Influence of beam incidence and irradiation parameters on stray neutron doses to healthy organs of pediatric patients treated for an intracranial tumor with passive scattering proton therapy.

PURPOSE: In scattering proton therapy, the beam incidence, i.e. the patient's orientation with respect to the beam axis, can significantly influence stray neutron doses although it is almost not documented in the literature. METHODS: MCNPX calculations were carried out to estimate stray neutron doses to 25 healthy organs of a 10-year-old female phantom treated for an intracranial tumor. Two beam incidences were considered in this article, namely a superior (SUP) field and a right lateral (RLAT) field. For both fields, a parametric study was performed varying proton beam energy, modulation width, collimator aperture and thickness, compensator thickness and air gap size. RESULTS: Using a standard beam line configuration for a craniopharyngioma treatment, neutron absorbed doses per therapeutic dose of 63µGyGy(-1) and 149µGyGy(-1) were found at the heart for the SUP and the RLAT fields, respectively. This dose discrepancy was explained by the different patient's orientations leading to changes in the distance between organs and the final collimator where external neutrons are mainly produced. Moreover, investigations on neutron spectral fluence at the heart showed that the number of neutrons was 2.5times higher for the RLAT field compared against the SUP field. Finally, the influence of some irradiation parameters on neutron doses was found to be different according to the beam incidence. CONCLUSION: Beam incidence was thus found to induce large variations in stray neutron doses, proving that this parameter could be optimized to enhance the radiation protection of the patient.

Configuration and validation of an analytical model predicting secondary neutron radiation in proton therapy using Monte Carlo simulations and experimental measurements.

PURPOSE: This study focuses on the configuration and validation of an analytical model predicting leakage neutron doses in proton therapy. METHODS: Using Monte Carlo (MC) calculations, a facility-specific analytical model was built to reproduce out-of-field neutron doses while separately accounting for the contribution of intra-nuclear cascade, evaporation, epithermal and thermal neutrons. This model was first trained to reproduce in-water neutron absorbed doses and in-air neutron ambient dose equivalents, H*(10), calculated using MCNPX. Its capacity in predicting out-of-field doses at any position not involved in the training phase was also checked. The model was next expanded to enable a full 3D mapping of H*(10) inside the treatment room, tested in a clinically relevant configuration and finally consolidated with experimental measurements. RESULTS: Following the literature approach, the work first proved that it is possible to build a facility-specific analytical model that efficiently reproduces in-water neutron doses and in-air H*(10) values with a maximum difference less than 25%. In addition, the analytical model succeeded in predicting out-of-field neutron doses in the lateral and vertical direction. Testing the analytical model in clinical configurations proved the need to separate the contribution of internal and external neutrons. The impact of modulation width on stray neutrons was found to be easily adjustable while beam collimation remains a challenging issue. Finally, the model performance agreed with experimental measurements with satisfactory results considering measurement and simulation uncertainties. CONCLUSION: Analytical models represent a promising solution that substitutes for time-consuming MC calculations when assessing doses to healthy organs.

Monte Carlo modeling of proton therapy installations: a global experimental method to validate secondary neutron dose calculations.

Monte Carlo calculations are increasingly used to assess stray radiation dose to healthy organs of proton therapy patients and estimate the risk of secondary cancer. Among the secondary particles, neutrons are of primary concern due to their high relative biological effectiveness. The validation of Monte Carlo simulations for out-of-field neutron doses remains however a major challenge to the community. Therefore this work focused on developing a global experimental approach to test the reliability of the MCNPX models of two proton therapy installations operating at 75 and 178 MeV for ocular and intracranial tumor treatments, respectively. The method consists of comparing Monte Carlo calculations against experimental measurements of: (a) neutron spectrometry inside the treatment room, (b) neutron ambient dose equivalent at several points within the treatment room, (c) secondary organ-specific neutron doses inside the Rando-Alderson anthropomorphic phantom. Results have proven that Monte Carlo models correctly reproduce secondary neutrons within the two proton therapy treatment rooms. Sensitive differences between experimental measurements and simulations were nonetheless observed especially with the highest beam energy. The study demonstrated the need for improved measurement tools, especially at the high neutron energy range, and more accurate physical models and cross sections within the Monte Carlo code to correctly assess secondary neutron doses in proton therapy applications.

