Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy.

Rapid recovery of CD4+ T cells after intensive chemotherapy is limited by an age-dependent decline in thymopoiesis. Here we sought to determine whether similar limitations exist for CD8+ T-cell regeneration. After intensive chemotherapy, CD8+ T cells had a faster effective doubling time than CD4+ T cells (median, 12.6 v 28.2 days, P < .05). Accordingly, at 3 months posttherapy, mean CD8+ T-cell number had returned to baseline, whereas mean CD4+ T-cell number was only 35% of pretherapy values (P < .05). These differences were primarily due to very rapid expansion of CD8+CD57+ and CD8+CD28- subsets. At 3 months posttherapy, there was no relationship between age and CD8+ T-cell number (R = -.02), whereas CD4+ T-cell number was inversely related to age (R = -.66) and there were no discernible differences in CD8+ recovery among patients with or without thymic enlargement, whereas CD4+ recovery was enhanced in patients with thymic enlargement after chemotherapy (P < .01). Therefore thymic-independent pathways of T-cell regeneration appear to rapidly regenerate substantial numbers of CD8+, but not CD4+ T cells, resulting in prolonged T-cell subset imbalance after T-cell depletion. These inherent distinctions between CD4+ v CD8+ T-cell regeneration may have significant implications for immunotherapeutic strategies undertaken to eradicate minimal residual neoplastic disease after cytoreductive chemotherapy.

In-111 pentetreotide scintigraphy in patients with neuroblastoma. Comparison with I-131 MIBG, N-Myc oncogene amplification, and patient outcome.

OBJECTIVE: 1. To evaluate the relative efficacy of In-111 pentetreotide and 1-131 radioiodinated meta-idobenzyl guanidine (MIBG) for detection of primary and metastatic neuroblastoma. 2. To assess the prognostic value of In-111 pentetreotide uptake. METHODS AND MATERIALS: Seven In-111 pentetreotide and seven I-131 MIBG scans were obtained in six patients with stage IV neuroblastoma and 1 with stage III ganglioneuroblastoma. Three scans were obtained at initial staging and four were obtained during therapy. Correlation was made with concomitant computed tomography scans, bone scans, N-myc oncogene amplification, and clinical outcome. RESULTS: Primary tumor was present in six patients and had been resected in 1. In-111 pentetreotide uptake was seen in two of six primary tumors, I-131 MIBG scan was positive in five of six. In-111 pentetreotide scan was positive in two of four patients with bone metastases, I-131 MIBG scan was positive in three of four. Both showed liver metastases in one patient and did not show bone marrow metastases in another. Overall sensitivity for primary or metastatic disease was 57% (four of seven) for In-111 pentetreotide and 86% (six of seven) for MIBG. Correlation between N-myc oncogene and In-111 pentetreotide uptake was seen in four of seven patients. In-111 pentetreotide uptake correlated with the clinical outcome in six patients with more than 1 year follow-up. Two patients with negative In-111 pentetreotide scans had unfavorable outcome. One patient died, and the other had local recurrence 15 months after diagnosis. Four patients with a positive scan are alive without disease on follow-up at 13-31 months after diagnosis. CONCLUSION: In-111 pentetreotide scintigraphy is less sensitive than I-131 MIBG for detecting active neuroblastoma. In-111 pentetreotide uptake on scintigraphy may correlate with the prognosis. However, a larger series of patients is needed for further evaluation.

Technetium-99m-DMSA renal cortical scintigraphy to detect experimental acute pyelonephritis in piglets: comparison of planar (pinhole) and SPECT imaging.

