Clinical effectiveness of combined whole body hyperthermia and external beam radiation therapy (EBRT) versus EBRT alone in patients with painful bony metastases: A phase III clinical trial study.

PURPOSE: To evaluate the response rate, pain relief duration, and time it took for pain to decline or resolve after radiation therapy (RT) with or without fever-range Whole Body Hyperthermia (WBH) in bony metastatic patients with mainly primary tumor of prostate and breast cancer leading to bone pain. MATERIALS & METHODS: Bony metastatic patients with pain score ≥4 on the Brief Pain Inventory (BPI) underwent RT of 30 Gy in 10 fractions in combination with WBH with nursing care under medical supervision versus RT-alone. WBH application time was 3-4 h in three fractions with at least 48-h intervals. All patients were stratified primary site, breast or prostate cancer vs others, BPI score, and exclusion criteria. The primary endpoint was complete response (CR) (BPI equal to zero with no increase of analgesics) within two months of follow-up. RESULTS: Based on this study, the RT-alone group showed the worst pain. The study was terminated after the enrollment of a total of 61 patients, 5 years after the first enrollment (April 2016 to February 2021). Finally, the CR rate in RT + WBH revealed the most significant difference with RT-alone, 47.4% versus 5.3% respectively within 2 months post-treatment (P-value <0.05). The time of complete pain relief was 10 days for RT + WBH, while the endpoint was not reached during the RT-alone arm. Pain progression or stable disease was observed in half of the patients in RT-alone group within 4 weeks after treatment. However, this score was near zero in RT + WBHT patients in two months post-treatment. CONCLUSIONS: WBH plus RT showed significant increases in pain relief and shorter response time in comparison with RT-alone for patients with bone metastatic lesions.

Fiebre prolongada, síndrome de Good y cáncer de colon: una asociación poco frecuente / Prolonged fever, Good syndrome and colon cancer: a rare association

Se define «síndrome febril prolongado¼ a todo cuadro de hipertermia que persiste al menos 10 días sin ser diagnosticado. El síndrome de Good es una inmunodeficiencia primaria del adulto que se caracteriza por presentar hipogammaglobulinemia, disminución de linfocitos B y anormalidades en los linfocitos T. Entre el 15 y el 20% de los casos de «fiebre de origen desconocido¼ ocurren debido a neoplasias, y el cáncer de colon representa menos del 1% de todos estos casos. Se presenta una paciente de 49 años admitida en el hospital por presentar síndrome febril con un mes de evolución, con antecedentes de síndrome de Good. Se le diagnostica cáncer de colon. (AU)

A prolonged febrile syndrome (PFS) is defined as any episode of hyperthermia that persists for at least 10 days without being diagnosed. Good's syndrome is a primary immunodeficiency in adults characterized by hypogammaglobulinemia, decreased B lymphocytes, and abnormalities in T lymphocytes. Between 15 to 20% of fever of unknown origin (FOD) cases are due to neoplasms, and colon cancer represents less than 1% of all these cases. A 49-year-old patient with a history of Good's syndrome was admitted to the hospital due to a febrile syndrome lasting for a month. She was diagnosed with colon cancer. (AU)

Assessment of the thermal tissue models for the head and neck hyperthermia treatment planning.

PURPOSE: To compare different thermal tissue models for head and neck hyperthermia treatment planning, and to assess the results using predicted and measured applied power data from clinical treatments. METHODS: Three commonly used temperature models from literature were analysed: "constant baseline", "constant thermal stress" and "temperature dependent". Power and phase data of 93 treatments of 20 head and neck patients treated with the HYPERcollar3D applicator were used. The impact on predicted median temperature T50 inside the target region was analysed with maximum allowed temperature of 44 °C in healthy tissue. The robustness of predicted T50 for the three models against the influence of blood perfusion, thermal conductivity and the assumed hotspot temperature level was analysed. RESULTS: We found an average predicted T50 of 41.0 ± 1.3 °C (constant baseline model), 39.9 ± 1.1 °C (constant thermal stress model) and 41.7 ± 1.1 °C (temperature dependent model). The constant thermal stress model resulted in the best agreement between the predicted power (P = 132.7 ± 45.9 W) and the average power measured during the hyperthermia treatments (P = 129.1 ± 83.0 W). CONCLUSION: The temperature dependent model predicts an unrealistically high T50. The power values for the constant thermal stress model, after scaling simulated maximum temperatures to 44 °C, matched best to the average measured powers. We consider this model to be the most appropriate for temperature predictions using the HYPERcollar3D applicator, however further studies are necessary for developing of robust temperature model for tissues during heat stress.

Severe immune-related hyperthermia followed by immune-related pneumonitis with PD-1 inhibitor (sintilimab) in small cell lung cancer: A case report.

Immune checkpoint inhibitors (ICIs) have achieved prominent efficacy in the treatment of numerous cancers, which is the most significant breakthrough in cancer therapy in recent years. However, ICIs are associated with a series of immune-related adverse events (irAEs). Pneumonitis is an uncommon but potentially fatal irAE. In the case reported here, a patient with advanced small cell lung cancer (SCLC) had rapid progression of disease following chemotherapy and received ICIs. The patient experienced severe immune-related hyperthermia followed by immune-related pneumonitis. Fortunately, a good clinical response was achieved after the patient received corticosteroids and tocilizumab.

Extended post-exercise hyperthermia in athletes with a spinal cord injury.

OBJECTIVES: Determine the extent and underlying causes of post-exercise hyperthermia in athletes with a spinal cord injury following exercise. DESIGN: Observational. METHODS: Thirty-one males (8 with tetraplegia [TP; C5-C8], 7 with high paraplegia [HP; T1-T5], 8 with low paraplegia [LP; T6-L1] and 8 able-bodied [AB]), recovered in 35°C/50%RH for 45min after 30-min of exercise at a metabolic heat production (Hprod) of 4.0W/kg (AB vs TP) or 6.0W/kg (AB vs HP vs LP). Esophageal (Tes), gastrointestinal (Tgi) and skin temperatures, Hprod, local sweat rate (LSR) and mean arterial pressure were measured. RESULTS: TP maintained a higher Tes (38.05°C [95% CI: 37.83°C, 38.28°C], AB: 36.77°C [36.56°C, 36.98°C], p<0.001) and Tgi (TP: 38.36°C [38.15°C, 38.58°C], AB: 37.26°C [37.04°C, 37.47°C], p<0.001), with peak values observed 45min post-exercise. Core temperatures all declined in HP, LP and AB, but HP maintained a higher Tes than AB (p=0.030), and higher Tgi than LP and AB (p=0.019). No differences in post-exercise Hprod were observed between TP and AB (p=0.264), or HP, LP and AB (p=0.124). Evaporative heat loss was estimated to be zero in TP, while back LSR was greater in HP than LP (p=0.009). Minimal dry heat loss occurred in SCI groups (TP: 9W/m2 [6, 12], HP: 4W/m2 [1, 6], LP: 2W/m2 [0, 5]). CONCLUSIONS: Substantial post-exercise hyperthermia is evident in TP (∼1.4°C hotter than AB after 45min of post-exercise recovery) due to minimal evaporation. HP have delayed post-exercise thermoregulatory recovery whereas LP respond similarly to AB.

The Role of Skeletal Muscles in Exertional Heat Stroke Pathophysiology.

The active participation of skeletal muscles is a unique characteristic of exertional heat stroke. Nevertheless, the only well-documented link between skeletal muscle activities and exertional heat stroke pathophysiology is the extensive muscle damage (e. g., rhabdomyolysis) and subsequent leakage of intramuscular content into the circulation of exertional heat stroke victims. Here, we will present and discuss rarely explored roles of skeletal muscles in the context of exertional heat stroke pathophysiology and recovery. This includes an overview of heat production that contributes to severe hyperthermia and the synthesis and secretion of bioactive molecules, such as cytokines, chemokines and acute phase proteins. These molecules can alter the overall inflammatory status from pro- to anti-inflammatory, affecting other organ systems and influencing recovery. The activation of innate immunity can determine whether a victim is ready to return to physical activity or experiences a prolonged convalescence. We also provide a brief discussion on whether heat acclimation can shift skeletal muscle secretory phenotype to prevent or aid recovery from exertional heat stroke. We conclude that skeletal muscles should be considered as a key organ system in exertional heat stroke pathophysiology.

