Patrick Brück

Dying of hematologic patients--treatment characteristics in a German University Hospital.

The treatment of hematologic patients in palliative situations remains a major challenge as there are special clinical needs, e.g., transfusions and the high risk for infectious complications with subsequent use of broad anti-infective treatment. Furthermore, most hematologic patients have a relatively long history of disease and are acquainted with “their” wards; that is why most are treated on these hematologic and not on specialized palliative wards. The standardized approach to the care of hematologic patients with curative treatment intention is probably not fully appropriate for palliative patients. In order to evaluate the current situation of treatment characteristics in a German university hospital, we retrospectively evaluated the medical documentation of all patients who died on a hematologic ward between 2005 and 2008. While we found a high number of chemotherapeutic, anti-infective, analgesic, and sedative treatments, of transfusions, of treatment on the intensive care units, and of invasive nature, non-somatic interventions were rather scarce. Symptom control, e.g., for bleeding events or pain, was frequently not adequately achieved. With regard to the palliative situation, a holistic approach with the maintenance of patients’ autonomy and the preference for dying at home, the treatment of hematologic patients in a palliative situation has to be reconsidered.

Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell carcinoma

There is increasing evidence that vitamin D metabolites influence carcinogenesis. Besides its role in mineral homoeostasis, calcitriol, the active metabolite of vitamin D (1,25(OH)2D3), is known to possess antiproliferative, proapoptotic and immunomodulatory effects in cancer. Concerning the synthesis of vitamin D, the hydroxylases CYP2R1, CYP27B1 and CYP24A1 play a critical role, and the latter molecule determines the biological half‐life of 1,25(OH)2D3, which is synthesized in the proximal renal tubules.

Polymorphisms of CXCR3-binding chemokines in type 1 diabetes

Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease. Although the precise mechanisms leading to the destruction of islet beta cells are unknown, diverse studies support a role of the CXCR3-binding chemokines. A combination of a case (n = 447)-control (n = 300) and family (n = 221) analysis was performed to investigate the role of the CXCL9 (rs10336, rs3733236) and CXCL10 (rs3921, rs35795399 and rs8878) polymorphisms and their interaction with HLA high-risk haplotypes DQ2(DQA*0501-DQB*0201)-DQ8(DQA*0301-DQB*0302) in T1D. In addition, the mRNA expression of these genes and of the CXCR3 in peripheral blood mononuclear cells (PBMCs) of T1D patients was studied. In the family analysis, an overtransmission of the allele T and G of the polymorphisms rs35795399 and rs8878 in the whole group (p = 0.0520 and p = 0.0290, respectively) as well as in combination with the HLA-high risk haplotypes (p = 0.0209 and 0.0340, respectively) were observed. In addition, the haplotype rs8878G-rs35795399T was more often transmitted from parents to affected offspring, whereas the haplotype rs8878A-rs35795399C was less often transmitted (p = 0.0130 and p = 0.0201, respectively). Nevertheless these associations did not remain significant after correction for multiple testing, and they could not be corroborated in the case-control analysis. Although we did not find an association of the CXCL9 and CXCL10 polymorphisms with type 1 diabetes in the German population, we cannot discard their role in other populations or other autoimmune diseases.

Nonsecretory Primary Plasma Cell Leukemia with Good Response to Thalidomide-Based Treatment

Primary plasma cell leukemia (PCL) is a rare hematologic disorder with distinct features. The criterion for the diagnosis of PCL is based on the finding of malignant plasma cells in the peripheral blood (more than 2 × 109/L or more than 20% of white blood cells). We report a case of a 74-year-old patient with primary nonsecretory PCL. Examination of blood smears led to the diagnosis of PCL, which was confirmed by bone marrow biopsy. Due to the patient’s impaired general condition, intensive chemotherapy could not be administered. After an oral induction chemotherapy consisting of cyclophosphamide and high-dose dexamethasone followed by one cycle of high-dose dexamethasone and thalidomide no evidence of the disease in the peripheral blood was detectable. Consequently, the patient was put on a thalidomide maintenance therapy. Six months after first diagnosis, the patient was found to have bone marrow and peripheral blood relapse with anemia and neutropenia in the clinical context of acute on chronic renal failure. After a limited response to further chemotherapy, the patient died 14 months after the first diagnosis while on dexamethasone maintenance. We conclude that monotherapy with thalidomide might be an alternative maintenance strategy with limited response duration for patients with primary PCL in impaired general condition.

Abstract 4773: Is upregulation of CYP2R1-, CYP27B1- and CYP24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Renal cell carcinoma (RCC) represent approximately 3-5% of all malignancies reported each year. Among these clear cell renal cell carcinoma (ccRCC) represent the most frequently diagnosed histological classification accounting for 80% of renal cell carcinoma. The incidence has been reported to be higher in countries located at higher latitudes. In this context UVB-light which is essential for the synthesis of vitamin D has been inversely associated with the development of diverse carcinomas including renal cell carcinoma. Further steps of vitamin D synthesis are performed by CYP2R1, CYP27B1 and CYP24. We therefore investigated the quantitative mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in patients (n=29) with ccRCC. For this purpose total RNA was isolated from tumor and corresponding adjacent healthy tissues of all patients and integrity was assessed on a denaturing agarose gel stained with ethidium bromide. Intact RNA was transcribed using random hexameric primers and reverse transcriptase. Reverse transcription was performed and amplified by real-time PCR. Statistic association was evaluated by Mann-Whitney-Test and Kruskal-Wallis-Test. A P value less than 0.05 was considered significant. mRNA of all three genes (CYP2R1, CYP27B1 and CYP24) was expressed in both normal and carcinoma tissue with a significant upregulation in carcinoma tissue compared to normal tissue (p<0.0001). In tumor tissue CYP24 displayed a significantly higher expression than CYP27B1 or CYP2R1. Furthermore CYP27B1 showed a higher expression than CYP2R1 (p<0.0001). No differences in the expression of CYP2R1, CYP27B1 and CYP24 were found in normal renal tissue. We therefore conclude that differing gene expression of CYP2R1, CYP27B1 and CYP24 in normal- and carcinoma tissue could be involved in the pathogenesis of renal cell carcinoma. Citation Format: Anja E. Urbschat, Patrick Paulus, Quirine Freiin von Quernheim, Patrick Bruck, Elizabeth Ramos-Lopez. Is upregulation of CYP2R1-, CYP27B1- and CYP24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2013-4773