UNLABELLED: The purpose of this study was to directly compare the sensitivity and specificity of SPECT and pinhole imaging for the detection of acute pyelonephritis using histology as the standard of reference. METHODS: Bilateral vesicoureteral reflux of infected urine was induced in 16 piglets (32 kidneys) by unroofing the intravesical ureter and subsequently instilling a broth culture of E. coli into the bladder. DMSA scans were obtained by both pinhole and SPECT techniques at 24 hr (4 piglets), 48 hr (5 piglets), 72 hr (4 piglets) and 10 days (3 piglets) after instillation of bacteria into the bladder. Kidneys were harvested immediately after scintigraphy for histopathologic examination. Results of the SPECT images, pinhole images and histologic findings were interpreted independently in a blinded fashion. The images of each kidney were classified as positive or negative for pyelonephritis regardless of the severity and number of lesions. To evaluate accuracy of SPECT and pinhole imaging for the detection of individual lesions, each kidney was arbitrarily divided into three zones (upper, middle and lower). Image findings were then compared with the pathology results for the presence or absence of pyelonephritis in each zone. RESULTS: Histopathology revealed pyelonephritis in 24 of 32 kidneys (58 of 96 zones). The sensitivity of the DMSA scan for detection of affected kidneys was 92% for SPECT and 83% for pinhole; overall accuracy was 88% for both. The sensitivity of SPECT for the detection of affected renal zones was slightly better than pinhole imaging (91% compared with 86%), but its specificity was lower (82% compared with 95%) resulting in a similar accuracy. Excluding four piglets where scans were obtained within 24 hr after instillation of bacteria into the bladder, the sensitivity of SPECT and pinhole for the detection of affected kidneys were 95% and 90%, respectively. Their overall accuracy were 96% and 92%. In this subgroup, the sensitivity, specificity and accuracy of SPECT for the detection of involved zones were 96%, 95% and 96%, respectively. The corresponding values for pinhole imaging were 90%, 95% and 92%, respectively. CONCLUSION: Although the sensitivity of SPECT for the detection of acute pyelonephritis is slightly better than pinhole DMSA scan, the overall accuracy of these two imaging techniques is essentially the same.

The role of 131 iodine-metaiodobenzylguanidine scanning in the correlative imaging of patients with neuroblastoma.

OBJECTIVE: Metaiodobenzylguanidine (MIBG) scans were studied to determine the impact of the scan results on the clinical treatment of pediatric patients with neural crest tumors. METHODS: Serial scans were reviewed retrospectively for 27 patients with neural crest tumors: 25 with initial diagnoses of neuroblastoma (NB), 1 with ganglioneuroblastoma, and 1 with ganglioneuroma (GN). Results were compared with bone scans and computed tomography scans, as well as surgical pathologic findings. RESULTS: At initial diagnosis, when compared with bone and computed tomographic scans, MIBG imaging did not identify any unsuspected lesions that resulted in a change in staging. Thirteen patients with NB who had initially positive MIBG scan results had serial studies that normalized during therapy. However, after completion of therapy, 8 of 13 had relapses of the disease. Although areas of active disease were well delineated by other standard imaging modalities for all 8, only 4 (50%) had MIBG study results that were positive in sites of relapse. There were 4 cases of GN (1 at diagnosis and 3 after therapy for NB) demonstrating an uptake of MIBG that was similar in appearance to that in NB. CONCLUSIONS: MIBG imaging did not change the staging or alter treatment during therapy for any patient. Normalization of positive study results was an unreliable indicator of outcome for children with NB. Furthermore, when relapse occurred, MIBG scans identified only 50% of those with active NB. The uptake of MIBG in GN was indistinguishable from that in NB. In this series, the results of serial MIBG studies did not have a significant impact on patient treatment.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE: We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS: Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS: Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION: ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.

Continuous intraoperative external monitoring of perfusate leak using iodine-131 human serum albumin during isolated perfusion of the liver and limbs.

Regional isolated perfusion using tumor necrosis factor (TNF) shows significant promise for treatment of cancer which is limited to limbs or organs. The high toxicity of TNF requires very sensitive real time monitoring of leakage in order to avoid serious patient complications. Human serum albumin labeled with iodine-131 is used with an externally mounted and collimated NaI(Tl) detector to track the leakage of blood from the isolated perfusion blood circuit into the general systemic vascular space. Blood activity levels measured using the monitor demonstrated a very good correlation with blood serum samples taken concurrently with external monitoring. External monitoring can reduce the risks of perfusion leakage intraoperatively with the precision necessary to safely perform isolated perfusion using TNF.

Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan.

PURPOSE: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma. We have evaluated the relationship of systemic TNF exposure to induction of several secondary mediators and incidence of systemic toxicity. PATIENTS AND METHODS: Nineteen patients with extremity melanoma (n = 16) or sarcoma (n = 3), underwent 90-minute ILP with TNF-alpha, interferon gamma (0.2 mg), and M (10 to 13 mg/L of limb volume) (TNF/IFN/M) (n = 12), or M alone (n = 7). Continuous intraoperative monitoring (CIM) for systemic leak from the perfusion circuit was performed using radioactive iodine-131 albumin. Cytokine levels in the perfusate and systemic circulation during and after ILP were measured by enzyme-linked immunosorbent assay. RESULTS: Systemic leaks > or = 1% from the perfusion circuit occurred in six patients who received TNF/IFN/M and in four who received M alone. Hypotension that required vasopressor support occurred in six of six patients with evidence of a leak (> or = 1%) and zero of six patients without a leak (< 1%). These six patients had significantly higher peak systemic TNF levels during and after perfusion than patients without a leak (2.8 and 8.2 ng/mL v 0.7 and 2.0 ng/mL, respectively; P < .05). All patients who received TNF/IFN/M had significantly greater increases in systemic interleukin-6 (IL-6) levels than in patients with M alone (12,395 +/- 10,374 pg/mL v 79.4 +/- 7.2 pg/mL, respectively; P < .001). Intracellular adhesion molecule (ICAM), IL-8, and TNF-R levels were also increased after ILP with TNF/IFN/M. CONCLUSION: ILP with TNF/IFN/M can be safely performed, as I131 albumin provides a sensitive measure of systemic leakage from the perfusion circuit. Patients with a measured leak of > or = 1% develop mild and transient postoperative hypotension with significantly higher systemic TNF levels and lower perfusate TNF levels than in patients without leaks.

Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy.

BACKGROUND: Inadequate reconstitution of CD4+ T lymphocytes is an important clinical problem complicating chemotherapy, human immunodeficiency virus infection, and bone marrow transplantation, but relatively little is known about how CD4+ T lymphocytes regenerate. There are two main possibilities: bone marrow-derived progenitors could reconstitute the lymphocyte population using a thymus-dependent pathway, or thymus-independent pathways could predominate. Previous studies have suggested that the CD45RA glycoprotein on CD4+ T lymphocytes is a marker for progeny generated by a thymus-dependent pathway. METHODS: We studied 15 patients 1 to 24 years of age who had undergone intensive chemotherapy for cancer. The absolute numbers of CD4+ T lymphocytes in peripheral blood and the expression of CD45 isoforms (CD45RA and CD45RO) on these lymphocytes were studied serially during lymphocyte regeneration after the completion of therapy. Radiographic imaging of the thymus was performed concomitantly. RESULTS: There was an inverse relation between the patients' ages and the CD4+ T-lymphocyte counts six months after therapy was completed (r = -0.92). The CD4+ recovery correlated quantitatively with the appearance of CD45RA+CD4+ T lymphocytes in the blood (r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytes in patients with thymic enlargement after chemotherapy than in patients without such enlargement (two-sided P = 0.015). CONCLUSIONS: Thymus-dependent regeneration of CD4+ T lymphocytes occurs primarily in children, whereas even young adults have deficiencies in this pathway. Our results suggest that rapid T-cell regeneration requires residual thymic function in patients receiving high-dose chemotherapy.

The role of positron emission tomography imaging in early assessment of the antitumor impact of biologics and cytotoxics.

In the evaluation of protocols for patients with cancer, clinicians are increasingly searching for diagnostic tests that will give an accurate indication of response to therapy and predict outcome. Although standard radiologic modalities such as computed tomography and magnetic resonance imaging can localize sites of disease and monitor changes in size of lesions, they cannot reliably determine tumor viability. Positron emission tomography provides the opportunity to quantitate parameters of tumor metabolism. There are numerous studies in the literature reviewing a wide variety of malignancies, and this is an exciting area of ongoing research.

