Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer.

BACKGROUND: The aim of this prospective study was to evaluate the value of F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) for early assessment of chemotherapy response in patients with advanced colorectal cancer. METHODS: Dynamic FDG-PET was carried out before and at 2 (n = 50) and 6 months (n = 19) after the start of treatment. Quantitative Patlak analysis [metabolic rate of glucose (MRGlu)] and a simplified method to measure glucose metabolism [standardized uptake value (SUV)] were evaluated. The predictive value of changes in glucose metabolism was assessed with Cox proportional regression analysis. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates. RESULTS: There was an increase in the rates of death (P = 0.049 for DeltaMRGlu PET1-2; P = 0.017 for DeltaSUV PET1-2; P = 0.032 for DeltaMRGlu PET1-3; P = 0.048 for DeltaSUV PET1-3) and progression (P = 0.026 for DeltaMRGlu PET1-2; P = 0.035 for DeltaSUV PET1-2; P = 0.041 for DeltaMRGlu PET1-3; P = 0.081 for DeltaSUV PET1-3) associated with worse response as assessed by PET on Cox proportional regression analysis. The OS and PFS analysis showed a significant predictive value at broad ranges of DeltaMRGlu and DeltaSUV cut-off levels. CONCLUSION: The degree of chemotherapy-induced changes in tumor glucose metabolism is highly predictive for patient outcome. The use of FDG-PET for therapy monitoring seems clinically feasible since simplified methods (SUV) are sufficiently reliable.

Preferential localization of systemically administered radiolabeled interleukin 1alpha in experimental inflammation in mice by binding to the type II receptor.

Previously, we have shown that systemically administered radiolabeled interleukin 1alpha (IL-1alpha) accumulates preferentially in inflammatory foci in mice. Since inflammation is characterized by influx of leukocytes, which represent IL-1 receptor (IL-1R) positive cells, radiolabeled IL-1 may specifically localize in inflammation by binding to its receptors on infiltrated leukocytes. This hypothesis was tested in a series of studies in mice with acute focal inflammations. Evidence for specific IL-1-IL-1R interaction in induced inflammation was found: microscopic autoradiography revealed that 125I-IL-1alpha localized at the site of inflammatory cells with time; 125I-myoglobin, a similar-sized protein with no known interactions in vivo, was not retained in the inflammation. Furthermore, the uptake 125I-IL-1alpha in inflammatory tissue was significantly lower in neutropenic mice than in immunocompetent mice (0.05+/-0.004 vs. 0.65+/-0.06% ID/g at 48 h after injection, P < 0.0007). Moreover, the uptake of 125I-IL-1alpha at the inflammatory site could be blocked with the anti-IL-1R type II antibody 4E2. At 48 h after injection, the uptake with and without blocking the type II IL-1R was 0.13+/-0.01 and 0. 65+/-0.05% ID/g, respectively (P < 0.0001). These in vivo studies provide evidence that systemically administered radiolabeled IL-1alpha localizes in inflammatory tissue by specific receptor binding, predominantly by binding to the type II IL-1R.

Scintigraphy with 99mTc-labeled heat-altered erythrocytes in diagnosing hyposplenia: prospective comparison to 99mTc-labeled colloids and colour-coded duplex ultrasonography.

