Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

Craniectomy size and decompression of the temporal base using the altered posterior question-mark incision for decompressive hemicraniectomy.

The altered posterior question-mark incision for decompressive hemicraniectomy (DHC) was proposed to reduce the risk of intraoperative injury of the superficial temporal artery (STA) and demonstrated a reduced rate of wound-healing disorders after cranioplasty. However, decompression size during DHC is essential and it remains unclear if the new incision type allows for an equally effective decompression. Therefore, this study evaluated the efficacy of the altered posterior question-mark incision for craniectomy size and decompression of the temporal base and assessed intraoperative complications compared to a modified standard reversed question-mark incision. The authors retrospectively identified 69 patients who underwent DHC from 2019 to 2022. Decompression and preservation of the STA was assessed on postoperative CT scans and CT or MR angiography. Forty-two patients underwent DHC with the standard reversed and 27 patients with the altered posterior question-mark incision. The distance of the margin of the craniectomy to the temporal base was 6.9 mm in the modified standard reversed and 7.2 mm in the altered posterior question-mark group (p = 0.77). There was no difference between the craniectomy sizes of 158.8 mm and 158.2 mm, respectively (p = 0.45), and there was no difference in the rate of accidental opening of the mastoid air cells. In both groups, no transverse/sigmoid sinus was injured. Twenty-four out of 42 patients in the modified standard and 22/27 patients in the altered posterior question-mark group had a postoperative angiography, and the STA was preserved in all cases in both groups. Twelve (29%) and 5 (19%) patients underwent revision due to wound-healing disorders after DHC, respectively (p = 0.34). There was no difference in duration of surgery. Thus, the altered posterior question-mark incision demonstrated technically equivalent and allows for an equally effective craniectomy size and decompression of the temporal base without increasing risks of intraoperative complications. Previously described reduction in wound-healing complications and cranioplasty failures needs to be confirmed in prospective studies to demonstrate the superiority of the altered posterior question-mark incision.

Revision surgery for cervical artificial disc: Surgical technique and clinical results.

OBJECTIVE: Cervical artificial disc replacement (C-ADR) was developed with the goal of preserving mobility of the cervical segment in patients with degenerative disc disease. So far, little is known about experiences with revision surgery and explantation of C-ADRs. Here, we report our experience with revision the third generation, Galileo-type disc prosthesis from a retrospective study of two institutions. PATIENTS AND METHODS: Between November 2008 and July 2016, 16 patients with prior implantation of C-ADR underwent removal of the Galileo-type disc prosthesis (Signus, Medizintechnik, Germany) due to a call back by industry. In 10 patients C-ADR was replaced with an alternative prosthesis, 6 patients received an ACDF. Duration of surgery, time to revision, surgical procedure, complication rate, neurological status, histological findings and outcome were examined in two institutions. RESULTS: The C-ADR was successfully revised in all patients. Surgery was performed through the same anterior approach as the initial access. Duration of the procedure varied between 43 and 80min. Access-related complications included irritation of the recurrent nerve in one patient and mal-positioning of the C-ADR in another patient. Follow up revealed two patients with permanent mild/moderate neurologic deficits, NDI (neck disability index) ranged between 10 and 42%. CONCLUSIONS: Anterior exposure of the cervical spine for explantation and revision of C-ADR performed through the initial approach has an overall complication rate of 18.75%. Replacements of the Galileo-type disc prosthesis with an alternative prosthesis or conversion to ACDF are both suitable surgical options without significant difference in outcome.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

BACKGROUND: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. RESULTS: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

Sacropelvic fixation versus fusion to the sacrum for spondylodesis in multilevel degenerative spine disease.

STUDY DESIGN: Retrospective study. OBJECTIVE: For successful multilevel correction and stabilization of degenerative spinal deformities, a rigid basal construct to the sacrum is indispensable. The primary objective of this study was to compare the results of two different sacropelvic fixation techniques to conventional stabilization to the sacrum in patients with multilevel degenerative spine disease. METHODS: A total of 69 patients with multisegmental fusion surgery (mean number of stabilized functional spinal units: 7.0 ± 3.3) with a minimum of 1-year follow-up were included. 32 patients received fixation to the sacrum (S1), 23 patients received S1 and iliac screw fixation (iliac) and 14 patients were treated with iliosacral plate fixation (plate). Primary outcome parameters were radiographic outcome concerning fusion in the segment L5-S1, rate of screw loosening, back and buttock pain reduction [numeric rating scale for pain evaluation: 0 indicating no pain, 10 indicating the worst pain], overall extent of disability after surgery (Oswestry Disability Index) and the number of complications. RESULTS: The three groups did not differ in body mass index, ASA score, the number of stabilized functional spinal units, duration of surgery, the number of previous spine surgeries, or postoperative complication rate. The incidence of L5-S1 pseudarthrosis after 1 year in the S1, iliac, and plate groups was 19, 0, and 29 %, respectively (p < 0.05 iliac vs. plate). The incidence of screw loosening after 1 year in the S1, iliac, and plate groups was 22, 4, and 43 %, respectively (p < 0.05 iliac vs. plate). Average Oswestry scores after 1 year in the S1, iliac, and plate groups were 40 ± 18, 42 ± 20, and 58 ± 18, respectively (p < 0.05 both S1 and iliac vs. plate). CONCLUSION: The surgical treatment of multilevel degenerative spine disease carries a significant risk for pseudarthrosis and screw loosening, mandating a rigid sacropelvic fixation. The use of an iliosacral plate resulted in an inferior surgical and clinical outcome when compared to iliac screws.

