Winfried Willinek

University of Bonn - Medical Center, Bonn, North Rhine-Westphalia, Germany

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Publications (20)73.12 Total impact

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    ABSTRACT: The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with (177)Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with (177)Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial (99m)Tc-DTPA clearance measurements. The median follow-up period was 58 months (range 4 - 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 - 42) and 53 months (95 % CI 46 - 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, p = 0.007), a high hepatic tumour burden (≥25 % liver volume, p = 0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p = 0.035). The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient's performance status, tumour burden and baseline plasma NSE level.
    European Journal of Nuclear Medicine 02/2014; · 4.53 Impact Factor
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    ABSTRACT: Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P < 0.05). The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification.
    Journal of Nuclear Medicine 01/2014; · 5.77 Impact Factor
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    ABSTRACT: BACKGROUND: The incidence of radionecrosis after radiosurgery is 5--20%. That radionecrosis after radiosurgery may be confused with a malignant tumor is a known phenomenon and problem. METHODS: Three similarly treated patients with cAVM, 1 patient with symptomatic radionecrosis and 2 patients with normal post-radiation MRI changes, were selected and studied in detail with magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS). 2 cAVM were located in eloquent locations and were classified as Spetzler-Martin grade (SM) III such that interdisciplinary radiosurgery was recommended; a third patient with a left frontal SM II cAVM refused surgery. 1 patient was male, and 2 were female. The patient's ages ranged from 38 to 62 years (median, 39 years). The nidus volume (= planning target volume = PTV) ranged from 2.75 to 6.89 ccm (median, 6.41 ccm). The single dose was 20 Gy at the isocenter of the PTV encompassing the 80 -- 90% isodose. The median follow-up period was 20 months (range, 16 -- 84 months). Toxicities were evaluated with the Common Terminology Criteria (CTC) for adverse events version 3.0. RESULTS: No patient suffered a bleeding from cAVM during the study period. A complete nidus occlusion was shown in all patients with time-resolved MRA. All patients showed radiogenic MRI changes, 1 patient showed excessive radionecrosis. This patient was oligosymptomatic and under temporary corticoid therapy symptoms resolved completely.Following patterns associated with radionecrosis in the MRS studies were identified in our collective:2D spectroscopic imaging (2D-SI) revealed much lower concentrations of metabolites in the lesion as compared to contralateral healthy tissue in all patients.Whereas regions with regular post-radiosurgery effects showed almost normal levels of Cho and a Cho/Cr ratio < 2.0, regions with radionecrosis were characterized by increased lipid levels and a Cho/Cr ratio > 2.0 in conjunction with decreased absolute levels of all metabolites, especially of Cr and NAA. CONCLUSIONS: MRS is an increasingly valuable tool for the differential diagnosis of radiation reactions. Specific patterns of MRS spectra in radionecrosis were identified; in synopsis with clinical parameters, these changes have to be taken into account to avoid misdiagnosis.
    Radiation Oncology 03/2013; 8(1):54. · 2.11 Impact Factor
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    ABSTRACT: Previous radiation therapy of the liver is a contraindication for performing (90)Y microsphere radioembolization, and its safety after internal radiation exposure through peptide receptor radionuclide therapy (PRRT) has not yet been investigated. METHODS: We retrospectively assessed a consecutive cohort of 23 neuroendocrine tumor (NET) patients with liver-dominant metastatic disease undergoing radioembolization with (90)Y microspheres as a salvage therapy after failed PRRT. Toxicity was recorded throughout follow-up and reported according to Common Terminology Criteria for Adverse Events (version 3). Radiologic (response evaluation criteria in solid tumors), biochemical, and symptomatic responses were investigated at 3 mo after treatment, and survival analyses were performed with the Kaplan-Meier method (log-rank test, P < 0.05). RESULTS: The median follow-up period after radioembolization was 38 mo (95% confidence interval, 18-58 mo). The mean previous cumulative activity of (177)Lu-DOTA-octreotate was 31.8 GBq. The mean cumulative treatment activity of (90)Y microspheres was 3.4 ± 2.1 GBq, administered to the whole liver in a single session (n = 8 patients), in a sequential lobar fashion (n = 10 patients), or to only 1 liver lobe (n = 5 patients). Only transient, mostly minor liver toxicity (no grade 4) was recorded. One patient (4.3%) developed a gastroduodenal ulcer (grade 2). The overall response rates for radiologic, biochemical, and symptomatic responses were 30.4%, 53.8%, and 80%, respectively. The median overall survival was 29 mo (95% confidence interval, 4-54 mo) from the first radioembolization session and 54 mo (95% confidence interval, 47-61 mo) from the first PRRT cycle. A tumor proliferation index Ki-67 greater than 5% predicted shorter survival (P = 0.007). CONCLUSION: Radioembolization is a safe and effective salvage treatment option in advanced NET patients with liver-dominant tumor burden who failed or reprogressed after PRRT. The lack of relevant liver toxicity despite high applied (90)Y activities and considerable previous cumulative activities of (177)Lu-octreotate is noteworthy and disputes internal radiation exposure by PRRT as a toxicity risk factor in subsequent radioembolization.
    Journal of Nuclear Medicine 09/2012; · 5.77 Impact Factor
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    ABSTRACT: Peptide receptor radionuclide therapy with 177Lu-octreotate is an effective treatment option for metastatic gastroenteropancreatic neuroendocrine tumors (GEP NET) and allows intratherapeutic imaging through a 177Lu-octreotate scan (LuS). The diagnostic value of this treatment scan is not yet established. This study aims to compare the sensitivity of LuS and bone scintigraphy (BS) regarding bone metastases and investigate potential implications of functional imaging results. We retrospectively analyzed 29 consecutive GEP NET patients with bone metastases and baseline BS treated with 177Lu-octreotate. A semi-quantitative scoring system was used for the comparative evaluation. Treatment outcome (time-to-progression of bone metastases) was correlated with the intra-individual imaging discrepancy (Kaplan-Meyer curves, log-rank test, p < 0.05). In 19 of 29 patients (65.5%) LuS was superior (LuS > BS), whereas in 10 patients (34.5%) both modalities were comparable. BS showed no additional (LuS-negative) metastatic bone lesions in our cohort. None of the investigated baseline characteristics was associated with imaging discrepancy. On the other hand, functional imaging discrepancy had no impact on treatment response (p = 0.43) or time-to-progression (p = 0.92). Intra-therapeutic 177Lu-octreotate imaging is superior over bone scintigraphy for detection of bone metastases in GEP NET. BS may help to distinguish osseous from non-osseous localization. The presence of an osteoblastic correlate in BS seems to have no impact on therapeutic outcome.
    Nuklearmedizin 03/2012; 51(3):95-100. · 1.67 Impact Factor
  • J NUCL MED MEETING ABSTRACTS. 01/2012; 53(1_MeetingAbstracts):1175-.
  • J NUCL MED MEETING ABSTRACTS. 01/2012; 53(1_MeetingAbstracts):227-.
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    ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM). We retrospectively analyzed a consecutive subgroup of 42 patients with BM of GEP NETs treated with PRRT ((177)Lu-octreotate, 4 intended cycles at 3 monthly intervals [10-14 wk]; mean activity per cycle, 8.1 GBq). Availability of restaging and outcome data was required for patient inclusion. Baseline characteristics, including age, tumor origin, performance score, Ki-67 index, tumor load, tumor uptake, plasma chromogranin A, and neuron-specific enolase, were analyzed regarding impact on tumor regression (modified M.D. Anderson criteria) and time to progression. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of P less than 0.05, and Cox proportional hazards model for uni- and multivariate analyses. Median follow-up was 32 mo. The observed response of BMs consisted of complete remission in 2 (4.8%), partial remission in 14 (33.3%), minor response in 5 (11.9%), stable disease in 16 (38.1%), and progressive disease in 5 (11.9%) patients. Median progression-free survival and overall survival (OS) were 35 mo (26-44, 95% confidence interval) and 51 mo (37-65, 95% confidence interval), respectively. Patients with responding BMs (complete remission, partial remission, or minor response) exhibited a trend toward better OS (median OS not reached after 53 mo) when compared to nonresponding patients (39 mo, P = 0.076). Only Ki-67 index (>10%) and chromogranin A level (>600 ng/mL) contributed to regression analysis. BM of GEP NETs is effectively controlled by PRRT, with long progression-free survival and OS. Poor patient condition and multifocality of BMs do not clearly affect treatment efficacy, possibly encouraging the use of PRRT in advanced bone metastatic disease. Larger studies are needed to assess predictors of treatment outcome in these patients.
    Journal of Nuclear Medicine 08/2011; 52(8):1197-203. · 5.77 Impact Factor
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    ABSTRACT: The role of the Ki-67 tumour proliferation index (PI) in predicting the efficacy of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic tumours (GEP-NET) remains undetermined. This single-centre analysis focused on the potential therapeutic impact of this immunohistochemical parameter. A total of 81 consecutive GEP-NET patients treated with (177)Lu-DOTA-octreotate (mean activity of 7.9 GBq per cycle, usually four treatment cycles at standard intervals of 3 months) were retrospectively analysed. Both an evaluable PI and tumour response (modified SWOG criteria) were required for patient inclusion. Response of tumours with a PI of ≤20% (partial response 40%, minor response 15%, stable disease 34%, progressive disease 11%) was comparable in all PI subsets, including those with a PI of 20%. However, G3 tumours (PI > 20%) showed progression in 71% of patients. Response to PRRT is consistent over the PI range of ≤20% (G1 + G2). Contrary to preliminary previous suggestions, a PI of 15% or 20% should not preclude candidates from somatostatin receptor-targeted radiotherapy.