AIM: Ultrasound may be a cheap alternative to scintigraphic determination of splenic function. We directly compared nanocolloid scintigraphy (NS), scintigraphy with heat-altered erythrocytes (ES), and colour-coded Doppler sonography (DS) in patients with chronic inflammatory bowel disease (CIBD). PATIENTS, METHODS: 35 patients were included into the study. Clearance rates were determined in ES, spleen/liver ratios (SLR) were measured scintigraphically in ES/NS. In DS, spleen size, echogenicity, and vascular resistance indices (RI) were determined. The results were compared to each other, to the clinical activity scores for CIBD, and to the course of the disease. RESULTS: Based on the blood erythrocyte clearance serving as standard, patients had a good (19 patients), impaired (5), or missing splenic function (11). There was a good correlation of the clearance to SLR in ES (0.63, p < 0.01). The 10 min / 45 min ES clearance showed a high correlation (Spearman-Rho 0.87, p < 0.01). The SLR in ES at 2, 5, 10 and 45 min also correlated well with each other (Spearman-Rho > 0.9, p < 0.01; SLR > 3.45 normal splenic function, SLR < 1.22 indicated hyposplenia). There were no correlations between the results of NS, DS, Howell-Jolly-bodies, or clinical parameters. Only ES and the erythrocyte clearance correlated well. Howell-Jolly-Bodies detected 1 of 11 patients with hyposplenia while false-positive in 4. CONCLUSION: Ultrasound and colloid scintigraphy show a low correlation with clearance of heat-altered erythrocytes. Only ES shows a good correlation in patients with CIBD. The clearance at 10 min already reliably determines splenic function. SLR may be determined after 10 minutes and is predictive of normal function if above 3.45 while SLR < 1.2 indicated hyposplenia.

Radiolabeled liposomes for scintigraphic imaging.

Liposomes have been investigated extensively as carriers for drugs in attempts to achieve selective deposition and/or reduced toxicity. Liposomes radiolabeled with gamma emitters such as (67)Ga, (111)In and (99m)Tc, can be used for imaging purposes. Liposomes as formulated in the past, are rapidly taken up by cells of the mononuclear phagocyte system (MPS), primarily those located in liver and spleen. The recent development of long-circulating liposomes (LCLs), yielded liposomes that oppose recognition by the MPS. The development of these LCLs with enhanced circulatory half-lives has broadened the potential of liposomes to scintigraphically visualize pathologic processes in vivo. Liposomes have been proposed for tumor imaging, infection imaging and blood pool imaging. Strategies have been developed that allow rapid, easy and efficient labeling of preformed liposomes with (111)In and (99m)Tc. There is now a vast body of preclinical evidence showing that LCLs can be used to image a wide variety of tumors as well as inflammatory lesions. The first studies in patients show that radiolabeled liposomes can image tumor and inflammatory lesions with good sensitivity and good specificity. Here, the present status of liposome-based radiopharmaceuticals for scintigraphic application is reviewed.

What is the best pre-therapeutic dosimetry for successful radioiodine therapy of multifocal autonomy?

PURPOSE: Dose calculation for radioiodine therapy (RIT) of multifocal autonomies (MFA) is a problem as therapeutic outcome may be worse than in other kinds of autonomies. We compared different dosimetric concepts in our patients. PATIENTS, METHODS: Data from 187 patients who had undergone RIT for MFA (Marinelli algorithm, volumetric compromise) were included in the study. For calculation, either a standard or a measured half-life had been used and the dosimetric compromise (150 Gy, total thyroid volume). Therapeutic activities were calculated by 2 alternative concepts and compared to therapeutic success achieved (concept of TcTUs-based calculation of autonomous volume with 300 Gy and TcTUs-based adaptation of target dose on total thyroid volume). RESULTS: If a standard half-life is used, therapeutic success was achieved in 90.2% (hypothyroidism 23,1%, n = 143). If a measured half-life was used the success rate was 93.1% (13,6% hypothyroidism, n = 44). These differences were statistically not significant, neither for all patients together nor for subgroups eu-, hypo-, or hyperthyroid after therapy (ANOVA, all p > 0.05). The alternative dosimetric concepts would have resulted either in significantly lower organ doses (TcTUs-based calculation of autonomous volume; 80.76 +/- 80.6 Gy versus 125.6 +/- 46.3 Gy; p < 0.0001) or in systematic over-treatment with significantly higher doses (TcTUs-adapted concept; 164.2 +/- 101.7 Gy versus 125.6 +/- 46.3 Gy; p = 0.0097). CONCLUSIONS: TcTUsbased determination of the autonomous volume should not be performed, the TcTUs-based adaptation of the target dose will only increase the rate of hypothyroidism. A standard half-life may be used in pre-therapeutic dosimetry for RIT of MFA. If so, individual therapeutic activities may be calculated based on thyroid size corrected to the 24h ITUs without using Marinelli's algorithm.

