Myocardial perfusion abnormalities in asymptomatic patients with systemic lupus erythematosus.

Accelerated coronary artery disease and myocardial infarction in young patients with systemic lupus erythematosus is well documented; however, the prevalence of coronary involvement is unknown. Accordingly, 26 patients with systemic lupus were selected irrespective of previous cardiac history to undergo exercise thallium-201 cardiac scintigraphy. Segmental perfusion abnormalities were present in 10 of the 26 studies (38.5 percent). Five patients had reversible defects suggesting ischemia, four patients had persistent defects consistent with scar, and one patient had both reversible and persistent defects in two areas. There was no correlation between positive thallium results and duration of disease, amount of corticosteroid treatment, major organ system involvement or age. Only a history of pericarditis appeared to be associated with positive thallium-201 results (p less than 0.05). It is concluded that segmental myocardial perfusion abnormalities are common in patients with systemic lupus erythematosus. Whether this reflects large-vessel coronary disease or small-vessel abnormalities remains to be determined.

Aluminemic disturbance of technetium-99m DTPA renal function measurement.

During follow-up study of a patient with surgically corrected unilateral renal ischemia, using computer image generated [99mTc]diethylenethiaminepentaacetic acid (DTPA) glomerular filtration rate (GFR) and [131I]orthoiodohippurate estimated renal plasma flow (ERPF), we observed prominent gastric and intestinal uptake of 99mTc. Profound alteration in the GFR results, but not the ERPF results, was also observed. Radiopharmaceutical breakdown was suspected and shown to be endogenous and due to hyperaluminemia at 28 ng/ml. These case findings add DTPA to the list of 99mTc radiopharmaceuticals that have previously been reported to have altered biodistribution when hyperaluminemia is present. The case findings also reaffirm the benefits of obtaining images to corroborate the validity of quantitative data and demonstrate that quantitative radionuclide renal function data are not independent of renal chemical handling.

Gallium-67 lung index computerization in interstitial pneumonitis.

To improve ease of use, precision, and reduce interobserver variability of the 67Ga lung index, we developed and tested a computer method that yields similar numeric values and uses previous indexing principles, except that the computer matrix unit is the fractional area assessed. Patients were referred for suspected interstitial lung disease. Fifty-three image studies were available for both manual and computer indexing. Linear regression analysis gave a correlation of 0.884. Decision matrix analysis of 58 different nonimmunosuppressed patients resulted in 93% sensitivity and 76% specificity. Receiver operating characteristic curve analysis showed that the ideal index cutoff was 50. Because there is tighter control over 67Ga uptake intensity and spatial distribution assessment, the computerized 67Ga index appears to perform better than the manual analysis.

Cellular basis for the elevated gallium-67 computed lung index in a rheumatoid lung patient.

A patient with high levels of serum rheumatoid factor and an open lung biopsy which showed high-grade interstitial pneumonia with large numbers of lymphocytes and plasmocytes had intense gallium uptake in the lungs. Lymphocytes and/or plasmocytes might be responsible for the gallium uptake even though neutrophils are usually credited with high-level uptake. Differential cell counts demonstrated plasmocyte and lymphocyte preponderance, but neutrophil paucity. In vitro cell cultures of purified neutrophils, monocytes, leukemic plasmocytes, and resting and stimulated lymphocytes with 67Ga showed that plasmocytes take up comparatively low levels of 67Ga, but that activated lymphocytes take up levels that approach neutrophils. It is probable that both rheumatoid lung plasmocytes and activated lymphocytes are responsible for the pulmonary 67Ga concentration in this patient.

Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma.

