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Orphanet Journal of Rare Diseases May 2020Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a... (Review)
Review
BACKGROUND
Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics.
METHODS
We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019.
RESULTS
Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported.
CONCLUSIONS
Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
Topics: Animals; Caenorhabditis elegans; Dogs; HEK293 Cells; Horses; Humans; Hyperthermia; Malignant Hyperthermia; Mice; Muscular Diseases; Mutation; Rabbits; Ryanodine Receptor Calcium Release Channel; Swine; Zebrafish
PubMed: 32381029
DOI: 10.1186/s13023-020-01384-x -
Environmental Research Nov 2023Photothermal therapy (PTT) is an emerging non-invasive method used in cancer treatment. In PTT, near-infrared laser light is absorbed by a chromophore and converted into... (Review)
Review
Photothermal therapy (PTT) is an emerging non-invasive method used in cancer treatment. In PTT, near-infrared laser light is absorbed by a chromophore and converted into heat within the tumor tissue. PTT for cancer usually combines a variety of interactive plasmonic nanomaterials with laser irradiation. PTT enjoys PT agents with high conversion efficiency to convert light into heat to destroy malignant tissue. In this review, published studies concerned with the use of nanoparticles (NPs) in PTT were collected by a systematic and comprehensive search of PubMed, Cochrane, Embase, and Scopus databases. Gold, silver and iron NPs were the most frequent choice in PTT. The use of surface modified NPs allowed selective delivery and led to a precise controlled increase in the local temperature. The presence of NPs during PTT can increase the reactive generation of oxygen species, damage the DNA and mitochondria, leading to cancer cell death mainly via apoptosis. Many studies recently used core-shell metal NPs, and the effects of the polymer coating or ligands targeted to specific cellular receptors in order to increase PTT efficiency were often reported. The effective parameters (NP type, size, concentration, coated polymers or attached ligands, exposure conditions, cell line or type, and cell death mechanisms) were investigated individually. With the advances in chemical synthesis technology, NPs with different shapes, sizes, and coatings can be prepared with desirable properties, to achieve multimodal cancer treatment with precision and specificity.
PubMed: 37487920
DOI: 10.1016/j.envres.2023.116526 -
Acta Psychiatrica Scandinavica Oct 2021Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality... (Review)
Review
OBJECTIVE
Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited.
METHODS
Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death.
RESULTS
683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14-8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71-7.32; p = 0.0004), severity of hyperthermia (Unit-OR = 1.30, 95%CI = 1.16-1.46; p < 0.0001), and older age (Unit-OR = 1.05, 95%CI = 1.02-1.07; p = 0.0014). Even in univariate, patient-level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long-acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n = 38/433 (8.8%) vs. second-generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality.
CONCLUSION
Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs.
Topics: Adult; Aged; Antipsychotic Agents; Humans; Incidence; Male; Neuroleptic Malignant Syndrome; Odds Ratio; Risk Factors
PubMed: 34358327
DOI: 10.1111/acps.13359 -
Journal of Clinical Neuromuscular... Dec 2019Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and...
OBJECTIVES
Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and discussing recent findings concerning the cause, frequency, evolution, and work-up of conditions manifesting as AHCE and normal or abnormal electromyography (EMG) respectively muscle biopsy.
METHODS
Systematic PubMed search.
RESULTS
There are numerous primary (hereditary) and acquired myopathies that manifest with permanent, recurrent, or temporary AHCE with/without myopathic EMG or muscle biopsy. AHCE particularly occurs at onset of these conditions, which include dystrophinopathies, myotilinopathies, calpainopathy, caveolinopathy, dysferlinopathy, central core disease, multicore disease, desminopathy, MD1, MD2, hypoPP, malignant hyperthermia susceptibility, Pompe disease, McArdle disease, myoadenylate deaminase-deficiency, CPT2-deficiency, mitochondrial disorders, or myopathy with tubular aggregates. Most likely, other primary myopathies manifest with AHCE as well, without having been reported. Patients with AHCE should be taken seriously and repeated CK determination must be conducted. If hyper-CKemia is persisting or recurrent, these patients should undergo an EMG and eventually muscle biopsy. If noninformative, genetic work-up by a panel or whole exome sequencing should be initiated, irrespective of the family history. Patients with AHCE should avoid excessive exercise, require sufficient hydration, require counseling with regard to the risk of malignant hyperthermia, and should inform anesthesiologists and surgeons about their condition before elective surgery.
