Background. Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10-20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI-H) means MS differ in normal and cancer cells of an individual. The cause of MSI-H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6.
Conclusions. MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC.
Matej Horvat, Uros Potocnik, Katja Repnik, Rajko Kavalar, Vesna Zadnik, Stojan Potrc and Borut Stabuc
Colorectal cancer (CRC) represents one of the most common malignancies worldwide. Research has indicated that functional gene changes such as single nucleotide polymorphism (SNP) influence carcinogenesis and metastasis and might have an influence on disease relapse. The aim of our study was to evaluate the role of SNPs in selected genes as prognostic markers in resectable CRC.
Patients and methods
In total, 163 consecutive patients treated surgically for CRC of stages I, II and III at the University Medical Centre in Maribor in 2007 and 2008 were investigated. DNA was isolated from formalin-fixed paraffin-embedded CRC tissue from the Department of Pathology and SNPs in genes SDF-1a, MMP7, RAD18 and MACC1 were genotyped using polymerase chain reaction followed by high resolution melting curve analysis or restriction fragment length polymorphism.
We found worse disease-free survival (DFS) for patients with TT genotype of SNP rs1990172 in gene MACC1 (p = 0.029). Next, we found worse DFS for patients with GG genotype for SNP rs373572 in gene RAD18 (p = 0.020). Higher frequency of genotype GG of MMP7 SNP rs11568818 was found in patients with T3/T4 stage (p = 0.014), N1/N2 stage (p = 0.041) and with lymphovascular invasion (p = 0.018). For MACC1 rs1990172 SNP we found higher frequency of genotype TT in patients with T3/T4 staging (p = 0.024). Higher frequency of genotype GG of RAD18 rs373572 was also found in patients with T1/T2 stage with disease relapse (p = 0.041).
Our results indicate the role of SNPs as prognostic factors in resectable CRC.
Peter Popovic, Borut Stabuc, Rado Jansa and Manca Garbajs
The purpose of this retrospective study was to evaluate treatment response, adverse events and survival rates of patients with intermediate stage HCC treated with superselective doxorubicin-loaded DC Bead transarterial chemoembolization (DEBDOX) under cone beam computed tomography (CBCT) control.
Patients and methods
Between October 2010 and June 2012, 35 consecutive patients with intermediate stage HCC (32 male, 3 female; average age, 67.5 ± 7.8 years; 22 patients Child-Pugh class A, 8 class B, 5 without cirrhosis) were treated with DEBDOX TACE. Portal vein thrombosis was observed in 6 (17.1%) patients. DEBDOX TACE was performed by superselective catheterization of feeding vessels followed by embolization with 100-300 μm microspheres loaded with 50-100 mg of doxorubicin. In all cases, CBCT was used during chemoembolization. Tumor response rates were defined according to mRECIST criteria.
Overall, 120 procedures were performed (mean, 3.2 per patients). We treated 97 lesions with an average diameter of 4.9 ± 1.9 cm. There were 32 minor and 2 (1.6%) major complications (one liver abscess and one cerebrovascular insult). After a mean follow-up of 27.7 ± 10.5 months, 94.3% of patients achieved an objective response to treatment (42.4% complete response and 57.6% partial response). Mean time to progression was 10.9 ± 5.3 months. Mean overall survival was 33.9 months (95% CI; 28.9 – 38.9 months), with 1- and 2- year survival of 97.1% and 65.7%, respectively.
Superselective DEBDOX TACE performed under CBCT control is a safe and effective method with high rates of tumor response and overall survival.
David Stubljar, Samo Jeverica, Tomislav Jukic, Miha Skvarc, Tadeja Pintar, Bojan Tepes, Rajko Kavalar, Borut Stabuc, Borut Peterlin and Alojz Ihan
Background.Helicobacter pylori infection is the main cause of gastric cancer. The disease progression is influenced by the host inflammatory responses, and cytokine single nucleotide polymorphisms (SNPs) may have a role in the course of the disease. The aim of our study was to investigate proinflammatory cytokine polymorphisms, previously associated with the development of gastric cancer, in a Slovenian population.
Patients and methods. In total 318 patients and controls were selected for the study and divided into three groups: (i) patients with gastric cancer (n = 58), (ii) patients with chronic gastritis (n = 60) and (iii) healthy control group (n = 200). H. pylori infection in patient groups was determined by serology, histology and culture. Four proinflammatory gene polymorphisms were determined (IL-1β, IL-1rα, TNF-α, TLR-4) in all subjects.
Results. We found a statistically significant difference between males and females for the groups (p = 0.025). Odds ratio (OR) for gastric cancer risk for females was 0.557 (95% confidence interval [CI]: 0.233―1.329) and for chronic gastritis 2.073 (95% CI: 1.005―4.277). IL-1B-511*T/T homozygous allele for cancer group had OR = 2.349 (95% CI: 0.583―9.462), heterozygous IL-1B-511*T had OR = 1.470 (95% CI: 0.583―3.709) and heterozygotes in TNF-A-308 genotype for chronic gastritis had OR = 1.402 (95% CI: 0.626―3.139). Other alleles had OR less than 1.
Conclusions. We could not prove association between gastric cancer and chronic gastritis due to H. pylori in any cytokine SNPs studied in Slovenian population. Other SNPs might be responsible besides infection with H. pylori for the progression from atrophy to neoplastic transformation.
Natasa Smrekar, David Drobne, Lojze M. Smid, Ivan Ferkolj, Borut Stabuc, Alojz Ihan and Andreja Natasa Kopitar
Dendritic cells play crucial roles in the control of inflammation and immune tolerance in the gut. We aimed to investigate the effects of tumor necrosis factor alpha (TNFa) inhibitors on intestinal dendritic cells in patients with inflammatory bowel disease and the potential role of intestinal dendritic cells in predicting the response to treatment.
Patients and methods
Intestinal biopsies were obtained from 30 patients with inflammatory bowel disease before and after treatment with TNFa inhibitors. The proportions of lamina propria dendritic cell phenotypes were analysed using flow cytometry. Disease activity was endoscopically assessed at baseline and after the induction treatment.
At baseline, the proportion of conventional dendritic cells was higher in the inflamed mucosa (7.8%) compared to the uninflamed mucosa (4.5%) (p = 0.003), and the proportion of CD103+ dendritic cells was lower in the inflamed mucosa (47.1%) versus the uninflamed mucosa (57.3%) (p = 0.03). After 12 weeks of treatment, the proportion of conventional dendritic cells in the inflamed mucosa decreased from 7.8% to 4.5% (p = 0.014), whereas the proportion of CD103+ dendritic cells remained unchanged. Eighteen out of 30 (60%) patients responded to their treatment by week 12. Responders had a significantly higher proportion of conventional dendritic cells (9.16% vs 4.4%, p < 0.01) with higher expression of HLA-DR (median fluorescent intensity [MFI] 12152 vs 8837, p = 0.038) in the inflamed mucosa before treatment compared to nonresponders.
A proportion of conventional dendritic cells above 7% in the inflamed inflammatory bowel disease mucosa before treatment predicts an endoscopic response to TNFa inhibitors.