Publications by authors named "Giusi Moffa"

18 Publications

  • Page 1 of 1

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

J Clin Epidemiol 2021 May 23. Epub 2021 May 23.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland.

Objectives: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement.

Methods: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions.

Results: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average.

Conclusions: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.
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http://dx.doi.org/10.1016/j.jclinepi.2021.05.011DOI Listing
May 2021

Influence of the introduction of caseload requirements on indication for visceral cancer surgery in Switzerland.

Eur J Surg Oncol 2021 Jun 16;47(6):1324-1331. Epub 2021 Apr 16.

Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Switzerland. Electronic address:

Background: In 2013 Swiss health authorities implemented annual hospital caseload requirements (CR) for five areas of visceral surgery. We assess the impact of the implementation of CR on indication for surgery in esophageal, pancreatic and rectal cancer.

Materials And Methods: Retrospective analysis of national registry data of all inpatient admissions between January 1st 2005 and December 31st 2015. Primary end-point was the age-adjusted resection rate for esophageal, pancreatic and rectal cancer among patients with at least one cancer-specific hospitalization per year. We calculated age-adjusted rate ratios for period effects before and after implementation of CR and odds ratios (OR) based on a generalized estimation equation. A relative increase of 5% in age-adjusted relative risk was set a priori as relevant from a health policy perspective.

Results: Age-adjusted resection rates before and after the implementation of CR were 0.12 and 0.13 (Relative Risk [RR] 1.08; 95%-Confidence Interval [CI] 0.85-1.36) in esophageal cancer, 0.22 and 0.26 (RR 1.17; 95%-CI 0.85-1.58) in pancreatic cancer and 0.38 and 0.43 (RR 1.14; 95%-CI 0.99-1.30) in rectal cancer. In adjusted models OR for resection after the implementation of CR were 1.40 (95%-CI 1.24-1.58) in esophageal cancer, 1.05 (95%-CI 0.96-1.15) in pancreatic cancer and 0.92 (95%-CI 0.87-0.97) in rectal cancer.

Conclusion: Implementation of CR was associated with an increase of resection rates above the a priori set margins in all resections groups. In adjusted models, odds for resection were significantly higher for esophageal cancer, while they remained unchanged for pancreatic and decreased for rectal cancer.
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http://dx.doi.org/10.1016/j.ejso.2021.04.006DOI Listing
June 2021

Antibiotic prescription monitoring and feedback in primary care in Switzerland: Design and rationale of a nationwide pragmatic randomized controlled trial.

Contemp Clin Trials Commun 2021 Mar 20;21:100712. Epub 2021 Jan 20.

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Introduction: Antibiotic consumption is highest in primary care, and antibiotic overuse furthers antimicrobial resistance. In our recently published pilot-RCT, we used monthly aggregated claims data to provide personalized antibiotic prescription feedback to general practitioners (GPs). The pilot-RCT has shown that personalized prescription feedback is a feasible and promising low-cost intervention to reduce antibiotic prescribing. Here, we describe the rationale and design of the follow-up RCT with 3426 GPs in Switzerland. We now have access to pseudonymized patient-level data from routinely collected health insurance data of the three largest health insurers in Switzerland.

Methods And Analysis: 1713 GPs randomized to the intervention group received once evidence-based treatment guidelines at the beginning, including region-specific antibiotic resistance information from the community and personalized feedback of their antibiotic prescribing, followed by quarterly personalized prescription feedback for two years. The first and the last mailings were sent out in December 2017 and September 2019, respectively. The 1713 GPs randomized to the control group were not notified about the study and they received no guidelines and no prescription feedback. The personalized prescription feedbacks and the analyses of the primary and secondary outcomes are entirely based on pseudonymized patient-level data from routinely collected health insurance data. The primary outcome is prescribed antibiotics per 100 patient consultations during the second year of intervention. The secondary outcomes include antibiotic use during the entire two-year trial period, use of broad-spectrum antibiotics, hospitalization rates (all-cause and infection-related), and antibiotic use in different age groups. If the feedback intervention proves to be efficacious, the intervention could be continued systemwide.

Ethics And Dissemination: The trial is publicly funded by the Swiss National Science Foundation (SNSF, grant number 407240_167066). The trial was approved by the ethics committee "Ethikkommission Nordwest-und Zentralschweiz" (EKNZ Project-ID 2017-00888). Results will be disseminated in peer-reviewed journals and international conferences.
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http://dx.doi.org/10.1016/j.conctc.2021.100712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897989PMC
March 2021

Association of Supporting Trial Evidence and Reimbursement for Off-Label Use of Cancer Drugs.

JAMA Netw Open 2021 03 1;4(3):e210380. Epub 2021 Mar 1.

Department of Medical Oncology, University Hospital Basel and University of Basel, Basel, Switzerland.

Importance: In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs.

Objective: To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system.

Design, Setting, And Participants: This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020.

Exposures: Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications.

Main Outcomes And Measures: The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models.

Results: Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27).

Conclusions And Relevance: These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926292PMC
March 2021

Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity.

J Antimicrob Chemother 2021 02;76(3):758-764

University of Basel, Basel, Switzerland.

Background: The extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study.

Methods: Retrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug-drug interactions (DDIs) database.

Results: For 175 included individuals, the median age was 78 years (IQR 76-81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5-10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3-4.7), renal impairment (OR: 2.7; 95% CI: 1.4-5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1-3.8) and female sex (OR: 8.3; 95% CI: 2.4-28.1).

Conclusions: Polypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.
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http://dx.doi.org/10.1093/jac/dkaa505DOI Listing
February 2021

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects.

Trials 2020 Oct 28;21(1):896. Epub 2020 Oct 28.

Department of Clinical Research, Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel and University of Basel, Spitalstrasse 12, 4031, Basel, Switzerland.

Background: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain.

Objectives And Methods: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs.

Discussion: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.
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http://dx.doi.org/10.1186/s13063-020-04808-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594472PMC
October 2020

Prediction of RECRUITment In randomized clinical Trials (RECRUIT-IT)-rationale and design for an international collaborative study.

Trials 2020 Aug 21;21(1):731. Epub 2020 Aug 21.

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Poor recruitment of patients is the predominant reason for early termination of randomized clinical trials (RCTs). Systematic empirical investigations and validation studies of existing recruitment models, however, are lacking. We aim to provide evidence-based guidance on how to predict and monitor recruitment of patients into RCTs. Our specific objectives are the following: (1) to establish a large sample of RCTs (target n = 300) with individual patient recruitment data from a large variety of RCTs, (2) to investigate participant recruitment patterns and study site recruitment patterns and their association with the overall recruitment process, (3) to investigate the validity of a freely available recruitment model, and (4) to develop a user-friendly tool to assist trial investigators in the planning and monitoring of the recruitment process.

Methods: Eligible RCTs need to have completed the recruitment process, used a parallel group design, and investigated any healthcare intervention where participants had the free choice to participate. To establish the planned sample of RCTs, we will use our contacts to national and international RCT networks, clinical trial units, and individual trial investigators. From included RCTs, we will collect patient-level information (date of randomization), site-level information (date of trial site activation), and trial-level information (target sample size). We will examine recruitment patterns using recruitment trajectories and stratifications by RCT characteristics. We will investigate associations of early recruitment patterns with overall recruitment by correlation and multivariable regression. To examine the validity of a freely available Bayesian prediction model, we will compare model predictions to collected empirical data of included RCTs. Finally, we will user-test any promising tool using qualitative methods for further tool improvement.

