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Purpose: Currently, it is unclear if the variation in proton relative biological effectiveness (RBE) at different positions in the spread-out Bragg peak (SOBP) should be taken into account for medical applications. To date, the majority of studies have examined cells irradiated in vitro. In this work RBE estimates have been made for intact tissue irradiated ex vivo. Materials and Methods: Irradiations were performed in the 200 MeV clinical proton beam produced at iThemba LABS (Cape Town, South Africa). The beam was modulated to produce either a 3-cm or a 7-cm SOBP. The number of intestinal crypts regenerated in jejunum sections of mice after single doses of protons was used as the biological end point. For this, a novel ex vivo irradiation technique was implemented to allow measurements at the very end of the SOBP where most variations in proton RBE can be expected. Results: The proton RBE at the very end of the 7-cm SOBP increases by 10% compared with the middle of the SOBP; the same 10% increas...

The present in vitro study aimed to assess the effects of combining the mTOR inhibitor RAD001 and temozolomide (TMZ) together with irradiation by either low-linear energy transfer (LET) radiation (γ-rays) or high-LET radiation (fast neutrons) on the growth and cell survival of the human glioblastoma cell line U-87. We observed a strong decrease in cell proliferation along with a concomitant increase in cell death as a function of the radiation dose. As expected, high-LET radiation was more effective and induced more sustained damage to DNA than low-LET radiation. While RAD001 in association with TMZ induced autophagic cell death, additional combination with either type of radiation did not further increase its occurrence. On the contrary, apoptosis remained at a low level in all experimental groups.

International audience; Purpose: To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts.Materials and methods: We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS.Results: HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS.Conclusions: Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation.

The effects of high-linear energy transfer (LET) radiations on lymphoid tissues and lymphocytes are not well understood. As a first approach to delineate these effects, the present work was conducted to assess the effects of high-LET radiations on murine spleen cells ex vivo and in vitro. BALB/c mice were irradiated whole-body with 65 MeV neutrons or 15 MV X rays at doses ranging from 0.2 to 3 Gy. Spleens were removed 1 day postirradiation and weighed, and single cell suspensions were prepared and cultured for several days. Apoptosis occurring in vitro was determined at different times by flow cytometry analysis of cells labeled with propidium iodide. It was found that irradiation with fast neutrons reduced spleen weight and cellularity to a greater extent than photons. Considering the spleen cellularity as end point, the relative biological effectiveness (RBE) of fast neutrons was 2. However, for both modes of irradiation, apoptosis of recovered spleen cells in vitro increased as a function of dose and the duration of culture. The level of apoptosis occurring at various times postirradiation was found to be identical for high- and low-LET radiations. Taken together, these results suggest that external as well as cellular factors might differentially modulate the sensitivity of lymphocytes to fast neutrons and photons.

Treatment of hepatocellular carcinoma (HCC) is a major concern for physicians as its response to chemotherapy and radiotherapy remains generally poor, due, in part, to intrinsic resistance to either form of treatment. We previously reported that an irradiation with fast neutrons, which are high-linear energy transfer (LET) particles, massively induced autophagic cell death in the human HCC SK-Hep1 cell line. In the present study, we tested the capacity of the mammalian target of rapamycin (mTOR) inhibitor RAD001 to augment the cytotoxicity of low and high-LET radiation in these cells. As mTOR is a key component in a series of pathways involved in tumor growth and development, it represents a potential molecular target for cancer treatment. Results indicate that RAD001, at clinically relevant nanomolar concentrations, enhances the efficacy of both high- and low-LET radiation in SK-Hep1 cells, and that the induction of autophagy may account for this effect. However, fast neutrons were found to be more efficient at reducing tumor cell growth than low-LET radiation.

Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and a major health problem since the choice of treatment is limited due to chemo- and radio-resistance. It was previously reported that high linear energy transfer (LET) radiation induced massive autophagic cell death in the human HCC SK-Hep1 cell line in vitro. This study analyzed the effects of high-LET radiation on the same HCC tumor model, orthotopically transplanted into nude mice. For this purpose, after surgical xenograft in the liver, animals were irradiated with fast neutrons and cell death occurring in the tumors was assessed with various techniques, including electron microscopy and probe-based confocal laser endomicroscopy. Results indicate that considerable autophagy and only limited apoptosis took place in the tumor xenografts after high-LET irradiation. These data confirm the previous in vitro results, suggesting that autophagy may act as a predominant mode of cell death in the efficacy of high-LET radiation.

The aim of the present study was to determine the cytotoxic consequences of high-linear energy transfer (LET) irradiation in the presence of oxaliplatin on hepatocellular carcinoma (HCC) cells in vitro. We attempted to correlate the induction of apoptosis and autophagy with the formation of DNA double-strand breaks (DSBs). SK-Hep1 cells were irradiated by 65 MeV neutrons in the presence of oxaliplatin and/or the poly(ADP-ribose) polymerase (PARP) inhibitor PJ34. DSBs were measured by the formation of gammaH2AX foci. Results show that in SK-Hep1 cells exposed to fast neutrons in the presence of oxaliplatin, DSBs occurred and persisted with time after irradiation. While apoptosis remained low in co-treated cells, autophagy was considerably increased after irradiation and augmented by the addition of oxaliplatin. Thus, autophagic cell death appears to play a prominent role in the cytotoxicity of the combined treatment and may be linked to the generation of heavy damage to DNA.

Due to the RBE variations, the carbon-ion doses (in Gy) are no longer sufficient to monitor adequately the biological effect of these radiations. Therefore, "RBE dose weighting factors" - W(RBE) - allowing for the RBE variations with energy, dose and biological system have to be introduced in the treatment plans in order to provide the physician with interpretable information. This paper compares the methods employed for this purpose at NIRS and GSI, which are specific of the beam delivery system of these institutions. NIRS has a "passive" beam delivery system where the dose distribution in the SOBP is determined by a Ridge filter. The dose distribution - and thus, the shaping of the filter - is chosen according to the clinical situation and determined with respect to W(RBE) factors in order to yield a biologically iso-effective SOBP. W(RBE )factors in the SOBP are at first derived from a RBE/LET function for HSG cells, then normalized to 3 at a LET of 80 keV/mum. The latter value of 3 corresponds to the clinical RBE of NIRS-neutrons, which were found to exhibit the same radiobiological properties as 80 keV/mum carbon-ions. GSI has a "dynamic" beam delivery system ("spot" or "voxel" scanning) making it possible to irradiate irregular volumes and to modulate the radiation intensity according to the radiosensitivity of different tissues and/or different sub-volumes. Due to the "power" and the resulting complexity of the system, W(RBE )factors are determined through an integrated calculation code allowing iterative interaction of both physical and radiobiological parameters. The "Local Effect Model" (LEM) was developed in this view with the aim of deriving carbon-ion W(RBE )factors from the parameters determining the response to photons. Advantages and weaknesses of the respective methods will be discussed.

The RBE of the new MIT fission converter epithermal neutron capture therapy (NCT) beam has been determined using intestinal crypt regeneration in mice as the reference biological system. Female BALB/c mice were positioned separately at depths of 2.5 and 9.7 cm in a Lucite phantom where the measured total absorbed dose rates were 0.45 and 0.17 Gy/ min, respectively, and irradiated to the whole body with no boron present. The gamma-ray (low-LET) contributions to the total absorbed dose (low- + high-LET dose components) were 77% (2.5 cm) and 90% (9.7 cm), respectively. Control irradiations were performed with the same batch of animals using 6 MV photons at a dose rate of 0.83 Gy/min as the reference radiation. The data were consistent with there being a single RBE for each NCT beam relative to the reference 6 MV photon beam. Fitting the data according to the LQ model, the RBEs of the NCT beams were estimated as 1.50 +/- 0.04 and 1.03 +/- 0.03 at depths of 2.5 and 9.7 cm, respectively. An alternative parameterization of the LQ model considering the proportion of the high- and low-LET dose components yielded RBE values at a survival level corresponding to 20 crypts (16.7%) of 5.2 +/- 0.6 and 4.0 +/- 0.7 for the high-LET component (neutrons) at 2.5 and 9.7 cm, respectively. The two estimates are significantly different (P = 0.016). There was also some evidence to suggest that the shapes of the curves do differ somewhat for the different radiation sources. These discrepancies could be ascribed to differences in the mechanism of action, to dose-rate effects, or, more likely, to differential sampling of a more complex dose-response relationship.

