Reliable Establishment of Human Sarcoma Xenografts in the Nude Rat

Purpose. The ability to establish consistent human tumor xenografts in experimental animals is a crucial part of preclinical investigations.The goal of this study was to develop a method of establishing a human tumor xenograft in the leg of a nude rat for evaluation of new surgical and molecular methods of treatments of human extremity sarcoma

Enhanced MDM2 Oncoprotein Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms

Purpose. MDM2 is an oncogene whose protein product may promote tumorigenesis by blocking wild-type p53 tumor suppressor mediated G 0/G1 cell cycle arrest, thereby inhibiting repair of damaged DNA prior to cell division. While MDM2 DNA amplification is frequently observed in human sarcoma, the mechanisms linking this amplification to MDM2 oncoprotein over-production as well as its functional significance have not been well characterized in patients with soft tissue sarcoma

A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia

Objective: Pilot trial comparing prism therapy and visual search training, for homonymous hemianopia, to standard care (information only). Methods: Prospective, multicentre, parallel, single-blind, three-arm RCT across fifteen UK acute stroke units. Participants: Stroke survivors with homonymous hemianopia. Interventions: Arm a (Fresnel prisms) for minimum 2 hours, 5 days/week over 6- weeks. Arm b (visual search training) for minimum 30 minutes, 5 days/week over 6-weeks. Arm c (standard care-information only).Inclusion criteria: Adult stroke survivors (>18 years), stable hemianopia, visual acuity better than 0.5logMAR, refractive error within 5Dioptres, ability to read/understand English, and provide consent. Outcomes: Primary outcomes were change in visual field area from baseline to 26 weeks and calculation of sample size for a definitive trial. Secondary measures included Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual, Short Form-12 questionnaires and Radner reading ability. Measures were post-randomisation at baseline and 6, 12, 26 weeks. Randomisation: Randomisation block lists stratified by site and partial/complete hemianopia. Blinding: Allocations disclosed to patients. Primary outcome assessor blind to treatment allocation. Results: 87 patients were recruited: 27 - Fresnel prisms, 30 – visual search training and 30 - standard care. 69% male; mean age 69 years (SD 12). At 26 weeks, full results for 24, 24 and 22 patients respectively were compared to baseline. Sample size calculation for a definitive trial determined as 269 participants per arm for a 200 degree2 visual field area change at 90% power. Non-significant relative change in area of visual field was 5%, 8% and 3.5% respectively for the three groups. Visual Function Questionnaire responses improved significantly from baseline to 26 weeks with visual search training (60 (SD19) to 68.4 (SD20)) Compared to Fresnel prisms (68.5 (SD16.4) to 68.2 (18.4): 7% difference) and standard care (63.7 (SD19.4) to 59.8 (SD22.7): 10% difference), p=0.05. Related adverse events were common with Fresnel prisms (69.2%; typically headaches). Conclusions: No significant change occurred for area of visual field area across arms over follow-up. Visual search training had significant improvement in vision-related quality of life. Prism therapy produced adverse events in 69%. Visual search training results warrant further investigation

Surgical management of retroperitoneal sarcoma and opportunities for global collaboration

Retroperitoneal sarcomas (RPS) are rare cancers that often reach massive size before detection. The mainstay of treatment for RPS is surgical resection, and complete resection is the only chance for potential cure. The management of RPS can be challenging and in individual cases, radiation and systemic therapy may be beneficial in both primary and recurrent disease. Further research through multi-institutional collaboration, ideally on a global level, is needed to better understand RPS and optimize management of this disease

Nuclear Skins and Halos in the Mean-Field Theory

Nuclei with large neutron-to-proton ratios have neutron skins, which manifest themselves in an excess of neutrons at distances greater than the radius of the proton distribution. In addition, some drip-line nuclei develop very extended halo structures. The neutron halo is a threshold effect; it appears when the valence neutrons occupy weakly bound orbits. In this study, nuclear skins and halos are analyzed within the self-consistent Skyrme-Hartree-Fock-Bogoliubov and relativistic Hartree-Bogoliubov theories for spherical shapes. It is demonstrated that skins, halos, and surface thickness can be analyzed in a model-independent way in terms of nucleonic density form factors. Such an analysis allows for defining a quantitative measure of the halo size. The systematic behavior of skins, halos, and surface thickness in even-even nuclei is discussed.Comment: 22 RevTeX pages, 22 EPS figures included, submitted to Physical Review

Imagine a world without cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Since the War on Cancer was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. Discussion Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patients own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. Summary Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie