Whole body hyperthermia : the development of and experience with a clinical method

Whole body hyperthermia is one of the methods available for the treatment of malignant turrours with heat. At the Rotterdam Radio-Therapeutic Institute this method was investigated in 27 patients in a period of 3 1/2 years. This thesis describes the results of this investigation. The final conclusions from this study are: the technique used for induction of WBHT is clinically useful and its efficiency is comparable to the efficiencies mentioned by other authors Who use a technique of transcutaneous energy input; - WBHT at 41.8°C for 2 hours is effective, but has to be canbined with either radiotherapy or cherrotherapy to obtain a valuable effect for the patient; In sane cases the treatment may unexpectedly induce severe toxicity. Therefore research should continue with regard to better alternatives such as local hyperthennia and/or a safer method of WBHI'-induction

Comparison of intratumor and intraluminal temperatures during locoregional deep hyperthermia of pelvic tumors

Purpose: To investigate whether intraluminal thermometry provides sufficient information to apply high quality deep hyperthermia in pelvic tumors. Patients and Methods: The intratumor and intraluminal temperatures of 48 patients were analyzed per cancer type: rectum (21 male, 14 female), cervix (n = 8), and bladder (n = 5). Temperature-dose parameters were calculated, temperature curves within each treatment session were compared, and correlation between intratumor and intraluminal temperatures was analyzed. Results: Intratumor and intraluminal temperatures at the same time points during individual treatments were highly correlated (mean correlation coefficient: 0.93). However, the quantitative level differed from 0.1 to 1.1 degrees C and the differences of the timetemperature graphs varied per tumor group. Average intratumor and intraluminal temperatures were not different in the four groups. Intratumor thermometry was found not superior over intraluminal thermometry to improve tumor temperature level and homogeneity by SAR steering. Conclusion: Intraluminal thermometry provides sufficient information to apply deep hyperthermia to individual patients with centrally located rectum, cervix or bladder cancer

Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia

Adding hyperthermia to standard radiotherapy (RT + HT) improves treatment outcome for patients with locally advanced cervical cancer (LACC). We investigated the effect of hyperthermia dose on treatment outcome for patients with LACC treated with RT + HT. We collected treatment and outcome data of 420 patients with LACC treated with hyperthermia at our institute from 1990 to 2005. Univariate and multivariate analyses were performed on response rate, local control, disease-specific survival and toxicity for these patients to search for a thermal dose response relationship. Besides commonly identified prognostic factors in LACC like tumour stage, performance status, radiotherapy dose and tumour size, thermal parameters involving both temperature and duration of heating emerged as significant predictors of the various end-points. The more commonly used CEM43T90 (cumulative equivalent minutes of T90 above 43 degrees C) was less influential than TRISE (based on the average T50 increase and the duration of heating, normalised to the scheduled duration of treatment). CEM43T90 and TRISE measured intraluminally correlate significantly and independently with tumour control and survival. These findings stimulate further technological development and improvement of deep hyperthermia, as they strongly suggest that it might be worthwhile to increase the thermal dose for LACC, either by treatment optimisation or by prolonging the treatment time. These results also confirm the beneficial effects from hyperthermia as demonstrated in our earlier randomised trial, and justify applying radiotherapy and hyperthermia as treatment of choice for patients with advanced cervical cancer. (c) 2009 Elsevier Ltd. All rights reserved

Study protocol of the DUtch PARkinson Cohort (DUPARC):a prospective, observational study of de novo Parkinson's disease patients for the identification and validation of biomarkers for Parkinson's disease subtypes, progression and pathophysiology

BACKGROUND: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology. METHODS/DESIGN: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included. DISCUSSION: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication. TRIAL REGISTRATION: NCT04180865; registered retrospectively, November 28th 2019

Temperature and thermal dose during radiotherapy and hyperthermia for recurrent breast cancer are related to clinical outcome and thermal toxicity: a systematic review

Objective: Hyperthermia therapy (HT), heating tumors to 40–45 °C, is a known radiotherapy (RT) and chemotherapy sensitizer. The additional benefit of HT to RT for recurrent breast cancer has been proven in multiple randomized trials. However, published outcome after RT + HT varies widely. We performed a systematic review to investigate whether there is a relationship between achieved HT dose and clinical outcome and thermal toxicity for patients with recurrent breast cancer treated with RT + HT. Method: Four databases, EMBASE, PubMed, Cochrane library and clinicaltrials.gov, were searched with the terms breast, radiotherapy, hyperthermia therapy and their synonyms. Final search was performed on 3 April 2019. Twenty-two articles were included in the systematic review, reporting on 2330 patients with breast cancer treated with RT + HT. Results: Thirty-two HT parameters were tested for a relationship with clinical outcome. In studies reporting a relationship, the relationship was significant for complete response in 10/15 studies, in 10/13 studies for duration of local control, in 2/2 studies for overall survival and in 7/11 studies for thermal toxicity. Patients who received high thermal dose had on average 34% (range 27%–53%) more complete responses than patients who received low thermal dose. Patients who achieved higher HT parameters had increased odds/probability on improved clinical outcome and on thermal toxicity. Conclusion: Temperature and thermal dose during HT had significant influence on complete response, duration of local control, overall survival and thermal toxicity of patients with recurrent breast cancer treated with RT + HT. Higher temperature and thermal dose improved outcome, while higher maximum temperature increased incidence of thermal toxicity