A retrospective analysis of bone scan abnormalities in mastocytosis: correlation with disease category and prognosis.

UNLABELLED: To investigate the usefulness of bone scintigraphy in systemic mastocytosis (SM), the scans of 73 patients were retrospectively reviewed and correlated with disease category. METHODS: A modification of a previously described method for bone scan classification in this disease was used. In addition to the group as a whole, two subsets of patients with multiple bone scans were identified for closer analysis: those with (n = 13) and without (n = 12) scintigraphic evidence of progression of disease. RESULTS: Overall, patients with more aggressive SM tended to have increasingly abnormal initial bone scans (p2 = 0.0003), although there was a considerable degree of overlap. Of patients undergoing serial studies, those with scintigraphic progression also tended to have more aggressive disease (p2 = 0.006) and a poorer prognosis than those with stable bone scans. CONCLUSIONS: Both the degree of abnormality on initial bone scan and progression of scintigraphic abnormalities with serial scanning appear to correlate with the presence of more aggressive systemic mastocytosis. Based on the patterns seen, in many cases this may be a reflection of bone marrow expansion, which in turn probably reflects increased marrow disease.

Abnormalities on ventilation/perfusion lung scans induced by bronchoalveolar lavage.

Studies were performed before and at varying times after lavage in 10 normal volunteers to assess whether bronchoalveolar lavage results in significant abnormalities on ventilation/perfusion lung scans and chest x-rays. Abnormal lung scans were obtained in six subjects, interpretable as intermediate (three scans), low (one scan) and very low (two scans) probability for pulmonary emboli. Defects varied from multisegmental to subsegmental in size, while chest x-rays were normal in all but one. Both the extent and frequency of defects tended to decrease with time; 24 hr after bronchoalveolar lavage only one of four subjects had a minimally abnormal scan. It is recommended that ventilation/perfusion lung scanning be delayed at least 24 hr following bronchoalveolar lavage to avoid problems in interpretation of defects which may merely be the result of the lavage.

Diagnostic imaging in the evaluation of the first urinary tract infection in infants and young children.

The evaluation of infants and children after the first urinary tract infection has undergone change in recent years. Standard diagnostic imaging studies are being utilized on a more frequent basis, because these procedures can provide information which often has a direct impact on patient care. Selection of the proper tests requires an understanding of how they are performed and the basis for their choice. The rationale for the use of different imaging studies and their application to patient care are discussed.

Umbilical cord care. A study of bacitracin ointment vs. triple dye.

Umbilical cord colonization rates were examined over a 4-year period following topical application of bacitracin (1978-1980) or triple dye (1980-1982). A total of 2402 cords were cultured: 1229 following bacitracin cord care and 1173 after triple dye application. Cords treated with bacitracin had significantly higher colonization rates when compared to triple dye prophylaxis. Bacterial colonization with Staphylococcus epidermidis and group B beta-hemolytic streptococcus was found only after bacitracin prophylaxis. Our data support the use of triple dye for routine cord care and suggest that bacitracin application may increase the rate of group B streptococcal colonization.

Temperature dependence of 1,6-diphenyl-1,3,5-hexatriene fluorescence in phophoslipid artificial membranes.

The fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene in phospholipid vesicles is a function of the physical state of the lipid. Below the phase transition, the polarization approaches the theoretical maximum for total immobilization while above the phase transition the fluorescence becomes nearly completely depolarized. The discontinuity in the temperature dependence of polarization occurs within a temperature range under 5 degrees C in the case of pure phospholipids, but for mixed phospholipids occurs over a temperature range greater than 20 degrees C. From these data, phase diagrams describing the gel-sol equilibrium can be constructed; the phase diagrams correspond well with those described in the literature which were constructed using spin-label probes or from x-ray diffraction patterns. The marked change in polarization at the phase transition may be related to the packing of the probe molecule into the lipid bilayer: fluorescence measurements on oriented bilayers indicate that below the phase transition the long axis of the probe is oriented perpendicular to the plane of the membrane while above the transition the probe is oriented randomly relative to the plane of the membrane.