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[english] Actinic keratosis is one of the most commonly treated skin conditions. A number of studies have recently been published on the treatment of this ailment using photodynamic therapy. The authors of this letter are concerned about the interpretation of some of these studies and would like to outline possible misinterpretations which may arise due to an incomplete analysis of the study reports available. Clearly, the “ideal” therapy for actinic keratosis should be a carefully chosen compromise between undesired side-effects and therapeutic efficacy and needs to be based on a consideration of all of the relevant clinical studies.[german] Aktinische Keratosen gehören zu den meistbehandelten Hautschäden. Eine Reihe der in den letzten Jahren veröffentlichten Studien beschäftigte sich mit ihrer Behandlung durch photodynamische Therapie. Die Bewertungen einiger dieser Studien veranlassten die Autoren dieses Briefes, mögliche Missinterpretationen der Daten herauszustellen, die infolge unvollständiger Analyse der einbezogenen Studienberichte und unvollständiger Berücksichtigung ihrer Randbedingungen auftreten können. Unbestritten ist dabei, dass die „ideale“ Therapie der aktinischen Keratose ein sorgfältig abgewogener Kompromiss zwischen therapeutischer Wirkung und unerwünschter Nebenwirkung sein muss, der auf der Berücksichtigung aller relevanten klinischen Studien und ihrer Randbedingungen basiert.

The heating characteristics of water-filtered infrared-A (wIRA) radiation were investigated in vivo in two body regions of healthy humans according to the quality standards of the European Society for Hyperthermic Oncology (ESHO) using an irradiance (infrared-A) of 146 W m−2 as recommended for clinical superficial hyperthermia (HT). wIRA was applied to the abdominal wall and lumbar region for 60 min. Skin surface temperature was limited to ≤43 °C. Tissue temperatures were measured invasively at 1-min intervals before, during and after wIRA exposure using five fiber-optical probes at depths of 1–20 mm. Significant differences between body regions occurred during the heating-up phase at depths of 5–15 mm. Thermal steady states were reached at depths ≤5 mm after exposures of 5–6 min, and ≤20 mm after 20 min. On average, the minimum requirements of ESHO were exceeded in both regions by the following factors: ≈3 for the heating rate, ≈2 for the specific absorption rate and ≈1.4 for the temperature rise. Tissue depths with T90 ≥ 40 °C and T50 > 41 °C were ≤10 mm, and ≤20 mm for Tmax ≤ 43 °C. The temperature decay time after termination of irradiation was 1–5 min. Corresponding temperatures were ≤42.2 °C for CEM43 and ≤41.8 °C for CEM43T90, i.e., they are inadequate for direct thermal cell killing. Thermography-controlled wIRA-HT complies with the ESHO criteria for superficial HT as a radiosensitizer and avoids the risk of thermal skin toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Tumor perfusion is considered to be the principal factor determining the build-up of therapeutically effective thermal fields. This assumes that malignancies have lower perfusions than their homologous tissues. This assumption, however, ignores the fact that several tumor types have higher perfusions than their healthy counterparts. Additionally, flow changes upon hyperthermia (39–43 °C) are non-predictable and extremely heterogeneous. Therefore, modeling temperature distribution further requires a more robust parameter, different in malignancies and healthy tissues, i.e., water content (Cw), which highly determines thermal properties upon electromagnetic irradiation. Method: Systematic literature reviews of Cw and specific heat capacities (cp) were conducted up to 28 February 2022, providing an updated, comprehensive data overview based on original manuscripts, reviews and databases. Results: Cw- and cp-values of cancers and their corresponding healthy tissues are presented. Strong correlations between these two parameters are described. In general, malignant tumors have distinctly higher Cw values than their homologous tissues. With increasing Cw in low-water-content normal tissues (<70 wt.%), cp rises exponentially from 1.5 to 3.3 J·g–1·K–1. In high-water-content normal tissues (≥70 wt.%), cp increases linearly from 3.5 to 3.8 J·g–1·K–1. In malignant tumors (>80 wt.%), cp rises linearly from 3.6 to 3.9 J·g–1·K–1. Cancers contain up to 27% more water than their tissues of origin and must be considered as ‘high-capacitance-tissues’. Conclusions: Hyperhydration of cancers result in higher cp-values, causing cancers to be better heat reservoirs than corresponding normal tissues upon electromagnetic irradiation. Reliable, tissue-/cancer-specific cp values must be considered when modeling temperature distributions in hyperthermic treatment. [ABSTRACT FROM AUTHOR]

