Risk and Mortality of Recurrent Breast Cancer in Stockholm 1985-2005

The purpose of this study was to estimate the risk and mortality of breast cancer recurrences in Swedish women, and to analyse changes over time and variations between patients in different risk groups. Such estimates are of key importance for modelling the cost-effectiveness of different strategies for adjuvant treatment of breast cancer. The study was based on all women diagnosed with breast cancer in Stockholm County between 1985 and 2005. Information about dates for locoregional recurrences, metastatic relapses, new contralateral tumours and death was collected. Cox proportional hazard and Weibull regression models were used to estimate survival functions, where year of diagnosis (dived into 5-year intervals), were included as explanatory variables in the models. The risk of recurrences has decreased during the last 20 years for all three types of recurrence; for metastatic relapse the 5-year risk was reduced from 12.9% to 6.0% from 1985-90 to 2000-2005 . Mortality has also been reduced, resulting in an increased 5-year survival from 52.6% to 64.1% after locoregional recurrence and from 10.4% to 15.5% for metastatic relapse. For contralateral tumours, with a 5-year survival rate of 74.6% in 1985-1990 and 78% 2000-2005, no significant increase was observed. Analysis of risk groups according to TNM classification showed large difference in the risk of metastatic breast cancer between the three defined groups, but small differences for the risk of locoregional recurrences and new contralateral tumours. The findings indicate that the early detection and new treatments have been successful in improving outcome for breast cancer patients and that it is important to use up-to-date information, when assessing the value of new treatment options.Breast cancer; Mortality; Survival; Recurrence; Sweden

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike

Health economics of breast cancer

Breast cancer is a major cause of morbidity and mortality. Resources are spent in order to prevent, diagnose, and treat breast cancer. Since health care resources are limited, these resources must be allocated in an optimal way in order to maximise health. Currently, there are several different interventions available for breast cancer, and new interventions are under development. As new technologies are developed, it is important to evaluate if these new technologies produce improvements in health at an acceptable cost compared to the older technologies. The purpose of this thesis was to contribute to the development in health economics of breast cancer. The specific aspects addressed were the cost of illness of breast cancer, the cost and quality of life in different states of breast cancer, and economic evaluations of breast cancer interventions. The cost of illness of breast cancer in Sweden was estimated using a prevalence based top-down approach. The total cost of breast cancer in 2002 in Sweden was estimated to approximately 3 billion SEK. Direct costs accounted for about 30% of the total cost, with indirect costs accounting for the remaining 70%. For direct costs, the main cost item was hospitalisation, followed by outpatient visits. For indirect costs, productivity losses due to mortality was the main cost driver. Resource use, cost and health related quality of life in different states of breast cancer were estimated based on a naturalistic observational study. Breast cancer was found to be associated with both substantial direct and indirect costs. The total cost was found to be higher for patients in their first year after primary breast cancer, for patients in their first year after a recurrence, and for patients with metastatic disease compared to patients in their second and following years after a primary breast cancer or recurrence. For patients aged less than 65, indirect costs accounted for a majority of the total cost. The study also found breast cancer to be associated with a reduction of the health related quality of life. This reduction was most pronounced for patients with metastatic disease. For all the different disease states, this reduction seems to be driven by pain and discomfort as well as anxiety and depression. Two computer simulation models were developed to project costs and benefits for treatments of breast cancer in the metastatic setting and the adjuvant setting respectively. Health economic data collected in the naturalistic observational study were used in the models. The cost-effectiveness of trastuzumab and chemotherapy compared to chemotherapy alone was estimated for Swedish women with metastatic breast cancer. In the adjuvant setting, the cost effectiveness of one year of adjuvant trastuzumab after adjuvant chemotherapy compared to adjuvant chemotherapy alone was estimated. In both the metastatic and the adjuvant setting, the addition of trastuzumab was found to be cost-effective. This thesis presents new information about the economic burden of breast cancer, as well as new data on the cost and quality of life for patients in different states of breast cancer. These data represent an important input for economic evaluations of breast cancer interventions, and will improve future economic evaluations of breast cancer. The economic evaluations presented in this thesis can be used for informed decisions about resource allocation for patients with breast cancer within the healthcare system

Cost of breast cancer in Sweden in 2002

Cost, Cost of illness, Breast cancer,

Tissue reaction and material biodegradation of a calcium sulfate/apatite biphasic bone substitute in rat muscle

Background/Objective: A biphasic ceramic bone substitute consisting of calcium sulfate and hydroxyapatite has been reported to give good clinical outcome regarding bone regeneration and may serve as a carrier for antibiotics in the treatment of bone infections. Often, the overlying muscle is in direct contact with the synthetic graft. The dissolving bone substitute induces inflammation, which may be harmful to the surrounding soft and muscle tissue. The aim of the present study was to evaluate the surrounding soft tissue reaction and the biodegradation of the biphasic bone substitute. Methods: Rods (3 mm × 6 mm) were cast and implanted in the rat abdominal rectus muscle. The rods were either soaked or not soaked in autologous bone marrow before insertion to induce bone formation. Thirty-two rats underwent bilateral operation. After 6 weeks and 12 weeks, the bone substitute material and the surrounding muscle were harvested. The right rod was evaluated by histology to study tissue reaction and the left rod was analysed with micro-computed tomography and scanning electron microscopy to study bone substitute degradation. Results: The muscle tissue around the material was similar at 6 weeks and 12 weeks, with or without prior treatment with bone marrow. The remaining material showed close contact with the muscle, and blood vessels penetrated the material in both groups. Wide bundles of collagen were embedded around the apatite particles, more at the 12-week time point. No bone formation was found, either at 6 weeks or 12 weeks, and scanning electron microscopy showed that the calcium sulfate phase was resorbed after 6 weeks with the calcium phosphate phase remaining intact. Micro-computed tomography showed significantly more hydroxyapatite at 6 weeks than after 12 weeks. Conclusion: Calcium sulfate hydroxyapatite bone substitute can be used as a carrier for antibiotics or other drugs, without adverse reaction due to the fast resorption of the calcium sulfate. No bone formation was seen despite treating the bone substitute with autologous bone marrow

SCN8A heterozygous variants are associated with anoxic-epileptic seizures

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants

Prevention of surgical site infection in total joint arthroplasty: An international tertiary care center survey

Background Prevention strategies are critical to reduce infection rates in total joint arthroplasty (TJA), but evidence-based consensus guidelines on prevention of surgical site infection (SSI) remain heterogeneous and do not necessarily represent this particular patient population. Questions/Purposes What infection prevention measures are recommended by consensus evidence-based guidelines for prevention of periprosthetic joint infection? How do these recommendations compare to expert consensus on infection prevention strategies from orthopedic surgeons from the largest international tertiary referral centers for TJA? Patients and Methods A review of consensus guidelines was undertaken as described by Merollini et al. Four clinical guidelines met inclusion criteria: Centers for Disease Control and Prevention's, British Orthopedic Association, National Institute of Clinical Excellence's, and National Health and Medical Research Council's (NHMRC). Twenty-eight recommendations from these guidelines were used to create an evidence-based survey of infection prevention strategies that was administered to 28 orthopedic surgeons from members of the International Society of Orthopedic Centers. The results between existing consensus guidelines and expert opinion were then compared. Results Recommended strategies in the guidelines such as prophylactic antibiotics, preoperative skin preparation of patients and staff, and sterile surgical attire were considered critically or significantly important by the surveyed surgeons. Additional strategies such as ultraclean air/laminar flow, antibiotic cement, wound irrigation, and preoperative blood glucose control were also considered highly important by surveyed surgeons, but were not recommended or not uniformly addressed in existing guidelines on SSI prevention. Conclusion Current evidence-based guidelines are incomplete and evidence should be updated specifically to address patient needs undergoing TJA