Understanding radiation-induced cardiovascular damage and strategies for intervention.

There is a clear association between therapeutic doses of thoracic irradiation and an increased risk of cardiovascular disease (CVD) in cancer survivors, although these effects may take decades to become symptomatic. Long-term survivors of Hodgkin's lymphoma and childhood cancers have two-fold to more than seven-fold increased risks for late cardiac deaths after total tumour doses of 30-40 Gy, given in 2 Gy fractions, where large volumes of heart were included in the field. Increased cardiac mortality is also seen in women irradiated for breast cancer. Breast doses are generally 40-50 Gy in 2 Gy fractions, but only a small part of the heart is included in the treatment fields and mean heart doses rarely exceeded 10-15 Gy, even with older techniques. The relative risks of cardiac mortality (1.1-1.4) are consequently lower than for Hodgkin's lymphoma survivors. Some epidemiological studies show increased risks of cardiac death after accidental or environmental total body exposures to much lower radiation doses. The mechanisms whereby these cardiac effects occur are not fully understood and different mechanisms are probably involved after high therapeutic doses to the heart, or part of the heart, than after low total body exposures. These various mechanisms probably result in different cardiac pathologies, e.g. coronary artery atherosclerosis leading to myocardial infarct, versus microvascular damage and fibrosis leading to congestive heart failure. Experimental studies can help to unravel some of these mechanisms and may identify suitable strategies for managing or inhibiting CVD. In this overview, the main epidemiological and clinical evidence for radiation-induced CVD is summarised. Experimental data shedding light on some of the underlying pathologies and possible targets for intervention are also discussed.

Mechanisms and dose-response relationships for radiation-induced cardiovascular disease.

Epidemiological studies have shown a clear association between therapeutic doses of thoracic irradiation and increased risk of cardiovascular disease in long-term cancer survivors. Survivors of Hodgkin's lymphoma and childhood cancers, for example, show 2- to >7-fold increases in risk of cardiac death after total tumour doses of 30-40 Gy, given in 2-Gy fractions. The risk of cardiac mortality increases linearly with dose, although there are large uncertainties for mean cardiac doses <5 Gy. Experimental studies show that doses of ≥ 2 Gy induce the expression of inflammatory and thrombotic molecules in endothelial cells. In the heart, this causes progressive loss of capillaries and eventually leads to reduced perfusion, myocardial cell death, and fibrosis. In large arteries, doses of ≥ 8 Gy, combined with elevated cholesterol, initiates atherosclerosis and predisposes to the formation of inflammatory, unstable lesions, which are prone to rupture and may cause a fatal heart attack or stroke. In contrast, doses <1 Gy inhibit inflammatory cell adhesion to endothelial cells and inhibit the development of atherosclerosis in mice. It seems likely that mechanisms other than accelerated atherosclerosis are responsible for cardiovascular effects after low total-body exposures of radiation (e.g. impaired T-cell immunity or persistent increase in systemic cytokines).

Temoporfin mediated photodynamic therapy in patients with local persistent and recurrent nasopharyngeal carcinoma after curative radiotherapy: a feasibility study.

BACKGROUND: The treatment of persistent and recurrent nasopharyngeal carcinoma (NPC) remains a challenge, especially in Indonesia. We investigated the safety and efficacy of temoporfin mediated photodynamic therapy (PDT) for patients with local persistent and recurrent NPC. MATERIAL AND METHODS: Twenty-two patients with persistent and recurrent NPC (maximum tumor depth < 10mm) underwent PDT under local anesthesia with use of a nasopharyngeal light applicator. Three different drug doses and light intervals have been administered: treatment arm A: 0.15 mg/kg Foscan; 96 h drug-light interval; B: drug dose of 0.10 mg/, 48 h drug-light interval; C: drug dose of 0.075 mg/kg, 24 h drug-light interval. Toxicity was measured by using the CTCAE 3.1 scale. RESULTS: Arm A consisted of eight patients, arms B and C consisted of seven patients. The treatment procedure was well tolerable under local anesthesia. The most common grade III toxicities for all groups is headache (n = 7; 33%). No grade IV toxicity was seen. One patient died 2 days after treatment due to a misdiagnosed pneumonia. In 17 of the 22 patients a biopsy was performed after 40 weeks and showed no tumor in all biopsies. Arm A seems, in addition to comparable toxicity, clinically more effective than arms B and C. CONCLUSION: The present study demonstrated that temoporfin mediated photodynamic therapy is a relatively simple technique that can be utilized to treat residual or recurrent nasopharyngeal cancer, restricted locally to the nasopharynx.

ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs--threshold doses for tissue reactions in a radiation protection context.

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

Brief communication: why sleep in a nest? Empirical testing of the function of simple shelters made by wild chimpanzees.

All great apes build nightly a structure ("nest" or "bed") that is assumed to function primarily as a sleeping-platform. However, several other nest function hypotheses have been proposed: antipredation, antipathogen, and thermoregulation. I tested these simple shelter functions of chimpanzee nests in an experiment for which I was the subject in Fongoli, Senegal. I slept 11 nights in chimpanzee nests and on the bare ground to test for differences in sleep quality, potential exposure to disease through bites from possible vectors, and insulation. No difference was found in the total amount of sleep nor in sleep quality; however, sleep was more disturbed on the ground. Differences in sleep disturbance between arboreal and ground conditions seemed primarily due to causes of anxiety and alertness, e.g., vocalizations of terrestrial mammals. Arboreal nest-sleeping seems to reduce risk of bites from possible disease vectors and provide insulation in cold conditions. This preliminary, but direct, test of chimpanzee nest function has implications for the evolutionary transition from limb-roosting to nest-reclining sleep in the hominoids, and from tree-to-ground sleep in the genus Homo.

Living archaeology: artefacts of specific nest site fidelity in wild chimpanzees.

Savanna chimpanzees are known to re-use areas of the landscape for sleep, and patterns of chimpanzee sleeping site re-use are proposed as a referential model for early hominin archaeological site formation. We recorded the prevalence of deformed but healed branches and remnants of dead branches found around fresh nests at the savanna site of Issa in Ugalla, Tanzania. These old nest scars were found in 79% of 112 beds. We also randomly selected potential nesting locations for a subset of 32 beds within the same trees, and found nest scars in only 19% of these "control" locations. We then monitored 275 nests for up to 19 months for decay, regeneration of new branches, and re-use. Of these 275 nest locations, 24% were re-used within the first nine months of monitoring, and most re-use occurred when the nest had already decayed and was not easily visible from the ground. After 18 months, the proportion of specific nest positions re-used increased to 48%. This fidelity is likely a result of the creation of ideally-shaped support structures and supple new growth for mattress material with successive use of nest locations. We propose that specific nest site re-use may not be a direct product of environmental determination, but a result of "niche construction" through formation of good building sites within trees. Environmental modification through construction behaviour may have influenced both chimpanzee and early hominin ranging, and thus leaves behind recognisable patterns of artefact deposition across the landscape.

Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients.

Radiation is an independent risk factor for cardiovascular and cerebrovascular disease in cancer patients. Modern radiotherapy techniques reduce the volume of the heart and major coronary vessels exposed to high doses, but some exposure is often unavoidable. Radiation damage to the myocardium is caused primarily by inflammatory changes in the microvasculature, leading to microthrombi and occlusion of vessels, reduced vascular density, perfusion defects and focal ischemia. This is followed by progressive myocardial cell death and fibrosis. Clinical studies also demonstrate regional perfusion defects in non-symptomatic breast cancer patients after radiotherapy. The incidence and extent of perfusion defects are related to the volume of left ventricle included in the radiation field. Irradiation of endothelial cells lining large vessels also increases expression of inflammatory molecules, leading to adhesion and transmigration of circulating monocytes. In the presence of elevated cholesterol, invading monocytes transform into activated macrophages and form fatty streaks in the intima, thereby initiating the process of atherosclerosis. Experimental studies have shown that radiation predisposes to the formation of inflammatory plaque, which is more likely to rupture and cause a fatal heart attack or stroke. This paper presents a brief overview of the current knowledge on mechanisms for development of radiation-induced cardiovascular and cerebrovascular damage. It does not represent a comprehensive review of the literature, but reference is made to several excellent recent reviews on the topic.

Performance of a dedicated light delivery and dosimetry device for photodynamic therapy of nasopharyngeal carcinoma: phantom and volunteer experiments.

UNLABELLED: The objective of this study was to develop a light delivery and measurement device for photodynamic therapy (PDT) in the nasopharyngeal cavity, which achieves a homogeneous and reproducible fluence rate distribution to a target area and provides proper shielding of predefined risk areas. MATERIALS AND METHODS: A flexible silicone applicator was developed, incorporating light delivery and dosimetry fibers. The applicator can be inserted through the mouth and fixed in the nasopharyngeal cavity. Tissue optical phantoms were prepared on the basis of optical properties measured in vivo using diffuse reflectance spectroscopy (DRS). The fluence rate over the length of the applicator surface was measured in air, in tissue optical phantoms and in five healthy volunteers. RESULTS: The fluence rate distribution over the applicator surface in air and tissue optical phantom was found to be more homogeneous (SD/mean 3.8% and 18.3%, respectively) than the fluence rate distribution in five volunteers (SD/mean ranging from 19% up to 52%). The maximum observed fluence rate build-up in the nasopharynx varied between subjects and ranged from a factor of 4.1-6.9. Shielding of the risk area such as the soft palate and tongue was effective. CONCLUSIONS: In air and in tissue optical phantoms the fluence rate distribution of the device was highly homogeneous. The observed inter-subject and intra-subject variations in fluence rate in healthy volunteers originated from differences in optical properties and nasopharyngeal geometry. Light delivery based on a single tissue surface measurement will not be adequate. In situ dosimetric measurements are required to determine the light fluence delivered to a geometrically complex site such as the nasopharynx. These observations should be taken in consideration when developing light applicators for PDT of the nasopharynx and other non-uniform surfaces.

Photodynamic therapy in the treatment of multiple primary tumours in the head and neck, located to the oral cavity and oropharynx.

OBJECTIVES: Multiple primary tumours are a common problem in the head and neck cancer patients. Curative surgery or radiotherapy of these tumours can be very mutilating or even impossible. This study aims at evaluating meta-tetrahydroxy-phenyl chlorin-mediated photodynamic therapy for second or multiple primary tumours in the head and neck. DESIGN: Retrospective study of all patients with second or multiple primary tumours treated by photodynamic therapy over a 10-year period. SETTING: All patients were treated in the Netherlands Cancer Institute, a tertiary referral centre for the head and neck cancer patients. PARTICIPANTS: A total of 27 patients with 42 the second or the multiple primary head and neck tumours were treated by photodynamic therapy (0.15 mg/kg meta-tetrahydroxy-phenyl chlorin). MAIN OUTCOMES MEASURES: Cure rates. RESULTS: Twenty-eight of 42 tumours were cured (67%). Cure rates for stage I or in situ disease were 85%versus 38% for stage II/III. CONCLUSIONS: Cure rates for photodynamic therapy of the multiple primary head and neck tumours were lower than previously described for first primaries, but were still very encouraging for this difficult patient population. The high cure rate obtained in stage I multiple primaries emphasises the importance of a meticulous follow-up of patients treated for the head and neck cancer to detect new tumours at a curable stage.

In vivo fluence rate measurements during Foscan-mediated photodynamic therapy of persistent and recurrent nasopharyngeal carcinomas using a dedicated light applicator.

