Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19

Background: Clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia," "side effects," "agranulocytosis," "TRS," or "bipolar affective disorder (BAF)" for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: We selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: We considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) Clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together. Background: Clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia," "side effects," "agranulocytosis," "TRS," or "bipolar affective disorder (BAF)" for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: We selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: We considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) Clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Download Full-text

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19

Brain Sciences ◽

10.3390/brainsci10110840 ◽

2020 ◽

Vol 10 (11) ◽

pp. 840

Author(s):

Ana Miruna Dragoi ◽

Ioana Radulescu ◽

Bogdana Adriana Năsui ◽

Anca Lucia Pop ◽

Valentin Nicolae Varlas ◽

...

Keyword(s):

Side Effects ◽

Bipolar Affective Disorder ◽

Healthcare Providers ◽

Case Series ◽

White Blood Count ◽

Eligibility Criteria ◽

Clozapine Dose ◽

Prophylactic Measures ◽

Increased Risk ◽

Stopping Treatment

Background: clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords “clozapine” and “schizophrenia”, “side effects”, “agranulocytosis”, “TRS”, or “bipolar affective disorder (BAF)” for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions’ severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Download Full-text

Clozapine. Pharmacodynamic Mechanisms, Potential Pharmacogenetic Biomarkers, and Risks in Schizophrenia. Particularities in the Context of Covid-19. An Updated Overview

10.20944/preprints202009.0724.v1 ◽

2020 ◽

Author(s):

Ana Miruna Dragoi ◽

Ioana Radulescu ◽

Anca Lucia Pop ◽

Bogdana Adriana Năsui ◽

Valentin Varlas ◽

...

Keyword(s):

Pulmonary Embolism ◽

Side Effects ◽

Early Onset ◽

Rating Scale ◽

White Blood Count ◽

Early Onset Schizophrenia ◽

Clozapine Therapy ◽

Prophylactic Measures ◽

Safety Margins ◽

Increased Risk

Background: Clozapine use is precarious due to its side effects - neurological, cardiovascular, and hematological; however, it is the gold standard in the therapy of resistant schizophrenia (TRS) in adults and harshly underused. Objective: Our purpose is to systematically examine the most recent data regarding clozapine in order to update the knowledge in pharmacological mechanisms, therapy benefits versus side effects to optimize its use in the context of a narrow and scarce of resources pathology, with particularities in the COVID-19 pandemic. (2) Data sources: We performed an accurate search in the primary sources of Databases (PubMed, BMC Public Health, Global Health, Cross Ref, Scopus, Web of Science, and Google Scholar) with specific keywords: “clozapine” and “schizophrenia,” “risks” agranulocytosis” “TRS” “bipolar affective disorder” “pregnancy” “early-onset schizophrenia” “resistance”. Study eligibility criteria: we extracted information regarding drug treatment, side effects profile, and efficacy for each trial; (3) Results: Of all the searched data we selected RCT’s, C.T.’s, reviews, systematic reviews, and meta-analyses; Data were converted and analyzed in a random-effects model. We included 45 studies, centered on six main topics in the search area: (a) treatment-resistant schizophrenia, (b) use in bipolar disorder, (c) side effects during the clozapine therapy - agranulocytosis, metabolic side effects, pharmacogenetic severity markers, dysmetabolic side effects, pulmonary embolism, seizure risk – (d) safety of clozapine in pregnancy, (e) clozapine resistance and ECT augmentation, (f) clozapine therapy and COVID-19 infection. Limitations: _______(4) Conclusions and implications of key findings: (a) The genetic vulnerability postulates predictors of severity so clozapine doses should be personalises for each patient based on pharmacogenetic testing; patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule; (b) Pulmonary embolism associated with clozapine has a mortality rate of 36.36%, prophylactic measures for venous thromboembolism for six months after initiating therapy is mandatory; (c) Convulsive episodes are not an indication for stopping the treatment, side effect (s.e.) incidence increases with the dose, the plasma concentration of clozapine (1300 ng/ml) it is a better s. e. predictor than the dosage; (d) clozapine refractory improves up to 69% early-onset schizophrenia, assesed by the Brief Psychiatric Rating Scale (BPRS) (e) more pharmacogenetic studies of the Romanian schizophrenic patients are needed in relation with the clozapine therapy in order to define more precise safety margins; (f) COVID-19 infection may enhance clozapine toxicity generating an increased risk of pneumonia therapy must be continued with proper monitoring of the white blood count and with the decrease of the clozapine dose by half until three days after the subside of the fever; psychiatrists and healthcare providers must act togheder. As in the past four decades, research has failed to generate effective novel psycho-pharmaceuticals, there is an urgent need to enhance the access to clozapine for people with TRS at the worldwide level. The progress of pharmacogenetic researches, endocrinology, genetic testing - offer the psychiatrists nowadays the chance to use this drug at its highest potential in a personalized manner for every patient - minimizing the adverse side-effects.

