Low-dose-rate total lymphoid irradiation: a new method of rapid immunosuppression.

Total Lymphoid Irradiation (TLI) has been successful in inducing immunosuppression in experimental and clinical applications. However, both the experimental and clinical utility of TLI are hampered by the prolonged treatment courses required (23 days in rats and 30-60 days in humans). Low-dose-rate TLI has the potential of reducing overall treatment time while achieving comparable immunosuppression. This study examines the immunosuppressive activity and treatment toxicity of conventional-dose-rate (23 days) vs low-dose-rate (2-7 days) TLI. Seven groups of Lewis rats were given TLI with 60Co. One group was treated at conventional-dose-rates (80-110 cGy/min) and received 3400 cGy in 17 fractions over 23 days. Six groups were treated at low-dose-rate (7 cGy/min) and received total doses of 800, 1200, 1800, 2400, 3000, and 3400 cGy over 2-7 days. Rats treated at conventional-dose-rates over 23 days and at low-dose-rate over 2-7 days tolerated radiation with minimal toxicity. The level of immunosuppression was tested using allogeneic (Brown-Norway) skin graft survival. Control animals retained allogeneic skin grafts for a mean of 14 days (range 8-21 days). Conventional-dose-rate treated animals (3400 cGy in 23 days) kept their grafts 60 days (range 50-66 days) (p less than .001). Low-dose-rate treated rats (800 to 3400 cGy total dose over 2-7 days) also had prolongation of allogeneic graft survival times following TLI with a dose-response curve established. The graft survival time for the 3400 cGy low-dose-rate group (66 days, range 52-78 days) was not significantly different from the 3400 cGy conventional-dose-rate group (p less than 0.10). When the total dose given was equivalent, low-dose-rate TLI demonstrated an advantage of reduced overall treatment time compared to conventional-dose-rate TLI (7 days vs. 23 days) with no increase in toxicity. This was accomplished without compromise of the immunosuppressant activity of TLI as demonstrated by comparable allogeneic skin graft survival times between the two 3400 cGy treatment groups. This clinical advantage would prove to be beneficial where immediate suppression of the immune system is desirable.

Total lymphoid irradiation and antigen-specific tolerance: future therapy for experimental myasthenia gravis?

Total lymphoid irradiation (TLI) is effective in the immunosuppressive treatment of human and experimental autoimmune disorders, including experimental autoimmune myasthenia gravis (EAMG). Under certain circumstances. TLI may facilitate the induction of specific tolerance to antigens present during or shortly after the TLI treatment. This study was designed to determine whether TLI could induce or enhance tolerance to acetylcholine receptor (AChR), the antigen in myasthenia gravis, or to other antigens. We presented the antigens in various potentially tolerogenic forms to rats that were first pre-treated with TLI, or controls treated with sham irradiation. Injection of deaggregated human gamma globulin (HGG), a classical tolerogen, was most effective; it produced antigen-specific tolerance, which was significantly enhanced by pre-treatment with TLI. Injection of HGG coupled to rat peritoneal cells induced a moderate degree of specific tolerance; in this case, pre-treatment with TLI added only nonspecific suppression. In contrast, AChR, either in solubilized form with no adjuvant, or coupled to syngeneic rat peritoneal cells, failed to induce tolerance, and actually primed the immune system, when given alone or in conjunction with TLI. Subsequent challenge with AChR resulted in an enhanced (secondary) anti-AChR antibody response. These results show that the nature of the antigen itself may predispose to tolerance or to immune stimulation. AChR appears to be highly immunogenic. However, if a tolerogenic fragment or form of AChR can be identified, its use in combination with TLI may result in specific tolerance. If such specific tolerance can be induced during an ongoing autoimmune reaction to AChR, it would be an effective treatment for myasthenia gravis.

The utility of a somatostatin-type receptor binding peptide radiopharmaceutical (P829) in the evaluation of solitary pulmonary nodules.

