Untch M.,Helios Klinikum |
Loibl S.,German Breast Group |
Bischoff J.,Universitats Frauenklinik |
Eidtmann H.,Universitats Frauenklinik |
And 15 more authors.
The Lancet Oncology | Year: 2012
Background: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy. Methods: In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN SLN+). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m 2 intravenously] plus cyclophosphamide [600 mg/m 2 intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m 2 intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554. Findings: Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group. Interpretation: This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy. Funding: GlaxoSmithKline, Roche, and Sanofi-Aventis. © 2012 Elsevier Ltd.
Rosahl S.K.,HELIOS Klinikum |
Rosahl S.K.,Albert Ludwigs University of Freiburg |
Rosahl S.,Albert Ludwigs University of Freiburg
Neurosurgery | Year: 2013
Background: Auditory brainstem implants have failed to produce consistent clinical results comparable to those with the cochlear implant, both with surface and penetrating electrodes. Objective: To determine neuromorphological constraints of the auditory brainstem implant interface. Methods: The size, shape, surface depth, and spatial orientation of 33 human cochlear nuclei in 20 brainstem specimens obtained at autopsy were systematically analyzed in 792 slices each with a thickness of 8 μm. Three-dimensional renderings of the cochlear nucleus complex were obtained from a true-to-scale model, and the resulting photographic views were arranged according to the axes of the brainstem. Results: The dimensions of the ventral and dorsal cochlear nuclei in the axial, coronal, and sagittal planes correlated linearly with each other. There were no significant side differences. Maximum dimensions of the whole cochlear nuclear complex were 8.01 × 1.53 × 3.76 mm. The appearance of the ventral and dorsal nuclei combined resembles a distorted X shape from a lateral view and an angulated wedge shape when viewed from above. Slanted into the depth of the brainstem above the facial nerve entrance, the superior boundary of the ventral nucleus is located more than 7 mm off the surface of the brainstem on average. Conclusion: In the absence of appropriate surface landmarks and imaging guidance, to gain tonotopic access to the human cochlear nucleus with surface and depth electrode remains a major challenge. Due to its location close to the surface, the dorsal cochlear nucleus is vulnerable to surgical manipulation and to tumors. © 2012 by the Congress of Neurological Surgeons.
Byrne R.A.,TU Munich |
Neumann F.-J.,Universitats Herzzentrum |
Mehilli J.,Ludwig Maximilians University of Munich |
Pinieck S.,TU Munich |
And 12 more authors.
The Lancet | Year: 2013
Background: The best way to manage restenosis in patients who have previously received a drug-eluting stent is unknown. We investigated the efficacy of paclitaxel-eluting balloons (PEB), paclitaxel-eluting stents (PES), and balloon angioplasty in these patients. Methods: In this randomised, open-label trial, we enrolled patients older than 18 years with restenosis of at least 50% after implantation of any limus-eluting stent at three centres in Germany between Aug 3, 2009, and Oct 27, 2011. Patients were randomly assigned (1:1:1; stratified according to centre) to receive PEB, PES, or balloon angioplasty alone by means of sealed, opaque envelopes containing a computer-generated sequence. Patients and investigators were not masked to treatment allocation, but events and angiograms were assessed by individuals who were masked. The primary endpoint was diameter stenosis at follow-up angiography at 6-8 months. Primary analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00987324. Findings: We enrolled 402 patients, of whom 137 (34%) were assigned to PEB, 131 (33%) to PES, and 134 (33%) to balloon angioplasty. Follow-up angiography at 6-8 months was available for 338 (84%) patients. PEB was non-inferior to PES in terms of diameter stenosis (38·0% [SD 21·5] vs 37·4% [21·8]; difference 0·6%, one-sided 95% CI 4·9%; p non-inferiority=0·007; non-inferiority margin of 7%). Findings were consistent in per-protocol analysis (pnon-inferiority= 0·011). PEB and PES were superior to balloon angioplasty alone (54·1% [25·0]; psuperiority<0·0001 for both comparisons). Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups. Interpretation: By obviating the need for additional stent implantation, PEB could be a useful treatment for patients with restenosis after implantation of a drug-eluting stent. Funding: Deutsches Herzzentrum. © 2013 Elsevier Ltd.