Download Full-text

Effects of prematurity on long-term renal health: a systematic review

BMJ Open ◽

10.1136/bmjopen-2020-047770 ◽

2021 ◽

Vol 11 (8) ◽

pp. e047770

Author(s):

Ananya Sangla ◽

Yogavijayan Kandasamy

Keyword(s):

Systematic Review ◽

Premature Birth ◽

Case Series ◽

Adverse Outcomes ◽

Human Studies ◽

Physical Parameters ◽

Eligibility Criteria ◽

Kidney Size ◽

Increased Risk

ObjectiveTo investigate the literature and determine if prematurity has an impact on long-term adverse kidney outcomes.DesignSystematic review.Data sourcesOVID Medline, PubMed, SCOPUS, CINAHL and EMBASE databases were searched for studies relating to the adverse outcomes of prematurity from 1990 to April 2021.Eligibility criteria for selecting studiesAll articles published between January 1990 and April 2021 that investigated whether premature infants developed long-term adverse renal outcomes were included in this review. Articles must have been human studies and written in English. Case series with less than 20 participants and case studies were excluded.Data extraction and synthesisOne reviewer completed the database searches. Article selection was performed independently and in a non-blinded manner by both reviewers. Initial screening was by title and abstract. Full texts of remaining articles were reviewed. Articles for which inclusion was unclear were re-reviewed by both reviewers, and a unanimous decision was taken as to whether they should be included. The Newcastle–Ottawa Scale was used for quality assessment of the included articles.ResultsThe literature search yielded 31 human studies, which investigated the short-term and long-term kidney outcomes of prematurity. These studies were conducted in 17 different countries. The most common outcomes measured were blood pressure (BP) and glomerular filtration rate. Other common outcomes measured included kidney size and mass, proteinuria, albuminuria, chronic kidney disease (CKD) and physical parameters such as height, weight and body mass index.ConclusionPrematurity is likely linked to increased risk of kidney dysfunction and high BP in childhood and into early adulthood. Premature birth conferred a twofold increased risk of CKD and extremely premature birth conferred a threefold increased risk of CKD. However, further larger multicentre studies are needed to draw definitive conclusions on the long-term kidney outcomes of prematurity.

Download Full-text

The Efficacy, Safety, and Side Effects of Intrapericardial Triamcinolone Treatment in Children with Post-surgical Pericardial Effusion: A Case Series

Pediatric Cardiology ◽

10.1007/s00246-021-02704-z ◽

2021 ◽

Author(s):

Manon H. van der Werff ◽

Hetty J. van der Kamp ◽

Johannes M. P. J. Breur

Keyword(s):

Side Effects ◽

Pericardial Effusion ◽

Septal Defect ◽

Case Series ◽

Close Monitoring ◽

Patient Records ◽

Electronic Patient Records ◽

Increased Risk ◽

Systemic Side Effects ◽

Asd Closure

AbstractIntrapericardial triamcinolone can be used to treat chronic pericardial effusion (PE) in adults; however, pediatric data are lacking. In this case series we aim to evaluate the efficacy, safety, and side effects of intrapericardial triamcinolone in children with PE. The incidence and treatment of post-surgical PE from 2009 to 2019 were determined using the institutional surgical database and electronic patient records. Furthermore, a retrospective analysis of efficacy, safety, and side effects of intrapericardial triamcinolone treatment for chronic post-surgical PE was performed. The incidence of postoperative PE requiring treatment was highest after atrial septal defect (ASD) closure when compared to other types of cardiac surgery (9.7% vs 4.3%). Intrapericardial treatment with triamcinolone resolved pericardial effusion in 3 out of 4 patients. All patients developed significant systemic side effects. Surgical ASD closure is associated with an increased risk of development of PE requiring treatment. Intrapericardial triamcinolone is an effective treatment for chronic postoperative PE in children, but is always associated with significant systemic side effects. Close monitoring and treatment of adrenal insufficiency are mandatory in these cases.