OBJECTIVE: Many neoplasms including small cell cancers more densely express somatostatin-type receptors or more avidly bind somatostatin than granulomatous and other nonmalignant processes. While non-small cell neoplasms of the lung have not yet been shown to demonstrate this receptor expression, previous studies have documented non-small cell lung cancer detection with somatostatin analog scintigraphy. This phenomenon can be conceivably exploited utilizing technetium Tc-99m P829 (P829), a unique low molecular weight somatostatin-type receptor binding polypeptide radiopharmaceutical. The objective of this study was to determine the ability of P829 scintigraphy to noninvasively differentiate malignant and nonmalignant solitary pulmonary nodules (SPNs). METHODS: The radiopharmaceutical technetium 99mTc-P829 was utilized for scintigraphy including single photon emission computed tomography. Thirty individuals with indeterminate SPNs of > or = 1 cm and significant risk factors for primary lung cancer were identified and underwent P829 scintigraphy. Tissue diagnosis was then established by transthoracic needle biopsy specimens. RESULTS: Fourteen subjects demonstrated abnormal P829 scans in the region of the radiographic abnormality. Twelve of this group had biopsy specimens revealing neoplasia. Two subjects with necrotizing granuloma on biopsy specimen had abnormal P829 scans in the region of the nodule. Sixteen subjects had no abnormal P829 tracer uptake in the region of the nodule. Fourteen subjects had benign diagnoses on biopsy specimens. One member of this group with a non-diagnostic biopsy specimen refused thoracotomy and remains radiographically stable at 24 months of follow-up. One subject with a squamous cell carcinoma demonstrated no P829 activity in the region of the nodule. The specificity of P829 scintigraphy based on transthoracic needle biopsy specimen was 88%. The sensitivity was 93%. P829 scintigraphy correctly identified or excluded malignancy in 27 of 30 subjects. CONCLUSIONS: P829 scintigraphy reliably identified or excluded malignancy in radiographically indeterminate solitary pulmonary nodules. The sensitivity and specificity compared favorably with the reported results of F-18 fluorodeoxyglucose positron emission tomographic imaging.

Behavioral sensitization to amphetamine is not accompanied by a decrease in the number of c-Fos containing cells in the striatum.

The expression of c-Fos-like immunoreactivity (FLI) and chronic Fos-related antigen-like immunoreactivity (FRALI) accompanying behavioral sensitization to amphetamine was assessed in male rat striatum. Animals were treated for four days with amphetamine (A; 5 mg/kg) or vehicle (V) and challenged with A or V on the fifth day. The number of FLI-positive cells in the striatum was enhanced in V-A and A-A groups as compared to control (V-V), while the number of FRALI-positive cells in the striatum was enhanced in the A-V and A-A groups as compared to control. These results suggest that the absence of a decrease in the number of striatal FLI-positive cells accompanying chronic amphetamine treatment is not due to antibody cross-reactivity with chronic FRAs, and that behavioral sensitization to amphetamine is not accompanied by a change in the number of striatal cells expressing c-Fos.

Fractionated intravenous administration of 90Y-labeled B72.3 GYK-DTPA immunoconjugate in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas, was coupled with linker-chelator GYK-DTPA using carbohydrate mediated conjugation chemistry and radiolabeled with yttrium-90. Single and double intravenous injections of radioimmunoconjugate were compared for acute and late normal tissue toxicity in 15 beagle dogs. The second injection was given 4 or 8 days after the first. Pharmacokinetics of the radioimmunoconjugate in blood, bone marrow and urine were similar for first and second injections. Only bone marrow (acute) and liver (late) toxicity were observed. Both liver and bone marrow toxicity were decreased by fractionation of the injections. After double injections, the total equitoxic dose was 15 and 60% higher for bone marrow and liver toxicity, respectively. The mechanisms of normal tissue protection offered by fractionated radioimmunoglobulin therapy (RIT) remain to be defined. Fractionated RIT will have a better therapeutic ratio than single injection RIT, if antitumor effects appear to be less susceptible to fractionation than normal tissues.

Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.

Blubber development in bottlenose dolphins (Tursiops truncatus).

