Hyperthermia Group Research Articles

Sepsis Bundle Compliance and Mortality according to Body Temperature of Patients with Sepsis in General Wards Identified Using the Rapid Response System

Purpose : This study aimed to investigate the difference in compliance with the sepsis bundle and mortality rates according to the body temperature of patients with sepsis in general wards identified using a rapid response system (RRS). Methods : A retrospective observational study of 1,083 patients with sepsis in general wards identified using the RRS from July 2018 to December 2022 was performed at a tertiary care hospital in South Korea. The patients were classified into hypothermia (＜36℃), normothermia (36-38℃), and hyperthermia (＞38℃) groups according to their body temperature at the time of RRS activation. Results : A total of 1,083 sepsis patients were analyzed, comprising 17 cases of hypothermia, 624 cases of normothermia, and 442 cases of hyperthermia. There were statistically significant differences among the body temperature groups in the rate of compliance with the sepsis bundle within 1 h (hypothermia: 64.7% vs. normothermia: 49.5% vs. hyperthermia: 60.4%, <i>p</i> =.010), the rate of compliance with the overall sepsis bundle, including lactate re-measurement (64.7% vs. 49.5% vs. 60.4%, <i>p</i> =.001), and the rate of blood culture testing (94.1% vs. 85.9% vs. 92.8%, <i>p</i> =.002). The 28-day mortality rates in the hypothermia, normothermia, and hyperthermia groups were 29.4%, 32.4%, and 16.5%, respectively (<i>p</i> ＜.001). Conclusion : There were statistically significant differences in compliance with the sepsis bundle and mortality rates according to body temperature. Patients with sepsis and normothermia showed lower compliance with the sepsis bundle and higher mortality rates. Therefore, it is recommended to develop strategies for the early recognition of patients with sepsis and normothermia and to improve compliance with the sepsis bundle.

The Impact of Photobiomodulation Therapy on Enhancing Spermatogenesis and Blood-Testis Barrier Integrity in Adult Male Mice Subjected to Scrotal Hyperthermia.

Introduction: Unhealthy lifestyle choices such as alcohol, chemicals, and heat stress can worsen male infertility. Heat stress can cause damage to the essential structure known as the blood-testis barrier (BTB). Photobiomodulation therapy (PBMT) has been employed in various studies to enhance sperm quality in individuals with genital inflammatory conditions in recent times. The current research sought to study how laser therapy affects spermatogenesis and the structure of the BTB in a mouse model of scrotal heat exposure. Methods: Thirty adult male NMRI mice, 8 weeks old, were divided into three groups: Control, Hyperthermia, and Hyperthermia+Laser 0.03 J/cm2. The animals in the hyperthermia group had their testicles exposed to water at 43 °C for 20 minutes five times every other day. Then, the testicles were exposed to laser radiation every other day for 35 days, lasting 3 minutes each time, with an energy density of 0.03 J/cm2. Animals were sacrificed, and sperm parameters, reactive oxygen species (ROS) and glutathione (GSH) levels, stereological parameters, and gene expression were assessed in the end. Results: The study showed that PBMT can significantly enhance sperm quality, quantity of spermatogenic cells, testicular volume, levels of ROS and GSH, and gene expression related to the blood-testis barrier. Conclusion: Currently, PBMT is a novel approach for addressing male infertility by preserving the integrity of the BTB in Sertoli cells, which in turn supports the growth and specialization of germ cells.

Combination of US hyperthermia and radiotherapy on a preclinical glioblastoma model

In this work the effect of combining ultrasound (US) hyperthermia (HT) with radiotherapy (RT) was investigated. The treatment was applied to a GBM xenograft nude mouse model obtained by injecting 2×106\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2 \ imes 10^{6}$$\\end{document} U87 luc+ cells. The combined treatment group received 6 Gy and HT at 43∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$43^\\circ$$\\end{document} for 8 min. The ultrasound field was generated by a closed-loop computationally controlled system, consisting of a High Intensity Focused Ultrasound (HIFU) transducer with centre frequency 3.57 MHz, a power amplifier, a function generator and a MATLAB controller. A mechanical cone adaptor has been designed to use the HIFU beam at a pre-defined post-focal distance. Two thermocouples were placed between the mechanical cone and the mice skin to measure and control the temperature during the HT treatment. Radiotherapy was carried out by using a dedicated small animal image guided radiotherapy system. Measurements of tumor volume performed with a caliper showed good tumor control for the RT-HT group with respect to the RT or control groups for up to 21 days after treatment. The mean value of the normalized (before therapy) tumor volume was almost equal to 0.5 for two weeks after treatment with an increase to 1.5 at sacrifice. The control and HT groups showed a higher value of about 1.5 during the first two weeks and 3.5 at the end of the follow-up period. We concluded that the use of HT as a radiosensitizer can improve the outcome for glioblastoma treatments.

