Carsten Bokemeyer

Publications of Carsten Bokemeyer

• Similar Incidences of TP53 Deletions in Extramedullary Organ Infiltrations, Soft Tissue and Osteolyses of Patients with Multiple Myeloma.

  Authors: Lisa Billecke, Eva Maria Murga Penas, Annette M May, Monika Engelhardt, Arnon Nagler, Merav Leiba, Ginette Schiby, Nicolaus Kröger, Jozef Zustin, Andreas Marx, Jakob Matschke, Markus Tiemann, Eray Goekkurt, Carsten Bokemeyer, Georgia Schilling

  Anticancer research. 05/2012; 32(5):2031-4.

  Extramedullary (EM) organ impairment in patients with multiple myeloma (MM) is a rare event, occurring mostly during disease relapse after high-dose chemotherapy with autologous or allogeneic stemExtramedullary (EM) organ impairment in patients with multiple myeloma (MM) is a rare event, occurring mostly during disease relapse after high-dose chemotherapy with autologous or allogeneic stem cell transplantation. This manifestation is commonly associated with an unfavourable outcome. Previous studies suggested a correlation between the clinical course of patients with MM and EM and the cytogenetic findings, e.g. deletion of TP53 on 17p13. We investigated patients with these rare plasma cell organ infiltrations (n=17) as well as bone lesions or soft tissue lesions, known to be a common clinical feature of MM (n=14), using a newly established method of fluorescence in situ hybridization in combination with cytoplasmic immunoglobulin staining (cIg-FISH) on paraffin-embedded sections and a specific probe for TP53 on 17p13. Results and The incidence of del(17)(p13) was similar in both groups but overall it was higher when compared to published data obtained from bone marrow samples and material originating from osteolyses. Further investigations on a larger patient cohort are needed in order to confirm these findings.

• VEGFR-1 expression levels predict occurrence of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma.

  Authors: Alexander Schultze, Isabel Ben Batalla, Sabine Riethdorf, Michael Bubenheim, Emre Yekebas, Andreas Erbersdobler, Uta Reichelt, Katharina E Effenberger, Thomas Schmidt, Jakob R Izbicki, Carsten Bokemeyer, Klaus Pantel, Walter Fiedler, Sonja Loges

  Clinical & experimental metastasis. 04/2012;

  Blocking angiogenesis by inhibiting VEGF represents an established therapeutic strategy in many cancers. The role of placental growth factor (PlGF) and of its receptor VEGFR-1 in tumor biology remainBlocking angiogenesis by inhibiting VEGF represents an established therapeutic strategy in many cancers. The role of placental growth factor (PlGF) and of its receptor VEGFR-1 in tumor biology remain more elusive. Currently, humanized monoclonal antibodies against PlGF are studied in early phase clinical trials because PlGF inhibition blocked murine tumor growth and angiogenesis. In contrast to mice exclusively expressing one PlGF isoform (PlGF-2), humans can produce four PlGF isoforms (PlGF1-4). Surprisingly nothing is yet known about expression of all four PlGF isoforms in human cancer, because until now mostly total PlGF levels or PlGF-1/2 were analyzed without discriminating further. In this study we determined mRNA expression levels of PlGF1-4 and of VEGFR-1 by QRT-PCR in human esophageal tumor tissue and investigated whether gene expression levels correlate with clinical data. PlGF-1 and -2 were expressed in virtually all analyzable tumors, whereas PlGF-3 and -4 were present in tumors of 59 and 74 % of patients, respectively. MRNA Expression levels of all four splice variants correlated with each other. In contrast, PlGF-1 and -2 mRNA expression was lower in esophageal control tissue and PlGF-3 and -4 mRNA were undetectable. VEGFR-1 was expressed by more than 80 % of patients. Interestingly, VEGFR-1 expression levels significantly correlate with presence of disseminated tumor cells (DTCs) in bone marrow. Patients with DTCs exhibit lower VEGFR-1 mRNA expression than patients without DTCs. Pending validation in other types of cancer, expression levels of VEGFR-1 might be useful as surrogate marker for DTCs.

• High level of Ets-related gene expression has high specificity for prostate cancer: a tissue microarray study of 11 483 cancers.