Secondary neutron doses received by paediatric patients during intracranial proton therapy treatments.

This paper's goal is to assess secondary neutron doses received by paediatric patients treated for intracranial tumours using a 178 MeV proton beam. The MCNPX Monte Carlo model of the proton therapy facility, previously validated through experimental measurements for both proton and neutron dosimetry, was used. First, absorbed dose was calculated for organs located outside the clinical target volume using a series of hybrid computational phantoms for different ages and considering a realistic treatment plan. In general, secondary neutron dose was found to decrease as the distance to the treatment field increases and as the patient age increases. In addition, secondary neutron doses were studied as a function of the beam incidence. Next, neutron equivalent dose was assessed using organ-specific energy-dependent radiation weighting factors determined from Monte Carlo simulations of neutron spectra at each organ. The equivalent dose was found to reach a maximum value of ∼155 mSv at the level of the breasts for a delivery of 49 proton Gy to an intracranial tumour of a one-year-old female patient. Finally, a thorough comparison of the calculation results with published data demonstrated the dependence of neutron dose on the treatment configuration and proved the need for facility-specific and treatment-dependent neutron dose calculations.

Percutaneous renal denervation and the second generation EnligHTN System.

Hypertension remains a major public health burden despite the plethora of therapeutic agents available for this disorder, compelling innovation of alternate therapies including interventional approaches where necessary. The kidney is a major player in the pathophysiology of this disease with increased sympathetic activity being the key factor in the initiation and maintenance of drug resistant hypertension in many patients. Thus renal denervation targeted at decreasing sympathetic drive is becoming the apparent choice in carefully selected patients with resistant hypertension who have exhausted all medical options. The Symplicity and EnligHTN trials using first and second generation catheters respectively have demonstrated that renal sympathetic denervation results in significant blood pressure reduction. The initial renal denervation catheter used in the Symplicity trial was a single electrode system. Refinement of this process has led to the EnligHTN catheter's design. This is a multielectrode self-expanding nitinol basket that allows the positioning of the thermal injury pattern to be pre-specified and in theory lead to better positioning of the lesions. We present a review of the premise behind renal artery denervation, discuss the data and early technologies focusing on the characteristics and utility of the first multielectrode renal denervation device, the EnligHTN renal denervation catheter.

Secondary neutron doses in proton therapy treatments of ocular melanoma and craniopharyngioma.

Monte Carlo simulations were used to assess secondary neutron doses received by patients treated with proton therapy for ocular melanoma and craniopharyngioma. MCNPX calculations of out-of-field doses were done for ∼20 different organs considering realistic treatment plans and using computational phantoms representative of an adult male individual. Simulations showed higher secondary neutron doses for intracranial treatments, ∼14 mGy to the salivary glands, when compared with ocular treatments, ∼0.6 mGy to the non-treated eye. This secondary dose increase is mainly due to the higher proton beam energy (178 vs. 75 MeV) as well as to the impact of the different beam parameters (modulation, collimation, field size etc.). Moreover, when compared with published data, the assessed secondary neutron doses showed similar trends, but sometimes with sensitive differences. This confirms secondary neutrons to be directly dependent on beam energy, modulation technique, treatment configuration and methodology.

[Update of clinical programs using hadrontherapy 2008-2012]. / Évolution des indications cliniques en hadronthérapie 2008-2012.

