Ronald J. Callahan

Self-organized patchiness in asthma as a prelude to catastrophic shifts

Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

TUMOUR-INFILTRATING LYMPHOCYTES AND INTERLEUKIN-2 IN TREATMENT OF ADVANCED CANCER

Tumour-infiltrating lymphocytes (TIL) were isolated and expanded from small tumour biopsy samples of twenty-eight patients (thirteen with malignant melanoma, seven with renal cell carcinoma, and eight with non-small-cell lung cancer). The patients were treated with autologous expanded TIL (about 10(10)) and continuous infusions of recombinant human interleukin-2(1-3 x 10(6) U/m2 per 24 h). 29% of the patients with renal cell cancer and 23% of those with melanoma achieved objective tumour responses lasting 3-14 months. Toxic side-effects were limited, and no patient required intensive-care monitoring. Adoptive immunotherapy with TIL and interleukin-2 may be an effective systemic approach to the treatment of some patients with malignant melanoma and renal cell carcinoma.

111In-Labeled Nonspecific Immunoglobulin Scanning in the Detection of Focal Infection

We performed radionuclide scanning after the intravenous injection of human IgG labeled with indium-111 in 128 patients with suspected focal sites of inflammation. Localization of 111In-labeled IgG correlated with clinical findings in 51 infected patients (21 with abdominal or pelvic infections, 11 with intravascular infections, 7 with pulmonary infections, and 12 with skeletal infections). Infecting organisms included gram-positive bacteria, gram-negative bacteria, Pneumocystis carinii, Mycoplasma pneumoniae, and Candida albicans. No focal localization of 111In-labeled IgG was observed in 63 patients without infection. There were five false negative results, and nine results were unusable. Serial scans were carried out in eight patients: continued localization correctly predicted relapse in six, and the absence of localization indicated resolution in two. To determine whether 111In-labeled IgG localization was specific for inflammation, we studied 16 patients with cancer. Focal localization occurred in 13 of these patients (5 with melanomas, 5 with gynecologic cancers, and 1 each with lymphoma, prostate cancer, and malignant fibrous histiocytoma). No localization was seen in patients with renal or colon cancer or metastatic medullary carcinoma of the thyroid. We conclude that 111In-labeled IgG imaging is effective for the detection of focal infection and that serial scans may be useful in assessing therapeutic efficacy. This technique may also be helpful in the evaluation of certain cancers.

Redistribution of regional and organ blood volume and effect on cardiac function in relation to upright exercise intensity in healthy human subjects.

To determine the effect of relative exercise intensity on organ blood volume and its relation to cardiac function, changes in relative blood volume and cardiac function were monitored with radionuclide techniques in 14 healthy volunteers. After labeling the subjects red cells with technetium 99m, we acquired data at rest, zero-load cycling, and at 50%, 75%, and 100% of maximal oxygen uptake. From rest to zero-load cycling, leg blood volume decreased 32 +/- 2% (mean +/- SEM), whereas relative end-diastolic blood volume increased 9.6 +/- 1.2%, and lung blood volume increased 18 +/- 2%, suggesting that the lungs may act as a blood volume buffer during periods of acutely increased venous return. With relative increasing exercise, leg blood volume stabilized, and then the blood volume in the abdominal organs decreased, further augmenting cardiopulmonary blood volume; leg blood volume and abdominal blood volume decreased by 23 +/- 2% and 19 +/- 2% from baseline, respectively, whereas thoracic blood volume increased 38 +/- 4%. In the abdomen, large decreases in blood volume were observed in the spleen (46 +/- 2%), kidney (24 +/- 4%), and liver (18 +/- 4%). In contrast, lung blood volume increased 50 +/- 4%, with the upper lung fields increasing more than the lower. Blood sampling revealed an increase in the hematocrit level by 4.3 +/- 0.4 units at peak exercise that paralleled the decrease in splenic blood volume (r2 = -0.64, p less than 0.001), suggesting a role for the spleen in augmenting cardiovascular performance by the release of concentrated red blood cells into general circulation. We conclude that upright exercise results in marked blood volume shifts from the legs and abdominal organs to the heart and lungs in a dynamic process correlating closely with oxygen consumption.

Rapid detection of Parkinson's disease by SPECT with altropane: A selective ligand for dopamine transporters

