Mohan Doss

Linear No-Threshold Model vs. Radiation Hormesis:

The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged.

Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT.

Objectives 18F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of 18F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. MethodsSuccessive whole-body PET/CT scans were done after the injection of 18F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. ResultsThe bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 &mgr;Gy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 &mgr;Sv/MBq from monkey data and 27±2 &mgr;Sv/MBq from human data. ConclusionBladder, kidneys, and liver have the highest uptake of injected 18F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of 18F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of 18F-HX4 is comparable with that of other 18F-based imaging agents.

Evidence Supporting Radiation Hormesis in Atomic Bomb Survivor Cancer Mortality Data

A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.

Low Dose Radiation Adaptive Protection to Control Neurodegenerative Diseases

Concerns have been expressed recently regarding the observed increased DNA damage from activities such as thinking and exercise. Such concerns have arisen from an incomplete accounting of the full effects of the increased oxidative damage. When the effects of the induced adaptive protective responses such as increased antioxidants and DNA repair enzymes are taken into consideration, there would be less endogenous DNA damage during the subsequent period of enhanced defenses, resulting in improved health from the thinking and exercise activities. Low dose radiation (LDR), which causes oxidative stress and increased DNA damage, upregulates adaptive protection systems that may decrease diseases in an analogous manner. Though there are ongoing debates regarding LDRs carcinogenicity, with two recent advisory committee reports coming to opposite conclusions, data published since the time of the reports have overwhelmingly ruled out its carcinogenicity, paving the way for consideration of its potential use for disease reduction. LDR adaptive protection is a promising approach to control neurodegenerative diseases, for which there are no methods of prevention or cure. Preparation of a compelling ethics case would pave the way for LDR clinical studies and progress in dealing with neurodegenerative diseases.

SHIFTING THE PARADIGM IN RADIATION SAFETY

The current radiation safety paradigm using the linear no-threshold (LNT) model is based on the premise that even the smallest amount of radiation may cause mutations increasing the risk of cancer. Autopsy studies have shown that the presence of cancer cells is not a decisive factor in the occurrence of clinical cancer. On the other hand, suppression of immune system more than doubles the cancer risk in organ transplant patients, indicating its key role in keeping occult cancers in check. Low dose radiation (LDR) elevates immune response, and so it may reduce rather than increase the risk of cancer. LNT model pays exclusive attention to DNA damage, which is not a decisive factor, and completely ignores immune system response, which is an important factor, and so is not scientifically justifiable. By not recognizing the importance of the immune system in cancer, and not exploring exercise intervention, the current paradigm may have missed an opportunity to reduce cancer deaths among atomic bomb survivors. Increased antioxidants from LDR may reduce aging-related non-cancer diseases since oxidative damage is implicated in these. A paradigm shift is warranted to reduce further casualties, reduce fear of LDR, and enable investigation of potential beneficial applications of LDR.

90Y -PET imaging: Exploring limitations and accuracy under conditions of low counts and high random fraction

PURPOSE (90)Y -positron emission tomography (PET) imaging is becoming a recognized modality for postinfusion quantitative assessment following radioembolization therapy. However, the extremely low counts and high random fraction associated with (90)Y -PET may significantly impair both qualitative and quantitative results. The aim of this work was to study image quality and noise level in relation to the quantification and bias performance of two types of Siemens PET scanners when imaging (90)Y and to compare experimental results with clinical data from two types of commercially available (90)Y microspheres. METHODS Data were acquired on both Siemens Biograph TruePoint [non-time-of-flight (TOF)] and Biograph microcomputed tomography (mCT) (TOF) PET/CT scanners. The study was conducted in three phases. The first aimed to assess quantification and bias for different reconstruction methods according to random fraction and number of true counts in the scan. The NEMA 1994 PET phantom was filled with water with one cylindrical insert left empty (air) and the other filled with a solution of (90)Y . The phantom was scanned for 60 min in the PET/CT scanner every one or two days. The second phase used the NEMA 2001 PET phantom to derive noise and image quality metrics. The spheres and the background were filled with a (90)Y solution in an 8:1 contrast ratio and four 30 min acquisitions were performed over a one week period. Finally, 32 patient data (8 treated with Therasphere(®) and 24 with SIR-Spheres(®)) were retrospectively reconstructed and activity in the whole field of view and the liver was compared to theoretical injected activity. RESULTS The contribution of both bremsstrahlung and LSO trues was found to be negligible, allowing data to be decay corrected to obtain correct quantification. In general, the recovered activity for all reconstruction methods was stable over the range studied, with a small bias appearing at extremely high random fraction and low counts for iterative algorithms. Point spread function (PSF) correction and TOF reconstruction in general reduce background variability and noise and increase recovered concentration. Results for patient data indicated a good correlation between the expected and PET reconstructed activities. A linear relationship between the expected and the measured activities in the organ of interest was observed for all reconstruction method used: a linearity coefficient of 0.89 ± 0.05 for the Biograph mCT and 0.81 ± 0.05 for the Biograph TruePoint. CONCLUSIONS Due to the low counts and high random fraction, accurate image quantification of (90)Y during selective internal radionuclide therapy is affected by random coincidence estimation, scatter correction, and any positivity constraint of the algorithm. Nevertheless, phantom and patient studies showed that the impact of number of true and random coincidences on quantitative results was found to be limited as long as ordinary Poisson ordered subsets expectation maximization reconstruction algorithms with random smoothing are used. Adding PSF correction and TOF information to the reconstruction greatly improves the image quality in terms of bias, variability, noise reduction, and detectability. On the patient studies, the total activity in the field of view is in general accurately measured by Biograph mCT and slightly overestimated by the Biograph TruePoint.