Blubber, the lipid-rich hypodermis of cetaceans, functions in thermoregulation, buoyancy control, streamlining, metabolic energy storage, and locomotion. This study investigated the development of this specialized hypodermis in bottlenose dolphins (Tursiops truncatus) across an ontogenetic series, including fetuses, neonates, juveniles, subadults, and adults. Blubber samples were collected at the level of the mid-thorax, from robust specimens (n = 25) that stranded along the coasts of North Carolina and Virginia. Blubber was dissected from the carcass and its mass, and the depth and lipid content at the sample site, were measured. Samples were prepared using standard histological methods, viewed by light microscopy, and digital images of blubber captured. Images were analyzed through the depth of the blubber for morphological and structural features including adipocyte size, shape, and numbers, and extracellular, structural fiber densities. From fetus to adult, blubber mass and depth increased proportionally with body mass and length. Blubber lipid content increased dramatically with increasing fetal length. Adult and juvenile blubber had significantly higher blubber lipid content than fetuses, and this increase was reflected in mean adipocyte size, which increased significantly across all robust life history categories. In juvenile, subadult, and adult dolphins, this increase in cell size was not uniform across the depth of the blubber, with the largest increases observed in the middle and deep blubber regions. Through-depth counts of adipocytes were similar in all life history categories. These results suggest that blubber depth is increased during postnatal growth by increasing cell size rather than cell number. In emaciated adults (n = 2), lipid mobilization, as evidenced by a decrease in adipocyte size, was localized to the middle and deep blubber region. Thus, in terms of both lipid accumulation and depletion, the middle and deep blubber appear to be the most metabolically dynamic. The superficial blubber likely serves a structural role important in streamlining the animal. This study demonstrates that blubber is not a homogeneous tissue through its depth, and that it displays life history-dependent changes in its morphology and lipid content.

Trichoepithelioma 100 years later: a case report supporting the use of radiotherapy.

Trichoepitheliomas are rare skin tumors which can cause significant cosmetic and functional impairment when they occur in the head and neck area. Multiple methods of treatment including plastic surgery, dermabrasion, cryosurgery and laser surgery have been reported in the literature. A 32-year-old male with multiple coalesced lesions in his ear canals was treated with radiation therapy after he failed more conventional methods of treatment. He is free of tumor in the radiated area 17.5 months after treatment with significant functional improvement. Various aspects of this tumor were reviewed. More data are still needed to define the proper place for radiation in the management of this disease.

Treatment of unresectable lung cancer with brachytherapy.

Endobronchial brachytherapy is an evolving treatment modality. Although standard clinical indications and dosage schedules have not yet been established, the wide range of individual experience overwhelmingly demonstrates its efficacy in palliating lung cancer patients who generally have limited treatment options. Although the exact complication rate is not known, it appears to be low and the potential benefits far outweigh the risks. The role of endobronchial brachytherapy for cure is less clear. For most instances "prolonged palliation" would be a more suitable term than "cure." Further data is needed to clarify the proper place of endobronchial brachytherapy as a boost to external beam radiation therapy. The dose, fractionation scheme, and timing relative to external beam radiation therapy are based on institutional preference at this time. The historical evolution, treatment technique, results, and complications of endobronchial brachytherapy are reviewed here.

Treatment of experimental myasthenia gravis with total lymphoid irradiation.

Total lymphoid irradiation (TLI) has been reported to be effective in the immunosuppressive treatment of certain human and experimental autoimmune disorders. We have investigated the effects of TLI in Lewis rats with experimental autoimmune myasthenia gravis (EAMG) produced by immunization with purified torpedo acetylcholine receptor (AChR). The radiation is given in 17 divided fractions of 200 rad each, and nonlymphoid tissues are protected by lead shielding. This technique suppresses the immune system, while minimizing side effects, and permits the repopulation of the immune system by the patient's own bone marrow cells. Our results show that TLI treatment completely prevented the primary antibody response to immunization with torpedo AChR, it rapidly abolished the ongoing antibody response in established EAMG, and it suppressed the secondary (anamnestic) response to a boost of AChR. No EAMG animals died during TLI treatment, compared with six control animals that died of EAMG. TLI produces powerful and prompt immunosuppression and may eventually prove useful in the treatment of refractory human myasthenia gravis.

