212 results on '"Kurek R"'
Search Results
52. Die kleine Tubargravidität - neue Möglichkeiten der laparoskopischen Diagnostik mittels Leuchtstab nach Fridrich
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Aydeniz, B., primary, Schauf, B., additional, Endress, A., additional, Kurek, R., additional, Fridrich, M., additional, and Wallwiener, D., additional
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- 2003
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53. Detection of thyroid peroxidase mRNA in peripheral blood of patients with malignant and benign thyroid diseases
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Roddiger, SJ, primary, Bojunga, J, additional, Klee, V, additional, Stanisch, M, additional, Renneberg, H, additional, Lindhorst, E, additional, Usadel, KH, additional, Kusterer, K, additional, Schumm-Draeger, PM, additional, and Kurek, R, additional
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- 2002
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54. A multicenter survey of complications associated with 21 676 operative hysteroscopies
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Aydeniz, B, primary, Gruber, I.V, additional, Schauf, B, additional, Kurek, R, additional, Meyer, A, additional, and Wallwiener, D, additional
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- 2002
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55. Lebensqualität beim Prostatakarzinom
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Bestmann, B., primary, Siebmann, J. U., additional, Kurek, R., additional, and Küchler, T., additional
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- 2002
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56. Die operative Laparoskopie: Weiterentwicklung und Komplikationsraten
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Aydeniz, B., primary, Schauf, B., additional, Kurek, R., additional, Schiebeler, A., additional, Riedinger, K., additional, Tepper-Wessels, K., additional, Messrogli, H., additional, Bastert, G., additional, and Wallwiener, D., additional
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- 2002
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57. Laparoskopische Gewebepräparation mittels endoskopischer, monopolarer, niederenergetischer, elektrochirurgischer Hochfrequenz-Nadelelektrode (MNNE) - Indikationsspektrum und Komplikationen
- Author
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Aydeniz, B., primary, Schauf, B., additional, Kurek, R., additional, Tepper-Wessels, K., additional, Schiebeler, A., additional, Söder, R., additional, Bastert, G., additional, Messrogli, H., additional, and Wallwiener, D., additional
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- 2001
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58. Herbal mixture PC-SPES stimulates proliferation of malignant and benign prostate cell lines
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Roddiger, S.J., primary, Albrecht, M., additional, Gutschank, W.M., additional, Aumuller, G., additional, Kurek, R., additional, Martin, T., additional, and Zamboglou, N., additional
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- 2001
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59. MULTIFUNKTIONALITÄT UND SYSTEMINTEGRATION IN DER MEDIZIN
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Endreß, A., primary, Wallwiener, D., additional, and Kurek, R., additional
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- 2001
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60. DIGITALE BILDDOKUMENTATION UND SYSTEMVERNETZUNG IM OP – ERSTE ERFAHRUNGEN MIT DEM AIDA/SCB-SYSTEM –
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Endreß, A., primary, Kurek, R., additional, and Wallwiener, D., additional
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- 2001
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61. 181 New 3D interstitial HDR brachytherapy technique combined with 3D external beam radiotherapy and androgen deprivation for localized prostate cancer: Preliminary results
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Martin, T., primary, Hey-Koch, S., additional, Strassmann, G., additional, Kolotas, C., additional, Rogge, B., additional, Heyd, R., additional, Dannenberg, T., additional, Kurek, R., additional, Baltas, D., additional, Tunn, U.W., additional, and Zamboglou, N., additional
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- 2000
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62. 146 Dose-volume histograms (DVH) and a conformal index (COIN) to evaluate implant quality of a new hdr brachytherapy technique for prostate cancer: Results in 616 implants
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Hey-Koch, S., primary, Martin, T., additional, Baltas, D., additional, Ioannidis, G., additional, Rogge, B., additional, Strassmann, G., additional, Kolotas, C., additional, Kurek, R., additional, Tunn, U.W., additional, and Zamboglou, N., additional
- Published
- 2000
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63. Intermittent Complete Androgen Blockade in PSA Relapse after Radical Prostatectomy and Incidental Prostate Cancer
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Kurek, R., primary, Renneberg, H., additional, Lübben, G., additional, Kienle, E., additional, and Tunn, UlfW., additional
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- 1999
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64. Radiation enhancement of Gemcitabine® In three human cervical cancer cell lines
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Wallwiener, D., primary, Kurek, R., additional, Angioli, R., additional, Janicek, M., additional, Penalver, M., additional, Blatter, J., additional, Eble, E., additional, Diel, I.J., additional, Bastert, G., additional, and Sevin, B.U., additional
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- 1997
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65. In vitro phototoxicity of a new phthalocyanine-immunoconjugate for use in photodynamic therapy
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Martin, Michael, primary, Kaul, Sepp, additional, Drechsler, Ute, additional, Geyer, M., additional, Kurek, R., additional, Hanack, Michael, additional, Seeger, Stefan, additional, Wallwiener, D., additional, and Wolfrum, Juergen M., additional
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- 1996
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66. Treatment of the Twin-Twin Transfusion Syndrome: Initial Experience Using Laser-Induced Interstitial Thermotherapy
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Sohn, C., primary, Wallwiener, D., additional, Kurek, R., additional, Hahn, U., additional, Schiesser, M., additional, and Bastert, G., additional
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- 1996
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67. Cutting characteristics of the Nd: YAG contact technique using a laser with tissue effect control, conical fibres and a normal bare fibre: First results of a physical, morphometrical and clinical study
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Kurek, R., primary, Hahn, U., additional, Martschoke, G., additional, and Wallwiener, D., additional
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- 1996
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68. In vitro phototoxicity of a new phthalocyanine-immunoconjugate for use in photodynamic therapy.
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Martin, Michael, Kaul, Sepp, Drechsler, Ute, Geyer, M., Kurek, R., Hanack, Michael, Seeger, Stefan, Wallwiener, D., and Wolfrum, Juergen M.
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- 1996
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69. Long-term effects on the intelligence of children treated for acute lymphoblastic leukemia.