The objective of this study was to evaluate the performance of a dedicated light applicator for light delivery and fluence rate monitoring during Foscan-mediated photodynamic therapy of nasopharyngeal carcinoma in a clinical phase I/II study. We have developed a flexible silicone applicator that can be inserted through the mouth and fixed in the nasopharyngeal cavity. Three isotropic fibers, for measuring of the fluence (rate) during therapy, were located within the nasopharyngeal tumor target area and one was manually positioned to monitor structures at risk in the shielded area. A flexible black silicon patch tailored to the patient's anatomy is attached to the applicator to shield the soft palate and oral cavity from the 652-nm laser light. Fourteen patients were included in the study, resulting in 26 fluence rate measurements in the risk volume (two failures). We observed a systematic reduction in fluence rate during therapy in 20 out of 26 illuminations, which may be related to photodynamic therapy-induced increased blood content, decreased oxygenation, or reduced scattering. Our findings demonstrate that the applicator was easily inserted into the nasopharynx. The average light distribution in the target area was reasonably uniform over the length of the applicator, thus giving an acceptably homogeneous illumination throughout the cavity. Shielding of the risk area was adequate. Large interpatient variations in fluence rate stress the need for in vivo dosimetry. This enables corrections to be made for differences in optical properties and geometry resulting in comparable amounts of light available for Foscan absorption.

Tumour seeding in peritoneal wound sites in relation to growth-factor expression in early granulation tissue.

The purpose of these experiments was to identify growth factors produced during the formation of a peritoneal wound in relation to tumour cell seeding and stimulated growth in granulation tissue. Gelfoam(c) gelatin sponge was implanted in the mesenteric fan of nude mice to initiate the granulation process. Human HT29 colon carcinoma cells were inoculated intraperitoneally at various times after sponge implantation and tumour growth in granulation tissue was determined. RNA isolated from granulation tissue was used for polymerase chain reaction analysis of the expression of specific growth factors and receptors [vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and lysophosphatic acid (LPA)], and for microarray analysis of differentially expressed genes in early vs. late granulation tissue. Inflammatory cells infiltrated the sponge within 1 day, followed by fibroblasts and the formation of an extracellular matrix. Tumour cell inoculation at 8 h to 3 days after sponge implantation resulted in extensive tumour formation in all cases. Inoculation at 10-28 days resulted in focal tumour growth in only 16-33% of the sponges. Low amounts of VEGF, TGF-beta(1-3), TGF-beta RIII and LPA receptors 1,2 were detected in early granulation tissue, with increased expression from day 10. Microarray analysis identified additional differentially expressed genes that may stimulate tumour take and growth in early granulation tissue.

In vivo bioluminescence imaging of locally disseminated colon carcinoma in rats.

Animal tumour models using orthotopic tumours for the evaluation of cancer therapies are of greater clinical relevance than subcutaneous models, but they also pose greater difficulties for measuring tumour size and quantifying response to treatment. In this study, we used noninvasive bioluminescence imaging to monitor the intraperitoneal growth of luciferase-transfected CC531 colorectal cells in adult WAG/RIJ rats. The bioluminescence signal correlated well with post-mortem assessment of tumour load by visual inspection of the peritoneal cavity at specific follow-up times. Using bioluminescence imaging, we were able to monitor peritoneal tumour growth sequentially in time and to calculate a tumour growth rate for each animal; this is not possible with invasive methods of evaluating tumour load. Bioluminescence imaging of rats treated with a single dose of cisplatin (4 mg x kg(-1), i.p.) demonstrated a significant delay in peritoneal tumour growth relative to saline controls (mean 45.0+/-s.d. 13.0 vs 28.2+/-10.3 days; P=0.04). Similar protocols evaluated by visual scoring of tumour load at 40 days after inoculation supported these findings, although no quantitative assessment of treatment-induced growth delay could be made by this method. This study shows that in vivo imaging of luciferase-transfected tumour cells is a useful tool to investigate the dynamics of disseminated tumour growth and efficacy of anticancer treatment in orthotopic models of peritoneal cancer in rats. It offers an attractive alternative to invasive methods, and requires fewer animals for measuring tumour response to therapy.

Pharmacokinetics and pharmacodynamics of cisplatin after intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC).