Hadrontherapy, a type of radiation therapy dealing with heavy charged particles, has become for the past decade one of the most sophisticated and attractive approach in the management of cancer. This is related with major technological innovations that have made available, at a relatively cheap cost, compact proton accelerators equipped with rotational gantries. The implementation of pencil beam scanning should also make treatment planning and delivery much easier and faster than conventional approaches. Until now, approximately 100,000 patients have been treated with protons worldwide. Due to more complex technological and biological challenges, light ion therapy - mainly carbon ions - has developed at a lower pace, except in Japan where most of the 15,000 treated patients have been enrolled. Current indications for protons include firstly, locally aggressive tumours non or incompletely resected, that are located close to critical normal structures: ocular melanomas, skull base and spinal canal low grade sarcomas, selected ENT carcinomas (like adenoid cystic); secondly, improvement of tolerance to radiations: delayed, mainly in paediatric malignancies, due to the exquisite sensitivity of organs under development (including to carcinogenesis); immediate, on bone marrow, mucosae… mainly in concomitant radiation-chemotherapy interactions (tested in esophagus, and lung). Most promising indications for carbon ions include inoperable highly radioresistant primaries, such as mucosal melanomas, high grade bone and soft part sarcomas, and pancreatic carcinomas. Altered fractionations are also of interests that could translate in clinical and economical benefits. Controversies have risen whether more common indications, like prostate, should also be explored.

Prostate cancer multifocality: impact on cancer biology and treatment recommendations.

Subtotal ablative therapies may be a compromise between radical therapy and active surveillance, but oncologic efficacy and quantification of the side effects need to be evaluated in clinical trials. Depending on the eligibility criteria and ablative templates performed, trials of subtotal therapy have the opportunity to provide the scientific community with probative data regarding the biologic and clinical significance of index lesions and further support the hypothesis that multifocality of disease is rarely clinically relevant. This article will review the contemporary pathologic data assessing the intraprostatic heterogeneity of clinically localized prostate cancer and discuss the implications of multifocal disease on clinical trials involving subtotal ablative therapies. We will also discuss limitations in the current definitions of clinical significance as well as the limitations of our current staging techniques.

[Protontherapy: basis, indications and new technologies]. / La protonthérapie : bases, indications et nouvelles technologies.

With over 70,000 patients treated worldwide, protontherapy has an evolution on their clinical applications and technological developments. The ballistic advantage of the Bragg peak gives the possibility of getting a high conformation of the dose distribution to the target volume. Protontherapy has accumulated a considerable experience in the management of selected rare malignancies such as uveal melanomas and base of the skull chordomas and chondrosarcomas. The growing interest for exploring new and more common conditions, such as prostate, lung, liver, ENT, breast carcinomas, as well as the implementation of large pediatric programs advocated by many experts has been challenged up to now by the limited access to operational proton facilities, and by the relatively slow pace of technical developments in terms of ion production, beam shaping and modelling, on-line verification etc. One challenge today is to deliver dynamic techniques with intensity modulation in clinical facilities as a standard treatment. We concentrate in this paper on the evolution of clinical indications as well as the potentialities of new technological concepts on ion production, such as dielectric walls and laser-plasma interactions. While these concepts could sooner or later translate into prototypes of highly compact equipments that would make easier the implantation of cost-effective hospital-based facilities, the feasibility of their clinical use must still be proved.

Secondary exposure for 73 and 200 MeV proton therapy.

Following modifications on the beam line at the Orsay Protontherapy Center, dose measurements were performed in order to make a dose map in the treatment rooms and in the delimited radiation-controlled area around beam line. Measurements were performed using tissue-equivalent proportional counters and rem-counters. Analysis of TEPC single event measurements showed that high LET components (>10 keV.microm(-1)) represent 90 to 99% of total dose equivalent in the treatment rooms and 50 to 90% in the controlled area and quality factors range, respectively between 2 and 15. A fast neutron component was identified in the treatment rooms, where dose equivalent rate varied between few microSv.h(-1) to some dozen of mSv.h(-1). In high-energy radiation field rem-counters underestimated TEPC values for neutron component. The variation between instruments response according to the location is linked to energetic spectrum variations and instrument characteristics.

Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients.

INTRODUCTION: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect. PATIENTS AND METHOD: Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas >/=7 mm thick or >/=15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed. RESULTS: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02). DISCUSSION: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose.

Proton beam therapy for iris melanomas.