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Kolotas, Christos, Daniel, Maria, Demetriou, Lucia, Martin, Thomas, Kurek, Ralf, Tonus, Caroline, Göbel, Ulrich, Schnabel, Thomas, Zamboglou, Nikolaos, Kolotas, C, Daniel, M, Demetriou, L, Martin, T, Kurek, R, Tonus, C, Göbel, U, Schnabel, T, and Zamboglou, N
- Subjects
INTELLIGENCE testing in children ,LYMPHOBLASTIC leukemia - Abstract
The purpose of this study was to investigate whether the intelligence quotient (IQ) in children treated for leukemia decreases in the years following whole brain irradiation. Twenty-seven leukemic children were assessed following a mean time lapse between radiotherapy and IQ measurement of 9 years. The IQ test used was the Hamburg Weschsler Intelligence Test for Adults. The IQ results did not differ significantly, p > 0.05, from the IQs of the general population. It was found that age and dose were not predictors of a decrease in IQ. The only predictor was time lapse between irradiation and IQ measurement, which we found to be indicative of an IQ decrease even after 9 years. Time lapse between irradiation is a useful predictor of IQ. [ABSTRACT FROM AUTHOR]
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- 2001
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70. Molecular detection of thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease by RT-PCR.
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Bojunga, J, Röddiger, S, Stanisch, M, Kusterer, K, Kurek, R, Renneberg, H, Adams, S, Lindhorst, E, Usadel, K H, and Schumm-Draeger, P M
- Subjects
THYROGLOBULIN ,MESSENGER RNA ,THYROID diseases - Abstract
The sensitive detection of circulating tumour cells in patients with differentiated thyroid cancer may precede the detection of relapse by other diagnostic studies - such as serum thyroglobulin - and thus may have important therapeutic and prognostic implications. We performed reverse transcription-polymerase chain reaction (RT-PCR) on blood samples from patients diagnosed with thyroid disease using two different RT-PCR sensitivities. Additionally, tissue specificity of TG mRNA-expression was determined using RNA extracts from 27 different human tissues. The lower limit of detection was 50-100 TG mRNA producing cells/ml blood using a 'normal' RT-PCR sensitivity and 10-20 cells/ml blood using a 'high' sensitivity. With the normal sensitivity TG mRNA was detected in 9/13 patients with thyroid cancer and metastasis, 63/137 patients with a history of thyroid cancer and no metastasis, 21/85 with non-malignant thyroid disease and 9/50 controls. With the high sensitivity TG mRNA was detected in 11/13 patients with thyroid cancer and metastasis, 111/137 patients with a history of thyroid cancer and no metastasis, 61/85 with non-malignant thyroid disease and 41/50 controls. Interestingly, using the normal RT-PCR sensitivity TG mRNA transcripts are specific for thyroid tissue and detectable in the peripheral blood of controls and patients with thyroid disease, which correlates with a diagnosis of metastasized thyroid cancer. However, with a high RT-PCR sensitivity, TG mRNA expression was found not to be specific for thyroid tissue and was not correlated with a diagnosis of thyroid cancer in patients. As a consequence, to date TG mRNA detected by RT-PCR in the peripheral blood cannot be recommended as a tumour marker superior to TG serum-level. [ABSTRACT FROM AUTHOR]
- Published
- 2000
71. New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D planning after transrectal implantation
- Author
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Martin, T., Kolotas, C., Dannenberg, T., Strassmann, G., Vogt, H.-G., Heyd, R., Rogge, B., Baltas, D., Kurek, R., and Tunn, U.
- Published
- 1999
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72. Changes of serum HER2 status during clinical course of metastatic breast cancer patients
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Tanja Fehm, Jäger W, Kraemer S, Sohn C, Solomayer-Meyberg G, Ef, Solomayer, Kurek R, Wallwiener D, and Gebauer G
- Subjects
Receptor, ErbB-2 ,Humans ,Breast Neoplasms ,Female ,Neoplasm Metastasis ,Retrospective Studies - Abstract
Serum HER2 testing allows the determination of the real-time HER2 status of breast cancer patients. The aim of this investigation was to study (i) whether changes of serum HER2 status occur during the clinical course of breast cancer and (ii) to evaluate the prognostic significance of serum HER2 status, at the time of first diagnosis of primary breast cancer and at the onset of metastatic disease, for survival after relapse (SAR).HER2 serum levels were retrospectively measured in 152 breast cancer patients at the time of first diagnosis of breast cancer and at the onset of metastatic disease by enzyme immunoassay.Twenty-seven out of 152 (18%) patients had elevated HER2 serum levels at the time of first diagnosis of breast cancer. In contrast, 56 out of 152 (37%) patients showed elevated serum HER2 levels when metastases were diagnosed. A change of serum HER2 status during clinical course was observed in 43 out of 152 (28%) patients. Serum HER2 status at the time of first diagnosis of breast cancer had no impact on survival after relapse (SAR) (p = 0.4). However, the median SAR for serum HER2-positive patients at the onset of metastatic disease was significantly shorter (8 months, 95% CI: 3-12) compared to patients serum HER2-negative at this time (18 months, 95% CI: 14-22) (p0.01).Serum HER2 status can change during the course of disease. Therefore, the serum HER2 status should be re-evaluated at the time of diagnosis of metastatic disease to optimize treatment decisions.
73. Influence of the FeS2 content in zinc concentrates on the ZnS oxidation and the reduction of zinc from sintered zinc and lead.
- Author
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Karwan T., Kurek R., Malinowski C., Karwan T., Kurek R., and Malinowski C.
- Abstract
Pyrite was found, by thermogravimetric investigations, to have a favourable influence on the oxidation rate of zinc sulphide and it is proposed that the mineralogical form of ferric sulphides be taken into account when evaluating zinc concentrate quality, as well as chemical composition. Tests on the reduction of zinc from sintered zinc and lead, directed to the ISP process, found that iron in zinc concentrates had a favourable effect; and iron in lead concentrates a negative effect on zinc production. The results also showed the CaO/SiO2 ratio to have a positive correlation with the production of zinc compounds from sintered lead and zinc., Pyrite was found, by thermogravimetric investigations, to have a favourable influence on the oxidation rate of zinc sulphide and it is proposed that the mineralogical form of ferric sulphides be taken into account when evaluating zinc concentrate quality, as well as chemical composition. Tests on the reduction of zinc from sintered zinc and lead, directed to the ISP process, found that iron in zinc concentrates had a favourable effect; and iron in lead concentrates a negative effect on zinc production. The results also showed the CaO/SiO2 ratio to have a positive correlation with the production of zinc compounds from sintered lead and zinc.