The purpose of this study was to assess apoptosis in hematopoietic tumor cells irradiated with carbon ions, in order to define its contribution to the cytotoxicity of these high-LET radiations.RDM4 (murine T lymphoma), MOLT-4, TK6 and WTK1 (human lymphoblastoid) cells were irradiated with 12C or 13C. Apoptosis was assessed by flow cytometry. Cell growth and activities of caspases were determined during the same periods.The ability of carbon ions to induce apoptosis markedly varied according to the cell line. MOLT-4 and TK6 cells underwent apoptosis at 1 Gy within 12 hours post-irradiation, whereas RDM4 and WTK1 showed little apoptosis under the same conditions.These results indicate that apoptosis contributes to the overall cytotoxicity of carbon ions towards hematopoietic tumor cells although other death mechanisms must also account for this cytotoxicity.

Purpose: Plasma citrulline, a nitrogen end product of glutamine metabolism in small-bowel enterocytes, was suggested as a marker of radiation-induced small-bowel epithelial cell loss in mice after single-dose whole-body irradiation. Our objective was to evaluate the feasibility of citrulline as a marker for radiation-induced small-intestinal mucosal atrophy in patients during and after abdominal fractionated radiotherapy. Methods and Materials: Twenty-three patients were studied weekly during treatment and at intervals of 2 weeks and 3 and 6 months after treatment by postabsorptive plasma citrulline concentration and clinical toxicity grading. The interrelationship between these variables and the correlation with small-bowel dose and volume parameters were investigated. Results: During fractionated radiotherapy, citrulline concentration significantly decreased as a function of the radiation dose (p < 0.001) and the volume of small bowel treated (p = 0.001). The plasma citrulline concentration correlated with clinical toxicity during the last 3 weeks of treatment. As a whole, citrulline concentration correlated better with radiation dose and volume parameters than clinical toxicity grading. Conclusions: In patients treated with fractionated radiation therapy for abdominal or pelvic cancer sites, plasma citrulline concentration may be a simple objective marker for monitoring epithelial cell loss, a major event in acute radiation-induced small-bowel toxicity. (C) 2004 Elsevier Inc.

Citrulline: a physiologic marker enabling quantitation and monitoring of epithelial radiation-induced small bowel damage.Lutgens LC, Deutz NE, Gueulette J, Cleutjens JP, Berger MP, Wouters BG, von Meyenfeldt MF, Lambin P.MAASTRO, Department of Radiation Therapy and Oncology, University Hospital Maastricht/Maastricht University, Maastricht, The Netherlands. l.lutgens@rtil.nlPURPOSE: Small bowel irradiation results in epithelial cell loss and consequently impairs function and metabolism. We investigated whether citrulline, a metabolic end product of small bowel enterocytes, can be used for quantifying radiation-induced epithelial cell loss. METHODS AND MATERIALS: NMRI mice were subjected to single-dose whole body irradiation (WBI). The time course of citrullinemia was assessed up to 11 days after WBI. A dose-response relationship was determined at 84 h after WBI. In addition, citrullinemia was correlated with morphologic parameters at this time point and used to calculate the dose-modifying factor (DMF) of glutamine and amifostine on acute small bowel radiation damage. RESULTS: After WBI, a time- and dose-dependent decrease in plasma citrulline level was observed with a significant dose-response relationship at 84 h. At this time point, citrullinemia significantly correlated with jejunal crypt regeneration (p < 0.001) and epithelial surface lining (p = 0.001). A DMF of 1.0 and 1.5 was computed at the effective dose 50 (ED50) level for glutamine and amifostine, respectively. CONCLUSIONS: Citrullinemia can be used to quantify acute small bowel epithelial radiation damage after single-dose WBI. Radiation-induced changes in citrullinemia are most pronounced at 3 1/2 to 4 days postirradiation. At this time point, citrullinemia correlates with morphologic endpoints for epithelial radiation damage

