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It has been well-established that cancer results in a hypercoagulable state and an increased risk for venous thromboembolism (VTE). More recently, it has been suggested that coagulation may also affect cancer progression and metastasis. Cancer patients with VTE are currently treated with the anticoagulant low molecular weight heparins (LMWHs). Preclinical studies have shown that LMWHs can inhibit metastasis formation in several types of cancer, but beneficial effects of LMWHs on survival have not been consistently found in clinical trials. Recently, a new class of anticoagulants are available for treatment of VTE, the so-called direct oral anticoagulant (DOACs), which include dabigatran and rivaroxaban, a direct thrombin and FXa inhibitor, respectively. However, the effects of DOACs on cancer are currently under studied.

Summary Objective Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS). Design In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mm for 0–48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well. Results Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed. Conclusions The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.

Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. Despite initial beneficial responses on metastatic tumor burden this is frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasis-initiating subpopulations of osteotropic cancers ("the seed") together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma ("the soil").

Purpose: Multidrug resistance (MDR) is a significant obstacle to successful chemotherapy and a major prognostic factor in osteosarcoma (OS). We have previously observed that the chemosensitivity of OS cell lines to doxorubicin depends on P-glycoprotein (Pgp) and can be predicted based on functional assays using 99mTc-Sestamibi (MIBI). These results prompted us to develop an orthotopic model of OS for in vivo imaging of MDR and pharmacological inhibition with MIBI.

It is clear from the work presented in this chapter and from work by others that BLI is perfectly suited to monitor gene expression in transgenic reporter mice and to detect and follow small numbers of cells noninvasively. As we have shown, it also enables the quantification of tumor cells within internal organs in animal models of cancer. BLI is a powerful tool in functional genomics of cancer development, progression, and metastasis and will allow us to identify in vivo molecular targets of cancer and their metastasis. The application of BLI in combination with new animal models for cancer will allow us to study very rapidly and conveniently the efficacy of new therapeutic approaches such as gene therapy stem cell therapy and antiangiogenic therapy, and when successful can be a first step towards clinical application. Furthermore, the development of new smart luciferase-based reporter constructs as well as new possibilities to create transgenic animals containing these reporter constructs will make noninvasive in vivo BLI also a powerful new tool in other small animal models of human biology and disease.

Summary Background TSH receptor antibodies (TBII) in Graves’ disease (GD) may be TSH receptor stimulating (TSAb) and blocking (TBAb) antibodies. In commercially available assays however, only total TBII titres can be measured, without discriminating between TSAb and TBAb. Objective To design a TBII bioassay to detect of TSAb and to correlate TSAb activity with severity of hyperthyroidism in de novo GD patients. Patients Thirty-five patients with de novo GD and 27 controls. Methods The JP-26–26 cell line, which constitutively expresses the TSH receptor (TSHR), was stably transfected with a cyclic adenosine monophosphate responsive element – luciferase construct. The clone B1 exhibited a near linear increase in luminescence from 0·2 mU/l to 50 mU/l bovine TSH and was used as a TBII bioassay. TBII, free T4 and TSH were measured in the sera of all patients and controls. Results In the sera of 35 GD patients, TBII titres did not correlate with serum free T4 concentrations. In contrast, a strong and highly significant correlation was found between TSHR stimulating activity (luminescence) as measured with the TBII bioassay and serum free T4 levels (R = 0·80, P

Bisphosphonates are used with increasing frequency in the management of skeletal complications in patients with breast cancer. In this paper, we have investigated whether bisphosphonates, besides their known beneficial effects on tumor-associated osteoclastic resorption, are capable of inhibiting breast cancer cell adhesion to bone matrix. For that we used two in vitro models for bone matrix (cortical bone slices and cryostat sections of trabecular bone from neonatal mouse tails). Four bone matrix-bound nitrogen-containing bisphosphonates (pamidronate, olpadronate, alendronate, and ibandronate) inhibited adhesion and spreading of breast cancer cells to bone dose-dependently, whereas etidronate and clodronate had little or no effect. Strikingly, the relative order of potency of the bisphosphonates in inhibiting the adhesion of cancer cells to cortical and trabecular bone corresponded to their relative antiresorptive potencies in vivo as well as their ranking in in vitro bone resorption assays with predictive value for their clinical efficacy. It appears that nitrogen-containing bisphosphonates alter selectively the adhesive properties of the extracellular bone matrix preventing the attachment of breast cancer cells to it. Besides the beneficial effects of bisphosphonates on tumor-induced osteoclastic resorption, the previously unrecognized effect presented in this paper makes these agents suitable for earlier pharmacologic intervention in patients with breast cancer at risk of developing bone metastases.