74. Radiation enhancement of Gemcitabine®In three human cervical cancer cell lines
- Author
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Wallwiener, D., Kurek, R., Angioli, R., Janicek, M., Penalver, M., Blatter, J., Eble, E., Diel, I.J., Bastert, G., and Sevin, B.U.
- Published
- 1997
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75. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial
- Author
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Nick, Thatcher, Fred R, Hirsch, Alexander V, Luft, Aleksandra, Szczesna, Tudor E, Ciuleanu, Mircea, Dediu, Rodryg, Ramlau, Rinat K, Galiulin, Beatrix, Bálint, György, Losonczy, Andrzej, Kazarnowicz, Keunchil, Park, Christian, Schumann, Martin, Reck, Henrik, Depenbrock, Shivani, Nanda, Anamarija, Kruljac-Letunic, Raffael, Kurek, Luis, Paz-Ares, Mark A, Socinski, Alexander, Spira, Thatcher, N, Hirsch, F, Luft, A, Szczesna, A, Ciuleanu, T, Dediu, M, Ramlau, R, Galiulin, R, Bálint, B, Losonczy, G, Kazarnowicz, A, Park, K, Schumann, C, Reck, M, Depenbrock, H, Nanda, S, Kruljac-Letunic, A, Kurek, R, Paz-Ares, L, Socinski, M, Bidoli, P, Eberhardt, Wilfried (Beitragende*r), and Wilke, Hansjochen (Beitragende*r)
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Maximum Tolerated Dose ,medicine.medical_treatment ,Medizin ,Phases of clinical research ,Kaplan-Meier Estimate ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,Disease-Free Survival ,Drug Administration Schedule ,Sex Factors ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm Invasiveness ,Lung cancer ,Necitumumab ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Aged, 80 and over ,Cisplatin ,Chemotherapy ,Dose-Response Relationship, Drug ,Performance status ,Cetuximab ,business.industry ,Age Factors ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Survival Analysis ,Gemcitabine ,Treatment Outcome ,Carcinoma, Squamous Cell ,Female ,Gentamicins ,business ,medicine.drug - Abstract
Background: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash-a class effect of EGFR antibodies-that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [
- Published
- 2015
76. [Transanal Endoscopic Microsurgery (TEM) is a surgical option to preserve fecal continence in selected low rectal cancers].
- Author
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Schaffitzel KM, Zu Putlitz S, Gölder SK, Kurek R, and Siech M
- Subjects
- Humans, Female, Male, Aged, Middle Aged, Retrospective Studies, Fecal Incontinence prevention & control, Fecal Incontinence etiology, Postoperative Complications epidemiology, Postoperative Complications prevention & control, Neoplasm Recurrence, Local prevention & control, Aged, 80 and over, Adenoma surgery, Adult, Treatment Outcome, Rectal Neoplasms surgery, Rectal Neoplasms pathology, Transanal Endoscopic Microsurgery methods
- Abstract
Introduction: Despite its existence for more than 40 years, the TEM method has not become widespread. The main reasons are the high acquisition costs, the sophisticated technology and alternative procedures (especially radical resection procedures), which provide greater oncological safety. However, avoiding major abdominal surgery with the creation of a stoma and higher complication rates can outweigh the higher risk of recurrence for some patients. We examined the results using V-TEM with reduced acquisition costs in the resection of adenomas and carcinomas and discussed its importance by literature ., Method: From 2003 to 2019, 154 patients with 170 findings were operated by V-TEM technology. Data on the operation and follow-up were collected and analyzed retrospectively., Results: The median age was 67 years, 89 patients were male and 65 female. V-TEM was performed on 79 carcinomas, 77 adenomas and 14 other findings. The complication rate was 21.2 %. R0 resection was achieved in 78.8 %. The adenoma recurrence rate was 7.3 %, the overall recurrence rate for carcinomas 11.9 %, local recurrences were observed in 6.8 %. The disease-specific survival is 100 % at 5 years and 94.2 % at ten years., Discussion: The successful use of TEM in adenomas and early carcinomas is undisputed. When treating carcinomas from a T1 high risk stage using TEM, recurrence rates higher than 10 % must be expected. Better results can be achieved with radical procedures, this is why they are considered the therapy of choice in these cases. However, there are no differences in terms of survival rates and TEM offers proven better postoperative quality of life. In particular, the combination of neoadjuvant procedures with TEM delivered promising results in more advanced stages. Further studies on TEM and the possibility of lower acquisition costs through modification to V-TEM could make the method more popular in the future., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)
- Published
- 2024
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77. Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.
- Author
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Hendrickson BA, Wang W, Ball G, Bennett D, Bhattacharyya A, Fries M, Kuebler J, Kurek R, McShea C, and Tremmel L
- Subjects
- United States, Drug Development
- Abstract
The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.
- Published
- 2021
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78. Global Regulatory Landscape for Aggregate Safety Assessments: Recent Developments and Future Directions.
- Author
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Ball G, Kurek R, Hendrickson BA, Buchanan J, Wang WW, Duke SP, Bhattacharyya A, Li M, O'Brien D, Weigel J, Wang W, Jiang Q, Ahmad F, Seltzer JH, Herrero-Martinez E, and Tremmel L
- Subjects
- Humans, Risk Assessment, Product Surveillance, Postmarketing
- Abstract
Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments. We will show how these trends lead to opportunities for closer interdisciplinary collaboration, for bridging the gap between preand postmarketing surveillance, and for a more proactive determination of patient populations with a positive benefit-risk profile for product use. We will conclude by pointing to ongoing and future work that seeks to provide specific solutions for ongoing aggregate safety evaluation.
- Published
- 2020
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79. Venous thromboembolism with EGFR monoclonal antibody necitumumab in stage IV non-small cell lung cancer: A retrospective cohort analysis.