AIMS: To describe the results in terms of local control, eye preservation and systemic evolution of iris melanomas treated by proton beam irradiation. METHODS: Retrospective review of the charts of patients with iris melanoma treated by proton beam therapy between April 1998 and September 2002. Ciliary body melanomas with iris involvement or tumours with extrascleral invasion were excluded. Treatment consisted of 60 Gy of proton beam irradiation delivered in four fractions to the tumour volume. RESULTS: A total of 21 patients were treated, median follow-up of 33 months (8-72 months). 15 patients presented a lesion with documented growth. The median clinical diameter was 5 mm (2-8 mm), the median ultrasound diameter 4.8 mm (2-7.7 mm) The patients were 6% T1, 57.1% T2, and 14.3% T3 all N0M0. The iridocorneal angle was invaded by the tumour in 71.4% of patients. At the end of follow-up, all patients were alive with no proven metastatic disease except one patient with suspicious liver lesions. None of the patients showed tumour progression or ocular relapse. The tumour response at 2 years was a flat lesion for 6.3% of cases, partial regression in 75% and stable in 18.8%. None of the patients required secondary enucleation. The main complication was cataract (45% within 24 months of treatment). Raised intraocular pressure was observed in 15% of patients but no neovascular glaucoma. CONCLUSIONS: Proton beam therapy shows potential utility for selected cases of localised iris melanomas allowing excellent local tumour control and eye preservation. Further follow-up on larger series is needed to confirm these results.

[Results of treating uveal melanoma with proton beam radiation: 10-year follow-up]. / Résultats du traitement du mélanome malin de l'uvée par faisceau de protons: 10 ans de recul.

PURPOSE: We analyzed the long-term results of uveal melanoma treatment with proton beam irradiation in a series of patients with a follow-up of at least 10 years. PATIENTS AND METHODS: The patients were treated with proton beam radiation between September 1991 and December 1992. They had an initial examination including visual acuity, funduscopy, A and B scan ultrasonography of the eye, fundus photographs and fluorescein angiography. General examination included chest radiography and B scan ultrasonography of the liver. All tumors received a total dose of 60 cobalt-Gray equivalents (applied in four daily fractions) at the Orsay proton therapy center. RESULTS: A total of 167 patients were treated with a median follow-up of 116 months. Their median age was 59 years. Thirteen tumors were anterior to the equator, 76 overlapped the equator and 78 were posterior to the equator. An initial retinal detachment was present in 41 cases. The optic disk was invaded in 10 cases. The median tumor diameter was 12 mm and the median tumor thickness was 5.8 mm. The mean initial acuity was 20/50. The survival rate was 62.93% at 10 years; 72.9% of deaths resulted from metastasis. Statistically significant risk factors for death identified in the multivariate analysis were tumor diameter greater than 12 mm (p=0.0004) and age over 60 years (p=0.0001). The metastasis rate at 10 years was 31%. The liver was affected in 97.8% of these patients. Risk factors for metastasis were the anterior site of the tumor, its volume greater than 0.4 cc and the presence of retinal detachment at diagnosis. The secondary enucleation rate at 10 years was 13.23%, mainly attributable to secondary neovascular glaucoma. The local recurrence rate was 6%. The visual acuity rate in 42.1% of patients was better than 20/100 at 10 years. Visual loss was mainly due to postradiation maculopathy and neuropathy. CONCLUSION: Our study confirms the long-term results found in the literature on proton beam radiation. This therapy allows good tumor control, an excellent eye retention rate, and good final visual acuity for approximately half of the patients.

[Treatment of uveal melanoma with iodine 125 plaques or proton beam therapy: indications and comparison of local recurrence rates]. / Traitement du mélanome choroïdien par disque d'iode 125 et faisceau de protons: indications respectives et comparaison des taux de récidive.