Therapeutic Effects of Exosome Therapy and Photobiomodulation Therapy on the Spermatogenesis Arrest in Male Mice After Scrotum Hyperthermia.

Introduction: In men, several factors cause infertility, among which we can mention damage to sperm due to high temperature. So far, various treatments have been proposed for it, but they have not been highly effective. The current study aimed to evaluate the effect of exosome therapy (EXO) and photobiomodulation therapy (PBMT) on spermatogenesis arrest in male mice after scrotum hyperthermia. Methods: In this experimental study, the animals were divided into four groups: control, scrotal hyperthermia, scrotal hyperthermia+EXO (100 μL/d) (mice were treated for 30 days), scrotal hyperthermia+PBMT (laser of 0.03 J/cm2 for 30 seconds/for 30 days). Hyperthermia was induced by exposure to the temperature of 43 °C for 20 minute every day for 5 times. After 6 weeks, the animals were sacrificed. Results: The treated groups showed a significant increase in sperm parameters, as compared to the hyperthermic groups. Moreover, these favorable effects were observed in relation to the volume of testicular tissue, the number of germ cells, Leydig cells and Sertoli cells, and the level of testosterone. Research on antioxidants showed a significant reduction in oxidized glutathione (GSSG) and reactive oxygen species (ROS) in the treatment groups in comparison to the hyperthermia group (P<0.001). Also, there has been a significant increase in the amount of hydrogen peroxide enzyme observed in the hyperthermia group as opposed to the treatment group (P<0.001). Conclusion: These findings show that EXO and PBMT can improve spermatogenesis caused by hyperthermia, reduce ROS and GSSG, and increase glutathione (GSH) and sperm quality.

Comparison of Clinical Outcomes between Rebound Hyperthermia and Non-Rebound Hypertherma Groups in Postcardiac Arrest Syndrome Patients Undergoing Targeted Temperature Management

Purpose : This retrospective study aims to provide basic data for intervention to improve clinical outcomes and identify the characteristics of the rebound hyperthermia (RHG) and non-rebound hyperthermia (NRHG) groups by checking body temperature in patients with post-cardiac arrest syndrome.Method : The study involved 118 patients who completed target temperature management (TTM) in an acute-care unit. Data were analyzed for frequency, percentages, mean, standard deviation, median, and quartiles, and compared using the chi-squared test and Mann–Whitney U-test.Results : Rebound hyperthermia (RH) was observed in 74 (62.7%) patients, predominantly male (69.5%), with an average age of 64.54 ± 15.98, and a body mass index of 23.22 ± 4.75kg/m&lt;sup&gt;2&lt;/sup&gt; (overweight). Hypertension (50%) was the most common co-morbidity, followed by diabetes and heart disease (33.1%). Neuron-specific enolase levels were higher in the NRHG 24, 48, and 72 hours after recovery of spontaneous circulation (p = .037, &lt;i&gt;p&lt;/i&gt;＜ .001, &lt;i&gt;p&lt;/i&gt;= .008). The APHCHE Ⅳ was also higher in the NRHG (&lt;i&gt;p&lt;/i&gt;＜ .001). RH occurred 25.49 (7.28–52.96) hours after TTM completion, lasting for 2 (1–3) hours. Temperature reduction strategies included notifying doctors, administering antipyretics, and nursing intervention, with the latter being the most common at 94.6%. Half of the subjects in the RHG and 77.3% in the NRHG fell into cerebral performance categories 3, 4, and 5 (&lt;i&gt;p&lt;/i&gt;= .003).Conclusion : RH is more likely a body mechanism related to CPR and TTM than a result of pathogenic infection. Therefore, we require an active intervention for hyperthermia, and a patient-specific nursing intervention protocol.

Suppressive Effects of Docosahexaenoic Acid Intake on Increased Seizure Susceptibility after Growth Due to Febrile Seizures in Infancy.