Changes in gastrointestinal cell integrity after marathon running and exercise-associated collapse.

PURPOSE: Endurance exercise and hyperthermia are associated with compromised intestinal permeability and endotoxaemia. The presence of intestinal fatty acid-binding protein (I-FABP) in the systemic circulation suggests intestinal wall damage, but this marker has not previously been used to investigate intestinal integrity after marathon running. METHODS: Twenty-four runners were recruited as controls prior to completing a standard marathon and had sequential I-FABP measurements before and on completion of the marathon, then at four and 24 h later. Eight runners incapacitated with exercise-associated collapse (EAC) with hyperthermia had I-FABP measured at the time of collapse and 1 hour later. RESULTS: I-FABP was increased immediately on completing the marathon (T0; 2593 ± 1373 ng·l-1) compared with baseline (1129 ± 493 ng·l-1; p < 0.01) in the controls, but there was no significant difference between baseline and the levels at four hours (1419 ± 1124 ng·l-1; p = 0.7), or at 24 h (1086 ± 302 ng·l-1; p = 0.5). At T0, EAC cases had a significantly higher I-FABP concentration (15,389 ± 8547 ng.l-1) compared with controls at T0 (p < 0.01), and remained higher at 1 hour after collapse (13,951 ± 10,476 ng.l-1) than the pre-race control baseline (p < 0.05). CONCLUSION: I-FABP is a recently described biomarker whose presence in the circulation is associated with intestinal wall damage. I-FABP levels increase after marathon running and increase further if the endurance exercise is associated with EAC and hyperthermia. After EAC, I-FABP remains high in the circulation for an extended period, suggesting ongoing intestinal wall stress.

Postembolization syndrome in endovascular interventions on the gonadal veins.

OBJECTIVE: The present study evaluated the incidence of postembolization syndrome (PES) after endovascular coil embolization of the gonadal veins (EEGV) in patients with pelvic congestion syndrome and investigated the appropriate medical treatment. METHODS: EEGV was performed in 70 female patients with pelvic congestion syndrome (left-sided in 58, right-sided in 3, and bilateral in 9 patients). For embolization, 0.035-in. coils with an 8- to 12-mm diameter and 10- to 20-cm length were used. Assessments of the EEGV results and possible PES symptoms were performed on days 1, 5, 10, 20, and 30 after the procedure and included transvaginal and transabdominal duplex ultrasound scanning of the pelvic veins and at the embolization site. RESULTS: PES had manifested with increased pelvic pain, tenderness along the embolized vein, and hyperthermia ≤37.5°C to 37.8°C and had developed in 14 patients (20%). For PES treatment, a nonsteroidal anti-inflammatory drug (diclofenac, 75 mg daily for 3-7 days; mean, 4.2 ± 1.1 days) and a venoactive drug (micronized purified flavonoid fraction, 1000 mg daily for 2 months) were used. Medical treatment was associated with a significant reduction in PES symptoms in all patients within 14 days and complete resolution by day 30 after embolization. duplex ultrasound scanning revealed thrombosis of parametrial veins in 12 of 56 patients (21.4%) with successful EEGV and 3 of 14 patients (21.4%) with PES. CONCLUSIONS: In patients who have undergone EEGV, increased pelvic pain, the occurrence of tenderness along the embolized vein, and the presence of hyperthermia should be considered as PES manifestations. In our study, PES occurred in 20% of the treated patients.

Activation of Preoptic Arginine Vasopressin Neurons Induces Hyperthermia in Male Mice.