Reversible osmotic blood-brain barrier (BBB) modification was used in 38 patients with glioblastoma to enhance the delivery of chemotherapeutic agents. The patients ranged in age from 14 to 70 years (mean, 43), and all had prior surgery and radiation; 5 had also received systemic chemotherapy. Karnofsky Performance Status (KPS) scores ranged from 60 to 100% (mean, 79) on admission to the treatment program. Barrier modification was achieved by intracarotid or intravertebral artery infusion of mannitol, and a chemotherapy regimen of methotrexate, cytoxan, and procarbazine was given in conjunction with barrier modification. The 38 glioblastoma patients were compared to two control groups of patients with glioblastoma; these encompassed 14 patients treated with surgery and radiation and 8 treated with surgery, radiation, and systemic chemotherapy. Survival analysis using the Cox Proportional Hazards Regression Model (corrected for age, sex, presence or absence of necrosis, and functional status) showed that patients receiving chemotherapy with BBB modification had a statistically significant (P = 0.0006) longer expected survival (17.5 months) than the control groups (12.8 and 11.4 months, respectively). Presently 16 patients of the barrier-enhanced treatment group are alive at 5 to 42 months from diagnosis (median, 20) with KPS scores ranging from 40 to 90% (median, 65). The neurological complications seen included a stroke-like syndrome in 3 patients (1 with decreased motor movement in the hand, 1 with marked hemiparesis, and 1 with hemiplegia), transient exacerbation of preexisting neurological deficits lasting 2 to 3 days, and a 15% incidence of seizures during or within 24 hours of the BBB modification. In 2 of the 38 patients, radiographic documentation of central nervous system tumor regression concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic BBB opening was seen. These studies indicate that chemotherapeutic drug delivery to tumors (as well as surrounding brain) can be augmented by osmotic BBB modification and that such therapy can result in a prolongation of survival.

Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system.

We evaluated the delivery of melanoma-specific radiolabeled monoclonal antibody (MAb) Fab fragments in a pilot study of three patients with melanoma metastatic to the central nervous system. Tumor samples demonstrated excellent immunohistochemical reactivity with Fab 96.5, specific for a 97,000-molecular-weight melanoma antigen (p97), or Fab 48.7, specific for a melanoma-associated proteoglycan antigen. All three patients received 131I-labeled tumor-specific Fab (5 to 7 mg, 1 mCi/mg) intravenously. On a separate occasion, two patients received 131I-labeled nonspecific Fab (5 to 7 mg, 1 mCi/mg). There was no uptake of either antibody into the region of the tumor (as documented by gamma camera brain images). However, there was increased uptake in the blood-brain barrier (BBB)-modified areas in all three patients when radiolabeled tumor-specific MAb was administered intravenously in conjunction with osmotic BBB opening. In one patient, the estimated cerebrovascular permeability X capillary surface area (PA) for the tumor-bearing hemisphere 3 hours after disruption was 1.16 X 10(-6) sec-1 compared to the PA of 0.395 X 10(-6) sec-1 in the nondisrupted hemisphere. Serial brain scans showed that greater than 90% of the radiolabeled antibody cleared from the brain by 72 hours. The highest radiation doses (rads) calculated per 7 mCi injection were: left brain (barrier-modified hemisphere), 5.46; right brain (non-barrier modified hemisphere), 1.68; thyroid, 98; stomach, 9.1; kidney, 39.9; and total body, 1.33. There seemed to be increased uptake of antibody in the tumor region after barrier modification in one patient, but antibody clearance from that region occurred at the same rate as from surrounding and apparently tumor-free brain. In one patient who had carcinomatous meningitis, we demonstrated antibody bound to only a fraction of the antigen binding sites on tumor cells in the cerebrospinal fluid after BBB modification. We have not shown distinct, persistent localization of antibody in brain tumor; studies investigating MAb dose and other parameters as the basis for this problem are under way.

Permeability of human brain tumor to 99mTc-gluco-heptonate and 99mTc-albumin. Implications for monoclonal antibody therapy.