Schmeer C.W.,University Hospital Jena |
Wohl S.G.,University Hospital Jena |
Wohl S.G.,Witten/Herdecke University |
Isenmann S.,HELIOS Klinikum |
Isenmann S.,Witten/Herdecke University
Cell and Tissue Research | Year: 2012
Visual impairment severely affects the quality of life of patients and their families and is also associated with a deep economic impact. The most common pathologies responsible for visual impairment and legally defined blindness in developed countries include age-related macular degeneration, glaucoma and diabetic retinopathy. These conditions share common pathophysiological features: dysfunction and loss of retinal neurons. To date, two main approaches are being taken to develop putative therapeutic strategies: neuroprotection and cell replacement. Cell replacement is a novel therapeutic approach to restore visual capabilities to the degenerated adult neural retina and represents an emerging field of regenerative neurotherapy. The discovery of a population of proliferative cells in the mammalian retina has raised the possibility of harnessing endogenous retinal stem cells to elicit retinal repair. Furthermore, the development of suitable protocols for the reprogramming of differentiated somatic cells to a pluripotent state further increases the therapeutic potential of stem-cell-based technologies for the treatment of major retinal diseases. Stem-cell transplantation in animal models has been most effectively used for the replacement of photoreceptors, although this therapeutic approach is also being used for inner retinal pathologies. In this review, we discuss recent advances in the development of cell-replacement approaches for the treatment of currently incurable degenerative retinal diseases. © 2012 Springer-Verlag.
Von Minckwitz G.,German Breast Group |
Von Minckwitz G.,Goethe University Frankfurt |
Schneeweiss A.,University of Heidelberg |
Loibl S.,German Breast Group |
And 22 more authors.
The Lancet Oncology | Year: 2014
Background: Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. Methods: Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m2 once a week) and non-pegylated liposomal doxorubicin (20 mg/m2 once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. Findings: 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. Interpretation: The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. Funding: GlaxoSmithKline, Roche, and Teva. © 2014 Elsevier Ltd.
Eggemann H.,Otto Von Guericke University of Magdeburg |
Ignatov A.,Otto Von Guericke University of Magdeburg |
Smith B.J.,Hannover Medical School |
Altmann U.,Justus Liebig University |
And 4 more authors.
Breast Cancer Research and Treatment | Year: 2013
To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient's age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer. © 2012 Springer Science+Business Media New York.
Dabritz J.,University of Munster |
Dabritz J.,The Interdisciplinary Center |
Jenke A.,Helios Klinikum |
Wirth S.,Helios Klinikum |
Foell D.,University of Munster
Journal of Pediatrics | Year: 2012
Objective: To determine whether longitudinal measurements of fecal S100A12, a fecal marker of intestinal inflammation, can identify very low birth weight infants at risk for necrotizing enterocolitis (NEC). Study design: This prospective study included 145 preterm infants with birth weight <1500 g. Meconium and stool samples (n = 843) were collected prospectively on alternate days for 4 weeks, and fecal S100A12 and calprotectin were measured by enzyme-linked immunosorbent assay. Results: Eighteen patients (12.4%) developed NEC. Gestational age and birth weight were significantly lower in the patients with NEC compared with unaffected reference infants. Fecal S100A12 levels were significantly higher in patients with severe NEC at onset of disease and also, in contrast to fecal calprotectin, at 4-10 days before onset of NEC compared with unaffected reference infants (ideal cutoff value, 65 μg/kg; sensitivity, 0.76; specificity, 0.56). Conclusions: Fecal S100A12 level may be a helpful marker for predicting disease severity and early risk assessment for subsequent development of NEC. However, the use of fecal S100A12 as a predictive biomarker for NEC in very low birth weight infants may be limited due to a high interindividual and intraindividual variability in S100A12 fecal excretion. Copyright © 2012 Mosby Inc. All rights reserved.