Analytical method transfer: improving interpretability with ratio-based statistical approaches.

After assay validation in an originating laboratory, an analytical method needs to be transferred to one or several production laboratories, because measured outcomes among the laboratories must agree. To state agreement, the locations (e.g. means) must be equivalent and the production laboratory must be non-inferior to the originating one concerning scales (e.g. standard deviations). Here, parametric and non-parametric approaches based on marginal confidence intervals for the ratio of locations and the ratio of scales are presented. These intervals are appropriate for a matched pairs design without repeated measurements. Results of simulation studies investigating the power and the control of the type I error are shown and limits of the approaches are discussed. In addition, a Bland-Altman plot with tolerance intervals is proposed. As illustrated in the example proportional differences greatly improve the interpretation of the results compared to absolute differences.

Mercaptopurine metabolite results in clinical gastroenterology practice.

BACKGROUND: Azathioprine (AZA) and its active metabolite mercaptopurine (MP) are frequently used in the management of inflammatory bowel disease. Measurement of the AZA/MP metabolites, thioguanine (TG) and methylmercaptopurine (MMP), has been suggested as a means to optimize therapy with AZA/MP in inflammatory bowel disease. AIM: To evaluate the results of initial AZA/MP metabolite panels sent by gastroenterologists during the first year of its widespread availability. METHODS: Initial AZA/MP metabolite panels sent by gastroenterologists to a single laboratory were reviewed and the metabolite panels were interpreted. RESULTS: Initial metabolite levels were reviewed for 9187 patients. Noncompliance was detected in 263 patients (3%) and under-dosing in 4260 patients (46%). 534 patients (6%) had levels that were consistent with preferential metabolism via the TPMT pathway. The therapeutic goal was achieved in 2444 patients (27%) and an additional 552 patients (6%) had appropriate TG levels but potential hepatotoxicity. 936 patients (10%) had potential TPMT deficiency, and 58 patients (1%) had potential TPMT absence and were at risk for leukopenia. 140 patients (2%) had too high a dose. CONCLUSIONS: Measurement of AZA/MP metabolites can be used by practising gastroenterologists to identify potential reasons for nonresponse to AZA or MP, and to identify patients at risk for certain drug-related toxicities.

Surveillance issues in inflammatory bowel disease: ulcerative colitis.

This review article on the surveillance of patients with ulcerative colitis provides an overview of the criteria for evaluating screening and surveillance programs and applies the criteria to the available evidence to determine the effectiveness of the surveillance of patients with ulcerative colitis. We examine the clinical outcomes associated with surveillance, the additional clinical time required to confirm the diagnosis of dysplasia and cancer, compliance with surveillance and follow-up, and the effectiveness of the individual components of a surveillance program, including colonoscopy and pathologist's interpretation. The disability associated with colectomy is considered, as are the cost and acceptability of surveillance programs. Patients with long-standing ulcerative colitis are at risk for developing colorectal cancer. Recommended surveillance colonoscopy should be supported. New endoscopic and histopathologic techniques to improve the identification of high-risk patients may enhance the effectiveness and cost-effectiveness of surveillance practices.

Effects of R-(+)-limonene on submerged cultures of the terpene transforming basidiomycete Pleurotus sapidus.

The biotransformation of limonene by the basidiomycete Pleurotus sapidus yielded cis/trans-carveol and carvone as the main products. The transformation period was extended from 4 days after direct addition to 12 days by gas phase addition of the substrate. After 2 days of transformation, 97% of the substrate had accumulated in the mycelium, while only 3% were present in the culture medium. Substrate toxicity led to a decrease of dry matter. Adaptation of the precultures with small amounts of substrate doubled the concentration of carveol and increased the concentration of carvone by a factor of 3-4. Total product concentrations of > 100 mg l-1 were reached.

Biotransformation of citronellol by the basidiomycete Cystoderma carcharias in an aerated-membrane bioreactor.

