Factors Affecting Sensitivity and Specificity of Screening Mammography and MRI in Women with an Inherited Risk for Breast Cancer

Background The MRISC study is a screening study, in which women with an increased risk of hereditary breast cancer are screened by a yearly mammography and MRI, and half-yearly clinical breast examination. The sensitivity found in this study was 40% for mammography and 71% for MRI and the specificity was 95 and 90%, respectively. In the current subsequent study we investigated whether these results are influenced by age, a BRCA1/2 mutation, menopausal status and breast density.Patients and methods From November 1999 to October 2003, 1909 eligible women were screened and 50 breast cancers were detected. For the current analysis, data of 4134 screening rounds and 45 detected breast cancers were used. For both imaging modalities, screening parameters, receiver operating characteristic (ROC) curves and uni- and multivariate odds ratios (ORs) were calculated. All analyses were separately performed for age at entry (< 40, 40–49, ≥50), mutation status, menopausal status and breast density.Results Sensitivity of MRI was decreased in women with high breast density (adjusted OR 0.08). False-positive rates of both mammography (OR_adj 1.67) and MRI (OR_adj 1.21) were increased by high breast density, that of MRI by pre-menopausal status (OR_adj 1.70), young age (OR_adj 1.58 for women 40–49 years versus women ≥50 years) and decreased in BRCA1/2 mutation carriers (OR_adj 0.74).In all investigated subgroups the discriminating capacity (measured by the area under the ROC-curve) was higher for MRI than for mammography, with the largest differences for BRCA1/2 mutation carriers (0.237), for women between 40 and 49 years (0.227) and for women with a low breast density (0.237).Conclusions This report supports the earlier recommendation that MRI should be a standard screening method for breast cancer in BRCA1/2 mutation carriers.     

Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance

Hereditary diffuse gastric cancer (HDGC) is a relatively rare disorder, with a mutated CDH1 gene as the only known cause. Carriers of a germline mutation in CDH1 have a lifetime risk of >80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. Little is known about other types of familial gastric cancer. The Dutch working group on hereditary gastric cancer has formulated guidelines for various aspects of medical management for families and individuals at high risk of developing gastric cancer, including criteria for referral, classification, diagnostics, and periodic gastric surveillance. These guidelines are not limited to HDGC and are therefore partially complementary to the guidelines on hereditary diffuse gastric cancer of the international gastric cancer linkage consortium (IGCLC 2010). In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. National and international collaboration is warranted to improve the quality of research by increasing the size of study cohorts.     

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk.     

Changes in immunological markers and influx of macrophages following trans‐scleral thermotherapy of uveal melanoma

Purpose: In trans‐scleral thermotherapy (TSTT), heat is applied through the sclera in order to target an intraocular uveal melanoma. Previously, it had been shown that in uveal melanoma, hyperthermia and transpupillary thermotherapy influenced expression of immunologically relevant proteins, such as S100, HLA and heat‐shock proteins (HSPs). We investigated whether TSTT induced similar changes. Methods: Experimental TSTT was applied on eleven uveal melanomas prior to enucleation. Each tumour sample was processed for histopathological examination; immunohistochemical analysis was performed to determine expression of S100, HLA, HSPs and macrophage markers. Results: In TSTT‐treated areas, expression of S100 and different HSPs was lost, while an upregulated expression of HSP GP96 was observed at the border of these areas. Expression levels of HLA‐A and HLA‐B varied between tumours and were not influenced by TSTT. The borders of the TSTT‐treated areas showed high numbers of infiltrating macrophages, which were predominantly of the M2 phenotype. Conclusion: TSTT has an effect on immunological parameters with local loss of expression of HSPs and S100. The influx of M2 macrophages around the TSTT‐treated areas indicates the presence of an innate immune reaction against the induced necrosis, suggesting that TSTT‐treated tumour cells are removed by a macrophage‐mediated tissue repair mechanism.