Klisch J.,HELIOS Klinikum |
Turk A.,Medical University of South Carolina |
Turner R.,Medical University of South Carolina |
Woo H.H.,Stony Brook University Medical Center |
Fiorella D.,Stony Brook University Medical Center
American Journal of Neuroradiology | Year: 2011
BACKGROUND AND PURPOSE: The PED is a new endoluminal construct designed to exclude aneurysms from the parent cerebrovasculature. We report the very late (>1 year) thrombosis of PED constructs in 2 patients. RESULTS: Two patients with very large fusiform basilar trunk aneurysms underwent parent artery reconstruction with the PED. Both patients were maintained on dual antiplatelet therapy throughout the first year following treatment. Follow-up conventional angiography, performed 12 months after treatment, demonstrated, in both patients, thrombosis of most of the aneurysm with minimal residual flow through the construct and into the aneurysm fundus. In response to the residual filling, clopidogrel was discontinued (aspirin therapy was maintained). Both patients presented with symptomatic acute occlusions of the PED constructs within 14 days of clopidogrel discontinuation. DISCUSSION: Patient 1 presented with constitutional symptoms that progressed to severe headache without other neurologic signs or symptoms. Occlusion of the PED construct was confirmed with conventional angiography. MR imaging demonstrated no evidence of infarction or parenchymal injury. The headaches were managed successfully with steroid therapy. Patient 2 presented with a syndrome of acute basilar occlusion with brain stem stroke. Complete occlusion was confirmed on angiography. Emergent thrombolysis with mechanical revascularization was performed successfully; however, the patient ultimately succumbed to the infarction. CONCLUSIONS: It appears that flow-diverting constructs built across large circumferential aneurysms may remain thrombogenic for much longer than conventional intracranial or peripheral bare metal stents. Constructs in these patients may remain susceptible to very late thrombosis, >1 year after implantation. These patients likely require long-term dual antiplatelet therapy (>1 year) to provide adequate prophylaxis against thrombosis. If these types of aneurysms demonstrate persistent residual filling months after PED reconstruction, operators should consider the placement of additional devices as an alternative to the discontinuation of 1 of the antiplatelet medications. Copyright © 2011 by the American Society of Neuroradiology.
Zhivov A.,University of Rostock |
Blum M.,Helios Klinikum |
Guthoff R.,University of Rostock |
Stachs O.,University of Rostock
British Journal of Ophthalmology | Year: 2010
Aim: To produce two-dimensional reconstruction maps of the subepithelial nerve plexus (SEP) in living cornea by in vivo laser scanning confocal microscopy in real time. Methods: In vivo confocal laser scanning microscopy (Heidelberg Retinal Tomograph II in conjunction with the Rostock Cornea Module) was performed on normal eyes (n=6) and eyes after laser-assisted in situ keratomileusis (LASIK) (n=4). Source data (frame rate 30 Hz) were used to create large-scale maps of the scanned area in Automatic Real Time composite mode. The algorithm aligns single live images onto the previously mapped composite image using landmark feature-based image processing. Results Real-time mapping of the SEP was performed on a large-scale area up to 3.2x3.2 mm (3072x3072 pixels) in healthy subjects and in post-LASIK patients. Two-dimensional structures of the SEP were imaged in all 10 eyes. Mapping quality as well as acquisition time were dependent on subject compliance and examiner experience. Conclusion: The described method permits real-time in vivo mapping of the SEP, thus providing the necessary basis for statistically robust conclusions concerning morphometric plexus alterations.
Klinzing S.,Friedrich - Schiller University of Jena |
Simon M.,Friedrich - Schiller University of Jena |
Reinhart K.,Friedrich - Schiller University of Jena |
Meier-Hellmann A.,Helios Klinikum |
Sakr Y.,Friedrich - Schiller University of Jena
Anesthesiology | Year: 2011
Background: The effects of moderate-dose vasopressin on gastric mucosal perfusion and its relation to global and hepatosplanchnic hemodynamic and oxygen transport variables were investigated in patients with severe sepsis. Methods: Vasopressin was administered at a dose of 0.04 IU • kg -1 • h over 4 h in 12 patients with severe sepsis who were receiving norepinephrine. During the study period, the norepinephrine infusion rate was reduced to keep mean arterial blood pressure constant. Hepatosplanchnic blood flow, oxygen delivery, and oxygen consumption (via hepatic venous catheterization using the Fick principle and continuous indocyanine green infusion technique), global hemodynamics (transpulmonary thermodilution method), and the difference between the gastric mucosal and arterial carbon dioxide tension (Pco2-gap) were measured at baseline and 4 h after the start of the vasopressin infusion. Results: The administration of 0.04 IU • kg -1 • h vasopressin over 4 h was associated with minimal changes in global hemodynamics. Heart rate decreased slightly from 99 [81-115] (median [interquartile range]) to 96 [74-109] beats/min (P = 0.016) and cardiac index from 3.7 [2.8-4.7] to 3.5 [2.7-3.6] L • min • m (P = 0.003). Global oxygen delivery index decreased significantly from 461 [375-637] to 419 [352-551] ml • min • m (P = 0.002), whereas hepatosplanchnic blood flow and oxygen uptake remained unchanged. Gastric mucosal Pco2-gap increased significantly from 13.3 [8.0-16.7] to 17.1 [10.3-28.7] mmHg (P = 0.002), suggesting that blood flow may have been redistributed away from the gut mucosa. Conclusions: Vasopressin at a dosage of 0.04 IU • kg -1 • h may impair gastric mucosal perfusion with minimal global hemodynamic effects. Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.