The basidiomycete Cystoderma carcharias transformed citronellol into 3,7-dimethyl-1,6,7-octanetriol as the main product. 3,7-Dimethyl-6,7-epoxy-1-octanol was identified as important intermediary product of the biotransformation, and the allylic diols 2,6-dimethyl-2-octene-1,8-diol, 3,7-dimethyl-5-octene-1,7-diol and 3,7-dimethyl-7-octene-1,6-diol were found to be minor products. Microbial formation of rose oxide, a flavour-impact component, was observed for the first time. The formation of the main products was inhibited by 70% after addition of 0.1 mmol l-1 cytochrome monooxygenase inhibitors. Formation of 3,7-dimethyl-1,6,7-octanetriol was effective in a bioreactor with aeration over a coil of a hydrophobic microporous polypropene capillary membrane. Production rates of up to 150 mg l-1 day-1 were reached and led to a product concentration of 866 mg l-1 (conversion rate: 52%). The total loss of the added volatile substrate via the exhaust air was 4.5% when this aeration method was used.

Performing a cost-effectiveness analysis: surveillance of patients with ulcerative colitis.

OBJECTIVE: To illustrate the principles of cost-effectiveness analysis, this third article in the "Primer on Economic Analysis for the Gastroenterologist" applies published criteria for appraising an economic analysis to a study of the cost-effectiveness of surveillance of patients with ulcerative colitis. METHODS: We review and apply the 10 standard criteria for critical appraisal and evaluation of cost-effectiveness analyses. SUMMARY: We outlined the development and critique of a decision analytic model that examines the cost-effectiveness of surveillance of patients with ulcerative colitis, and we compared the cost-effectiveness of surveillance of patients with ulcerative colitis to other well-accepted medical practices.

ERCP and sphincterotomy in the context of laparoscopic cholecystectomy: academic and community practice patterns and results.

OBJECTIVE: To study the effect of practice setting and practitioner experience on the use and results of ERCP and sphincterotomy in the context of laparoscopic cholecystectomy. METHODS: Data were collected on 780 ERCPs performed before or after laparoscopic cholecystectomy. Biliary endoscopists at four academic centers and 33 community-based gastroenterologists of varying experience participated. RESULTS: Indications for perioperative ERCP were similar in academic centers and community practice, but academic experts performed a significantly higher proportion of postoperative procedures. Success rates were high for all participants, although the least experienced group of community-based gastroenterologists had a significantly lower rate of success with sphincterotomy. Complication rates did not vary significantly among participants. CONCLUSIONS: Experienced community-based gastroenterologists can perform ERCP and sphincterotomy in the context of laparoscopic cholecystectomy with results comparable to those of academic experts. Gastroenterologists with a life-time experience of fewer than 200 ERCPs have lower success rates for sphincterotomy than more experienced practitioners in either practice setting. ERCP performed in community or academic settings can provide safe and effective management of common bile duct stones and biliary leaks or strictures that occur after laparoscopic cholecystectomy.

Patient-controlled analgesia for conscious sedation during endoscopic retrograde cholangiopancreatography: a randomized controlled trial.

BACKGROUND: Adequate comfort is essential to patients undergoing invasive procedures. This study was designed to evaluate whether patient-controlled analgesia could improve sedation for ERCP. METHODS: Patients were randomized to receive standard sedation (n = 31) or patient-controlled analgesia (n = 31). The patients were blinded to the randomization. After the procedure the patient, physician, and nurse each rated their satisfaction with sedation using a verbal rating scale. RESULTS: There was no significant difference between the patient's mean satisfaction score for the conventional and patient-controlled analgesia groups (9.3 and 9.6, respectively, p = 0.5). The physicians rated sedation higher in the conventional group compared with the patient-controlled analgesia group (8.6 and 8.2, respectively, p = 0.02). Physicians and nurses' scores correlated (r = 0.53, p = 0.0001), but there was no correlation between scores reported by either physicians or nurses and the patients' scores (r = 0.2 and r = 0.05, respectively). Oxygen saturation less than 90% occurred for more than 1 minute in three patients who received standard sedation but in none who used patient-controlled analgesia. CONCLUSION: This trial demonstrates that patient-controlled analgesia during ERCP is as effective as standard sedation with respect to patient satisfaction. Physicians and nurses, however, are not good proxies for assessing patient satisfaction.

Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis.