  Authors: Sarah Minner, Andreas M Luebke, Martina Kluth, Carsten Bokemeyer, Fritz Jänicke, Jakob Izbicki, Thorsten Schlomm, Guido Sauter, Waldemar Wilczak

  Histopathology. 03/2012;

  Minner S, Luebke A M, Kluth M, Bokemeyer C, Jänicke F, Izbicki J, Schlomm T, Sauter G & Wilczak W (2012) Histopathology High level of Ets-related gene expression has high specificity for prostateMinner S, Luebke A M, Kluth M, Bokemeyer C, Jänicke F, Izbicki J, Schlomm T, Sauter G & Wilczak W (2012) Histopathology High level of Ets-related gene expression has high specificity for prostate cancer: a tissue microarray study of 11 483 cancers Aims:  TMPRSS2-ERG fusion resulting in strong Ets-related gene (ERG) overexpression occurs in about 50% of prostate cancers. This study was undertaken to determine the prevalence of ERG overexpression in other tumour types as well as in normal tissues. Methods and results:  A total of 11 483 tumours and 72 different normal tissue types were analysed in a tissue microarray format. Strong nuclear ERG overexpression was found in 36.7% of prostate carcinomas as well as in various vascular tumours, including Kaposi sarcomas (91.7%), angiosarcomas (100%) and haemangiomas (90.9%). Moderate to strong nuclear ERG immunostaining was also observed in thymoma (6.1%). Weak to moderate ERG staining was found in a small number of squamous cell carcinomas of the skin, squamous carcinomas of the lung, malignant mesotheliomas, carcinosarcomas of the uterus, gastrointestinal stromal tumours, hepatocellular carcinomas, teratomas of the testis, anaplastic carcinomas of the thyroid, giant cell tumours of the tendon sheath and benign fibrous histiocytomas of the skin. ERG overexpression was not seen in 8886 samples from 132 other tumour types and subtypes. Within normal tissues, immunohistochemically detectable ERG overexpression was restricted to endothelial cells and subsets of lymphocytes. Conclusions:  The high specificity of ERG expression in both normal and neoplastic tissues suggests a very narrow biological role for ERG in highly selected tissues.

• The Contemporary Role of Chemotherapy for Advanced Testis Cancer: A Systematic Review of the Literature.

  Authors: Fabio Calabrò, Peter Albers, Carsten Bokemeyer, Chris Martin, Lawrence H Einhorn, Alan Horwich, Susanne Krege, Hans Joachim Schmoll, Cora N Sternberg, Gedske Daugaard

  European urology. 03/2012;

  CONTEXT: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basisCONTEXT: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basis of randomised trials and prognostic factors. OBJECTIVE: This review summarises the evolving role of chemotherapy in the treatment of previously treated and untreated patients with metastatic GCTs and outlines the current standard treatment. EVIDENCE ACQUISITION: Randomised and nonrandomised trials of first-line, salvage, and palliative therapy were reviewed. EVIDENCE SYNTHESIS: Three cycles of standard bleomycin, etoposide, and platinum (BEP) can be considered the gold-standard treatment in good-risk patients, and four cycles of the same combination can result in cure in approximately 80% of intermediate-risk and 50% of poor-risk patients. The routine use of high-dose chemotherapy in patients with intermediate- or poor-prognosis GCT has not improved treatment outcome, but the role of tumour marker decline during the first cycles may provide useful prognostic information. Prognostic variables in patients who experience treatment failure after cisplatin-based chemotherapy can be used to guide salvage strategies, and many new drugs or combinations have shown activity in this setting. Patients and physicians should be aware of the risk of short- and long-term toxicity of treatments, and guidelines for screening and prevention of this risk should be established. CONCLUSIONS: A risk-based strategy offers the best chance of cure, even in patients with refractory GCT.

• Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials.

  Authors: Carsten Bokemeyer, Eric Van Cutsem, Philippe Rougier, Fortunato Ciardiello, Steffen Heeger, Michael Schlichting, Ilhan Celik, Claus-Henning Köhne

  European journal of cancer (Oxford, England : 1990). 03/2012;

  BACKGROUND: The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC)BACKGROUND: The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies. METHODS: Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests. RESULTS: In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p<0.001) and ORR (odds ratio 2.16; p<0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours. CONCLUSION: Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

• Peroxiredoxins 3 and 4 are overexpressed in prostate cancer tissue and affect the proliferation of prostate cancer cells in vitro.

