A new, simplified endoscopic scoring system for predicting clinical outcome in gastric low-grade intraepithelial neoplasia: the "e-cout system".

BACKGROUND AND OBJECTIVES: The clinical outcomes of gastric low-grade intraepithelial neoplasia (LGIN) exhibit significant diversity, and the current reliance on endoscopic biopsy for diagnosis poses limitations in devising appropriate treatment strategies for this disease. This study aims to establish a prognostic prediction scoring system (e-Cout system) for gastric LGIN, offering a theoretical foundation for solving this clinical challenge. METHODS: Retrospectively selecting 1013 cases meeting the inclusion and exclusion criteria from over 300,000 cases of upper gastrointestinal endoscopy performed at the Digestive Endoscopy Center of our hospital between 2000 and 2022, the cohort included 484 cases as development cohort and 529 cases for validation. Employing relevant statistical analysis, we used development cohort data to establish the e-Cout system for gastric LGIN, and further used validation cohort data to for internal validation. RESULTS: In the developmental stage, based on accordant regression coefficients, we assigned point values to six risk factors for poor prognosis: 4 points for microvessel (MV) distortion, 3 points for MV thickening, 2 points for ulcer, and 1 point each for lesion size > 2cm, disease duration > 1 year, and hyperemia and redness on the lesion surface. Patients were then categorized into four risk levels: low risk (0-1 point), medium risk (2-3), high risk (4-6), and very high risk (≥7). During the validation stage, significant differences in the three different outcomes of gastric LGIN were observed across all risk levels. The probability of reversal and progression showed a significant decrease and increase, respectively, with escalating of risk levels, and these differences were statistically significant (P< 0.001). CONCLUSIONS: The proposed e-Cout system holds promise in aiding clinicians to predict the probability and risk levels of different clinical outcomes in patients with gastric LGIN. This system is expected to provide an improved foundation and guidance for the selection of clinical strategies for this disease.

Computer-aided diagnosis system for optical diagnosis of colorectal polyps under white light imaging.

OBJECTIVES: This study presents a novel computer-aided diagnosis (CADx) designed for optically diagnosing colorectal polyps using white light imaging (WLI).We aimed to evaluate the effectiveness of the CADx and its auxiliary role among endoscopists with different levels of expertise. METHODS: We collected 2,324 neoplastic and 3,735 nonneoplastic polyp WLI images for model training, and 838 colorectal polyp images from 740 patients for model validation. We compared the diagnostic accuracy of the CADx with that of 15 endoscopists under WLI and narrow band imaging (NBI). The auxiliary benefits of CADx for endoscopists of different experience levels and for identifying different types of colorectal polyps was also evaluated. RESULTS: The CADx demonstrated an optical diagnostic accuracy of 84.49%, showing considerable superiority over all endoscopists, irrespective of whether WLI or NBI was used (P < 0.001). Assistance from the CADx significantly improved the diagnostic accuracy of the endoscopists from 68.84% to 77.49% (P = 0.001), with the most significant impact observed among novice endoscopists. Notably, novices using CADx-assisted WLI outperform junior and expert endoscopists without such assistance. CONCLUSIONS: The CADx demonstrated a crucial role in substantially enhancing the precision of optical diagnosis for colorectal polyps under WLI and showed the greatest auxiliary benefits for novice endoscopists.

Impact of pancreatic and biliary stent on post-endoscopic papillectomy complications: A single-center retrospective study.

BACKGROUND: Endoscopic papillectomy (EP) is recommended as the first-line therapy for ampullary tumors, despite a relatively high incidence of complications. Pancreatic and/or biliary stents are placed at the endoscopist's discretion to prevent post-EP complications. The present study aimed to evaluate the efficacy of different stents. METHODS: A total of 117 patients who underwent EP and met the criteria between June 2006 and October 2022 were enrolled in the study. These patients were divided into a pancreatic stent group (PS group, n = 47), a biliary stent group (BS group, n = 38), and a two-stent group (PBS [PS and BS] group, n = 32). Relevant clinical data were collected and compared among the three groups. Multivariate logistic analyses were performed to explore risk factors for post-EP complications. RESULTS: The incidence of all complications was 37.6% (44/117). Pancreatitis and hemorrhage were the two most common complications with incidence rates of 14.5% (17/117) and 17.9% (21/117). The incidence rates of post-EP pancreatitis were 10.6% (5/47), 23.7% (9/38), and 9.4% (3/32) in the PS group, BS group, and PBS group, respectively, with no significant differences. There were also no significant differences in other complications among the three groups. Age (odds ratio [OR]: 0.95; 95% confidence interval [CI]: 0.91-0.99; P = 0.022) was independently associated with post-EP pancreatitis while tumor size (OR: 1.66; 95% CI: 1.06-2.60; P = 0.028) was independently associated with post-EP hemorrhage. CONCLUSIONS: While pancreatic stenting is the first choice to prevent post-EP pancreatitis, biliary stenting could also be considered as a substitute for patients with difficulties in pancreatic cannulation. Two-stent (biliary and pancreatic stent) placement is unnecessary unless it is required due to other concerns.

