The Dutch Cancer Society Cancer Risk Test

The Dutch Cancer Society developed the 'KWF Kanker Risico Test' (Cancer Risk Test) to improve the information available to the Dutch population regarding cancer risk factors. This Internet test, based under licence on the American 'Your Disease Risk' test, informs users about risk factors for 12 common types of cancer. The test provides an estimate of individual risk of a specific type of cancer and gives specific lifestyle advice that could lower that risk. This paper describes the development of the test, how it works, and its strengths and limitations.     

Prediction of Helicobacter pylori in Gastric Specimens by Inflammatory and Morphological Histological Evaluation

Statistical correlations and predictive values were calculated for 330 gastrointestinal biopsies and tissues, of which 248 were from the stomach from 115 patients in this retrospective study, which graded 10 inflammatory and 14 morphological mucosal and submucosal abnormalities and compared them with the presence of Helicobacter pylori. Analysis revealed that 78 (31.5%) of the 248 stomach biopsies and tissues showed H. pylori, and 21 (8.5%) had non-Helicobacter-like bacteria, such as rods and cocci. Inflammatory components had high correlations, with specimens containing polymorphonuclear leukocytes (PMNs) showing high specificities and predictive values for a positive test, whereas the chronic inflammatory components had high sensitivities and predictive values for a negative test. Positive morphological correlations existed for mucus depletion, degeneration, regeneration, and ulceration, but intestinal metaplasia and adenocarcinoma had negative correlations. The antrum was most commonly infected, suggesting that intact healthy antral morphology and the neutral mucin in the surface epithelial cells represents the optimal environment for infection. Also, 8.5% of the gastric biopsies and tissues showed non-Helicobacter bacteria associated with inflammation, thus raising the question of colonization versus pathogenesis.     

A strabismus susceptibility locus on chromosome 7p

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.     

Correlation of interferon‐inducible chemokine plasma levels with disease severity in systemic sclerosis

Objective

To measure interferon (IFN)–inducible chemokines in the plasma of patients with systemic sclerosis (SSc) and investigate whether the chemokine levels are correlated with disease severity.

Methods

Plasma levels of the IFN‐inducible chemokines IFNγ‐inducible protein 10 (IP‐10/CXCL10), IFN‐inducible T cell α chemoattractant (I‐TAC/CXCL11), and monocyte chemoattractant protein 1 (CCL2) were measured in SSc patients and examined for correlation with the IFN gene expression signature. A composite IFN‐inducible chemokine score was generated for chemokines showing a correlation with the IFN gene signature (IP‐10 and I‐TAC), and this score was compared between 266 patients with SSc enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort and 97 matched control subjects. Subsequently, the correlation between the IFN‐inducible chemokine score at baseline and markers of disease severity was assessed. In addition, the course of the IFN‐inducible chemokine score over time was examined.

Results

The plasma IFN‐inducible chemokine score correlated with the IFN gene expression signature, and this score was higher in SSc patients compared to controls. The IFN‐inducible chemokine score was also associated with the absence of anti–RNA polymerase III antibodies and presence of anti–U1 RNP antibodies, but not with disease duration, disease type, or other autoantibodies. The chemokine score correlated with concomitantly obtained scores on the Medsger Severity Index for muscle, skin, and lung involvement in SSc, as well as the forced vital capacity, diffusing capacity for carbon monoxide, and creatine kinase levels. The association of the chemokine score with disease severity was independent of the presence of anti–U1 RNP or other potential confounders (age, sex, ethnicity, disease duration, and treatment with immunosuppressive agents). Finally, there was not a significant change in the IFN‐inducible chemokine score over time.

Conclusion

The IFN‐inducible chemokine score is a stable serologic marker of a more severe form of SSc and may be useful for risk stratification of patients, regardless of disease type (limited or diffuse) or duration of disease.

     

Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies.

PURPOSE: ONYX-015 is a genetically modified adenovirus with a deletion of the E1B early gene and is therefore designed to replicate preferentially in p53-mutated cells. A Phase II trial of intralesional ONYX-015 was conducted in patients with hepatobiliary tumors to determine the safety and efficacy of such a treatment. EXPERIMENTAL DESIGN: All patients had biopsy-proven, measurable tumors of the liver, gall bladder, or bile ducts that were beyond the scope of surgical resection. Patients received intralesional injections of ONYX-015 at either 6 x 10(9) or 1 x 10(10) plaque-forming units/lesion up to a total dose of 3 x 10(10) plaque-forming units, and i.p. injections were allowed in patients with malignant ascites. The status of p53 was assessed by immunohistochemistry or Affymetrix GeneChip microarray analysis. Studies were conducted for viral shedding and for the presence of antiadenoviral antibodies before and after the injection of ONYX-015. Patients were assessed for response and toxicity. RESULTS: Twenty patients were enrolled, and 19 patients were eligible. Half of the patients had primary bile duct carcinomas. Serious toxicities (> grade 2) were uncommon and included hepatic toxicity (three patients), anemia (one patient), infection (one patient), and cardiac toxicity (one patient, atrial fibrillation). Sixteen patients were evaluable for response. Among these evaluable patients, 1 of 16 (6.3%) had a partial response, 1 of 16 (6.3%) had prolonged disease stabilization (49 weeks), and 8 of 16 (50%) had a >50% reduction in tumor markers. Of the 19 eligible patients, 18 (94.7%) had specimens available for p53 analysis. Fifteen of these 18 patients (83.3%) had evidence of p53 mutation by one or both methods, although the methods correlated poorly. Viral shedding was confined to bile (two of two patients) and ascites (four of four patients). Pretreatment adenoviral antibodies were present in 14 of 14 patients and increased by 33.2% after ONYX-015 treatment. CONCLUSIONS: Intralesional treatment with ONYX-015 in patients with hepatobiliary tumors is safe and well tolerated, and some patients had evidence of an anticancer effect. The high incidence of p53 mutations in these tumors makes this a logical population in which to test this therapy but precludes definitive evaluation about the necessity of a p53 mutation for ONYX-015 clinical activity.