OBJECTIVES: Accurate preoperative prediction of choledocholithiasis is essential in order to minimize patient risk and curtail health care expenditures. This study was designed to identify independent risk factors for choledocholithiasis in patients who had undergone cholecystectomy for symptomatic cholelithiasis and to develop a predictive model based on those factors. METHODS: The charts of 1264 consecutive patients who had undergone cholecystectomy at one of three North Carolina hospitals between January 1, 1989 and December 31, 1991 were reviewed; 465 of these patients had confirmed presence or absence of choledocholithiasis by cholangiography and/or common bile duct exploration and were eligible for analysis. Candidate predictor variables included age and maximum preoperative values for each of the following: temperature, alkaline phosphatase, bilirubin, AST, amylase, white blood cell count, and common bile duct diameter. Model development and validation were conducted using standard data-splitting (60% "training," 40% "test") and logistic regression techniques. RESULTS: Choledocholithiasis was confirmed in 115 (25%) of the 465 eligible patients. Univariate analysis identified bilirubin, common bile duct diameter, AST, temperature, alkaline phosphatase, and age as predictors. Multivariable analysis subsequently identified bilirubin, common bile duct diameter, AST, alkaline phosphatase, and age as independent predictors of choledocholithiasis. A final model containing these variables (except age, whose contribution to the model was small) accurately predicted choledocholithiasis (c-index = 0.76). CONCLUSIONS: Accurate estimates of choledocholithiasis risk can be made using maximum preoperative bilirubin, common bile duct diameter, AST, and alkaline phosphatase values. Use of the model may help physicians select those patients with symptomatic cholelithiasis who would most likely benefit from further investigation to exclude choledocholithiasis.

Effect of different coffees on esophageal acid contact time and symptoms in coffee-sensitive subjects.

The purpose of this study was to correlate the effects of different coffees on esophageal acid contact, heartburn, and regurgitation in patients with coffee-sensitivity. Twenty volunteers with coffee-sensitivity were studied in a double-blind, 3 period, crossover study examining the effect of three regular (caffeinated) coffees (a coffee from the USA--"A"; a "treated" coffee from Europe--"B"; and an "untreated" coffee from Europe--"C") before and after a high-fat test meal. The median acid contact times for coffees A, B, and C were 6.5%, 9%, and 10.5%, respectively (A vs. C, p = 0.005). Significantly fewer patients reported any symptoms with coffee A compared with coffee C (p < 0.05). Symptoms were usually more frequent and severe after the test meal. There was a trend toward fewer and less severe symptoms with the treated coffee (B) compared with its untreated counterpart (C). Our conclusions are as follows: (a) Different coffees induce variations in gastroesophageal reflux in coffee-sensitive individuals. (b) Coffee can be treated in a manner which decreases heartburn symptoms by 75% while decreasing acid contact by only 14%. (c) Gastroesophageal reflux and symptoms of coffee sensitivity increase with the concomitant ingestion of food. (d) Symptoms of dyspepsia appear to be influenced by variations in both the coffee itself and characteristics of susceptible individuals. (e) Although gastroesophageal reflux is important in the genesis of coffee-sensitivity, there must be other factors which act in concert with reflux to produce symptoms of coffee-sensitivity.

Clinical trials. How should they be designed?

The fundamental principles of clinical trial design include (1) a priori formulation of a specific research question, (2) precise description of the population to be studied, (3) limitation of the effects of chance by predetermining the study hypothesis and using methods that account for multiple statistical testing, (4) calculation of the sample size necessary to answer the research question, and (5) limitation of the potential bias whenever possible through blinding and random allocation of subjects to treatment and control groups (Table 2). Although the randomized controlled trial is regarded as the gold standard for determination of efficacy of therapy, cost and sample size are frequently rate-limiting. Other techniques have been developed to supplement clinical trials and include meta-analysis, data base (observational) research, and decision analysis. In the current climate of concern over staggering health care costs and variable practice patterns, research emphases are shifting from cost containment to maximizing value of health-related services and assessing patient outcomes.

Evaluation of state efforts to improve systems of care for children and adolescents with severe emotional disturbances: the CASSP (Child and Adolescent Service System Program) initial cohort study.

In 1984, the National Institute of Mental Health (NIMH) began funding its Child and Adolescent Service System Program (CASSP). In this paper, we present findings from a descriptive study of the experiences of the initial cohort of states to receive CASSP grants, conceived and conducted when the projects were approaching the end of their fifth and final year of NIMH funding. Detailed case studies were conducted of each of the 10 initial cohort projects, and the findings analyzed across projects. Data were collected from three major sources: (1) existing documentation about the projects, (2) site visits to each of the projects, and (3) information from relevant secondary sources. Findings suggest that the initial cohort projects utilized a variety of strategies and encountered a variety of barriers and facilitating factors. The projects generally implemented the intended CASSP program and did so by using a variety of strategies. The projects were judged by stakeholders in their states to have influenced the service systems in their states in the intended directions: toward a more comprehensive system of care that emphasizes community-based treatment; toward better integrated, more collaborative efforts among the state agencies involved; toward a more detailed understanding on the part of system stakeholders of the mental health problems of children and adolescents who have severe emotional disturbances, and of the influence of those problems on the lives of the children and their families; and toward increased involvement by parents and other family members in the care of these children and adolescents.