  Authors: Ramesh Ummanni, Frederico Barreto, Simone Venz, Christian Scharf, Christine Barett, Heiko A Mannsperger, Jan Christoph Brase, Ruprecht Kuner, Thorsten Schlomm, Guido Sauter, Holger Sültmann, Ulrike Korf, Carsten Bokemeyer, Reinhard Walther, Tim H Brümmendorf, Stefan Balabanov

  Journal of proteome research. 03/2012; 11(4):2452-66.

  The present study aimed to investigate the proteome profiling of surgically treated prostate cancers. Hereto, 2D-DIGE and mass spectrometry were performed for protein identification, and dataThe present study aimed to investigate the proteome profiling of surgically treated prostate cancers. Hereto, 2D-DIGE and mass spectrometry were performed for protein identification, and data validation for peroxiredoxin 3 and 4 (PRDX3 and PRDX4) was accomplished by reverse phase protein arrays (RPPA). The Formal Concept Analysis (FCA) method was applied to assess whether the TMPRSS2-ERG gene fusion could influence the degree of overexpression of PRDX3 and PRDX4 in prostate cancer. Lastly, we performed an in vitro functional characterization of both PRDX3 and PRDX4 using the classical human prostate cancer cell lines DU145 and LNCaP. Reverse phase protein arrays verified that the overexpression of both PRDX3 and PRDX4 in tumor samples is negatively correlated with the presence of the TMPRSS2-ERG gene fusion. Functional characterization of PRDX3 and PRDX4 activity in PCa cell lines suggests a role of these members of the peroxiredoxin family in the pathophysiology of this tumor entity.

• Proteomic Profiling of Germ Cell Cancer Cells Treated with Aaptamine, a Marine Alkaloid with Antiproliferative Activity.

  Authors: Sergey A Dyshlovoy, Ina Naeth, Simone Venz, Michael Preukschas, Henning Sievert, Christine Jacobsen, Larisa K Shubina, Manuela Gesell Salazar, Christian Scharf, Reinhard Walther, Marcel Krepstakies, Poornima Priyadarshini, Joachim Hauber, Sergey N Fedorov, Carsten Bokemeyer, Valentin A Stonik, Stefan Balabanov, Friedemann Honecker

  Journal of proteome research. 03/2012;

  Aaptamine is a marine compound isolated from the sponge Aaptos aaptos showing antiproliferative properties via an undefined mode of action. We analyzed the effects of aaptamine treatment on theAaptamine is a marine compound isolated from the sponge Aaptos aaptos showing antiproliferative properties via an undefined mode of action. We analyzed the effects of aaptamine treatment on the proliferation and protein expression of the pluripotent human embryonal carcinoma cell line NT2. Effects on proliferation, cell cycle distribution, and induction of apoptosis were analyzed. At lower concentrations, including the IC(50) of 50 μM, aaptamine treatment resulted in a G2/M phase cell cycle arrest, whereas at higher concentrations, induction of apoptosis was seen. Differentially expressed proteins were assessed by 2D-PAGE and mass spectrometry, followed by verification and analysis of protein modifications of the most significantly up- and down-regulated proteins. Aaptamine treatment at the IC(50) for 48 h resulted in alteration of 10 proteins, of which five each showed up- and down-regulation. Changes in the 2D map were frequently noticed as a result of post-transcriptional modifications, e.g., of the hypusine modification of the eukaryotic initiation factor 5A (eIF5A). Observed alterations such as increased expression of CRABP2 and hypusination of eIF5A have previously been identified during differentiation of pluripotent cells. For the first time, we describe changes in protein expression caused by aaptamine, providing valuable information regarding the mode of action of this compound.

• Bone metastases in germ cell tumor patients.

  Authors: Karin Oechsle, Carsten Bokemeyer, Christian Kollmannsberger, Frank Mayer, Lars Arne Berger, Christoph Oing, Friedemann Honecker

  Journal of cancer research and clinical oncology. 02/2012;

  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,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.

• Sequential Versus Single High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: Long-Term Results of a Prospective Randomized Trial.

