3p. The final logistic regression model achieved area under the receiver operating characteristic curve 0.89 (95% CI: 0.87-0.93), 93.88% sensitivity and 80.72% specificity in an independent validation cohort. Mutated gene, menopausal status or having preemptive oophorectomy did not affect classification performance. Circulating microRNAs may be used to identify BRCA1/2 mutations in patients of high risk of cancer, offering an opportunity to reduce screening costs.

Brachytherapy boost improves survival and decreases risk of developing distant metastases compared to external beam radiotherapy alone in intermediate and high risk group prostate cancer patients.

BACKGROUND AND PURPOSE: Despite several prospective trials showing a clinical benefit of combining external beam radiotherapy (EBRT) with brachytherapy boost (BTB) for the treatment of intermediate- and high-risk prostate cancer (PCa) patients, none of these trials was designed to test for a survival difference. In this study, we aimed to collect a large multi-institutional database to determine whether BT boost was associated with a statistically significant improvement in survival and a reduction of distant metastases based on real-world data. MATERIAL AND METHODS: We collected the data of patients treated for intermediate- or high-risk PCa with definitive EBRT or BTB, with or without androgen deprivation therapy (ADT), between January 2003 and December 2014 at two tertiary institutions. The statistical endpoints included overall survival (OS), freedom from distant metastases (FFDM), and metastases-free survival (MFS). The impact of treatment modality was assessed using Cox regression models and log-rank testing after one-to-one propensity score matching. RESULTS: A total of 1641 patients treated with EBRT (n = 1148) or high-dose-rate BTB (n = 493) were analyzed. The median survival and clinical follow-up were 117.8 (IQR 78-143.3) and 60.7 months, respectively. The radiotherapy modality (BTB) remained an independent prognostic factor for OS (HR 0.75; 95% CI 0.63-0.88; p < 0.001), FFDM (HR 0.54; 95% CI 0.4-0.73; p < 0.001), and MFS (HR 0.72; 95% CI 0.61-0.85; p < 0.001). After propensity score matching, the remaining 986 patients were well-balanced in terms of age, maximum PSA, ISUP grade group, and TNM T stage. OS (p < 0.001), FFDM (p = 0.001) and MFS (p < 0.001) were significantly higher in the BTB group. CONCLUSIONS: There is a strong positive association between BTB and OS, FFDM, and MFS in PCa patients treated with definitive RT for intermediate- or high-risk PCa.

The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy.

The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient's immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman's ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.

Cytokine TGFß Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development).

Introduction: TGF-ß and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-ß1, TGF-ß2, and TGF-ß3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-ß SNPs are associated with the elevated plasma level of TGF-ß1, an increased level of total IgE, and an increased risk of remodeling of bronchi. Methods: The analysis of selected TGF-ß1, TGF-ß2, TGF-ß3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong's test. Results: Minor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity. Discussion: Derived predictive models suggest the analysis of selected SNPs in TGF-ß genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer.

We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)-mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)-positive (ER+) breast cancer (BCa) cell lines to anti-ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR-dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2-promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER-PR complexes; and (d) reversed P4-triggered deregulation of ER-dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression-free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), an ER-dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2-mediated abrogation of P4-induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2-JunB axis abolishes the modulatory effects of PR on ER-associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR-targeting therapeutic strategies.

A Translational Model to Improve Early Detection of Epithelial Ovarian Cancers.

Neural network analyses of circulating miRNAs have shown potential as non-invasive screening tests for ovarian cancer. A clinically useful test would detect occult disease when complete cytoreduction is most feasible. Here we used murine xenografts to sensitize a neural network model to detect low volume disease and applied the model to sera from 75 early-stage ovarian cancer cases age-matched to 200 benign adnexal masses or healthy controls. The 14-miRNA model efficiently discriminated tumor bearing animals from controls with 100% sensitivity down to tumor inoculums of 50,000 cells. Among early-stage patient samples, the model performed well with 73% sensitivity at 91% specificity. Applied to a population with 1% disease prevalence, we hypothesize the model would detect most early-stage ovarian cancers while maintaining a negative predictive value of 99.97% (95% CI 99.95%-99.98%). Overall, this supports the concept that miRNAs may be useful as screening markers for early-stage disease.