Purpose: The quality assurance guidelines of the European Society for Hyperthermic Oncology (ESHO) specify the requirements for appropriate superficial heating using phantoms. In this current piglet study, we have examined these requirements under in vivo conditions. Materials and methods: The evaluation is based on simultaneous, invasive temperature measurements at 8 different depths between 2 and 20 mm in the thigh of anesthetized piglets during irradiation with water-filtered infrared radiation (wIRA). Temperature probes were equally distributed in an area of 10 cm diameter of homogeneously irradiated skin. Piglets were irradiated to 126.5 mW cm-2 in the spectral range of IR-A. Results: Heating rates and specific absorption rates were in full accordance with the ESHO standards. Due to early onset of thermoregulation, the desired temperature rise of 6 K at a depth of 5 mm was achieved after about 10 min of exposure, i.e. 4 min later than required for phantoms. After reaching thermal steady state, on average T 90 ≥ 40 °C occurred in tissue depths up to 20 mm, T 50 ≥ 41 °C up to 16 mm, and a mean CEM43 T 90 ≈ 1 min was calculated for depths up to 8 mm. Conclusions: Piglet data are comparable with preliminary literature data assessed in vivo in the abdominal wall and in recurrent breast cancer of humans. The potential of wIRA-HT for adequate treatment of superficial tissues/cancers in the clinical setting thus is confirmed. To ensure therapeutically needed doses of wIRA-HT, irradiation times should be extended. [ABSTRACT FROM AUTHOR]

Purpose: The temporal and spatial formation of the temperature field and its changes during/upon water-filtered infrared-A (wIRA)-irradiation in porcine skin and subcutis were investigated in vivo in order to get a detailed physical basis for thermotherapy of superficial tumors and infections caused by thermosensitive microbial pathogens (e.g., Mycobacterium ulcerans causing Buruli ulcer). Methods: Local wIRA-hyperthermia was performed in 11 anesthetized piglets using 85.0mW cm-2, 103.2mW cm-2 and 126.5mW cm-2, respectively. Invasive temperature measurements were carried out simultaneously in 1-min intervals using eight fiber-optical probes at different tissue depths between 2 and 20 mm, and by an IR thermometer at the skin surface. Results: Tissue temperature distribution depended on incident irradiance, exposure time, tissue depths and individual 'physiologies' of the animals. Temperature maxima were found at depths between 4 and 7 mm, exceeding skin surface temperatures by about 1-2 K. Tissue temperatures above 37 °C, necessary to eradicate M. ulcerans at depths <20 mm, were reached reliably. Conclusions: wIRA-hyperthermia may be considered as a novel therapeutic option for treatment of local skin infections caused by thermosensitive pathogens (e.g., in Buruli ulcer). To ensure temperatures required for heat treatment of superficial tumors deeper than 4 mm, the incident irradiance needed can be controlled either by (a) invasive temperature measurements or (b) control of skin surface temperature and considering possible temperature increases up to 1-2 K in underlying tissue. [ABSTRACT FROM AUTHOR]

Thermography-controlled, water-filtered infrared-A (wIRA) is a novel, effective and approved heating technique listed in the ESHO quality assurance guidelines for superficial hyperthermia clinical trials (2017). In order to assess the special features and the potential of wIRA-hyperthermia (wIRA-HT), detailed and updated information about its physical and photobiological background is presented. wIRA allows for (a) application of high irradiances without skin pain and acute grade 2-4 skin toxicities, (b) prolonged, therapeutically relevant exposure times using high irradiances (150-200 mW/cm2) and (c) faster and deeper heat extension within tissues. The deeper radiative penetration depth is mainly caused by forward Mie-scattering. At skin surface temperatures of 42-43 °C, the effective heating depth is 15 mm (T ≥ 40 °C) and 20 mm (T ≥ 39.5 °C). Advantages of wIRA include its contact-free energy input, easy power steering by a feed-back loop, extendable treatment fields, real-time and noninvasive surface temperature monitoring with observation of dynamic changes during HT, and - if necessary - rapid protection of temperature-sensitive structures. wIRA makes the compliant heating of ulcerated and/or bleeding tumors possible, allows for HT of irregularly shaped and diffusely spreading tumors, is independent of individual body contours, allows for very short 'transits' between HT and RT (1-4 min) or continuous heating between both therapeutic interventions. New treatment options for wIRA-HT may include malignant melanoma, vulvar carcinoma, skin metastases of different primary tumors, cutaneous T-and B-cell lymphoma, large-area hemangiomatosis, inoperable squamous cell, basal cell and eccrine carcinoma of the skin with depth extensions ≤20 mm. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess the interindividual variability of spectral remittance and spectral transmittance of visible and infrared-A radiations interacting with human skin and subcutaneous tissue, and direct measurements were taken in vivo using healthy persons of different skin color types. Up to wavelengths of about 900 nm, both spectral remittance and spectral transmittance depended significantly on the individual contents of melanin and hemoglobin in the skin, whereas the contents of water and lipids mainly determined spectral slopes of both characteristics of interaction for wavelengths above about 900 nm. In vivo measured data of spectral transmittance showed approximately similar decreases with tissue thickness between about 900 nm and 1100 nm as compared with model data which were calculated using spectral absorption and scattering coefficients of skin samples in vitro published by different authors. In addition, in vivo measured data and in vitro-based model calculations of spectral remittance were approximately comparable in this wavelength range. In contrast, systematic but individually varying differences between both methods were found for both spectral remittance and spectral transmittance at wavelengths below about 900 nm, where interaction of radiation was significantly affected by both melanin and hemoglobin. [ABSTRACT FROM AUTHOR]