  Authors: Anja Lorch, Antje Kleinhans, Andrew Kramar, Christian K Kollmannsberger, Jörg T Hartmann, Carsten Bokemeyer, Oliver Rick, Jörg Beyer

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 01/2012;

  PURPOSETo evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT). PATIENTS AND METHODSBetweenPURPOSETo evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT). PATIENTS AND METHODSBetween November 1999 and November 2004, 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of cisplatin 100 mg/m(2), etoposide 375 mg/m(2), and ifosfamide 6 g/m(2) (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m(2) and etoposide 1,500 mg/m(2) (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2), etoposide 1,800 mg/m(2), and cyclophosphamide 6,400 mg/m(2) (CEC, arm B) followed by autologous stem-cell reinfusion. Long-term progression-free survival (PFS) and overall survival (OS) 6 years after random assignment of the last patient were compared by using the log-rank test.ResultsOverall, 108 and 103 patients were randomly assigned to arms A and B, respectivelyl. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; P = .01). As of December 2010, nine (5%) of 211 patients were lost to follow-up; 94 (45%) of 211 are alive and 88 (94%) of 94 patients are progression free. Five-year PFS is 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; P = .454). Five-year OS is 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; P = .057). CONCLUSIONPatients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT. Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT.

• Longitudinal analysis of tetanus- and influenza-specific IgG antibodies in myeloma patients.

  Authors: Sebastian Kobold, Tim Luetkens, Britta Marlen Bartels, Yanran Cao, York Hildebrandt, Orhan Sezer, Henrike Reinhard, Julia Templin, Katrin Bartels, Nesrine Lajmi, Friedrich Haag, Carsten Bokemeyer, Nicolaus Kröger, Djordje Atanackovic

  Clinical & developmental immunology. 01/2012; 2012:134081.

  Background. Multiple myeloma (MM) and its therapies may induce a severely compromised humoral immunity. We have performed a longitudinal analysis of IgG-antibody responses against influenza virusBackground. Multiple myeloma (MM) and its therapies may induce a severely compromised humoral immunity. We have performed a longitudinal analysis of IgG-antibody responses against influenza virus (FLU) and tetanus toxoid (TT) as surrogate markers for the B cell-mediated immunity in MM patients. Methods. 1094 serum samples of 190 MM patients and samples from 100 healthy donors were analyzed by ELISA for FLU- and TT-specific antibodies. Results. MM patients evidenced lower levels of FLU- and TT-specific antibodies than healthy controls (P < 0.001). Immunoreactivity decreased with progressing disease and worsening clinical status. Levels of FLU- and TT-specific antibodies increased shortly (0-6 months) after alloSCT (P < 0.001), a time-period during which intravenous immunoglobulin (IVIG) is routinely applied. Thereafter, antibody concentrations declined and remained suppressed for 3 years in the case of FLU-specific and for more than 5 years in the case of TT-specific antibodies. Conclusions. We found that MM is associated with a profound disease- and therapy-related immunosuppression, which is compensated for a few months after alloSCT, most likely by application of IVIG. This and the differences regarding the recovery of anti-FLU and anti-TT antibody titers during the following years need to be taken into account for optimizing IVIG application and immunization after alloSCT.

• Characterization of Enterobacter cloacae pneumonia: a single-center retrospective analysis.

  Authors: Jan K Hennigs, Hans Jörg Baumann, Stefan Schmiedel, Pierre Tennstedt, Ingo Sobottka, Carsten Bokemeyer, Stefan Kluge, Hans Klose

  Lung. 12/2011; 189(6):475-83.

  Enterobacter cloacae (E. cloacae) is a Gram-negative rod commonly found on intensive care units (ICU) causing severe infections with high mortality. Specific characteristics of E. cloacae pneumonia,Enterobacter cloacae (E. cloacae) is a Gram-negative rod commonly found on intensive care units (ICU) causing severe infections with high mortality. Specific characteristics of E. cloacae pneumonia, however, have not been identified. Evaluation of clinical and microbiological records of patients with positive respiratory samples for E. cloacae was performed by a 1-year retrospective study in a large university hospital. Ninety-seven of 115 eligible patients with E. cloacae-positive respiratory samples developed pneumonia. Patients were predominantly male (68%), older (median age = 62 years), and immunodeficient (54%). Seventy-eight percent required ICU admission, of which 97% required mechanical ventilation. Ventilator-associated pneumonia (VAP) occurred in 58%. Those who developed E. cloacae VAP had undergone twice as many surgical procedures under translaryngeal intubation prior to VAP onset (89 vs. 48%, P < 0.0001). Overall, E. cloacae VAP mortality was 24%. In E. cloacae VAP patients, presence of translaryngeal tubes (P = 0.02) and female gender (P = 0.0003) were associated with poor survival. Multivariate analysis confirmed male sex as a protective factor (relative risk: 0.39; P = 0.007). Enterobacter cloacae causes VAP with high mortality, predominantly in women. Risk factors for E. cloacae pneumonia seem to match those for VAP. The presence of translaryngeal endotracheal tubes seems to be the specific factor for E. cloacae VAP.

