Markus Luster

In peptide receptor radionuclide therapy with (90)Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity, which can be safely administered in many patients. A higher tumor to kidneys absorbed dose ratio might be achieved by optimizing the amount of injected peptide and activity, as recent studies have shown different degrees of receptor saturation for normal tissue and tumor. The aim of this work was to develop and to implement a modeling method for treatment planning to determine the optimal combination of peptide amount and pertaining therapeutic activity for each patient. A whole body physiologically based pharmacokinetic (PBPK) model was developed. General physiological parameters were taken from the literature. Individual model parameters were fitted to series (N = 12) of planar gamma camera and serum measurements ((111)In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated ...

The aim of this work was the development of a software tool for treatment planning prior to molecular radiotherapy, which comprises all functionality to objectively determine the activity to administer and the pertaining absorbed doses (including the corresponding error) based on a series of gamma camera images and one SPECT/CT or probe data. NUKDOS was developed in MATLAB. The workflow is based on the MIRD formalism For determination of the tissue or organ pharmacokinetics, gamma camera images as well as probe, urine, serum and blood activity data can be processed. To estimate the time-integrated activity coefficients (TIAC), sums of exponentials are fitted to the time activity data and integrated analytically. To obtain the TIAC on the voxel level, the voxel activity distribution from the quantitative 3D SPECT/CT (or PET/CT) is used for scaling and weighting the TIAC derived from the 2D organ data. The voxel S-values are automatically calculated based on the voxel-size of the imag...

Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. The cornerstone in current guidelines for follow-up is by measuring the thyroid specific tumour marker, thyroglobulin in serum. Most patients can be followed by this method, but some thyroid cancer patients have antithyroglobulin antibodies in serum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in the immunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminated from following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulin antibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resulted in publication of an expert position paper, providing a flow scheme for these particular patients. The current review summarises the literature which is the b...

Technical aspects and results of the dosimetric assessments of postoperative radioiodine ablation in the framework of an international, prospective, controlled, randomized, comparative study of the effectiveness of ablation therapy with 3.7 GBq (131)I in differentiated thyroid cancer after stimulation with recombinant human TSH (rhTSH) or by thyroid hormone withdrawal (THW) are presented. Sixty-three patients were randomized after thyroidectomy to either the THW or the rhTSH group. Scintigraphic neck images were acquired starting 48 h after radioiodine administration to assess biokinetics in the thyroid remnant. The activity in blood samples was quantified and data from whole-body probe measurements and scintigraphic whole-body scans were combined to deduce retention curves in blood and whole body, respectively. The absorbed dose to the blood was calculated using a modified approach based on the formalism of the MIRD Committee of the Society of Nuclear Medicine. The effective half-t...

... Dr. Bryan Haugen has consulted for Genzyme Corporation in the past 2 years. Dr. Ernest Mazzaferri has received hon-orariums from Genzyme Corporation in the past 2 years for lectures. Dr. Bruce Robinson has acted an Advisor to Gen-zyme Corporation. ...

Even though the presence of antithyroglobulin antibodies (TgAbs) represents a significant problem in the follow-up of patients with differentiated thyroid cancer (DTC), the current guidelines on the management of DTC that have been published in recent years contain no text concerning the methods to be used for detecting such antibody-related interference in thyroglobulin (Tg) measurement or how to manage TgAb-positive patients in whom Tg cannot be used reliably as a tumor marker. An international group of experts from the European Thyroid Association Cancer Research Network who are involved in the care of DTC patients met twice to form a consensus opinion on how to proceed with treatment and follow-up in TgAb-positive DTC patients based on the available evidence in the literature. Here we will report on the consensus opinions that were reached regarding technical and clinical issues. This clinical opinion article provides an overview of the available evidence and the resulting consensus recommendations. The current literature does not provide sufficient data for giving evidence-based answers to many questions arising in the care of TgAb-positive DTC patients. Where insufficient evidence was available, a thorough discussion by a group of physician-scientists, all of whom have a distinguished track record in thyroid cancer care, was held to arrive at a consensus expert opinion. The questions and answers discussed were then summarized into an algorithm for the management of TgAb-positive patients. We were able to define 26 consensus expert recommendations and a resulting algorithm for the care of TgAb-positive DTC patients.

Anti-CD45 antibody is predominantly used in the treatment of acute leukemia. CD45 is stably expressed on all leukocytes and their precursors, and therefore the liver and spleen constitute major antigen sinks. Thus, as the red marrow is the target organ, in radioimmunotherapy with anti-CD45 antibody, preloading with unlabeled antibody is a method to increase the absorbed dose to the target cells. In a previous study, a method to individually determine the optimal preload for five patients with acute leukemia was developed. Here, this method is examined and improved using two pretherapeutic measurement series and a refined pharmacokinetic model. To obtain the biodistribution of 111In-labeled anti-CD45 antibody under different saturation conditions, two measurement series one with and one without preloading were conducted in five patients. For each patient, two physiologically based pharmacokinetic models were fitted to the data and the corrected Akaike information criterion was used to identify the model, which was empirically most supported. The resultant parameter values were compared to values reported in the literature. To individually determine the optimal amount of unlabeled antibody for therapy, computer simulations for preloads ranging from 0 to 60 mg were performed based on the estimated parameters of each patient. The prediction power of the model was assessed by comparing the simulated therapeutic serum curves to the actual 90Y measurements. Visual inspection showed good fits and the adjusted R2 was >0.90 for all patients. All parameters were in a physiologically reasonable range. The relative deviation of the predicted area under the therapeutic serum curve and the measured curve was 15%-33%. The optimal preloading increased the marrow-over-liver selectivity up to 3.9 fold compared to the simulated biodistribution using a standard dose (0.5 mg/kg). The presented method can be used to individually determine the optimal preload and the corresponding residence times in radioimmunotherapy with anti-CD45 antibody.

Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable ("low risk") papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages. The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization. The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases. These evidence-based recommendations for surgical therapy reflect various "treatment corridors" that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.

Although recombinant human TSH (rhTSH) is widely used in differentiated thyroid cancer (DTC) to aid diagnostic follow-up procedures and radioiodine thyroid remnant ablation, almost all clinical investigation was in adults. The aim of this study was to characterize rhTSH clinical safety and peak TSH response in DTC patients 18 yr old or younger. We conducted a retrospective study involving 23 tertiary referral centers in 12 European, Asian, and Oceanian countries. One hundred DTC patients (69% female, 31% male, 84% papillary, 61% N1, 18% M1) ages 4.9-18 yr at first rhTSH administration were studied. A total of 181 rhTSH courses were administered (range, one to eight per patient; 42% of patients received two or more courses), 92% using the approved adult regimen (one 0.9 mg im injection daily on two consecutive days), 34% including thyroid hormone withdrawal for less than 7 d ("mini-THW"). Clinical adverse event (AE) incidence, type, and severity, and peak post-rhTSH serum TSH concentrations were assessed. No clinical AEs occurred in 88% of rhTSH courses. Most common clinical AEs were nausea (5% of courses) and vomiting (3%). Multiple or severe AEs were rare (0.6% and 2.8% of courses, respectively); serious AEs were absent. Peak TSH concentration post-rhTSH exceeded 25 mU/liter in approximately 98% of courses. In logistic regression analyses, the rhTSH regimen, "mini-THW," peak TSH concentration, body mass index (BMI), or peak TSH concentration/unit of BMI were not associated with clinical AE occurrence. In analyses of covariance, higher BMI was associated with lower peak TSH concentrations. rhTSH was clinically well tolerated in pediatric DTC patients although courses preponderantly comprised the adult regimen, and repeated courses were frequent. Both the adult and reduced-dose regimens almost always sufficiently elevate TSH in children and adolescents.

The use of 131I for radioablative therapy in patients with differentiated thyroid cancer (DTC) requires a sufficient serum concentration of TSH for efficient thyroid tissue uptake of iodine. We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppression therapy (THST), the standard method to increase serum TSH, was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to very poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. Ten patients had undergone thyroidectomy, and most (9 of 11) had received prior ablative RIT after THST withdrawal. Baseline thyroglobulin levels ranged from 25 to nearly 30,000 ng/mL, reflecting the heterogeneity of the patient population. In 7 cases (5 patients), posttherapy thyroglobulin levels assessed at a mean of 4.3 months (range, 2-10 months) after 131I therapy were decreased by at least 30% compared to pretherapy levels. In follow-up visits, an additional 3 patients showed marked clinical improvement or decreased or stabilized tumor burden in whole body scans compared to pretherapy scans. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow ablative RIT after effective TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of this new agent, already demonstrated to be effective for use with 131I for diagnostic purposes.

The purpose of this study was to prospectively determine the diagnostic accuracy of diffusion-weighted imaging (DWI) using MRI in the staging of thoracic lymph nodes in patients with lung cancer, and to compare the performance to that of PET/CT. 20 consecutive patients (pts) with histologically proven lung cancer were included in this study. In all pts FDG-PET/CT was routinely performed to stage lung carcinoma. Additionally, MRI (1.5T) was performed including native T1w, T1w post contrast medium, T2w, and DWI sequences. Regarding the N stage based on the results of the PET/CT there were 5 patients with N0, 3 patients with N1, 5 patients with N2 and 7 patients with N3. Image analysis was performed by two radiologists (R1 and R2), respectively. The reviewers had to chose between 1 (at least one lymph node within a station is malignant) or 0 (no lymph nodes suspicious for malignancy). First the T1 post contrast sequence was analyzed. In a second step the DWI sequence (b=800) was analyzed. Both steps were performed in a blinded fashion. MR imaging with or without DWI only agreed with the results of the PET/CT regarding the N stage in 80% of the patients-15% were understaged and 5% overstaged. There was excellent interobserver agreement; the N-staging result only differed in 1 patient for DWI, resulting in correlation coefficients of 0.98 for DWI and 1.0 for MRI. Compared to PET-CT MRI overstaged one and understaged 4 patients, while DWI overstaged one and understaged 3 patients. This resulted in correlation coefficients of 0.814 (R1 and R2) for MRI and 0.815 (R1) and 0.804 (R2) for DWI. Regarding the ADC values there were no significant differences between ipsilateral hilar (1.03 mm(2)/s ± 0.13), subcarinal (0.96 mm(2)/s±0.24), ipsilateral mediastinal (1.0mm(2)/s ± 0.18), contralateral mediastinal (0.93 mm(2)/s ± 0.23) and supraclavicular (0.9 mm(2)/s ± 0.23) lymph nodes. Diffusion-weighted imaging does not show a clear advantage over conventional MR protocols in the N-staging of lung cancer. MRI with or without DWI shows a moderately correlation with PET/CT with a tendency for understaging.

Objective: Several studies have suggested that iodine may influence thyroid hormone status, and perhaps antibody production, in patients with autoimmune thyroid disease. To date, studies have been carried out using large amounts of iodine. Therefore, we evaluated the effect of small doses of iodine on thyroid function and thyroid antibody levels in euthyroid patients with Hashimoto's thyroiditis who were living

Pediatric thyroid cancer is a rare disease with an excellent prognosis. Compared with adults, epithelial-derived differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid cancer, presents at more advanced stages in children and is associated with higher rates of recurrence. Because of its uncommon occurrence, randomized trials have not been applied to test best-care options in children. Even in adults that have a 10-fold or higher incidence of thyroid cancer than children, few prospective trials have been executed to compare treatment approaches. We recognize that treatment recommendations have changed over the past few decades and will continue to do so. Respecting the aggressiveness of pediatric thyroid cancer, high recurrence rates, and the problems associated with decades of long-term follow-up, a premium should be placed on treatments that minimize risk of recurrence and the adverse effects of treatments and facilitate follow-up. We recommend that total thyroidectomy and central compartment lymph node dissection is the surgical procedure of choice for children with DTC if it can be performed by a high-volume thyroid surgeon. We recommend radioactive iodine therapy for remnant ablation or residual disease for most children with DTC. We recommend long-term follow-up because disease can recur decades after initial diagnosis and therapy. Considering the complexity of DTC management and the potential complications associated with therapy, it is essential that pediatric DTC be managed by physicians with expertise in this area.