The Prognostic Value of PI-RADS Score in CyberKnife Ultra-Hypofractionated Radiotherapy for Localized Prostate Cancer.

Prostate Imaging-Reporting and Data System (PI-RADS) has been widely implemented as a diagnostic tool for significant prostate cancer (PCa); less is known about its prognostic value, especially in the setting of primary radiotherapy. We aimed to analyze the association between PI-RADS v. 2.1 classification and risk of metastases, based on a group of 152 patients treated with ultra-hypofractionated stereotactic CyberKnife radiotherapy for localized low or intermediate risk-group prostate cancer. We found that all distant failures (n = 5) occurred in patients diagnosed with a PI-RADS score of 5, and axial measurements of the target lesion were associated with the risk of developing metastases (p < 0.001). The best risk stratification model (based on a combination of greatest dimension, the product of multiplication of PI-RADS target lesion axial measurements, and age) achieved a c-index of 0.903 (bootstrap-validated bias-corrected 95% CI: 0.848−0.901). This creates a hypothesis that PI-RADS 5 and the size of the target lesion are important prognostic factors in early-stage PCa patients and should be considered as an adverse prognostic measure for patients undergoing early treatment such as radiation or focal therapy.

Clinical significance of CD34, podoplanin and Ki-67 expression in patients with locally advanced squamous cell cervical carcinoma.

The aim of the study was to assess immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with cervical squamous cell carcinoma (SCC) staged IIB and IIIB, a relationship with selected clinical and histological parameters and its prognostic significance. This prospective study included 52 patients. Microvessel density (MVD) by CD34, lymphatic vessel density (LVD) by podoplanin and the Ki-67 index in specimens from paraffin blocks with cervical SCC tissues were examined. The relationship between these data and selected clinical and histological parameters was analysed. Positive correlation of MVD and the Ki-67 index was observed. No correlation was observed for MVD, LVD and the Ki-67 index in the tumour with staging, grading, length of treatment and squamous cell carcinoma antigen (SCC-Ag) concentration before and after treatment. The expression of MVD, LVD and the Ki-67 index in cervical SCC did not contribute to the risk of relapse and cancer-related death. No relationship was found for MVD, LVD and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum SCC-Ag level. MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death.Impact StatementWhat is already known on this subject? In many patients, invasive cervical squamous cell carcinoma (SCC) is diagnosed in a locally advanced stage, when the prognosis depends on many well-known factors connected with tumour biology, staging and general condition of the patient. Despite numerous studies, the value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of these patients is still not well defined.What do the results of this study add? In our prospective study, no relationship for microvessel density (MVD), lymphatic vessel density (LVD) and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum squamous cell carcinoma antigen (SCC-Ag) level was found. Additionally, MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death.What are the implications of these findings for clinical practice and/or further research? Our study underlines the limited value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with locally advanced cervical SCC. Further research should be focussed on identifying and validating novel prognostic and predictive factors.

Validation of the Elderly Traumatic Brain Injury Score: Observational Case Control Study.