Download Full-text

The therapy is making me sick: how online portal communications between breast cancer patients and physicians indicate medication discontinuation

Journal of the American Medical Informatics Association ◽

10.1093/jamia/ocy118 ◽

2018 ◽

Vol 25 (11) ◽

pp. 1444-1451 ◽

Cited By ~ 7

Author(s):

Zhijun Yin ◽

Morgan Harrell ◽

Jeremy L Warner ◽

Qingxia Chen ◽

Daniel Fabbri ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Cancer Patients ◽

Hormonal Therapy ◽

Medical Center ◽

Healthcare Providers ◽

Breast Cancer Patients ◽

Online Portal ◽

Medication Discontinuation ◽

Increased Risk

Abstract Objective Online platforms have created a variety of opportunities for breast patients to discuss their hormonal therapy, a long-term adjuvant treatment to reduce the chance of breast cancer occurrence and mortality. The goal of this investigation is to ascertain the extent to which the messages breast cancer patients communicated through an online portal can indicate their potential for discontinuing hormonal therapy. Materials and Methods We studied the de-identified electronic medical records of 1106 breast cancer patients who were prescribed hormonal therapy at Vanderbilt University Medical Center over a 12-year period. We designed a data-driven approach to investigate patients’ patterns of messaging with healthcare providers, the topics they communicated, and the extent to which these messaging behaviors associate with the likelihood that a patient will discontinue a prescribed 5-year regimen of therapy. Results The results indicates that messaging rate over time [hazard ratio (HR) = 1.373, P = 0.002], mentions of side effects (HR = 1.214, P = 0.006), and surgery-related topics (HR = 1.170, P = 0.034) were associated with increased risk of early medication discontinuation. In contrast, seeking professional suggestions (HR = 0.766, P = 0.002), expressing gratitude to healthcare providers (HR = 0.872, P = 0.044), and mentions of drugs used to treat side effects (HR = 0.807, P = 0.013) were associated with decreased risk of medication discontinuation. Discussion and Conclusion This investigation suggests that patient-generated content can inform the study of health-related behaviors. Given that approximately 50% of breast cancer patients do not complete a course of hormonal therapy as described, the identification of factors associated with medication discontinuation can facilitate real-time interventions to prevent early discontinuation.

Download Full-text

Bowel ischaemia after endovascular aneurysm repair

VASA ◽

10.1024/0301-1526/a000698 ◽

2018 ◽

Vol 47 (4) ◽

pp. 273-277

Author(s):

Christopher Lowe ◽

Oussama El Bakbachi ◽

Damian Kelleher ◽

Imran Asghar ◽

Francesco Torella ◽

...

Keyword(s):

Case Reports ◽

Endovascular Aneurysm Repair ◽

Artery Occlusion ◽

Bibliographic Databases ◽

Bowel Ischaemia ◽

Prophylactic Measures ◽

Increased Risk ◽

Prisma Statement ◽

Meta Analyses ◽

Aneurysm Repair

Abstract. The aim of this review was to investigate presentation, aetiology, management, and outcomes of bowel ischaemia following EVAR. We present a case report and searched electronic bibliographic databases to identify published reports of bowel ischaemia following elective infra-renal EVAR not involving hypogastric artery coverage or iliac branch devices. We conducted our review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. In total, five cohort studies and three case reports were included. These studies detailed some 6,184 infra-renal elective EVARs, without procedure-related occlusion of the hypogastric arteries, performed between 1996 and 2014. Bowel ischaemia in this setting is uncommon with an incidence ranging from 0.5 to 2.8 % and includes a spectrum of severity from mucosal to transmural ischaemia. Due to varying reporting standards, an overall proportion of patients requiring bowel resection could not be ascertained. In the larger series, mortality ranged from 35 to 80 %. Atheroembolization, hypotension, and inferior mesenteric artery occlusion were reported as potential causative factors. Elderly patients and those undergoing prolonged procedures appear at higher risk. Bowel ischaemia is a rare but potentially devastating complication following elective infra-renal EVAR and can occur in the setting of patent mesenteric vessels and hypogastric arteries. Mortality ranges from 35 to 80 %. Further research is required to identify risk factors and establish prophylactic measures in patients that have an increased risk of developing bowel ischaemia after standard infra-renal EVAR.

Download Full-text

Dental Implant Placement in Patients with a History of Medications Related to Osteonecrosis of the Jaws: A Systematic Review

Journal of Oral Implantology ◽

10.1563/aaid-joi-d-19-00351 ◽

2020 ◽

Author(s):

Judd Sher ◽

Kate Kirkham-Ali ◽

Denny Luo ◽

Catherine Miller ◽

Dileep Sharma

Keyword(s):

Systematic Review ◽

At Risk ◽

Drug Therapy ◽

Dental Implant ◽

Case Series ◽

Cochrane Central Register ◽

Bisphosphonate Treatment ◽

Implant Placement ◽

Increased Risk ◽

History Of

The present systematic review evaluates the safety of placing dental implants in patients with a history of antiresorptive or antiangiogenic drug therapy. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. PubMed, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and OpenGrey databases were used to search for clinical studies (English only) to July 16, 2019. Study quality was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases using a modified Newcastle-Ottawa scale and the Joanna Briggs Institute critical appraisal checklist for case series. A broad search strategy resulted in the identification of 7542 studies. There were 28 studies reporting on bisphosphonates (5 cohort, 6 case control, and 17 case series) and one study reporting on denosumab (case series) that met the inclusion criteria and were included in the qualitative synthesis. The quality assessment revealed an overall moderate quality of evidence among the studies. Results demonstrated that patients with a history of bisphosphonate treatment for osteoporosis are not at increased risk of implant failure in terms of osseointegration. However, all patients with a history of bisphosphonate treatment, whether taken orally for osteoporosis or intravenously for malignancy, appear to be at risk of ‘implant surgery-triggered’ MRONJ. In contrast, the risk of MRONJ in patients treated with denosumab for osteoporosis was found to be negligible. In conclusion, general and specialist dentists should exercise caution when planning dental implant therapy in patients with a history of bisphosphonate and denosumab drug therapy. Importantly, all patients with a history of bisphosphonates are at risk of MRONJ, necessitating this to be included in the informed consent obtained prior to implant placement. The James Cook University College of Medicine and Dentistry Honours program and the Australian Dental Research Foundation Colin Cormie Grant were the primary sources of funding for this systematic review.

Download Full-text

Cardiovascular Disease in Spondyloarthritides

Current Vascular Pharmacology ◽

10.2174/1570161117666190426164306 ◽

2020 ◽

Vol 18 (5) ◽

pp. 473-487 ◽

Cited By ~ 4

Author(s):

Charalampos Papagoras ◽

Paraskevi V. Voulgari ◽

Alexandros A. Drosos

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Healthcare Providers ◽

Cardiovascular Death ◽

Point Of View ◽

Treat To Target ◽

Inflammatory Joint Diseases ◽

Scientific Organizations ◽

Increased Risk ◽

Risk Patients

The spondyloarthritides are a group of chronic systemic inflammatory joint diseases, the main types being ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Evidence accumulating during the last decades suggests that patients with AS or PsA carry an increased risk for cardiovascular disease and cardiovascular death. This risk appears to be mediated by systemic inflammation over and above classical cardiovascular risk factors. The excess cardiovascular risk in those patients has been formally acknowledged by scientific organizations, which have called physicians’ attention to the matter. The application by Rheumatologists of new effective anti-rheumatic treatments and treat-to-target strategies seems to benefit patients from a cardiovascular point of view, as well. However, more data are needed in order to verify whether anti-rheumatic treatments do have an effect on cardiovascular risk and whether there are differences among them in this regard. Most importantly, a higher level of awareness of the cardiovascular risk is needed among patients and healthcare providers, better tools to recognize at-risk patients and, ultimately, commitment to address in parallel both the musculoskeletal and the cardiovascular aspect of the disease.

Download Full-text

Death Rate Due to COVID-19 in Alzheimer’s Disease and Frontotemporal Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-200940 ◽

2020 ◽

Vol 78 (2) ◽

pp. 537-541

Author(s):

Jordi A. Matias-Guiu ◽

Vanesa Pytel ◽

Jorge Matías-Guiu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Death Rate ◽

Case Series ◽

Care Homes ◽

Relevant Factor ◽

Increased Risk ◽

Care Facilities ◽

Probability Of Death

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

Download Full-text

NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.528 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii126-ii126

Author(s):

Amber Ruiz ◽

Jerome Graber

Keyword(s):

Treatment Response ◽

Mismatch Repair ◽

Case Series ◽

Germline Mutations ◽

Molecular Characteristics ◽

Loss Of Function ◽

Dna Mismatch ◽

Mutational Burden ◽

Increased Risk ◽

Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

Download Full-text