T4 Colon Cancer - Current Management.

Colorectal cancer is the third most often encountered type of cancer and represents the third leading cause of cancer related deaths, on both sexes. One of the most important prognostic parameters is the tumor's stage at the time of the diagnosis. T4 cancers represent advanced tumors associated with penetration of the visceral peritoneum (T4a) and/or direct invasion in adjacent structures (T4b). Preoperative diagnosis is influenced by the inability of the existent imaging modalities to accurately differentiate the true invasion from the simple, inflammatory adherence to the neighboring structures. As a consequence surgical treatment must follow the principle of en bloc resection; however the ability of achieving an R0 resection depends on the tumor location, invaded organ, and the type of the surgical procedure required. Neoadjuvant treatment for advanced colon cancer it may be very difficult to be applied. This review is focused on preoperative workup, therapeutic strategies and subsequent results in advanced T4 colon cancers.

The Association between Nod2 R702w Polymorphism and Susceptibility to Colorectal Cancer in Romanian Patients.

It is well recognized that the inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). More susceptibility IBD genes have been reported, NOD2 being one of the most extensively investigated. The aim of this study was to evaluate a possible correlation between NOD2 rs2066844 C>T (also known as Arg702Trp or R702W) variant and CRC risk in a Romanian population. A total of 373 Romanian subjects (108 patients diagnosed with sporadic CRC and 265 controls) were enrolled in this hospital-based case-control study. The NOD2 R702W variants were detected by Real-time PCR using a predesigned TaqMan Genotyping Assay. The association between the genetic risk variant and CRC was expressed as odds ratios (OR) with 95% confidence intervals (CI). We did not find any statistically significant difference when we compared CC genotype with CT genotype (OR 1.1, 95% CI: 0.46-2.61; p=0.83) between CRC patients and controls. No TT homozygous genotype was detected. Also, we compared allele frequencies and no correlation was found (OR 1.09, 95% CI: 0.47-2.56; p=0.84). No association was found in the stratified analysis by tumor site, Dukes' stage and histological subtype. Our study suggests that the NOD2 R702W variant is not associated with CRC risk in the Romanian population. Further data from different and larger populations is required to determine whether NOD R702W SNP has effects on susceptibility to CRC.

A rare occurrence of three consecutive autosomal trisomic pregnancies in a couple without offspring.

BACKGROUND: Trisomies are the most common chromosomal abnormalities, being a major cause of pregnancy loss in the first trimester. Data from preimplantation embryos support the concept of recurrent aneuploidy in women with recurrent abortion. CASE: The authors report a rare case with three different consecutive trisomic pregnancies: 47,XY,+21, 47,XX,+9, and 47,XX,+18. All pregnancies resulted from the same relationship and no consanguinity was present. Standard clinical cytogenetic analysis indicated that both members had normal peripheral blood karyotype, with no evidence of mosaicism in either patient or her partner. CONCLUSION: The present report sup- ports the hypothesis that some women have a higher risk for nondisjunction than others of the same age. Counseling a couple with re- current trisomies is difficult and future research on genetics of cell division are required to assist them.

Array CGH - A Powerful Tool in Molecular Diagnostic of Pathogenic Microdeletions - Williams-Beuren Syndrome - A Case Report.

Williams-Beuren syndrome (WBS) (OMIM 194050) is caused by interstitial deletions or duplications of the 7q11.23 chromosomal region and characterised through a complex phenotype. We described a case diagnosed clinically and genetically confirmed through aCGH. Genetic assessment identified three microdeletions with a total size of 1.35 Mb located at 7q11.23. The deleted regions encompasses more than 30 genes including several protein coding genes such as ELN, LIMK1, FZDS, WBSCR22, WBSCR27, WBSCR28, STX1A, CLDN3, CLDN4, LAT2, ABHD11 or EIF4H .

ARG5 rs2245214 C/G Polymorphism Frequency in a Romanian Population.

PURPOSE: The aim of this study was to assess the frequency of a key autophagy gene ATG5 rs2245214 C/G polymorphism in a Romanian volunteer cohort, as there are no data regarding an Eastern European population. MATERIAL/METHODS: DNA was extracted from peripheral blood of 105 Romanian unrelated volunteers. The ATG5 rs2245214 C/G polymorphism was genotyped by Real-Time PCR using allelic discrimination TaqMan assay. RealTime PCR was performed on a ViiA™ 7 Real Time PCR System. Hardy-Weinberg equilibrium of allele frequencies at individual loci was assessed using the Chi-squared test. RESULTS: The genotype frequencies in controls were distributed in accordance with Hardy-Weinberg equilibrium (χ² = 1.07; p = 0.3). We found CC genotype in 53 subjects (50.48 %), CG genotype in 40 (38.10 %) and GG genotype in 12 subjects (11.42 %).The G risk allele was found in 52 individuals, and the frequency of the minor G allele was 0.3. CONCLUSION: This is the first report on a Romanian population regarding the frequency of the ATG5 gene rs2245214 polymorphism. Our results are slightly different to the distribution pattern from other Caucasian populations and larger studies including various ethnic groups are required.

Genetic Factors Involved in the Development and Progression of Nonalcoholic Fatty Liver Disease.

PURPOSE: The aim of our study was to identify the possible involvement of adiponutrine polymorphysm and of human leukocyte antigens (HLA) in the development of non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS: We included in this study a total of 138 subjects with non-invasive diagnosis of non-alcoholic hepatic steatosis. The patatin-like phospholipase domain containing protein 3 (PNPLA3) rs738409 (adiponutrine) polymorphism was genotyped by allelic discrimination TaqMan PCR assay (5' nuclease assay), using predesigned TaqMan SNP Genotyping Assays. Class I and II HLA antigens were determined by the polymerase chain reaction sequence specific oligonucleotide method (ADN-PCR-SSO). The results were compared with the same data from the control group subjects. RESULTS: For PNPLA 3 polymorphism we found [CC] genotype in 82 subjects (59,42%), [GC] genotype in 45 (32,61%) and [GG] genotype in 11 subjects (7,97%). The frequency of minor [G] risk allele was 0.25. We found class I and II HLA antigens HLA A24, HLA B15, HLA DR15, HLA DR16, HLA DQ3 and HLA DQ5 more frequent in subjects with hepatic steatosis without any other risk factor and HLA-A2, HLA-32, HLA B18, HLA B49 and HLA B53 in patients with obesity or metabolic syndrome. CONCLUSIONS: Our results are consistent with the literature and show an association of PNPLA3 rs738409 polymorphism with hepatic steatosis. Regarding histocompatibility antigens, we studied for the first time in our country the relationship between HLA and non-alcoholic fatty liver disease.

NOD2 Arg702Trp Polymorphism in Romanian Patients with Gastric Cancer.

PURPOSE: Our study aimed to assess a possible correlation between NOD2 Arg702Trp (rs2066844) polymorphism and gastric cancer risk in a Romanian population. MATERIAL/METHODS: A total of 322 subjects (72 patients with gastric adenocarcinoma and 250 healthy controls) were included. Genomic DNA was extracted from blood leukocytes and NOD2 Arg702Trp polymorphism was genotyped by Real-Time PCR using specific TaqMan probes. RESULTS: No statistically significant difference was observed between gastric cancer patients and controls when we compared one genotype with other genotype (the CC genotype serves as reference) (OR 0.45, 95% CI: 0.10 - 2.05) or when we compared allele frequencies (the C allele serves as reference) (OR 0.46, 95% CI: 0.11 - 2.04). We examined separately the association of this polymorphism with tumor site and histologic type and no correlation was found. CONCLUSION: NOD2 Arg702Trp polymorphism is not associated with gastric cancer risk and further investigations are needed to elucidate the contribution of NOD2 gene in gastric carcinogenesis.

VEGF-A and VEGF-B mRNA expression in gastro-oesophagela cancers

INTRODUCTION: Angiogenesis is essential for the local growth, invasion and metastasis of the tumours. Vascular endothelial growth factors (VEGFs) play a crucial role in tumour angiogenesis. The aim of our study was to quantify the expression of several VEGF family molecules in human gastro-oesophageal cancers and to analyse possible correlations between genes expression and clinico-pathological features. MATERIALS AND METHODS: Gene expression was quantified in 43 gastro-oesophageal paired samples using qRT-PCR with TaqMan probes specific to VEGF-A, including soluble transcript variants and VEGF-B genes. RESULTS: VEGF-A, including the studied splice variants and VEGF-B mRNAs were expressed in both tumour and peritumour mucosa. The expression of VEGF-A and its isoforms was higher in tumour compared with paired peritumour mucosa, while no significant difference was observed in VEGF-B expression. VEGF-A expression tended to correlate with tumour invasion. CONCLUSION: VEGF-A has a tendency to over-express in gastro-oesophageal cancers, while VEGF-B does not seem involved in these tumours. Further studies are required to establish the utility of anti-VEGF-A therapy and to find biomarkers for pathogenesis or response to therapy in gastro-oesophageal tumours (AU)

Different patterns of Toll-like receptor 2 polymorphisms in populations of various ethnic and geographic origins.

Upon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation of TLR2, which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymous TLR2 polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of the TLR2 polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.

Hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) or Strümpell-Lorrain syndrome is a heterogeneous group of inherited disorders, with prevalence ranged from 4.3 to 9.6 cases per 100,000 population. A common feature of these disorders is the slowly progressive and often severe spasticity, noticeably especially in the low limbs. Conventionally, HSP is divided into two clinical groups, uncomplicated (pure spastic paraplegia) or complicated HSP depending on the presence of other neurological features in addition to spastic paraparesis. Inheritance may be autosomal dominant, autosomal recessive or rarely X-linked, but autosomal dominant inheritance is most commonly associated with pure forms of the disease, whereas autosomal recessive HSP shows greater phenotypic variability, including several well-defined syndromes. Genetic studies have revealed as many as 31 different chromosomal HSP loci. We investigated two subjects, brother and sister, who were diagnosed using the criteria for a diagnosis of HSP proposed by Fink (1996), as "definitely affected" with HSP. As some particularities, we noticed an iliopsoas pseudohypertrophy in male patient and a mild atrophy in female, maybe due to degeneration of anterior columns. Family history recorded the presence of same manifestations in relatives. The pedigree of patients revealed some anomalies that could be related with the pathology. Our findings supported the diagnosis of complicated form of HSP in both cases.

Merosin-deficient congenital muscular dystrophy type 1A.

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is the most common form of congenital muscular dystrophy. MDC1A is caused by mutation of the laminin alpha-2 gene (LAMA2), localized to chromosome 6q22-23. The diagnosis of merosin-deficient CMD is based on the clinical findings of severe congenital hypotonia, weakness, with high blood levels of creatine kinase, WM abnormalities, and dystrophy associated with negative immunostaining of biopsied muscle for merosin. We investigated clinical and laboratory a patient: a girl with merosin-deficient congenital muscular dystrophy type 1A. Clinically the particularity of the case is the association of merosin-negative congenital muscular dystrophy (MN-CMD) with congenital feet deformity. The level of serum creatine kinase is elevated 1045 U/L. Immunohistochemistry show presence of dystrophin, lack of merosin, also the utrophin is normally expressed. Nerve conduction studies are normally, while electromyography suggested a myopathic process with early recruitment and decreased amplitude and duration of response. Magnetic resonance imaging: MRI T1 and MRI T2 show hypointensity and diffuse hyperintensity respectively in the white matter. Supratentorial MRI images showed hypotrophy of the corpus callosum and almost absent cingulate gyrus. In addition, hypophysis is reduced size.

Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a group of genetic peripheral neuropathies that is associated with a broad variety of clinical genetic features. Most CMT syndromes are characterized by a progressive muscle weakness and atrophy with a distally pronounced sensory dysfunction. Bone deformities as pes cavus or hammertoes are frequent. The severity of disability varies considerably between different subclasses. Physical examination, electrophysiological testing and family history are current methods to investigate a patient affected by CMT. We used these methods for clinical assessment of two cases. Whenever available molecular genetic testing establishes the certain diagnosis and defines the type of CMT.

The endoscopic and morphological forms of early gastric cancer.

The early gastric cancer is an endoscopic notion in which gastric cancer is strictly placed to mucosis and submucosis without extensive manifestations. It is the form with favorable prognosis and better survival at 5 and 10 years. Our study tries to systematize the debut forms of early gastric cancer and their association with the lesions with malignisation risk. We also try to evaluate the incidence of endoscopic and histopathologic forms of early gastric cancer found in an internal medicine division. Our study included 435 patients with gastric cancer endoscopic and histologic diagnosed. Statistically, 64.36% were men and 35.64% were women, the mean age 48 +/- 7 years. The endoscopic forms of early gastric cancer were type I: protruded in 19 cases, type II: superficially in eight cases, type III: excavated in six cases. Early gastric cancer is diagnosed with difficulty, it represents in 7.58% of the gastric cancer, being most frequently asymptomatic. The endoscopic forms frequently found in early gastric cancer in the population were type I: protruded and type IIa: superficially elevated. The histopathological examination is compulsory at this form of gastric cancer, while in advanced gastric cancer endoscopy is often sufficient for diagnosis. Analysing the histopathological results of cases diagnosed with early gastric cancer we found: 22 cases with intestinal type and 11 cases diffuse type. Microscopically, 15 were intramucosal and 18 had submucosal invasion. I and IIa lesions were predominantly located at the antrum and are histologically differentiated adenocarcinoma. Differentiated carcinoma frequently produces an elevated lesion and the border is well demarcated. There are frequent opportunities to detect gastric cancer in the early phase and the patient can expect a complete cure by the surgical operation or endoscopical mucosal resection.

Darier disease and Hailey-Hailey disease.

Darier disease (DD) and Hailey-Hailey disease (HHD) are autosomal dominantly inherited genodermatosis, caused by mutations in ATP2A2 gene and ATP2C1 respectively. We investigated clinical and laboratory two patients - a men with Darier disease and a woman with Hailey-Hailey disease. The patient with Darier disease has mucosal lesions and dental modifications associated with mild mental retardation. At Hailey-Hailey case, the skin lesions are associated with neuropsychiatric and endocrinologic disorders. In both cases, the mutation is inherited from parents. Even if this diseases have similar features, clinical, genetical and histopathological they are distinct entities.

Genetic and clinical considerations in six cases with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, caused by mutations in the NF1 gene. The NF1 gene encoding neurofibromin protein, which is strongly expressed in the nervous system and with the role as a negative regular of the ras proteins signal. All six cases with neurofibromatosis type 1 were clinical and laboratory investigated. The frequently symptoms are "café au lait" spots and neurofibromas. In two cases, the disease is associated with essential hypertension and, in other two cases with kyphoscoliosis. The novo mutations in NF1 gene cause the disease in three cases, and in other three cases, the mutation is inherited (two cases on father side and one case on mother side).

Giant retroperitoneal sarcomas.

Retroperitoneal sarcomas are rare malignant tumors, which are developing from mesenchymal stem cells residing in muscle, fat, and connective tissues. Underlying the rarity of this kind of tumors in general population, the aim of this paper is to present three cases of retroperitoneal sarcomas operated in Surgical Department of Military Hospital of Craiova (a retroperitoneal liposarcoma, a dedifferentiated liposarcoma and a malignant fibrous histiocytoma). From clinical point of view, we note the poverty of symptoms and non-specificity of these and a great tolerability of retroperitoneal space that offers the possibility for a great development of the tumor. CT-scan and MRI are the best investigations for diagnosis but surgical exploration is the best way for a good evaluation of these tumors. From histological point of view, we try to present new features about these kinds of tumors in order to classify them. Results of surgery correlated with complementary therapies were good without per-operative mortality or postoperative morbidity but we noted a recidive of one tumor (with different histological pattern) 21 months after the surgical intervention. The rarity of retroperitoneal sarcomas, combined with the vast array of histologic subtypes, has complicated our understanding of these tumors and impeded the development of effective therapies.