Discussion: This research will contribute to a better understanding of participant recruitment to RCTs, which could enhance efficiency and reduce the waste of resources in clinical research with a comprehensive, concerted, international effort.
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http://dx.doi.org/10.1186/s13063-020-04666-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441612PMC
August 2020

Prevalence of potential drug-drug interactions in patients of the Swiss HIV Cohort Study in the era of HIV integrase inhibitors.

Clin Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and comedications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of HIV integrase inhibitors (INIs), characterized by more favorable interaction profiles.

Methods: The prevalence of PDDIs in treated HIV positive individuals was assessed for the period: 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged) or of weak clinical significance (yellow flagged).

Results: In 9'298 included individuals, median age was 51 years (IQR 43; 58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (32%) based regimens. In the entire cohort, 68% received > 1 comedication, 14% had polypharmacy (> 5 comedications) and 29% had > 1 PDDI. Among individuals with comedication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber - mostly with cardiovascular drugs - and 20% yellow flagged PDDIs) compared to 59% in 2008. Two percent had red flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared to 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of comedications was higher.

Conclusions: Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for comedications in this aging population impeded lower rates of PDDIs.
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http://dx.doi.org/10.1093/cid/ciaa918DOI Listing
July 2020

Risk of Emergency Surgery or Death After Initial Nonoperative Management of Complicated Diverticulitis in Scotland and Switzerland.

JAMA Surg 2020 07;155(7):600-606

Academic Coloproctology, University of Edinburgh/Western General Hospital, Edinburgh, United Kingdom.

Importance: National guidelines on interval resection for prevention of recurrence after complicated diverticulitis are inconsistent. Although US and German guidelines favor interval colonic resection to prevent a perceived high risk of recurrence, UK guidelines do not.

Objectives: To investigate patient management and outcomes after an index inpatient episode of nonoperatively managed complicated diverticulitis in Switzerland and Scotland and determine whether interval resection was associated with the rate of disease-specific emergency surgery or death in either country.

Design, Setting, And Participants: This secondary analysis of anonymized complete national inpatient data sets included all patients with an inpatient episode of successfully nonoperatively managed complicated diverticulitis in Switzerland and Scotland from January 1, 2005, to December 31, 2015. The 2 countries have contrasting health care systems: Switzerland is insurance funded, while Scotland is state funded. Statistical analysis was conducted from February 1, 2018, to October 17, 2019.

Main Outcomes And Measures: The primary end point defined a priori before the analysis was adverse outcome, defined as any disease-specific emergency surgical intervention or inpatient death after the initial successful nonsurgical inpatient management of an episode of complicated diverticulitis, including complications from interval elective surgery.

Results: The study cohort comprised 13 861 inpatients in Switzerland (6967 women) and 5129 inpatients in Scotland (2804 women) with an index episode of complicated acute diverticulitis managed nonoperatively. The primary end point was observed in 698 Swiss patients (5.0%) and 255 Scottish patients (5.0%) (odds ratio, 0.98; 95% CI, 0.81-1.19). Elective interval colonic resection was undertaken in 3280 Swiss patients (23.7%; median follow-up, 53 months [interquartile range, 24-90 months]) and 231 Scottish patients (4.5%; median follow-up, 57 months [interquartile range, 27-91 months]). Death after urgent readmission for recurrent diverticulitis occurred in 104 patients (0.8%) in Switzerland and 65 patients (1.3%) in Scotland. None of the investigated confounders had a significant association with the outcome apart from comorbidity.

Conclusions And Relevance: This study found no difference in the rate of adverse outcome (emergency surgery and/or inpatient death) despite a 5-fold difference in interval resection rates.
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http://dx.doi.org/10.1001/jamasurg.2020.0757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221865PMC
July 2020

Secondary hyperparathyroidism: recurrence after total parathyroidectomy with autotransplantation.

Swiss Med Wkly 2019 12 4;149:w20160. Epub 2019 Dec 4.

Department of General and Visceral Surgery, University Hospital Basel, Switzerland.