Purpose:Evaluation of the efficacy and toxicity of a new setup of thermographically controlled water-filtered infra-red-A (wIRA) superficial hyperthermia (HT) combined with hypofractionated re-irradiation (re-RT) to treat large-sized breast cancer recurrences. Methods:Records of 73 heavily pre-irradiated patients with 103 treatment regions, treated from September 2009 to July 2015 were retrospectively analysed. Sixty-four patients with macroscopic disease were treated with 94 regions including 46 patients with lymphangiosis carcinomatosa. Hypofractionated RT consisted of 4 Gy once per week up to a total dose of 20 Gy delivered within 1–4 min after wIRA-HT. Heating of tumour nodules and diffusely spreading cancer lesions was performed under real-time thermographic temperature monitoring, maintaining the maximum skin temperature in the ROI between 42 °C and 43 °C, achieving intratumoural temperatures up to a depth of 2 cm between 39.5 °C and 42 °C. Seventeen patients received re-re-irradiation (re-re-RT) using the same HT/RT-treatment schedule. Results:Response rates in patients with macroscopic disease: 61% CR, 33% PR, 5% NC and 1% PD. Local control throughout life time after CR of macroscopic disease: 59%. All nine patients with microscopic disease had CR and local control throughout lifetime. Only grade 1 toxicities were observed. Conclusions:Application of thermographically controlled wIRA-HT combined with extremely low-dose re-irradiation provides good local control throughout lifetime of heavily pre-treated breast cancer recurrences. The twin wIRA radiator provides a sufficiently homogeneous heat deposition for the treatment of larger areas. The time lag between HT and re-RT is substantially reduced. The possibility of re-re-RT opens new therapeutic options for the future. [ABSTRACT FROM PUBLISHER]

Objectives: Vitamin D (VitD) deficiency is a health problem prevalent not only in the elderly but also in young adults. The primary objective of our observational pilot study “MUVY” (Mood, UVR, Vitamin D in Young women) was to test both the short-term and long-term effects of a series of three suberythemal UV radiation (UVR) exposures on the VitD status and well-being of young healthy women during winter in a repeat measure design. Methods: 20 healthy young women (Fitzpatrick skin types I–III, aged 21–25 years) received three full body broad band UVR exposures with an escalating erythemally weighted dose schedule during one week in winter, and completed self-report questionnaires monitoring symptoms of depression (Beck Depression Inventory, BDI) and affective state/well-being (Profile of Mood States, POMS) at baseline and three days after the last UVR exposure. 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in serum at baseline, and at study days 8, 36 and 50. Results: Mean baseline 25(OH)D level was 54.3 nmol/L (standard deviation (s.d.) = 24.1), with seven women having VitD deficient status. Relevant symptoms of depression, as indicated by low BDI total scores (0–8), were absent. After the three UVR exposures the increment of 25(OH)D was an average of 13.9 nmol/L (95% confidence interval (CI) = 9.4–18.4) and 26.2 pmol/L (95%CI = 7.2–45.1) for 1,25(OH)2D. Δ25(OH)D, and corresponding baseline levels were significantly and inversely associated (rho = -0.493, p = 0.027). Only 25(OH)D remained significantly increased above baseline for at least six weeks after the last UVR exposure. A strong inverse correlation of the POMS subscale “Vigor/Activity” and the increment in 1,25(OH)2D was found (rho = -0.739, p<0.001) at day 8. Conclusions: Three suberythemal whole body UVR exposures during one week are a simple and suitable method for improving 25(OH)D levels during winter, for at least six weeks, and especially in young women with VitD deficient status. Trial Registration: German Clinical Trials Register (Deutsches Register Kinischer Studien) [ABSTRACT FROM AUTHOR]

