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.

Cost-effectiveness of HER2 testing and trastuzumab therapy for metastatic breast cancer.

BACKGROUND: Trastuzumab is a monoclonal antibody that together with chemotherapy significantly improves time to progression and overall survival for metastatic breast cancer patients with tumours overexpressing HER2. The aim of this study was to analyse the cost-effectiveness of HER2 testing and trastuzumab in combination with chemotherapy compared with chemotherapy alone from a societal perspective in a Swedish setting. MATERIAL AND METHODS: We used a Markov state transition model to simulate HER2 testing and subsequent treatment in a hypothetical cohort of 65 year old metastatic breast cancer patients. Outcomes included life-time costs, quality adjusted life years (QALY), and cost per QALY gained. Five different testing and treatment strategies were evaluated. RESULTS: We estimated the cost per QALY gained to be about 485,000 SEK for the strategy of IHC testing for all patients, with FISH confirmation of 2+ and 3+, and trastuzumab and chemotherapy treatment for FISH positive patients. For the strategy of FISH testing for all patients, with trastuzumab and chemotherapy for FISH positive patients, we estimated the cost per QALY gained to about 561,000 SEK. The remaining testing and treatment strategies were dominated. Results were sensitive to changes in utilities, the risk of breast cancer related death, and test characteristics. CONCLUSION: Our analysis indicate that FISH testing for all patients with trastuzumab and chemotherapy treatment for FISH positive patients is a cost-effective treatment option from a societal perspective.

Cost of breast cancer in Sweden in 2002.

Breast cancer is the most common cancer among Swedish women and an important cause of illness and death. The aim of this study was to estimate the total cost of breast cancer in Sweden in 2002, using a top-down prevalence-based cost-of-illness approach. The total cost of breast cancer in Sweden in 2002 was estimated at 3.0 billion SEK (1 euro = 9.4 SEK). The direct costs were estimated at 895 million SEK and constituted 30% of the total cost. Indirect costs were estimated at 2.1 billion SEK and constituted 70% of the total cost. The main cost driver was production losses caused by premature mortality, amounting to 52% of the indirect costs. The reason that indirect costs were the dominant cost is because most newly detected breast cancers occur in patients aged below 65, thus causing significant production losses due to sick leave, early retirement, and premature mortality.

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 related quality of life in different states of breast cancer.

OBJECTIVES: The aim of this study was to describe the health related quality of life (HRQoL) in different breast cancer disease states using preference-based measures. MATERIAL AND METHODS: A total of 361 consecutive breast cancer patients attending the breast cancer outpatient clinic at Karolinska University hospital Solna for outpatient visits between April and May 2005 were included in the study. The EQ-5D self classifier and a direct Time Trade Off (TTO) question were used to estimate the HRQoL in different breast cancer disease states. RESULTS: Patients in their first year after a primary breast cancer had a mean EQ-5D index value of 0.696 (95% confidence interval (CI): 0.634-0.747)). Patients in their first year after a recurrence had a mean EQ-5D index value of 0.779 (CI: 0.700-0.849). Patients who had not had a primary breast cancer diagnosis or a recurrence during the previous year had a mean EQ-5D index value of 0.779 (CI: 0.745-0.811). Patients with metastatic disease reported the lowest HRQoL values, and had a mean EQ-5D index value of 0.685 (CI: 0.620-0.735). The main driver behind the reduction in HRQoL was pain and discomfort as well as anxiety and depression. TTO values were higher for all diseases states compared to the EQ-5D index values. CONCLUSION: This study shows that breast cancer is associated with a reduction in HRQoL. This effect is most pronounced for patients with metastatic disease.

Resource use and costs associated with different states of breast cancer.

OBJECTIVES: This study investigated the direct medical resource use and cost, informal care cost, and indirect cost associated with breast cancer in different states of the disease in normal clinical practice. METHODS: A retrospective database analysis was used to estimate direct medical resource use and cost, and a patient questionnaire was used to evaluate informal care and work capacity in different states of breast cancer. RESULTS: For patients younger than 65 years of age, the first year after a primary diagnosis total cost amounted to 280,000 SEK ($39,000) and the first year after a local or contralateral recurrence total cost was 351,000 SEK ($48,900). The second and following years after primary breast cancer or recurrence had substantially lower total cost, amounting to 94,000 SEK ($13,000). For patients with metastatic disease, the annual total cost was estimated to 334,000 SEK ($46,500). For patients older than 65 years of age, the total cost for the first year after a primary diagnosis amounted to 80,000 SEK ($11,200) and the total cost for the first year after a local or contralateral recurrence was 92,000 SEK ($12,900). The total cost for the second and following years after primary breast cancer or recurrence was estimated to 18,000 SEK ($2,600), and the total annual cost for patients with metastatic was 122,000 SEK ($17,000). CONCLUSIONS: Both direct medical costs and indirect cost vary substantially between disease states. For patients under 65 year of age, indirect costs accounted for more than 50 percent of the total cost.

Productivity improvements in hepatitis C treatment: impact on efficacy, cost, cost-effectiveness and quality of life.

OBJECTIVE: The treatment of chronic hepatitis C has advanced considerably during the past 15 years. The aim of this study was to evaluate the impact of different key developments from a health-economic perspective. MATERIAL AND METHODS: Costs and health-related quality-of-life data from a follow-up of Swedish patients treated for hepatitis C in clinical practice were used together with clinical trial data and natural history data in order to create a mathematical model that could be used to evaluate the advancement in hepatitis C therapy. The efficacy of treatment, costs and cost-effectiveness were evaluated for both current as well as proposed treatment strategies. A sensitivity analysis was used to assess how results were affected when key variables changed. RESULTS: Current genotype-guided pegylated interferon and ribavirin is a cost-effective treatment strategy. A proposed treatment strategy involving a reduction in the length of treatment for certain patient subgroups with genotypes 1, 2 and 3, as well as an increase in the length of treatment for patients with genotype 1 and slow virological response was estimated to be a cost-effective future treatment alternative. These results were insensitive to changes in costs and risks associated with chronic hepatitis. CONCLUSION: Although the costs for treatment of hepatitis C have increased significantly over the past decade, the improvements have provided the health-care system with cost-effective options in the treatment of patients with chronic hepatitis C.