- Author
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Young K, Paz-Ares L, Thatcher N, Spigel DR, Shahidi J, Soldatenkova V, Grau G, Kurek R, and Shepherd FA
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Carcinoma, Non-Small-Cell Lung pathology, Cohort Studies, Female, Humans, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Retrospective Studies, Treatment Outcome, Venous Thromboembolism pathology, Antibodies, Monoclonal adverse effects, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Non-Small-Cell Lung complications, Lung Neoplasms complications, Venous Thromboembolism chemically induced
- Abstract
Introduction: Metastatic non-small cell lung cancer (NSCLC) is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance for patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC., Methods: Four trials of 1st-line treatment for Stage IV NSCLC were analyzed: two randomized phase 3 studies of cisplatin/gemcitabine ±neci in squamous NSCLC (SQUIRE: N = 1079) and cisplatin/pemetrexed ±neci in non-squamous NSCLC (INSPIRE: N = 616); JFCL (N = 161), a randomized phase 2 trial of carboplatin/paclitaxel ±neci in squamous NSCLC; and JFCK (N = 61), a single arm phase 2 trial of cisplatin/gemcitabine +neci in squamous NSCLC. A Cox proportional hazards model with VTE as a time-dependent covariate was used for overall survival (OS) analyses., Results: Neci + chemo was associated with an increased risk of VTE (Relative Risk [RR]: 1.579; 95% CI: 1.155-2.158). History of VTE (RR: 1.899; 95% CI: 1.142-3.156) and prior cardiac/cardiovascular events (RR: 1.514; 95% CI: 1.102-2.082) were associated with increased risk of VTE. Decreased VTE risk was seen with: male sex (RR: 0.696; 95% CI: 0.502-0.964), eastern European geographic region (RR: 0.387; 95% CI: 0.267-0.562) and squamous cell pathology (RR: 0.653; 95% CI: 0.483-0.883). VTE occurrence showed no association with OS (HR: 1.121; 95% CI: 0.930-1.351)., Conclusion: Our data suggest that certain patient characteristics such as prior history of VTE and non-squamous histology might be associated with an increased risk of on-treatment VTE in NSCLC, although in this study, overall survival was not affected. Further studies to develop measures for identifying high-risk patients are needed to inform treatment decisions as well as VTE management and prophylaxis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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80. EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study.
- Author
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Genova C, Socinski MA, Hozak RR, Mi G, Kurek R, Shahidi J, Paz-Ares L, Thatcher N, Rivard CJ, Varella-Garcia M, and Hirsch FR
- Subjects
- Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological pharmacology, Carcinoma, Squamous Cell pathology, Female, Humans, Lung Neoplasms pathology, Male, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Gene Dosage genetics, In Situ Hybridization, Fluorescence methods, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Introduction: Necitumumab is a monoclonal antibody targeting EGFR. In the SQUIRE trial, the addition of necitumumab to chemotherapy for squamous cell lung cancer significantly improved overall survival (OS) (hazard ratio [HR] = 0.84); in a post hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend toward improved OS (HR = 0.70) and progression-free survival (PFS) (HR = 0.71) with the addition of necitumumab. We present the analysis of granular EGFR FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification, as both were included in the FISH-positive category., Methods: Available specimens from SQUIRE underwent FISH analysis in a central laboratory, and each sample was evaluated by using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed., Results: Samples were available for 557 of 1093 patients; 208 patients (37.3%) were FISH-positive, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of necitumumab resulted in a statistically significant increase in PFS (6.08 versus 5.13 months [p = 0.044]) and nonstatistically significant increase in OS (12.6 versus 9.5 months [p = 0.133]); among patients with gene amplification, the addition of necitumumab did not significantly improve PFS (7.4 versus 5.6 months; [p = 0.334]) but did improve OS (14.8 versus 7.6 months; [p = 0.033])., Conclusions: EGFR copy number gain by FISH might have a role as a predictive biomarker for necitumumab in squamous cell lung cancer. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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81. Phase I study of the second-generation, recombinant, human EGFR antibody necitumumab in Japanese patients with advanced solid tumors.
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Tamura Y, Nokihara H, Honda K, Tanabe Y, Asahina H, Yamada Y, Enatsu S, Kurek R, Yamamoto N, and Tamura T
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized, Asian People, Cohort Studies, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Treatment Outcome, Antibodies, Monoclonal therapeutic use, ErbB Receptors immunology, Neoplasms drug therapy
- Abstract
Purpose: To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available., Methods: In this phase I study, patients aged ≥20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0-1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed., Results: Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1-4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations >40 µg/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients., Conclusions: Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle.
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- 2016
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82. Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors.
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Smith DC, Powderly J, Lee JJ, Shepard DR, Wallin J, Chaudhary A, Chao GY, Ng WT, Mitchell MI, Grau G, Kurek R, and LoRusso P
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antineoplastic Agents adverse effects, Female, Humans, Male, Middle Aged, Neoplasms pathology, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents administration & dosage, Electrocardiography, Long QT Syndrome chemically induced, Neoplasms drug therapy
- Abstract
Purpose: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors., Methods: Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations., Results: Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration-QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation., Conclusions: The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.
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- 2016
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83. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.
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Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda S, Kruljac-Letunic A, Kurek R, Paz-Ares L, and Socinski MA
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, Cisplatin administration & dosage, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Gentamicins administration & dosage, Humans, Kaplan-Meier Estimate, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Staging, Proportional Hazards Models, Risk Assessment, Sex Factors, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer., Methods: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058., Findings: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations., Interpretation: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease., Funding: Eli Lilly and Company., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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84. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.
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Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, and Socinski MA
- Subjects
- Aged, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brazil, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin administration & dosage, Disease Progression, Disease-Free Survival, Drug Administration Schedule, Europe, Female, Glutamates administration & dosage, Guanine administration & dosage, Guanine analogs & derivatives, Humans, Kaplan-Meier Estimate, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Pemetrexed, Risk Factors, Time Factors, Treatment Outcome, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC)., Methods: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111., Findings: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group., Interpretation: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin., Funding: Eli Lilly and Company., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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85. KLF6 loss of function in human prostate cancer progression is implicated in resistance to androgen deprivation.
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Liu X, Gomez-Pinillos A, Loder C, Carrillo-de Santa Pau E, Qiao R, Unger PD, Kurek R, Oddoux C, Melamed J, Gallagher RE, Mandeli J, and Ferrari AC
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- Alternative Splicing genetics, Cell Line, Tumor, Cell Proliferation, Cell Survival, DNA Mutational Analysis, Exons genetics, Humans, Kruppel-Like Factor 6, Male, Transcription, Genetic, Transcriptional Activation genetics, Androgens deficiency, Disease Progression, Kruppel-Like Transcription Factors genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Proto-Oncogene Proteins genetics
- Abstract
Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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86. Optimal treatment for patients with ectopic pregnancies and a history of fertility-reducing factors.
