Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

[Bone metastasis in prostate cancer]

Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited.

Mini invasive skeletal muscle biopsy technique with a tri-axial end cut needle.

OBJECTIVE: Skeletal Muscle Biopsy is a minor surgical procedure for the diagnosis of different neuromuscular pathological conditions and has recently gained popularity also in the research field of age-related muscular modifications and sarcopenia. Few studies focused on the application of mini-invasive muscular biopsy in both normal and pathological conditions. The aim of our study was to describe a mini invasive ultrasound-guided skeletal muscular biopsy technique in complete spinal cord injured (SCI) patients and healthy controls with a tri-axial end-cut needle. PATIENTS AND METHODS: Skeletal muscle biopsies were collected from 6 chronic SCI patients and 3 healthy controls vastus lateralis muscle with a tri-axial end cut needle (Biopince© - Angiotech). Muscle samples were stained for ATPase to determine fibers composition, moreover, gene expression of cyclooxygenase-1 (COX-1) and prostaglandin E2 receptor has been analyzed by Real Time RT-PCR. RESULTS: All the procedures were perfomed easily without failures and complications. Control tissue was macroscopically thicker than SCI one. Control specimen displayed an equal distribution of type I and type II fibers, while SCI sample displayed a prevalence of type II fibers SCI specimen displayed a significant reduction in COX-1 gene expression. This mini-invasive approach was easy, accurate and with low complication rate in performing skeletal muscle biopsy in both SCI patients and controls. CONCLUSIONS: This technique could be useful in conditions in which the overall quantity of specimen required is small like for molecular biology analysis. For histological diagnostic purposes and/or conditions in which the original tissue is already pathologically modified, this technique should be integrated with more invasive techniques.

Childhood trauma: methods for the identification of physeal fractures in non-adult skeletal remains

Objectives Today, fractures at the growth plate (or physis) are common injuries in children, but provide challenges of identification in skeletonized remains. Clinical studies provide detailed information on the mechanisms, locations, age of occurrence, and complications associated with physeal fractures, enabling the development of new criteria for identifying this injury in non-adults. To test these criteria, skeletal remains from five rural and urban medieval cemeteries were examined. Methods The sample consisted of 961 skeletons (0-17 years) with open epiphyses. Macroscopic observation looked for any irregularities of the metaphysis or epiphysis which was consistent with the clinical appearance of physeal fractures or resulting complications. Radiographic examination was applied to identify fracture lines or early growth arrest. Results This study revealed 12 cases of physeal trauma (1.2%). Physeal fractures occurred predominantly at the distal end (75%), and while they were identified in all age categories, they were most frequent in those aged 12-17 years (0.2% TPR). The humerus was the most commonly affected location (3/12 or 25%). Conclusions This study highlights the potential for recognizing physeal fractures in children of all ages, enhancing our understanding of non-adult trauma, and enabling us to assign a more precise age of the injury to build up a picture of their activities in the past.

Reconstructive Microsurgery and Tissue Engineering in Musculo-Skeletal Oncology - Innovative Techniques

Tumors involving bone and soft tissues are extremely challenging situations. With the recent advances of multi-modal treatment, not only the type of surgery has moved from amputation to limb-sparing procedures, but also the survivorship has improved considerably and reconstructive techniques have the goal to allow a considerably higher quality of life. In bone reconstruction, tissue engineering strategies are the main area of research. Re-vascularization and re-vitalisation of a massive allograft would considerably improve the outcome of biological reconstructions. Using a rabbit animal model, in this study we showed that, by implanting a vascular pedicle inside a weight bearing massive cortical allograft, the bone regeneration inside the allograft was higher compared to the non-vascularized implants, given the patency of the vascular pedicle. Improvement in the animal model and the addition of Stem Cells and Growth factors will allow a further improvement in the results. In soft tissue tumors, free and pedicled flaps have been proven to be of great help as reconstruction strategies. In this study we analyzed the functional and overall outcome of 14 patients who received a re-innervated vascularized flap. We have demonstrated that the use of the innovative technique of motor re-innervated muscular flaps is effective when the resection involves important functional compartments of the upper or lower limb, with no increase of post-operative complications. Although there was no direct comparison between this type of reconstruction and the standard non-innervated reconstruction, we underlined the remarkable high overall functional scores and patient satisfaction following this procedure.