Decrease of (99m)Tc-uptake in autonomous thyroid tissue in Germany since the 1970s. Clinical implications for radioiodine therapy.

AIM: The clinical relevance of thyroidal autonomy, i.e. the risk of a patient to become hyperthyroid after exposure to iodine, can be estimated by measurement of the thyroidal (99m)Tc uptake under suppression of TSH (TcTUs). The upper tolerable limit has been set to 2% some 25 years ago. Considering the increase in nutritional iodine uptake over the last 15 years, we wanted to find out if the TcTUs per ml of autonomous volume may have changed. PATIENTS, METHODS: We performed a pilot study in 1166 randomly chosen patients from 1980-2003 with different kinds of benign thyroid disorders to determine changes in TcTU or TcTUs over time. A second analysis was performed in 1063 patients from 1987-2004 with unifocal autonomy (UFA). In these patients, the volume of the autonomous tissue can be determined precisely thus allowing for exact determination of TcTUs per ml of autonomous volume. RESULTS: The pilot study demonstrated that the TcTUs or the TcTU has been falling over the last 25 years in all benign thyroid disorders (p < 0.01). The total thyroid volume has also been decreasing in all disorders. In the second analysis of UFA only, 500 from the 1063 patients fulfilled the inclusion criteria. In these patients, the TcTUs per ml of autonomous volume has fallen from an average of 0.48% to an average of 0.28%. These results are statistically significant as determined by ANOVA testing (p = 0.032). CONCLUSION: As the TcTUs in relation to autonomous volume has dropped by approximately 40% over the last 25 years, the upper limit for a normal TcTUs should be reduced to 1-1.4%, dependent on regional factors.

Development and characterization of anti-renal cell carcinoma x antichelate bispecific monoclonal antibodies for two-phase targeting of renal cell carcinoma.

To test a two-step approach for radioimmunotargeting of renal cell cancer, quadroma cells secreting antichelate x anti-renal cell carcinoma bispecific antibodies were obtained by somatic cell fusion. Five monoclonal antibodies against the chelate 1,4,7-triazaheptane-N,N',N"-pentaacetic acid (DTPA) were produced and characterized. Competitive binding assays indicated that the anti-DTPA antibodies reacted with DTPA chelated with indium, yttrium, chromium, iron, or zinc. The affinity constants of the anti-DTPA antibodies for 111In-DTPA ranged from 0.19 to 0.23 nM-1. Using different chelates, a remarkable chelate specificity of the anti-DTPA antibodies was demonstrated. The chelates recognized by the antibodies DTIn1, DTIn2, and DTIn4 share a N(N")-diacetic acid group, whereas the chelates recognized by DTIn3 share a N'-acetic acid group, suggesting the presence of different essential structures within the DTPA molecule that determine the reactivity of the antibodies. Five anti-DTPA antibody-producing hybridomas were used for somatic cell fusion with hybridoma G250 directed against renal cell carcinoma, resulting in three bispecific antibody-producing quadroma cell lines. The bispecific monoclonal antibodies were purified from ascites fluid using protein A affinity chromatography followed by hydroxylapatite chromatography and/or cation exchange chromatography. Of the total IgG amount present in the ascites fluid, 10-15% represented the bispecific antibodies. These bispecific antibodies will allow testing and optimization of a two-step approach for radioimmunotargeting of chelated radionuclides.

Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate.