Febrile seizures are seizures accompanied by a fever and frequently occur in children six months to five years of age. Febrile seizures are classified as simple or complex, and complex febrile seizures increase the risk of temporal lobe epilepsy after growth. Therefore, it is important to interfere with epileptogenesis after febrile seizures to prevent post-growth epilepsy. The present study challenged nutritional intervention using docosahexaenoic acid (DHA). Febrile seizures were induced in mice at the age of 10 d using a heat chamber, and seizure sensitivity was examined using pentylenetetrazol (PTZ) administration after growth. PTZ increased the seizure score and shortened the latency in the complex febrile seizure group compared to the control, hyperthermia and simple febrile seizure groups. Mice in the complex febrile seizure group showed abnormal electroencephalograms pre- and post-PTZ administration. Therefore, seizure susceptibility increases the episodes of complex febrile seizures. DHA supplementation after febrile seizures clearly suppressed the increased seizure susceptibility due to complex febrile seizures experienced in infancy. DHA also attenuated microglial activation after complex febrile seizures. Taken together, DHA suppressed microglial activation following complex febrile seizures, which may contribute to protecting the brain from post-growth seizures. The intake of DHA in infancy may protect children from high fever-induced developmental abnormalities.

Triage body temperature and its influence on patients with acute myocardial infarction

BackgroundFever can occur after acute myocardial infarction (MI). The influence of body temperature (BT) after hospital arrival on patients with acute MI has rarely been investigated.MethodsPatients who were diagnosed with acute MI in the emergency department (ED) of a tertiary teaching hospital between 1 January 2020 and 31 December 2020 were enrolled. Based on the tympanic temperature obtained at the ED triage, patients were categorized into normothermic (35.5°C-37.5°C), hypothermic (< 35.5°C), or hyperthermic (> 37.5°C) groups. The primary outcome was in-hospital cardiac arrest (IHCA), while the secondary outcomes were adverse events. Statistical significance was set at p < 0.05.ResultsThere were 440 enrollees; significant differences were found among the normothermic (n = 369, 83.9%), hypothermic (n = 27, 6.1%), and hyperthermic (n = 44, 10.0%) groups in the triage respiratory rate (median [IQR]) (20.0 [4.0] cycles/min versus 20.0 [4.0] versus 20.0 [7.5], p = 0.009), triage heart rate (88.0 [29.0] beats/min versus 82.0 [28.0] versus 102.5 [30.5], p < 0.001), presence of ST-elevation MI (42.0% versus 66.7% versus 31.8%, p = 0.014), need for cardiac catheterization (87.3% versus 85.2% versus 72.7%, p = 0.034), initial troponin T level (165.9 [565.2] ng/L versus 49.1 [202.0] versus 318.8 [2002.0], p = 0.002), peak troponin T level (343.8 [1405.9] ng/L versus 218.7 [2318.2] versus 832.0 [2640.8], p = 0.003), length of ICU stay (2.0 [3.0] days versus 3.0 [8.0] versus 3.0 [9.5], p = 0.006), length of hospital stay (4.0 [4.5] days versus 6.0 [15.0] versus 10.5 [10.8], p < 0.001), and infection during hospitalization (19.8% versus 29.6% versus 63.6%, p < 0.001) but not in IHCA (7.6% versus 14.8% versus 11.4%, p = 0.323) or any adverse events (50.9% versus 48.1% versus 63.6%, p = 0.258). Multivariable analysis showed no significant association of triage BT with IHCA or any major complication.ConclusionTriage BT did not show a significant association with IHCA or adverse events in patients with acute MI. However, triage BT could be associated with different clinical presentations and should warrant further investigation.

Therapeutic hyperthermia for the treatment of infection-a narrative review.

Modulating body temperature, mostly through the use of antipyretics, is a commonly employed therapeutic intervention in medical practice. However, emerging evidence suggests that hyperthermia could serve as an adjuvant therapy for patients with infection. We performed a narrative review to explore the application of therapeutic hyperthermia in the treatment of infection. A number of studies have been performed in the pre-antibiotic era, enrolling patients with neurosyphilis and gonococcal infections, with reported cure rates at around 60%-80%. We have outlined the potential molecular and immunological mechanisms explaining the possible beneficial effects of therapeutic hyperthermia. For some pathogens increased temperature exerts a direct negative effect on virulence; however, it is presumed that temperature driven activation of the immune system is probably the most important factor affecting microbial viability. Lastly, we performed a review of modern-era studies where modulation of body temperature has been used as a treatment strategy. In trials of therapeutic hypothermia in patients with infection worse outcomes have been observed in the hypothermia group. Use of antipyretics has not been associated with any improvement in clinical outcomes. In modern-era therapeutic hyperthermia achieved by physical warming has been studied in one pilot trial, and better survival was observed in the hyperthermia group. To conclude, currently there is not enough data to support the use of therapeutic hyperthermia outside clinical trials; however, available studies are in favor of at least a temperature tolerance strategy for non-neurocritical patients.

Hyperthermia maintains death receptor expression and promotes TRAIL-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand activates apoptotic pathways and could potentially be used in anticancer treatments. However, oral squamous cell carcinoma cells are known to be resistant to tumor necrosis factor-related apoptosis-inducing ligand-induced cell death. It has been previously reported that hyperthermia upregulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in other cancers. As such, we evaluated whether hyperthermia upregulates tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in a tumor necrosis factor-related apoptosis-inducing ligand-resistant oral squamous cell carcinoma cell line. The oral squamous cell carcinoma cell line HSC3 was cultured and divided into hyperthermia and control groups. We investigated the antitumor effects of recombinant human tumor necrosis factor-related apoptosis-inducing ligand using cell proliferation and apoptosis assays. Additionally, we measured death receptor 4 and 5 levels, and determined death receptor ubiquitination status, as well as E3 ubiquitin ligase targeting of death receptor in both hyperthermia and control groups before recombinant human tumor necrosis factor-related apoptosis-inducing ligand administration. Treatment with recombinant human tumor necrosis factor-related apoptosis-inducing ligand produced greater inhibitory effects in the hyperthermia group than in the control group. Moreover, death receptor protein expression in the hyperthermia group was upregulated on the cell surface (and overall), although death receptor mRNA was downregulated. The half-life of death receptor was several hours longer in the hyperthermia group; concomitantly, E3 ubiquitin ligase expression and death receptor ubiquitination were downregulated in this group. Our findings suggested that hyperthermia enhances apoptotic signaling by tumor necrosis factor-related apoptosis-inducing ligand via the suppression of death receptor ubiquitination, which upregulates death receptor expression. These data suggest that the combination of hyperthermia and tumor necrosis factor-related apoptosis-inducing ligand has implications in developing a novel treatment strategy for oral squamous cell carcinoma.

Rebounds of sevoflurane concentration during simulated trigger-free pediatric and adult anesthesia

BackgroundIn trigger-free anesthesia a volatile anesthetic concentration of 5 parts per million (ppm) should not be exceeded. According to European Malignant Hyperthermia Group (EMHG) guideline, this may be achieved by removing the vapor, changing the anesthetic breathing circuit and renewing the soda lime canister followed by flushing with O2 or air for a workstation specific time. Reduction of the fresh gas flow (FGF) or stand-by modes are known to cause rebound effects. In this study, simulated trigger-free pediatric and adult ventilation was carried out on test lungs including ventilation maneuvers commonly used in clinical practice. The goal of this study was to evaluate whether rebounds of sevoflurane develop during trigger-free anesthesia.MethodsA Dräger® Primus® was contaminated with decreasing concentrations of sevoflurane for 120 min. Then, the machine was prepared for trigger-free anesthesia according to EMHG guideline by changing recommended parts and flushing the breathing circuits using 10 or 18 l⋅min− 1 FGF. The machine was neither switched off after preparation nor was FGF reduced. Simulated trigger-free ventilation was performed with volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) including various ventilation maneuvers like pressure support ventilation (PSV), apnea, decreased lung compliance (DLC), recruitment maneuvers, prolonged expiration and manual ventilation (MV). A high-resolution ion mobility spectrometer with gas chromatographic pre-separation was used to measure sevoflurane in the ventilation gas mixture in a 20 s interval.ResultsImmediately after start of simulated anesthesia, there was an initial peak of 11–18 ppm sevoflurane in all experiments. The concentration dropped below 5 ppm after 2–3 min during adult and 4–18 min during pediatric ventilation. Other rebounds of sevoflurane > 5 ppm occurred after apnea, DLC and PSV. MV resulted in a decrease of sevoflurane < 5 ppm within 1 min.ConclusionThis study shows that after guideline-compliant preparation for trigger-free ventilation anesthetic machines may develop rebounds of sevoflurane > 5 ppm during typical maneuvers used in clinical practice. The changes in rate and direction of internal gas flow during different ventilation modes and maneuvers are possible explanations. Therefore, manufacturers should provide machine-specific washout protocols or emphasize the use of active charcoal filters (ACF) for trigger-free anesthesia.

Transcriptional Regulation of the Colorectal Cancer Stem Cell Markers, Nanog and Oct4, Induced by a Thermodynamic-Based Therapy Approach.

Cancer stem cells (CSC), as responsible issues to cancer development and progression, play a crucial role in tumorigenesis, recurrence, metastasis, and chemoresistance. Both hyperthermia and photodynamic therapy (PDT) may be effective for cancer treatment, particularly when combined with other therapeutic approaches. This study aimed to evaluate the effect of hyperthermia combined with PDT on colorectal CSC and the gene expression of the CSC markers, presenting a more effective approach for cancer therapy. The study was conducted in the Pasteur institute of Iran, Tehran, Iran in 2018. We evaluated the anticancer role of hyperthermia, Gold nanoparticles coated with curcumin (Cur-GNPs) in PDT and combination of the two approaches on cell viability and the expression of CSC markers, Nanog and Oct4 in colorectal cancer cell line HT-29. The cytotoxicity effect of Cur-GNPs against the cells was assessed in vitro. The cell viability was assessed using MTT assay, and the expression analysis of the CSC genes was evaluated using a q-real-time PCR. Cell viability was decreased by PDT (P=0.015) and the combination therapy (P=0.006) but not by hyperthermia alone (P=0.4), compared to control. Also, the expression of CSC markers, Nanog and Oct4 was shown to significantly down-regulate in all hyperthermia, PDT and combination groups. Hyperthermia combined with PDT was indicated to be more efficient in eliminating tumors than hyperthermia or PDT alone.

Hyperthermia alters neurobehavior by affecting cell proliferation and neuronal survival in young male rats

Maintenance of body temperature within physiological range is critical for the fetal and neonatal development. Hyperthermia is one of the most frequently encountered pediatric complaints and may cause neurological disorders due to neuronal injury. In this study, we aimed to investigate the effects of hyperthermia on behavioral alterations, neuronal survival, apoptosis, and cell proliferation in young male Sprague-Dawley rats. Twenty-one 13-day-old rats were randomly divided into three groups (n = 7 per group). Body temperature was increased to 39°C and 41°C in a hyperthermia induction chamber for 30 min, whereas the animals in control group were maintained at 36°C. Twenty-four hours after hyperthermia, animals were subjected to the open field test, elevated-O-maze test, and grip strength test to assess the locomotor activity, anxiety, and motor function. Neuronal survival, apoptosis, and cell proliferation were investigated in cortex, hippocampal dentate gyrus (DG) and CA1 regions, and corpus callosum (CC). Decreased locomotor activity and motor function and increased anxiety were observed in the hyperthermia groups, and these were more pronounced in the 41°C group. Neuronal survival was significantly decreased in DG, CA1, and CC in the hyperthermia groups (**p < 0.01). Apoptosis was significantly induced in cortex, DG, and CC of the animals exposed to heat (*p < 0.05). In addition, cell proliferation positivity decreased significantly only in DG and CC of the animals exposed to heat (*p < 0.05). Our results suggest that neurobehavioral deficits caused by hyperthermia may be due to the increased apoptosis and neuronal cell death and decreased cell proliferation in the brain of postnatal developing rats.

Malignant Hyperthermia in Belgium: 35 years of practice-led research

As of 1986 a laboratory for the diagnosis of Malignant Hyperthermia (MH) was established at the University of Antwerp which since then served as the national reference laboratory for this rare anesthetic complication. Our unit is an accredited lab within the network of the European Malignant Hyperthermia Group and thus has had the chance to attain a solid practical expertise in this disorder, as well as to collaborate in several multicentre studies on MH. The present review summarizes what collaborative international research has taught us about MH over the last 3,5 decades, and covers evolving insights in such topics as pathophysiology, clinical presentation, treatment, anesthesia for patients with an increased risk of developing MH, molecular genetics, diagnostic work-up and relationship to other myopathies.

Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia

BackgroundA major bottleneck to the introduction of noninvasive presymptomatic diagnostic tests for the pharmacogenetic disorder malignant hyperthermia is the lack of functional data for associated variants. MethodsWe screened 50 genes having a potential role in skeletal muscle calcium homeostasis using the HaloPlex™ (Agilent Technologies, Santa Clara, CA, USA) target enrichment system and next-generation sequencing. Twenty-one patients with a history of a clinical malignant hyperthermia reaction together with a positive in vitro contracture test were included. Eight variants in RYR1 were subsequently introduced into the cDNA for the human ryanodine receptor gene and tested in cultured human embryonic kidney (HEK293) cells for their effect on calcium release from intracellular stores in response to the ryanodine receptor-1 agonist 4-chloro-m-cresol using fura-2 as calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group scoring matrix and ClinGen RYR1 variant curation expert panel guidelines. ResultsPotentially causative RYR1 variants were identified in 15 patients. Of these, two families carried two RYR1 variants, five variants had been previously reported as ‘pathogenic’, two variants had been previously reported as ‘likely benign’, and eight were of ‘uncertain significance’. Of these eight variants, four showed hypersensitivity to 4-chloro-m-cresol. Three variants were reclassified as either ‘pathogenic’ or ‘likely pathogenic’. Two were classified as ‘benign’, whilst three remained of ‘uncertain significance’. ConclusionsThree (p.Tyr1711Cys, p.Val2280Ile, and p.Arg4737Gln) additional variants can be added to the list of RYR1 disease-associated variants managed by the European Malignant Hyperthermia Group. These can therefore be used diagnostically in the future. Three variants (p.Glu2348Gly, p.Asn2634Lys, and p.Arg3629Trp) that remained classified as of uncertain significance require further family studies or a different functional test to determine clinical relevance in malignant hyperthermia.

Analysis of risk factors of hyperpyrexia suffered by post neurosurgical patients after removal of drainage tube

To analyze the risk factors of hyperthermia after removal of drainage tubes in patients after neurosurgery. The clinical data of 146 patients after neurosurgery with indwelling drainage tubes admitted to the department of critical care medicine of Pecking University Third Hospital from January 2019 to July 2021 were analyzed retrospectively. The patients were divided into hyperthermia group (body temperature ≥ 39 centigrade) and non-hyperthermia group (body temperature < 39 centigrade) according to whether their body temperatures within 24 hours after removal of drainage tubes. General clinical data and outcomes of the two groups were collected, and different tendentious scores were matched with the hyperthermia group and non-hyperthermia group based on Glasgow coma score (GCS), respectively. After such matching, the clinical baseline characteristics [age, gender, admission diagnosis, major complications, acute physiology and chronic health evaluation II (APACHE II) at admission, GCS], number of days of drainage tubes retention, location of drainage tubes, microbial culture results before removal of drainage tubes, white blood cell (WBC) and neutrophil ratio (NEU%) before and after removal of drainage tubes as well as clinical outcomes of the cohort patients were analyzed. The primarily outcome was in-hospital mortality, and then the length of intensive care unit (ICU) stay. A total of 146 patients after neurosurgery were included, 28 of which developed hyperthermia after removal of drainage tubes. The GCS scores at admission in the hyperthermia group were significantly lower than that in the non-hyperthermia group, while the proportion of hypertension and diabetes in the hyperthermia group was significantly higher than that in the non-hyperthermia group. Based on GCS scores, the two groups, each of which included 28 patients, were matched with tendentious scores, and there was no significant difference in gender, age, GCS scores and the proportion of hypertension and diabetes between the two groups. The main disease for patients upon admission was cerebral hemorrhage (53.6%, 30/56). The proportion of indwelling ventricular drainage tube retention in the hyperthermia group was significantly higher than that in the non-hyperthermia group [32.1% (9/28) vs. 7.1% (2/28), P < 0.05], but there was no significant difference in the location of other drainage tubes between the two groups. The proportion of lumbar puncture in the hyperthermia group was also significantly higher than that in the non-hyperthermia group [25.0% (7/28) vs. 0 (0/28), P < 0.05]. Compared with the non-hyperthermia group, WBC [×109/L: 13.0 (9.5, 15.2) vs. 11.5 (8.8, 13.3)] of 1 day before removal of drainage tubes, NEU% [0.892 (0.826, 0.922) vs. 0.843 (0.809, 0.909)] after removal of drainage tubes and positive rate of drainage-fluid culture or drainage-tube-tip culture [7.1% (2/28) vs. 0% (0/28)] in the hyperthermia group increased, but there were not significant differences. There was no significant difference in the proportion of pulmonary, urinary system and blood flow infection before removal of drainage tubes in the two groups. In terms of primary outcomes, compared with the non-hyperthermia group, the length of ICU stay [days: 17.0 (8.0, 32.3) vs. 8.5 (1.0, 16.8), P < 0.05] in the hyperthermia group was significantly prolonged, and the in-hospital mortality [35.7% (10/28) vs. 10.7% (3/28), P < 0.05] in the hyperthermia group was obviously increased. The positive rate of carbapenem-resistant bacteria culture [32.1% (9/28) vs. 3.6% (1/28), P < 0.05] in the hyperthermia group during hospitalization was significantly higher than that in the non-hyperthermia group. Hyperthermia after removal of drainage tubes for patients after neurosurgery can significantly prolong the length of ICU stay and increase the in-hospital mortality, which may be related to the secondary infection caused by indwelling intracranial drainage tubes and the intracranial spread of bacteria caused by removal of drainage tubes, as well as the intracranial multidrug-resistant bacterial infection caused by the drainage tubes.

The Role of Intraperitoneal Intraoperative Chemotherapy with Paclitaxel in the Surgical Treatment of Peritoneal Carcinomatosis from Ovarian Cancer-Hyperthermia versus Normothermia: A Randomized Controlled Trial.

