12 results on '"Pietsch, T."'
Search Results
2. BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.
- Author
-
Ebrahimi A, Waha A, Schittenhelm J, Gohla G, Schuhmann MU, and Pietsch T
- Subjects
- Adult, Humans, Methylation, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Repressor Proteins genetics, CREB-Binding Protein genetics, Central Nervous System Neoplasms diagnostic imaging, Central Nervous System Neoplasms genetics, Neoplasms, Neuroepithelial diagnostic imaging, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioma genetics
- Abstract
Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
3. No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.
- Author
-
Rüdiger R, Geiser F, Ritter M, Brossart P, Keyver-Paik MD, Faridi A, Vatter H, Bootz F, Landsberg J, Kalff JC, Herrlinger U, Kristiansen G, Pietsch T, Aretz S, Thomas D, Radbruch L, Kramer FJ, Strassburg CP, Gonzalez-Carmona M, Skowasch D, Essler M, Schmid M, Nadal J, Ernstmann N, Sharma A, Funke B, and Schmidt-Wolf IGH
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neoplasms mortality, Retrospective Studies, Young Adult, Emigrants and Immigrants, Matched-Pair Analysis, Neoplasms therapy
- Abstract
Background: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany., Methods: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression)., Results: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives., Conclusion: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.
- Published
- 2021
- Full Text
- View/download PDF
4. Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.
- Author
-
Jünger ST, Mynarek M, Wohlers I, Dörner E, Mühlen AZ, Velez-Char N, von Hoff K, Rutkowski S, Warmuth-Metz M, Kortmann RD, Timmermann B, Rahmann S, Klein-Hitpass L, von Bueren AO, and Pietsch T
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Ependymoma epidemiology, Female, Follow-Up Studies, Germany epidemiology, Humans, Infant, Infratentorial Neoplasms epidemiology, Male, Retrospective Studies, Risk Assessment standards, Ependymoma genetics, Ependymoma pathology, Infratentorial Neoplasms genetics, Infratentorial Neoplasms pathology
- Abstract
Introduction: Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols., Methods: Tumor samples of 134 patients aged 0.2-15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis., Results: Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures., Conclusion: The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.
- Published
- 2019
- Full Text
- View/download PDF
5. A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.
- Author
-
Budde MK, Kuhn W, Keyver-Paik MD, Bootz F, Kalff JC, Müller SC, Bieber T, Brossart P, Vatter H, Herrlinger U, Wirtz DC, Schild HH, Kristiansen G, Pietsch T, Aretz S, Geiser F, Radbruch L, Reich RH, Strassburg CP, Skowasch D, Essler M, Ernstmann N, Landsberg J, Funke B, and Schmidt-Wolf IGH
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Genital Neoplasms, Female therapy, Germany ethnology, Head and Neck Neoplasms therapy, Humans, Kaplan-Meier Estimate, Male, Matched-Pair Analysis, Middle Aged, Progression-Free Survival, Retrospective Studies, White People, Young Adult, Genital Neoplasms, Female ethnology, Genital Neoplasms, Female mortality, Head and Neck Neoplasms ethnology, Head and Neck Neoplasms mortality
- Abstract
Background: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016., Methods: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment., Results: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis., Conclusions: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.
- Published
- 2019
- Full Text
- View/download PDF
6. H3F3A-G34R mutant high grade neuroepithelial neoplasms with glial and dysplastic ganglion cell components.
- Author
-
Andreiuolo F, Lisner T, Zlocha J, Kramm C, Koch A, Bison B, Gareton A, Zanello M, Waha A, Varlet P, and Pietsch T
- Subjects
- Adolescent, Humans, Male, Mutation, Brain pathology, Histones genetics, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology, Neuroglia pathology
- Abstract
The recently described malignant neuro-epithelial tumors with histone H3F3A point mutations at G34 (NET-H3-G34) occur most often in cerebral hemispheres of teenagers and young adults, and have a generally adverse prognosis. These tumors have been histologically classified as glioblastoma or primitive neuroectodermal tumor (PNET) in the past, and have not been defined as a separate entity in the revised WHO classification of tumors of the CNS 2016. Here, we report two cases of NET-H3-G34 with glial and dysplastic ganglion cell components affecting teenagers. Patients were treated with surgery and radiochemotherapy with temozolomide. One patient underwent partial resection and deceased 21 months after diagnosis, while the other patient is alive without evidence of disease 15 months after total resection. So far, a dysplastic ganglion cell component has not been described in NET-H-G34, and its presence raises a possible relation to (anaplastic) gangliogliomas. Genome-wide copy number analysis did not provide unequivocal evidence that these tumors represent anaplastic variants of gangliogliomas, as opposed to NET-H3-G34. Our observations expand the morphologic spectrum of NET-H3-G34. Further cases of NET-H3-G34 with dysplastic ganglion cells should be clinically followed to find differences or similarities in their biological behavior, as compared to NET-H3-G34 and anaplastic gangliogliomas.
- Published
- 2019
- Full Text
- View/download PDF
7. Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.
