Breast stromal fibroblasts from histologically normal surgical margins are pro‐carcinogenic

There is evidence that normal breast stromal fibroblasts (NBFs) suppress tumour growth, while cancer‐associated fibroblasts (CAFs) promote tumourigenesis through functional interactions with tumour cells. Little is known about the biology and the carcinogenic potential of stromal fibroblasts present in histologically normal surgical margins (TCFs). Therefore, we first undertook gene expression analysis on five CAF/TCF pairs from breast cancer patients and three NBF samples (derived from mammoplasties). This comparative analysis revealed variation in gene expression between these three categories of cells, with a TCF‐specific gene expression profile. This variability was higher in TCFs than in their paired CAFs and also NBFs. Cytokine arrays show that TCFs have a specific secretory cytokine profile. In addition, stromal fibroblasts from surgical margins expressed high levels of α‐SMA and SDF‐1 and exhibited higher migratory/invasiveness abilities. Indirect co‐culture showed that TCF cells enhance the proliferation of non‐cancerous mammary epithelial cells and the epithelial‐to‐mesenchymal transition of breast cancer cells. Moreover, TCF and CAF cells increased the level of PCNA, MMP‐2 and the phosphorylated/activated form of Akt in normal breast luminal fibroblasts in a paracrine manner. Furthermore, TCFs were able to promote the formation and growth of humanized orthotopic breast tumours in nude mice. Interestingly, these TCF phenotypes and the extent of their effects were intermediate between those of NBFs and CAFs. Together, these results indicate that stromal fibroblasts located in non‐cancerous tissues exhibit a tumour‐promoting phenotype, indicating that their presence post‐surgery may play important roles in cancer recurrence. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Xanthogranulomatous cholecystitis on fusion of the planes of the liver

Xanthogranulomatous cholecystitis (CXG) is a rare entity of cholecystitis, characterized by the presence of xanthogranulomas within the gallbladder wall, that could be misdiagnosed as a vesicular carcinoma. We report a case of 66-year-old man with xanthogranulomatous cholecystitis associated with an incidental finding of a fusion of the planes of the liver which is a rare anatomic variant. Imaging especially ultrasounds, CT scan, and MRI play a key role in the characterization of those anomaly, thus avoiding a non–suitable surgical procedure.     

Characterizing SOD1 mutations in Spain: The impact of genotype,age and sex in the natural history of the disease

Background and purpose

The aim of this study was to describe the frequency and distribution of SOD1 mutations in Spain, and to explore factors contributing to their phenotype and prognosis.

Methods

Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers.

Results

In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of SOD1, including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months).

Conclusions

These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.