Shielding design and dose assessment for accelerator based neutron capture therapy.

Preparations are ongoing to test the viability and usefulness of an accelerator source of epithermal neutrons for ultimate use in a clinical environment. This feasibility study is to be conducted in a shielded room located on the Massachusetts Institute of Technology campus and will not involve patient irradiations. The accelerator production of neutrons is based on the 7Li(p, n)7Be reaction, and a maximum proton beam current of 4 mA at an energy of 2.5 MeV is anticipated. The resultant 3.58 x 10(12) neutrons s-1 have a maximum energy of 800 keV and will be substantially moderated. This paper describes the Monte Carlo methods used to estimate the neutron and photon dose rates in a variety of locations in the vicinity of the accelerator, as well as the shielding configuration required when the device is run at maximum current. Results indicate that the highest absorbed dose rate to which any individual will be exposed is 3 microSv h-1 (0.3 mrem h-1). The highest possible yearly dose is 0.2 microSv (2 x 10(-2) mrem) to the general public or 0.9 mSv (90 mrem) to a radiation worker in close proximity to the accelerator facility. The shielding necessary to achieve these dose levels is also discussed.

Comparative teratogenicity of three retinoids: the arotinoids Ro 13-7410, Ro 13-6298 and Ro 15-1570.

Three retinoids of the arotinoid series, namely the free carboxylic acid Ro 13-7410, its ethyl ester Ro 13-6298, and the new arotinoid ethyl sulfone Ro 15-1570, were tested for their embryotoxic and teratogenic activity in rats. The retinoids were administered orally on either day 9 or 13 of gestation. Treatment on day 9 of gestation resulted mainly in malformations of the head and the trunk; whereas, on day 13 limb malformations were prominent. Ro 13-7410 and Ro 13-6298 were about 1000 times more embryotoxic and teratogenic than retinoic acid but induced a similar malformation pattern to retinoic acid. In contrast, the sulfur-containing arotinoid Ro 15-1570 was active at similar dose levels to retinoic acid but caused a peculiar malformation pattern on day 13 of gestation. This finding supports the hypothesis that the arotinoid ethyl sulfone Ro 15-1570 has unique biological properties, inducing no bone toxicity in adult rats and distinctly affecting limb development.

Pharmacokinetics, tissue distribution and placental permeability of tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (a retinoidal benzoic acid derivative) in hamsters.

Tritiated tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (TTNPB; Ro 13-7410) was administered as a single oral bolus to pregnant hamsters (day 8) to determine the maternal plasma pharmacokinetic profile and peripheral tissue distribution patterns. Blood and tissue, including embryo or fetus, were collected at specific time intervals to 96 h and assayed for total radioactive compounds and/or parent retinoid. No lag time was required to describe retinoid absorption (t 1/2 pi = 1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t 1/2 e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 micrograms/kg [3H]2-TTNPB occurred in liver greater than fetus greater than adrenal greater than lung approximately equal to kidney greater than plasma; after 1000 micrograms/kg, maternal liver accumulated the highest concentration followed by plasma greater than fetus = placenta = uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted greater than 90% of the total circulating radioactivity. TTNPB was absorbed and cleared more slowly, concentrated in the conceptus to a higher degree and possessed greater intrinsic activity than the naturally-occurring tetraene retinoids. These properties contribute to the marked teratogenic activity of TTNPB as compared to the tetraene retinoids.

Pharmacokinetics, tissue distribution, and placental permeability of all-trans- and 13-cis-N-ethyl retinamides in pregnant hamsters.

Retinamides have clinical applications in therapy of dermatologic disease, have cancer chemopreventive/chemotherapeutic activities, and possess larger therapeutic ratios than their acidic congeners. The N-ethyl-all-trans-retinamide (NERA) and its 13-cis congener (CNERA) failed to induce terata in hamsters, but an equivalent oral dose of all-trans- or 13-cis-retinoic acid was associated with a significant teratogenic response. Following intubation of 11.4 mg/kg of [3H]NERA or [3H]CNERA to pregnant hamsters during a sensitive stage of development, radioactivity accumulated in maternal bladder and liver. Although plasma concentrations of the parent retinamides declined to nondetectable levels within 12 hr of dosing, near-peak concentrations of retinamide metabolites persisted in maternal plasma until termination of the study (96 hr). Cis/trans isomerization of each retinamide at C13 occurred, but only 15-20% of the total dose could be accounted for as parent retinamide and its C13 isomer. The retinamides were not metabolized to detectable concentrations of circulating all-trans- or 13-cis-retinoic acid. Although the label associated with the retinamides and their biotransformation products crossed the placenta, there was no evidence for preferential accumulation in embryonic or fetal tissues. The results presented here show that the reduced teratogenic potency of retinamides compared to acidic retinoids cannot be ascribed to reduce placental transfer.

Comparative distribution, pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, retinyl acetate and 9-cis-retinal in hamsters.

Pregnant hamsters were given a single oral dose (35 mumol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid: 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.

Fixative evaluation and histologic appearance of embryonic rodent tissue.