A novel self-inflatable balloon for treating refractory benign esophageal strictures: a prospective, single-arm, multicenter study.

BACKGROUND AND AIM: Current treatments for refractory benign esophageal strictures (BESs) often take several years and have poor effects. The authors propose a novel method of self-help inflatable balloon (SHIB) and evaluate its efficacy and safety. METHODS: A prospective, multicenter study was conducted from January 2019 to March 2022. All enrolled patients were diagnosed with refractory BESs and received SHIB. The primary endpoint was the clinical success rate at 12 months after removing SHIB. The secondary endpoints were the number of days of placing SHIB, and changes from baseline in BMI and health-related quality of life at 1, 3, 6, and 12 months. RESULTS: The clinical success rate was 51.2% (21/41) with the median days of placing SHIB being 104.0 days (range: 62.0-134.5 days), which was higher in the endoscopic group compared to the caustic and surgery groups (63.3 vs. 28.6% vs. 0, P=0.025). All patients (100%) showed significant improvement in dysphagia scores during placing SHIB. Although 20 patients (48.8%) experienced recurrent stricture, the median stricture length was decreased (P<0.001) and the median intervention-free interval was prolonged (P<0.001). In all patients, the mean BMI at and health-related quality of life at 1, 3, 6, and 12 months were significantly increased compared with baseline (P<0.05). On multivariate analysis, stricture etiology and wearing time were independent predictors of recurrent stricture. CONCLUSIONS: The SHIB has high efficacy and safety in treating refractory BESs of different origins, especially for endoscopic resection. Stricture etiology and wearing time were independent predictors of recurrent stricture.

Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives.

Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.

Per-oral endoscopic myotomy is safe and effective for pediatric patients with achalasia: A long-term follow-up study.

BACKGROUND: Per-oral endoscopic myotomy (POEM) is emerging as a prefer treatment option for pediatric achalasia. However, data are limited on the long-term efficacy of POEM in children and adolescents with achalasia. AIM: To evaluate the safety and long-term efficacy of POEM for pediatric patients with achalasia and compare those outcomes with adult patients. METHODS: This retrospective cohort study was conducted in patients with achalasia who underwent POEM. Patients aged under 18 years were included in the pediatric group; patients aged between 18 to 65 years who underwent POEM in the same period were assigned to the control group. For investigation of long-term follow-up, the pediatric group were matched with patients from the control group in a 1:1 ratio. The procedure-related parameters, adverse events, clinical success, gastroesophageal reflux disease (GERD) after POEM, and quality of life (QoL) were evaluated. RESULTS: From January 2012 to March 2020, POEM was performed in 1025 patients aged under 65 years old (48 in the pediatric group, 1025 in the control group). No significant differences were observed in the occurrence of POEM complications between the two groups (14.6% vs 14.6%; P = 0.99). Among the 34 pediatric patients (70.8%) who underwent follow-up for 5.7 years (range 2.6-10.6 years), clinical success was achieved in 35 patients (35/36; 97.2%). No differences were observed in post-POEM GERD occurrence (17.6% vs 35.3%; P = 0.10). QoL was significantly improved in both groups after POEM. CONCLUSION: POEM is safe and effective for pediatric patients with achalasia. It can achieve significant symptoms relief and improve QoL.

Linked color imaging vs Lugol chromoendoscopy for esophageal squamous cell cancer and precancerous lesion screening: A noninferiority study.