• Unusual course of myelodysplastic syndrome with presumed familial origin.

  Authors: Ulrike Bacher, Sunday Ocheni, Philippe Schafhausen, Anthony Oyekunle, Judith Dierlamm, Axel Rolf Zander, Carsten Bokemeyer, Torsten Haferlach, Nicolaus Kröger

  Acta haematologica. 09/2011; 126(4):234-7.

  No abstract available.

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• Current standards and new trends in the primary treatment of colorectal cancer.

  Authors: Alexander Stein, Djordje Atanackovic, Carsten Bokemeyer

  European journal of cancer (Oxford, England : 1990). 09/2011; 47 Suppl 3:S312-4.

• Epidermal growth factor receptor protein expression and genomic alterations in renal cell carcinoma.

  Authors: Sarah Minner, Dorothea Rump, Pierre Tennstedt, Ronald Simon, Eike Burandt, Luigi Terracciano, Holger Moch, Waldemar Wilczak, Carsten Bokemeyer, Margit Fisch, Guido Sauter, Christian Eichelberg

  Cancer. 08/2011;

  BACKGROUND: Epidermal growth factor receptor (EGFR) is involved in the progression of many cancer types and represents an important therapeutic target. METHODS: To determine the role of EGFR in renalBACKGROUND: Epidermal growth factor receptor (EGFR) is involved in the progression of many cancer types and represents an important therapeutic target. METHODS: To determine the role of EGFR in renal cell carcinoma (RCC), the authors analyzed 1088 tumors in a tissue microarray format by using immunohistochemistry and fluorescence in situ hybridization (FISH). A subset of 63 cancers was sequenced for EGFR exon 18 through 21 mutations. RESULTS: EGFR expression was observed in 83.8% of clear cell carcinomas, in 68.2% of papillary carcinomas, in 75% of chromophobe carcinomas, and in 50% of oncocytomas. Within clear cell carcinomas, the expression level of EGFR was associated with high tumor grade (P < .0001), advanced pathologic tumor classification (P < .0001), and, to a lesser extent, lymph node status (P = .0326). FISH analysis revealed increased EGFR copy numbers (high polysomy) in 5.5% of tumors and amplification in 0.1% of tumors. EGFR copy number increases were associated with EGFR protein expression (P = .0015). Within clear cell carcinomas, EGFR copy number increases were associated with high tumor grade (P < .0001), advanced pathologic tumor classification (P = .0472), and lymph node status (P = .0065). No exon 18 through 21 mutations were identified in 63 sequenced tumors. CONCLUSIONS: The authors concluded that increased EGFR expression occurs in a fraction of patients who have RCC with an unfavorable histologic phenotype. EGFR copy number gain represents 1 possible cause for EGFR overexpression; however, many over expressing tumors have a normal genotype. High polysomy (which is suggested to be predictive of a response to tyrosine kinase inhibitors) occurs in 5.6% of RCCs. Thus, the potential utility of anti-EGFR medications may be worth further investigation in a small but significant subset of patients with RCC. Cancer 2011;. © 2011 American Cancer Society.

• EAU guidelines on testicular cancer: 2011 update.

  Authors: Peter Albers, Walter Albrecht, Ferran Algaba, Carsten Bokemeyer, Gabriella Cohn-Cedermark, Karim Fizazi, Alan Horwich, Maria Pilar Laguna

  European urology. 08/2011; 60(2):304-19.

  On behalf of the European Association of Urology (EAU), guidelines for the diagnosis, therapy, and follow-up of testicular cancer were established. This article is a short version of the EAUOn behalf of the European Association of Urology (EAU), guidelines for the diagnosis, therapy, and follow-up of testicular cancer were established. This article is a short version of the EAU testicular cancer guidelines and summarises the main conclusions from the guidelines on the management of testicular cancer. Guidelines were compiled by a multidisciplinary guidelines working group. A systematic review was carried out using Medline and Embase, also taking Cochrane evidence and data from the European Germ Cell Cancer Consensus Group into consideration. A panel of experts weighted the references, and a level of evidence and grade of recommendation were assigned. There is a paucity of literature especially regarding longer term follow-up, and results from a number of ongoing trials are awaited. The choice of treatment centre is of the utmost importance, and treatment in reference centres within clinical trials, especially for poor-prognosis nonseminomatous germ cell tumours, provides better outcomes. For patients with clinical stage I seminoma, based on recently published data on long-term toxicity, adjuvant radiotherapy is no longer recommended as first-line adjuvant treatment. The TNM classification 2009 is recommended. These guidelines contain information for the standardised management of patients with testicular cancer based on the latest scientific insights. Cure rates are generally excellent, but because testicular cancer mainly affects men in their third or fourth decade of life, treatment effects on fertility require careful counselling of patients, and treatment must be tailored taking individual circumstances and patient preferences into account.

• ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy.

  Authors: Sarah Minner, Malaika Enodien, Hüseyin Sirma, Andreas M Luebke, Antje Krohn, Pascale S Mayer, Ronald Simon, Pierre Tennstedt, Julia Müller, Laura Scholz, Jan C Brase, Alvin Y Liu, Hartmut Schlüter, Klaus Pantel, Udo Schumacher, Carsten Bokemeyer, Thomas Steuber, Markus Graefen, Guido Sauter, Thorsten Schlomm

  Clinical cancer research : an official journal of the American Association for Cancer Research. 07/2011; 17(18):5878-88.

  About 50% of prostate cancers have TMPRSS2-ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive andAbout 50% of prostate cancers have TMPRSS2-ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes. A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines. ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity. The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials.

• Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia.

  Authors: Djordje Atanackovic, Tim Luetkens, Benjamin Kloth, Gregor Fuchs, Yanran Cao, York Hildebrandt, Sabrina Meyer, Katrin Bartels, Henrike Reinhard, Nesrine Lajmi, Susanna Hegewisch-Becker, Georgia Schilling, Uwe Platzbecker, Guido Kobbe, Thomas Schroeder, Carsten Bokemeyer, Nicolaus Kröger

  American journal of hematology. 07/2011; 86(11):918-22.

  Cancer-testis antigens (CTA) represent attractive targets for tumor immunotherapy. However, a broad picture of CTA expression in acute myeloid leukemia (AML) is missing. CTA expression was analyzedCancer-testis antigens (CTA) represent attractive targets for tumor immunotherapy. However, a broad picture of CTA expression in acute myeloid leukemia (AML) is missing. CTA expression was analyzed in normal bone marrow (BM) as well as in AML cell lines before and after treatment with demethylating agents and/or histone acetylase inhibitors. Presence of selected CTA with a strictly tumor-restricted expression was then determined in samples of patients with AML before and after demethylating therapy. Screening AML cell lines for the expression of 20 CTA, we identified six genes (MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and SPO11) with an AML-restricted expression. Analyzing the expression of these CTA in blast-containing samples from AML patients (N = 64), we found all samples to be negative for MAGE-A3 and SPO11 while a minority of patients expressed ROPN1 (1.6%), SCP-1 (3.1%), or SLLP1 (9.4%). The only CTA expressed in substantial proportion of patients (53.1%) was PRAME. Following demethylating treatment with 5'-aza-2'-deoxycytidine, we observed an increased or de novo expression of CTA, in particular of SSX-2, in AML cell lines. In AML patients, we detected increased expression of PRAME and induction of SSX-2 after demethylating therapy with 5-azacytidine. With the exception of PRAME, CTA are mostly absent from AML blasts. However, demethylating treatment induces strong expression of CTA, particularly of SSX-2, in vitro and in vivo. Therefore, we propose that CTA-specific immunotherapy for AML should preferentially target PRAME and/or should be combined with the application of demethylating agents opening the perspective for alternative targets like CTA SSX-2.

• Succinate reverses in-vitro platelet inhibition by acetylsalicylic acid and P2Y receptor antagonists.

  Authors: Brigitte Spath, Arne Hansen, Carsten Bokemeyer, Florian Langer

  Platelets. 07/2011; 23(1):60-8.