YingExperimental determination of the RBE of new isotopes for brachytherapy implants (e.g. iodine-125 and palladium-103) remains a very difficult problem, especially in small animals, where the seeds cannot be implanted easily in the planned geometry in a reproducible way. This technical note describes an original device that makes it possible to irradiate a segment of the intestine in mice for the purpose of determining the RBE for crypt regeneration. The device is a length of tube (3.4 mm and 7 mm internal and external diameter, respectively) whose external surface has been longitudinally grooved and into which the seeds can be squeezed (each groove holds either one or two seeds). The tube is composed of two sections. This seed container can be surgically positioned around an intestinal ansa while the mice are anesthetized. The mean dose rates in the intestine (for eight seeds) were found to be 86.3 +/- 5.9 and 79.0 +/- 5.4 cGy/h for 29.2 MBq (1 U) iodine and 28.6 MBq (1 U) palladium seeds, respectively. So far, more than 100 mice have been irradiated successfully. Full dose-effect relationships can be obtained using the same seeds and applying them successively in different groups of animals (which ensured the accuracy of the relative doses).

Despite many recent technical advances, including the use of accelerated high linear energy transfer (LET) particles, cancer radiotherapy remains poorly effective in controlling certain types of tumors due to the frequent failure of malignant cells to undergo a cell death program after radiation exposure. Inactivating molecular components of signalling networks that are involved in tumor radioresistance thus represents an approach to improve cancer radiotherapy. Growing evidence suggests that one such component is the mammalian target of rapamycin (mTOR), a protein kinase that is commonly hyperactive in human tumors. We therefore evaluated the potent and selective mTOR inhibitor RAD001 (everolimus) for its capacity to enhance the effects of low-LET (X-rays and gamma rays) and high-LET (65MeV neutrons) radiation in two human cancer cell lines: SK-Hep1 (hepatocellular carcinoma) and U-87 (glioblastoma). Cellular growth (SRB assay) and the occurrence of DNA double-strand breaks (DSBs, determined by γH2AX foci) and cell death (apoptosis and autophagy, assessed by several methods) were monitored at various times post-irradiation. Clonogenic survival assays and western blotting of mTOR were also performed. RAD001 (20nM) was added to cell cultures 1 hr before the irradiation and maintained throughout the experiments. Irradiation was administered as a single fraction, at doses ranging from 2 to 16Gy. While highly resistant to low-LET radiation, both cell lines proved less resistant to fast neutrons, in agreement with previous studies. When associated with either type of radiation, RAD001 strongly reduced cell growth and also affected clonogenic survival, albeit marginally. Moreover, RAD001 treatment combined with neutron irradiation was found to induce the highest levels of γH2AX foci persistence and cytotoxicity in both cell lines. However, the type of cell death differed radically between the two cell lines. In the SK-Hep1 line, whereas only a low percent of cells underwent apoptosis after irradiation, the percent of autophagic cells was elevated and further enhanced by RAD001. By contrast, in the U-87 line, apoptosis contributed for a large part of cell death after irradiation, but its occurrence was decreased by the addition of RAD001 while the incidence of autophagic cells was concomitantly increased. Our results indicate that a correlation may exist between the persistence of DSBs and the induction of autophagy. Furthermore, autophagic cell death appears to account, almost completely in SK-Hep1 and partially in U-87, for the overall cytotoxicity induced by the combination of RAD001 and irradiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1466. doi:1538-7445.AM2012-1466