BACKGROUND: Traumatic brain injury (TBI) poses a particular health risk for the elderly. The recently developed elderly TBI (eTBI) score combines the prognostic information of the risk factors characteristic of the geriatric population. We aimed to determine its validity and reliability on an independent sample. METHODS: We present a retrospective analysis of 506 consecutive patients after TBI aged ≥65 years. The previously described nomogram and the eTBI score were used. The primary outcome measure was mortality or vegetative state at 30 days after hospital admission. RESULTS: Mortality or vegetative state rate was 21.3%. The nomogram and eTBI Score showed similar predictive performance with accuracy of 83.8% (95% confidence interval 80.2%-87%) and 84.4% (95% confidence interval 80.8%-87.6%), respectively. On the basis of the Youden index and C4.5 algorithm, we divided patients according to the 3-tier pattern into low-, high-, and medium-risk groups. The outcome prediction in the first 2 groups was correct in 93.1% (survival in the low-risk group) and 94.4% (mortality in the high-risk group). Patients included in the medium-risk group usually required surgical treatment (85.3%) and were characterized by increased mortality or vegetative state (55%). Among patients with eTBI ≥5 (n = 221), there was no difference in outcome between those treated conservatively and surgically. CONCLUSIONS: This is the first study confirming the validity of the eTBI Score and its close association with outcome of geriatric population after TBI. The novel 3-tier risk stratification scheme was applicable to both conservatively and surgically treated patients.

Plasma Amino Acids May Improve Prediction Accuracy of Cerebral Vasospasm after Aneurysmal Subarachnoid Haemorrhage.

Aneurysmal subarachnoid haemorrhages (aSAH) account for 5% of strokes and continues to place a great burden on patients and their families. Cerebral vasospasm (CVS) is one of the main causes of death after aSAH, and is usually diagnosed between day 3 and 14 after bleeding. Its pathogenesis remains poorly understood. To verify whether plasma concentration of amino acids have prognostic value in predicting CVS, we analysed data from 35 patients after aSAH (median age 55 years, IQR 39-62; 20 females, 57.1%), and 37 healthy volunteers (median age 50 years, IQR 38-56; 19 females, 51.4%). Fasting peripheral blood samples were collected on postoperative day one and seven. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis was performed. The results showed that plasma from patients after aSAH featured a distinctive amino acids concentration which was presented in both principal component analysis and direct comparison. No significant differences were noted between postoperative day one and seven. A total of 18 patients from the study group (51.4%) developed CVS. Hydroxyproline (AUC = 0.7042, 95%CI 0.5259-0.8826, p = 0.0248) and phenylalanine (AUC = 0.6944, 95%CI 0.5119-0.877, p = 0.0368) presented significant CVS prediction potential. Combining the Hunt-Hess Scale and plasma levels of hydroxyproline and phenylalanine provided the model with the best predictive performance and the lowest leave-one-out cross-validation of performance error. Our results suggest that plasma amino acids may improve sensitivity and specificity of Hunt-Hess scale in predicting CVS.

The clinician's guide to radiotherapy complications.

Radiotherapy is one of the oldest cancer treatment modalities, used for over 100 years. As its efficacy has been steadily increasing due to the introduction of novel treatment methods, adverse events (AEs) still pose a major obstacle limiting the therapeutic benefits in some patients and negatively impacting treatment outcomes. In light of the technological progress, the focus has been shifted from improving the efficacy to safeguarding patients from the most severe AEs through improvements of safety and accuracy of radiation delivery. Currently, with radiation therapy being an effective treatment associated with frequent therapeutic success and leading to increased and prolonged survival, the problem of treatment­related AEs is growing as there are numerous survivors whose health and quality of life may be adversely affected. Due to the limited access to radiation oncologists, patients presenting with AEs are often referred to other professionals for advice, and as survivorship prolongs, the AEs may aggravate current patient comorbidities or reveal undiagnosed diseases. Thus, it is important that doctors other than oncologists be familiar with the fundamentals of radiation therapy-related AEs and their management. In this review, we present the most common and severe AEs of radiotherapy associated with damage to the nervous, respiratory, cardiovascular, gastrointestinal, and urogenital systems. We also describe the pathogenesis of these AEs, and provide guidelines for prevention, risk assessment, diagnosis, and treatment. Novel findings and future perspectives in this field are also elucidated, including examples of ongoing clinical trials aimed not only at improving treatment outcomes but also at reducing the risk of radiotherapy complications in cancer treatment survivors.