    European Journal of Nuclear Medicine 03/2011; 38(3):459-66. · 4.53 Impact Factor
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    ABSTRACT: Magnetic resonance angiography (MRA) is an established noninvasive imaging modality for detection and evaluation of vascular pathologies in children with congenital heart disease. Standard first-pass (FP)-MRA uses a 3-dimensional MRA sequence with an extracellular contrast agent, in which spatial resolution is limited by breath-hold duration, and image quality (IQ) is limited by motion artifacts. The purpose of this study was to compare the diagnostic confidence, IQ, and image artifacts of standard FP-MRA to a high-resolution, motion compensated steady-state (SS)-MRA of the thoracic vasculature in children and adolescents with congenital heart disease using a blood-pool contrast agent (gadofosveset trisodium). SS-MRA of the thoracic vasculature (technically successful in 90% of patients) offers superior diagnostic confidence and IQ compared with FP-MRA and shows fewer motion-related image artifacts. In addition, SS-MRA revealed findings missed by FP-MRA. Therefore, SS-MRA may prove specifically beneficial for imaging of thoracic vessels that are small and/or subject to motion.
    JACC. Cardiovascular imaging 05/2010; 3(5):504-13. · 14.29 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the feasibility of a flat-detector C-arm-guided radiographic technique (cone-beam computed tomography [CBCT]) for percutaneous radiologic gastrostomy (PRG) insertion. Eighteen patients (13 men and 5 women; mean age 62 years) in whom percutaneous endoscopic gastrostomy (PEG) had failed underwent CBCT-guided PRG insertion. PEG failure or unsuitability was caused by upper gastrointestinal tract obstruction in all cases. Indications for gastrostomy were esophageal and head and neck malignancies, respectively. Before the PRG procedure, initial C-arm CBCT scans were acquired. Three- and 2-dimensional soft-tissue reconstructions of the epigastrium region were generated on a dedicated workstation. Subsequently, gastropexy was performed with T-fasteners after CBCT-guided puncture of the stomach bubble, followed by insertion of an 14F balloon-retained catheter through a peel-away introducer. Puncture of the stomach bubble and PRG insertion was technically successful in all patients without alteration of the epigastric region. There was no malpositioning of the tube or other major periprocedural complications. In 2 patients, minor complications occurred during the first 30 days of follow-up (PRG malfunction: n = 1; slight infection: n = 1). Late complications, which were mainly tube disturbances, were observed in 2 patients. The mean follow-up time was 212 days. CBCT-guided PRG is a safe, well-tolerated, and successful method of gastrostomy insertion in patients in whom endoscopic gastrostomy is not feasible. CBCT provides detailed imaging of the soft tissue and surrounding structures of the epigastric region in one diagnostic tour and thus significantly improves the planning of PRG procedures.
    CardioVascular and Interventional Radiology 08/2009; 33(2):315-20. · 2.09 Impact Factor
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    ABSTRACT: To alleviate congenital high airway obstruction syndrome (CHAOS) from laryngeal atresia by percutaneous minimally-invasive fetoscopic tracheal decompression using laser. The procedure was performed via one trocar under general maternofetal anesthesia in a human fetus with CHAOS from laryngeal atresia at 21+6 weeks of gestation. Normalization of the lung-heart size relationship was observed within days after the procedure. The fetus was delivered by ex utero intrapartum treatment (EXIT) in order to perform a tracheotomy at 31+1 weeks of gestation and survived hospital treatment to discharge. Percutaneous minimally-invasive fetoscopic decompression of the fetal trachea via a single trocar is feasible in human fetuses with CHAOS from laryngeal atresia.
    Fetal Diagnosis and Therapy 03/2009; 25(1):67-71. · 1.90 Impact Factor
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    ABSTRACT: A percutaneous minimally invasive fetoscopic approach was attempted for closure of a spina bifida aperta in two fetuses with L5 lesions. The goal was to obviate the need for postnatal neurosurgery to manage this condition. The percutaneous fetoscopic procedures were performed by a two-layer approach at respectively 22+/-2 and 22+/-4 weeks of gestation. The fetuses were delivered respectively at 32+/-6 and 32+3 weeks of gestation. Their neural cords were completely covered although in small areas skin closure was incomplete. Postnatally, complete skin closure occurred beneath an occlusive draping within 2 to 3 weeks such that neurosurgical intervention was not required. Both neonates showed reversal of hindbrain herniation, near-normal leg function, and satisfactory bladder and bowel function. For one of the two fetuses, ventriculoperitoneal shunt insertion was not required. Percutaneous minimally invasive fetoscopic patch closure of spina bifida aperta offers a substantially less maternal trauma than open fetal surgical repair and currently may even obviate the need for postnatal neurosurgical repair. With a little further improvement in surgical techniques and a better understanding of incorporating surgical patches into the fetus, complete skin closure seems possible in the near future.
