[Show abstract][Hide abstract] ABSTRACT: Background:
Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET.
Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1-FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse.
Consecutive FMISO-PET positive volumes could be classified as moderately stable with Dice conformity indices of 62% and 58% up to the second week of treatment. Substantial volumetric variation during treatment was observed, with more than 20% geographic miss in all patients and more than 40% in half of the patients. The localisation of the maximum standardised uptake value (SUVmax) differed with a mean distance of 7.0 mm and 13.5 mm between the pre-therapeutic and first or second FMISO-PET during treatment. A stable hypoxic consensual volume (i.e. overlap of pre-therapeutic FMISO and intra-treatment FMISO subvolumes up to week two, generated by different contouring methods) was determined for six patients with imaging information of local recurrence. Three of these six local recurrences were located within this consensual volume.
Our data suggest that selective dose painting to hypoxic tumour subvolumes requires adaptation during treatment and sufficient margins. An alternative strategy is to escalate the dose to the gross tumour volume, accepting lesser escalation of dose outside hypoxic areas if indicated by constraints for organs at risk.
[Show abstract][Hide abstract] ABSTRACT: 4′,6-Diamidine-2-phenylindole (DAPI) is a common fluorochrome that is able to bind to deoxyribonucleic acid (DNA) with distinct, sequence-dependent enhancement of fluorescence. This work presents the synthesis of a new multifunctional compound that includes the fluorescent dye as a 99mTechnetium (99mTc) carrier. A new technique for the bioconjugation of DAPI with 6-hydrazinonicotinic acid (HYNIC) through an amide linkage was developed. The radiolabelling was performed with HYNIC as a chelator and N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) as a coligand. Furthermore, experimental evidence showed that 99mTc complexes with DAPI as DNA-binding moieties are detectable in living Fischer rat thyroid follicular cell line 5 (FRTL5) and their nuclei. The investigations indicated further that the new HYNIC-DAPI derivative is able to interact with double-stranded DNA. This establishes the possibility of locating 99mTc in close proximity to biological structures of living cells, of which especially the genetic information-carrying cell compartments are at the centre of interest. In this context, further investigations are related to the radiotoxic effects of DNA-bound 99mTc-HYNIC-DAPI derivatives and dosimetric calculations.
Medicinal Chemistry Communication 03/2015; 6(5). DOI:10.1039/C4MD00574K · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose which can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive as different organs at risk are in target. However, advantages of both single treatments are combined, e.g. precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of preclinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.
The British journal of radiology 03/2015; 88(1051):20150042. DOI:10.1259/bjr.20150042 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical reviews are an important part of the medical literature offering the reader condensed information on a specific topic. In radiology and nuclear medicine most clinical reviews have a subjective character as they have been written in a rather narrative way. Based on their low level of evidence these narrative reviews are frequently not being considered for establishment of clinical guidelines. The aim of this paper is to aid the reader in writing a good clinical review by highlighting the different aspects of a systematic review.
[Show abstract][Hide abstract] ABSTRACT: This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.
[Show abstract][Hide abstract] ABSTRACT: The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient would have been examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardized imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardized uptake value harmonization in multicentre settings
European journal of nuclear medicine and molecular imaging 12/2014; 42(2). DOI:10.1007/s00259-014-2961-x · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a previous study, we demonstrated the first evidence that the asphericity (ASP) of pretherapeutic FDG uptake in the primary tumor provides independent prognostic information in patients with head and neck cancer. The aim of this work was to confirm these results in an independent patient group examined at a different site.
FDG-PET/CT was performed in 37 patients. The primary tumor was delineated by an automatic algorithm based on adaptive thresholding. For the resulting ROIs, the metabolically active part of the tumor (MTV), SUVmax, SUVmean, total lesion glycolysis (TLG) and ASP were computed. Univariate Cox regression with respect to progression free survival (PFS) and overall survival (OS) was performed. For survival analysis, patients were divided in groups of high and low risk according to the parameter cut-offs defined in our previous work. In a second step, the cut-offs were adjusted to the present data. Univariate and multivariate Cox regression was performed for the pooled data consisting of the current and the previously described patient group (N = 68). In multivariate Cox regression, clinically relevant parameters were included.
Univariate Cox regression using the previously published cut-off values revealed TLG (hazard ratio (HR) = 3) and ASP (HR = 3) as significant predictors for PFS. For OS MTV (HR = 2.7) and ASP (HR = 5.9) were significant predictors. Using the adjusted cutoffs MTV (HR = 2.9/3.3), TLG (HR = 3.1/3.3) and ASP (HR = 3.1/5.9) were prognostic for PFS/OS. In the pooled data, multivariate Cox regression revealed a significant prognostic value with respect to PFS/OS for MTV (HR = 2.3/2.1), SUVmax (HR = 2.1/2.5), TLG (HR = 3.5/3.6), and ASP (HR = 3.4/4.4).
Our results confirm the independent prognostic value of ASP of the pretherapeutic FDG uptake in the primary tumor in patients with head and neck cancer. Moreover, these results demonstrate that ASP can be determined unambiguously across different sites.
European journal of nuclear medicine and molecular imaging 11/2014; 42(3). DOI:10.1007/s00259-014-2953-x · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale and Objectives
The purpose of this study was to evaluate the sensitivity and specificity of positron emission tomography/magnetic resonance imaging (PET/MR) with 18F-fluorodeoxyglucose (FDG) for nodal involvement in malignant lymphoma.
Materials and Methods
Twenty-seven patients with malignant lymphoma (16 men and 11 women; mean age, 45 years) were included in this retrospective study. The patients underwent FDG PET/MR after intravenous injection of FDG (176–357 MBq FDG, 282 MBq on average). Follow-up imaging and histology served as the standard of reference.
One-hundred and twenty-seven (18.1%) of 702 lymph node stations were rated as having lymphoma involvement based on the standard of reference. One-hundred and twenty-four (17.7%) of 702 lymph node stations were rated as positive by FDG PET/MR. The sensitivity and specificity of FDG PET/MR for lymph node station involvement were 93.8% and 99.4%.
FDG PET/MR is feasible for lymphoma staging and has a high sensitivity and specificity for nodal involvement in lymphoma. Comparison with PET/CT is necessary to determine whether FDG PET/MR can replace PET/CT for lymphoma staging.
[Show abstract][Hide abstract] ABSTRACT: 99mTc is the standard radionuclide used for nuclear medicine imaging. In addition to gamma irradiation, 99mTc emits low-energy Auger and conversion electrons that deposit their energy within nanometers of the decay site. To study the potential for DNA damage, direct DNA binding is required. Plasmid DNA enables the investigation of the unprotected interactions between molecules and DNA that result in single-strand breaks (SSBs) or double-strand breaks (DSBs); the resulting DNA fragments can be separated by gel electrophoresis and quantified by fluorescent staining. This study aimed to compare the plasmid DNA damage potential of a 99mTc-labeled HYNIC-DAPI compound with that of 99mTc pertechnetate (99mTcO4−). pUC19 plasmid DNA was irradiated for 2 or 24 hours. Direct and radical-induced DNA damage were evaluated in the presence or absence of the radical scavenger DMSO. For both compounds, an increase in applied activity enhanced plasmid DNA damage, which was evidenced by an increase in the open circular and linear DNA fractions and a reduction in the supercoiled DNA fraction. The number of SSBs elicited by 99mTc-HYNIC-DAPI (1.03) was twice that caused by 99mTcO4− (0.51), and the number of DSBs increased fivefold in the 99mTc-HYNIC-DAPI-treated sample compared with the 99mTcO4− treated sample (0.02 to 0.10). In the presence of DMSO, the numbers of SSBs and DSBs decreased to 0.03 and 0.00, respectively, in the 99mTcO4– treated samples, whereas the numbers of SSBs and DSBs were slightly reduced to 0.95 and 0.06, respectively, in the 99mTc-HYNIC-DAPI-treated samples. These results indicated that 99mTc-HYNIC-DAPI induced SSBs and DSBs via a direct interaction of the 99mTc-labeled compound with DNA. In contrast to these results, 99mTcO4− induced SSBs via radical formation, and DSBs were formed by two nearby SSBs. The biological effectiveness of 99mTc-HYNIC-DAPI increased by approximately 4-fold in terms of inducing SSBs and by approximately 10-fold in terms of inducing DSBs.
