Carbon nanotubes (CNTs) are structurally described as sheets of six-membered carbon atom rings (i.e., graphene) rolled up into cylinders. CNTs with only one layer are known as single-walled CNTs (SWCNTs), and those with two or more layers are known as multiwalled CNTs (MWCNTs). Cup-stacked carbon nanotubes and carbon nanohorns are also sometimes called CNTs.1−3 Currently, these very attractive carbon materials and nanomaterials are a subject of vigorous product development in a broad range of fields.4−11 The reasons are that CNTs have useful electrical, thermal, and mechanical characteristics, and their base material performance can be improved by combination with other materials.12−23 A recent industrial application of CNTs as an electrode additive to lithium-ion batteries is based on their excellent electrical characteristics. Addition of CNTs prevents battery deterioration and substantially lengthens time to recharging. It is doubtless that the demand for high-performance batteries will grow increasingly with multifunctionalization of personal computers and mobile phones, development of new mobile terminals, spread of electric vehicles, and other factors.24−30 Composite materials with the excellent mechanical characteristics of CNTs have already been used in sporting goods such as golf clubs, tennis rackets, and bicycles. CNTs are also expected to have applications that reduce the weight of aircraft and automobiles.10,14,31−35 A wide variety of advantages are gained from the use CNTs in precision parts as well. CNTs are also used in transistors and memory devices, and enhance their efficiency. The use of CNTs in various displays and TV screens continues to increase in rate. CNTs are also widely used in products designed to prevent static electricity, to shield electromagnetic waves, to store electricity, and for other purposes.36−45 Furthermore, Japan is now facing nuclear energy issues stemming from the accident at Tokyo Electric Power Company’s Fukushima No. 1 nuclear power plant. As a result, CNTs are expected to play a major role in developing new energy sources such as solar photovoltaic power generation and wind power generation.46−52

In the medical field, extensive research activities are underway to develop new CNTs biomaterials for use in the treatment and diagnosis of disease. For example, application of CNTs to cancer treatment and diagnosis, such as in drug delivery systems (DDSs) for treatment of cancer, hyperthermia, and in vivo imaging, has been investigated.53−57 In a study that aimed at applying CNTs to regenerative medicine, CNTs were found to work excellently as scaffold materials for nerve and bone tissue regeneration.58−63 Furthermore, R&D activities are underway to improve the mechanical strength and durability of implants by combining CNTs with existing biomaterials.64−67 Besides, numerous ideas have been put forth about how CNTs can be used in the treatment of a variety of diseases.

Figure ​Figure11 shows the trend in the number of articles found in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed 20 March 2014) by searches using “carbon nanotubes” and “biomaterials” as keywords. The number has been soaring since 2005, suggesting that CNTs research has become a highly competitive field worldwide over the past few years. Of course, numerous articles on the biological applications of CNTs do exist that cannot be captured with these two simple keywords, and the graphic representation of this trend is no more than an indicator of the increase in this research over time.



Figure 1

Time trends for the number of articles found in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed 20 March 2014) by search using “carbon nanotubes” and “biomaterials” as keywords. Recent years have seen ...

Safe clinical use of carbon nanotubes as innovative biomaterials.

Background: Spinal metastases can lead to significant morbidity and reduction in quality of life due to spinal cord compression (SCC). Between 5% and 20% of patients with spinal metastases develop metastatic spinal cord compression during the course of their disease. An early study estimated average survival for patients with SCC to be between 3 and 7 months, with a 36% probability of survival to 12 months. An understanding of the natural history and early diagnosis of spinal metastases and prediction of collapse of the metastatic vertebrae are important.

Objective: To undertake a systematic review to examine the natural history of metastatic spinal lesions and to identify patients at high risk of vertebral fracture and SCC.

Data sources: The search strategy covered the concepts of metastasis, the spine and adults. Searches were undertaken from inception to June 2011 in 13 electronic databases [MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases (NHS Centre for Reviews and Dissemination); Science Citation Index and Conference Proceedings (Web of Science); UK Clinical Research Network (UKCRN) Portfolio Database; Current Controlled Trials; ClinicalTrials.gov].

Review methods: Titles and abstracts of retrieved studies were assessed by two reviewers independently. Disagreement was resolved by consensus agreement. Full data were extracted independently by one reviewer. All included studies were reviewed by a second researcher with disagreements resolved by discussion. A quality assessment instrument was used to assess bias in six domains: study population, attrition, prognostic factor measurement, outcome measurement, confounding measurement and account, and analysis. Data were tabulated and discussed in a narrative review. Each tumour type was looked at separately.

