Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases

Macrophages generally constitute a major component of tumor stroma, and possess either tumor growth promoting or inhibiting capabilities. Classically activated macrophages exert cytotoxicity and produce inflammatory cytokines, which limits tumor growth. By contrast, alternatively activated or M2 macrophages induce tumor progression by stimulating angiogenesis and proliferation. Previously we showed that resident macrophages control metastatic spread of coloncarcinoma cells in liver and peritoneal tumor models. However, it is proposed that newly recruited macrophages develop into tumor-associated M2 macrophages, as they are exposed to a microenvironment that favors alternative activation. Previously we showed that monocyte migration was diminished after flavonoid treatment in an experimental autoimmune encephalomyelitis animal model. In the present study, we investigated the role of newly recruited macrophages in colon carcinoma development, by using the flavonoids rutin and luteolin to reduce monocyte migration into peritoneal tumors. Increased tumor development was observed in animals that were treated with rutin and luteolin. Immunohistochemical analyses showed that the number of ED2⁺ resident macrophages was normal in tumors of animals that received rutin and luteolin treatment. However, the number of ED1⁺ cells (marker immature macrophages) was reduced, indicating decreased macrophage recruitment. Thus, inhibition of monocyte migration promotes tumor growth, supporting that not only resident, but also newly recruited macrophages limit peritoneal colon carcinoma metastases development.     

Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases

We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21(WAF1/CIP1) in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27(KIP1) was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21(WAF1/CIP1), p27(KIP1), and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation.     

Successful Combination of Sunitinib and Girentuximab in Two Renal Cell Carcinoma Animal Models: A Rationale for Combination Treatment of Patients with Advanced RCC

Anti-angiogenic treatment with tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined sunitinib, targeting the endothelial cells with Girentuximab (monoclonal antibody cG250, recognizing carbonic anhydrase IX (CAIX) targeting the tumor cells to study the effect of sunitinib on the biodistribution of Girentuximab because combination of modalities targeting tumor vasculature and tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day sunitinib, or vehicle for 7 to 14 days. Three days before start or cessation of treatment mice were injected i.v. with 0.4 MBq/5 μg ¹¹¹In-Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the tumor vasculature and CAIX expression and to confirm Girentuximab uptake.NU12 appeared to represent a sunitinib sensitive tumor: sunitinib treatment resulted in extensive necrosis and decreased microvessel density (MVD). Accumulation of Girentuximab was significantly decreased when sunitinib treatment preceded the antibody injection but remained unchanged when sunitinib followed Girentuximab injection. Cessation of therapy led to a rapid neovascularization, reminiscent of a tumor flare. SK-RC-52 appeared to represent a sunitinib-resistant tumor: (central) tumor necrosis was minimal and MVD was not affected. Sunitinib treatment resulted in increased Girentuximab uptake, regardless of the sequence of treatment. These data indicate that sunitinib can be combined with Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy.Abbreviations: mRCC, metastatic renal cell carcinoma; CAIX, carbonic anhydrase IX; cG250/girentuximab, chimeric monoclonal antibody G250; MVD, microvessel density; ccRCC, clear cell renal cell carcinoma; VEGF, vascular endothelial growth factor; RIT, radioimmunotherapy; TKI, tyrosine kinase inhibitor     

Hyperthermia treatment planning for cervical cancer patients based on electrical conductivity tissue properties acquired in vivo with EPT at 3 T MRI

Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT-based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with ΔT90 = ?1.37?°C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients ΔT90 was less than 0.6?°C; for one patient it was 1.5?°C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures.     

Designing health plan contracts for people with disabilities

Purpose: In the USA, private businesses and the federal government contract with health plan companies to arrange and provide for specific health benefits and services. Most contracts are designed around acute care services for people without disabilities. We wanted to design a health benefit programme tailored to the needs of people with disabilities. Method: We convened two expert panels. The first, comprised of experts on government programme payments and benefit design, identified key services of a programme providing care for people with disabilities. The second panel, comprised of representatives of health plan companies, simulated the contract evaluation process. Results: Model health benefit programmes for people with disabilities are similar to programmes for people without disabilities, but should provide and pay for care co-ordination, non-medical benefits, and unlimited therapy while incorporating self-directed care. As existing health plan companies consider whether or not to sign a contract to provide these programmes, operational issues carry as much weight as financial factors. Conclusion: Purchasers seeking to contract with health plans to provide innovative programmes for people with disabilities must be willing to consider pilot projects, and to give the health plan companies projected utilization and cost data so they can predict their financial risk.