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Becker S, Solomayer E, Hornung R, Kurek R, Banys M, Aydeniz B, Franz H, Wallwiener D, and Fehm T
- Subjects
- Adult, Female, Fertility, Follow-Up Studies, Humans, Pregnancy, Prospective Studies, Salpingectomy, Treatment Outcome, Young Adult, Infertility, Female epidemiology, Rupture, Spontaneous surgery
- Abstract
Purpose: With most ectopic pregnancy (EP) cases now diagnosed and treated early, a major concern has become future reproductive outcome. The aim of this study was to evaluate long-term reproductive outcome after salpingotomy versus salpingectomy in patients with and without additional fertility-reducing factors., Methods: As part of a prospective follow-up study, 261 patients underwent laparoscopic management of EP at our institution. History was taken specifically looking at preexisting risk factors for reduced fertility. Patients were then followed with regard to future reproductive events., Results: Of 261 patients, 196 (75%) reported a subsequent desire for pregnancy. 145 patients had undergone salpingotomy and 51 salpingectomy. In patients without prior history of fertility-reducing factors, the subsequent intrauterine pregnancy rates were >90% for both salpingotomy and salpingectomy groups irrespective of the surgical approach. In patients with preexisting fertility-reducing factors, postoperative intrauterine pregnancy rates were 75% in the salpingotomy group, but only 40% in the salpingectomy group (p < 0.05), showing maximal effect for conservative surgery., Conclusion: Laparoscopic salpingotomy is of particular benefit for patients with additional fertility-reducing factors desirous of future pregnancy. Reproductive outcome is excellent in patients without such risk factor, irrespective of the surgical approach.
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- 2011
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87. Pemetrexed with or without matuzumab as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer.
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Schiller JH, von Pawel J, Schütt P, Ansari RH, Thomas M, Saleh M, McCroskey RD, Pfeifer W, Marsland TA, Kloecker GH, Sebastian M, Pirker R, Kurek R, Beadman C, and Socinski MA
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung psychology, ErbB Receptors antagonists & inhibitors, Female, Glutamates administration & dosage, Glutamates adverse effects, Guanine administration & dosage, Guanine adverse effects, Guanine therapeutic use, Humans, Lung Neoplasms pathology, Lung Neoplasms psychology, Male, Middle Aged, Neoplasm Staging, Pemetrexed, Quality of Life, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Glutamates therapeutic use, Guanine analogs & derivatives, Lung Neoplasms drug therapy
- Abstract
Introduction: This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer., Methods: Patients received pemetrexed 500 mg/m every 3 weeks either alone (n = 50) or in combination with matuzumab at either 800 mg weekly (n = 51) or 1600 mg every 3 weeks (n = 47). The primary end point was objective response, as assessed by an independent review committee., Results: Tumor EGFR expression was detected in 87% of randomized patients. The objective response rate for the pooled matuzumab-treated arms was 11% compared with 5% for pemetrexed alone (p = 0.332). Apart from one patient in the pemetrexed alone group, all responses occurred in patients whose tumors expressed EGFR. The objective response rate for patients receiving weekly matuzumab was 16% compared with 2% for those receiving matuzumab every 3 weeks. There was also a trend for improved overall survival in patients receiving matuzumab weekly versus every 3 weeks (12.4 months versus 5.9 months, respectively, versus 7.9 months for pemetrexed alone). The combination of pemetrexed and matuzumab demonstrated an acceptable safety profile, with the most common grade 3/4 adverse event being neutropenia., Conclusion: Although the analysis on the pooled matuzumab-treated arms did not demonstrate a statistically significant improvement in objective response for the addition of matuzumab to pemetrexed compared with pemetrexed alone, the trends for improvement in objective response and overall survival for pemetrexed plus weekly matuzumab compared with pemetrexed alone warrant confirmation in additional clinical trials.
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- 2010
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88. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis.
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Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, and Steeg PS
- Subjects
- Adenosine Triphosphate metabolism, Brain Neoplasms genetics, Brain Neoplasms surgery, Breast Neoplasms genetics, Cell Line, Tumor, Cell Survival physiology, Female, Gene Knockdown Techniques, Glucose metabolism, Hexokinase genetics, Humans, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Reproducibility of Results, Up-Regulation, Brain Neoplasms enzymology, Brain Neoplasms secondary, Breast Neoplasms enzymology, Breast Neoplasms pathology, Hexokinase biosynthesis
- Abstract
Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMgamma3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target.
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- 2009
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89. Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer.
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Schittenhelm MM, Kollmannsberger C, Oechsle K, Harlow A, Morich J, Honecker F, Kurek R, Störkel S, Kanz L, Corless CL, Wong KK, Bokemeyer C, and Heinrich MC
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized, Biomarkers, Tumor analysis, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Cohort Studies, DNA Mutational Analysis, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, erbB-1, Humans, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras), Retrospective Studies, ras Proteins genetics, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Paclitaxel administration & dosage
- Abstract
Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non-small cell lung cancer (NSCLC) that express EGFR. We recently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matuzumab displays potent antitumor activity in some patients, not all patients respond well to treatment. Whether dysregulation of EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown. We sought to determine molecular predictive factors for therapy response in a phase I/II study patient cohort treated with matuzumab+/-paclitaxel. Twenty-three cases [including one complete response (CR), three partial responses (PR), 10 stable diseases (SD)] were screened using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), PCR/sequencing and denaturing wave high performance liquid chromatography (D-HPLC) for expression, amplification, and mutation status of EGFR and downstream signaling pathways. All patients with PR or CR displayed an either high overall or single-cell EGFR expression in the majority of cells. In addition, all of the moderate responders, who achieved SD after at least two cycles of therapy, showed diffuse EGFR expression rates and/or strong single-cell EGFR expression. In contrast, 44% of the nonresponders showed low overall or single-cell EGFR expression levels. No low-expressing EGFR cases were present within the responder group. In addition, among patients with a gain-of-function mutation in KRAS primary therapy failure and/or short responses to therapy were observed. Our data suggest that EGFR expression and KRAS mutation status is predictive for clinical response to matuzumab +/- paclitaxel in patients with advanced NSCLC.
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- 2009
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90. [Toxoplasma gondii, an unusual organism with the human as "intermediate host"].