Results: In all, 2425 potentially relevant articles were identified, of which 31 met the inclusion criteria. No study examined natural history alone. Seventeen studies reported retrospective data, 10 were prospective studies, and three were other study designs. There was one systematic review. There were no randomised controlled trials (RCTs). Approximately 5782 participants were included. Sample sizes ranged from 41 to 859. The age of participants ranged between 7 and 92 years. Types of cancers reported on were lung alone (n= 3), prostate alone (n= 6), breast alone (n= 7), mixed cancers (n= 13) and unclear (n= 1). A total of 93 prognostic factors were identified as potentially significant in predicting risk of SCC or collapse. Overall findings indicated that the more spinal metastases present and the longer a patient was at risk, the greater the reported likelihood of development of SCC and collapse. There was an increased risk of developing SCC if a cancer had already spread to the bones. In the prostate cancer studies, tumour grade, metastatic load and time on hormone therapy were associated with increased risk of SCC. In one study, risk of SCC before death was 24%, and 2.37 times greater with a Gleason score 7 than with a score of < 7 (p= 0.003). Other research found that patients with six or more bone lesions were at greater risk of SCC than those with fewer than six lesions [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.012 to 8.35, p= 0.047]. For breast cancer patients who received a computerised tomography (CT) scan for suspected SCC, multiple logistic regression in one study identified four independent variables predictive of a positive test: bone metastases 2 years (OR 3.0 95% CI 1.2 to 7.6; p= 0.02); metastatic disease at initial diagnosis (OR 3.4, 95% CI 1.0 to 11.4; p= 0.05); objective weakness (OR 3.8, 95% CI 1.5 to 9.5; p= 0.005); and vertebral compression fracture on spine radiograph (OR 2.6, 95% CI 1.0 to 6.5; p= 0.05). A further study on mixed cancers, among patients who received surgery for SCC, reported that vertebral body compression fractures were associated with presurgery chemotherapy (OR 2.283, 95% CI 1.064 to 4.898; p= 0.03), cancer type [primary breast cancer (OR 4.179, 95% CI 1.457 to 11.983; p= 0.008)], thoracic involvement (OR 3.505, 95% CI 1.343 to 9.143; p= 0.01) and anterior cord compression (OR 3.213, 95% CI 1.416 to 7.293; p= 0.005).

Limitations: Many of the included studies provided limited information about patient populations and selection criteria and they varied in methodological quality, rigour and transparency. Several studies identified type of cancer (e.g. breast, lung or prostate cancer) as a significant factor in predicting SCC, but it remains difficult to determine the risk differential partly because of residual bias. Consideration of quantitative results from the studies does not easily allow generation of a coherent numerical summary, studies were heterogeneous especially with regard to population, results were not consistent between studies, and study results almost universally lacked corroboration from other independent studies.

Conclusion: No studies were found which examined natural history. Overall burden of metastatic disease, confirmed metastatic bone involvement and immediate symptomatology suggestive of spinal column involvement are already well known as factors for metastatic SCC, vertebral collapse or progression of vertebral collapse. Although we identified a large number of additional possible prognostic factors, those which currently offer the most potential are unclear. Current clinical consensus favours magnetic resonance imaging and CT imaging modalities for the investigation of SCC and vertebral fracture. Future research should concentrate on: (1) prospective randomised designs to establish clinical and quality-of-life outcomes and cost-effectiveness of identification and treatment of patients at high risk of vertebral collapse and SCC; (2) Service Delivery and Organisation research on magnetic resonance imaging (MRI) scans and scanning (in tandem with research studies on use of MRI to monitor progression) in order to understand best methods for maximising use of MRI scanners; and (3) investigation of prognostic algorithms to calculate probability of a specified event using high-quality prospective studies, involving defined populations, randomly selected and clearly identified samples, and with blinding of investigators.