Increasing evidence indicates that dopamine (DA) transporter density declines in Parkinsons disease (PD). 2β‐Carbomethoxy‐3β‐(4‐fluorophenyl)‐n‐(1‐iodoprop‐1‐en‐3‐yl) nortropane (IACFT, Altropane™) is a cocaine analog with high affinity and selectivity for dopamine transporter (DAT) sites in the striatum. In this study, single photon emission computed tomography (SPECT) with [123I]altropane was used to measure DAT density in seven healthy volunteers (five males, age 37–75, and two females, ages 26 and 39) and eight male patients with Parkinsons disease (age 14–79, Hoehn and Yahr stage: 1.5–3 (n = 5) and 4–5 (n = 3)). Dynamic SPECT images and arterial blood samples were acquired over 1.5–2 hr and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B′max/KD) for striatal (Str) DAT sites was calculated by two methods using occipital cortex (Occ) as a reference. In the first method, tissue time–activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (StrTAC − OccTAC) was fitted to a gamma variate function and the maximum divided by OccTAC at the same time was used to estimate BP. In five of the PD patients, the SPECT data were compared with the results of PET with [18F] 6‐fluoro DOPA (FD‐PET). Plasma analysis indicated that [123I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [123I]altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 h after injection. Both methods of analysis revealed a 7.6%/decade reduction in BP and average striatal values (corrected to age 25) were 1.83 ± 0.22 and 2.09 ± 0.20 by methods 1 and 2. In all the PD patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for DA; most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD‐PET. For total striatum, age‐corrected BP was significantly (P < 0.001) reduced; 0.83 ± 0.06 (method 1), 0.84 ± 0.07 (method 2). BPs measured by the two methods were remarkably similar and highly correlated r2 = 0.88, (P < 0.001). These results indicate that [123I]altropane is an excellent SPECT ligand for imaging the DAT/DA neurons in human brain. The high selectivity and rapid striatal accumulation of the ligand allows for accurate quantitation of DAT sites in less than 2 hr. The results further demonstrate that [123I]altropane is an effective marker for PD. Synapse 29:128–141, 1998.

Tumor-derived interleukin-2-dependent lymphocytes in adoptive immunotherapy of lung cancer

SummaryA trial of adoptive immunotherapy was performed in which long-term cultured, interleukin-2 (IL2)-dependent T-lymphocytes were administered to patients with metastatic adenocarcinoma of the lung. Lymphocytes were isolated from explants of cancer tissues that were cultured in medium with recombinant IL-2. These T-cells expressed surface markers of activation, and killed a broad panel of tumor targets. Intravenously injected 111indium-labeled T-cell blasts distributed primarily to lungs, liver, and spleen. Despite a paucity of infused lymphocytes detected by external imaging at sites of tumor, five of seven patients showed reduction of their cancers. However, in no case was greater than 50% reduction of total tumor burden achieved. Evidence of increased delayed cutaneous hypersensitivity to protein antigens was observed in three patients following therapy. We conclude that long-term cultured tumor-derived T-cells can be transferred safely into humans and that these cells may be capable of enhancing immune responses and mediating tumor reduction in vivo.

Detection of acute inflammation with 111In-Labeled nonspecific polyclonal IgG

The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionuclide methods, such as Gallium-67 (67Ga)-citrate and Indium-111 (111In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that nonspecific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent.

Usefulness of oral dipyridamole suspension for stress thallium imaging without exercise in the detection of coronary artery disease

Stress thallium imaging with intravenous dipyridamole permits assessment of coronary artery disease (CAD) without the need for exercise. However, intravenous dipyridamole is available in the United States only on an experimental basis. To study the use of oral dipyridamole as a clinically available alternative to intravenous dipyridamole for this purpose, 100 patients underwent thallium imaging with oral dipyridamole. Each patient received 300 mg of pulverized tablets in a 30-ml suspension. Maximal increase in mean heart rate and decrease in mean blood pressure occurred 30 minutes after ingestion. At 45 minutes, 2 mCi of thallium was given intravenously and serial imaging was begun within 7 minutes. The serum dipyridamole level (mean +/- standard deviation) 45 minutes after 300 mg was administered orally (3.7 +/- 2.2 micrograms/ml) was similar to that 5 minutes after 0.56 mg/kg was given intravenously (4.6 +/- 1.3 micrograms/ml). Fifty-five patients had some adverse effects between 15 and 75 minutes after oral ingestion, including nausea, headache, dizziness, chest pain (25 patients) and electrocardiographic changes (14 patients). Intravenous aminophylline was used to resolve these adverse effects in 21 patients. There were no severe arrhythmias, myocardial infarctions or deaths. Of the 43 patients with angiographically documented CAD, 39 had an initial perfusion defect that redistributed on the delayed images. When the results in patients who had undergone catheterization were analyzed by individual segment, the presence of thallium redistribution was associated with normal or hypokinetic contrast left ventriculographic wall motion of that segment, whereas the presence of a persistent defect was associated with akinesia or dyskinesia (Fishers standardized Z = 9.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

Detection of gastrointestinal bleeding with 99mTc-labeled red blood cells

Using a modified in vivo Tc-99M red cell labeling technique, gastrointestinal bleeding scintigraphy was performed in 100 patients with GI bleeding. Sixty-two patients with melena or bright red blood per rectum had positive scintiscans. In comparison to results of angiography, endoscopy, surgery and contrast radiography, radionuclide scintigraphy correctly located the site of bleeding in 83% of patients. The procedures could be performed over a 24 hr period which increased the sensitivity of the test since 85% of the scintiscans were positive at one hr or greater after the onset of imaging. The procedure was more sensitive than angiography in detecting sources of GI bleeding. We conclude that GI bleeding scintigraphy 99mTc-red cells in an accurate and effective method to detect upper and lower GI bleeding in patients with acute intermittent gastrointestinal bleeding.