Christiane Jakob

Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF‐prolyl hydroxylase‐2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2‐deficient myeloid cells and T‐lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future.

Intimal Pulmonary Artery Sarcoma Presenting as Severe Dyspnea and Right Heart Insufficiency

Background: Pulmonary artery sarcoma is a rare tumor with a poor prognosis. Case Report: We report the case of a 64-year-old man with an intimal pulmonary artery sarcoma presenting with severe high oxygen flow-demanding dyspnea and weight loss of 12 kg in the last 6 months. On echocardiography, right heart insufficiency, markedly elevated right ventricular pressure, a pressure gradient along the right outflow tract, and a tumor mass adherent to the wall of the truncus pulmonalis were detected. The tentative diagnosis by echocardiographic findings was pulmonary artery sarcoma. Computed tomography of the thorax and 18-fluorodeoxyglucose positron emission tomography showed an advanced local tumor manifestation. Surgical resection of the tumor to improve hemodynamics confirmed the diagnosis. Conclusions: Pulmonary artery sarcoma should be considered as a rare differential diagnosis in patients with dyspnea due to right heart failure, particular in the case of additional weight loss, and echocardiographic examination is a useful first diagnostic approach in establishing the diagnosis.

Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS).

The mammalian‐target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro‐proliferative and anti‐apoptotic stimuli and is involved in regulatory T‐cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion‐dependent/neutropenic or relapsed/refractory to 5‐azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower‐ and 11 higher‐risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower‐risk group and 296 days in the higher‐risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro‐inflammatory T‐helper‐cell subsets within the peripheral blood or BM. We conclude that mTOR‐modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.

Deletion 13q14 in Plasma Cells of a Patient with Lupus Erythematosus and Autoimmune Hepatitis

The molecular mechanisms that lead to autoantibody production and autoimmune disease remain poorly defined. Based on a clinical observation in a patient with lupus erythematosus and autoimmune hepatitis we here provide the first evidence that (i) a particular cytogenetic aberration (deletion (13)(q14)) could be detected in a proportion of plasma cells and that (ii) the surface marker CD56 could be used to enrich for plasma cells with this cytogenetic aberration.

Abstract 5526: Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive surgery. Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5526. doi:1538-7445.AM2012-5526

Deutsche Osteoonkologische Gesellschaft gegründet

zudem Dr. Holger Uhthoff, Speyer (Schatzmeister) und Prof. Dr. M. Heinrich Seegenschmiedt, Hamburg (Schriftführer) an. Zu Beisitzern wurden PD Dr. Christian Eberhardt, Hanau, Prof. Dr. Tanja Fehm, Tübingen, Prof. Dr. Franz Jakob, Würzburg, und PD Dr. Florian Schütz, Heidelberg berufen. Die Gesellschaft umfasst derzeit 45 Gründungsmitglieder. Mitglied werden kann jeder, der sich wissenschaftlich mit dem Gebiet der Osteoonkologie beschäftigt. Die Gesellschaft wird als Verein eingetragen und die Gemeinnützigkeit wird beantragt.

Multislice spiral computed tomography of an orthotopic severe combined immunodeficient mouse model for lung adenocarcinoma

Summary Background and Aim: In recent years, much research interest has been rightfully directed towards modelling human disease. The increasing demand of laboratory animals has led to a major impetus in small animal imaging. We evaluated the feasibility of using multislice spiral CT (MSCT) technology in a severe combined immunodeficiency (SCID) mouse model for non-small cell lung cancer. Materials and Methods: Mice (n = 14) were implanted orthotopically with the human non-small cell lung adenocarcinoma cell line A 549. Mice were scanned with MSCT and sacrificed 7 days (n = 3), 14 days (n = 3), and 21 days (n = 5) after tumor cell implantation, respectively. Histopathology was performed. Tumor size as revealed by imaging and pathology was correlated. A group of animals (n = 3) received anti-cancer treatment with seco-CBI-Q-galatoside. Those mice were scanned with MSCT 21 days after tumor implantation and sacrificed, and histopathologic work-up was performed. Results: A total of 14 mice with 14 macroscopically visible and 5 microscopically appreciable adenocarcinomas of the lung were examined. All macroscopically visible tumors were readily depicted with MSCT except from 2 lesions of 1 mm in diameter. MSCT accurately displayed the different tumor sizes in treated vs. non-treated animals. Discussion: MSCT proved to be a valuable tool for imaging of a murine lung cancer model. This evidences a potential use of this technology in small animal lung cancer imaging.