BACKGROUND: HIPEC is a new treatment modality for abdominal cancers that combines cytoreductive surgery with Hyperthermic, Intraoperative Peritoneal Chemotherapy, followed by systemic chemotherapy. A significant survival benefit has been shown for HIPEC compared with systemic therapy alone. However, it is not clear what is the contribution of i.p. drug delivery and what influence the mild hyperthermia has on the uptake of cisplatin in abdominal tumors. MATERIALS AND METHODS: We used a peritoneal perfusion system in rats to compare the pharmacokinetics and pharmacodynamics of cisplatin, after normothermic (37 degrees C/90 minutes) and hyperthermic (40 degrees C/90 minutes) intra-peritoneal perfusion, with an i.p. bolus injection. RESULTS: Hyperthermic perfusion with 15 micrograms/ml (in 200 ml) cisplatin gave equivalent plasma drug levels to a maximum tolerated dose (MTD) i.p. bolus injection of 4 mg/kg (36 micrograms/ml in 20 ml). The drug concentration in small (1-5 mm) intra-peritoneal tumors was also comparable for both these treatments, and for normothermic perfusion. CONCLUSION: Mild hyperthermic perfusion with cisplatin (40 degrees C/90 minutes) did not improve drug uptake in small intra-peritoneal tumors, relative to normothermic perfusion or i.p. bolus injection.

Foscan uptake and tissue distribution in relation to photodynamic efficacy.

Clinical photodynamic therapy (PDT) schedules are based on the assumption that optimum drug-light intervals are times at which there is a maximum differential between photosensitiser retention in the tumour and surrounding normal tissue. However, vascular-mediated effects contribute to tumour destruction by PDT; therefore, plasma sensitiser levels and endothelial cell drug exposure could also be important determinants of PDT response. The purpose of this study was to investigate the influence of tumour, tissue and plasma concentrations of the photosensitiser Foscan (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response. Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were injected (i.v.) with a single dose of (14)C-labelled mTHPC, or with two doses, separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured at 5 min to 120 h after drug administration. The PDT tumour and skin responses were evaluated by illuminating separate groups mice at intervals of 5 min to 120 h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin increased during the first 24 h after a single injection, and remained almost constant for at least 120 h. The second injection produced a further, rapid increase in mTHPC levels in tumours and skin, with steady state being maintained from 20 min to 120 h. By contrast, PDT response of both tumours and skin were maximal for illumination at 1-3 h after drug, with very little response when illumination was given 48-120 h after drug. There was no significant correlation between tumour or skin drug level and PDT response. There was, however, a significant correlation between plasma drug levels and tumour or skin response, excluding an initial distribution time of 20 min. These studies demonstrate a pronounced disassociation between tumour drug levels and optimum drug-light intervals for PDT response with Foscan. We suggest that the PDT effect, in both tumours and normal tissues, is largely mediated via vascular damage and that the selectivity of PDT is not based on differential tumour drug uptake.

Intraoperative photodynamic therapy after pleuropneumonectomy in patients with malignant pleural mesothelioma: dose finding and toxicity results.

OBJECTIVE: To determine the optimal administered dose of meta-tetrahydroxyphenylchlorin (mTHPC) for intraoperative photodynamic therapy (IPDT) in resected malignant pleural mesothelioma (MPM). The primary objective of this combination treatment was to improve local tumor control. DESIGN: Phase I/II dose escalation study. SETTING: Two Dutch cancer centers. PATIENTS: The study included 28 patients (2 women, 26 men), with pathologically confirmed MPM. The mean age was 57 years (age range, 37 to 68 years), and the World Health Organization performance score was 0 to 1. Epithelial mesotheliomas were found in 17 patients, a sarcomatous mesothelioma was found in 1 patient, and mixed epithelial sarcomatous mesotheliomas were found in 10 patients. METHODS: Patients were injected with 0.075 mg/kg (4 patients), 0.10 mg/kg (19 patients), or 0.15 mg/kg (5 patients) mTHPC 4 or 6 days before undergoing surgery and IPDT. Complete surgical resection (i.e., pleuropneumonectomy) was followed by integral illumination with monochromatic light of 652 nm (10 J/cm(2)). The real-time fluence rate measurements were performed using four isotropic detectors in the chest cavity to calculate the total light dose. RESULTS: Dose-limiting toxicity was reached at the level of 0.15 mg/kg mTHPC. Three patients died in the perioperative period, and one death was directly related to photodynamic therapy. Real-time dosimetry identified 12 patients in whom additional illumination had to be given to the diaphragmatic sinuses, which were unavoidably shielded during integral illumination. In two patients, illumination was cancelled due to the insufficient resectability of the tumor. The median survival time for all 28 patients was 10 months. Local tumor control, 9 months after treatment, was achieved in 13 of the 26 patients treated with IPDT. CONCLUSION: IPDT using mTHPC, combined with a pleuropneumonectomy, resulted in local control of disease in 50% of the treated cases. The considerable toxicity associated with the procedure, however, precludes its recommendation for widespread use. Stricter patient selection and improvements of the IPDT technique may reduce the toxicity.