BACKGROUND: Lugol chromoendoscopy (LCE) has served as a standard screening technique in high-risk patients with esophageal cancer. Nevertheless, LCE is not suitable for general population screening given its side effects. Linked color imaging (LCI) is a novel image-enhanced endoscopic technique that can distinguish subtle diff-erences in mucosal color. AIM: To compare the diagnostic performance of LCI with LCE in detecting esophageal squamous cell cancer and precancerous lesions and to evaluate whether LCE can be replaced by LCI in detecting esophageal neoplastic lesions. METHODS: In this prospective study, we enrolled 543 patients who underwent white light imaging (WLI), LCI and LCE successively. We compared the sensitivity and specificity of LCI and LCE in the detection of esophageal neoplastic lesions. Clinicopathological features and color analysis of lesions were assessed. RESULTS: In total, 43 patients (45 neoplastic lesions) were analyzed. Among them, 36 patients (38 neoplastic lesions) were diagnosed with LCI, and 39 patients (41 neoplastic lesions) were diagnosed with LCE. The sensitivity of LCI was similar to that of LCE (83.7% vs 90.7%, P = 0.520), whereas the specificity of LCI was greater than that of LCE (92.4% vs 87.0%, P = 0.007). The LCI procedure time in the esophageal examination was significantly shorter than that of LCE [42 (34, 50) s vs 160 (130, 189) s, P < 0.001]. The color difference between the lesion and surrounding mucosa in LCI was significantly greater than that observed with WLI. However, the color difference in LCI was similar in different pathological types of esophageal squamous cell cancer. CONCLUSION: LCI offers greater specificity than LCE in the detection of esophageal squamous cell cancer and precancerous lesions, and LCI represents a promising screening strategy for general populations.

Radiosensitivity in Non-Small-Cell Lung Cancer by MMP10 through the DNA Damage Repair Pathway.

NSCLC (non-small-cell lung cancer) is an aggressive form of lung cancer and accompanies high morbidity and mortality. This study investigated the function and associated mechanism of MMP10 during radiotherapy of NSCLC. MMP10 expression in patients and their overall survival rate were assessed through GEPIA. Protein expression was tested by western blotting. Radioresistance was detected in vitro by apoptosis and clonogenic assay. The extent of DNA damage and repair was revealed by the comet test and γH2AX foci test. High MMP10 levels in specimens of lung adenocarcinoma were related to poor patient outcomes. Clonogenic and apoptosis assays revealed that MMP10 knockdown in A549 cells initiated radiosensitization. Furthermore, MMP10 siRNA increased damage to the DNA in NSCLC cells, while MMP10 was observed to participate in DNA damage repair post-ionizing radiation. Thus, after irradiation, MMP10 plays an essential role in NSCLC through the repair pathway of DNA damage; regulating MMP10 for NSCLC radiosensitivity might have potential treatment implications in radiotherapy of NSCLC.

Safety and Efficacy of the Supine Position with the Right Shoulder Raised versus the Left Lateral Position in Peroral Endoscopic Myotomy for Achalasia: A Large-Sample Retrospective Study.

Background: The correct surgical position is very important in the treatment of peroral endoscopic myotomy (POEM) for achalasia, which can make the procedure safer and more efficient. Currently, there are two commonly used positions: the supine position with the right shoulder raised and the left lateral position. This study aims to evaluate the differences in the safety and efficacy of these two positions. Methods: We conducted a retrospective study of 702 patients with achalasia undergoing POEM from December 2010 to December 2020. These patients were divided into the supine position with the right shoulder raised group (n = 579) and the left lateral position group (n = 123). The efficacy of POEM and adverse events were analyzed. Results: The clinical characteristics were similar in both groups, and there were no significant differences between the two groups in the Eckardt score change, lower esophageal sphincter (LES) basal pressure or residual pressure after POEM (all p > 0.05). The mean operative time in the supine position with the right shoulder raised group was significantly shorter than that in the left lateral position group (43.5 min vs. 54.6 min, respectively, p < 0.001). In addition, the differences between the two groups in terms of gas-related complications, such as pneumoperitoneum, pneumomediastinum, and subcutaneous emphysema were statistically significant (all p < 0.05). Conclusions: The efficacy of POEM was comparable between the two groups. However, the supine position with the right shoulder raised significantly reduced the operative time and the rate of procedure-related adverse events, especially gas-related complications.

Clinical characteristics of smoking-related chronic pancreatitis.