CONCLUSIONS
Recurrent AHCE should be taken seriously and managed with conventional work-up. If noninformative, genetic work-up should follow irrespective of the family history.
Topics: Creatine Kinase; Humans; Mass Screening; Mitochondrial Diseases; Muscular Diseases
PubMed: 31743252
DOI: 10.1097/CND.0000000000000269 -
Radiation Oncology (London, England) Sep 2022Soft tissue sarcomas (STS) represent a diverse group of rare malignant tumors. Currently, five to six weeks of preoperative radiotherapy (RT) combined with surgery... (Review)
Review
BACKGROUND
Soft tissue sarcomas (STS) represent a diverse group of rare malignant tumors. Currently, five to six weeks of preoperative radiotherapy (RT) combined with surgery constitute the mainstay of therapy for localized high-grade sarcomas (G2-G3). Growing evidence suggests that shortening preoperative RT courses by hypofractionation neither increases toxicity rates nor impairs oncological outcomes. Instead, shortening RT courses may improve therapy adherence, raise cost-effectiveness, and provide more treatment opportunities for a wider range of patients. Presumed higher rates of adverse effects and worse outcomes are concerns about hypofractionated RT (HFRT) for STS. This systematic review summarizes the current evidence on preoperative HFRT for the treatment of STS and discusses toxicity and oncological outcomes compared to normofractionated RT.
METHODS
We conducted a systematic review of clinical trials describing outcomes for preoperative HFRT in the management of STS using PubMed, the Cochrane library, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Embase, and Ovid Medline. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Trials on retroperitoneal sarcomas, postoperative RT, and hyperthermia were excluded. Articles published until November 30th, 2021, were included.
RESULTS
Initial search yielded 94 articles. After removal of duplicate and ineligible articles, 13 articles qualified for analysis. Eight phase II trials and five retrospective analyses were reviewed. Most trials applied 5 × 5 Gy preoperatively in patients with high-grade STS. HFRT courses did not show increased rates of adverse events compared to historical trials of normofractionated RT. Toxicity rates were mostly comparable or lower than in trials of normofractionated RT. Moreover, HFRT achieved comparable local control rates with shorter duration of therapy. Currently, more than 15 prospective studies on HFRT + / - chemotherapy are ongoing.
CONCLUSIONS
Retrospective data and phase II trials suggest preoperative HFRT to be a reasonable treatment modality for STS. Oncological outcomes and toxicity profiles were favorable. To date, our knowledge is mostly derived from phase II data. No randomized phase III trial comparing normofractionated and HFRT in STS has been published yet. Multiple ongoing phase II trials applying HFRT to investigate acute and late toxicity will hopefully bring forth valuable findings.
Topics: Humans; Prospective Studies; Radiation Dose Hypofractionation; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms
PubMed: 36104789
DOI: 10.1186/s13014-022-02072-9 -
Neuromuscular Disorders : NMD Dec 2020Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with...
Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with other syndromes that have a clear genetic background, in particular RYR1-related malignant hyperthermia. Through a literature review, performed according to the PRISMA guidelines, we aimed to report the clinical features of both syndromes, and the results of genetic testing performed. 10 case series and 99 case reports were included, comprising 134 patients. A male predominance of 58% was found. The median age was 35 (range 4-84) years. Eight patients experienced recurrent episodes of rhabdomyolysis. Genetic analysis was performed in eleven patients (8%), revealing four RYR1 variants, three likely benign (p.Asp849Asn, p.Arg4645Gln, p.Arg4645Gln) and one variant of uncertain significance (p.Ala612Thr). This review underlines that a subset of patients with neuroleptic malignant syndrome and serotonin syndrome develop recurrent episodes of rhabdomyolysis. This recurrent pattern suggests a possible underlying (genetic) susceptibility. However, the genetic background of neuroleptic malignant syndrome and serotonin syndrome has only been investigated to a very limited degree so far. The increasing availability of next generation sequencing offers an opportunity to identify potentially associated genetic backgrounds, especially in patients with recurrent episodes or a positive family history.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Malignant Hyperthermia; Middle Aged; Mutation; Neuroleptic Malignant Syndrome; Phenotype; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel; Serotonin Syndrome; Young Adult
PubMed: 33250373
DOI: 10.1016/j.nmd.2020.10.010 -
Frontiers in Cell and Developmental... 2022Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost... (Review)
Review
Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.
PubMed: 36158215
DOI: 10.3389/fcell.2022.984311 -
Thoracic Cancer Apr 2022Breast and ovarian cancer account for over 30% of malignant pleural effusions (MPEs). Treatment of the metastatic disease requires control of the MPE. Even though... (Review)
Review
Hyperthermic intrathoracic chemotherapy for the treatment of malignant pleural effusion caused by breast and ovarian cancer: A systematic literature review and pooled analysis.
OBJECTIVES
Breast and ovarian cancer account for over 30% of malignant pleural effusions (MPEs). Treatment of the metastatic disease requires control of the MPE. Even though primarily symptomatic, the treatment of the MPE can potentially affect the oncological course of the disease. The aim of this review is to analyze the effectiveness of intrathoracic chemotherapy in the treatment of MPE caused by breast and ovarian cancer.
METHODS
A systematic literature research was conducted up until May 2021. Studies published in English on patients undergoing either surgical or interventional intrapleural chemotherapy were included.
RESULTS
Thirteen studies with a total of 497 patients were included. Analysis was performed on 169 patients with MPE due to breast cancer and eight patients with MPE secondary to ovarian cancer. The pooled success rates of intrathoracic chemotherapy for controlling the MPE were 59.1% and 87.5%, respectively. A survival analysis was not possible with the available data. The overall toxicity of the treatment was low.
CONCLUSIONS
Intrathoracic chemotherapy achieves symptomatic control of the MPE in 59.1% of patients with metastatic breast cancer and 87.5% of patients with metastatic ovarian cancer. This is inferior to other forms of surgical pleurodesis. Data from small case series and studies on intraperitoneal chemotherapy show promising results. However, formal oncological studies on the use of intrathoracic chemotherapy for metastatic breast or ovarian cancer are lacking. Further prospective pilot studies are needed to assess the therapeutic oncological effects of this treatment.
Topics: Breast Neoplasms; Female; Humans; Hyperthermia, Induced; Ovarian Neoplasms; Pleural Effusion, Malignant; Pleurodesis
PubMed: 35194945
DOI: 10.1111/1759-7714.14361 -
Journal of the Academy of... 2023Patients with cerebral palsy, a group of movement disorders with motor, and possibly communication and behavioral features that mimic catatonic signs, may benefit from... (Review)
Review
BACKGROUND
Patients with cerebral palsy, a group of movement disorders with motor, and possibly communication and behavioral features that mimic catatonic signs, may benefit from efforts to improve the detection and treatment of comorbid catatonia. Given that cerebral palsy frequently co-occurs with conditions associated with catatonia, such as autism spectrum disorder, epilepsy, intellectual disability, and mood and psychotic disorders, lifetime prevalence of catatonia in this population may be high.
OBJECTIVE
This study aimed to systematically review the literature on catatonia and the related condition of neuroleptic malignant syndrome (NMS) in patients with cerebral palsy while presenting 2 additional cases of catatonia.
METHODS
We used the terms "cerebral palsy" in combination with "catatoni∗," related terms for catatonia, and "neuroleptic malignant syndrome" to query Ovid MEDLINE (1948 to November 28, 2022), PsycINFO, Cumulative Index to Nursing, and Allied Health Literature, and Embase for applicable case reports. The Neuroleptic Malignant Syndrome Information Service database was also manually searched.
RESULTS
In addition to our 2 catatonia reports, we identified 10 reports of catatonia in patients with cerebral palsy, as well as 8 reports of NMS. Patients with both conditions responded well, and sometimes rapidly, to treatment. Notably, of the 5 patients with catatonia and cerebral palsy who received electroconvulsive therapy, 2 developed recurrent self-limited hyperthermia posttreatment. We also identified several cases of baclofen withdrawal, which can be life threatening because of seizure risk, presenting with NMS-like features in patients with cerebral palsy who had malfunctioning intrathecal baclofen pumps for spasticity management.
CONCLUSIONS
Given frequent comorbidity of conditions associated with catatonia in patients with cerebral palsy, as well as routine treatment with medications that can induce NMS, such as metoclopramide and anticholinergics, catatonia and NMS may be underreported in the cerebral palsy patient population, despite being highly treatable. Possible underdiagnosis of catatonia in patients with cerebral palsy may be because of misattribution of overlapping features between the 2 conditions to cerebral palsy. Clinicians should be aware of possible recurrent self-limited fever when using electroconvulsive therapy to treat patients with catatonia and cerebral palsy while also being vigilant for intrathecal baclofen withdrawal when encountering NMS-like features in patients with cerebral palsy.
Topics: Humans; Antipsychotic Agents; Catatonia; Baclofen; Autism Spectrum Disorder; Neuroleptic Malignant Syndrome; Cerebral Palsy; Paralysis
PubMed: 36586471
DOI: 10.1016/j.jaclp.2022.12.008 -
European Respiratory Review : An... Sep 2019Debulking surgery and hyperthermic intrathoracic chemotherapy (HITHOC) has been successfully used in the treatment of thoracic tumours. Few authors report on the...
INTRODUCTION
Debulking surgery and hyperthermic intrathoracic chemotherapy (HITHOC) has been successfully used in the treatment of thoracic tumours. Few authors report on the feasibility of its use in patients with lung cancer and malignant pleural effusion. The aim of this study was to evaluate the efficacy and results of debulking surgery and HITHOC in the treatment of selected patients with nonsmall cell lung cancer (NSCLC) and malignant pleural effusion.
METHODS
A systematic review was conducted in MEDLINE in accordance with PRISMA guidelines. The word search included: "hyperthermic intrathoracic chemotherapy and/or HITHOC or hyperthermic intrapleural". Inclusion criteria were only those studies reporting a sufficient amount of data on HITHOC and surgery for lung cancer. Single case reports and review articles were excluded.
RESULTS
20 articles were selected as they related to the topic of HITHOC and lung cancer. Most were from China (n=8) and Japan (n=6). Only four out of the 20 articles had sufficient data for this review. In total, data for 21 patients were collected. Debulking surgery ranged from wedge resection to pneumonectomy and pleurectomy. Mean survival was 27 months and median survival was 18 months (range 1-74 months). 13 patients out of 21 (62%) were alive at 1 year and six (28.5%) were alive at 2 years. 10 patients were still alive at the time of the respective publication in the 21 patients included. Systemic toxicity and treatment-related mortality were nil. There were insufficient data to perform a meta-analysis.
CONCLUSION
Although reported survival in this systematic review is encouraging, available evidence concerning debulking surgery and HITHOC in N0-N1 NSCLC with malignant pleural effusion is weak. Better evidence in the form of a randomised controlled trial is mandatory.
Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cytoreduction Surgical Procedures; Female; Humans; Hyperthermia, Induced; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pleural Effusion, Malignant; Pneumonectomy; Risk Factors; Time Factors; Treatment Outcome
PubMed: 31366459
DOI: 10.1183/16000617.0018-2019