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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 -
Frontiers in Physiology 2022Ca levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca... (Review)
Review
Ca levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1 (RyR1). Calsequestrin (Casq) is a protein that binds large amounts of Ca in the lumen of the SR terminal cisternae, near sites of Ca release. There is general agreement that Casq is not only important for the SR ability to store Ca, but also for modulating the opening probability of the RyR Ca release channels. About 20 years ago we generated a mouse model lacking Casq1 (Casq1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of Casq1 caused a striking remodeling of membranes of SR and of transverse tubules (TTs), and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca content, smaller Ca transients, and severe SR depletion during repetitive stimulation. After the initial studies, we discovered that Casq1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying these syndromes involved excessive SR Ca leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how Casq1-null mice could survive without the most important SR Ca binding protein was a puzzling issue that was not solved. The mystery was finally solved in 2020, when we discovered that in Casq1-null mice the SR undergoes adaptations that result in constitutively active store-operated Ca entry (SOCE). SOCE is a mechanism that allows skeletal fibers to use external Ca when SR stores are depleted. The post-natal compensatory mechanism that allows Casq1-null mice to survive involves the assembly of new SR-TT junctions (named Ca entry units) containing Stim1 and Orai1, the two proteins that mediate SOCE.
PubMed: 36311237
DOI: 10.3389/fphys.2022.1033300 -
Anaesthesiology Intensive Therapy 2022Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising...
INTRODUCTION
Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising relaxants. The estimated incidence of MH is between 1 : 10,000 and 1 : 250,000 anaesthetic procedures. In Poland the incidence of MH is unknown. Dantrolene is imported as a life-saving drug and temporally authorised for sale. The aim of the study is to assess the incidence of MH and access to dantrolene in the Mazovia Province.
METHODS
Anonymous questionnaires were sent to anaesthesia departments in the Mazovia Province after prior contact by phone and e-mail. The survey was approved by the local ethical review board.
RESULTS
Completed surveys were received from 60 respondents which represents 72% of anaesthesiology departments in Mazovia. In the last 5 years there have been 4 episodes of MH in the Mazovia Province. Three patients survived the MH crisis. In a centre that did not have access to dantrolene, the patient died. Dantrolene is found only in 11 (18.3%) anaesthesiology departments in Mazovia. Only 6 (10%) hospitals are able to administer dantrolene within 5 minutes of suspecting MH crisis, while 5 centres may receive it after a few days. Only 38% of units have an algorithm for dealing with MH crisis in the operating theatres.
CONCLUSIONS
MH is rare, but if untreated, it can be fatal. Therefore prompt diagnosis and treatment are crucial to avoid fatal outcome. Every centre using inhalational anaesthetics and/or succinylcholine should have dantrolene. To ensure the safety of our patients, we must be better prepared.
Topics: Anesthetics, Inhalation; Dantrolene; Humans; Malignant Hyperthermia; Operating Rooms; Succinylcholine
PubMed: 35579281
DOI: 10.5114/ait.2022.115348 -
IUBMB Life Dec 2019Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body... (Review)
Review
Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body temperature to highly irreversible levels, which causes death in around three of four cases. The trigger anesthetics cause an anomalous, continued ascent in myoplasmic calcium levels. Possible mechanisms by which continuous release of sodium, calcium from skeletal muscle plasma membrane and sarcoplasmic reticulum stores respectively can produce the profound hyperthermia are discussed.
Topics: Anesthesia; Anesthetics; Calcium; Dantrolene; Humans; Malignant Hyperthermia; Muscle, Skeletal; Sodium-Calcium Exchanger; TRPC Cation Channels
PubMed: 31381266
DOI: 10.1002/iub.2138 -
Cureus Sep 2020Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) share similar clinical characteristics. These conditions can present... (Review)
Review
Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) share similar clinical characteristics. These conditions can present life-threatening situations due to exposure to different drugs. A similar genetic predisposition is suspected between these syndromes as well. This review aims to consolidate the knowledge about the genetics of these disorders and find possible correlations among them to frame the best possible approaches using different drugs without producing life-threatening complications that can be preventable. As a method, we collected data using PubMed with a Medical Subject Headings (MeSH) strategy. The inclusion criteria were as follows: full papers, studies conducted on humans, papers published in the English language, and study types that included case reports, journal articles, multicenter studies, clinical studies, observational studies, or clinical trials. Studies involving animals, articles that were without a visible abstract, study types that included clinical reviews, systematic reviews, or meta-analyses were excluded. 146 papers were reviewed, and 130 papers were removed for no possible extraction of data, duplication of the data, or the study outcome was not compatible with the objective of this review. Ultimately, a total of 17 papers were used for the discussion of this article. As a result of this review, we found no genetic association between NMS, SS, and MH development. Finally, we conclude that NMS, SS, and MH presentation are caused by different mutations which are not associated. However, because of the life-threatening clinical presentation of these conditions, genetic tests should be suggested in patients with a family history of these disorders before administering any pertinent drug that increases the risk of developing all these syndromes.
