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Oechsle K.,University of Hamburg | Bokemeyer C.,University of Hamburg | Kollmannsberger C.,British Columbia Cancer Agency | Mayer F.,University of Tuebingen Medical Center | And 3 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose Little data exist on characteristics, treatment, and outcome of patients with bone metastases from germ cell cancer. Methods A total of 434 patients with poor prognosis germ cell cancer, who underwent primary high-dose chemotherapy (HD-CTX) within two phase II trials, were retrospectively analyzed. Results 40 patients (9%) presented with primary bone metastases. Bone metastases were significantly more frequently observed in patients with primary mediastinal tumors, yolk sac tumor histology, and synchronous liver metastases. Overall response rate to HD-CTX was 85%. 20% of patients underwent consolidating radiotherapy, and 10% had resection of bone metastases revealing necrosis in all cases. Progression-free survival rate after primary treatment was 63% and, including salvage treatment after first relapse, overall long-term survival rate was 75%. Four patients (0.9%) relapsed with isolated bone metastases, all with bone metastases at primary diagnosis. None had previously received surgery or radiotherapy and all died within 1 year. 10 patients with primary bone metastases showed recurrences at other localizations. No patient relapsed with bone plus other metastases or with de novo bone metastases. Conclusions Bone metastases were associated with a primary mediastinal nonseminoma, yolk sac histology, and liver metastases at first diagnosis. In this cohort of patients receiving HD-CTX as first-line treatment, 63% achieved long-term progression-free survival. Skeletal relapses were rare, but showed dismal outcome. © Springer-Verlag 2012. Source

Feigl G.C.,University of Tuebingen Medical Center
Journal of neurosurgery | Year: 2010

Causes of pituitary insufficiencies as a side effect of Gamma Knife surgery (GKS) following irradiation of the hypothalamopituitary axis are still under debate. In an investigation of pituitary insufficiencies after GKS, the authors' main focus is on what role can be attributed to the hypothalamus with regard to endocrinological changes in hypothalamopituitary function following GKS. A total of 108 patients consecutively treated between April 1992 and July 2003 were included in this retrospective study. All patients had undergone either transsphenoidal or transcranial surgery prior to GKS. The spot dosimetry method was used to determine doses delivered to structures of the hypothalamopituitary axis. For statistical analyses, endocrine insufficiency and deterioration in pituitary function were defined as a decrease in hormonal blood levels below the normal range for 1 or more anterior pituitary lobe hormones. Additionally, an analysis of the rate of patients requiring hormone replacement therapy after GKS due to new endocrinopathies was performed. Complete patient records of 61 male and 47 female patients with a mean age of 51.9 years (range 9.1-81.2 years) were available for our investigation. The overall tumor control rate was 97% and the endocrinological cure rate was 61.2%. Mean treatment doses in patients with and without new endocrine insufficiencies (shown as with/without insufficiencies and followed by probability values) were as follows: 1.3/0.8 Gy to the hypothalamus(p = 0.2); 2.2/1.6 Gy to the median eminence (p = 0.1); 6.5/4.1 Gy to the pituitary stalk (p = 0.004); and 12.4/9.5Gy to the pituitary gland (p = 0.05). The median overall duration of follow-up after GKS was 6.7 years, with 84 patients(77.7%) whose follow-up was longer than 12 months. The median follow-up time after GKS in patients who developed a new pituitary dysfunction was 79.5 months (6.6 years, SD 3.8 years), and the median follow-up time inpatients with no new insufficiencies was 78.4 months (6.5 years, SD 4 years). Gamma Knife surgery is a safe and effective treatment for patients with residual and recurrent pituitary adenomas. The rate of pituitary insufficiencies after GKS is still lower than that after conventional radiotherapy.Very low radiation doses are directed to the hypothalamus, and thus this structure does not play a major role in the development of pituitary insufficiencies after GKS. The results of this study show that patients in whom the pituitary stalk and pituitary gland receive a high mean point dose are more likely to develop pituitary insufficiencies after GKS than those who receive a lower dose. (DOI: 10.3171/2010.8.GKS10959). Source

