Iva Kirac

Common variation near CDKN1A , POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10−10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10−10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10−10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

Systematic Meta-Analyses and Field Synopsis of Genetic Association Studies in Colorectal Cancer

BACKGROUND Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/). METHODS We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. RESULTS We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. CONCLUSION The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.

Single-incision laparoscopic surgery (SILS) for totally extraperitoneal (TEP) inguinal hernia repair: first case

To the Editors There has been an open debate in the most recent literature on possible progress in laparoscopic surgery, aiming mainly at benefits of minimization of surgical trauma and improvement of cosmesis. Natural-orifice transluminal endoscopic surgery (NOTES) and single-incision laparoscopic surgery (SILS) have emerged as approaches whose advantages and possible applications are being explored and tested currently. Operations eligible for NOTES approach are determined by the availability of entry point or hollow organ, availability of endoscopic instruments, and occasional necessity for hybrid or laparoscopic assistance. SILS on the other hand enables the application of a wide range of already existing instruments, implying less of a learning curve, lower costs, and lack of necessity for penetration through the hollow organ, which itself carries certain complications. The main point for reducing the number of incisions prevails: each incision risks morbidity of bleeding, incisional hernia, and organ damage, and decreases cosmesis. SILS was first described in 1998 in laparoscopic appendectomy [1] and cholecystectomy [2], but enthusiasm was limited until recently due to insufficient technical support. Revival was initiated by Hirano et al. in 2005 with its application in urology [3]. Return of SILS cholecystectomy and application in obesity surgery followed [4, 5]. Technical approaches that enabled this revival were several adjacently placed trocars, special multilumen ports that allow simultaneous multiple instruments insertion [6], gelports [7], bent and articulating instruments, and adjustments in laparoscopes, which are all commercially available. Based on Cohrane 2005 systematic review [8] TAPP was associated with higher rates of port-site hernias and visceral injuries whilst there appear to be more conversions with TEP. Vascular injuries and deep/mesh infections were rare and there was no obvious difference between the groups. No studies reporting economic evidence were identified. Very limited data were available on learning effects, but these data suggest that operators become experienced at between 30 and 100 procedures. However, there were not enough data to support either one unanimously. Arguments discerning open and laparoscopic hernia repair are well known and we will not pursue them in this letter. We chose TEP, with the strongest argument of not entering the abdominal cavity and avoiding potential injury to intra-abdominal structures. Indications are bilateral and recurrent inguinal hernia and patient choice if dealing with primary hernia. We started performing TEP in 1996 and have so far performed more than 1,000 procedures without major complications. Until now we used three-port access as a standard approach and single or double mesh placement after adequate reposition and field preparation. In this technical modification—right primary indirect inguinal hernia TEP repair—we used a single vertical midline infraumbilical skin incision 2.5 cm long. Dissection of subcutaneous tissue to the anterior sheet of rectus J. Filipovic-Cugura I. Kirac (&) M. Bekavac-Beslin Department of Surgery, University Hospital Sestre milosrdnice, Vinogradska 29, 10000 Zagreb, Croatia e-mail: ikirac@kbsm.hr

Comparison of Single Incision Laparoscopic Totally Extraperitoneal and Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair: Initial Experience

BACKGROUND AND PURPOSE Laparoendoscopic single-site (LESS) surgery has been implemented recently in many laparoscopic (LAP) surgical procedures. We report our initial experience with LESS totally extraperitoneal (LESS-TEP) inguinal hernia repair in relation to conventional LAP-TEP. PATIENTS AND METHODS Between November 2008 and May 2009, 25 LESS-TEP repairs of inguinal hernia and 29 LAP-TEP repairs of inguinal hernia were performed in 44 patients. Data regarding patient demographics, type of hernia, operative time, complications, postoperative hospital stay, and recurrence were prospectively collected and analyzed. RESULTS All 44 patients were men, aged 17 to 84 years. Of 44 men, 3 had bilateral inguinal hernias in the LESS-TEP group and 7 in the LAP-TEP group. The operative time for bilateral LESS-TEP was 60 ± 15.3 min (range 40-70 min) and 40 ± 21.6 min (range 20-100 min) for unilateral LESS-TEP, while for bilateral hernia LAP-TEP it was 60 ± 24.8 min (range 40-100 min) and for unilateral LAP-TEP it was 50 ± 14.2 min (range 40-80 min). Comparison of operative times in the LESS-TEP and LAP-TEP groups between the first and second half cohort resulted in significant reduction of operative time in the second half of the LESS-TEP group (P<0.001). There were no intraoperative complications. Discharge was within 72 hours for most patients in both groups. There was one early recurrence (mesh displacement) during a median follow-up period of 11.5 ± 2.5 months in the LESS-TEP group and no recurrences during the 11 ± 1.6 months in the LAP-TEP group. CONCLUSION In our experience, LESS-TEP is a safe and feasible procedure with a short learning curve. In all analyzed parameters, it is comparable to conventional LAP-TEP. Further studies that compare LESS-TEP and conventional multiport LAP-TEP repairs with long-term follow-up evaluation are needed to confirm the initial experience.