Histopathologic study of early hamster embryos was carried out after fixation in Zenker's solution, alcoholic formalin, Bouin's fluid, 10% neutral buffered formalin, or 3% glutaraldehyde and staining with hematoxylin and eosin. Fixation in Zenker's fluid followed by postfixation in neutral buffered formalin provided superior preservation of normal embryonic subcellular detail as compared to the other candidate processing techniques.

Structure-activity relationships of retinoids in developmental toxicology. III. Contribution of the vitamin A beta-cyclogeranylidene ring.

The teratogenic potency of congeners of all-trans-retinoic acid (all-trans-RA) containing modifications or substitution of the naturally occurring beta-cyclogeranylidene ring was determined in Golden hamsters and compared to that of all-trans-RA. The following ring-modified retinoids were screened: phenyl (Ro 8-8717), furyl (Ro 8-9750), 4-methoxy-2,3,6-trimethylphenyl (Ro 21-6667), which also has a thiomethylene group in place of the trans-8,9 double bond of the etretin side chain, 4-hydroxy-2,3,6-trimethylphenyl (Ro 11-4768), 2-chloro-3,6-dimethyl-4-methoxyphenyl (Ro 12-0995), 2-(1-methoxyethyl)-5,5-dimethyl-1-cyclopentenyl (Ro 10-1770), 2-acetyl-5,5-dimethyl-1-cyclopentenyl (Ro 8-7699), and 10,11-epoxy-11,11-dimethyl (juvenile hormone III), which also has the bonds corresponding to the 7,8- and 11,12-double bond of the retinoid skeleton saturated. The retinoids Ro 12-4824, Ro 12-4825, and SRI2712-24 had C4-keto, C18-hydroxyl, and C18-methyl substituents, respectively. Motretinid (Ro 11-1430) had both 4-methoxy-2,3,6-trimethylphenyl ring and ethyl amide polar group modifications. Single oral retinoid doses administered to pregnant dams at 10:00 AM on Day 8 neither induced signs of hypervitaminosis A nor induced weight loss in any of the treated groups. Teratogenically active retinoids induced a malformation syndrome identical to that induced by all-trans-RA. At retinoid doses that were associated with malformations in all of the fetuses, embryolethality remained near that of vehicle-treated controls. The phenyl retinoid Ro 8-8717 was embryolethal but was not teratogenic. The ethyl amide derivative of the human and animal teratogen etretinate, motretinid, was teratogenic only at the highest dose administered, 350 mg/kg. The retinoids Ro 12-4824, Ro 12-4825, Ro 8-7699, and SRI 2712-24 were as potent as all-trans-RA. The chlorine substituted retinoid, Ro 12-0995, was sixfold more teratogenic than all-trans-RA, and the cyclopentene retinoid, Ro 10-1770, was 19 times more potent than all-trans-RA. The retinoids with furyl or epoxy group substitution for the cyclohexenyl ring were devoid of teratogenic activity up to equimolar doses of 75 mg/kg of all-trans-RA, and Ro 21-6667 was teratogenically inactive at a dose equivalent to 150 mg/kg of all-trans-RA. Major modifications of the beta-cyclogeranylidene ring can be made without altering teratogenic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Structure-toxicity relationships of the tetramethylated tetralin and indane analogs of retinoic acid.

The teratogenicity of retinoids containing either tetramethylated tetralin (Ro 13-6307 or Ro 13-2389) or tetramethylated indane (Ro 13-4306) ring system substitutions was compared to the teratogenic potency of all-trans-retinoic acid. Single oral doses, administered to Syrian Golden hamsters at 10:00 A.M. on day 8 of gestation, induced a syndrome of malformations identical to that induced by treatment with all-trans-retinoic acid. These retinoids failed to induce signs of maternal hypervitaminosis A at doses associated with a significant teratogenic response. The tetramethylated tetralin retinoids and indane retinoid were 18 and 2.4 times as embryotoxic on a molar basis, respectively, as all-trans-retinoic acid. Introduction of a supplementary ring in the side-chain restricted polyene chain flexibility and maintained the hydrophobic plane of the chain. The present results are consistent with previous studies showing that the presence of or biotransformation to a free acid congener was necessary for retinoid teratogenic activity in hamsters and that increasing conformational restriction of acidic retinoids increased teratogenic potency.

Hernia through the foramen of Winslow: a complication of cholecystectomy. A case report.

In 151 years since first described, there have been 112 reported cases of hernia through the foramen of Winslow (HFW). All thus far have described HFW as a primary entity. The case reported appears to be unique with HFW as a surgical complication. HFW is the least common of internal hernias. The primary symptom is pain referred from the herniated organ and the hepatoduodenal ligament. An interesting sign is that the patient is found curled up or stooped over for pain relief. Anatomic factors implicated in HFW are an enlarged epiploic foramen, a floppy cecum and ascending colon, or abnormal length of small bowel mesentery. Tension on these structures causes pain with the torso extended. Distention of bowel in the lesser sac mimics gastric obstruction. Organs herniated are: small bowel (63%); cecum, ascending colon, and terminal ileum (30%); and transverse colon (7%). Of 25 cases reported since 1966, cecal herniation comprised two-thirds. The diagnosis may be made radiologically and the treatment is surgical. The case and a review of the literature are presented with attention to the anatomy. Also provided are the signs and symptoms of this interesting and perplexing diagnosis.