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Kurek R, Vollmar P, and Scheid PL
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- Animals, Brain parasitology, Cats, Dopamine metabolism, Female, Humans, Infant, Newborn, Mice, Pregnancy, Rats, Toxoplasmosis parasitology, Toxoplasmosis transmission, Toxoplasmosis, Congenital nursing, Toxoplasmosis, Congenital parasitology, Virulence, Host-Parasite Interactions physiology, Toxoplasma pathogenicity, Toxoplasmosis nursing
- Published
- 2008
91. Loss of Drop1 expression already at early tumor stages in a wide range of human carcinomas.
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Marmé A, Zimmermann HP, Moldenhauer G, Schorpp-Kistner M, Müller C, Keberlein O, Giersch A, Kretschmer J, Seib B, Spiess E, Hunziker A, Merchán F, Möller P, Hahn U, Kurek R, Marmé F, Bastert G, Wallwiener D, and Ponstingl H
- Subjects
- Breast Neoplasms genetics, Cell Line, Tumor, Cytoskeletal Proteins, Exons, Female, Humans, Neoplasm Staging, Neoplasms pathology, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms genetics, RNA, Messenger analysis, Two-Hybrid System Techniques, Gene Expression Regulation, Neoplastic, Neoplasms genetics, Nerve Tissue Proteins genetics, Nuclear Proteins genetics
- Abstract
In a study on gene deregulation in ovarian carcinoma we found a mRNA coding for a 350 kDa protein, Drop1, to be downregulated 20- to 180-fold in the majority of ovarian and mammary carcinomas. The mRNA is encoded by a set of exons in the 5' region of the SYNE1 gene. Immunohistochemical staining for Drop1 protein by a specific monoclonal antibody corresponds to the pattern seen for the mRNA. cDNA arrays of matched pairs of tumor and normal tissue and in situ hybridizations confirmed the drastic loss of Drop1 mRNA as a common feature in uterus, cervix, kidney, lung, thyroid and pancreas carcinomas, already at early tumor stages and in all metastases. Two-hybrid studies suggest a role of this deficiency in the malignant progression of epithelial tumors., ((c) 2008 Wiley-Liss, Inc.)
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- 2008
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92. Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex.
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Wang LG, Johnson EM, Kinoshita Y, Babb JS, Buckley MT, Liebes LF, Melamed J, Liu XM, Kurek R, Ossowski L, and Ferrari AC
- Subjects
- 5' Untranslated Regions genetics, Cell Line, Tumor, DNA Primers, DNA-Binding Proteins metabolism, Disease Progression, Genes, Reporter, Humans, Immunohistochemistry, Luciferases genetics, Male, Oligonucleotide Array Sequence Analysis, Repressor Proteins genetics, Transcription Factors metabolism, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics, Receptors, Androgen genetics, Transcription Factors deficiency, Transcription Factors genetics
- Abstract
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC.
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- 2008
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93. Breast cancer proteomics reveals correlation between estrogen receptor status and differential phosphorylation of PGRMC1.
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Neubauer H, Clare SE, Wozny W, Schwall GP, Poznanovic S, Stegmann W, Vogel U, Sotlar K, Wallwiener D, Kurek R, Fehm T, and Cahill MA
- Subjects
- Amino Acid Substitution, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular pathology, Cell Line, Tumor, Electrophoresis, Gel, Two-Dimensional, Estrogens, Female, Humans, Membrane Proteins genetics, Neoplasm Proteins genetics, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Phosphorylation, Phosphoserine metabolism, Protein Isoforms metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptors, Progesterone genetics, Recombinant Fusion Proteins metabolism, Wound Healing genetics, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast metabolism, Carcinoma, Intraductal, Noninfiltrating metabolism, Carcinoma, Lobular metabolism, Estrogen Receptor alpha metabolism, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Protein Processing, Post-Translational, Proteomics, Receptors, Progesterone metabolism
- Abstract
Introduction: Breast tumors lacking the estrogen receptor-alpha (ER-alpha) have increased incidence of resistance to therapy and poorer clinical prognosis., Methods: Whole tissue sections from 16 cryopreserved breast cancer tumors that were either positive or negative for the ER (eight ER positive and eight ER negative) were differentially analyzed by multiplex imaging of two-dimensional PAGE gels using 54 cm isoelectric focusing. Differentially detected spots of Progesterone Receptor Membrane Component 1 (PGRMC1) were shown to differ in phosphorylation status by differential two dimensional polyacrylamide gel electrophoresis of phosphatase-treated tumor proteins. Site directed mutagenesis was used to create putative phosphorylation site point mutants in PGRMC1. Stable transfectants of these mutants in MCF7 cells were assayed for their survival after oxidative stress, and for AKT kinase phosphorylation. Immune fluorescence using anti-PGRMC1 monoclonal antibody 5G7 was performed on breast cancer tissue microarrays., Results: Proteins significantly differentially abundant between estrogen receptor negative and estrogen receptor positive tumors at the 0.1% level were consistent with published profiles, suggesting an altered keratin pool, and increased inflammation and wound responses in estrogen receptor negative tumors. Two of three spots of PGRMC1 were more abundant in estrogen receptor negative tumors. Phosphatase treatment of breast tumor proteins indicated that the PGRMC1 isoforms differed in their phosphorylation status. Simultaneous mutation of PGRMC1 serine-56 and serine-180 [corrected] fully abrogated the sensitivity of stably transfected MCF7 breast cancer cells to peroxide-induced cell death. Immune fluorescence revealed that PGRMC1 was primarily expressed in ER-negative basal epithelial cells of mammary ductules. Even in advanced tumors, high levels of ER or PGRMC1 were almost mutually exclusive in individual cells. In five out of five examined ductal in situ breast cancers of comedo type, PGRMC1 was expressed in glucose transporter 1 negative or positive poorly oxygenated cells surrounding the necrotic core, surrounded by a more distal halo of ER-positive cells., Conclusions: PGRMC1 phosphorylation may be involved in the clinical differences that underpin breast tumors of differing ER status.
- Published
- 2008
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94. Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain.
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Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM, Kurek R, Vega-Valle E, Feigenbaum L, Halverson D, Vortmeyer AO, Steinberg SM, Aldape K, and Steeg PS
- Subjects
- Animals, Brain Neoplasms genetics, Breast Neoplasms genetics, Cell Adhesion physiology, Cell Line, Tumor, Female, Humans, Mice, Mice, Inbred BALB C, Neoplasm Transplantation, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptor, ErbB-2 genetics, Transfection, Transplantation, Heterologous, Brain Neoplasms enzymology, Brain Neoplasms secondary, Breast Neoplasms enzymology, Breast Neoplasms pathology, Receptor, ErbB-2 biosynthesis
- Abstract
Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2-amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2-overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 microm(2); P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system.
