Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

PURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS: Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION: Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.     

Molecular heterogeneity of sporadic adult Burkitt-type leukemia/lymphoma as revealed by PCR and cytogenetics: correlation with morphology, immunology and clinical features.

Chromosomal translocations involving the MYC oncogene are a hallmark of Burkitt lymphoma but they are only found in a varying frequency in mature Burkitt-type acute lymphoblastic leukemia (B-ALL). We have investigated samples of 56 sporadic Burkitt leukemia/lymphoma patients for the translocations t(8;14)(q24;q32), t(2;8)(p11;q24) and t(8;22)(q24;q11). Long PCR was used for detecting the immunoglobulin heavy chain (IgH) translocation and cytogenetics and/or fluorescence in situ hybridization for detecting the 'variant' MYC translocations. A total of 29 samples (51.8%) were t(8;14)-positive by long PCR. Approximately one-third had a chromosomal breakpoint in the IgH joining region while the others had breakpoints in the IgH switch regions. Among them were two cases with a previously unreported MYC translocation into the IgE switch region. Long PCR was more reliable compared to conventional cytogenetics for detecting the t(8;14). Epstein-Barr virus was detected in high copy number in two (3.6%) t(8;14)-positive cases by real-time quantitative PCR. Human herpesvirus 8 was not detected in any case by nested PCR. A typical L3 or L3-compatible cytomorphology was highly predictive (>80%) but not specific of a MYC translocation. A total of 34 patients were treated according to the GMALL B-ALL therapy protocols and there was no significant difference in overall survival between patients with or without t(8;14).     

Detection of spontaneous CD4+ T-cell responses in melanoma patients against a tyrosinase-related protein-2-derived epitope identified in HLA-DRB1*0301 transgenic mice.

PURPOSE: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell-based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified. Whereas a number of HLA class I-presented TRP-2-derived epitopes are known, information about HLA class II-presented antigenic ligands recognized by CD4+ T helper (Th) cells is limited. EXPERIMENTAL DESIGN: The search for TRP-2-derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301 ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in human T-cell cultures. RESULTS: This strategy led to the characterization of TRP-2(60-74) as an HLA-DRB1*0301-restricted Th epitope. Importantly, TRP-2(60-74)-reactive human CD4+ Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03+ melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-2(60-74)-reactive T cells, suggesting that these T cells were already activated in vivo. CONCLUSION: Peptide TRP-2(60-74) might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.     

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.     

Characterization of supercritical fluid extracts of St. John's wort (Hypericum perforatum L.) by HPLC-MS and GC-MS.

Supercritical fluid extracts (carbon dioxide without modifiers) of St. John's Wort (Hypericum perforatum L., Clusiaceae) were analyzed by GC-MS, HPLC-DAD and HPLC-DAD-MS. Besides the dominating phloroglucinols hyperforin (36.5 +/- 1.1%) and adhyperforin (4.6 +/- 0.1%), the extracts mainly contained alkanes (predominantly nonacosane), fatty acids and wax esters. The apolar components tended to accumulate in a waxy phase resting a top of the hyperforin-enriched phase. No components of higher polarity like naphthodianthrones were found. A set of hyperforin oxidation products was detected and tentatively assigned using HPLC-MS.     

CYP1A2 and NAT2 genotype/phenotype relations and urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a human dietary intervention study.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.     

Empfehlungen und Standards für die Analgosedierung kinderkardiologischer Patienten

Monatsschrift Kinderheilkunde - Bei kinderkardiologischen Patienten bzw. Kindern mit angeborenen Herzfehlern werden häufig diagnostische oder therapeutische Prozeduren durchgeführt, die...     

Trends in the diagnosis of melanoma at a university center over time

Background and objectives: The aim of this study is to show data regarding trends in the diagnosis of melanoma over the last ten years by looking at the University Clinic of Dermatology in Vienna as an example. Patients and methods: All excised melanocytic lesions from 1998 to 2008 were included. Results: The ratio of excisions of benign to malignant lesions fell from 7:1 (1998) to 4:1 (2008). The mean percentage of in situ melanomas was 39% in 1998 and did not change significantly over time and no change was seen in tumor thickness of invasive melanomas. The median invasion depth was 0.7 mm in 1998 and 0.65 mm in 2008. The absolute number of diagnosed melanomas did not change significantly over time. Conclusion: The proportion of in situ melanomas was consistently high. Tumor thickness stayed at a low level, whereas the number of excised benign melanocytic lesions decreased significantly.     

Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy

CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action.