Radiolabeled monoclonal antibodies (mAbs) can target tumors selectively. Sustained activity levels in nontarget tissues limit their application. Pretargeting approaches using bispecific mAbs (bsmAbs) or the biotinavidin interaction have been proposed to improve tumor:nontumor ratios. Pretargeting a tumor and subsequently administering the radioactivity as a low molecular weight ligand fundamentally changes the pharmacokinetics of the radiolabel. In previous studies, we have shown successful radioimmunotargeting of diethylenetriaminepentaacetic acid (DTPA) labeled with indium-111 to renal cell carcinoma (RCC) after pretargeting in nude mice. In this study, we aimed to optimize further a pretargeting strategy in nude mice with RCC xenografts based on a bispecific anti-RCC x anti-DTPA mAb. Using this two-step approach, we studied whether the use of a bivalent chelate ((111)In-diDTPA) could improve radioimmunotargeting. The (111)In-diDTPA dose greatly affected the uptake of the radiolabeled chelate in the tumor. At a low (111)In-diDTPA dose (< or = 7 pmol), tumor uptake of (111)In-diDTPA was very high [>50% injected dose (ID)/g, 1 h postinjection (p.i.)], whereas at higher doses (> or = 20 pmol), tumor uptake of (111)In-diDTPA decreased (<30% ID/g). With monovalent (111)In-DTPA uptake of the radiolabel in the tumor was much lower (<10% ID/g, 1 h p.i.). Furthermore, the bivalent chelate accreted rapidly in the tumor (78% ID/g, 4 h p.i.) and was virtually completely retained in the tumor during several days p.i. (92% ID/g, 72 h p.i.). Clearance of the (111)In-diDTPA from the blood and kidneys was rapid and complete without the need to clear the bsmAb from the blood, probably due to the relative lability of the univalent bsmAb-diDTPA complexes in the blood. As a result, with this two-step pretargeting approach tumor:blood ratios increased up to values as high as 3500 at 72 h p.i. High doses of diDTPA could be targeted preferentially to the tumor, indicating that this approach could also be used for radioimmunotherapy. Tumors could be imaged up to 1 week p.i. of 50 microCi of (111)In-diDTPA. Quantitative analysis of the images confirmed the biodistribution data and indicated that, at 20 h p.i., 50 +/- 15% of the whole-body activity was localized in the tumor. In conclusion, these studies indicate that the use of bivalent chelates can very effectively optimize two-step targeting of tumors with bsmAbs. Our data indicate that this approach could optimize radioimmunotherapy.

Intratumoral distribution of two consecutive injections of chimeric antibody G250 in primary renal cell carcinoma: implications for fractionated dose radioimmunotherapy.

Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.

Diagnosing infection in febrile granulocytopenic patients with indium-111-labeled human immunoglobulin G.

PURPOSE: Delineation of focal infection is a major problem in the management of febrile granulocytopenic patients. The utility of indium-111-labeled human nonspecific immunoglobulin G (In-111-IgG), a newly developed radiopharmaceutical for imaging focal inflammation, was reported in patients with adequate WBC counts. In the present study, we investigated whether In-111-IgG scintigraphy could be used to locate infection in granulocytopenic patients. MATERIALS AND METHODS: Granulocytopenic rats with focal infection were imaged after In-111-IgG injection. Thereafter, In-111-IgG scintigraphy was performed in 20 granulocytopenic patients. Images were obtained 4, 24, and 48 hours after injection of 75 mBq In-111-IgG. Scintigraphic findings were compared with clinical, roentgenologic, and ultrasonographic methods and culture results. RESULTS: In the animal model high In-111-IgG accumulation was observed in the infectious focus. In the patients, 13 proven pulmonary, abdominal, joint, and soft tissue infections of both bacterial and fungal origin were detected adequately. In-111-IgG uptake not due to verified inflammation was observed in the large bowel of two patients. A thoracic wall infiltrate showing only mild inflammatory activity was not detected. Small toxoplasmosis lesions in heart, liver, and kidneys were obscured by physiologic In-111-IgG activity in these organs. CONCLUSIONS: In-111-IgG scintigraphy is a useful technique to delineate focal infection in patients with granulocytopenia. Accumulation of the radiopharmaceutical does not appear to be granulocyte-mediated. In-111-IgG is a safe and convenient radiopharmaceutical that probably contributes to the early diagnosis of focal infection in granulocytopenic patients.