Radiation-induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel.

PURPOSE: To assess the effects of kidney irradiation on glomerular adenosine diphosphatase (ADPase) activity and intraglomerular microthrombus formation, and their correlation to the development of renal functional impairment. METHODS AND MATERIALS: C3H/HenAf-nu(+) mice were given single-dose or fractionated kidney irradiations. Glomerular ADPase activity was measured using a cerium-based histochemical method. Microthrombus formation within the glomeruli was assessed by a semiquantitative immunohistochemical analysis of fibrinogen/fibrin deposits. Renal function was assessed by the [(51)Cr]EDTA retention assay. RESULTS: The ADPase activity was significantly reduced, to approximately 50% of pretreatment value, 4--40 weeks after 10--16 Gy single-dose irradiation and at 44 weeks after 20 x 2 Gy. No dose--effect relationship was found. An approximately fourfold increase in glomerular fibrinogen/fibrin staining was observed at 1 year after irradiation. This increase was not influenced by treating the mice with daily, oral clopidogrel, a platelet ADP receptor antagonist, which reduced platelet aggregation by more than 75%. Radiation-induced impairment of glomerular filtration was also not affected by the clopidogrel treatment. CONCLUSION: These data indicate that irradiation significantly reduced glomerular ADPase activity, which correlated with an increased glomerular fibrinogen/fibrin deposition. We were not able to reduce these prothrombotic changes, nor to protect against radiation nephropathy, by pharmacological intervention with an ADP-receptor antagonist.

Wedge-shaped applicator for additional light delivery and dosimetry in the diaphragmal sinus during photodynamic therapy for malignant pleural mesothelioma.

In situ light dosimetry during photodynamic therapy (PDT) of malignant pleural mesothelioma (MPM) after tumour resection facilitates the delivery of a controlled light distribution to the inner thoracic surface. Illumination of the diaphragm-induced sinus, however, remains difficult. Our aim was to develop a wedge-shaped light applicator with incorporated light dosimetry to deliver an additional fluence limited to the sinus. The wedge-shaped applicator contains a cylindrical diffuser for light delivery and two isotropic detectors for simultaneous light dosimetry. These detectors were placed at strategic positions where the fluence rate is maximal or minimal (middle and edge). Prior to its clinical use, the performance of the sinus light applicator was tested in several optical tissue phantoms with different optical properties. The fluence rate distribution over the surface of the applicator showed little change when the wedge was submerged in four different optical phantoms. During clinical PDT of MPM the applicator had to be re-located manually four times in order to give an additional fluence of approximately 2 J cm(-2) to the entire sinus. The light applicator enables dosimetry-controlled light delivery for additional illumination of the sinus region that is often under-illuminated during thoracic integral illumination of MPM.

Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal cell carcinoma: a phase I/II study.

BACKGROUND: Photodynamic therapy (PDT) is a convenient and effective method of treating small superficial tumours. New second-generation photosensitizers offer some advantages over first-generation sensitizers such as haematoporphyrin derivatives. OBJECTIVES: To define the optimal treatment parameters (drug dose, light dose and time interval) using meta-tetrahydroxyphenylchlorin (mTHPC) as a photosensitizer in patients with multiple basal cell carcinomas (BCCs). METHODS: Light of 652 nm (100 mW cm(-2)) was used for illuminating different tumours (n = 187) with light doses of 5--15 J cm(-2). Following an intravenous injection of 0.1 mg kg(-1) mTHPC each patient (n = 5) was illuminated on 4 consecutive days. Each day at least three BCCs per patient were treated with PDT. RESULTS: Response evaluation at 6, 12 and 18 months showed maximum responses for illumination with 10 or 15 J cm(-2) on days 1 or 2 after injection (86% complete responses). Normal tissue reactions (oedema and erythema) around the treatment site were more severe on day 1 than after longer intervals. CONCLUSIONS: mTHPC is a very effective photosensitizer; short illumination times can result in long-term cures with good cosmetic healing and with skin phototoxicity of short duration.

