Venous thromboembolism (VTE) is a clinically important complication for both hospitalised and ambulatory cancer patients. In the current study, the frequency, demographics and risk (according to tumour site) of VTE were examined among patients seen at outpatient DVT (deep-vein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed with cancer, for an overall rate of cancer-associated VTE of 13.6% in this outpatient population. Patients with cancer-associated VTE were significantly older than cancer-free VTE cases (66.4 +/- 12.7 vs. 58.8 +/- 18.5 years; p<0.0001). The frequency of cancer-associated VTE peaked earlier among females than males, occurring in the sixth (137/639, 21.4% vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs. 197/1096, 18%; p=0.036). VTE was described most frequently in common cancers - breast, prostate, colorectal and lung (56.1% of cases). The risk of VTE varied widely across 17 cancer types. Calculating odds ratios (OR) to assess the effect size of cancer type on VTE risk, the highest odds were observed for patients with pancreatic cancer (OR 9.65, 95% confidence interval [CI] (5.51-16.91). Tumours of the head and neck had higher odds than previously reported (OR 8.24, 95% CI 5.06-13.42). Reduced risk estimates were observed for skin cancers (melanoma and non-melanoma: OR 0.89, 95% CI 0.42-1.87; OR 0.74, 95% CI, 0.32-1.69, respectively). We conclude that outpatients have a similar rate of cancer-associated VTE as VTE patient populations previously reported, that cancer-associated VTE occurs in an older age group and earlier in females and that outpatients exhibit distinct tumour site-specific risk from that described among hospitalised cancer patients.

Rhabdomyosarcomas are characterized by loss of heterozygosity (LOH) at chromosome region 11p15.5, a region known to contain several imprinted genes including insulin-like growth factor 2 (IGF2), H19, and p57(KIP2). We analyzed 48 primary tumour samples and found distinct genetic changes at 11p15.5 in alveolar and embryonal histological subtypes. LOH was a feature of embryonal tumours, but at a lower frequency than previous studies. Loss of imprinting (LOI) of the IGF2 gene was detected in 6 of 13 informative cases, all harbouring PAX3-FKHR or PAX7-FKHR fusion genes characteristic of alveolar histology. In contrast, H19 imprinting was maintained in 14 of 15 informative cases and the case with H19 LOI had maintenance of the IGF2 imprint indicating separate mechanisms controlling imprinting of IGF2 and H19. The adult promoter of IGF2, P1, was used in 5 of 14 tumours and its expression was unrelated to IGF2 imprinting status implying a further mechanism of altered IGF2 regulation. The putative tumour suppressor gene p57(KIP2) was expressed in 15 of 29 tumours and expression was unrelated to allele status. Moreover, in tumours with p57(KIP2) expression, there was no evidence for inactivating mutations, suggesting that p57(KIP2) is not a tumour suppressor in rhabdomyosarcoma.

Summary Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.

This study provides evidence of very high D-dimer levels in patients with cancer who do not have VTE. This suggests that elevated D-dimer levels in patients with VTE and malignancy are not solely due to presence of thrombus. High D-dimer levels in malignancy are likely to reflect the biology of the underlying tumour, with higher levels observed in breast, prostate and bowel cancers.

No abstract