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

SMAD7 Variant rs4939827 Is Associated with Colorectal Cancer Risk in Croatian Population

Background Twenty common genetic variants have been associated with risk of developing colorectal cancer (CRC) in genome wide association studies to date. Since large differences between populations exist, generalisability of findings to any specific population needs to be confirmed. Aim The aim of this study was to perform an association study between risk variants: rs10795668, rs16892766, rs3802842 and rs4939827 and CRC risk in Croatian population. Methods An association study was performed on 320 colorectal cancer cases and 594 controls recruited in Croatia. We genotyped four variants previously associated with CRC: rs10795668, rs16892766, rs3802842 and rs4939827. Results SMAD7 variant rs4939827 (18q21.1) was significantly associated with CRC risk in Croatian population. C allele was associated with a decreased risk, odds ratio (OR): 0.70 (95% CI: 0.57-0.85, P=3.5E-04). Compared to TT homozygotes, risk was reduced by 34% in heterozygotes (OR=0.66, 95% CI: 0.47-0.92) and by 52% in CC homozygotes (OR=0.48, 95% CI: 0.33-0.72). Conclusion Our results show association of rs4939827 with colorectal cancer risk in Croatian population. The higher strength of the association in comparison to other studies suggests population-specific environmental or genetic factors may be modifying the association. More studies are needed to further describe role of rs4939827 in CRC. Likely reason for failure of replication for other 3 loci is inadequate study power.

Diagnosis and Management of Acute and Early Complications of/after Bariatric Surgery

The number of obese people is over one billion worldwide, and the trend is increasing. Frequent failure of conservative approach has been observed. Therefore, various surgical techniques, such as bariatric surgery, are accepted today as a safe and effective treatment of morbid obese condition, and are associated with low perioperative morbidity and mortality rates. The most popular and commonly performed procedures are those related to minimum complications and adequate weight loss: laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass. Since major and minor complications occur in the perioperative, early and late postoperative period, we discuss most frequent complications and importance of early recognition as well as adequate interventions.

Incidence and mortality trends of gastric and colorectal cancers in Croatia, 1988-2008

Aim To estimate the incidence and mortality trends of gastric and colorectal cancers in Croatia between 1988 and 2008. Methods Incidence data for the period 1988-2008 were obtained from the Croatian National Cancer Registry. The number of deaths from gastric and colorectal cancers was obtained from the World Health Organization mortality database. Joinpoint regression analysis was used to describe changes in trends by sex. Results Gastric cancer incidence rates declined steadily during the study period, with estimated annual percent change (EAPC) of -3.2% for men and -2.8% for women. Mortality rates in men decreased, with EAPC of -5.0% from 1988-1995 and -2.5% from 1995-2008. Mortality rates in women decreased, with EAPC of -3.2% throughout the study period. For colorectal cancer in men, joinpoint analysis revealed increasing trends of both incidence (EAPC 2.9%) and mortality (EAPC 2.1%).In women, the increase in incidence was not significant, but mortality in the last 15 years showed a significant increase of 1.1%. Conclusion The incidence and mortality trends of gastric cancer in Croatia are similar to other European countries, while the still increasing colorectal cancer mortality calls for more efficient prevention and treatment.

Breast and gynecological cancers in Croatia, 1988-2008.

Aim To analyze and interpret incidence and mortality trends of breast and ovarian cancers and incidence trends of cervical and endometrial cancers in Croatia for the period 1988-2008. Methods Incidence data were obtained from the Croatian National Cancer Registry. The mortality data were obtained from the World Health Organization (WHO) mortality database. Trends of incidence and mortality were analyzed by joinpoint regression analysis. Results Joinpoint analysis showed an increase in the incidence of breast cancer with estimated annual percent of change (EAPC) of 2.6% (95% confidence interval [CI], 1.9 to 3.4). The mortality rate was stable, with the EAPC of 0.3% (95% CI, -0.6 to 0.0). Endometrial cancer showed an increasing incidence trend, with EAPC of 0.8% (95% CI, 0.2 to 1.4), while cervical cancer showed a decreasing incidence trend, with EAPC of -1.0 (95% CI, -1.6 to -0.4). Ovarian cancer incidence showed three trends, but the average annual percent change (AAPC) for the overall period was not significant, with a stable trend of 0.1%. Ovarian cancer mortality was increasing since 1992, with EAPC of 1.2% (95% CI, 0.4 to 1.9), while the trend for overall period was stable with AAPC 0.1%. Conclusion Incidence trends of breast, endometrial, and ovarian cancers in Croatia 1988-2008 are similar to the trends observed in most of the European countries, while the modest decline in cervical cancer incidence and lack of decline in breast cancer mortality suggest suboptimal cancer prevention and control.

Cytokeratin 20 positive cells in blood of colorectal cancer patients as an unfavorable prognostic marker

Objectives: Cytokeratin 20 (CK20) is one of the most investigated markers for the detection of circulating colorectal cancer (CRC) cells by reverse transcription polymerase chain reaction (RT-PCR). The aim of this study was to evaluate prognostic value of RT-PCR detection of circulating CRC cells using CK20 as a marker, and to compare the value of preoperative and postoperative blood sample analysis for that purpose. Methods: Ribonucleic acid (RNA) was isolated from mononuclear cell fraction of blood samples taken from 95 CRC patients before and after tumor resection and from 23 healthy volunteers and assayed by real-time RT-PCR for CK20 expression. Results: In patients positive for CK20 postoperatively both progression-free survival (PFS) and overall survival were significantly shorter than in patients negative for CK20 postoperatively, while the difference between patients positive and negative for CK20 preoperatively was not statistically significant in terms of neither PFS nor overall survival. Conclusion: Our results have shown prognostic value of circulating cancer cells detected in postoperative blood samples from CRC patients using CK20 as marker for RT-PCR, which has potential implications for treatment of these patients. In clinical practice, CK20 expression profile could be a factor in weighting treatment options in CRC patients. In cases where multiple treatment options are possible, patients with positive postoperative CK20 expression could be candidates to receive more aggressive treatment.