Increased glomerular Vwf after kidney irradiation is not due to increased biosynthesis or endothelial cell proliferation.

Kuin, A., Citarella, F., Oussoren, Y. G., Van der Wal, A. F., Dewit, L. G. H. and Stewart, F. A. Increased Glomerular Vwf after Kidney Irradiation is not due to Increased Biosynthesis or Endothelial Cell Proliferation. Radiat. Res. 156, 20-27 (2001). Irradiation of the kidney induces dose-dependent, progressive renal functional impairment, which is partly mediated by vascular damage. It has previously been demonstrated that reduced renal function is preceded by an increased amount of von Willebrand factor (Vwf) in the glomerulus. The underlying mechanism and significance of this observation are unknown but, since it is an important mediator of platelet adhesion, Vwf in increased amounts could be implicated in glomerular thrombosis, resulting in impairment of renal function. Increased Vwf could be the result of increased biosynthesis by endothelial cells, or from increased numbers of endothelial cells after compensatory proliferation induced by irradiation, or it could be secondary to other events. In the present study, expression levels of mRNA for glomerular Vwf and glomerular cell proliferation rates were measured in control mouse kidneys and after irradiation with a single dose of 16 Gy. There were no significant changes in mRNA ratios for Vwf/beta-actin at 10 to 30 weeks after irradiation compared with unirradiated samples, whereas increased amounts of Vwf protein were seen in the glomeruli at these times. Labeling studies with IdU or staining for Ki67 demonstrated that glomerular proliferation was increased from 10 to 30 weeks after irradiation. Despite the increased proliferation rates, there was an absence of glomerular hyperplasia and no increase in the endothelial cell surface coverage in the glomeruli. Staining with antibodies against smooth muscle actin (SMAalpha) revealed that the observed proliferation mainly involved mesangial cells. These results indicate that the increased presence of glomerular Vwf after irradiation is not due to an increased number of endothelial cells per glomerulus, or to an increased production of Vwf. It is presumably secondary to other events, such as increased release of Vwf by damaged endothelial cells or entrapment of Vwf in the irradiated mesangial matrix.

Photodynamic therapy for malignant mesothelioma: preclinical studies for optimization of treatment protocols.

Effective photodynamic therapy (PDT) depends on the optimization of factors such as drug dose, drug-light interval, fluence rate and total light dose (or fluence). In addition sufficient oxygen has to be present for the photochemical reaction to occur. Oxygen deficits may arise during PDT if the photochemical reaction consumes oxygen more rapidly than it can be replenished, and this could limit the efficacy of PDT. In this study we investigated the influence of the drug-light interval, illumination-fluence rate and total fluence on PDT efficacy for the photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC). The effect of increasing the oxygenation status of tumors during PDT was also investigated. PDT response was assessed from tumor-growth delay and from cures for human malignant mesothelioma xenografts grown in nude mice. Tumor-bearing mice were injected intravenously with 0.15 or 0.3 mg.kg-1 mTHPC, and after intervals of 24-120 h, the subcutaneous tumors were illuminated with laser light (652 nm) at fluence rates of 20, 100 or 200 mW.cm-2. Tumor response was strongly dependent on the drug-light interval. Illumination at 24 h after photosensitization was always significantly more effective than illumination at 72 or 120 h. For a drug-light interval of 24 h the tumor response increased with total fluence, but for longer drug-light intervals even high total fluences failed to produce a significant delay in tumor regrowth. No fluence-rate dependence of PDT response was demonstrated in these studies. Nicotinamide injection and carbogen breathing significantly increased tumor oxygenation and increased the tumor response for PDT schedules with illumination at 24 h after photosensitizer injection.