Arginine vasopressin (AVP) is a neuropeptide acting as a neuromodulator in the brain and plays multiple roles, including a thermoregulatory one. However, the cellular mechanisms of action are not fully understood. Carried out are patch clamp recordings and calcium imaging combined with pharmacological tools and single-cell RT-PCR to dissect the signaling mechanisms activated by AVP. Optogenetics combined with patch-clamp recordings were used to determine the neurochemical nature of these neurons. Also used is telemetry combined with chemogenetics to study the effect of activation of AVP neurons in thermoregulatory mechanisms. This article reports that AVP neurons in the medial preoptic (MPO) area release GABA and display thermosensitive firing activity. Their optogenetic stimulation results in a decrease of the firing rates of MPO pituitary adenylate cyclase-activating polypeptide (PACAP) neurons. Local application of AVP potently modulates the synaptic inputs of PACAP neurons, by activating neuronal AVPr1a receptors and astrocytic AVPr1b receptors. Chemogenetic activation of MPO AVP neurons induces hyperthermia. Chemogenetic activation of all AVP neurons in the brain similarly induces hyperthermia and, in addition, decreases the endotoxin activated fever as well as the stress-induced hyperthermia.

Traumatic brain injury induced temperature dysregulation: What is the role of ß blockers?

BACKGROUND: Traumatic brain injury (TBI) is associated with sympathetic discharge that leads to posttraumatic hyperthermia (PTH). Beta blockers (ßß) are known to counteract overactive sympathetic discharge. The aim of our study was to evaluate the effect of ßß on PTH in critically-ill TBI patients. METHODS: We performed retrospective cohort analysis of the Medical Information Mart for Intensive Care database. We included all critically ill TBI patients with head Abbreviated Injury Scale (AIS) score of 3 or greater and other body region AIS score less than 2 who developed PTH (at least one febrile episode [T > 38.3°C] with negative microbiological cultures (blood, urine, and bronchoalveolar lavage). Patients on preinjury ßß were excluded. Patients were stratified into (ßß+) and (ßß-) groups. Propensity score matching was performed (1:1 ratio) controlling for patient demographics, injury parameters and other medications that influence temperature. Outcomes were the number of febrile episodes, maximum temperature, and the time interval between febrile episodes. Multivariate linear regression was performed. RESULTS: We analyzed 4,286 critically ill TBI patients. A matched cohort of 1,544 patients was obtained: 772 ßß + (metoprolol, 60%; propranolol, 25%; and atenolol, 15%) and 772 ßß-. Mean age was 63.4 ± 15.4 years, median head AIS score of 3 (3-4), and median Injury Severity Score of 10 (9-16). Patients in the ßß+ group had a lower number of febrile episodes (8 episodes vs. 12 episodes; p = 0.003), lower median maximum temperature (38.0°C vs. 38.5°C; p = 0.025), and a longer median time between febrile episodes (3 hours vs. 1 hour; p = 0.013). On linear regression, propranolol was found to be superior in terms of reducing the number of febrile episodes and the maximum temperature. However, there was no significant difference between the three ßß in terms of reducing the time interval between febrile episodes (p = 0.582). CONCLUSION: Beta blockers attenuate PTH by decreasing the frequency of febrile episodes, increasing the time interval between febrile episodes, and reducing the maximum rise in temperature. ßß may be a potential therapeutic modality in PTH. LEVEL OF EVIDENCE: Therapeutic, level IV.

The magnitude of physical exercise-induced hyperthermia is associated with changes in the intestinal permeability and expression of tight junction genes in rats.

We investigated whether the magnitude of exercise-induced hyperthermia influences intestinal permeability and tight junction gene expression. Twenty-nine male Wistar rats were divided into four groups: rest at 24 °C and exercise at 13 °C, 24 °C or 31 °C. The exercise consisted of a 90-min treadmill run at 15 m/min, and different ambient temperatures were used to produce distinct levels of exercise-induced hyperthermia. Before the experimental trials, the rats were treated by gavage with diethylenetriaminepentaacetic acid labeled with technetium-99 metastable as a radioactive probe. The rats' core body temperature (TCORE) was measured by telemetry. Immediately after the trials, the rats were euthanized, and the intestinal permeability was assessed by measuring the radioactivity of blood samples. The mRNA levels of occludin and zonula occludens-1 (ZO-1) genes were determined in duodenum samples. Exercise at 24 °C increased TCORE to values close to 39 °C, without changing permeability compared with the resting trial at the same environment. Meanwhile, rats' TCORE exceeded 40 °C during exercise at 31 °C, leading to greater permeability relative to those observed after exercise in the other ambient temperatures (e.g., 0.0037%/g at 31 °C vs. 0.0005%/g at 13 °C; data expressed as medians; p < 0.05). Likewise, the rats exercised at 31 °C exhibited higher mRNA levels of ZO-1 and occludin genes than the rats exercised at 24 °C or 13 °C. The changes in permeability and gene expression were positively and significantly associated with the magnitude of hyperthermia. We conclude that marked hyperthermia caused by exercise in the warmer environment increases intestinal permeability and mRNA levels of tight junction genes.