Findings of intramediastinal gossypiboma with F-18 FDG PET in a melanoma patient.

FDG PET/CT scan was performed to evaluate recurrence in an asymptomatic 64-year-old man with a history of melanoma in the left posterior ear. PET/CT images showed an intense ring-shaped area of FDG activity in the posterior mediastinum in a large posterior mediastinal mass. However, further evaluation indicated that this activity was caused by an intramediastinal gossypiboma after coronary artery bypass graft surgery 4 years before the PET/CT scan.

Point/Counterpoint: Low-dose radiation is beneficial, not harmful

Suggestions for topics suitable for these Point/Counterpoint debates should be addressed to Colin G. Orton, Professor Emeritus, Wayne State University, Detroit: ortonc@comcast.net. Persons participating in Point/Counterpoint discussions are selected for their knowledge and communicative skill. Their positions for or against a proposition may or may not reflect their personal opinions or the positions of their employers.

Applications of a PET device with 1.5 mm FWHM intrinsic spatial resolution to breast cancer imaging

Operation of a high resolution compact clinical PET Scanner (PEM Flex/spl trade/) device as a breast scanner is described. The device features high spatial resolution (1.5 mm FWHM intrinsic resolution) as a result of small crystals and compact position-sensitive photomultipliers. The compactness of the system allows it to reside within a stereotactic X-ray mammography unit, or as a separate standalone system capable of breast compression. The gamma rays are detected for a volumetric reconstruction by two heads, each of which contains 2,028 2 mm by 2 mm by 10 mm lutetium-containing crystals. The heads travel within X-ray transparent compression paddles. A window is provided in one of the paddles for direct correlation with ultrasound transducers and for interventional access. To enable real-time interventions, images are reconstructed and displayed while the detectors are still acquiring data. The maximum-likelihood reconstruction provides quantitative images with threefold improved contrast as compared to simple back-projections.

INWORKS study: risk of leukaemia from protracted radiation exposure

An interesting Article on the eff ects of protracted low-dose radiation exposure on leukaemia mortality was published in The Lancet Haematology. The authors emphasise that their results provide direct estimates of the linear-type risk of leukaemia from protracted radiation doses in ranges typical of environmental, diagnostic medical, and occupational exposure. Certainly, we believe that the Article provides much important information on the health eff ects of low-dose radiation in man. However, we would like to express our concerns that the conclusions could lead to a misunderstanding on the part of the general public and radiation workers, particularly about the health eff ects of low-dose radiation, such as those received in daily life or in the workplace. Since the evidence regarding the health eff ects of low-dose radiation exposure are inconclusive, the authors’ conclusion of a signifi cant and linear risk of leukaemia in the low-dose range might be premature. The primary outcome of the Article was the identifi cation of a lineartype association between protracted low-dose radiation exposure and leukaemia without heterogeneity (excluding chronic lymphocytic leukaemia) in France, the UK, and the USA. However, we believe the readers need further information with regard to why and how the pooled analysis was done on the basis of the data of the three countries selected from the 15-country study, 2 which did not show a signifi cant leukaemia risk; why workers with potential exposure to neutron and internal contamination were included in this three-country study contrary to the 15-country study; and how the authors dealt with potential confounders (such as medical exposure, smoking, etc), which are important factors in the association of low-dose radiation with cancer mortality. The studies on protracted exposure to low-dose radiation have reported inconsistent results across diff erent designs and radiation settings. The Techa River study provides signifi cant results on leukaemia risk, although the radiation dose used is not well recognised. The study on radiation workers in Japan does not fi nd a signifi cant leukaemia risk, and in the latest analysis of 14·2 yearmortality follow-ups on more than 200 000 radiation workers, the excess relative risk per Sv for leukaemia excluding chronic lymphocytic leukaemia is estimated to be negative at −0·27 per Sv, despite a dose range similar to that in the three-country study. Furthermore, the study reported that smoking is a strong confounder in associations between low-dose radiation and cancer mortality. The mortality analysis of atomic bomb survivors does not support the linearity of leukaemia risk. The signifi cance and linearity of risks of low and protracted radiation exposure and leukaemia are still controversial, and we think that drawing conclusions at this point is premature.