/pdf/a-systematic-review-of-evidence-on-malignant-spinal-1sm7ymwgak.pdf

A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression

Weight-dependent loading of the skeleton plays an important role in establishing and maintaining bone mass and strength. This review focuses on mechanical signaling induced by body weight as an essential mechanism for maintaining bone health. In addition, the skeletal effects of deviation from normal weight are discussed. The magnitude of mechanical strain experienced by bone during normal activities is remarkably similar among vertebrates, regardless of size, supporting the existence of a conserved regulatory mechanism, or mechanostat, that senses mechanical strain. The mechanostat functions as an adaptive mechanism to optimize bone mass and architecture based on prevailing mechanical strain. Changes in weight, due to altered mass, weightlessness (spaceflight), and hypergravity (modeled by centrifugation), induce an adaptive skeletal response. However, the precise mechanisms governing the skeletal response are incompletely understood. Furthermore, establishing whether the adaptive response maintains the mechanical competence of the skeleton has proven difficult, necessitating the development of surrogate measures of bone quality. The mechanostat is influenced by regulatory inputs to facilitate non-mechanical functions of the skeleton, such as mineral homeostasis, as well as hormones and energy/nutrient availability that support bone metabolism. Although the skeleton is very capable of adapting to changes in weight, the mechanostat has limits. At the limits, extreme deviations from normal weight and body composition are associated with impaired optimization of bone strength to prevailing body size.

/pdf/influence-of-body-weight-on-bone-mass-architecture-and-3n53s52t7g.pdf

Influence of body weight on bone mass, architecture and turnover

Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. The majority of patients are diagnosed in advanced disease stage. Bone metastasis is the most frequent complication in NSCLC resulting in osteolytic lesions. The perfect balance between bone-resorbing osteoclasts and bone-forming osteoblasts activity is lost in bone metastasis, inducing osteoclastogenesis. In NSCLC, the epidermal growth factor receptor (EGFR) pathway is constitutively activated. EGFR binds Amphiregulin (AREG) that is overexpressed in several cancers such as colon, breast and lung. Its levels in plasma of NSCLC patients correlate with poor prognosis and AREG was recently found as a signaling molecule in exosomes derived from cancer cell lines. Exosomes have a key role in the cell-cell communication and they were recently indicated as important actors in metastatic niche preparation. In the present work, we hypothesize a role of AREG carried by exosomes derived from NSCLC in bone metastasis induction. We observed that NSCLC-exosomes, containing AREG, induce EGFR pathway activation in pre-osteoclasts that in turn causes an increased expression of RANKL. RANKL is able to induce the expression of proteolytic enzymes, well-known markers of osteoclastogenesis, triggering a vicious cycle in osteolytic bone metastasis.

Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway.

The metastasis is the spread of cancer from one part of the body to another Two-thirds of patients with cancer will develop bone metastasis Breast, prostate and lung cancer are responsible for more than 80% of cases of metastatic bone disease The spine is the most common site of bone metastasis A spinal metastasis may cause pain, instability and neurological injuries The diffusion through Batson venous system is the principal process of spinal metastasis, but the dissemination is possible also through arterial and lymphatic system or by contiguity Once cancer cells have invaded the bone, they produce growth factors that stimulate osteoblastic or osteolytic activity resulting in bone remodeling with release of other growth factors that lead to a vicious cycle of bone destruction and growth of local tumour

https://downloads.hindawi.com/journals/ijso/2011/107969.pdf

Physiopathology of Spine Metastasis

Pathologic fractures of the femur because of bone metastases seriously affect the quality of life of cancer patients. Different surgical options are indicated to achieve a durable and solid fixation, depending on several clinical, prognostic and mechanical factors. Locked intramedullary nailing is currently used to treat pathologic femoral fractures in patients with multiple metastases when the trochanteric region or shaft is mainly involved. This study evaluates intramedullary nailing for treatment of patients with pathologic femoral fractures, focussing on complications, clinical and functional outcomes and survival rates. The series included 80 pathologic fractures treated with a titanium alloy Proximal Nail (Standard or Antirotation) or Lateral Anterograde Femoral Nail (PFN, PFNA or LAFN, Synthes) inserted in a locked static mode. Acrylic cement was used to fill the bone cavity after nail insertion in eight patients; percutaneous cementoplasty was simultaneously performed in 11 cases of severe ipsilateral acetabular osteolysis. Postoperative outcomes focussed on pain relief, postoperative mobility and quality of life and they were analysed retrospectively using QOL-ACD and ECOG. Eleven patients (13.75%) suffered from non-fatal DVT post-surgery, with no pulmonary embolism. Six patients (7.5%) developed superficial wound infections and two patients (2.5%) developed pnaeumonia. There was no loss of reduction, breakage, screw pull out, or hardware or implant failure that required component substitution or revision. Lung histotype and the contemporary presence of cerebral and visceral metastases appeared to be predisposing factors in reducing survival time. All patients attained satisfactory pain relief, early deambulation and a marked clinical improvement during the first 6-10 postoperative months, with gradual worsening thereafter from deterioration of their general condition due to cancer progression. The patients' survival rate was 40% at 1 year, 25% at 2 years and 15% at 3 years. Results confirm that multiple factors related to patients and primary cancer may affect survival rate after femoral fracture. Intramedullary nailing should be indicated for pathologic fractures at femoral diaphysis and metaphysis when cancer is in an advanced stage. This procedure offers good and durable stability, and enables pain relief, early postoperative mobilisation and weight-bearing, thus improving the quality of life of cancer patients.

