Explore the vast range of titles available.

Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy.

Background: Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. Patients and Methods: Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. Results: In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. Conclusion: The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy. Keywords: massive parallel sequencing, NSCLC, immunotherapy, epitope, processing escape, deep learning

Hydraulic head and gradient measurements underpin practically all investigations in hydrogeology. There is sufficient information in the literature to suggest that head measurement errors can impede the reliable detection of flow directions and significantly increase the uncertainty of groundwater flow rate calculations. Yet educational textbooks contain limited content regarding measurement techniques, and studies rarely report on measurement errors. The objective of our study is to review currently accepted standard operating procedures in hydrological research and to determine the smallest head gradients that can be resolved. To this aim, we first systematically investigate the systematic and random measurement errors involved in collecting time-series information on hydraulic head at a given location: (1) geospatial position, (2) point of head, (3) depth to water, and (4) water level time series. Then, by propagating the random errors, we find that with current standard practice, horizontal head gradients <10-4 are resolvable at distances ⪆170 m. Further, it takes extraordinary effort to measure hydraulic head gradients <10-3 over distances <10 m. In reality, accuracy will be worse than our theoretical estimates because of the many possible systematic errors. Regional flow on a scale of kilometres or more can be inferred with current best-practice methods, but processes such as vertical flow within an aquifer cannot be determined until more accurate and precise measurement methods are developed. Finally, we offer a concise set of recommendations for water level, hydraulic head and gradient time-series measurements. We anticipate that our work contributes to progressing the quality of head time-series data in the hydrogeological sciences and provides a starting point for the development of universal measurement protocols for water level data collection.

OBJECTIVE: A study was designed to reevaluate hemoconcentration as an early marker of severe and/or necrotizing pancreatitis and compare it against contrast-enhanced CT, the gold standard to diagnose acute necrotizing pancreatitis. METHODS: This prospective study covers the years 1988–1999 for 316 patients (202 male, 114 female) with a first attack of acute pancreatitis. The role of the hematocrit as an early marker of severe and/or necrotizing pancreatitis has been retrospectively evaluated against the prospectively obtained data. They all underwent a CT within 72 h after admission. In addition to the CT-controlled diagnosis of interstitial/necrotizing pancreatitis, the following variables were used to assess severity: initial organ failure according to the Atlanta classification; indication for artificial ventilation and/or dialysis; Ranson score adjusted for etiology; Imrie score; Balthazar score; length of stay in intensive care unit (ICU); total hospital stay; development of pancreatic pseudocysts; indication for operation (necrosectomy); and mortality. Hemoconcentration on admission was defined as a hematocrit level >43.0% for male and >39.6% for female patients. Logistic regression was used to assess the correlation between hemoconcentration and the severity of variables. RESULTS: Hematocrit, as a single parameter measured on admission, had the same sensitivity and negative predictive value as the more complicated Ranson and Imrie scores obtained only after 48 h. However, its specificity, positive predictive value, and total accuracy were lower. Hemoconcentration significantly correlated with the Balthazar score (differential diagnosis between interstitial and necrotizing pancreatitis), stay in ICU, and total hospital stay. Sensitivity and specificity of the hematocrit cut-off level of 43.0% for male and 39.6% for female patients to detect necrotizing pancreatitis were 74% and 45%, respectively. The positive predictive value was 24% and the negative predictive value 88%. Receiver operation characteristics (ROC) curve values for several cut-offs did not result in more ideal levels. CONCLUSION: Hemoconcentration does not significantly correlate with important clinical outcome variables of acute pancreatitis including organ failure and mortality rate. Its prognostic value is comparable to the more complicated Ranson and Imrie scores obtained only after 48 h. The major value of this single easily obtainable and cheap parameter on admission lies in its high negative predictive value. In the absence of hemoconcentration, contrast-enhanced CT may be unnecessary on admission unless the patient does not improve.

A study was designed to reevaluate hemoconcentration as an early marker of severe and/or necrotizing pancreatitis and compare it against contrast-enhanced CT, the gold standard to diagnose acute necrotizing pancreatitis. This prospective study covers the years 1988–1999 for 316 patients (202 male, 114 female) with a first attack of acute pancreatitis. The role of the hematocrit as an early marker of severe and/or necrotizing pancreatitis has been retrospectively evaluated against the prospectively obtained data. They all underwent a CT within 72 h after admission. In addition to the CT-controlled diagnosis of interstitial/necrotizing pancreatitis, the following variables were used to assess severityinitial organ failure according to the Atlanta classification; indication for artificial ventilation and/or dialysis; Ranson score adjusted for etiology; Imrie score; Balthazar score; length of stay in intensive care unit (ICU); total hospital stay; development of pancreatic pseudocysts; indication for operation (necrosectomy); and mortality. Hemoconcentration on admission was defined as a hematocrit level >43.0% for male and >39.6% for female patients. Logistic regression was used to assess the correlation between hemoconcentration and the severity of variables. Hematocrit, as a single parameter measured on admission, had the same sensitivity and negative predictive value as the more complicated Ranson and Imrie scores obtained only after 48 h. However, its specificity, positive predictive value, and total accuracy were lower. Hemoconcentration significantly correlated with the Balthazar score (differential diagnosis between interstitial and necrotizing pancreatitis), stay in ICU, and total hospital stay. Sensitivity and specificity of the hematocrit cut-off level of 43.0% for male and 39.6% for female patients to detect necrotizing pancreatitis were 74% and 45%, respectively. The positive predictive value was 24% and the negative predictive value 88%. Receiver operation characteristics (ROC) curve values for several cut-offs did not result in more ideal levels. Hemoconcentration does not significantly correlate with important clinical outcome variables of acute pancreatitis including organ failure and mortality rate. Its prognostic value is comparable to the more complicated Ranson and Imrie scores obtained only after 48 h. The major value of this single easily obtainable and cheap parameter on admission lies in its high negative predictive value. In the absence of hemoconcentration, contrast-enhanced CT may be unnecessary on admission unless the patient does not improve.