Oechsle K.,University of Hamburg | Kollmannsberger C.,British Columbia Cancer Agency | Honecker F.,University of Hamburg | Mayer F.,University of Tuebingen Medical Center | And 4 more authors.
European Urology | Year: 2011

Background: Chemotherapy including gemcitabine, oxaliplatin, and/or paclitaxel has shown efficacy in germ cell tumor patients after progression during cisplatin-based chemotherapy or relapse after high-dose chemotherapy including complete responses in 5-15%. Objective: Most studies have been published with a short follow-up. We present the long-term outcome of two previously reported trials. Design, setting, and participants: Two phase 2 trials have evaluated chemotherapy with gemcitabine plus oxaliplatin alone (GO) or plus paclitaxel (GOP) including a total of 76 patients (35 GO and 41 GOP) [1,2]. At first publication, 29 patients were still alive and 9 patients (12%) were free of disease after chemotherapy with or without surgery: GO, 3 of 35 (9%) and GOP, 6 of 41 (15%). Measurements: Survival and follow-up time were calculated using the Kaplan-Meier method from the beginning of study treatment until the date of death or the date of the last follow-up. Results and limitations: After a median follow-up of 19 mo (2-86 mo) for the 29 patients still alive, 11% of all patients (8 of 76) were free of disease for >2 yr: 1 of 35 patients (3%) after GO and 7 of 41 patients (17%) after GOP. Three patients with complete remission (CR), two after GO and one after GOP, relapsed. Two others treated with GOP were rendered disease free: One patient with partial remission and short follow-up underwent secondary surgery, and another patient, who had relapsed 2 mo after GOP, achieved a CR after salvage treatment. Overall survival time is ≥33 mo (range: ≥28-59 mo) in these eight patients. Conclusions: Long-term survival can be achieved in about 10-15% of patients with cisplatin-refractory or multiply relapsed germ cell tumor with GO(P) chemotherapy. Aggressive secondary surgery following partial remission is a crucial part of this salvage treatment. © 2011 European Association of Urology. Source

Schmoll H.-J.,Martin Luther University of Halle Wittenberg | Wittig B.,Free University of Berlin | Arnold D.,Albert Ludwigs University of Freiburg | Riera-Knorrenschild J.,University of Marburg | And 6 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2014

Purpose: This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC). Methods: Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16). Results: The hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29-1.08; P = 0.07) and 0.55 (95 % CI 0.3-1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26-0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31-1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3-1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation. Conclusions: MGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703. © 2014 The Author(s). Source

Lengerke C.,University of Tuebingen Medical Center | Wingert R.,Massachusetts General Hospital | Beeretz M.,University of Tuebingen Medical Center | Grauer M.,University of Tuebingen Medical Center | And 5 more authors.
Developmental Biology | Year: 2011

Cdx transcription factors regulate embryonic positional identities and have crucial roles in anteroposterior patterning (AP) processes of all three germ layers. Previously we have shown that the zebrafish homologues cdx1a and cdx4 redundantly regulate posterior mesodermal derivatives inducing embryonic blood cell fate specification and patterning of the embryonic kidney. Here we hypothesize that cdx factors restrict formation of anterior mesodermal derivatives such as cardiac cells by imposing posterior identity to developing mesodermal cells. We show that ectopic expression of Cdx1 or Cdx4 applied during the brief window of mesoderm patterning in differentiating murine embryonic stem cell (ESC) strongly suppresses cardiac development as assayed by expression of cardiac genes and formation of embryoid bodies (EB) containing "beating" cell clusters. Conversely, in loss-of-function studies performed in cdx-deficient zebrafish embryos, we observed a dose-dependent expansion of tbx5a+ anterior-lateral plate mesoderm giving rise to cardiac progenitors. However, further cardiac development of these mesodermal cells required additional suppression of the retinoic acid (RA) pathway, possibly due to differential activity of inhibitory RA signals in cdx mutants. Together, our data suggest that cdx proteins affect cardiogenesis by regulating the formation of cardiogenic mesoderm and together with the RA pathway control the early development of cardiac precursor cells. © 2011 Elsevier Inc. Source

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