Objective: The pathogenesis of chronic pancreatitis (CP) is not completely clear. With further studies, smoking is toxic to the pancreas. This study classified smoking-related CP as a new etiology of CP and defined the cutoff of smoking. Design: Patients with CP admitted from January 2000 to December 2013 were included in the study. The characteristics were compared between smoking patients, drinking patients, and a group of patients who never smoke or drink (control group). The cumulative rates of steatorrhea, diabetes mellitus (DM), pancreatic pseudocyst (PPC), pancreatic stone, and biliary stricture after the onset of CP were calculated, respectively. Results: A total of 1,324 patients were included. Among them, 55 were smoking patients, 80 were drinking patients, and 1,189 were controls. The characteristics of smokers are different from the other two groups, especially in age at the onset and diagnosis of CP, initial manifestation, and type of pain. The development of DM (P = 0.011) and PPC (P = 0.033) was significantly more common and earlier in the smokers than in the other two groups. Steatorrhea also developed significantly more in the smokers than in the controls (P = 0.029). Smokers tend to delay the formation of pancreatic stones and steatorrhea. Conclusion: The clinical characteristics of smoking-related CP is different from CP of other etiologies. A new type of CP, smoking-related CP, was put forward. Smoking-related CP should be separated from idiopathic CP and defined as a new independent subtype of CP different from alcoholic CP or idiopathic CP.

Changhai advanced endoscopy courses for ERCP (CHANCE) training program: A short-term training model in China.

BACKGROUND: There is huge shortage of ERCP practitioners (ERCPists) in China, and ERCP training is urgently needed. ChangHai Advanced eNdoscopy Courses for ERCP (CHANCE) is a 4-month program for ERCP training since 2004. This study evaluated the efficiency of this short-term training model, and reported on the ERCP careers of the trainees following completion of the CHANCE program. METHODS: This study was a retrospective investigation included all the CHANCE trainees from Jan 2004 to Dec 2014. Questionnaires were sent to all trainees. The career competence percentage, ERCP careers and predictive factors of career competence were investigated and analyzed. RESULTS: A total of 413 trainees participated in the CHANCE program over 11 years covered by the survey and 258 questionnaires were valid for the study. The mean (SD) age of the trainees was 35.36 (4.17), and the male to female ratio was 4.4:1. The average follow-up time was 7.77 (3.44) years. A total of 173 (67.1%) trainees had achieved career competence. In terms of ERCP careers, the mean annual ERCP volume was 120.60 (96.67), with a complication percentage of 8.2%. Hospital qualification, compliance with follow-up learning guidance, participating academic activity, and practitioner type were identified predictive factors of career competence. CONCLUSIONS: As a short-term training program, the CHANCE achieved an acceptable career competence percentage, providing endoscopists more chances to learn ERCP and giving them appropriate training guidance for career competence. This training mode is worth promoting in developing countries with shortage of ERCPists.

Pancreatic extracorporeal shock wave lithotripsy for a patient concurrent with autosomal dominant polycystic kidney disease: a case report.

Whether pancreatic extracorporeal shock wave lithotripsy (ESWL) is safe for patients with autosomal dominant polycystic kidney disease (ADPKD) is unclear. A woman in her early 30s was admitted to our hospital because of intermittent upper abdominal pain and recurrent pancreatitis. The imaging results confirmed the diagnosis of pancreatic stones and ADPKD. We performed pancreatic ESWL using a third-generation lithotripter to pulverize the pancreatic stones. A maximum of 5000 shock waves was delivered per therapeutic session. A second session of ESWL was performed the next day. The patient developed no adverse events or complications related to pancreatic ESWL. Three years after treatment, the patient had developed no relapse of pancreatitis or abdominal pain. Shock waves do not lead to complications such as hematuria, cyst rupture, or deterioration of the inner bleeding of renal cysts. Multiple kidney cysts are not a contraindication for pancreatic ESWL.

NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

Rapid formation of a radiolucent pancreatic stone: a case report (with video).

BACKGROUND: Over 90% of pancreatic stones are radiopaque and can be treated with endoscopy or surgery. However, radiolucent stones are different than radiopaque stones in nature and formation, and therefore, treatment varies.Case presentation: A 25-year-old woman was admitted because of recurrent acute pancreatitis. Imaging examinations confirmed the diagnosis of chronic pancreatitis (CP), and which revealed the existence of radiolucent stones. Endoscopic retrograde cholangiopancreatography (ERCP) was performed and abundant protein-like radiolucent stones were extracted. Three 10F, 7-cm plastic stents were placed. However, the stents were completely occluded by radiolucent stones 1 month later. A nasopancreatic tube was then inserted and flushed regularly, but protein-like stones formed continuously. After multidisciplinary consultation, the following conservative treatment strategy was applied: 1) no more endotherapy; 2) a diet with 40% to 50% of calories from fat was recommended; 3) no pancreatic enzyme replacement therapy; and 4) regular exercise. The above advice aimed to stimulate the secretion of pancreatic fluid to achieve auto-flushing of the pancreatic duct and prevent protein-like stones from depositing. No acute pancreatitis recurred during the 5-year follow-up. CONCLUSIONS: This strategy was effective for auto-flushing the pancreatic duct in patients with radiolucent pancreatic stones after the main pancreatic duct stricture was resolved.

