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Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioc acid, is the most widely studied and most effective radioprotective drug at present, it is nevertheless clear from animal studies that it has important shortcomings as the ideal radioprotector in clinical radiotherapy. More effective and less toxic radioprotective drugs are needed. For this reason, a chemical radioprotector screening program has been initiated at the Fox Chase Cancer Center under a contract with the National Cancer Institute. Most of the 20 compounds that have now entered the screening program provide good protection of the mouse hematopoietic system as indicated by 30 day survival following the radiation LD100/30. Administration of a radioprotector dose equal to one half of the maximum tolerated dose (MTD/2) gave hematopoietic dose reduction factors (DRF's) as high as 2.3. No radioprotector appeared to be superior to WR-2721, although four others gave DRF's exceeding 1.8.

Twentyfour patients treated with irradiation to either their pelvis or their chest for neoplastic disease were included in a randomized study of radioprotection with sodium meclofenamate (Meclomen) (SM). Seventeen patients received SM 100 mg, p.os, t.i.d., and seven received placebo. The long-range radiation related chronic gastrointestinal and urinary tract toxicity was diminished by SM. At 12 months post irradiation, SM treated patients experienced less gastrointestinal and urinary symptoms, as well as less measured bladder contraction, than the controls. Acute gastrointestinal signs of radiotoxicity, however, seemed to have been enhanced by SM. The treated patients suffered from nausea, vomiting, and diarrhea. These acute toxic effects were temporary and reversible.

The paper reports on 14 patients with surgical complications following radioenterocolitis. The most serious complications are peritonitis after perforation and manifest intestinal ileus. Pathogenesis, symptomatics and therapeutical possibilities are discussed. The own cases are analysed and conclusions are drawn for the practice.

It is clear that the risk of toxicity to normal tissues in combined therapy is reduced by separating drug administration and radiation exposure in time. The short-term interaction of drugs and radiation aimed at producing enhanced tumour cell kill is difficult to demonstrate in vivo in animal experiments and unlikely to be important in clinical practice. Increased toxicity of normal tissues in man has been manifest both in terms of early and late reactions and probably also in carcinogenesis. In the latter context choice of drug and possibly sequencing may be important in minimising the risk of tumour induction. There are few experimental studies examining moderately long time intervals between drug and radiation exposure. The administration of chemotherapy prior to irradiation may be less toxic than the converse sequence, although clinical data supporting this contention are limited at the present time.

Individual and population doses on Danish territory are calculated from hypothetical, severe core-melt accidents at the Swedish nuclear plant at Barsebäck. The release fractions for these accidents are taken from WASH-1400. Based on parametric studies, doses are calculated for very unfavourable, but not incredible weather conditions. The probability of such conditions in combination with wind direction towards Danish territory is estimated. Doses to bone marrow, lungs, GI-tract and thyroid are calculated using dose models developed at Risø. These doses are found to be consistent with doses calculated with the models used in WASH-1400.

Three different means of diminishing discomfort during radiation therapy of the gastrointestinal tract are demonstrated and discussed: 1. Use of the smallest possible treatment volumes in medically well developed regions with good possibilities for follow-up of all patients. 2. Regular consultations, with advice concerning food intake and dental hygiene 3. Use of the drug sucralfate, which may improve tolerance against the radiation-induced damage to the gastrointestinal mucosa.

Out of 134 patients irradiated below the diaphragm to a dose of 40 Gy for Hodgkin's disease at the Institut Gustave-Roussy, 19 (14%) were subsequently found to present with radiation injuries of the gastrointestinal tract. Since five patients presented with two different injuries, 24 radiolesions were observed. Most of them (17 out of 24) were gastric or duodenal. Twelve (out of 24) were ulcers. Nine patients required surgery. A complete cure of the radiation injuries was obtained in 15 out of 19 patients. Sex, age, stage, histology or initial chemotherapy were not found to play a role in the occurrence of radiation damage. On the contrary, the role of a previous exploratory laparotomy appeared important; for the patients who underwent laparotomy and irradiation, the complication rate was 23%. For the patients treated by irradiation alone, the complication rate was 7% (p less than 0.01). Fractionation was found to be another important parameter: for 52 patients treated using 3 weekly fractions of 3.3 Gy, the complication rate was 25%, compared to 8% (p less than 0.01) for 76 patients treated using 4 weekly fractions of 2.5 Gy. Combining these two factors, we found a 42% complication rate for the group of patients who underwent laparotomy and who were treated by means of 3 fractions of 3.3 Gy per week, whereas patients irradiated using 4 weekly fractions of 2.5 Gy, without any previous laparotomy, had only a 5% complication risk (p less than 0.001).

The He-Ne laser is generally considered as a "cold" or "soft" laser. However, the present study indicates that doses from 0.3 to 0.5 J/cm2 of He-Ne laser caused intensive damage that was mainly observed on the plasma membrane and the mitochondria of the midgut cells of Drosophila auraria larvae. In contrast, doses less than 0.3 J/cm2 of the He-Ne laser didn't cause any visible effect, as measured by the electron microscope. The possible use of the He-Ne laser and the subsequent effect in relation to its application in acupuncture and therapeutic research is discussed.