The RBE of p(75) + Be neutrons relative to d(50) + Be neutrons has been determined for chromosome aberrations induced in Allium cepa (onion) roots. Two biological criteria were selected: the average number of aberrations (mainly fragments) per cell in anaphase and telophase, and the percentage of aberration-free cells. The influence of sampling time (3 to 7 h incubation) between irradiation and fixation was investigated systematically. This factor did not significantly influence the results. The RBE values of p(75) + Be neutrons compared to those of d(50) + Be neutrons were 0.85 (0.79-0.91) and 0.87 (0.80-0.95) for the first and the second criteria, respectively. In previous experiments for the same beams, we found an RBE of 0.90 (0.86-0.94) for survival of V79 cells (D0 ratio), 0.96 (0.93-0.99) for the intestinal crypt cell system, and 0.83 (0.70-0.96) for Vicia faba growth delay.

In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung carcinomas, severe pulmonary toxicity was observed. In this framework, the objective of this study was to investigate the effect of dFdC on the tolerance of the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung tolerance was assessed by the LD50 at 7-180 days after irradiation. For irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h interval between administration of dFdC and irradiation, the LD50 reached 13.29 (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached 13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung tolerance after single-dose irradiation. However, a proper phase I-II trial should be designed before any routine use of combined dFdC and radiotherapy in the thoracic region.

Male C57Bl/Cnb and BALB/c mice were exposed to single and fractionated d(50) + Be neutrons or 137Cs gamma rays at 12 weeks of age and were followed for life-shortening and disease incidence as ascertained by autopsy and histological examinations at the time of spontaneous death. Fractionation schedules used were 10 exposures at 24-h intervals and 8 exposures at 3-h intervals for gamma rays, and 8 exposures at 3-h intervals for neutrons. The data were analyzed by the Kaplan-Meier procedure using as criteria causes of death and possible causes of death. Individual groups were compared by a modified Wilcoxon test according to Hoel and Walburg (J. Natl. Cancer Inst. 49, 361-372 (1972)). No significant difference was found in C57Bl/Cnb and BALB/c male mice between a single gamma-ray exposure and a single neutron exposure. Gamma-ray fractionation was clearly less effective in reducing survival time than a single exposure. In contrast, fractionation of neutrons was slightly, although not significantly, more effective in reducing survival time than a single exposure. The relative biological effectiveness (RBE) for life-shortening for d(50)-Be neutrons compared to gamma rays is of the order of 1 to 2 for a single exposure to neutrons and between 2 and 3 for fractionated neutrons compared to a single exposure to gamma rays. Neutron irradiation caused somewhat more cancer than gamma irradiation, and the RBE for cancer induction may be higher, probably between 2 and 3 in the range of 1 to 3 Gy, although the present data do not allow a more precise assessment.

Fast neutron therapy is currently carried out in about 20 centers throughout the world. More than 10,000 patients have been treated, and for some the follow-up reaches 15 years, making it ...

Relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) values of different neutron beams produced at the variable energy cyclotron "Cyclone" of Louvain-la-Neuve (Belgium) were determined. The neutrons were obtained by bombarding a beryllium target with 34-, 45-, 65-, or 75-MeV protons or with 50-MeV deuterons. The biological system was growth inhibition in Vicia faba bean roots. Taking the p(65) + Be neutron beam as a reference, RBE values were found equal to 1.36 +/- 0.2, 1.20 +/- 0.1, 1.00 (ref), 0.98 +/- 0.1, and 1.18 +/- 0.1, respectively; the doses corresponding to 50% growth inhibition were 0.39, 0.44, 0.53, 0.54, and 0.45 Gy. For the same beams, OER values were found equal to 1.55 +/- 0.1, 1.38 +/- 0.1, 1.29 +/- 0.1, 1.41 +/- 0.1, and 1.60 +/- 0.2, respectively.

times (N X D8 or N X 2Di), the number of fractions N being adapted to their size in order to reach a suitable rate of survival. The overall treatment time for each compared protocol was kept constant. Intervals i between the two subfractions 2DA of 3.5 and 24 hr were studied. No significant difference appeared in the variation of Dr as a function of D, related to interval i for the two considered intervals.