Background: The treatment of ovarian carcinomatosis with cytoreductive surgery and HIPEC is still controversial. The effect and pharmacokinetics of the chemotherapeutics used (especially taxanes) are currently under consideration. Methods: A phase II, simple blind and randomized controlled trial (NTC02739698) was performed. The trial included 32 patients with primary or recurrent ovarian carcinomatosis undergoing cytoreductive surgery (CRS) and intraoperative intraperitoneal chemotherapy with paclitaxel (PTX): 16 in hyperthermic (42–43 °C) and 16 in normothermic (37 °C) conditions. Tissue, serum and plasma samples were taken in every patient before and after intraperitoneal chemotherapy to measure the concentration of PTX. To analyze the immunohistochemical profile of p53, p27, p21, ki67, PCNA and caspase-3 and the pathological response, a scale of intensity and percentage of expression and a grouped Miller and Payne system were used, respectively. Perioperative characteristics and morbi-mortality were also analyzed. Results: The main characteristics of patients, surgical morbidity, hemotoxicity and nephrotoxicity were similar in both groups. The concentration of paclitaxel in the tissue was higher than that observed in plasma and serum, although no statistically significant differences were found between the two groups. No statistically significant association regarding pathological response and apoptosis (caspase-3) between both groups was proved. There were no statistically significant differences between the normothermic and the hyperthermic group for pathological response and apoptosis. Conclusions: The use of intraperitoneal PTX has proven adequate pharmacokinetics with reduction of cell cycle and proliferation markers globally without finding statistically significant differences between its administration under hyperthermia versus normothermia conditions.

Malignant Hyperthermia and Absence of Ryanodine Receptors in a Child Presenting for Ptosis Repair

Introduction: Malignant hyperthermia (MH) is a hypermetabolic condition caused by a genetic cell membranes channel disruption leading to increased calcium release from the sarcoplasmic reticulum after exposure to triggering agents. Central Core Disease (CCD) is a rare inherited neuromuscular disorder with a wide spectrum of phenotypic presentations. Clinically, there is muscle weakness of variable degree and histopathologically there is evidence of core formation in the muscle fibers. Additional features may occur, including skeletal abnormalities such as foot deformities, scoliosis, or hip displacement. Association of CCD with a mutation of the ryanodine receptor RYR1 and MH is high. If not properly treated, MH could be fatal. Purpose: This study aims towards increasing the awareness of pediatricians, surgeons and anesthesiologists about possible occurrence of MH in patients presenting with only mild “clinical” signs of congenital myopathies such as CCD. Careful diagnostic investigations should be performed prior to surgical interventions and extreme caution during anesthesia. Material and Methods: We report the case of a 3 years old girl, with a history of ptosis, scoliosis, and good muscle tone, who developed unexpected MH during the surgical repair of her ptosis. The critically ill child was transferred to Pediatric Intensive Care Unit (PICU) for management of her MH. The management was done following the guidelines of the European Malignant Hyperthermia Group published in the British Journal of Anesthesia 2010. The patient responded well to treatment. She had a muscle biopsy done after recovery. Discussion: Early management and dantrolene administration are the most important factors to minimize MH morbidity and mortality. MH susceptibility is known in patients carrying mutations in the RYR1 receptors. In our case, RYR1 staining was negative on the muscle biopsy specimen suggesting abnormal or absent RYR1 function, with the presence of occasional cores. These findings, in addition to the ophthalmological and orthopedic history were diagnostic of CCD. In Vitro Contracture Testing (IVCT) was not done because it was not available. Genetic testing was refused by the parents due to financial reasons. Conclusion: In patients presenting with symptoms suggestive of muscle weakness, such as ptosis and scoliosis, and variable muscle tone; congenital myopathies should be considered. CCD and RYR1 receptors deficiency or mutation, if present, may lead to a possible risk of fatal MH, which can be prevented.

The efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of EGFR.

Background: The study aims to explore the efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of epidermal growth factor receptor (EGFR).Patients and methods: We included 205 advanced NSCLC patients who were received hyperthermia plus other treatment (hyperthermia group) or non- hyperthermia and other treatments (non- hyperthermia group). The OS and progression free survival (PFS) were retrospectively estimated. Using Kaplan-Meier and the log-rank test compare the OS and PFS between the groups.Results: The median follow-up was 22 months. The Univariate analysis have shown that 1-year OS and PFSfirst rates in the hyperthermia group and non- hyperthermia group were 83.3% vs 71.5% (P=0.010) and 62.0% vs 42.7% (P=0.001). The subgroup analyses revealed that patients didn’t have EGFR mutant who received hyperthermia had significantly higher 1 year OS and PFSfirst rates than those treated with non- hyperthermia (OS: 79.1% vs 65.2% P=0.037, PFS: 64.2% vs 36.5%, P=0.001). For patients with EGFR mutation, there was no significant difference between the two groups. The PFSfirst in first-line and PFSpost in posterior-line was no significant difference between the groups.Conclusions: This retrospective study revealed that adding hyperthermia to the treatment of NSCLC patients without EGFR mutation had better prognosis than those who did not adding hyperthermia to the regimen. Moreover, adding hyperthermia in first-line or in posterior-line treatment was no significant difference. However, these results need more prospective studies to confirm the conclusions.

