25-Hydroxyvitamin D serum levels and melanoma risk: a case-control study and evidence synthesis of clinical epidemiological studies.

There is accumulating evidence that the vitamin D pathway may play a role in melanoma. The aim of this study was to investigate the association between 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of cutaneous melanoma. A case-control study with 137 incident cases of melanoma (serum samples collected at the time of diagnosis) and 99 healthy controls (serum samples collected between October and April) was carried out and evaluated in the framework of an evidence synthesis of clinical epidemiological studies on the topic to facilitate comparisons and summarize the scientific evidence produced so far. There was a statistically significant difference in the median levels of serum vitamin D between melanoma patients and healthy controls (18.0 vs. 27.8 ng/ml, P<0.001). Among melanoma patients, 66.2%, compared with 15.2% of healthy controls, had vitamin D deficiency (≤20 ng/ml), whereas vitamin D sufficiency (≥30 ng/ml) was observed in only 7.4% of melanoma patients and in 37.4% of the healthy controls (P<0.001). A multivariate model including age, sex, and BMI showed a statistically significant inverse association between melanoma and vitamin D sufficiency versus deficiency (odds ratio=0.04; 95% confidence interval: 0.02-0.10, P<0.001). Also, vitamin D insufficiency versus deficiency was significantly inversely associated with melanoma (odds ratio=0.13; 95% confidence interval: 0.06-0.27, P<0.001). These results suggest that both deficient and insufficient serum levels of vitamin D are associated with melanoma and that a trend seems to be present with a reduced risk of melanoma when vitamin D approaches normal values.

Diagnostic accuracy of 3T magnetic resonance imaging in the preoperative localisation of parathyroid adenomas: comparison with ultrasound and 99mTc-sestamibi scans.

OBJECTIVES: To evaluate the diagnostic performance of 3TMRI in comparison with ultrasound (US) and 99mTc-sestamibi scan for presurgical localisation of parathyroid adenomas (PTAs) in patients with primary hyperparathyroidism (PHPT). METHODS: Fifty-seven patients affected by PHPT were prospectively enrolled and underwent US, 99mTc-sestamibi and 3TMRI. T2-weighted and post-contrast T1-weighted Iterative decomposition of water and fat with Echo Asymmetry and Least squares estimation (IDEAL) sequences were acquired. Diagnostic performance of US, 99mTc-sestamibi and MRI in localising PTAs to correct quadrant were compared according to surgical and pathological findings. RESULTS: According to surgical findings, US correctly localised 41/46 PTAs (sensitivity of 89.1%; specificity 97.5%; PPV 93.1% and NPV 95.6%); 99mTc-sestamibi correctly localised 38/46 PTAs (sensitivity 83.6%, specificity 98.3%, PPV 95% and NPV 93.7%). US and 99mTc-sestamibi combined had a sensitivity of 93.4% (43/46 PTAs), specificity of 98.3%, PPV 95% and NPV 98.3%. MRI correctly localised 45/46 PTAs (sensitivity 97.8%; specificity 97.5%; PPV 93.7% and NPV 99.2%). MRI was able to detect six adenomas missed by 99mTc-sestamibi and two adenomas missed by US. MRI and US were able to detect all enlarged parathyroid glands in patients with multiglandular disease. MRI identified six of seven ectopic adenomas. CONCLUSIONS: Our study demonstrated high diagnostic performance of 3T MRI in the preoperative PTAs quadrant localisation, as well as in patients with multiglandular disease and ectopic PTAs. MRI may be preferred to adequately select patient candidates for minimally invasive parathyroidectomy (MIP). KEY POINTS: • PTA(s) quadrant localisation by 3TMRI was more accurate than US+99mTc-sestamibi. • MRI identified all enlarged glands in multiglandular disease similarly to US. • MRI identified 6/7 ectopic PTAs similarly to 99mTc-sestamibi. • Presurgical PTA(s) localisation by 3TMRI select the optimal candidates for MIP.

Misdiagnosis of vertebral fractures on local radiographic readings of the multicentre POINT (Prevalence of Osteoporosis in INTernal medicine) study.

