Differing Von Hippel Lindau Genotype in Paired Primary and Metastatic Tumors in Patients with Clear Cell Renal Cell Carcinoma

In sporadic clear cell renal cell carcinoma (CCRCC), the von Hippel Lindau (VHL) gene is inactivated by mutation or methylation in the majority of primary (P) tumors. Due to differing effects of wild-type (WT) and mutant (MT) VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization analysis studies have reported genetic differences between paired P and metastatic (M) tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s) in patients with CCRCC. Using paraffin-embedded specimens, genomic DNA from microdissected samples (>80% tumor) of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GenBank Accession No. AF010238). Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40%) patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients

Update on Dendritic Cell-Induced Immunological and Clinical Tolerance.

Dendritic cells (DCs) as highly efficient antigen-presenting cells are at the interface of innate and adaptive immunity. As such, they are key mediators of immunity and antigen-specific immune tolerance. Due to their functional specialization, research efforts have focused on the characterization of DCs subsets involved in the initiation of immunogenic responses and in the maintenance of tissue homeostasis. Tolerogenic DCs (tolDCs)-based therapies have been designed as promising strategies to prevent and control autoimmune diseases as well as allograft rejection after solid organ transplantation (SOT). Despite successful experimental studies and ongoing phase I/II clinical trials using autologous tolDCs in patients with type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and in SOT recipients, additional basic research will be required to determine the optimal DC subset(s) and conditioning regimens for tolDCs-based treatments in vivo. In this review, we discuss the characteristics of human DCs and recent advances in their classification, as well as the role of DCs in immune regulation and their susceptibility to in vitro or in vivo manipulation for the development of tolerogenic therapies, with a focus on the potential of tolDCs for the treatment of autoimmune diseases and the prevention of allograft rejection after SOT

A Decision Analysis To Determine the Appropriate Treatment for Low-Risk Myelodysplastic Syndromes

Abstract Patients with low-risk myelodysplastic syndromes (MDS), defined as refractory anemia (RA), RA with ringed sideroblasts (RARS), or International Prognostic Scoring System (IPSS) scores of 0–1.0, are treated with growth factors (GF) or chemotherapy (Chemo) in the setting of transfusion dependence. Predictive models (PM) for response to GF have been developed based on red blood cell (RBC) transfusion needs and erythropoietin (epo) levels, but report no difference in survival among good, intermediate, and poor PM groups (the PM good group has few transfusion needs and a low epo level, while the PM poor group has high transfusion needs and high epo levels: Jadersten et al. Blood2005;106:803). The optimal therapy (chemo vs. GF) based on response rates (RR) and survival has not been defined. Methods: We performed a decision analysis to determine the optimal therapy for low-risk MDS patients. Patients receiving chemo (n=417) or GF (n=382) were identified from a MEDLINE search on the keywords MDS, RA, RARS, treatment, GF, and chemo. Original articles with individual patient characteristics, RA or RARS MDS subtypes, and documented effect of therapy were included. From 1985 to 2005, 137 papers representing 2,301 patients with low-risk MDS were reviewed. Individual data was available on 799 patients. Chemo included differentiating agents, immunomodulators, and non-ablative cytotoxic agents; GF included erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. IPSS was calculated when sufficient data were available. RR were standardized and recalibrated according to the International Working Group (IWG) criteria and included complete response, partial response, and hematologic improvement. Median survival in GF patients derived from the Jadersten et al. study, and was validated with data from GF patients in our database. Survival in chemo patients was determined from the database. Cut-points for which treatment strategy to choose, based on RR and survival, were calculated. Results: Baseline variables for chemo patients included (median (range)): age 65(21–83) years; requiring 2(0–8) units RBC transfusions/month; having an epo level of 279(17–4590). IPSS score was 0–1.0 in 88.3% of patients. GF patients were older (72 years, range 43–87), but with similar transfusion needs, IPSS scores, and epo levels to chemo patients. Overall, patients receiving chemo had a RR of 41.5% and a median survival of 78 months, compared to 46% and 44 months, respectively, for GF patients. Survival and RR differences were not statistically significant. Using the decision model, patients in a PM good response group should receive GF unless chemo can yield a RR at a cut-point of >34.1%. Patients in the PM intermediate response group should receive chemo if the RR to chemo is >10.6%; and those in the PM poor response group should receive chemo if the RR to chemo is >3.2%. RR and median survivals for chemo patients did not differ when they were classified according to the three PM response groups. Conclusions: Based on available survival data, low-risk MDS patients falling into a good response predictive group (low RBC transfusion needs and low epo levels) should be treated with GF unless chemo RR are >34.1%. Other low-risk MDS patients should probably be treated with chemo. Additional cost and quality of life data are needed to incorporate into future decision models