Background: Secondary hyperparathyroidism (sHPTH) is common in patients with end-stage chronic kidney disease. If drug therapy fails, total parathyroidectomy with autotransplantation of parathyroid tissue into the forearm (PTX-AT) is the most widely used procedure. High recurrence rates of sHPTH following PTX-AT are reported in the literature.

Objective: The aim of this study was to evaluate recurrences of sHPTH following PTX-AT in detail in order to develop strategies to prevent recurrences in the future.

Methods: This retrospective study analysed a single-centre cohort of 42 patients who underwent PTX-AT for sHPTH at a tertiary centre in Switzerland. Postoperative PTH levels were evaluated to determine the recurrence and persistence rates and the time to recurrence. Furthermore, the peri- and postoperative outcomes were assessed. Patients on dialysis and patients with a functioning kidney transplant suffering tertiary HPTH were analysed separately.

Results: Intraoperative measurements showed that serum PTH decreased to 6.9% (3.3–15.0%) of the preoperative baseline level. After a median follow-up of 89.5 months (IQR 31.9–152.9), persistence of sHPTH was found in five patients (11.9%) and recurrence in four patients (9.5%), giving a total recurrence rate of 21.4%.

Conclusion: Recurrence of sHPTH after PTX remains a problem, occurring in every fifth patient. In our experience, the introduction of intraoperative PTH measurement has helped to lower the rates of persistence and recurrence. Further reductions in the recurrence rate might be achieved with novel, more accurate pre- and intraoperative imaging techniques.
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http://dx.doi.org/10.4414/smw.2019.20160DOI Listing
December 2019

Reporting Quality of Journal Abstracts for Surgical Randomized Controlled Trials Before and After the Implementation of the CONSORT Extension for Abstracts.

World J Surg 2019 Jun 20:2371-2378. Epub 2019 Jun 20.

Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Adequate reporting is crucial in full-text publications but even more so in abstracts because they are the most frequently read part of a publication. In 2008, an extension for abstracts of the Consolidated Standards of Reporting Trials (CONSORT-A) statement was published, defining which items should be reported in abstracts of randomized controlled trials (RCTs). Therefore, we compared the adherence of RCT abstracts to CONSORT-A before and after the publication of CONSORT-A.

Methods: RCTs published in the five surgical journals with the highest impact factor were identified through PubMed for 2005-2007 and 2014-2016. Adherence to 15 CONSORT-A items and two additional items for abstracts of non-pharmacological trials was assessed in duplicate. We compared the overall adherence to CONSORT-A between the two time periods using an unpaired t test and explored adherence to specific items.

Results: A total of 192 and 164 surgical RCT abstracts were assessed (2005-2007 and 2014-2016, respectively). In the pre-CONSORT-A phase, the mean score of adequately reported items was 6.14 (95% confidence interval [CI] 5.90-6.38) and 8.11 in the post-CONSORT-A phase (95% CI 7.83-8.39; mean difference 1.97, 95% CI 1.60-2.34; p < 0.0001). The comparison of individual items indicated a significant improvement in 9 of the 15 items. The three least reported items in the post-CONSORT-A phase were randomization (2.4%), blinding (13.4%), and funding (0.0%). Specific items for non-pharmacological trials were rarely reported (approximately 10%).

Conclusion: The reporting in abstracts of surgical RCTs has improved after the implementation of CONSORT-A. More importantly, there is still ample room for improvement.
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http://dx.doi.org/10.1007/s00268-019-05064-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722149PMC
June 2019

Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1.

Brain Pathol 2019 05 21;29(3):336-350. Epub 2018 Dec 21.

Laboratory of Brain Tumor Biology, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.

Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in an mTORC1-independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counteract OPA1 trans-activation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked-down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. Thus, PI3K/AKT-SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.
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http://dx.doi.org/10.1111/bpa.12670DOI Listing
May 2019

Mutational interactions define novel cancer subgroups.

Nat Commun 2018 10 19;9(1):4353. Epub 2018 Oct 19.

Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.

Large-scale genomic data highlight the complexity and diversity of the molecular changes that drive cancer progression. Statistical analysis of cancer data from different tissues can guide drug repositioning as well as the design of targeted treatments. Here, we develop an improved Bayesian network model for tumour mutational profiles and apply it to 8198 patient samples across 22 cancer types from TCGA. For each cancer type, we identify the interactions between mutated genes, capturing signatures beyond mere mutational frequencies. When comparing mutation networks, we find genes which interact both within and across cancer types. To detach cancer classification from the tissue type we perform de novo clustering of the pancancer mutational profiles based on the Bayesian network models. We find 22 novel clusters which significantly improve survival prediction beyond clinical information. The models highlight key gene interactions for each cluster potentially allowing genomic stratification for clinical trials and identifying drug targets.
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http://dx.doi.org/10.1038/s41467-018-06867-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195543PMC
October 2018

Effectiveness of a Chlorhexidine Dressing on Silver-coated External Ventricular Drain-associated Colonization and Infection: A Prospective Single-blinded Randomized Controlled Clinical Trial.

Clin Infect Dis 2018 11;67(12):1868-1877

Department of Neurosurgery, University of Basel, Switzerland.

Background: Observational studies have shown that dressings containing chlorhexidine gluconate (CHX) lower the incidence external ventricular drain (EVD)-associated infections (EVDAIs). This prospective, randomized controlled trial (RCT) studies the efficacy of CHX-containing dressings in reducing bacterial colonization.

Methods: In this RCT, patients aged ≥18 years undergoing emergency EVD placement were randomly given either a CHX-containing or an otherwise identical control dressing at the skin exit wound. The primary end-point was bacterial regrowth in cultured skin swab samples of the EVD exit wound. The secondary end-points were catheters processed by sonication, clinically diagnosed EVDAI and surgical treatment of hydrocephalus.

Results: From October 2013 to January 2016, a total of 57 patients were randomized to receive either a CHX or a control dressing (29 and 28 patients, respectively). Cutaneous bacterial regrowth at the EVD exit wound was significantly reduced over time (geometric mean ratio, 0.18; 95% confidence interval, .08-.42; P < .001). The incidence of colonized catheters was lower in the CHX group (5 of 28; 18%) than in the control group (10 of 27; 33%), with less microbial colonization on the subcutaneous portion. The infection rate was 4 of 28 (14%) in the CHX group, compared with 7 of 27 (26%) in the control group, with a substantially lower hydrocephalus treatment rate (7 of 28 [25%] vs 14 of 27 [52%], respectively).

Conclusion: Our data support the use of CHX dressings to reduce EVD exit site contamination, potentially reducing EVDAIs and permanent cerebrospinal fluid diversion procedures for hydrocephalus.

Clinical Trials Registration: NCT02078830.
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http://dx.doi.org/10.1093/cid/ciy393DOI Listing
November 2018

Using Directed Acyclic Graphs in Epidemiological Research in Psychosis: An Analysis of the Role of Bullying in Psychosis.

Schizophr Bull 2017 10;43(6):1273-1279

Division of Psychiatry, University College London, London, UK.

Modern psychiatric epidemiology researches complex interactions between multiple variables in large datasets. This creates difficulties for causal inference. We argue for the use of probabilistic models represented by directed acyclic graphs (DAGs). These capture the dependence structure of multiple variables and, used appropriately, allow more robust conclusions about the direction of causation. We analyzed British national survey data to assess putative mediators of the association between bullying victimization and persecutory ideation. We compared results using DAGs and the Karlson-Holm-Breen (KHB) logistic regression commands in STATA. We analyzed data from the 2007 English National Survey of Psychiatric Morbidity, using the equivalent 2000 survey in an instant replication. Additional details of methods and results are provided in the supplementary material. DAG analysis revealed a richer structure of relationships than could be inferred using the KHB logistic regression commands. Thus, bullying had direct effects on worry, persecutory ideation, mood instability, and drug use. Depression, sleep and anxiety lay downstream, and therefore did not mediate the link between bullying and persecutory ideation. Mediation by worry and mood instability could not be definitively ascertained. Bullying led to hallucinations indirectly, via persecutory ideation and depression. DAG analysis of the 2000 dataset suggested the technique generates stable results. While causality cannot be fully determined from cross-sectional data, DAGs indicate the relationships providing the best fit. They thereby advance investigation of the complex interactions seen in psychiatry, including the mechanisms underpinning psychiatric symptoms. It may consequently be used to optimize the choice of intervention targets.
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http://dx.doi.org/10.1093/schbul/sbx013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737513PMC
October 2017

Refining Pathways: A Model Comparison Approach.

PLoS One 2016 1;11(6):e0155999. Epub 2016 Jun 1.

Department of Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.

Cellular signalling pathways consolidate multiple molecular interactions into working models of signal propagation, amplification, and modulation. They are described and visualized as networks. Adjusting network topologies to experimental data is a key goal of systems biology. While network reconstruction algorithms like nested effects models are well established tools of computational biology, their data requirements can be prohibitive for their practical use. In this paper we suggest focussing on well defined aspects of a pathway and develop the computational tools to do so. We adapt the framework of nested effect models to focus on a specific aspect of activated Wnt signalling in HCT116 colon cancer cells: Does the activation of Wnt target genes depend on the secretion of Wnt ligands or do mutations in the signalling molecule β-catenin make this activation independent from them? We framed this question into two competing classes of models: Models that depend on Wnt ligands secretion versus those that do not. The model classes translate into restrictions of the pathways in the network topology. Wnt dependent models are more flexible than Wnt independent models. Bayes factors are the standard Bayesian tool to compare different models fairly on the data evidence. In our analysis, the Bayes factors depend on the number of potential Wnt signalling target genes included in the models. Stability analysis with respect to this number showed that the data strongly favours Wnt ligands dependent models for all realistic numbers of target genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889067PMC
July 2017

Considering unknown unknowns: reconstruction of nonconfoundable causal relations in biological networks.

J Comput Biol 2013 Nov;20(11):920-32

Institute of Functional Genomics, Computational Diagnostics Group, University of Regensburg , Regensburg, Germany .

Our current understanding of cellular networks is rather incomplete. We over look important but so far unknown genes and mechanisms in the pathways. Moreover, we often only have a partial account of the molecular interactions and modifications of the known players. When analyzing the cell, we look through narrow windows leaving potentially important events in blind spots. Network reconstruction is naturally confined to what we have observed. Little is known on how the incompleteness of our observations confounds our interpretation of the available data. Here we ask which features of a network can be confounded by incomplete observations and which cannot. In the context of nested effects models, we show that in the presence of missing observations or hidden factors a reliable reconstruction of the full network is not feasible. Nevertheless, we can show that certain characteristics of signaling networks like the existence of cross-talk between certain branches of the network can be inferred in a nonconfoundable way. We derive a test for inferring such nonconfoundable characteristics of signaling networks. Next, we introduce a new data structure to represent partially reconstructed signaling networks. Finally, we evaluate our method both on simulated data and in the context of a study on early stem cell differentiation in mice.
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http://dx.doi.org/10.1089/cmb.2013.0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822397PMC
November 2013

Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells.

Nat Commun 2013 ;4:2610

1] German Cancer Research Center (DKFZ), Div. Signalling and Functional Genomics, and Heidelberg University, Dept. Cell and Molecular Biology, Faculty of Medicine Mannheim, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany [2].

Aberrant regulation of the Wnt/β-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or β-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or β-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind β-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or β-catenin depend on Wnt ligands and their secretion for a sufficient level of β-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls.
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http://dx.doi.org/10.1038/ncomms3610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826636PMC
June 2014