- Author
-
Schäfer N, Gielen GH, Rauschenbach L, Kebir S, Till A, Reinartz R, Simon M, Niehusmann P, Kleinschnitz C, Herrlinger U, Pietsch T, Scheffler B, and Glas M
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms pathology, Disease Progression, Epigenesis, Genetic drug effects, Epigenesis, Genetic physiology, Female, Glioblastoma diagnosis, Glioblastoma genetics, Glioblastoma pathology, Humans, Longitudinal Studies, Male, Middle Aged, Molecular Targeted Therapy trends, Neoplasm Recurrence, Local genetics, Patient Care Planning, Retrospective Studies, Young Adult, Biomarkers, Tumor genetics, Brain Neoplasms therapy, Genetic Heterogeneity, Glioblastoma therapy, Molecular Targeted Therapy methods, Neoplasm Recurrence, Local therapy
- Abstract
Background: Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples., Methods: Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-β, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTOR
Ser2448 ) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1., Results: Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue., Conclusions: The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.- Published
- 2019
- Full Text
- View/download PDF
8. Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma.
- Author
-
Ronellenfitsch MW, Zeiner PS, Mittelbronn M, Urban H, Pietsch T, Reuter D, Senft C, Steinbach JP, Westphal M, and Harter PN
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Antibodies, Monoclonal, Humanized pharmacology, Basic Helix-Loop-Helix Transcription Factors metabolism, Calcium-Binding Proteins, Cohort Studies, DNA Modification Methylases metabolism, DNA Repair Enzymes metabolism, DNA-Binding Proteins metabolism, ErbB Receptors immunology, Female, Humans, Male, Microfilament Proteins, Necrosis etiology, Necrosis metabolism, Phosphorylation drug effects, Quinazolines, Ribosomal Protein S6 metabolism, Time Factors, Treatment Outcome, Tumor Suppressor Proteins metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Brain Neoplasms drug therapy, Glioblastoma diet therapy, Mechanistic Target of Rapamycin Complex 1 metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects
- Abstract
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
- Published
- 2018
- Full Text
- View/download PDF
9. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.
- Author
-
Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P, Zhang CH, Fraser M, Tse K, Poon R, Shih DJ, Baskin B, Ray PN, Bouffet E, Dirks P, von Bueren AO, Pfaff E, Korshunov A, Jones DT, Northcott PA, Kool M, Pugh TJ, Pomeroy SL, Cho YJ, Pietsch T, Gessi M, Rutkowski S, Bognár L, Cho BK, Eberhart CG, Conter CF, Fouladi M, French PJ, Grajkowska WA, Gupta N, Hauser P, Jabado N, Vasiljevic A, Jung S, Kim SK, Klekner A, Kumabe T, Lach B, Leonard JR, Liau LM, Massimi L, Pollack IF, Ra YS, Rubin JB, Van Meir EG, Wang KC, Weiss WA, Zitterbart K, Bristow RG, Alman B, Hawkins CE, Malkin D, Clifford SC, Pfister SM, Taylor MD, and Tabori U
- Subjects
- Adolescent, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Cell Survival radiation effects, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellar Neoplasms radiotherapy, Child, Child, Preschool, Cohort Studies, Female, Humans, International Cooperation, Male, Medulloblastoma mortality, Medulloblastoma pathology, Medulloblastoma radiotherapy, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells radiation effects, Radiotherapy adverse effects, Tumor Suppressor Protein p53 metabolism, Young Adult, beta Catenin genetics, beta Catenin metabolism, Cerebellar Neoplasms genetics, Lithium pharmacology, Medulloblastoma genetics, Mutation genetics, Tumor Suppressor Protein p53 genetics, Wnt Proteins metabolism, Wnt Signaling Pathway drug effects
- Abstract
TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
- Published
- 2014
- Full Text
- View/download PDF
10. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.
- Author
-
Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, and Grundy RG
- Subjects
- Biomarkers, Tumor, Child, Clinical Trials as Topic, Cohort Studies, Disease-Free Survival, Humans, Infant, Brain Neoplasms pathology, Ependymoma pathology
- Abstract
Background: Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading., Results: In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial., Conclusions: We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.
- Published
- 2011
- Full Text
- View/download PDF
11. RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study.
- Author
-
Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kölbl O, Pietsch T, Proescholdt M, Rümmele P, Muigg A, Stockhammer G, Hegi M, Bogdahn U, and Hau P
- Subjects
- Adolescent, Adult, Aged, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms mortality, Combined Modality Therapy, Dacarbazine administration & dosage, Dacarbazine adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Drug Administration Schedule, Drug Therapy, Combination, Drug-Related Side Effects and Adverse Reactions, Female, Glioblastoma diagnosis, Glioblastoma mortality, Humans, Male, Middle Aged, Polyethylene Glycols adverse effects, Temozolomide, Young Adult, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms radiotherapy, Dacarbazine analogs & derivatives, Doxorubicin analogs & derivatives, Glioblastoma drug therapy, Glioblastoma radiotherapy, Polyethylene Glycols administration & dosage
- Abstract
Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for., Methods: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression., Results: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison., Conclusion: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.
- Published
- 2009
- Full Text
- View/download PDF
12. Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells.
- Author
-
Glassmann A, Molly S, Surchev L, Nazwar TA, Holst M, Hartmann W, Baader SL, Oberdick J, Pietsch T, and Schilling K
- Subjects
- Animals, Cerebellar Neoplasms pathology, Cerebellum pathology, Exons, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Polymerase Chain Reaction, Protein Splicing genetics, Purkinje Cells pathology, Tumor Cells, Cultured, Cell Transformation, Neoplastic pathology, Cerebellum growth & development, Gene Expression Regulation, Developmental, Microfilament Proteins genetics, Neoplasm Proteins genetics
- Abstract
Background: Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens., Results: During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site., Conclusion: Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.
- Published
- 2007
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.