Clypeotheca, a new skeletal structure in scleractinian corals : a potential stress indicator

Physiological responses to environmental stress are increasingly well studied in scleractinian corals. This work reports a new stress-related skeletal structure we term clypeotheca. Clypeotheca was observed in several livecollected common reef-building coral genera and a two to three kya subfossil specimen from Heron Reef, Great Barrier Reef and consists of an epitheca-like skeletal wall that seals over the surface of parts of the corallum in areas of stress or damage. It appears to form from a coordinated process wherein neighboring polyps and adjoining coenosarc seal themselves off from the surrounding environment as they contract and die. Clypeotheca forms from inward skeletal centripetal growth at the edges of corallites and by the merging of flange-like outgrowths that surround individual spines over the surface of the coenosteum. Microstructurally, the merged flanges are similar to upsidedown dissepiments and true epitheca. Clypeotheca is interpreted primarily as a response to stress that may help protect the colony from invasion of unhealthy tissues by parasites or disease by retracting tissues in areas that have become unhealthy for the polyps. Identification of skeletal responses of corals to environmental stress may enable the frequency of certain types of environmental stress to be documented in past environments. Such data may be important for understanding the nature of reef dynamics through intervals of climate change and for monitoring the effects of possible anthropogenic stress in modern coral reef habitats.

The neuro-muscular and musculo-skeletal characterization of children with joint hypermobility

In children, joint hypermobility (typified by structural instability of joints) manifests clinically as neuro-muscular and musculo-skeletal conditions and conditions associated with development and organization of control of posture and gait (Finkelstein, 1916; Jahss, 1919; Sobel, 1926; Larsson, Mudholkar, Baum and Srivastava, 1995; Murray and Woo, 2001; Hakim and Grahame, 2003; Adib, Davies, Grahame, Woo and Murray, 2005:). The process of control of the relative proportions of joint mobility and stability, whilst maintaining equilibrium in standing posture and gait, is dependent upon the complex interrelationship between skeletal, muscular and neurological function (Massion, 1998; Gurfinkel, Ivanenko, Levik and Babakova, 1995; Shumway-Cook and Woollacott, 1995). The efficiency of this relies upon the integrity of neuro-muscular and musculo-skeletal components (ligaments, muscles, nerves), and the Central Nervous System’s capacity to interpret, process and integrate sensory information from visual, vestibular and proprioceptive sources (Crotts, Thompson, Nahom, Ryan and Newton, 1996; Riemann, Guskiewicz and Shields, 1999; Schmitz and Arnold, 1998) and development and incorporation of this into a representational scheme (postural reference frame) of body orientation with respect to internal and external environments (Gurfinkel et al., 1995; Roll and Roll, 1988). Sensory information from the base of support (feet) makes significant contribution to the development of reference frameworks (Kavounoudias, Roll and Roll, 1998). Problems with the structure and/ or function of any one, or combination of these components or systems, may result in partial loss of equilibrium and, therefore ineffectiveness or significant reduction in the capacity to interact with the environment, which may result in disability and/ or injury (Crotts et al., 1996; Rozzi, Lephart, Sterner and Kuligowski, 1999b). Whilst literature focusing upon clinical associations between joint hypermobility and conditions requiring therapeutic intervention has been abundant (Crego and Ford, 1952; Powell and Cantab, 1983; Dockery, in Jay, 1999; Grahame, 1971; Childs, 1986; Barton, Bird, Lindsay, Newton and Wright, 1995a; Rozzi, et al., 1999b; Kerr, Macmillan, Uttley and Luqmani, 2000; Grahame, 2001), there has been a deficit in controlled studies in which the neuro-muscular and musculo-skeletal characteristics of children with joint hypermobility have been quantified and considered within the context of organization of postural control in standing balance and gait. This was the aim of this project, undertaken as three studies. The major study (Study One) compared the fundamental neuro-muscular and musculo-skeletal characteristics of 15 children with joint hypermobility, and 15 age (8 and 9 years), gender, height and weight matched non-hypermobile controls. Significant differences were identified between previously undiagnosed hypermobile (n=15) and non-hypermobile children (n=15) in passive joint ranges of motion of the lower limbs and lumbar spine, muscle tone of the lower leg and foot, barefoot CoP displacement and in parameters of barefoot gait. Clinically relevant differences were also noted in barefoot single leg balance time. There were no differences between groups in isometric muscle strength in ankle dorsiflexion, knee flexion or extension. The second comparative study investigated foot morphology in non-weight bearing and weight bearing load conditions of the same children with and without joint hypermobility using three dimensional images (plaster casts) of their feet. The preliminary phase of this study evaluated the casting technique against direct measures of foot length, forefoot width, RCSP and forefoot to rearfoot angle. Results indicated accurate representation of elementary foot morphology within the plaster images. The comparative study examined the between and within group differences in measures of foot length and width, and in measures above the support surface (heel inclination angle, forefoot to rearfoot angle, normalized arch height, height of the widest point of the heel) in the two load conditions. Results of measures from plaster images identified that hypermobile children have different barefoot weight bearing foot morphology above the support surface than non-hypermobile children, despite no differences in measures of foot length or width. Based upon the differences in components of control of posture and gait in the hypermobile group, identified in Study One and Study Two, the final study (Study Three), using the same subjects, tested the immediate effect of specifically designed custom-made foot orthoses upon balance and gait of hypermobile children. The design of the orthoses was evaluated against the direct measures and the measures from plaster images of the feet. This ascertained the differences in morphology of the modified casts used to mould the orthoses and the original image of the foot. The orthoses were fitted into standardized running shoes. The effect of the shoe alone was tested upon the non-hypermobile children as the non-therapeutic equivalent condition. Immediate improvement in balance was noted in single leg stance and CoP displacement in the hypermobile group together with significant immediate improvement in the percentage of gait phases and in the percentage of the gait cycle at which maximum plantar flexion of the ankle occurred in gait. The neuro-muscular and musculo-skeletal characteristics of children with joint hypermobility are different from those of non-hypermobile children. The Beighton, Solomon and Soskolne (1973) screening criteria successfully classified joint hypermobility in children. As a result of this study joint hypermobility has been identified as a variable which must be controlled in studies of foot morphology and function in children. The outcomes of this study provide a basis upon which to further explore the association between joint hypermobility and neuro-muscular and musculo-skeletal conditions, and, have relevance for the physical education of children with joint hypermobility, for footwear and orthotic design processes, and, in particular, for clinical identification and treatment of children with joint hypermobility.