Altered cholinergic innervation in De Novo Parkinson's disease with and without cognitive impairment

BACKGROUND: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention. OBJECTIVE: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment. METHODS: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed. RESULTS: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala. CONCLUSION: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease

BACKGROUND: Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. OBJECTIVE: To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. METHODS: In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. RESULTS: Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). CONCLUSIONS: Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum

Thermal Therapy For Cancer

Hyperthermia (HT) means using controlled temperatures of 40-45°C for cancer treatment. HT is applied with different methods e.g. superficial-HT, locoregional deep-HT, interstitial-HT, intracavity-HT, and whole body-HT. HT can apply in different tumor sites such as breast cancer, melanoma, head and neck, cervix cancer, and glioblastoma. Literatures show that addition of HT to radiotherapy, chemotherapy, or both, will result better tumor response rate, local control, and survival rate; without increasing toxicity. HT can also improve palliative effects in patient. In recent years, due to substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumors, thermometry, and treatment planning; HT is becoming more clinically accepted in Europe and the USA. HT, as an adjunct cancer treatment modality, is certainly a promising approach; however, it is not well known yet worldwide. Therefore, it seems there is need to know more about that. The purpose of this review is to provide an overview on the application of HT combined with conventional cancer treatment modalities, mainly radiotherapy. The article also introduces mechanism of HT, heating delivery modes, thermometry, and it summarizes results of randomized trials form Western research groups.

Intra-patient comparison between two annular phased array applicators, Sigma-60 and Sigma-Eye: Applied RF powers and intraluminally measured temperatures

Purpose: To investigate whether one can replace the Sigma-60 with the Sigma-Eye applicator (or vice versa) during a deep hyperthermia treatment series without a loss in quality of the treatment. Patients and methods: Hyperthermia data of all 48 patients with locally advanced cervical cancer who were treated with both applicators were analysed. In this study no use was made of the longitudinal SAR steering option of the Sigma-Eye. Hence, the Sigma-Eye was used as a Sigma-60 with a modified shape and water bolus. Power and intraluminal temperature were analysed. Sub-group analyses were performed for six groups, categorised according to the reasons for switching between the applicators. Results: The `all patient' analysis showed a significant difference for radio frequency (RF) power indices as applied to the two applicators, but for temperatures no difference between applicators was found. Sub-group analyses showed a consistent difference for RF power indices, i.e. the RF power for the Sigma-Eye was 8-29% higher than that for Sigma-60. In contrast, in about 90% of patients the number of switch-offs was 8-62% lower when the Sigma-Eye was applied. Similarly, in 73% of patients total switch-off time was 18-150% lower for the Sigma-Eye than for the Sigma-60. For the largest sub-group (n=23), patients treated with the Sigma-Eye all had temperature indices slightly lower (Delta T=0.2-0.5 degrees C) than those for the Sigma-60 (p < 0.028). For the other five sub-groups no relevant difference was found between temperatures obtained by the two applicators. Conclusion: In the case of severe patient discomfort with the Sigma-60 or Sigma-Eye applicator, or if achieved temperatures are not satisfactory, one can freely switch between both applicators without loss of hyperthermia treatment quality

Thermoradiotheraphy of cancer: an effective approach

Hyperthermia (HT) means using controlled temperatures of 40-45°C for cancer treatment. HT is applied with differentmethods e.g. superficial-HT, locoregional deep-HT, interstitial-HT, intracavity-HT, and whole body-HT. HT can apply indifferent tumor sites such as breast cancer, melanoma, head and neck, cervix cancer, and glioblastoma. The Literature suggests that addition of HT to radiotherapy, chemotherapy, or both, will result better tumor response rate, local control, and survival rate; without increasing toxicity. HT can also improve palliative effects in patient. In recent years, due to substantial technical improvements made in achieving selected increaseof temperatures in superficial and deep-seated tumors,thermometry, and treatment planning; HT is becoming moreclinically accepted in Europe and the USA. HT, as an adjunctcancer treatment modality, is certainly a promising approach;however, it is not well known yet worldwide. Therefore, itseems there is need to know more about that. The purpose of this review is to provide an overview on the application of HT combined with conventional cancer treatment modalities,mainly radiotherapy. The article also introduces mechanism of HT, heating delivery modes, thermometry, and it summarizes results of randomized trials from Western research groups