Risk Factors Analysis and Nomogram Development for Pancreatic Pseudocyst in Idiopathic Chronic Pancreatitis.

OBJECTIVE: The study concerns identifying risk factors and developing nomogram for pancreatic pseudocyst (PPC) in idiopathic chronic pancreatitis (ICP) to facilitate early diagnosis. METHODS: From January 2000 to December 2013, ICP patients admitted to our center were enrolled. Cumulative incidence of PPC was determined by Kaplan-Meier method. Patients were randomized into training group and validation group in a 2:1 ratio. Risk factors of PPC were determined through Cox proportional hazards regression model based on training cohort. The nomogram was constructed according to risk factors. RESULTS: Totally, 1633 ICP patients were included with a median follow-up duration of 9.8 years. Pancreatic pseudocyst was observed in 14.7% (240/1633) of patients after ICP onset. The cumulative incidences of PPC were 8.2%, 10.4%, and 12.9% at 3, 5, and 10 years after ICP onset, respectively. Male sex, smoking history, history of severe acute pancreatitis, and chronic pain at/before diagnosis of ICP and complex pathologic changes in main pancreatic duct were recognized as risk factors of PPC development. The nomogram constructed with these risk factors achieved good concordance indexes. CONCLUSIONS: Risk for PPC could be estimated through the nomogram. High-risk patients were suggested to be followed up closely to help early diagnosis of PPC.

Isoliquiritigenin ameliorates caerulein-induced chronic pancreatitis by inhibiting the activation of PSCs and pancreatic infiltration of macrophages.

Chronic pancreatitis (CP) is characterized by persistent inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Currently, the clinical therapeutic scheme of CP is mainly symptomatic treatment including pancreatic enzyme replacement, glycaemic control and nutritional support therapy, lacking of specific therapeutic drugs for prevention and suppression of inflammation and fibrosis aggravating in CP. Here, we investigated the effect of isoliquiritigenin (ILG), a chalcone-type dietary compound derived from licorice, on pancreatic fibrosis and inflammation in a model of caerulein-induced murine CP, and the results indicated that ILG notably alleviated pancreatic fibrosis and infiltration of macrophages. Further in vitro studies in human pancreatic stellate cells (hPSCs) showed that ILG exerted significant inhibition on the proliferation and activation of hPSCs, which may be due to negative regulation of the ERK1/2 and JNK1/2 activities. Moreover, ILG significantly restrained the M1 polarization of macrophages (RAW 264.7) via attenuation of the NF-κB signalling pathway, whereas the M2 polarization was hardly affected. These findings indicated that ILG might be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.

Classification of Early-Onset and Late-Onset Idiopathic Chronic Pancreatitis Needs Reconsideration.

Bimodal classification of idiopathic chronic pancreatitis (ICP) into early-onset (<35 years) and late-onset (>35 years) ICP was proposed in 1994 based on a study of 66 patients. However, bimodal distribution wasn't sufficiently demonstrated. Our objective was to examine the validity and relevance of the age-based bimodal classification of ICP. We analyzed the distribution of age at onset of ICP in our cohort of 1633 patients admitted to our center from January 2000 to December 2013. Classify ICP patients into early-onset ICP(a) and late-onset ICP(a) according to different cut-off values (cut-off value, a = 15, 25, 35, 45, 55, 65 years old) for age at onset. Compare clinical characteristics of early-onset ICP(a) and late-onset ICP(a). We found slightly right skewed distribution of age at onset for ICP in our cohort. There were differences between early-onset and late-onset ICP with respect to basic clinical characteristics and development of key clinical events regardless of the cut off age at onset i.e. 15, 25, 35, 45 or even higher. The validity of the bimodal classification of early-onset and late-onset ICP could not be established in our large patient cohort and therefore such a classification needs to be reconsidered.