Hyperthermia and protein homeostasis: Cytoprotection and cell death.

Protein homeostasis or proteostasis, the correct balance between production and degradation of proteins, is an essential pillar for proper cellular function. Among the several cellular mechanisms that disrupt homeostatic conditions in cancer cells, hyperthermia (HT) has shown promising anti-tumor effects. However, cancer cells are also capable of thermoresistance. Indeed, HT-induced protein denaturation and aggregation results in the up regulation of heat shock proteins, a group of molecular chaperones with cytoprotective and anti-apoptotic properties via stress-inducible transcription factor, heat shock factor 1(HSF1). Heat shock proteins assist in the refolding of misfolded proteins and aids in their elimination if they become irreversibly damaged by various stressors. Furthermore, HSF1 also initiates the unfolded protein response in the endoplasmic reticulum (ER) to assist in the protein folding capacity of ER and also promotes the translation of pro-survival proteins' mRNA such as activating transcription factor 4 (ATF 4). Moreover, HT associated induction of microRNAs is also involved in thermal resistance of cancer cells via up-regulation of anti-apoptotic Bcl-2 proteins and down regulation of pro-apoptotic Bax and caspase 3 activities. Another cellular protection in response to stressors is Autophagy, which is regulated by the Mammalian target of rapamycin (mTOR) protein. Kinase activity in mTOR phosphorylates HSF1 and promotes its nuclear translocation for heat shock protein synthesis. Over-expression of heat shock proteins are reported to up-regulate Beclin-1, an autophagy initiator. Moreover, HT-induced reactive oxygen species (ROS) generation is sensitized by transcription factor NF-E2 related factor 2 (Nrf2) and activates the cellular expression of antioxidants and autophagy gene. Furthermore, ROS also potentiates autophagy via activation of Beclin-1. Inhibition of thermotolerance can potentiate HT-induced apoptosis. Here, we outlined that heat stress alters cellular proteins which activates cellular homeostatic processes to promote cell survival and make cancer cells thermotolerant.

[Forgotten Baby Syndrome: dimensions of the phenomenon and new research perspectives]. / Bambini dimenticati in auto: dimensioni del fenomeno e nuove prospettive di ricerca.

Forgotten Baby Syndrome (FBS) defines the phenomenon of forgetting a child in a parked vehicle. FBS is in constant growth with significant repercussions for the parent, the family and society. Scientific research on the topic is very limited. Literature referring to FBS focuses mostly on the clinical conditions that cause the death of the children involved. However, the circumstances in which such episodes occur are very rarely analyzed. One of the major limit of research in this field is related to the sources of information, which are limited to media in most cases and, therefore, are scarcely reliable. Monitoring the phenomenon in the United States showed that out of a total of 171 cases, 73% concerned children who had been left in the car by an adult. Half of the adults were unaware, or had forgotten the child. In most cases, these episodes involve adults who have perfectly intact both psychic and cognitive functions. Therefore, the dynamics underling the occurrence of such episodes seem to be incomprehensible. At the end of the analysis carried out it can be considered that the cases of death of minors following abandonment in vehicles, are to be considered connected to the normal functioning of the Working Memory (WM) functionality. The link between WM deficits and frankly psychopathological conditions remains residual and it still requires careful differential screening. Finally, the hypothesis of the occurrence of transient and/or acute circumstances of exogenous origin, which may affect WM's performance, remains to be considered. Considering these deaths as events that, in most cases, are of criminal relevance they may require the intervention of psychologists and psychiatrists during the process. In this prospective the assumption of a broader point of view can have a significant impact on the descriptive capacity in clinical-forensic field.

The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis.

We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a ß3 agonist, UCP-1 and PGC-1α were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the ß3 agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A ß3 antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An α1 /α2b antagonist or a 5HT1A agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.