Volumetric staging in radiotherapy for oropharyngeal cancers.

INTRODUCTION: Despite routine use of 3D radiotherapy planning in radical radio(chemo)therapy for oropharyngeal cancers, volumetric data have not been implemented in initial staging. We analyzed 228 oropharyngeal cancer cases treated at one institution between 2004 and 2014 to compare the predictive value of volumetric staging and tumor nodal metastasis staging system (TNM) and determine whether they could be complementary for the estimation of survival. METHODS: This retrospective study analyzed 228 consecutive oropharyngeal cancer cases treated with radiotherapy (76.9%) or concurrent radiochemotherapy (23.1%) between 2004 and 2014. The volumetric parameters included primary gross tumor volume (pGTV), metastatic lymph nodes gross tumor volume (nGTV), and total gross tumor volume (tGTV), and were compared with the 7th edition of the TNM staging system. RESULTS: Median overall survival (OS) was 30.3 months. In the receiver operating characteristic analysis, tGTV had the highest area under the curve (AUC) of 0.66, followed by pGTV (AUC,0.64), nGTV (AUC 0.62), and TNM (AUC 0.6). The median OS for patients with tGTV ⩽32.2 mL was 40.5 months, compared to 15.4 months for >32.2 mL (p < 0.001). This threshold allowed for a statistically significant difference in survival between TNM stage IV cases with low and high tumor volume (p < 0.001). Despite both TNM and tGTV reaching statistical significance in univariate analysis, only the tGTV remained an independent prognostic factor in the multivariate analysis (hazard ratio 1.07, confidence interval 1.02-1.12, p = 0.008). CONCLUSIONS: tGTV is an independent prognostic factor, characterized by a higher discriminatory value than the TNM staging system, and can be used to further divide stage IV cases into subgroups with significantly different prognosis.

Deep Learning-based Recalibration of the CUETO and EORTC Prediction Tools for Recurrence and Progression of Non-muscle-invasive Bladder Cancer.

Despite being standard tools for decision-making, the European Organisation for Research and Treatment of Cancer (EORTC), European Association of Urology (EAU), and Club Urologico Espanol de Tratamiento Oncologico (CUETO) risk groups provide moderate performance in predicting recurrence-free survival (RFS) and progression-free survival (PFS) in non-muscle-invasive bladder cancer (NMIBC). In this retrospective combined-cohort data-mining study, the training group consisted of 3570 patients with de novo diagnosed NMIBC. Predictors included gender, age, T stage, histopathological grading, tumor burden and diameter, EORTC and CUETO scores, and type of intravesical treatment. The models developed were externally validated using an independent cohort of 322 patients. Models were trained using Cox proportional-hazards deep neural networks (deep learning; DeepSurv) with a proprietary grid search of hyperparameters. For patients treated with surgery and bacillus Calmette-Guérin-treated patients, the models achieved a c index of 0.650 (95% confidence interval [CI] 0.649-0.650) for RFS and 0.878 (95% CI 0.873-0.874) for PFS in the training group. In the validation group, the c index was 0.651 (95% CI 0.648-0.654) for RFS and 0.881 (95% CI 0.878-0.885) for PFS. After inclusion of patients treated with mitomycin C, the c index for RFS models was 0.6415 (95% CI 0.6412-0.6417) for the training group and 0.660 (95% CI 0.657-0.664) for the validation group. Models for PFS achieved a c index of 0.885 (95% CI 0.885-0.885) for the training set and 0.876 (95% CI 0.873-0.880) for the validation set. Our tool outperformed standard-of-care risk stratification tools and showed no evidence of overfitting. The application is open source and available at https://biostat.umed.pl/deepNMIBC/. PATIENT SUMMARY: We created and validated a new tool to predict recurrence and progression of early-stage bladder cancer. The application uses advanced artificial intelligence to combine state-of-the-art scales, outperforms these scales for prediction, and is freely available online.