Value of positron emission tomography with [F-18]fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study.

PURPOSE: To assess prospectively the value of fluor-18-deoxyglucose (FDG) positron emission tomography (PET), in addition to conventional diagnostic methods (CDM), as a staging modality in candidates for resection of colorectal liver metastases. PATIENTS AND METHODS: In 51 patients analyzed for resection of colorectal liver metastases, clinical management decisions were recorded after a complete work-up with CDM. Afterward, FDG-PET scans were performed and any change of clinical management according to FDG-PET results was carefully documented. Discordances between FDG-PET and CDM results were identified and related to the final diagnosis by histopathology, intraoperative findings, and follow-up. RESULTS: In 10 (20%) out of 51 patients, clinical management decisions based on CDM were changed after FDG-PET findings were known. FDG-PET detected unresectable pulmonary (n = 5) and hepatic metastases (n = 1) and ruled out extrahepatic (n = 2) and hepatic disease (n = 2). Due to FDG-PET, eight patients were spared unwarranted liver resection or laparotomy and two other patients were identified as candidates for liver resection. When the results of FDG-PET were regarded as decisive in a retrospective analysis, potential change of management was 29% (15 patients). FDG-PET and CDM showed discordant extrahepatic results in 11 patients (22%) and discordant hepatic results in eight patients (16%). Compared with CDM, FDG-PET resulted in true upstaging (n = 11), true downstaging (n = 5), false upstaging (n = 1), and false downstaging (n = 2). The detection rate of liver metastases on a lesion basis was generally better for computed tomography than for FDG-PET (80% v 65%); this was related to tumor size. CONCLUSION: FDG-PET as a complementary staging method improves the therapeutic management of patients with colorectal liver metastases, especially by detecting unsuspected extrahepatic disease.

Efficacy of fluorine-18-deoxyglucose positron emission tomography in detecting tumor recurrence after local ablative therapy for liver metastases: a prospective study.

PURPOSE: The aims of this prospective study were to investigate the potential role of fluorine-18-deoxyglucose (FDG) positron emission tomography (PET) in determining the efficacy of the local tumor ablative process and to determine the added value of FDG-PET in the detection of tumor recurrence during follow-up. PATIENTS AND METHODS: Twenty-three patients with unresectable colorectal liver metastases were followed up after local ablative therapy consisting of a standard protocol including FDG-PET scanning, computed tomography (CT) scanning, and carcinoembryonic antigen measurements. The mean follow-up period was 16 months (range, 10 to 21 months). RESULTS: Ninety-six lesions was treated, 56 by local ablative treatment. Within 3 weeks after local ablative treatment, 51 lesions became photopenic on FDG-PET, while five lesions (in five patients) showed persistent activity on FDG-PET. In four of five FDG-PET-positive lesions, a local recurrence developed during follow-up; one FDG-PET-positive lesion turned out to be an abscess. None of the FDG-PET-negative lesions developed a local recurrence during a mean follow-up period of 16 months. During follow-up, 11 patients showed recurrence in the liver outside of the treated area. In all cases, previously negative FDG-PET scans became positive. Extrahepatic recurrence was encountered in nine patients during follow-up; FDG-PET showed all nine cases of tumor recurrence. There was one false-positive FDG-PET caused by an intra-abdominal abscess. In all patients, the time point of detection of recurrence by FDG-PET was considerably earlier than the detection by CT. CONCLUSION: FDG-PET seems to have a significant impact in measuring treatment efficacy directly after local ablative therapy. Furthermore, FDG-PET has an added value in patient follow-up because it reveals recurrences earlier than conventional diagnostic modalities.

Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250.

PURPOSE: Pharmacokinetics, biodistribution, immunogenicity, and imaging characteristics of iodine 131 (131I)-labeled chimeric monoclonal antibody (mAb) G250 (cG250) were studied in patients with renal cell carcinoma (RCC) to determine the therapeutic potential of this antibody. PATIENTS AND METHODS: Sixteen patients with RCC received a single intravenous (IV) infusion of 6 mCi 131I-labeled cG250. Five protein dose levels were investigated (2 to 50 mg). Planar scintigraphic images were acquired, and normal tissue biopsies and tumor samples were obtained of surgery (7 days postinjection). The immunogenicity of cG250 was investigated using a sandwich enzyme-linked immunosorbent assay (ELISA) and dosimetric analysis was performed. RESULTS: In all patients with antigen-positive tumors (n = 13), the primary tumors and all known metastases were clearly visualized. Overall uptake, expressed as the percentage of the injected dose (%ID), in the primary tumors ranged from 2.4 to 9.0. Focally, 131I-cG250 uptake as high as 0.52% ID/g was observed. However, intratumoral uptake was highly heterogeneous. 131I-cG250 uptake in nontumorous tissues remained low. Dosimetric analysis showed that up to .48 Gy/mCi was guided to the primary tumors. Selected "hot areas" within these tumors received up to .72 Gy/mCi. A bone metastasis received .23 Gy/mCi and regional lymph node metastases received .20 Gy/mCi. Minimal human antichimeric antibody (HACA) levels were detected in two of 16 patients. CONCLUSION: 131I-cG250 tumor uptake is among the highest reported in clinical studies with antitumor antibodies in solid tumors. Since tumor-sterilizing levels may be guided to the tumor when high doses 131I-cG250 are administered (> 100 mCi) and cG250 appears to be immunosilent, cG250 is a promising vehicle for radioimmunotherapy in RCC.

Diagnosis of Candida lung abscesses by 18F-fluorodeoxyglucose positron emission tomography.

In three patients with catheter-associated candidaemia, use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) led to the diagnosis of Candida lung abscesses, which was confirmed by computed tomography and a favourable response to antifungal therapy. It was concluded that FDG-PET is a promising new imaging technique that enables early identification of sites of disseminated candidiasis, and that this technique can be used in the evaluation of therapy.

Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250.

Clinical tumor targeting studies with chimeric monoclonal antibody G250 (cG250) in renal cell carcinoma (RCC) patients indicated the potential use of this antibody for radioimmunotherapy. Here we report on a phase I activity dose escalation study to determine the safety, the maximum tolerable dose (MTD), and the possible therapeutic potential of 131I-labeled cG250 in patients with progressive metastatic RCC. All patients (n = 12) received a diagnostic i.v. infusion of 5 mg of cG250 labeled with 222 MBq of 131I. If accumulation of the antibody in metastatic lesions was observed, patients were hospitalized and a second, therapeutic, i.v. infusion of 5 mg of cG250 labeled with a high dose of 131I was administered (n = 8). Three patients per dose level were entered, starting at 1665 MBq/m2. If no dose-limiting toxicity occurred, the study continued at the next dose level (555 MBq/m2 increase). Most patients experienced mild nausea without vomiting. No other complaints were reported during hospitalization. In two of two patients who received a dose of 2775 MBq/m2, grade IV hematological toxicity was observed, which was defined as dose limiting. Thus, the MTD was set at 2220 MBq/m2. In one patient (2220 MBq/m2), stable disease (lasting 3-6 months) was achieved, whereas another patient (2220 MBq/m2) showed a partial response that is ongoing (>9 months). The minor responses observed in this phase I trial in patients with an advanced stage of RCC are encouraging and warrant further study in a phase II setting at the MTD to determine the efficacy of radioimmunotherapy for metastatic RCC.

Pro-inflammatory cytokines in lung and blood during steroid-induced Pneumocystis carinii pneumonia in rats.

To gain more insight into the role of cytokines in Pneumocystis carinii pneumonia (PCP) we followed pro-inflammatory cytokine profiles in rats with steroid-induced PCP at 2-week intervals. The cytokines measured were immunoreactive interleukin-1beta (IL-1beta), bioactive interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). In vivo cytokine concentrations were determined in three compartments, i.e., bronchoalveolar lavage (BAL) fluid, lung homogenates, and plasma. Lipopolysaccharide (LPS) -stimulated cytokine production by alveolar cells and in whole-blood cultures was measured ex vivo. P carinii load and host inflammatory response, as determined by lung/body weight ratio and 111indium-IgG biodistribution were monitored throughout developing PCP. IL-1beta was elevated in lung homogenates (600, range <20-1260 pg/mL) and IL-6 in BAL fluid (48, range <20-115 pg/mL), whereas the pro-inflammatory cytokine concentrations were not increased in plasma. Thus in rats with PCP elevated pro-inflammatory cytokine concentrations were found to be restricted to the lung compartments. Corticosteroids did not significantly influence cytokine concentrations, but showed profound inhibitory effects on ex vivo cytokine production. The LPS-stimulated cytokine production by alveolar cells gradually decreased during the 6 weeks after the start of the steroid injections, whereas the production in whole blood cultures was immediately and completely suppressed.

The value of tests predicting renovascular hypertension in patients with renal artery stenosis treated by angioplasty.

The aim of this study was to evaluate tests predicting renovascular hypertension. This was done by relating the results of renal vein renin tests, the captopril test, and renal scintigraphic tests to the blood pressure outcome 12 months after relief of renal artery stenosis by percutaneous transluminal renal angioplasty in 31 patients. Cure was seen in eight (26%). Improved blood pressure was obtained in 12 patients (39%), and in 11 patients (35%), the result for blood pressure was a failure. The accuracies of the two mathematical models used to analyze the renal vein renin assays were 44% and 60%. The captopril test showed a sensitivity of 36% and an accuracy of 43%. Renal captopril technetium Tc 99m-labeled pentetic acid scintigraphy gave a sensitivity of 60%. Stepwise logistic regression analysis of clinical variables in relation to blood pressure response revealed age as the only factor significantly related to blood pressure outcome. We conclude that the tests used are unfit for helping select patients for percutaneous transluminal renal angioplasty and that age may have an important influence on outcome.

Utility of scintigraphic methods in patients with fever of unknown origin.

BACKGROUND: We assessed the utility of scintigraphy with indium 111-labeled polyclonal human IgG scintigraphy in patients with fever of unknown origin that fulfilled the criteria of temperature of 38.3 degrees C or more for at least 3 weeks and no diagnosis during 1 week of hospital admission. We compared the utility of this technique with results of scintigraphic techniques reported in the literature. METHODS: Data for all patients seen at our university hospital in whom 111In-IgG scanning was performed were analyzed and checked for the criteria for fever of unknown origin. The literature on the utility of scintigraphic techniques in patients with fever of unknown origin was reviewed. RESULTS: We studied 24 patients with fever of unknown origin. In 13 patients, focal 111In-IgG accumulation was observed. In nine (38%) of those, the positive 111In-IgG scintigram led to the final diagnosis; in the other four patients (17%), the scintigraphic findings were not helpful. In the 11 patients with negative 111In-IgG scans, extensive diagnostic workup produced no infection as the final diagnosis in nine patients (38%), one had an abscess in a renal cyst that was detected several months later, and in the other the cause of fever was an infected intravenous line. The overall sensitivity and specificity of 111In-IgG scintigraphy were 81% and 69%, respectively. The positive predictive value was 69% and the negative predictive value was 82%. CONCLUSIONS: Our results show that 111In-IgG scintigraphy significantly contributed to the diagnostic process in patients with fever of unknown origin. A positive scan increased the likelihood of finding the cause of the fever, and a negative scan ruled out an inflammatory component with a high degree of certainty. These data compare favorably with data in the literature concerning other radiopharmaceuticals; a larger prospective evaluation of this technique is indicated.

Pretreatment with recombinant human TSH changes the regional distribution of radioiodine on thyroid scintigrams of nodular goiters.

In a recent study, we demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h thyroid radioactive iodine uptake in patients with nodular goiter. The purpose of the present study was to investigate whether rhTSH pretreatment induces changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in these patients. Anterior planar thyroid 123I scintigrams were obtained in 26 patients with a nodular goiter (23 women and 3 men; age, 62 +/- 9 yr, mean +/- SD; thyroid weight, 165 +/- 72 g) 24 h after administration of a diagnostic dose of radioiodine. All patients were studied twice: first, without rhTSH pretreatment (baseline study), and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg rhTSH (n = 16), given 24 h before radioiodine administration (rhTSH study). For quantification of regional differences in radioiodine uptake, a region of interest method was used. Upon visual inspection, baseline scintigrams showed a heterogeneous uptake of radioiodine. In general, rhTSH scintigrams also showed heterogeneous radioiodine uptake. In some patients, the distribution of radioiodine in the rhTSH scintigram was considerably more homogeneous than in the baseline scintigram. In a few patients, originally "cold" areas had changed into "hot" ones, whereas originally hot areas had changed into cold ones. Quantification of regional radioiodine uptake showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter. In conclusion, a single, low dose of rhTSH not only doubled 24-h radioactive iodine uptake but also caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.

Bone mineral density and bone turnover before and after surgical cure of Cushing's syndrome.

We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry in 20 patients with Cushing's syndrome (CS) (14 pre- and 2 postmenopausal women, 4 men) before and in 18 of them also at regular intervals after surgical cure (median duration of follow-up, 36 months). In addition, in the premenopausal women with CS, fasting blood samples and 2-h fasting urine samples for measurement of biochemical parameters of bone and collagen metabolism were collected before and in 9 of them also at regular intervals during the first 2 yr after surgery. Marked osteopenia was present in most patients with active CS (Z-scores: lumbar spine -1.45 +/- 1.44 and femoral neck -1.50 +/- 1.02; mean +/- SD). No consistent change in BMD was observed at 3 and 6 months after surgery. Thereafter BMD increased considerably in almost all patients. For the 15 patients with a follow-up of at least 1 yr, Z-scores at the last evaluation were -0.65 +/- 1.27 for the lumbar spine and -0.98 +/- 1.02 for the femoral neck (both P < 0.002 compared with pretreatment values). In the premenopausal patients, the increase in BMD both in the lumbar spine and in the femoral neck at 24 months was inversely correlated with age (r = -0.733, P < 0.03, and r = -0.667, P < 0.05, respectively). Serum levels of osteocalcin, bone alkaline phosphatase, carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen, and the cross-linked telopeptide of type I collagen were not significantly different between the group of 14 premenopausal patients with active CS and a control group of 18 age-matched healthy premenopausal women. However, the urinary hydroxyproline/creatinine ratio was significantly higher in patients with CS (24.6 +/- 9.6 vs. 16.2 +/- 3.5 mumol/mmol, P < 0.01). In all 9 premenopausal patients, serum levels of osteocalcin increased considerably between 0 and 3 months (from 1.04 +/- 0.20 to 3.82 +/- 0.30 nmol/L) (mean +/- SEM, P < 0.0001), indicating a prompt increase of osteoblast activity. Also serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen, and cross-linked telopeptide of type I collagen, and the urinary hydroxyproline/creatinine ratio increased significantly between 0 and 3 months. Thereafter these levels decreased gradually. We conclude that marked osteopenia in the lumbar spine and femoral neck is present in most patients with active Cushing's syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)