Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro.

AIMS/HYPOTHESIS: Type 2 diabetes and obesity are associated with increased risk of site-specific cancers. We have investigated whether metabolic alterations at the level of adipose-derived differentiating cells may affect specific phenotypes of breast cancer cells. METHODS: Growth profiles of breast cancer cell lines were evaluated in co-cultures with differentiated adipocytes or their precursor cells and upon treatment with adipocyte conditioned media. Production and release of cytokines and growth factors were assessed by real-time RT-PCR and multiplex-based ELISA assays. RESULTS: Co-cultures with either differentiated mouse 3T3-L1 or human mammary adipocytes increased viability of MCF-7 cells to a greater extent, when compared with their undifferentiated precursors. Adipocytes cultured in 25 mmol/l glucose were twofold more effective in promoting cell growth, compared with those grown in 5.5 mmol/l glucose, and activated mitogenic pathways in MCF-7 cells. Growth-promoting action was also enhanced when adipocytes were incubated in the presence of palmitate or oleate. Interestingly, 3T3-L1 and human adipocytes released higher amounts of keratinocyte-derived chemokine/IL-8, the protein 'regulated upon activation, normally T expressed, and secreted' (RANTES), and IGF-1, compared with their precursor cells. Their levels were reduced upon incubation with low glucose and enhanced by fatty acids. Moreover, both undifferentiated cells and differentiated adipocytes from obese individuals displayed about twofold higher IGF-1 release and MCF-7 cell growth induction than lean individuals. Finally, inhibition of the IGF-1 pathway almost completely prevented the growth-promoting effect of adipocytes on breast cancer cells. CONCLUSIONS/INTERPRETATION: IGF-1 release by adipocytes is regulated by glucose and fatty acids and may contribute to the control of cancer cell growth in obese individuals.

Spinal dural arteriovenous fistulas: clinical features in 80 patients.

The aim of this study was to describe the clinical spectrum of spinal dural arteriovenous fistulas (SDAF) in a large group of patients. We studied the records of 80 patients who were diagnosed with an SDAF in six hospitals over a 15 year period (1985-2001). We extracted data on demographic variables, initial symptoms, symptoms at the time of diagnosis, level of SDAF, and medical history. Most patients were middle aged men, and most SDAF were located in the midthoracic region. The median time to diagnosis of 80 patients with an SDAF was 15 months (range 7 days-197 months). The most common initial symptoms were gait disturbances (34%), numbness (24%), and paresthesias (21%). At the time of diagnosis, most common symptoms were micturition problems (80%), leg weakness (78%), and numbness in the legs or buttocks (69%). The combination of all three symptoms was present in 58% of patients. Any symptoms or signs related to sacral segments had developed in 67 patients (84%). Fifteen patients (19%) had become wheelchair bound. SDAF is difficult to diagnose, and the delay between first symptoms and treatment is often long. In middle aged men who present with disturbances of gait with ascending motor and sensory deficits, and who subsequently report impaired voiding or other sphincter disturbance, SDAF is one of the first diagnoses that should spring to mind.

Prediction of spinal epidural metastases.

CONTEXT: Early diagnosis and treatment of spinal epidural metastases (SEM) is of the utmost importance to prevent neurological deficit due to spinal cord compression. Magnetic resonance imaging (MRI) has become the final tool in that diagnostic process. However, access to MRI is still limited in The Netherlands, requiring cost-effective use. It is generally acknowledged that patients with systemic cancer who present with a radiculopathy or myelopathy should undergo an MRI. However, the diagnostic policy in patients with systemic cancer who present with recently developed back pain is still a matter of debate. OBJECTIVE: To identify the patients with back pain in whom MRI can safely be omitted because of a low risk of SEM. METHODS: In a prospective series of 170 consecutive patients with cancer with recently developed back pain, prediction of spinal metastatic disease (SMD) and especially SEM was studied by means of a multivariate risk analysis of the parameters of the standard neurological evaluation (medical history, neurological examination, and plain films of the whole spine). Magnetic resonance imaging was used as the criterion standard. We calculated the risk implications of omitting MRI in patients with an estimated risk below different cutoff points. RESULTS: Spinal metastatic disease was diagnosed in 80 patients (47%); of these, 31 had SEM. A metastatic abnormality on plain films was the strongest independent predictor for SMD. Other important predictors were night pain, progressive pain, and Karnofsky score. Advanced age, exacerbation of pain during recumbency, and osteoporotic fracture imply a low risk of SMD. Night pain and the Karnofsky score proved to be the main predictors for SEM. A plain film showing an osteoporotic fracture strongly decreased the risk of SEM. The discriminating value of the multivariate analysis was too low, and too few patients can be excluded from undergoing MRI on the basis of the standard neurological checkup. To identify all the patients with SMD (P<.01), MRI would be excluded in only 7 patients. Identification of all patients with SEM (P<.001) reduced the number of MRIs by 21 at the expense of plain films of the whole spine for any patient. CONCLUSIONS: Selection of patients with cancer with back pain at risk of SEM was not possible with the standard neurological checkup. After intake by the neurologist, the next step should be MRI of the whole spine.

[Spinal dural arteriovenous fistula: a treatable cause of loss of strength in the legs]. / De spinale durale arterioveneuze fistel: een behandelbare oorzaak van krachtverlies in de benen.

In a 59-year-old male suffering from progressive gait disorder with paraparesis and sensory disturbances in the legs, two spinal dural arteriovenous fistulas on levels Tv and LIII were demonstrated by spinal angiography. Both fistulas were embolised with glue, which resulted in complete relief of his symptoms. Spinal dural arteriovenous fistulas are localized in the dura, extramedullary, and are most often found in males over forty. Signs and symptoms are caused by venous congestion and ischaemia of the spinal cord. Treatment is by means of embolisation or surgical ligation. Early diagnosis and treatment are important, since delay causes development of irreversible myelopathy.

Lumbar epidural lipomatosis causing neurogenic claudication in two obese patients.

Two obese patients suffering from neurogenic claudication caused by lumbar epidural lipomatosis are described. Although lumbar epidural lipomatosis is most often related to prolonged use of steroid drugs, obesity has also been reported as a possible cause. Both CT and MRI can demonstrate excess epidural fat; because of the possibility of sagittal views MRI is to be preferred. In one of our patient with neurogenic claudication the excess epidural fat normalised completely after considerable weight reduction and symptoms resolved. Therefore weight reduction might be the initial therapy in an obese patient with symptomatic epidural lipomatosis. When weight reduction fails or when there are urgent clinical reasons, surgical removal of the excess amount of epidural fat should be considered.

[Sneddon's syndrome: an unusual cause of cerebral infarct at a relatively young age]. / Het syndroom van Sneddon: een zeldzame oorzaak van een herseninfarct op relatief jonge leeftijd.

Sneddon's syndrome was diagnosed in a man of 56, and two women aged 48 and 22 years. It is a rare disease characterised by the combination of skin lesions (livedo racemosa) and cerebral infarctions at a relatively early age. Apart from the clinical presentation, the diagnosis can sometimes be confirmed by a typical microscopical image of a biopsy taken from a region adjacent to the livedo (endothelitis, perivascular lymphocyte infiltration and hypertrophy of the artery wall). The cause of the syndrome is unknown and a specific therapy is lacking. Early recognition of Sneddon's syndrome may protect patients against unnecessary ancillary investigations.