Exposures of the skin with electromagnetic radiation of wavelengths between 670 nm and 1400 nm are often used as a general treatment to improve wound healing and reduce pain, for example, in chronic diabetic skin lesions. We investigated the effects of water-filtered infrared A ( wIRA) and of narrow-band IR-A provided by a light-emitting diode LED ( LED- IR-A) irradiation in vitro on 3T3 fibroblast cultures under defined conditions with and without glyoxal administration. Glyoxal triggers the formation of advanced glycation end products, thereby mimicking a diabetic metabolic state. Cell viability and apoptotic changes were determined by flow cytometry after vital staining with Annexin V, YO- PRO-1 and propidium iodide ( PI), and by SubG1 assay. Mitochondrial function and oxidative stress were examined by vital staining for radical production, mitochondrial membrane potential ( MMP) and the ratio of reduced-to-oxidized glutathione ( GSH/ GSSG). The metabolic state was monitored by a resazurin conversion assay. The numbers of apoptotic cells were reduced in cultures irradiated with wIRA or LED- IR-A. More mitochondria showed a well-polarized MMP after wIRA irradiation in glyoxal damaged cells. LED- IR-A treatment specifically restored the GSH/ GSSG ratio. The immediate positive effects of wIRA and LED- IR-A observed in living cells, particularly on mitochondria, reflect the therapeutic benefits of wIRA and LED- IR-A. [ABSTRACT FROM AUTHOR]

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In many recent publications, supposed athermal effects of water-filtered infrared A (wIRA) irradiation are discussed. Those effects are mainly attributed to wavelengths in the range from 780 to 1440 nm, and should not result from warming of cellular water or any aqueous medium surrounding the irradiated sample caused by wIRA absorption. Athermal effects are considered to be induced directly by absorption of different wavelengths of the wIRA spectrum by cellular molecules or structures except water. To distinguish between thermal and athermal effects, irradiated samples have to be subjected to a very effective and precise temperature homeostasis. Any experimental effects can only be attributed to pure athermal effects, if the temperature of the irradiated samples is verifiably constant and does not result in hyperthermia. Here, data of temperature distribution in Petri dishes of different types filled with aqueous medium are presented which were estimated by model calculation for different setups of cooling. Additionally, the real temperature development was directly measured. Such a cooling unit enables long-term application of high wIRA irradiances and large doses without any detectable warming of the irradiated samples, in single cell layers. Using such a setup, thermal and athermal effects can be compared and in addition to that quantified. [ABSTRACT FROM AUTHOR]

Skin exposure to infrared (IR) radiation should be limited in terms of irradiance, exposure time and frequency in order to avoid acute or chronic damage. Recommendations aimed at protecting humans from the risks of skin exposure to IR ( e.g. ICNIRP, ACGIH) are only defined in terms of acute effects ( e.g. heat pain and cardiovascular collapse), whereas the actual exposure conditions ( e.g. spectral distribution, exposure geometry, frequency and number of exposures, thermal exchange with the environment, metabolic energy production and regulatory responses) are not taken into consideration. Since the IR component of solar radiation reaching the Earth’s surface is mainly IR-A, and considering the increased use of devices emitting artificially generated IR-A radiation, this radiation band is of special interest. A number of in vitro and/or in vivo investigations assessing cellular or tissue damage caused by IR-A radiation have been undertaken. While such studies are necessary for the development of safety recommendations, the results of measurements undertaken to examine the interaction between skin and IR radiation emitted from different sources presented in this study, together with the detailed examination of the literature reveals a wide spectrum of contradictory findings, which in some instances may be related to methodological shortcomings or fundamental errors in the application of physical and photobiological laws, thus highlighting the need for physically and photobiologically appropriate experiments. [ABSTRACT FROM AUTHOR]

(1) Background: Mild hyperthermia (mHT, 39-42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term , changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O 2 diffusivities, acidosis- and heat-related enhanced O 2 unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O 2 tensions in tumors.