- Published
- 2007
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95. Proteomic expression profiling of breast cancer.
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Neubauer H, Fehm T, Schütz C, Speer R, Solomayer E, Schrattenholz A, Cahill MA, and Kurek R
- Subjects
- Female, Genomics, Humans, Protein Array Analysis, Breast Neoplasms metabolism, Neoplasm Proteins analysis, Proteomics methods
- Abstract
Breast cancer is one of the most common cancers observed in women in industrialized Western countries. The development of novel diagnostic methods and the application of modern systemic therapies have significantly optimized early detection and therapy of breast cancer. However, many patients are currently overtreated. Traditionally, tumours have been categorized on the basis of histopathological criteria. However, staining pattern and intensity of cancer cells are not sufficient to reflect the molecular events driving tumour development and progression. Therefore, new genomic, transcriptomic and proteomic techniques are applied to clinical samples aiming to identify new targets for a therapy tailored for an individual patient. After an introduction to common genomic and transcriptomic profiling technologies and their relevance for clinical use, we will focus on analytical and preanalytical applications for the identification of new therapeutic targets by protein profiling, with a special emphasis on two-dimensional gel-technologies (2D-PAGE), particularly as they apply to the study of breast cancer.
- Published
- 2007
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96. Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment.
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Ferrari AC, Stone NN, Kurek R, Mulligan E, McGregor R, Stock R, Unger P, Tunn U, Kaisary A, Droller M, Hall S, Renneberg H, Livak KJ, Gallagher RE, and Mandeli J
- Subjects
- Aged, Disease Progression, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Prostate-Specific Antigen, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Sensitivity and Specificity, Treatment Outcome, Biomarkers, Tumor analysis, Lymphatic Metastasis diagnosis, Prostatic Neoplasms pathology
- Abstract
Purpose: Thirty percent of patients treated with curative intent for localized prostate cancer (PC) experience biochemical recurrence (BCR) with rising serum prostate-specific antigen (sPSA), and of these, approximately 50% succumb to progressive disease. More discriminatory staging procedures are needed to identify occult micrometastases that spawn BCR., Patients and Methods: PSA mRNA copies in pathologically normal pelvic lymph nodes (N0-PLN) from 341 localized PC patients were quantified by real-time reverse-transcriptase polymerase chain reaction. Based on comparisons with normal lymph nodes and PLN with metastases and on normalization to 5 x 10(6) glyceraldehyde-3'-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) and a threshold of PSA-N 100 or more were selected for continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS) compared with established risk factors., Results: At median follow-up of 4 years, the BFFS of patients with PSA-N 100 or more versus PSA-N less than 100 was 55% and 77% (P = .0002), respectively. The effect was greatest for sPSA greater than 20 ng/mL, 25% versus 60% (P = .014), Gleason score 8 or higher, 21% versus 66% (P = .0002), stage T3c, 18% versus 64% (P = .001), and high-risk group (50% v 72%; P = .05). By continuous analysis PSA-N was an independent prognostic marker for BCR (P = .049) with a hazard ratio of 1.25 (95% CI, 1.001 to 1.57). By categorical analysis, PSA-N 100 or more was an independent variable (P = .021) with a relative risk of 1.98 (95% CI, 1.11 to 3.55) for BCR compared with PSA-N less than 100., Conclusion: PSA-N 100 or more is a new, independent molecular staging criterion for localized PC that identifies high-risk group patients with clinically relevant occult micrometastases in N0-PLN, who may benefit from additional therapy to prevent BCR.
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- 2006
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97. Expression of human endogenous gammaretroviral sequences in endometriosis and ovarian cancer.
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Hu L, Hornung D, Kurek R, Ostman H, Blomberg J, and Bergqvist A
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- Base Sequence, Cloning, Molecular, Endogenous Retroviruses genetics, Endometrium metabolism, Female, Gammaretrovirus genetics, Humans, Molecular Sequence Data, Ovary metabolism, Polymerase Chain Reaction, RNA, Viral analysis, RNA, Viral blood, Sequence Analysis, DNA, Endogenous Retroviruses metabolism, Endometriosis metabolism, Gammaretrovirus metabolism, Ovarian Neoplasms metabolism
- Abstract
Endogenous retroviruses (ERVs) probably originate from ancient germ cell infections by exogenous retroviruses. A high expression of retroviruses in reproductive tissue increases the risk of viral transmission to germ line cells. We therefore investigated the expression of human ERVs (HERVs) in normal endometrium, endometriosis, normal ovaries, and ovarian cancer. Four real-time PCRs (QPCRs) for HERV-E, HERV-I/T, HERV-H, and HERV-W, respectively, and an expression control gene were used. HERV-E RNA expression was significantly higher in endometriotic tissue (average, SD) than in normal endometrium (average, SD), both measured as ratios versus control gene expression and as. HERV-E and HERV-W RNA were higher in normal ovarian tissue than in ovarian cancer. This illustrates that HERV expression is not automatically higher in malignant tissues. The other HERV PCRs did not show expression patterns as distinctive as HERVE and HERV-W in the two kinds of reproductive tissue. A small number of candidate HERV-E loci from which the transcription took place were identified by sequencing of amplimers. The role of HERV-E and HERV-W in endometriosis merits further investigation.
- Published
- 2006
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98. Progression-specific genes identified by expression profiling of matched ductal carcinomas in situ and invasive breast tumors, combining laser capture microdissection and oligonucleotide microarray analysis.