PLoS ONE 08/2014; 9(8-8):e104653. DOI:10.1371/journal.pone.0104653 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
68Ga-labelled compounds are increasingly used for somatostatin-receptor scintigraphy because of their favourable biokinetic properties, a higher tumour-to-background contrast and higher diagnostic accuracy compared to the gamma-emitting tracer 111In-DTPA-octreotide. Recently, we have introduced the new tracer 68Ga-DOTA-3-iodo-Tyr3-Thr8-octreotide (68Ga-HA-DOTATATE). The present study demonstrates the biodistribution and radiation dosimetry of this tracer in humans.
Seven men were enrolled in this analysis. Every patient underwent a 20 min dynamic PET scan after intravenous injection of about 114 ± 9 MBq of 68Ga-HA-DOTATATE. This was followed by two whole-body scans at 30 min p. i. and 120 min p. i. Blood radioactivity concentration was determined non-invasively from a ROI drawn over the aorta. Urine was collected until the time of the last scan. Liver, spleen, kidneys and urinary bladder wall were included in the dosimetric estimation that was carried out with the software package OLINDA 1.0.
Physiological 68Ga-HA-DOTATATE uptake was observed in the pituitary gland, thyroid, salivary glands, liver, spleen, kidneys, urinary bladder, adrenals and intestine. Organs with the highest absorbed dose were spleen (0.26 ± 0.11 mSv/MBq), kidneys (0.14 ± 0.03 mSv/MBq) and liver (0.12 ± 0.02 mSv/MBq).The estimated effective dose was 0.024 ± 0.001 mSv/MBq.
Our study demonstrates biokinetics and radiation exposure of the 68Ga-labelled tracer HA-DOTATATE to be comparable to other 68Ga-labelled SSR analogues in clinical use.
[Show abstract][Hide abstract] ABSTRACT: Purpose: Based on the authors’ previous findings concerning the radiotoxicity of99mTc, the authors compared the cellular survival under the influence of this nuclide with that following exposure to the Auger electron emitter 123I. To evaluate the relative biological effectiveness (RBE) of both radionuclides, knowledge of the absorbed dose is essential. Thus, the authors present the dose calculations and discuss the results based on different models of the radionuclide distribution. Both different target volumes and the influence of the uptake kinetics were considered.
Medical Physics 06/2014; 41(6):062503. DOI:10.1118/1.4876296 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diagnostic imaging with positron emission tomography (PET) is becoming increasingly more involved in oncological therapy management.
How can PET be helpful in oncological surgery?
After a short introduction into the basic principles of PET the current state of imaging as well as indications and limitations of the method are described.
The PET is a functional and quantitative imaging technique, enabling detection and characterization of tumors. It is applied in pretherapeutic staging as well as in follow-up and therapy assessment. The use of PET changes the therapy management in about one third of all oncology patients. New radiopharmaceuticals and novel technologies expand the diagnostic potential.
Hybrid imaging with PET computed tomography (CT) and PET magnetic resonance imaging (MRI) further improves diagnostic imaging and increases the acceptance of PET further.
Der Chirurg 05/2014; 85(6). DOI:10.1007/s00104-013-2666-x · 0.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Standard uptake values (SUV) as well as tumor-to-blood standard uptake ratios (SUR) measured with[18F-]fluorodeoxyglucose (FDG) PET are time dependent. This poses a serious problem for reliablequantification since variability of scan start time relative to the time of injection is a persistent issue inclinical oncological Positron emission tomography (PET). In this work, we present a method for scantime correction of, both, SUR and SUV.
Assuming irreversible FDG kinetics, SUR is linearly correlated to Km (the metabolic rate of FDG),where the slope only depends on the shape of the arterial input function (AIF) and on scan time. Consideringthe approximately invariant shape of the AIF, this slope (the `Patlak time¿) is an investigationindependent function of scan time. This fact can be used to map SUR and SUV values from differentinvestigations to a common time point for quantitative comparison. Additionally, it turns out thatmodelling the invariant AIF shape by an inverse power law is possible which further simplifies thecorrection procedure. The procedure was evaluated in 15 fully dynamic investigations of liver metastasesfrom colorectal cancer and 10 dual time point (DTP) measurements. From each dynamic study,three `static scans¿ at T = 20, 35, and 55 min post injection (p.i.) were created, where the last scandefined the reference time point to which the uptake values measured in the other two were corrected.The corrected uptake values were then compared to those actually measured at the reference time.For the DTP studies, the first scan (acquired at 78.1 ± 15.9 min p.i.) served as the reference, and theuptake values from the second scan (acquired 39.2 ± 9.9 min later) were corrected accordingly andcompared to the reference.