BACKGROUND: Osteoporotic vertebral fractures (VFs) are often misdiagnosed because asymptomatic and occurring in the absence of specific trauma. Further, diagnostic assessment of VFs may be suboptimal. AIM OF THE STUDY: To assess the misdiagnosis of vertebral fractures on local radiographic readings in the cohort of patients enrolled in the POINT study. METHODS: We enrolled hospitalised patients, admitted for any cause to the Internal Medicine Units of 37 hospitals participating to the cross-sectional previously published POINT study. The assessment of VFs was performed both by local radiologists and by two expert skeletal radiologists, by using semiquantitative method (SQ). To better evaluate mild vertebral deformities, the two central radiologists also used the algorithm-based qualitative assessment (ABQ). RESULTS: The radiographs of 661 patients (401 females; mean age 75.8±8.0) were evaluated. The inter-reader percent agreement between two central expert radiologists per-vertebra assessment was excellent (99.78%; k=0.984; 95% CI, 0.977-0.991). Central reading identified 318/661 (48.1%) patients with at least one VF. Local and central readings agreed in 502/661 (75.9%) patients, resulting in a fair reproducibility (k=0.52; 95% confidence interval 0.44-0.59). Diagnostic performance parameters of local readings were: sensitivity 76.1%; specificity 75.8%; PPV 74.46%; NPV 77.38%). By examining 9254 vertebrae, central and local readers diagnosed 665 (7.2%) and 562 (6.1%) VFs respectively. Misdiagnosis (102 false positives and 205 false negatives) mainly occurred for mild VFs. Local readings identified correctly 460 out 665 VFs diagnosed by central readings, resulting in sensitivity of 69.2% and PPV of 81.8%. CONCLUSIONS: Following a standardized protocol of acquisition techniques and of interpretation criteria, an excellent agreement between local and central readings for moderate and severe vertebral fractures resulted. However a significant amount of mild vertebral fractures, that are the most of VFs, were misdiagnosed by local radiologists. In order to improve VFs assessment, the radiologists should be trained and sensitized in relation to the relevant clinical significance of osteoporotic VFs identification.

Antiproliferative Effects of 1α-OH-vitD3 in Malignant Melanoma: Potential Therapeutic implications.

Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow's thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1α hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1α-hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25-hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1α-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1α-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options.

Coexistence of epilepsy and Brugada syndrome in a family with SCN5A mutation.

Cardiac arrhythmias are associated with abnormal channel function due to mutations in ion channel genes. Epilepsy is a disorder of neuronal function also involving abnormal channel function. It is increasingly demonstrated that the etiologies of long QT syndrome and epilepsy may partly overlap. However, only a few genetic studies have addressed a possible link between cardiac and neural channelopathies. We describe a family showing the association between Brugada syndrome and epilepsy in which a known mutation in the SCN5A gene (p.W1095X, c.3284G>A) was identified. We suggest that this mutation can be responsible for cardiac and brain involvement, probably at different developmental age in the same individual. This observation confirms the possibility that SCN5A mutations may confer susceptibility for recurrent seizure activity, supporting the emerging concept of a genetically determined cardiocerebral channelopathy.

Diagnostic performance of vertebral fracture assessment by the lunar iDXA scanner compared to conventional radiography.

The purpose of this study was to evaluate the diagnostic performance of vertebral fracture assessment (VFA) using the Lunar iDXA scanner. Conventional spinal radiographs and images acquired by dual-energy X-ray absorptiometry (DXA) of 350 subjects (269 females, 81 males) were evaluated by two different readers. We visualized 4,476/4,550 (98.4 %) vertebrae from T4 to L4 on VFA images compared to 4,535/4,550 (99.7 %) on radiographs. Among the visualized vertebrae, 205/4,535 (4.5 %) and 190/4,476 (4.2 %) were identified as nonfracture deformities by reading of radiographs and VFA, respectively. Vertebral fractures (VFs) were 231 in 126 patients and 228 in 125 patients by semiquantitative assessment of radiographs (SQ-Rx) and by VFA, respectively. There was excellent agreement between the two techniques and high diagnostic performance of VFA both on a per-vertebra basis (k score = 0.984, 95 % CI 0.972-0.996, sensitivity 98.68 %, specificity 99.91 %, PPV 98.25 %, NPV 99.93 %) and on a per-patient basis (k score = 0.957, 95 % CI 0.925-0.988, sensitivity 96.83 %, specificity 98.66 %, PPV 97.60 %, NPV 98.22 %). In older patients (≥65 years) affected by moderate or severe osteoarthritis, SQ-Rx and VFA identified 96 VFs and 95 versus 90 vertebral deformities, respectively. This study demonstrates that most vertebrae are evaluable using the iDXA scanner, with improved VFA diagnostic performance even in discriminating mild VFs from vertebral deformities. Therefore, VFA may be appropriate as an alternative to conventional radiography in patients at high risk of VF who are undergoing DXA bone densitometry and in the follow-up of osteoporotic patients on treatment.

Vertebral morphometry by X-ray absorptiometry: which reference data for vertebral heights?

INTRODUCTION: The recent improvement in the resolution of dual-energy X-ray absorptiometry (DXA) images enables most vertebral levels to be seen adequately and thus DXA may be a worthwhile alternative to radiologic morphometry for the identification of vertebral fractures (VF). In this multicenter study, we have derived reference data for vertebral heights and their ratios in Italian women using morphometric X-ray absorptiometry (MXA). METHODS: DXA scans were acquired in 1254 consecutive pre- and postmenopausal women, (mean age 63.7 ± 11.3, range 26-88 yrs), referred to six osteoporosis centers. MXA analysis of these images was performed by the same operator measuring vertebral heights and height ratios from L4 to T4. We calculated measures of central tendency and dispersion of vertebral heights and vertebral ratios using different approaches (mean and standard deviation as well as median and interquartile range of raw data, mean and standard deviation of trimmed data using an iterative algorithm, and mean and standard deviation of not fractured vertebrae). RESULTS: Independently of the approach that we used, all the measures of central tendency were similar, while significant differences were found when compared with reference ranges in other populations. The vertebral heights of our sample at every vertebral level were significantly smaller than both Rea population and the Lunar reference values, even after normalization. Splitting data according to age groups, there was a decrease in the vertebral heights and ratios between the younger and older women. CONCLUSIONS: This study demonstrates that reference data for MXA should be population specific and age matched.

Transient osteoporosis of the hip.

Transient osteoporosis of the hip (TOH) is not an uncommon condition, usually with a benign course. The syndrome classically affects women during the last trimester of pregnancy, but also middle aged men. Recently, TOH has been described in non pregnant women. The pathophysiology of the disease is uncertain, though several hypotheses have been suggested. Joint pain is the main symptom. TOH is a self-limited condition, which resolves spontaneously with complete recovery within several months in most cases.

Bisphosphonate treatment in ochronotic osteoporotic patients.

In ochronotic patients, abnormalities in bone metabolism leading to increased bone loss have been reported. Therefore, we attempted antiresorptive therapy to (almost) partially reverse bone loss in four out of five osteopenic or osteoporotic ochronotic patients, two men and two women, aged 56-82 years. Each patient was treated with a 70-mg tablet of alendronate weekly and 1,000 mg/day of elemental calcium, such as gluconolactate or carbonate, throughout 24 months. Before starting therapy, and after 1 and 2 years of treatment, the bone mineral density (BMD) at the femoral subregions and at the lumbar spine was measured (in grams per square centimeter and as a T score) by dual energy X-ray absorptiometry. A 50-year-old osteopenic ochronotic man refusing the treatment underwent the same checks. The BMD was measured in all patients on the same densitometer by the same operator. The results showed a progressive decrease of the femoral subregion BMD measurements both in the bisphosphonate-treated patients and in the untreated patient. In particular, the percentage differences with respect to the basal values of the total femur BMD measurements ranged from -0.52 to -6.72% in the first year and from -5.29 to -9.05% in the second year. The lumbar spine BMD measurements provided spuriously overestimated results. Moreover, two treated patients and the untreated patient experienced fragility fractures of the femur. The study showed that osteoporosis and fragility fractures are prominent manifestations in the natural history of ochronosis. Matrix microdamage, osteocyte viability, and collagen cross-linking impairment, due to homogentisic acid and to its polymer, might be the processes involved. For this reason, the bisphosphonate therapy was ineffective.

Morphometric X-ray absorptiometry in the assessment of vertebral fractures in renal transplant patients.

BACKGROUND: Bone mineral density (BMD) is widely employed to evaluate the risk of fractures, but more than mineral content is bone quality that accounts for bone strength. In fact, occasionally, subjects with normal or only mildly reduced BMD also experience pathologic fractures. In metabolic bone disease, like renal transplantation, the agreement between fractures and BMD is less predictable. We assessed the prevalence of vertebral fractures by means of a new, DEXA-based method (morphometric absorptiometry, MXA) and compared its concordance with the two mostly employed radiological techniques (Visual semi-quantitative, SQ, and morphometric radiography, MRX) in an asymptomatic population of transplanted patients. Moreover, the association of bone fractures with low BMD values was examined. METHODS: Fifty-three renal transplant patients underwent spinal radiographs and BMD measurements by DEXA. In order to obtain a morphometric assessment, a lateral DEXA scan was performed. RESULTS: Patients with vertebral fracture were 17/53 (32%) with both SQ and MRX, and 12/53 (23%) with MXA (chi(2) = n.s.). A single fracture was detected in 9/53 patients (17%) with SQ and MRX, and in 4/53 (7.5%) with MXA; multiple fractures were 8/53 (15%) with any technique. With SQ as the standard reference, predictive indexes were excellent with MRX (invariably 100%) and quite good with MXA (sensitivity 70.6%; specificity 100%). Of the total of 689 vertebrae, 49 were fractured with SQ, 54 with MRX and 41 with MXA. Mild deformities were present in 21 (SQ), 26 (MRX) and 13 (MXA) vertebral bodies, respectively, while moderate-severe deformities were 28 with any technique. Again, with SQ as standard reference, predictive indexes were good (MRX: sensitivity 100%, specificity 99.2%; MXA: sensitivity 83.7%, specificity 100%). When we classified patients according to BMD T-score values, SQ and MRX recognized fractures in 4/18 normal (22%), 10/22 osteopenic (45%) and 3/13 osteoporotic (23%). With MXA 3/18 (17%) normal, 6/22 (27%) osteopenic and 3/13 (23%) osteoporotic were fractured. The lower performance of MXA was very likely due to the poor quality of images from the upper thoracic spine of obese subjects. CONCLUSIONS: Prevalence of vertebral fractures in renal transplant patients is quite high and randomly associated with reduced BMD. A surveillance of the spine by Rx, implemented with vertebral morphometry, is therefore warranted to recognize the disease. (MXA is a reliable alternative technique, especially in more severely affected individuals.) MXA, although less sensitive than the conventional techniques because of possible technical biases, is very specific, and can be proposed for follow-up purposes in this population of patients.