Inhibition of the mToR pathway with everolimus can modulate heat shock genes and ERCC1 gene expression and improves outcomes on serous ovarian cancer in HIPEC in vitro model.

e17541 Background: Worldwide, epithelial ovarian cancer accounts for a significant percentage of malignancies and is the most lethal neoplasm of the gynecological system, mainly due to silent manifestation and late diagnosis. Predominantly, around 70% of newly diagnosed women with epithelial ovarian cancer have the locally advanced or metastatic stage (III/IV). The extensive peritoneal dissemination of epithelial ovarian cancer might occur at the time of primary tumor diagnosis or related to disease relapse after previous treatment. Therefore, understanding the dynamic of peritoneal dissemination is of utmost importance, as peritoneal carcinomatosis is frequently associated with disease morbidity and mortality. Methods: In this study, we cultivated ovarian cancer cells using the OV-90 cell line (high-grade serous) and assessed citoxicity using MTT assay. Initially, the ovarian cancer cells were treated with everolimus 18 nM (37˙C) for 24 hours for both experimental and control groups. Subsequently, two experimental groups were treated with cisplatin in normothermia (Group 1) and hyperthermia (Group 2) (37˙C and 41˙C, respectively) while the control group was treated with phosphate-buffered saline solution 1X at 37˙C (Group 3) and 41˙C (Group 4) for 24 hours. After the first treatment, we re-supplemented each group under the same beforementioned conditions and incubated it for three additional hours. Moreover, the RNA extracts of each sample set were submitted to RT-PCR for the obtention of the qRT-PCR material. Lastly, we compared the expression of the ERCC1 gene and heat shock genes amongst the different intervention groups. Results: There statistical difference concerning cytotoxicity between treatment with everolimus and heated cisplatin versus treatment with everolimus and cisplatin in normothermia. We observed that the ERCC1 and TRAP 1 genes were downregulated in OV-90 cell lines under heated conditions compared to the normothermia group. Conclusions: The use of everolimus in HIPEC in vitro model increases the cytotoxic response and suggest that inhibition of the mTOR pathway modulates the expression of heat shock genes e ERCC1 gene improving outcomes. Nevertheless, there is still a need for studies evaluating the effectiveness of everolimus in preclinical trials under hyperthermic conditions.

Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair.

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be clinically effective, but the mechanisms by which hyperthermia enhances the sensitivity of cells to chemotherapeutic drugs has not yet been elucidated.MethodsTo identify the key molecules involved in thermochemotherapy, this study used mass spectrometry (MS)-based quantitative proteomics technology to analyze the effects of thermochemotherapy on the heat-sensitive ovarian cancer cell line A2780. We divided the A2780 cell line into four groups, one group served as blank control, and the other three groups were stimulated by oxaliplatin, stimulated by hyperthermia at 42 ℃, and stimulated by hyperthermia combined with oxaliplatin. Samples were then collected for tandem mass tag (TMT) labeling, high-performance liquid chromatography fractionation, and MS-based quantitative proteomics for analysis The differentially expressed proteins were quantitatively compared and identified, and Gene Ontology (GO) assessment and cluster analyses were performed. Finally, the above MS results were verified again by Western blotting experiments.ResultsA total of 349 differentially expressed proteins were identified between cells treated with chemotherapy alone (group B) and cells treated with a combination of chemotherapy and hyperthermia (group D). There were 145 upregulated proteins and 204 downregulated proteins. Among the top 20 proteins with significantly different expression levels, nearly two-thirds were involved in DNA damage repair. These proteins were subsequently verified by Western blot analysis. Indeed, consistent with MS data, the expression of the RBL1 protein was significantly upregulated in cells treated with thermochemotherapy (group D) compared to cells treated with chemotherapy alone (group B).ConclusionsIn heat-sensitive ovarian cancer cells, the damage repair of tumor cell DNA is disturbed by hyperthermia, making it unable to fully repair when damaged by chemotherapeutic drugs. As a result, hyperthermia enhances the efficacy of chemotherapeutic drugs. RBL1, as a tumor suppressor gene, may be associated with the repair of DNA damage, and thus it may be a key target for hyperthermia to enhance the sensitivity of thermosensitive cells to chemotherapeutic drugs.