Cancers are complex, heterogeneous, dynamic and aggressive diseases exhibiting a series of characteristic biophysical traits which complement the original biological hallmarks of cancers favouring progressive growth, metastasis, and contributing to immune evasion and treatment resistance. One of the prevalent differences between most solid tumors and their corresponding, healthy tissues is a significantly higher water content (hyperhydration) in cancers. As a consequence, cancers have distinctly higher (Fick's) diffusion coefficients D [cm 2  s -1 ] for the respiratory gases O 2 and CO 2 , the key substrate glucose, and for the oncometabolite lactate. In addition, cancers have (a) clearly increased specific heat capacities c p [J g -1  K -1 ], thus representing high-capacity-tissues upon therapeutic heating induced by electromagnetic irradiation, and (b) higher thermal conductivities k [W m -1  K -1 ], i.e., increased abilities to conduct heat. Therefore, in diffusion analyses (e.g., when describing critical O 2 and glucose supplies or CO 2 removal, and the development of hypoxic subvolumes) and for modeling temperature distributions in hyperthermia treatment planning, these specific cancer-related data must be considered in order to reliably reflect oncologic thermo-radiotherapy settings., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: Tumor perfusion is considered to be the principal factor determining the build-up of therapeutically effective thermal fields. This assumes that malignancies have lower perfusions than their homologous tissues. This assumption, however, ignores the fact that several tumor types have higher perfusions than their healthy counterparts. Additionally, flow changes upon hyperthermia (39-43 °C) are non-predictable and extremely heterogeneous. Therefore, modeling temperature distribution further requires a more robust parameter, different in malignancies and healthy tissues, i.e., water content (C w ), which highly determines thermal properties upon electromagnetic irradiation., Method: Systematic literature reviews of C w and specific heat capacities (c p ) were conducted up to 28 February 2022, providing an updated, comprehensive data overview based on original manuscripts, reviews and databases., Results: C w - and c p -values of cancers and their corresponding healthy tissues are presented. Strong correlations between these two parameters are described. In general, malignant tumors have distinctly higher C w values than their homologous tissues. With increasing C w in low-water-content normal tissues (<70 wt.%), c p rises exponentially from 1.5 to 3.3 J·g -1 ·K -1 . In high-water-content normal tissues (≥70 wt.%), c p increases linearly from 3.5 to 3.8 J·g -1 ·K -1 . In malignant tumors (>80 wt.%), c p rises linearly from 3.6 to 3.9 J·g -1 ·K -1 . Cancers contain up to 27% more water than their tissues of origin and must be considered as 'high-capacitance-tissues'., Conclusions: Hyperhydration of cancers result in higher c p -values, causing cancers to be better heat reservoirs than corresponding normal tissues upon electromagnetic irradiation. Reliable, tissue-/cancer-specific c p values must be considered when modeling temperature distributions in hyperthermic treatment.

Ultraviolet irradiation represents a well-established treatment modality for inflammatory skin diseases. The aim of this study was to investigate the mechanisms of ultraviolet B radiation-induced keratinocyte insensitivity towards interferon-gamma. Flow cytometric analyses indicated that ultraviolet B radiation temporarily inhibits the interferon-gamma-induced activation of primary keratinocyte and HaCaT cells as measured by reduced intercellular adhesion molecule-1 (CD54) and HLA-DR upregulation. Western blot experiments have suggested that this is mediated by the ultraviolet B radiation-induced inhibition of signal transduction and transcription factor-1 phosphorylation. Neither interleukin-10 neutralization nor interleukin-10 addition had any effect on the ultraviolet B radiation-induced inhibition of interferon-gamma induced intercellular adhesion molecule-1 expression. Furthermore, the supernatant from ultraviolet B-irradiated cells failed to inhibit the interferon-gamma-induced CD54 and HLA-DR upregulation in nonradiated HaCaT cells. Moreover, irradiated cells from whom the supernatant was withdrawn 4 h after irradiation still showed a diminished interferon-gamma-induced response after 24 h. Thus, not soluble but intracellular factors might be involved in the ultraviolet B radiation-induced inhibition of interferon-gamma-induced keratinocyte activation. Therefore, we analyzed the expression of members of suppressors of cytokine-signaling (SOCS) molecules using real-time polymerase chain reaction. We found a fast and strong upregulation of SOCS1 and SOCS3 but not of SOCS2 after ultraviolet B radiation. Similarly, ultraviolet B radiation induced the expression of these particular SOCS molecules in lesional psoriatic skin. As SOCS molecules are known inhibitors of signal transduction and transcription factor phosphorylation, which is essential for interferon-gamma-induced intercellular adhesion molecule-1 and HLA-DR upregulation, this may explain the interferon-gamma unresponsiveness after ultraviolet B radiation.