Citations

Abstract Introduction: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, which is the most prevalent kidney cancer among adults. Of the patients who develop this disease, over 1/3 will already present with advanced or metastatic disease during initial diagnosis due to the lack of symptoms in early stages. RCC demonstrates considerable resistance to radiation and traditional chemotherapeutics. Despite advances in the development of targeted anti-cancer treatments, no current drug therapy leads to significant improvement in long term survival in patients with advanced disease with the rare exception of those who respond to immunotherapy. Additionally, patients inevitably develop drug resistance. Therefore new molecular targets for therapy are sorely needed. Our group has identified stearoyl coA desaturase (SCD1) as a novel molecular target in ccRCC. We examined its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current FDA approved regimens. Methods: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decrease tumor cell proliferation and induce apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of SCDi treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum (ER) stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of SCDi with temsirolimus synergistically inhibits tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. These findings support the further evaluation of targeting SCD1 as an anti-cancer strategy in a phase I clinical trial. Citation Format: Christina A. von Roemeling, Laura Marlow, Thomas Caulfield, Kevin Wu, Winston Tan, Han Tun, John A. Copland, Adam Mathias, Chuck Harrison, Louis Dawson, Beth Hollister. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. [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 LB-210. doi:10.1158/1538-7445.AM2013-LB-210

SummaryChildren and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (≥25% blasts) and/or CNS‐positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375 mg/m2) and the standard chemotherapy arm of our previously reported French‐American‐British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease ± leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3‐year event‐free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76–96%) in the entire cohort and 93% (95% CI, 61–99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy ± rituximab for high‐risk patients is currently under investigation.

AbstractVitamin D deficiency is common among patients with end‐stage liver disease (ESLD). The primary aim of our study was to assess the prevalence of vitamin D deficiency, secondary hyperparathyroidism, and bone disease in patients with ESLD awaiting LT.MethodsWe retrospectively studied 190 patients at our center. Serum total 25‐hydroxyvitamin D (25‐OH D), parathyroid hormone (PTH), calcium, and bone mineral analysis (BMA) were recorded. Standard World Health Organization (WHO) criteria were used to diagnose osteopenia/osteoporosis. Only patients with normal serum creatinine were analyzed.ResultsThirty‐two of 190 patients were excluded from the final analysis (missing serum total 25‐OH D levels in three patients and elevated serum creatinine, 29 patients). 105 of 158 (66.4%) evaluable patients had 25‐OH D levels <25 ng/mL. Patients included in the analysis (n = 158) were divided according to serum total 25‐OH D levels: 0–10 ng/mL (n = 23), 11–20 ng/mL (n = 64), and >20 ng/mL (n = 71). There were no significant differences in mean serum PTH and corrected calcium levels among the three subgroups. Only three patients had elevated serum PTH. Patients with total 25‐OH D ≤ 10 ng/mL had higher model for end‐stage liver disease (MELD) scores vs. those with 25‐OH D > 20 ng/mL (13.3 ± 3, range 8–21, vs. 11.9 ± 3.4, range 6–29, p = 0.004). Irrespective of vitamin D status, bone disease was present in 64.6% of patients.ConclusionLow vitamin D levels and bone disease are common among patients with ESLD awaiting LT. Despite a high prevalence of low serum total 25‐OH D, our cohort maintained normal corrected calcium levels and did not develop secondary hyperparathyroidism. We propose that free serum 25‐OH D and vitamin D‐binding protein may be necessary to accurately establish the diagnosis of vitamin D deficiency in the setting of ESLD. Additional studies are needed to further define mechanisms of bone disease in patients with ESLD.

Key Points Distinct clusters exist within polycythemia vera, essential thrombocythemia, and myelofibrosis. Clusters are not direct surrogates for current prognostic scores.

AbstractTranslational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

SummaryLaboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non‐Hodgkin lymphoma (B‐NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III‐IV, bone marrow+ and/or central nervous system+ mature B‐NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well‐tolerated and there were no grade III–IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2× upper limit of normal had a significantly elevated uric acid level (P = 0·005), increased incidence of TLS (P−0·005) and lower glomerular filtration rate (GFR; P < 0·001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (P = 0·0007) and only 1·3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.