    Surgical Endoscopy 10/2008; 23(4):890-5. · 3.43 Impact Factor
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    ABSTRACT: This is the second part of a two-part series on the clinical applications of high-field-strength (3.0-T) magnetic resonance (MR) imaging and spectroscopy. In this part, the current level of evidence regarding the use of higher magnetic field strengths for cardiac imaging techniques (including the assessment of cardiac anatomy and function), breast and pelvic imaging, musculoskeletal applications, pediatric imaging, and MR spectroscopy is presented. Published data are interpreted from the perspective of the clinical radiologist. Specific difficulties associated with high-field-strength MR for body imaging and for spectroscopic applications are reviewed and compared with the expected or documented added value of high-field-strength MR for clinical patient care. The overall number of studies published on clinical body high-field-strength MR is still small, and there is evidence for a clinical advantage for selected, but not all, body MR imaging applications. Even without published evidence, clinical experience suggests substantial clinical advantages for musculoskeletal and pediatric applications.
    Radiology 05/2008; 247(1):16-35. · 6.34 Impact Factor
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    ABSTRACT: Since digital subtraction angiography (DSA) carries a low risk of morbidity, and is associated with patient discomfort and higher cost, our objective was to determine whether high-resolution 3-D time-of-flight MR angiography (TOF-MRA) at 3 T may replace DSA in the follow-up of patients after coiling of an intracranial aneurysm. This prospective study included 50 consecutive patients with a ruptured and subsequently coiled intracranial aneurysm. All patients were followed up at a mean of 14 months after coiling with DSA and high-resolution 3-D TOF-MRA at 3 T generating 0.02 mm3 isotropic voxels. One examiner used DSA and TOF-MR angiograms to assess the need for and risk of retreatment; these data were used to calculate intermodality agreement. Another two examiners independently assessed aneurysm occlusion by DSA and TOF-MRA according to the Raymond scale; these data were used to calculate interobserver agreement. Discrepancies between DSA and TOF-MRA were found in three patients (intermodality agreement kappa=0.86). While DSA indicated complete aneurysm occlusion, TOF-MRA showed small neck remnants in the three patients. Coils on all DSA projections obscured these three neck remnants. Interobserver agreement was higher for DSA (kappa=0.82) than for TOF-MRA (kappa=0.68), which was in part due to the complexity of the information provided by TOF source images and reconstructions. 3-D TOF-MRA at 3 T is not only an adjunctive tool but is ready to replace DSA in the follow-up of patients with previously coiled intracranial aneurysms. Additional DSA may only be performed in complex and not clearly laid out aneurysms.
    Neuroradiology 02/2008; 50(5):383-9. · 2.70 Impact Factor
  • Ultraschall in Der Medizin - ULTRASCHALL MED. 01/2008; 29.
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    ABSTRACT: Molecular imaging of functional parameters such as apoptosis (programmed cell death) in vivo opens new possibilities in clinical diagnostic and scientific research. Especially in the case of cardiovascular diseases that are mainly responsible for both morbidity and mortality in Western industrial nations, innovative non-invasive examination strategies are necessary for early diagnosis of these diseases. Since apoptosis unlike necrosis is present even after minor alterations of the microenvironment of cells and has been shown to be involved in a large number of cardiovascular diseases, there are currently several experimental studies underway with the goal of imaging apoptosis in vivo. The review discusses the basics of apoptosis in myocardial infarction, myocarditis, atherosclerosis, restenosis after angioplasty and stent implantation, currently used imaging techniques, achieved results, and future possibilities for molecular imaging of apoptosis.
    RöFo - Fortschritte auf dem Gebiet der R 09/2007; 179(8):780-9. · 2.76 Impact Factor
  • Rofo-fortschritte Auf Dem Gebiet Der Rontgenstrahlen Und Der Bildgebenden Verfahren - ROFO-FORTSCHR RONTGENSTRAHL. 01/2007; 179(8):780-789.
  • Ingrid Böhm, Winfried Willinek, Hans H Schild
    The American Journal of Gastroenterology 11/2006; 101(10):2439-40. · 9.21 Impact Factor
  • Gefässchirurgie 16(1):49-54. · 0.24 Impact Factor