BALB/c male mice (12 weeks old) were exposed to a single or fractionated exposure of 137Cs gamma rays. The fractionated dose was split into 10 equal doses delivered at an interval of 1 day. The causes and possible causes of spontaneous death were ascertained by autopsy and histological examination, and the data were treated by competing risk analysis. Life shortening followed a linear dose dependency and was about the same for fractionated (38.1 +/- 3.1 days/Gy) as for single (46.2 +/- 4.3 days/Gy) exposure. Death from tumor disease was enhanced and that from nonstochastic lung and kidney diseases was reduced after fractionated compared to single exposure.

The sensitivities of six human cell lines to 50-MeV neutrons were studied using the colony-forming assay in vitro. Two models were used to fit the survival curves: the linear-quadratic (L-Q) model and the single-hit multitarget model with initial slope. The quality of the resulting fits was compared with two analytical procedures. One measured the accuracy of the fits, and the other led to an estimation of the validity of the parameters obtained. The L-Q model responded satisfactorily to these two procedures and could be used to demonstrate that: (1) neutron action can be explained adequately by the same model of cell killing that applies to γ rays; (2) neutron survival curves were different for each cell line; (3) the neutron survival parameters change differently for each line in comparison to γ-ray survival parameters; and (4) the biological parameters determining the differences among cell lines are of utmost importance in determining radiosensitivities at high and low linear energy transfers. Relativ...

The histological appearance of intestinal mucosa in BALB/c/sup +/ mice was studied after fractionated irradiation. Daily doses of 200 and 350 rad were given to the abdomen to investigate recovery mechanisms. After 200 rad/day (1000 rad/week), the average number of nuclei per tangential section of crypts increased in two steps and reached 117, 112, 151, 140, and 145% of the control value after 2,3,4,5, and 6 weeks. The average numbers of mitoses and of (/sup 3/H)thymidine-labeled nuclei per crypt also increased to 155, 155, 160, 207, and 221% and 190, 140, 131, 192, and 230% of the controls, respectively. These data suggest an increase in the stem cell compartment, which is estimated at 1.4 times its normal value after 4 to 6 weeks. The length of the mitotic cycle T/sub c/ was measured using the usual (/sup 3/H)thymidine labeling technique after 5000 rad/5 weeks, given in daily fractions of 200 rad. T/sub c/ was reduced from 14 to 9 hr, this reduction mainly concerning the G/sub 1/ phase (from 5 to 1 hr) and to a smaller extent the S phase (from 7 to 6 hr). Intestinal mucosa tends to compensate for cell destruction by two mechanisms: a reduction inmore » the duration of the mitotic cycle and an increase in the size of the stem cell compartment. At 200 rad/day, an important compensation is achieved and the animals are able to tolerate the irradiation for about 6 weeks. At 350 rad/day, however, increased cell production can no longer compensate for cell destruction and the animals die after the third week.« less

Male BALB/c mice, 12 weeks old, were given a single exposure of either /sup 137/Cs ..gamma.. rays or d(50)-Be neutrons at a dose rate of 3 Gy/min. The animals were kept until death, and causes of death or possible causes of death were ascertained by autopsy and histology. The data were evaluated by competing risk methods. The survival time dose-effect curve for both types of exposure was linear and did not differ significantly (slopes: 55.8 +/- 4.0 days/Gy for neutrons and 46.2 +/- 4.3 days/Gy for ..gamma.. rays). The incidence of different diseases also was similar for both groups expect that more carcinomas, sarcomas, and myeloid leukemias seemed to occur after neutron exposure and that nonstochastic lung and kidney diseases seemed to arise at lower doses.