"Critical loss" in the eighth and ninth decades.

Data from the last survivors of the New York State Psychiatric Institute Twin study were examined to determine if the previously identified relationship between "critical loss" and 5-year survivorship still held true for persons in their eighth and ninth decades of life. Twenty-two subjects (age range 83 to 99 years) were tested in 1973 and by 1978, 12 had died, making it possible to retrospectively examine the relationship between survivorship and critical loss. "Critical loss" did not distinguish survivors from decedents, but presence or absence of OBS did distinguish the groups, with seven of eleven decedents and none of eight survivors being so diagnosed. Survivors did not differ significantly from non-survivors in annual rate of decline on any of the three "critical loss" tests (Vocabulary, Similarities, Digit Symbol Substitution), though survivors had higher mean scores on all three tests.

Endometrial stromal tumors, their varied radiographic patterns.

There is a spectrum of endometrial stromal neoplasms which extends from borderline benign to low-grade malignant. These have a definite tendency to metastasize. Proper diagnosis is important because they have an excellent prognosis with long-term survival even with evidence of recurrence or metastases. Aggressive treatment is mandatory. This represents the first report of the radiographic spectrum of the entity as seen in 7 cases. The patients are usually in middle age and present with vaginal bleeding. Not previously stressed is the presence of diarrhea in many of them. Prior uterine surgery even for "fibroids" should be viewed with suspicion. A pelvic mass was usually seen on plain films, intervenous pyelogram (IVP), or barium enema (BE). Ultrasound showed a mixed cystic configuration of the tumors, whereas computed tomography (CT) demonstrated a definitely solid mass. The lesions simulated primary carcinoma of the colon, retroperitoneal tumor, and pelvic inflammatory disease. Metastases to the lung and the bone were also identified.

Metabolic influences of fiber size in aerobic and anaerobic locomotor muscles of the blue crab, Callinectes sapidus.

Diameters of some white locomotor muscle fibers in the adult blue crab, Callinectes sapidus, exceed 500 microm whereas juvenile white fibers are <100 microm. It was hypothesized that aerobically dependent processes, such as metabolic recovery following burst contractions, will be significantly impeded in the large white fibers. In addition, dark aerobic fibers of adults, which rely on aerobic metabolism for both contraction and recovery, grow as large as the white fibers. These large aerobic fibers are subdivided, however, thus decreasing the effective diameter of each metabolic functional unit and enabling aerobic contraction. The two goals of this study were: (1) to characterize the development of subdivisions in the dark levator muscle fibers and (2) to monitor post-contractile metabolism as a function of fiber size in aerobic and anaerobic levator muscles. Dark levator muscle fibers from crabs ranging from <0.1 g to >190 g were examined with transmission electron microscopy to determine the density of mitochondria and subdivision diameters. Across all size classes, there was a constant mitochondrial fractional area (25% of the total subdivision area) and subdivision size (mean diameter of 36.5+/-2.7 microm). Thus, blue crab dark levator fibers are unusual in having metabolic functional units (subdivisions) that do not increase in size during development while the contractile functional units (fibers) grow hypertrophically. The body mass scaling of post-contractile lactate dynamics was monitored during recovery from anaerobic, burst exercise in white and dark muscle, and in hemolymph. There were no differences among size classes in lactate accumulation during exercise in either muscle. However, in white fibers from large crabs, lactate continued to increase after exercise, and lactate removal from tissues required a much longer period of time relative to smaller crabs. Differences in lactate removal among size classes were less pronounced in dark fibers, and post-contractile lactate accumulation was significantly higher in white than in dark fibers from large animals. These data suggest that the large white fibers invoke anaerobic metabolism following contraction to accelerate certain phases of metabolic recovery that otherwise would be overly slow. This implies that, in addition to the typical mass-specific decrease in oxidative capacity that accompanies increases in animal mass, aerobic metabolic processes become increasingly limited by surface area to volume and intracellular diffusion constraints in developing white muscle fibers.