  High on-treatment platelet reactivity has been associated with adverse cardiovascular events in patients receiving anti-platelet agents, but the molecular mechanisms underlying this phenomenon remainHigh on-treatment platelet reactivity has been associated with adverse cardiovascular events in patients receiving anti-platelet agents, but the molecular mechanisms underlying this phenomenon remain incompletely understood. Succinate, a citric acid cycle intermediate, is released into the circulation under conditions of mitochondrial dysfunction due to hypoxic organ damage, including sepsis, stroke, and myocardial infarction. Because the G protein-coupled receptor (GPCR) for succinate, SUCNR1 (GPR91), is present on human platelets, we hypothesized that succinate-mediated platelet stimulation may counteract the pharmacological effects of cyclooxygenase-1 and ADP receptor antagonists. To test this hypothesis in a controlled in-vitro study, washed platelets from healthy donors were treated with acetylsalicylic acid (ASA) or small-molecule P2Y(1) or P2Y(12) inhibitors and subsequently analyzed by light transmittance aggregometry using arachidonic acid (AA), ADP and succinate as platelet agonists. Aggregation in response to succinate alone was highly variable with only 29% of donors showing a (mostly delayed) platelet response. In contrast, succinate reproducibly and concentration-dependently (10-1000 µM) enhanced platelet aggregation in response to low concentrations of exogenous ADP. Furthermore, while succinate alone had no effect in the presence of platelet inhibitors, responsiveness of platelets to ADP after pretreatment with P2Y(1) or P2Y(12) antagonists was fully restored, when platelets were co-stimulated with 100 µM succinate. Similarly, succinate completely (at 1000 µM) or partially (at 100 µM) reversed the inhibitory effect of ASA on AA-induced platelet aggregation. In contrast, succinate failed to restore platelet responsiveness in the presence of both ASA and the P2Y(12) antagonist, suggesting that concomitant signaling via different GPCRs was required. Essentially identical results were obtained, when flow cytometric analysis of surface CD62P expression was used as a different readout for platelet activation. In summary, extracellular succinate may have a co-stimulatory role in platelet aggregation and, by (partially) antagonizing the effects of platelet inhibitors, may contribute to the inter-individual variability frequently observed in platelet function testing.

• Long-term survival after treatment with gemcitabine and oxaliplatin with and without paclitaxel plus secondary surgery in patients with cisplatin-refractory and/or multiply relapsed germ cell tumors.

  Authors: Karin Oechsle, Christian Kollmannsberger, Friedemann Honecker, Frank Mayer, Cornelius F Waller, Jörg T Hartmann, Ina Boehlke, Carsten Bokemeyer

  European urology. 06/2011; 60(4):850-5.

  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-doseChemotherapy 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%. Most studies have been published with a short follow-up. We present the long-term outcome of two previously reported trials. 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). 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%). 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. 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. 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.

• Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer.

  Authors: Sarah Minner, Franziska Kraetzig, Michael Tachezy, Ergin Kilic, Markus Graefen, Waldemar Wilczak, Carsten Bokemeyer, Hartwig Huland, Guido Sauter, Thorsten Schlomm

  Human pathology. 06/2011; 42(12):1946-52.

  Activated leukocyte cell adhesion molecule (CD166) is a member of the immunoglobulin superfamily and is aberrantly expressed in different tumors, including prostate cancer. To learn more on theActivated leukocyte cell adhesion molecule (CD166) is a member of the immunoglobulin superfamily and is aberrantly expressed in different tumors, including prostate cancer. To learn more on the prevalence and clinical significance of activated leukocyte cell adhesion molecule expression in prostate cancer, a tissue microarray containing 3261 primary prostate cancers treated by radical prostatectomy was used. A total of 2390 different prostate cancers were analyzed by immunohistochemistry in a tissue microarray format. Activated leukocyte cell adhesion molecule immunostaining in cancers was compared with clinical follow-up, which was available for 1746 patients. Membranous activated leukocyte cell adhesion molecule immunostaining was recorded in 1663 (69.6%) of cases. High activated leukocyte cell adhesion molecule expression levels were significantly associated with favorable tumor features (pT: P = .0015; pN: P = .0008; preoperative prostate-specific antigen: P = .0057) and a lower risk of a biochemical recurrence (P = .0067). Cytoplasmatic activated leukocyte cell adhesion molecule staining was usually associated with membranous staining. The small number of cancers with pure cytoplasmatic staining did not reveal any particularities with respect to clinical outcome or tumor phenotype. It is concluded that activated leukocyte cell adhesion molecule protein is almost always expressed in prostate cancer and that decreased levels of activated leukocyte cell adhesion molecule expression may lead to an aggressive behavior of tumor cells. The abundant presence of activated leukocyte cell adhesion molecule and its membranous localization in prostate cancer epithelium make activated leukocyte cell adhesion molecule a potentially attractive structure for targeted therapy.