PubMed: 33123448
DOI: 10.7759/cureus.10635 -
Sports Medicine - Open May 2023Exertional heat stroke (EHS) is a medical emergency, occurring when the body generates more heat than it can dissipate, and frequently associated with exertional...
INTRODUCTION
Exertional heat stroke (EHS) is a medical emergency, occurring when the body generates more heat than it can dissipate, and frequently associated with exertional rhabdomyolysis (ERM). In the present study we aimed to (I) identify clinical features and risk factors, (II) describe current prehospital management, (III) investigate long-term outcomes including the impact on mental health, and review the guidance received during restarting activities. We hope that our approach will improve individual and organizational heat illness preparedness, and improve follow-up care.
METHODS
We performed a prospective online survey and retrospective medical record review among athletes and military personnel with an episode of EHS/ERM in the Netherlands between 2010 and 2020. We evaluated prehospital management, risk factors, clinical features and long-term outcomes at 6 and 12 months after the event, including mental health symptoms. Furthermore, we investigated what guidance participants received during follow-up, and assessed the patients' perspective on these outcomes.
RESULTS
Sixty participants were included, 42 male (70%) and 18 female (30%), of which 47 presented with EHS (78%) and 13 with ERM (22%). Prehospital management was inconsistent and in the majority of participants not conducted according to available guidelines. Self-reported risk factors included not feeling well-acclimatized to environmental heat (55%) and peer pressure (28%). Self-reported long-term symptoms included muscle symptoms at rest (26%) or during exercise (28%), and neurological sequelae (11%). Validated questionnaires (CIS, HADS and SF-36) were indicative of severe fatigue (30%) or mood/anxiety disorders (11%). Moreover, 90% expressed a lack of follow-up care and that a more frequent and intensive follow-up would have been beneficial for their recovery process.
CONCLUSION
Our findings indicate major inconsistencies in the management of patients with EHS/ERM, emphasizing the compelling need for implementing standardized protocols. Based on the results of long-term outcome measures, we recommend to counsel and evaluate every patient not only immediately after the event, but also in the long-term.
PubMed: 37204519
DOI: 10.1186/s40798-023-00570-y -
Advanced Science (Weinheim,... Jul 2023Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the...
Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au-cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor-associated antigens release through ATO-induced ferroptosis and photothermal-induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1-6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long-term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti-programmed death-ligand 1 (PD-L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.
Topics: Mice; Humans; Animals; Contrast Media; Photothermal Therapy; Phototherapy; Hyperthermia, Induced; Mice, Inbred Strains; Ultrasonography; Liver Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37162268
DOI: 10.1002/advs.202300878 -
Materials Today. Bio Mar 2021Bioactive glasses and glass-ceramics are well-proven potential biomaterials for bone-tissue engineering applications because of their compositional flexibility. Many... (Review)
Review
Bioactive glasses and glass-ceramics are well-proven potential biomaterials for bone-tissue engineering applications because of their compositional flexibility. Many research groups have been focused to explore the utility of bioactive glass-ceramics beyond bone engineering to hyperthermia treatment of cancer. Hyperthermia refers to raising the temperature of tumor close to 44°C at which malignant cells perish with negligible harm to normal cells. Hyperthermia can be employed by many means such as by ultrasonic waves, electromagnetic waves, infrared radiations, alternating magnetic fields, etc. Magnetic bioactive glass-ceramics are advantageous over other potential candidates for thermoseeds such as nanofluids, superparamagnetic nanoparticles because they can bond not only to the natural bone but also with soft tissues in few cases, which helps regenerating the affected part due to its bioactive nature. Strict restrictions on clinical settings ( < ) force the research activities to be more focused on material characteristics to raise the implant temperature to required ranges. Lots of efforts have been made in past years to tackle these challenges and design best-suited glass-ceramics for hyperthermia treatment. This review aims to provide essential information on the concept of hyperthermia treatment of cancer and recent developments in the field of bioactive glass-ceramics for cancer treatment. The advantages and disadvantages of magnetic glass-ceramics over other potential thermoseed materials are highlighted. In this field, the major challenges are to develop magnetic glasses, which have fast and bulk crystallization with optimized magnetic phases with lower Curie and Neel temperatures.
PubMed: 33778466
DOI: 10.1016/j.mtbio.2021.100100 -
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