INTRODUCTION: This retrospective study compared the rate of local recurrence after irradiation of uveal melanoma treated with iodine 125 plaques or proton beam therapy. PATIENTS AND METHODS: Iodine 125 plaques were used to treat all uveal melanomas between the end of 1989 and 1991. Since 1991, we have used iodine plaques for small anterior tumors and proton beam for other tumors. We use a plaque with a larger diameter than the tumor diameter (2-4mm) with a dose of 90Gy at the apex. Proton beam therapy is used for all tumors at the equator or posterior to the equator not thicker than 12mm. The dose given is 60Gy cobalt equivalent in four fractions. For each patient, the initial size and location of the tumor were noted as well as the follow-up each year: the outcome for the eye (local recurrence, ocular conservation, and functional results), the occurrence of metastasis, and survival. A statistical analysis was performed. RESULTS: Between December 1989 and September 1998, 1272 patients were treated: 926 (72.8%) were treated with proton beam irradiation and 346 (27.8%) with iodine 125 plaques. The median follow-up was 5 years (60 months). For the patients treated with proton beam therapy, the mean age was 58 years, the tumor location was anterior to the equator for 3.8%, at the equator for 43.6%, and posterior to the equator for 52.6%. The mean tumor diameter was 13.4mm and the mean tumor thickness was 5.69mm. For the patients treated with iodine 125 plaques, the mean age was 61.5 years. The location of the tumor was anterior to the equator for 34.4%, at the equator for 46.5%, and posterior to the equator for 19.1%. The mean tumor diameter was 11.5mm and the mean tumor thickness was 5.12mm. The recurrence rate was 4% for the proton beam treatment and 3.75% for iodine plaques. There was no statistical difference. DISCUSSION: In the literature, the rate of local recurrence is usually higher with iodine 125 plaques than proton beam therapy. We discuss the risk factors for local recurrence after iodine 125 plaques: tumor diameter, lower dose to the tumor apex and lower dose rate, and posterior location of the tumor. We found a higher mortality rate in patients who presented local recurrence. CONCLUSION: When we use iodine 125 plaques for anterior tumors with the proper dose and dose rate to the apex of the tumor, we do not find more recurrence than with proton beam therapy.

[Results of proton beam irradiation for treatment of choroidal melanoma]. / Résultats du traitement du mélanome de la choroïde par faisceau de protons.

PURPOSE: To evaluate the results of proton beam irradiation of choroidal melanomas on a large series of patients. PATIENTS AND METHODS: Retrospective analysis of a series of patients treated with proton beam irradiation between 1991 and December 1998. The data were analyzed to evaluate the local tumor control as well as the general progression and metastatic rate of the patients. Statistical analysis served to isolate risk factors for relapse or metastasis. RESULTS: We treated 1062 patients during the study period, with a median follow-up of 38 months. Local control was obtained for 97.1% of the patients. Tumors anterior to the equator were at risk for relapse. The survival rate was 92% at 2 years and 78% at 5 years. 73.1% of the 1062 patients died from metastasis, 6.1% of living patients presented with metastatic disease. The risk factors for death were the initial diameter, the age of the patient, and large tumor volume at diagnosis. Metastasis were essentially hepatic (94.6%). Risk factors for metastasis were: a large tumor volume, a lesion anterior or straddling the equator and the age of the patient. Ocular complications may induce a visual loss of 0.1 and less in 47% of the patients, due to optic nerve head and macular ischemia. 6% of the patients required secondary enucleation due to local complications (neovascular glaucoma). CONCLUSION: Proton beam irradiation of choroidal melanoma allows good tumor control and eye retention. The survival prognosis is associated with the initial volume of the tumor. The functional results may be improved and new therapeutics are needed to treat metastatic disease.

Intraocular inflammation after proton beam irradiation for uveal melanoma.

AIM: To describe the inflammatory reaction that can occur following proton beam irradiation of uveal melanomas based on a large series of patients and to try to determine the risk factors for this reaction. METHODS: Data from a cohort of patients with uveal melanoma treated by proton beam irradiation between 1991 and 1994 were analysed. The presence of inflammation was recorded and evaluated. Kaplan-Meier estimates and statistical analysis of general and tumour related risk factors were performed. RESULTS: 28% of patients treated during this period presented with ocular inflammation (median follow up 62 months). Risks factors were essentially tumour related and were correlated with larger lesions (height > 5 mm, diameter > 12 mm, volume > 0.4 cm(3)). Multivariate analysis identified initial tumour height and irradiation of a large volume of the eye as the two most important risk factors. Ocular inflammation usually consisted of mild anterior uveitis, resolving rapidly after topical steroids and cycloplegics. The incidence of inflammation after proton beam irradiation of melanomas seems higher than previously reported and is related to larger lesions. Evidence of inflammation associated with uveal melanoma has been described and seems to be associated with tumour necrosis (spontaneous or after irradiation). The appearance of transient inflammation during the follow up of these patients may be related to the release of inflammatory cytokines during tumour necrosis. CONCLUSION: Inflammation following proton beam irradiation is not unusual. It is correlated with larger initial tumours and may be related to tumour necrosis.