A total of 62 patients with advanced tumours have now been treated by a fractionated course of radiotherapy, with misonidazole. The prime purpose of the administration of the drug to these patients was to determine safe dosage and suitable regimes for use in clinical radiotherapy. The reaction of normal tissues did not seem enhanced but there was an impression of increased tumour response.

The effects of a single 400 R whole-body dose of X-irradiation on the regional 5HT content of the gastrointestinal (G. I.) tract were studied from four hours to 40 days after irradiation. The total 5HT content of various G.I. tissues was determined and 5HT was also determined per unit of body weight, wet weight of tissue and tissue protein. Irradiation caused an immediate decrease of the amine content of various G.I. regions in adult rats. This was followed by recovery, the degree of which varied in different regions. Some minor morphological changes were seen in enterochromaffin cells one and two days after irradiation but not later. The effects of irradiation on the G.I. tissues were stronger in young rats, in whom no complete recovery of 5HT occurred within 45 days. The present results support the view that irradiation exerts a direct damaging effect on the gastrointestinal 5HT storage, which is associated with liberation of 5HT from amine-containing cells. The duration of the effect varies with age and intestinal segment concerned.

These experiments were designed to test the hypothesis that bone marrow damage contributes to lethality when the endpoint used is LD50 for gastrointestinal damage. Specific pathogen-free mice were irradiated to the total body, total abdomen, or to the total body followed by rescue with syngeneic bone marrow cells. The relationship between animal survival and jejunal crypt survival was also examined under these three experimental conditions. The LD50/10 after total abdominal irradiation (15.6 Gy) was higher than that for total body irradiation (11.4 Gy). Rescue with syngeneic bone marrow cells after total body irradiation also increased the LD50 10 days to 14.6 Gy. The proportion of animals surviving after total body irradiation depended on the number of bone marrow cells injected as a rescue inoculum. Hence gastrointestinal death after total body irradiation is influenced by bone marrow depletion. Crypt survival, however, was similar following all three experimental procedures. These data, therefore, demonstrate a dissociation between a clonogenic and lethality assay of intestinal damage. Furthermore, a comparison of crypt survival at the LD50 under the different conditions showed that a factor of 10 times more crypts were needed to rescue a mouse from gut lethality when the total body was irradiated than when only the total abdomen was treated. Hence, the concept of the intestinal "tissue rescuing unit" as a precise and constant number of crypts is inappropriate and will vary with the experimental conditions.

The literature on taste aversion learning is reviewed and discussed, with particular emphasis on those studies that have used exposure to ionizing radiation as an unconditioned stimulus to produce a conditioned taste aversion. The primary aim of the review is to attempt to define the mechanisms that lead to the initiation of the taste aversion response following exposure to ionizing radiation. Studies using drug treatments to produce a taste aversion have been included to the extent that they are relevant to understanding the mechanisms by which exposure to ionizing radiation can affect the behavior of the organism.

The contribution of radiological examinations to the evaluation of radiation lesions of the digestive tube in 17 children is discussed. The lesions observed were stenosis, submucous infiltration, and mesenteritis from vasculitis. Ali the patients had been treated with high irradiation doses varying from 3,000 to 5,500 rads. Clinical manifestations appeared after intervals of from 2 months to 13 years, but the anatomical lesions seemed to occur early and to show little change once they were established. Except when an acute occlusion was present, radiological examination consisted of a barium meal and follow through, able to demonstrate anomalies in the folds, stenosis, dilatation, or thickening and matting of the intestinal loops.

Rats that were fasted and/or fed diets consisting of whole milk, dry milk, milk supplement, orange juice, low calcium, or low vitamin D were gavaged with 238Pu nitrate to measure plutonium absorption. All dietary variations resulted in increases in both absorption and retention. The increases ranged between 2 and 20 times the absorption values obtained for rats fed commercial chow. Sucklings of dams fed a calcium-deficient diet also exhibited increased 238Pu absorption. The results indicate that nutrition is an important factor influencing gastrointestinal absorption of plutonium.

Twenty-one women with biopsy proven aortic node metastases from previously untreated carcinoma of the uterine cervix were treated with high dose irradiation to the pelvis and para-aortic areas. The majority received 6000 rads to the pelvis and para-aortic nodes by split course therapy plus 2500 rads by intracavitary radium to point A; 57.1% sustained severe complications to the stomach, small intestine or colon. Only 14.2% are surviving over 2 years free of recurrence. Though approximately 40% of women with Stages III and IV cervical cancer will have metastases to the para-aortic nodes, to date there is no satisfactory therapy that results in a significant number of such women surviving free of recurrent cervical cancer.

