Targeting Bone Metastases: New Drugs for New Targets

Bone metastases development requires multistep and multicellular machinery consisting not only of processes shared with any types of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). The aim of this review is to depict the complex sequence of events from early cancer cells dissemination to the onset of clinically detectable bone lesions with particular attention to those molecular targets that have been investigated in order to find out new therapeutical approaches helpful in reducing clinical sequelae of skeletal metastases.     

Cellular Players in Breast Cancer Bone Metastases

The current paradigm for bone metastasis is that there is a mutual interaction between osteoclasts and cancer cells, known as the tumor/bone vicious cycle. This model is based largely on findings in immune compromised animals showing amelioration of bone metastases by targeting the osteoclasts. Thus, osteoclast inhibitors are the standard of care in breast cancer bone metastasis. However, clinical studies demonstrate only a 28 % reduction in skeletal-related events in patients with bone metastases treated with bisphosphonates, and currently, there is limited evidence supporting anti-resorptive therapies in reducing the overall incidence of bone metastasis or extending survival. These data indicate that other cells, in addition to the osteoclasts, control tumor growth in bone. This review will discuss the role of the osteoclast, and then focus on additional cellular players, thus expanding the model of bone metastasis pathophysiology to include immune and stromal components.     

A Status Report on the Management of Solid Tumours

Summary: A status report on the management of solid tumours.
Progressive improvements in the management of certain paediatric and haematological malignancies have provided guidelines for the current approaches to the management of the more common solid tumours of adults. These include precise histopathological grading; comprehensive evaluation of extent of disease; staging classifications accurately correlated with prognosis and progressive evaluation of available therapeutic modalities for all stages of disease in an attempt to define the best combination of local and systemic forms of therapy.
Breast cancer is reviewed in detail as an example of the more responsive tumours where screening programs; improvements in pathological and clinical staging and the introduction of systemic chemotherapy together with optimal use of other methods of treatment for the various stages of disease gives hope for a significant improvement in long term survival statistics.
Lung cancer has also been reviewed as an example of the more resistant types of cancer where screening programmes and current therapy including the use of combination chemotherapy have given minor encouragement but not had a definite influence on long term survival. Some further gains may still be achieved with currently available techniques but major improvements will probably require the development of better therapeutic tools including radiotherapy with high linear energy transfer particles; new chemotherapeutic agents and specific forms of immunotherapy. It is also quite possible that completely different forms of therapy for these resistant tumours will be necessary to reach the desired goal of long term improvement in survival.     

Development and Validation of a Prognostic Score to Predict Survival in Adult Patients With Solid Tumors and Bone Marrow Metastases

Bone marrow metastasis (BMM) in patients with solid cancers is indicative of advanced-stage disease with a poor prognosis. The clinical features and outcomes remain unclear. We aimed to develop a scoring system to predict survival in these patients to help with clinical decision making.A total of 165 adult patients diagnosed with solid cancers and BMM between 2000 and 2014 were selected as the derivation cohort. A risk model was developed using multivariate logistic regression from the derivation cohort and a marrow metastases prognostic score (MMPS) was generated. An independent cohort of 156 patients from 3 other hospitals was selected using the same recruiting criteria to validate the MMPS as a predictor of survival.The MMPS was calculated based on 4 independent prognostic variables: the Eastern Cooperative Oncology Group performance scale, site of cancer, platelet count, and neutrophil-to-lymphocyte ratio. Patients in both the derivation and validation cohorts were stratified into good, intermediate, and poor prognostic groups based on their MMPS. The median survival in each risk group of the derivation cohort was 241, 58, and 11 days for the good, intermediate, and poor prognostic groups, respectively, and 305, 65, and 9 days, respectively, in the validation cohort. The c-statistic values for prediction of mortality at 3, 6, and 12 months were significantly higher for the MMPS than for the Eastern Cooperative Oncology Group performance scale in both cohorts.We developed a risk model that accurately predicted survival in adult patients with solid cancers and BMM. This scoring system may help patients and clinicians with treatment decisions.     

