Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes

Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement

Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Impact of reirradiation of painful osseous metastases on quality of life and function:a secondary analysis of the NCIC CTG SC.20 randomized trial

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Revisiting classification of pain from bone metastases as mild, moderate, or severe based on correlation with function and quality of life

The objective of our study was to determine the optimal cut points for classification of pain scores as mild, moderate, and severe based on interference with function and quality of life (QOL). We evaluated 822 patients who completed the Brief Pain Inventory (BPI) and/or the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30) prior to receiving repeat radiation therapy for previously irradiated painful bone metastases. Optimal cut points for mild, moderate, and severe pain were determined by the MANOVA that yielded the largest F ratio for the between category effect on the seven interference items of BPI and the six functional domains of QOL (physical, role, emotional, cognitive, social functioning, and global QOL) as indicated by Pillai's Trace, Wilk's λ, and Hostelling's Trace F statistics. For BPI and for QOL domains separately, the two largest F ratios for Wilk's λ, Pillai's Trace, and Hotelling's Trace F statistics were from the cut points 4, 8 and 6, 8. When combining both, the optimal cut points were 4, 8 with 1-4 (mild), 5-8 (moderate), and 9-10 (severe). With this classification, the mean scores of all the seven interference items in BPI and the six functional domains were all highly statistically different. Patients with severe pain survived significantly shorter than those with mild and moderate pain (p < 0.0001). Our analysis supports the classification of pain scores as follows: 1-4 as mild pain, 5-8 as moderate pain, and 9-10 as severe pain. This may facilitate conduct of future clinical trial

Sensitivity and specificity of assessing coronary bypass graft patency with ultrafast computed tomography: Results of a multicenter study

AbstractBecause a significant number of all patients seen by cardiologists have had coronary bypass surgery, a relatively noninvasive method of assessing coronary bypass graft patency would be very helpful. Ultrafast computed tomography, by virtue of its rapid data acquisition time and reasonable spatial resolution, may be useful in this regard. To determine the sensitivity, specificity and predictive accuracy of this imaging modality as compared with cardiac catheterization, a multicenter study was undertaken.There were two parts to the study. Part I involved the evaluation of 179 grafts in 74 patients studied in the five participating centers between March 1985 and August 1986. Twenty-nine percent of these graft studies were found to be technically inadequate and were excluded before patency determinations began. The remaining group of 127 bypass grafts in 62 patients had studies adequate for interpretation. Fifty-one grafts werl to the left anterior descending coronary artery or a diagonal branch, 37 to branches of the left circumflex artery and 28 to the right coronary artery or a posterior descending vessel; in addition, there were 11 internal mammary artery bypass grafts primarily into the left anterior descending or diagonal artery distribution. The sensitivity of detecting angiographically open grafts was 93.4%, the specificity of detecting angiographically closed grafts 88.9% and the predictive accuracy was 92.1%. A subsequent study (Part 2) was performed 9 months later to assess the ability to carry out technically adequate examinations. Of the 138 consecutive graft examinations (50 patients) included in this part of the study, 94.2% of the examinations were found to be technically adequate.From these data it is concluded that 1) Ultrafast computed tomography is a very useful, minimally invasive technique for evaluating coronary artery bypass graft patency, and 2) technically adequate studies can be effectively performed in the majority of patients with bypass grafts

Gender and age make no difference in the re-irradiation of painful bone metastases:A secondary analysis of the NCIC CTG SC.20 randomized trial

Biological, physical and clinical aspects of cancer treatment with ionising radiatio