Fifty patients with non-Hodgkin's lymphoma were treated with total abdominal irradiation to a dose of 3000 rad by anterior and posterior fields treated the same day. Fourteen patients developed complications, four with intestinal obstruction due to stenosis and three with total or partial intestinal irradiation damage. These bowel complications were only seen in patients who had previously had a laparotomy. The ways of preventing these complications are discussed. We have studied renal function by means of clinical examination, biologic and radiologic investigations, and scanning in 75 patients who have received splenic irradiation to a dose of 4000 rad. With a mean follow-up time of 36 months, this study has shown that there was no significant change in blood pressure or in biochemical measurements. However, at the 17th month, nephrotomograms demonstrated cortical atrophy of the upper role of the kidney; at the 8th month, low uptake in the irradiated area was seen on 197Hg neohydrine scanning and a decrease in renal plasma flow in the left kidney during dynamic studies with Hippuran.

Fifty-six sites in 49 patients were irradiated by a 7 day/week accelerated fractionation schedule to conventional tumor doses. Daily doses were 180 to 200 rad in 85% of sites. Patients were analyzed for normal tissue tolerance. A 7 day/week accelerated fractionation appears clinically tolerable at 180 rad per fraction.

Advances in surgical techniques, in chemotherapy, and in radiation therapy have led to improved survival in children treated for cancer. Children cured of cancer will soon form a significant fraction of our adult population. As we follow such survivors, we have become more aware of long-term side effects of treatment. This is not a reason to withhold therapy. Instead, careful followup of oncology patients is needed to document the late effects, to identify the etiologic agents, and to alter treatment to give the least toxic therapy without sacrificing quality or duration of survival.

When major volumes of the abdomen are the tolerable dose is frequently limited by the tolerance of the small intestine and other gastrointestinal tissues. In an attempt to increase the tolerable dose, a twice-daily, 5 day/week fractionation scheme was used. One hundred and thirty-nine patients were started on treatment for abdominal and pelvic malignancies, of whom 124 received the planned dose, usually in the prescribed time. Fifty-five hundred to 6000 rad in about 8 weeks was administered to large volumes of the pelvis and abdomen, frequently with "boost" radiation to 7500 rad to limited volumes. Ninety percent of the patients were able to complete treatment without interruption. In 90% of all cases there were no late radiation-related complications. The acute reactions and late complications have been comparable to those incurred when total doses 20-30% less are administered with one fraction per day. The survival rates of these patients indicates a probable improvement in therapeutic ratio. The physical techniques, areas treated, and time-dose sequence are described. A detailed analysis by primary organ, patient characteristics, performance status, types of complications, cause of death, and survival characteristics is presented.

Radiation therapy directed at the abdomen may damage the digestive tract, the type and extent of injury depending on the dose of the radiation and the radiation sensitivity of the gut. Characteristic early changes are manifest in the mucosa of the gut: for later ulceration, changes in the collagen tissues and particularly in the vascular channels occur. This paper describes and characterizes injuries to the esophagus, stomach, small intestine and colon. It emphasizes the importance of recognizing radiation-induced damage to the gut which may occur early or late after radiation.

Two thiophosphoroate radiation protectors (WR-2721 and WR-151327) were assessed for their ability to modify the effects of neutron or gamma irradiation on the gastrointestinal tract. Three neutron sources (DOSAR, JANUS, and FERMILAB) were compared to the response obtained after 60Co irradiation. The end points studied were intestinal stem cell survival and LD50(6). DOSAR and JANUS, both fission-spectrum neutrons, showed somewhat different gut sensitivities [LD50(6)] of about 240 and 400 cGy respectively. The intestinal LD50 obtained with FERMILAB neutrons (25 meV) was closer (875 cGy) to that obtained after 60Co (1068 cGy) irradiation. WR-151327 protected against the lethal effects of fission neutron (DOSAR and JANUS) to a greater degree (DMF = 2.2) than with lower LET sources such as FERMILAB neutrons (DMF = 1.7) or 60Co (DMF = 1.7). The results did not correlate with the intestinal stem cell assays where WR-2721 when compared to WR-151327 showed either similar (DOSAR; fission spectrum neutrons) or somewhat better (60Co and FERMILAB neutrons) protection. Possible explanations for the differing results are discussed.

Three-hundred Balb/C mice were used to assess the effect of vasopressin on the response of the gastrointestinal tract to irradiation. Median lethal doses were determined for control and vasopressin treated animals in which the whole abdomen was irradiated. There was a significant difference in LD50/6 (882 +/- 27 for controls vs. 1051 +/- 23 for vasopressin-treated animals). In addition studies demonstrated a significant difference in the survival rate of jejunal crypts at 800 and 1,000 rads.

The possibilities of surgical treatment for sequelae from radiotherapy in different organs and apparatuses are examined. Clinical severity of such sequelae is correlated to the causal factors: dose and its distribution with time, physiological status and volume of the irradiated tissues, association of the radiotherapy with chemotherapy and/or surgical treatments. For sequelae in the soft tissue the main question is to find trophic tissues for surgical wounds; plastic surgery is very often unavoidable. For osseous sequelae, when the administered dose was relatively low, conservative treatments are sufficient to cure. As regards sequelae of the digestive tract derivative surgical treatment is advisable, rather than resections with end to end anastomoses, when the administered dose is rather high; after low doses, sequelae are most frequently represented by easily removable bridles. For sequelae in the brain, nervous plexuses, heart, eye, surgical treatment can be useful, even if frequently with palliative results. The opportunity of integration of medical and surgical treatments is also examined.