Elective foot and ankle surgery : activity and perioperative complications in Queensland public hospitals, Australia

Objective: To conduct an audit of elective foot and ankle surgery in Queensland public hospitals and to compare the frequency of these procedures performed to other states and territories of Australia. ---------- Methods: ICD-10-AM data was used to extract elective foot and ankle procedures from the Data Services Unit of Queensland Health, and the Australian Institute of Health and Welfare between the years of 2000 and 2004. ---------- Results During the 4-year audit period 3846 primary procedures were performed during the 4-year period with a complication rate of 2.2% during the hospital admission period. Mean length of stay was 1.7 days. Post-operative infection rates were 0.26%. With the exception of Tasmania and the Northern Territory, Queensland performs the least number of elective foot and ankle procedures per capita per year in Australia. ---------- Conclusions This is the first reported audit of elective foot and ankle surgery for Queensland public hospitals. Complication rates cannot be directly compared to the literature as this data could only capture complications within hospital admission period. Fewer elective foot and ankle procedures were performed in Queensland public hospitals compared to all other mainland states of Australia during the data collection period.

Mesenchymal stem cells

Cell based therapies as they apply to tissue engineering and regenerative medicine, require cells capable of self renewal and differentiation, and a prerequisite is to be able to prepare an effective dose of ex vivo expanded cells for autologous transplants. The in vivo identification of a source of physiologically relevant cell types suitable for cell therapies therefore figures as an integral part of tissue engineering. Stem cells serve as a reserve for biological repair, having the potential to differentiate into a number of specialised cell types within the body; they therefore represent the most useful candidates for cell based therapies. The primary goal of stem cell research is to produce cells that are both patient specific, as well as having properties suitable for the specific conditions for which they are intended to remedy. From a purely scientific perspective, stem cells allow scientists to gain a deeper understanding of developmental biology and regenerative therapies. Stem cells have acquired a number of uses for applications in regenerative medicine, immunotherapy, gene therapy, but it is in the area of tissue engineering that they generate most excitement, primarily as a result of their capacity for self-renewal and pluripotency. A unique feature of stem cells is their ability to maintain an uncommitted quiescent state in vivo and then, once triggered by conditions such as disease, injury or natural wear or tear, serve as a reservoir and natural support system to replenish lost cells. Although these cells retain the plasticity to differentiate into various tissues, being able to control this differentiation process is still one of the biggest challenges facing stem cell research. In an effort to harness the potential of these cells a number of studies have been conducted using both embryonic/foetal and adult stem cells. The use of embryonic stem cells (ESC) have been hampered by strong ethical and political concerns, this despite their perceived versatility due to their pluripotency. Ethical issues aside, other concerns raised with ESCs relates to the possibility of tumorigenesis, immune rejection and complications with immunosuppressive therapies, all of which adds layers of complications to the application ESC in research and which has led to the search for alternative sources for stem cells. The adult tissues in higher organisms harbours cells, termed adult stem cells, and these cells are reminiscent of unprogrammed stem cells. A number of sources of adult stem cells have been described. Bone marrow is by far the most accessible source of two potent populations of adult stem cells, namely haematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (BMSCs). Autologously harvested adult stem cells can, in contrast to embryonic stem cells, readily be used in autografts, since immune rejection is not an issue; and their use in scientific research has not attracted the ethical concerns which have been the case with embryonic stem cells. The major limitation to their use, however, is the fact that adult stem cells are exceedingly rare in most tissues. This fact makes identifying and isolating these cells problematic; bone marrow being perhaps the only notable exception. Unlike the case of HSCs, there are as yet no rigorous criteria for characterizing MSCs. Changing acuity about the pluripotency of MSCs in recent studies has expanded their potential application; however, the underlying molecular pathways which impart the features distinctive to MSCs remain elusive. Furthermore, the sparse in vivo distribution of these cells imposes a clear limitation to their study in vitro. Also, when MSCs are cultured in vitro, there is a loss of the in vivo microenvironment, resulting in a progressive decline in proliferation potential and multipotentiality. This is further exacerbated with increased passage numbers in culture, characterized by the onset of senescence related changes. As a consequence, it is necessary to establish protocols for generating large numbers of MSCs but without affecting their differentiation potential. MSCs are capable of differentiating into mesenchymal tissue lineages, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Recent findings indicate that adult bone marrow may also contain cells that can differentiate into the mature, nonhematopoietic cells of a number of tissues, including cells of the liver, kidney, lung, skin, gastrointestinal tract, and myocytes of heart and skeletal muscle. MSCs can readily be expanded in vitro and can be genetically modified by viral vectors and be induced to differentiate into specific cell lineages by changing the microenvironment–properties which makes these cells ideal vehicles for cellular gene therapy. MSCs can also exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways, and this property allows them to overcome the issue of immune rejection. Despite the many attractive features associated with MSCs, there are still many hurdles to overcome before these cells are readily available for use in clinical applications. The main concern relates to in vivo characterization and identification of MSCs. The lack of a universal biomarker, sparse in vivo distribution, and a steady age related decline in their numbers, makes it an obvious need to decipher the reprogramming pathways and critical molecular players which govern the characteristics unique to MSCs. This book presents a comprehensive insight into the biology of adult stem cells and their utility in current regeneration therapies. The adult stem cell populations reviewed in this book include bone marrow derived MSCs, adipose derived stem cells (ASCs), umbilical cord blood stem cells, and placental stem cells. The features such as MSC circulation and trafficking, neuroprotective properties, and the nurturing roles and differentiation potential of multiple lineages have been discussed in details. In terms of therapeutic applications, the strengths of MSCs have been presented and their roles in disease treatments such as osteoarthritis, Huntington’s disease, periodontal regeneration, and pancreatic islet transplantation have been discussed. An analysis comparing osteoblast differentiation of umbilical cord blood stem cells and MSCs has been reviewed, as has a comparison of human placental stem cells and ASCs, in terms of isolation, identification and therapeutic applications of ASC in bone, cartilage regeneration, as well as myocardial regeneration. It is my sincere hope that this book will update the reader as to the research progress of MSC biology and potential use of these cells in clinical applications. It will be the best reward to all contributors of this book, if their efforts herein may in some way help the readers in any part of their study, research, and career development.

Resident-funded retirement village valuations : complications with the application of the DCF

Retirement village assets are different from traditional residential assets due to their operation in accordance with statutory legislation. Designed for independent living, retirement villages provide either detached or semi-detached residential dwellings with car parking and small private yards with community facilities providing a shared congregational area for village activities and socialising. In essence, the village operator provides the land and buildings to the residents who pay an amount on entry for the right of occupation. On departure from the units an agreed proportion of either the original purchase price or the sale price is paid to the outgoing resident. As ongoing levies are typically offset by ongoing operational expenses the market value of the operator's interest in the retirement village is therefore predominantly based upon the estimated future income from deferred management fees and capital gain upon roll-over receivable by the operator in accordance with the respective residency agreements. Given the lumpiness of these payments, there is general acceptance that the most appropriate approach to valuation is through discounted cash flow (DCF) analysis. There is however inconsistency between valuers across Australia in how they undertake their DCF analysis, leading to differences in reported values and subsequent confusion among users of valuation services. To give guidance to valuers and enhance confidence from users of valuation services this paper investigates the five major elements of DCF methodology, namely cash flows, escalation factors, holding period, terminal value and discount rate.