Intramedullary nailing for treatment of pathologic femoral fractures due to metastases

Metastases are the most common malignancies involving bone; breast, prostate, lung and thyroid are the main sites of primary cancer. However, up to 30 % of patients present with bone metastases of unknown origin, where the site of the primary neoplasm cannot be identified at the time of diagnosis despite a thorough history, physical examination, appropriate laboratory testing and modern imaging technology (CT, MRI, PET). Sometimes only extensive histopathological investigations on bone specimens from biopsy can suggest the primary malignancy. At other times, a bone lesion can have such a highly undifferentiated histological appearance that a precise pathological classification on routine hematoxylin–eosin-stained section is not possible. The authors reviewed the relevant literature in an attempt to investigate the epidemiology of the histological primaries finally identified in patients with bone metastases from occult cancer, and a strategy of management and treatment of bone metastases from occult carcinomas is suggested. Lung, liver, pancreas and gastrointestinal tract are common sites for primary occult tumors. Adenocarcinoma is the main histological type, accounting for 70 % of all cases, while undifferentiated cancer accounts for 20 %. Over the past 30 years, lung cancer is the main causative occult primary for bone metastases and has a poor prognosis with an average survival of 4–8 months. Most relevant literature focuses on the need for standardized diagnostic workup, as surgery for bone lesions should be aggressive only when they are solitary and/or the occult primaries have a good prognosis; in these cases, identification of the primary tumor may be important and warrants special diagnostic efforts. However, in most cases, the primary site remains unknown, even after autopsy. Thus, orthopedic surgery has a mainly palliative role in preventing or stabilizing pathological fractures, relieving pain and facilitating the care of the patient in an attempt to provide the most appropriate therapy for the primary tumor as soon as possible. 5

/pdf/bone-metastases-of-unknown-origin-epidemiology-and-1zwbmtw9zq.pdf

Bone metastases of unknown origin: epidemiology and principles of management

Background In lung cancer patients, metastases to soft tissues (STs), including skeletal muscle, subcutaneous tissue and skin, are rarely reported. Besides, lung cancer, primary carcinomas of the kidney and colon are the most commonly associated with ST metastases. Aim To determine the prevalence, clinical-pathological features and treatment options of ST metastases originating from lung carcinoma. Materials and methods A literature search was performed using the following terms: lung cancer, ST metastasis, skeletal muscle metastasis, cutaneous metastasis, subcutaneous metastasis. Results Autopsy series have detected STs metastases in 0.75-9% of patients who died from metastatic lung carcinoma. Pain and the presence of a palpable mass are the most frequent clinical features. The biopsy is recommended after MRI for diagnosis. Due to the rarity of ST metastases, the differential diagnosis must be posed especially with primary ST sarcomas. The type of treatment depends on the patient's clinical status and prognosis, and includes observation, radiotherapy, chemotherapy and surgery. Conclusions In lung cancer patients, ST metastases are rare, but not exceptional. Their presence should be suspected in the presence of a palpable mass either painful or asymptomatic. Radiological and histological examinations are required for the definite diagnosis. The choice of treatment should be based on considerations related to the stage of the primary tumor and the patient's global health status.

Soft tissue metastases in lung cancer: a review of the literature.

Introduction The concept of impending fracture has been developed to help address this difficult skeletal-related problem. There is no consensus on the subject in the literature and a specific definition of impending fracture has not been outlined. Discussion There is disagreement in the literature on the best criteria for the diagnosis of impending fracture. A method of discrimination for patients who need preventative treatment for a metastatic lesion has not yet been established. Conclusions Current score systems consider variables like size, location and treatment response and are easy to remember. However, these score systems have never been evaluated prospectively and rigorously, their sensitivity is low and they do not take into account potentially relevant factors that can influence patient prognosis. A consistent tool to evaluate impending fractures would be of great value to guide the treatment of metastatic bone disease.

Maria Silvia Spinelli

Papers

Physiopathology of Spine Metastasis

Intramedullary nailing for treatment of pathologic femoral fractures due to metastases

Bone metastases of unknown origin: epidemiology and principles of management

Soft tissue metastases in lung cancer: a review of the literature.

Impending fracture: A difficult diagnosis