For the dynamic data, the observed difference between uncorrected values and values at referencetime was (¿52 ± 4.5)% at T = 20 min and (¿31 ± 3.7)% at T = 35 min for SUR and (¿30 ± 6.6)%at T = 20 min and (¿16 ± 4)% at T = 35 min for SUV. After correction, the difference was reducedto (¿2.9 ± 6.6)% at T = 20 min and (¿2.7 ± 5)% at T = 35 min for SUR and (1.9% ± 6.2)% atT = 20 min and (1.7 ± 3.3)% at T = 35 min for SUV. For the DTP studies, the observed differencesof SUR and SUV between late and early scans were (48 ± 11)% and (24 ± 8.4)%, respectively. Aftercorrection, these differences were reduced to (2.6 ± 6.9)% and (¿2.4 ± 7.3)%, respectively.
If FDG kinetics is irreversible in the targeted tissue, correction of SUV and SUR for scan time variabilityis possible with good accuracy. The correction distinctly improves comparability of lesionuptake values measured at different times post injection.
EJNMMI Research 04/2014; 4(1):18. DOI:10.1186/2191-219X-4-18
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate the effect of radiation dose-escalation on local control in hypoxic versus non-hypoxic hypoxic tumours defined using [18F]fluoromisonidazole ([18F]FMISO) PET.
Materials and methods
FaDu human squamous cell carcinomas (hSCCs) growing subcutaneously in nude mice were subjected to [18F]FMISO PET before irradiation with single doses of 25 or 35 Gy under normal blood flow conditions. [18F]FMISO hypoxic volume (HV) and maximum standardised uptake value (SUVmax) were used to quantify tracer uptake. The animals were followed up for at least 120 days after irradiation. The endpoints were permanent local tumour control and time to local recurrence.
HV varied between 38 and 291 mm3 (median 105 mm3). Non-hypoxic tumours (HV below median) showed significantly better local control after single dose irradiation than hypoxic tumours (HV above median) (p = 0.046). The effect of dose was significant and not different in non-hypoxic and in hypoxic tumours (HR = 0.82 [95% CI 0.71; 0.93], p = 0.002 and HR = 0.86 [0.78; 0.95], p = 0.001, respectively). Dose escalation resulted in an incremental increase of local tumour control from low-dose hypoxic, over low-dose non-hypoxic and high-dose hypoxic to high-dose non-hypoxic tumours. SUVmax did not reveal significant association with local control at any dose level.
The negative effect of [18F]FMISO HV on permanent local tumour control supports the prognostic value of the pre-treatment [18F]FMISO HV. Making the assumption that variable [18F]FMISO uptake in different FaDu tumours which all have the same genetic background may serve as an experimental model of intratumoural heterogeneity, the data support the concept of dose-escalation with inhomogeneous dose distribution based on pre-treatment [18F]FMISO uptake. This result needs to be confirmed in other tumour models and using fractionated radiotherapy schedules.
Radiotherapy and Oncology 04/2014; 111(1). DOI:10.1016/j.radonc.2014.02.005 · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the diagnostic value of PET/MR (positron emission tomography/magnetic resonance imaging) with FDG (18F-fluorodeoxyglucose) for lymph node staging in head and neck cancer.
This prospective study was approved by the local ethics committee; all patients signed informed consent. Thirty-eight patients with squamous cell carcinoma of the head and neck region underwent a PET scan on a conventional scanner and a subsequent PET/MR on a whole-body hybrid system after a single intravenous injection of FDG. The accuracy of PET, MR and PET/MR for lymph node metastases were compared using receiver operating characteristic (ROC) analysis. Histology served as the reference standard.
Metastatic disease was confirmed in 16 (42.1%) of 38 patients and 38 (9.7%) of 391 dissected lymph node levels. There were no significant differences between PET/MR, MR and PET and MR (p>0.05) regarding accuracy for cervical metastatic disease. Based on lymph node levels, sensitivity and specificity for metastatic involvement were 65.8% and 97.2% for MR, 86.8% and 97.0% for PET and 89.5% and 95.2% for PET/MR.
In head and neck cancer, FDG PET/MR does not significantly improve accuracy for cervical lymph node metastases in comparison to MR or PET.
European journal of radiology 04/2014; 83(7). DOI:10.1016/j.ejrad.2014.03.023 · 2.37 Impact Factor