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Schuetz CS, Bonin M, Clare SE, Nieselt K, Sotlar K, Walter M, Fehm T, Solomayer E, Riess O, Wallwiener D, Kurek R, and Neubauer HJ
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma in Situ metabolism, Carcinoma in Situ pathology, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Cell Movement genetics, Cluster Analysis, Disease Progression, Epithelial Cells pathology, Female, Gene Amplification, Gene Expression Profiling, Humans, Microdissection methods, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, Protein Biosynthesis genetics, RNA, Messenger genetics, RNA, Neoplasm genetics, Reverse Transcriptase Polymerase Chain Reaction, Breast Neoplasms genetics, Carcinoma in Situ genetics, Carcinoma, Ductal, Breast genetics
- Abstract
Becoming invasive is a crucial step in breast cancer oncogenesis. At this point, a lesion carries the potential for spreading and metastasis--a process, whose molecular characteristics still remain poorly understood. In this article, we describe a matched-pair analysis of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of nine breast ductal carcinomas to identify novel molecular markers characterizing the transition from DCIS to IDC. The purpose of this study was to better understand the molecular biology of this transition and to identify candidate genes whose products might serve as prognostic markers and/or as molecular targets for treatment. To obtain cellular-based gene expression profiles from epithelial tumor cells, we combined laser capture microdissection with a T7-based two-round RNA amplification and Affymetrix oligonucleotide microarray analysis. Altogether, a set of 24 tumor samples was analyzed, comprised of nine matched DCIS/IDC and replicate DCIS/IDC preparations from three of the nine tumors. Cluster analysis on expression data shows the robustness and reproducibility of the techniques we established. Using multiple statistical methods, 546 significantly differentially expressed probe sets were identified. Eighteen candidate genes were evaluated by RT-PCR. Examples of genes already known to be associated with breast cancer invasion are BPAG1, LRRC15, MMP11, and PLAU. The expression of BPAG1, DACT1, GREM1, MEF2C, SART2, and TNFAIP6 was localized to epithelial tumor cells by in situ hybridization and/or immunohistochemistry, confirming the accuracy of laser capture microdissection sampling and microarray analysis.
- Published
- 2006
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99. Breast cancer proteomics by laser capture microdissection, sample pooling, 54-cm IPG IEF, and differential iodine radioisotope detection.
- Author
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Neubauer H, Clare SE, Kurek R, Fehm T, Wallwiener D, Sotlar K, Nordheim A, Wozny W, Schwall GP, Poznanović S, Sastri C, Hunzinger C, Stegmann W, Schrattenholz A, and Cahill MA
- Subjects
- Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Cell Extracts chemistry, Cryopreservation, Drug Resistance, Neoplasm, Female, Humans, Hydrogen-Ion Concentration, Iodine Radioisotopes analysis, Mutation, Receptors, Estrogen genetics, Receptors, Progesterone genetics, Tamoxifen therapeutic use, Breast Neoplasms chemistry, Electrophoresis, Gel, Two-Dimensional methods, Lasers, Microdissection methods, Neoplasm Proteins analysis, Proteomics methods
- Abstract
The presence of progesterone receptor (PR) in estrogen receptor (ER)-positive breast cancer is associated with a good prognosis, and indicates that tumors are likely to respond to tamoxifen. However, ER+/PR- tumors respond less well. To reveal the potential molecular mechanism of this phenomenon, we sought to identify differential protein abundances between invasive ductal carcinoma cells from cryopreserved ER+/PR+ and ER+/PR- mammary tumor specimens. Because current proteomics methods are hampered in the examination of most primary human tumor samples by the extreme tissue heterogeneity, we used laser capture microdissection (LCM) to isolate tumor cells and developed a sample pooling strategy to analyze small sample protein lysates. Proteins from LCM-harvested tumors were pooled into four sub-pools from each condition of three tumors/sub-pool, and proteins from respective paired sub-pools were co-electrophoresed by 2-DE using 54-cm IEF over pH 4-9. Abundance ratios were accurately quantified by a differential multiplex radioactive ProteoTope method at low attomole levels ( approximately 3.6 microg protein per labeling reaction, <180 ng per multiplex protein sample per 54-cm gel). Applying this approach, differentially displayed proteins were identified by MS using comigrating non-radioactively labeled tumor proteins. They include decreased cytochrome b5 and transgelin, and more abundant CRABP-II, cyclophilin A, Neudesin, and hemoglobin in ER+/PR+ tumors versus ER+/PR- providing a possible explanation for differential susceptibility against tamoxifen as a result of deregulated cytochrome b5-dependent metabolism. This study demonstrates the potential of ProteoTope and LCM to enable extremely sensitive and precise differential analyses from well-defined primary clinical specimen.
- Published
- 2006
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100. The class I PITP giotto is required for Drosophila cytokinesis.
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Giansanti MG, Bonaccorsi S, Kurek R, Farkas RM, Dimitri P, Fuller MT, and Gatti M
- Subjects
- Actomyosin metabolism, Alleles, Amino Acid Sequence, Animals, Drosophila metabolism, Drosophila Proteins analysis, Drosophila Proteins genetics, Drosophila Proteins metabolism, Genetic Complementation Test, Male, Microtubule-Associated Proteins metabolism, Models, Biological, Molecular Sequence Data, Phospholipid Transfer Proteins analysis, Phospholipid Transfer Proteins genetics, Secretory Vesicles metabolism, Spermatocytes cytology, Spermatocytes metabolism, Cytokinesis physiology, Drosophila cytology, Drosophila Proteins physiology, Phospholipid Transfer Proteins physiology
- Abstract
Phosphatidylinositol transfer proteins (PITPs) are highly conserved polypeptides that bind phosphatidylinositol or phosphatidylcholine monomers, facilitating their transfer from one membrane compartment to another . Although PITPs have been implicated in a variety of cellular functions, including lipid-mediated signaling and membrane trafficking, the precise biological roles of most PITPs remain to be elucidated . Here we show for the first time that a class I PITP is involved in cytokinesis. We found that giotto (gio), a Drosophila gene that encodes a class I PITP, serves an essential function required for both mitotic and meiotic cytokinesis. Neuroblasts and spermatocytes from gio mutants both assemble regular actomyosin rings. However, these rings fail to constrict to completion, leading to cytokinesis failures. Moreover, gio mutations cause an abnormal accumulation of Golgi-derived vesicles at the equator of spermatocyte telophases, suggesting that Gio is implicated in membrane-vesicle fusion. Consistent with these results, we found that Gio is enriched at the cleavage furrow, the ER, and the spindle envelope. We propose that Gio mediates transfer of lipid monomers from the ER to the equatorial membrane, causing a specific local enrichment in phosphatidylinositol. This change in membrane composition would ultimately facilitate vesicle fusion, allowing membrane addition to the furrow and/or targeted delivery of proteins required for cytokinesis.
- Published
- 2006
- Full Text
- View/download PDF
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