Cardiac Toxicity of Targeted Therapies Used in the Treatment for Solid Tumours: A Review

Cardiotoxicity associated with conventional cytostatics is a known phenomenon and is related to their general cytotoxic effects. This damage to the myocardium is usually irreversible. Despite the attempts to optimize safety profile of targeted anticancer drugs during their development, evidence shows that these new treatment modalities also have cardiotoxic potential or may adversely affect vascular system. Over the last years, a significant number of these agents have been introduced in medical practice. Arterial hypertension, arrhythmias, left ventricular dysfunction and a heart failure are the most frequent cardiovascular adverse effects of targeted anticancer agents, but this toxicity seems to be reversible. To enable early interventions and to minimize these cardiovascular adverse effects, health care professionals have to be well-informed and familiar with the safety profiles of the drugs they administered, the patient's cardiovascular condition and co-morbidities, and they must regularly monitor their patients for potential adverse effects. The aim of this paper is to provide an overview of cardiotoxic effects caused by targeted anticancer drugs used in the treatment of solid tumours. We discuss pathophysiological mechanisms, diagnostics and treatment, risk factors and options for prevention.     

Molecular and Biological Mechanisms of Bone Metastasis

Metastatic disease is the cause of death in the majority of cancer patients. Bone marrow is a preferential site of metastasis in breast and prostate cancer, responsible for the majority of skeletal metastases. Micrometastases are often present in the bone marrow of cancer patients and may progress to overt metastases. The survival of these cells and the development of bone metastases depend on the growth support provided by the bone microenvironment and the ability of cancer cells to adapt to this environment, often mimicking the behaviour and gene expression of cells of the bone and bone marrow environment. Experimental evidence suggests that the growth support provided by the bone microenvironment is active during bone resorption. Increased bone turnover as it occurs with hormonal deprivation, therefore, might be a risk factor for developing bone metastases. Interference with bone turnover, however, offers a novel target for preventive and adjuvant therapies. In this review possible mechanisms and factors involved in the development and progression of bone metastases, as well as the molecular, biological and physiological processes of metastases, especially to the bone, are discussed. Furthermore the role of bisphosphonates in the prevention and treatment of bone metastases is reviewed.     

Small Cystic Pancreatic Neuroendocrine Neoplasm with Huge Liver and Bone Metastases

Pancreatic neuroendocrine neoplasms occasionally have a cystic component. We herein report a case of multiple hepatic tumors, including a huge one and a 24-mm sized pancreatic cystic lesion. The hepatic tumor showed an enhancement pattern consistent with hepatic adenoma. The pancreatic cystic lesion revealed a thickened outside border and a solid inside component, which was enhanced following a contrast study, suggesting cystic pancreatic neuroendocrine neoplasm. Surgical resection was performed. After the surgery, somatostatin receptor scintigraphy detected an occult lumbar spine metastasis. Huge multiple liver and bone metastases of the neuroendocrine neoplasm G2 component were seen, with a G1 small primary lesion.     

Metastasis of Solid Tumors in Bone Marrow: A Study from Northern India

The metastasis of bone marrow by the solid tumors is a sign of advanced stage of disease and poor prognosis. The aim of this study was to assess the pattern of bone marrow involvement of different solid tumors and their correlation with hematological findings. In a retrospective study we evaluated 434 aspirates and 76 biopsy sections from 124 cases of different types of solid tumors previously diagnosed on the basis of their clinical and histopathological findings. The hematological profile of the patients was done and correlated with the bone marrow findings. The study was carried out at a medical college hospital of northern India. Out of 124 cases of solid tumors 31 (25%) have metastasized to bone marrow. The highest number 25 (36%) of bone marrow involvement was seen in carcinoma prostate followed by gastric carcinoma and melanoma (25%) The least number (14.2%) cases of bone marrow metastasis were observed in endometrial carcinoma. Anemia was found the commonest (71.4%) hematological finding followed by thrombocytopenia in 45.1% cases. The bone marrow examination is an easy, convenient, sensitive and cost effective procedure for assessment of staging and monitoring of prognosis of solid tumors.     

