The antiquity of hydrocephalus: the first full palaeo-neuropathological description

The Pathology Museum of the University of Florence houses a rich collection of anatomical specimens and over a hundred waxworks portraying pathological conditions occurring in the nineteenth century, when the museum was established. Clinical and autopsy findings of these cases can still be retrieved from the original museum catalogue, offering a rare opportunity for retrospective palaeo-pathological diagnostics. We present a historical case of severe hydrocephalus backed by modern-day anthropological, radiological and molecular analyses conducted on the skeleton of an 18-month-old male infant deceased in 1831. Luigi Calamai (1796-1851), a wax craftsman of La Specola workshop in Florence, was commissioned to create a life-sized wax model of the child's head, neck and upper thorax. This artwork allows us to appreciate the cranial and facial alterations determined by 30 lb of cerebrospinal fluid (CSF) accumulated within the cerebral ventricular system. Based on the autopsy report, gross malformations of the neural tube, tumours and haemorrhage could be excluded. A molecular approach proved helpful in confirming sex. We present this case as the so-far most compelling case of hydrocephalus in palaeo-pathological research

Patterns of genomic instability in gastric cancer: clinical implications and perspectives.

In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to the transcriptional silencing of various genes in gastric carcinogenesis. Intriguingly, more recently in addition to CpG island hypermethylation, a global DNA demethylation, that precedes genomic damage, has been observed in GC. Thus, epigenetic alterations may play a relevant role in gastric carcinogenesis as alternative mechanisms. Evidence suggests that although MSI, CIN and CIMP phenotypes can be distinguished from one another, there might be some degree of overlap. This review describes our current knowledge of the instability pathways in gastric carcinogenesis and the potential clinical applications for different forms of genomic instability in GC

Patterns of genomic instability in gastric cancer: clinical implications and perspectives

In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to the transcriptional silencing of various genes in gastric carcinogenesis. Intriguingly, more recently in addition to CpG island hypermethylation, a global DNA demethylation, that precedes genomic damage, has been observed in GC. Thus, epigenetic alterations may play a relevant role in gastric carcinogenesis as alternative mechanisms. Evidence suggests that although MSI, CIN and CIMP phenotypes can be distinguished from one another, there might be some degree of overlap. This review describes our current knowledge of the instability pathways in gastric carcinogenesis and the potential clinical applications for different forms of genomic instability in G

Microsatellite instability in thyroid tumours and tumour-like lesions

Fifty-one thyroid tumours and tumour-like lesions were analysed for instability at ten dinucleotide microsatellite loci and at two coding mononucleotide repeats within the transforming growth factor β (TGF-β) type II receptor (TβRII) and insulin-like growth factor II (IGF-II) receptor (IGFIIR) genes respectively. Microsatellite instability (MI) was detected in 11 out of 51 cases (21.5%), including six (11.7%) with MI at one or two loci and five (9.8%) with Ml at three or more loci (RER+ phenotype). No mutations in the TβRII and IGFIIR repeats were observed. The overall frequency of MI did not significantly vary in relation to age, gender, benign versus malignant status and tumour size. However, widespread MI was significantly more frequent in follicular adenomas and carcinomas than in papillary and Hürthle cell tumours: three out of nine tumours of follicular type (33.3%) resulted in replication error positive (RER+), versus 1 out of 29 papillary carcinomas (3.4%, P = 0.01), and zero out of eight Hürthle cell neoplasms. Regional lymph node metastases were present in five MI-negative primary cancers and resulted in MI-positive in two cases. © 1999 Cancer Research Campaig

BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases.

Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G > A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included in this study, carried the CHEK2 1100delC, IVS2+1G > A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy

Gastric adenomas: relationship between clinicopathological findings, Helicobacter pylori infection, APC mutations and COX-2 expression.

Gastric adenomas are rare neoplastic growths characterized by localized polypoid proliferations of dysplastic epithelium that tend to progress to infiltrating adenocarcinoma. Therefore, the identification of molecular markers that could reliably recognize adenomas at risk of progression is advocated in the clinical management. In this study we investigated, in a series of gastric adenoma specimens from an area at high risk of gastric cancer, the relationship between clinicopathological characteristics of adenoma and Helicobacter pylori infection, APC mutational status, and COX-2 and the down-stream enzyme mPGES1 expression. Helicobacter pylori infection, detected in 24%, and 33% by histology and PCR analyses, respectively, did not show any relationship with growth pattern, localization, size, dysplasia grade and presence of synchronous cancer. Pathogenetic mutations of MCR region (codons 1269-1589) of the APC gene were detected only in one case corresponding to a single, small size, low grade, H. pylori-negative adenoma. The expression of COX-2 largely matched that of mPGES(1). Both were overexpressed in 79% of cases showing a relationship with high-grade dysplasia, size >10 mm and presence of a synchronous carcinoma. In conclusion, COX-2 may play a key role in the development and progression of gastric adenoma and could be an attractive target in the management of gastric adenoma at major risk of cancer development

Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC

Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany

We studied the presence of microsatellite instability (MSI) in a series of 108 gastric cancers (GCs) previously identified in an epidemiological study carried out in a high-risk area around Florence, To investigate associations between MSI and GC family history, 34 cases (31.5%) who had a GC-affected first-degree relative were included in the series, A family history positive for colorectal cancer was reported quite rarely (5.6%). The analysis of 6 microsatellite loci in DNA from paired normal tissue and tumor samples microdissected from paraffin-embedded specimens revealed varying degrees of instability: 56 cases (51.8%) did not show instability at any of the 6 loci; 19 (17.6%) showed instability at 1 locus; 16 (14.8%) showed instability at 2 loci; 11 (10.2%) showed instability at 3 loci; 4 (3.7%) showed instability at 4 loci; and 2 (1.9%) showed instability at 5 loci, The replication error-positive (RER+) phenotype, defined as the presence of MSI at 2 or more loci, had a frequency of 30.6% (33 of 108) and tended to be positively associated with female sex, intestinal histological type, advanced tumor stage, vascular invasion, positive GC family history, and blood group of A type, No correlation emerged between age at diagnosis and RER+ phenotype, whereas a significant association with the RER+ phenotype was shown by the antral location. A multivariate analysis adjusting for a selected group of potential confounding factors confirmed the strong association of the RER+ phenotype with the antral location (P = 0.001) and with a positive GC family history (P < 0.05). Survival analyses at 5 and 8 years showed no difference between RER+ and RER-patients, even when corrected for stage distribution. By the microdissection technique, we also used microsatellite allele patterns to investigate intratumoral heterogeneity and genetic relationships between tumors and adjacent dysplasia and/or intestinal metaplasia. Areas of metaplasia and dysplasia demonstrated MSI only in cases with MSI-positive tumors, In MSI-positive tumors, there was consistent evidence of intratumoral microsatellite allele heterogeneity, indicating the presence of genetically divergent tumor cell clones within the same neoplasm

BRCA1 and BRCA2 mutations in central and southern Italian patients.

Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied