Jan C. Roos

Performance of Immuno–Positron Emission Tomography with Zirconium-89-Labeled Chimeric Monoclonal Antibody U36 in the Detection of Lymph Node Metastases in Head and Neck Cancer Patients

Purpose: Immuno–positron emission tomography (PET), the combination of PET with monoclonal antibodies (mAb), is an attractive option to improve tumor detection and to guide mAb-based therapy. The long-lived positron emitter zirconium-89 (89Zr) has ideal physical characteristics for immuno-PET with intact mAbs but has never been used in a clinical setting. In the present feasibility study, we aimed to evaluate the diagnostic imaging performance of immuno-PET with 89Zr-labeled-chimeric mAb (cmAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC), who were at high risk of having neck lymph node metastases. Experimental Design: Twenty HNSCC patients, scheduled to undergo neck dissection with or without resection of the primary tumor, received 75 MBq 89Zr coupled to the anti-CD44v6 cmAb U36 (10 mg). All patients were examined by computed tomography (CT) and/or magnetic resonance imaging (MRI) and immuno-PET before surgery. Six patients also underwent PET with 18F-fluoro-2-deoxy-d-glucose. Immuno-PET scans were acquired up to 144 hours after injection. Diagnostic findings were recorded per neck side (left or right) as well as per lymph node level (six levels per side), and compared with histopathologic outcome. For this purpose, the CT/MRI scores were combined and the best of both scores was used for analysis. Results: Immuno-PET detected all primary tumors (n = 17) as well as lymph node metastases in 18 of 25 positive levels (sensitivity 72%) and in 11 of 15 positive sides (sensitivity 73%). Interpretation of immuno-PET was correct in 112 of 121 operated levels (accuracy 93%) and in 19 of 25 operated sides (accuracy 76%). For CT/MRI, sensitivities of 60% and 73% and accuracies of 90% and 80% were found per level and side, respectively. In the six patients with seven tumor-involved neck levels and sides, immuno-PET and 18F-fluoro-2-deoxy-d-glucose PET gave comparable diagnostic results. Conclusion: In this study, immuno-PET with 89Zr-cmAb U36 performed at least as good as CT/MRI for detection of HNSCC lymph node metastases.

Radiation Dosimetry of 89Zr-Labeled Chimeric Monoclonal Antibody U36 as Used for Immuno-PET in Head and Neck Cancer Patients

Immuno-PET is an appealing concept in the detection of tumors and planning of antibody-based therapy. For this purpose, the long-lived positron emitter 89Zr (half-life, 78.4 h) recently became available. The aim of the present first-in-humans 89Zr immuno-PET study was to assess safety, biodistribution, radiation dose, and quantification of the 89Zr-labeled chimeric monoclonal antibody (cmAb) U36 in patients with head and neck squamous cell carcinoma (HNSCC). In addition, the performance of immuno-PET for detecting lymph node metastases was evaluated, as described previously. Methods: Twenty HNSCC patients, scheduled to undergo surgical tumor resection, received 75 MBq of 89Zr-cmAb U36 (10 mg). Immuno-PET scans were acquired at 1, 24, 72, or 144 h after injection. The biodistribution of the radioimmunoconjugate was evaluated by ex vivo radioactivity measurement in blood and in biopsies from the surgical specimen obtained at 168 h after injection. Uptake levels and residence times in blood, tumors, and organs of interest were derived from quantitative immuno-PET studies, and absorbed doses were calculated using OLINDA/EXM 1.0. The red marrow dose was calculated using the residence time for blood. Results: 89Zr-cmAb U36 was well tolerated by all subjects. PET quantification of blood-pool activity in the left ventricle of the heart showed a good agreement with sampled blood activity (difference equals 0.2% ± 16.9% [mean ± SD]) except for heavy-weight patients (>100 kg). A good agreement was also found for the assessment of mAb uptake in primary tumors (mean deviation, −8.4% ± 34.5%). The mean absorbed red marrow dose was 0.07 ± 0.02 mSv/MBq and 0.09 ± 0.01 mSv/MBq in men and women, respectively. The normal organ with the highest absorbed dose was the liver (mean dose, 1.25 ± 0.27 mSv/MBq in men and 1.35 ± 0.21 mSv/MBq in women), thereafter followed by kidneys, thyroid, lungs, and spleen. The mean effective dose was 0.53 ± 0.03 mSv/MBq in men and 0.66 ± 0.03 mSv/MBq in women. Measured excretion via the urinary tract was less than 3% during the first 72 h. Conclusion: 89Zr immuno-PET can be safely used to quantitatively assess biodistribution, uptake, organ residence times, and radiation dose, justifying its further clinical exploitation in the detection of tumors and planning of mAb-based therapy.

Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia

In order to determine if a serious disease like childhood acute lymphoblastic leukaemia (ALL) and the treatment necessary to cure the patients has long term effects on bone mass, we assessed bone mineral density (BMD) and several parameters involved in bone formation in a group of young adult survivors of ALL.

Swallowing after major surgery of the oral cavity or oropharynx: a prospective and longitudinal assessment of patients treated by microvascular soft tissue reconstruction.

The aim of this study was to analyze swallowing outcome in advanced oral/oropharyngeal cancer patients treated with microvascular reconstructive surgery and adjuvant radiotherapy.

Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck

Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25xa0mg (n=3), 50xa0mg (n=4), and 100xa0mg (n=3). Patients received 2xa0mg of 750xa0MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1xa0h and after 21xa0h, and patients underwent surgery at 48xa0h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48xa0h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti–human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8±11.5xa0h, 76.1±21.8xa0h, and 68.5±21.2xa0h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9±5.9, 26.2±3.1, and 15.4±1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group, respectively, while the tumor to bone marrow ratios for these groups were 1.7±0.5, 3.2±1.1, and 2.0±0.6, respectively. Conclusion: 99mTc-BIWA 4 can safely be administered to patients with HNSCC, with absence of detectable HAHA responses. The 50-mg dose level showed the highest tumor uptake and tumor to nontumor ratios. These findings support the use of BIWA 4 for RIT studies in patients with HNSCC.

Computed tomography and granulocyte scintigraphy in active inflammatory bowel disease. Comparison with endoscopy and operative findings.

The accuracy of computed tomography (CT) and [99mTc]HMPAO granulocyte scintigraphy (GS) for detection of bowel localization, inflammatory activity, and complications in acute inflammatory bowel disease (IBD) was prospectively studied in 32 patients. Of each bowel segment, findings on CT and GS were scored by one blinded observer. Findings on operation or endoscopy served as the gold standard. In Crohns disease (CD, 17 patients), CT detected bowel pathology (sensitivity 71%, specificity 98%), abscesses (sensitivity and specificity 100%), and fistulas (sensitivity 80%, specificity 100%). In CD, GS had a sensitivity of 79% and a specificity of 98% for detection of inflammatory activity. The detection of complications with GS was poor. Segmental inflammatory activity correlated with endoscopy-operative findings for CT (r=0.86,P<0.0001) and GS (r=0.86,P<0.0001). In ulcerative colitis (UC, 15 patients), GS predicted proximal extension of bowel involvement better than CT. In CD, CT is superior to GS for localization of both active and fibrostenotic bowel disease, and in detection of abscesses and fistulas. In UC, GS showed proximal extension more accurately than CT.

Effects of 10 years of growth hormone (GH) replacement therapy in adult GH-deficient men

Objectiveu2002 GH‐deficient adults have changes in body composition, bone mineral density (BMD) and lipid profile that can be altered by GH substitution. However, long‐term data on GH substitution (up to 10 years of follow‐up) are limited.

Effect of long-term growth hormone treatment on bone mass and bone metabolism in growth hormone-deficient men

Long‐term GH treatment in GH‐deficient men resulted in a continuous increase in bone turnover as shown by histomorphometry. BMD continuously increased in all regions of interest, but more in the regions with predominantly cortical bone.

Ten-Year Longitudinal Relationship Between Physical Activity and Lumbar Bone Mass in (Young) Adults†

Little is known about the influence of long‐term daily physical activity (PA) on lumbar bone mass after peak bone mass has been reached, that is, during [young] adulthood. The purpose of this study was to investigate the longitudinal relationship between PA and lumbar bone mineral density (LBMD) in healthy subjects over a 10‐year period. The data reported here relate to 225 male and 241 female participants in the Amsterdam Growth and Health Longitudinal Study, who were measured at the mean ages of 27, 32, and/or 36. LBMD, habitual daily PA, total body weight, and calcium intake were assessed at each measurement point. The effects of two aspects of PA were analyzed: the mechanical (MECHPA; sum of all ground reaction forces) and metabolic (METPA; weighted metabolic score of intensity, frequency, and duration) components, each within a separate model. Multilevel analysis was used to investigate the relationship between PA and LBMD over the 10‐year period. Gender, total body weight, and calcium intake were included in the analysis as covariates. The results indicated that MECHPA was a significant positive linear predictor of LBMD for males (r = 0.09; p < 0.001) but not for females. For the METPA, no linear longitudinal relationship with LBMD was found. The results suggest that there is a metabolic threshold at which extra PA becomes “deleterious” and METPA in its totality becomes ineffective for LBMD. It is concluded that during the (young) adult period, between 27 and 36 years of age, PA causing mechanical loading on the skeleton has a small positive influence on LBMD in males.

Evaluation of strength of healing fractures with dual energy Xray absorptiometry.

Dual energy xray absorptiometry was investigated as a method for evaluation of the strength of closed tibial fractures. In 40 goats, a closed midshaft fracture was created in the left tibia. The fractures were stabilized with an external fixator. After 2 weeks (n = 21) and after 4 weeks (n = 19), both tibias were explanted and, using dual energy xray absorptiometry, bone mineral density and bone mineral content were measured in a 1 cm region. With nondestructive bending tests, area ratio and stiffness index were determined and torsional strength and torsional stiffness were determined with a torsional test to failure. Linear regression analysis was used to calculate the squared correlation coefficients for the relations between dual energy xray absorptiometry and the outcome of the mechanical tests. The squared correlation coefficients for the relation between bone mineral density and torsional strength, torsional stiffness, and area ratio and stiffness index were 0.72, 0.76, 0.64, and 0.72, respectively. The squared correlation coefficients for the relation between bone mineral content and these mechanical parameters were 0.72, 0.77, 0.63, and 0.77, respectively. The results using dual energy xray absorptiometry indicate the strength of healing closed fractures. Additional research is required to investigate specific aspects of this technique.