[Neovascular glaucoma following proton-beam therapy. Case report]. / Glaucome néovasculaire compliquant la protonthérapie. A propos d'une observation.

A 52-year-old-male patient was treated for a posterior choroid melanoma of the right eye. When it was diagnosed, it measured 6mm in thickness and 11.9mm for the largest diameter and had a typical mushroom shape. General investigations found no metastatic disease. It was treated with proton-beam irradiation. Seven years later, the patient experienced increased intraocular pressure associated with cataract and pain. The patient finally accepted enucleation, as the vision of this eye was completely lost and the eye had become painful. Histologic analysis of the eye showed changes affecting both the anterior and the posterior segments of the eye, mostly related to the tumor and the consequences of treatment. Neovascular glaucoma is a major complication that very often leads to enucleation.

[Optic neuropathy after proton-beam therapy for malignant choroidal melanoma]. / Neuropathie optique après protonthérapie pour mélanome malin de la choroïde.

Proton-beam irradiation is a conservative therapy commonly used for the treatment of uveal malignant melanomas. Some adverse effects such as optic neuropathy can compromise the visual outcome. We were interested in determining the risk factors for radiation papillopathy. Since there is currently no effective therapy, this is an interesting way to improve prevention of optic neuropathy. Six hundred sixty-two eyes had more than 24 month follow-up after proton-beam irradiation for uveal melanoma. In five hundred twenty-two cases, the clinical examination of the optic nerve head by ophthalmoscopy was possible. One-hundred eleven optic discs were pathologic, whereas 411 remained disease-free. Retrospective study of these two groups allowed to quantify the risk factors for optic neuropathy. The irradiation of more than 2mm of optic nerve at 30 Grays-equivalents appeared to be the major risk factor for optic neuropathy. For a given irradiation dose, the observed pattern of clinical responses was heterogeneous. These results are discussed and compared to the previous published reports. Visual results and life prognosis are also discussed, considering the optic nerve head status. Proton-beam therapy can preserve the optic nerve when the tumor location allows to keep it away from the irradiation-field. Patients must be informed about the risk of optic neuropathy after proton-beam irradiation.

Effectiveness of protons and argon ions in initiating lipid peroxidation in low-density lipoproteins.

In this study, human low-density lipoprotein (LDL) vesicles were irradiated with 73 MeV protons (LET of 1 keV/microm) and 11.4 MeV/nucleon argon ions (LET of 1.52 MeV/pm) and the effectiveness of charged particles in initiating peroxidation of LDLs was investigated. The LDL suspension (6 g/l) was exposed to protons and to argon ions in a dose range of 24 Gy to 2.4 kGy. Irradiations were carried out at the synchrocyclotron at the CPO and at the UNILAC of the GSI. After irradiation three chemical assays were used to study the progression of peroxidation of LDLs: the formation of conjugated dienes, the formation of thiobarbituric acid-reactive substances (TBARS) and the increase in the relative electrophoretic mobility of the LDLs. The results were compared with those obtained after gamma irradiation. For protons the yields of the peroxidation products were 10 times lower than after gamma irradiation. However, for doses below 200 Gy, protons appeared to be more effective than gamma rays in damaging the protein moiety, as deduced from the observed increase in the relative electrophoretic mobility of the LDLs. The irradiation with argon ions led to a negligible formation of peroxidation products, but an increase in the relative electrophoretic mobility of the LDLs was observed. The results are indicative of a lower yield of lipid peroxidation after irradiation with high-LET particles. In contrast, protons and argon ions appear to be more effective in inducing bulk protein and phospholipid damage than gamma rays.