The variable penetration of chemotherapeutic drugs into brain and tumor is more dependent upon lipid solubility than upon size. In contrast, the molecular weight of virus- and tumor-specific monoclonal antibodies appears to limit uptake. The authors have studied eight patients with malignant brain tumors in order to compare tumor uptake of an iodinated contrast agent evaluated by computerized tomography scanning with uptake of the low and high molecular weight imaging agents technetium-99m (99mTc)-glucoheptonate and 99mTc-albumin, respectively, measured by radionuclide brain scanning. The agent 99mTc-labeled albumin was chosen for evaluation because its molecular weight (68,000) is similar to that of the most clinically promising monoclonal antibody fragment, the immunoglobulin (Ig) G Fab monomeric fragment. The radionuclide brain scans in the eight patients showed highly variable permeability of brain tumor to these markers, with uptake of the high molecular weight marker in the tumor being much less than that of the low molecular weight radionuclide. A clinical implication of these studies is that the success of monoclonal antibody therapy in the treatment of malignant brain tumors may require techniques to increase permeability of the blood-brain barrier and blood-tumor barrier to protein.

Importance of collimator selection for quantitative 131I scintigraphy.

Aberrant 131I orthoiodohippurate renal plasma flow values were obtained when our image-based method was moved from an old to a new gamma camera. We suspected inadequate collimation as the reason for this problem because we observed increased septal penetration and scatter. Camera effects were largely eliminated because both our old and new cameras had 1/2'' thick crystals. We report here the effects of two high and three medium energy collimators upon the fraction of syringe image count beyond the syringe image, and upon the correlation of these non-image count fractions with geometric collimator parameters. We also report the effects of these same collimators upon kidney-to-background count ratios, using patient relevant abdominal phantoms. The percentage counts beyond the syringe image varied from 33 to 57%. The phantom kidney-to-background ratios varied from 3.7 to 2.0. We conclude that image-based quantitative measurements are strongly dependent on collimator selection. The data also provide a user basis for collimator evaluation, selection and design, and have implications for 131I and 111In antibody imaging.

Asynchronous capsule formation in the gastrointestinal tract of the prairie rattlesnake (Crotalus viridis viridis) induced by Mesocestoides sp. tetrathyridia.

The prairie rattlesnake (Crotalus viridis viridis) was experimentally infected with tetrathyridia of Mesocestoides sp. Individual snakes were killed at 4 wk increments, and sections of the stomach, small intestine, large intestine and attached mesenteries were examined for nonencapsulated and encapsulated tetrathyridia. Capsule formation was asynchronous with 9 to 80% encapsulated metacestodes. The distribution of tetrathyridia in the wall of all segments of the gastrointestinal tract is presented as evidence that this metacestode is principally a tissue dwelling parasite.

Osmotic blood-brain barrier modification: clinical documentation by enhanced CT scanning and/or radionuclide brain scanning.

Results of initial clinical trials of brain tumor chemotherapy after osmotic blood-brain barrier disruption are promising. In general, the procedure is well tolerated. The major complication has been seizures. In this report, data are presented which indicate that the etiology of these seizures is related to the use of contrast agent (meglumine iothalamate) to monitor barrier modification. A series of 19 patients underwent a total of 85 barrier modification procedures. Documentation of barrier disruption was monitored by contrast-enhanced computed tomographic (CT) scanning, radionuclide brain scanning, or a combination of both techniques. In 56 procedures (19 patients) monitored by enhanced CT, seizures occurred a total of 10 times in eight patients. Twenty-three barrier modification procedures (in nine of these 19 patients) documented by nuclear brain scans alone, however, resulted in only one focal motor seizure in each of two patients. In eight of the 19 patients who had seizures after barrier disruption and enhanced CT scan, four subsequently had repeat procedures monitored by radionuclide scan alone. In only one of these patients was further seizure activity noted; a single focal motor seizure was observed. Clearly, the radionuclide brain scan does not have the sensitivity and spatial resolution of enhanced CT, but at present it appears safer to monitor barrier modification by this method and to follow tumor growth between barrier modifications by enhanced CT. Four illustrative cases showing methods, problems, and promising results are presented.