High-dose chemotherapy with peripheral blood progenitor cell support for patients with non-small cell lung cancer: the experience of the European Group for Bone Marrow Transplantation (EBMT) Solid Tumours Working Party

We report the experience of the EBMT Solid Tumours Working Party (STWP) using high-dose chemotherapy (HDCT) with PBPC support in patients with non-small cell lung cancer (NSCLC). Between 1989 and 2004, 36 NSCLC patients (27 men and 9 women), median age 53.5 years (range: 24-62) were treated with 63 HDCT courses. A high-dose carboplatin-based regimen was used in 53% of the cases. Thirty-two patients had relapsed/metastatic disease, while four classified as stage IIIB received HDCT followed by radiotherapy. No treatment-related death occurred. Of 25 patients who were planned to receive multi-cycle HDCT, 4 cases (16%) interrupted the treatment early due to prolonged severe toxicities and 4 (16%) due to progressive disease. Of 36 evaluable patients, 3 (8%) achieved a complete remission and 13 (36%) had a partial remission at an overall response rate of 44%. Of these, one patient with stage IIIB and one with stage IV are alive disease free at 71+ and 149+ months, respectively. After a median follow-up of 48 months (range: 6-149), median survival was 7 months (range: 1-149). Despite one anecdotal case, HDCT did not show significant activity, but induced relevant morbidity in NSCLC patients.     

骨形态发生蛋白-2在动脉钙化中作用的研究进展

骨形态发生蛋白-2作为转化生长因子-β细胞因子超家族中的一员,在血管发育及血管病理生理过程(包括很可能参与冠状动脉粥样硬化发展的内皮的活化)中起重要作用,尽管其在骨化中研究得比较透彻,但其在血管钙化中作用比较复杂,研究也比较少,现就其目前的研究和进展做一综述。     

Hydration Mechanisms of Alkali-Activated Cementitious Materials with Ternary Solid Waste Composition

Considering the recent eco-friendly and efficient utilization of three kinds of solid waste, including calcium silicate slag (CSS), fly ash (FA), and blast-furnace slag (BFS), alkali-activated cementitious composite materials using these three waste products were prepared with varying content of sodium silicate solution. The hydration mechanisms of the cementitious materials were analyzed by X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, and energy dispersive spectroscopy. The results show that the composite is a binary cementitious system composed of C(N)-A-S-H and C-S-H. Si and Al minerals in FA and BFS are depolymerized to form the Q⁰ structure of SiO₄ and AlO₄. Meanwhile, β-dicalcium silicate in CSS hydrates to form C-S-H and Ca(OH)₂. Part of Ca(OH)₂ reacts with the Q⁰ structure of AlO₄ and SiO₄ to produce lawsonite and wairakite with a low polymerization degree of the Si-O and Al-O bonds. With the participation of Na⁺, part of Ca(OH)₂ reacts with the Q⁰ structure of AlO₄ and the Q³ structure of SiO₄, which comes from the sodium silicate solution. When the sodium silicate content is 9.2%, the macro properties of the composites effectively reach saturation. The compressive strength for composites with 9.2% sodium silicate was 23.7 and 35.9 MPa after curing for 7 and 28 days, respectively.     

Endobronchial Metastases from Colon Cancer without Liver Metastases: Report of Eight Cases

Purpose The liver is the most common site of hematogenous spread from colon tumors. Pulmonary metastases from colon cancer result, in most of the cases, from hepatic metastases. Methods We describe eight cases of colorectal cancers in which endobronchial metastases have been developed without any evidence of liver involvement. Results Median age was 62 years old. In most of the patients, the primary cancer developed in the left side. The median time from colorectal presentation to pulmonary onset was four years. Dyspnea was the major symptom in all cases. Pulmonary involvement included endobronchial metastasis in all cases. CT scan of the chest showed bilateral, diffuse, large, nodular infiltrates without lymph nodes enlargement and without pleural effusion. Endobronchial therapy brought symptomatic relief in all cases; however, two-year follow-up showed only 50 percent survival rate. Conclusions Endobronchial metastasis should be suspected in patients with colon cancer with respiratory symptoms, even without known liver metastasis. To the best of our knowledge, such a case series has not been published yet.