Transcript CD81-215 may be a long noncoding RNA of stromal origin with tumor-promoting role in colon cancer.

The role of tetraspanin CD81 in malignant transformation is best studied in colorectal cancer, and it appears that other transcripts beside the fully coding mRNA may also be dysregulated in malignant cells. Recent data from a comprehensive pan-cancer transcriptome analysis demonstrated differential activity of two alternative CD81 gene promoters in malignant versus nonmalignant gut mucosa. The promoter active in gut mucosa gives rise to transcripts CD81-203 and CD81-213, while the promoter active in colon and rectal cancer gives rise to transcripts CD81-205 and CD81-215. Our study aimed to explore the biomarker potential of the transcripts from the alternative CD81 gene promoters in colon cancer, as well as to investigate their structure and potential function using in silico tools. The analysis of the transcripts' expression in several colon cell lines cultivated in 2D and 3D and a set of colon cancer and healthy gut mucosa samples by qPCR and RNA sequencing suggested their low expression and stromal origin. Expression patterns in tumor and nontumor tissue along with in silico data suppose that the transcript CD81-215 may be a noncoding RNA of stromal origin with possible involvement in signaling related to malignant transformation.

Pilot proteomic study of locally advanced rectal cancer before and after neoadjuvant chemoradiotherapy indicates high metabolic activity in non-responders' tumor tissue.

PURPOSE: In the search for candidate predictive biomarkers to evaluate response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer, only a few studies report proteomic profiles of tumor tissue before and after nCRT. The aim of our study was to determine differentially expressed proteins between responders and non-responders before and after the therapy in order to identify candidate molecules for prediction and follow-up of response to nCRT. EXPERIMENTAL DESIGN: The study has included tissue sections of rectal tumor and non-tumor mucosa from five responders and five non-responders taken before and after nCRT from patients with locally advanced rectal cancer. Extracted proteins were analyzed by LC-MS/MS analysis followed by a set of bioinformatics analyses. RESULT: Proteomics analysis provided a mean of approximately 1050 protein identifications per sample. A comparison of proteomic profiles between responders and non-responders has identified 18 differentially expressed proteins. Pathway analysis demonstrated high metabolic activity in non-responders' tumors before nCRT, indicating the presence of intrinsic chemoradioresistance in these subjects. Two proteins associated with poor prognosis in colorectal cancer, ADAM10 and CAD, were identified as candidate predictive biomarkers as they were present in non-responders only. CONCLUSIONS AND CLINICAL RELEVANCE: Shortlisted proteins from our study should be further validated as candidate biomarkers for response to routinely applied nCRT protocols.

Laparoscopic Gastrectomy for Cancer: Cut Down Complications to Unveil Positive Results of Minimally Invasive Approach.

Several randomized controlled trials and meta-analyses have confirmed the advantages of laparoscopic surgery in early gastric cancer, and there are indications that this may also apply in advanced distal gastric cancer. The study objective was to evaluate the safety and effectiveness of laparoscopic gastrectomy (LG), in comparison to open gastrectomy (OG), in the management of locally advanced gastric cancer. The single-center, case-control study included 204 patients, in conveyance sampling, who underwent radical gastrectomy for locally advanced gastric cancer. Out of 204 patients, 102 underwent LG, and 102 patients underwent OG. The primary endpoints were safety endpoints, i.e., complication rates, reoperation rates, and 30-day mortality rates. The secondary endpoints were efficacy endpoints, including perioperative characteristics and oncological outcomes. Even though the overall complication rate was higher in the OG group compared to the LG group (30.4% and 19.6%, respectively), the difference between groups did not reach statistical significance (p = 0.075). No significant difference was identified in reoperation rates and 30-day mortality rates. Time spent in the intensive care unit (ICU) and overall hospital stay were shorter in the LG group compared to the OG group (p < 0.001). Although the number of retrieved lymph nodes is oncologically adequate in both groups, the median number is higher in the OG group (35 vs. 29; p = 0.024). Resection margins came out to be negative in 92% of patients in the LG group and 73.1% in the OG group (p < 0.001). The study demonstrated statistically longer survival rates for the patients in the laparoscopic group, which particularly applies to patients in the most prevalent, third stage of the disease. When patients with the Clavien-Dindo grade ≥II were excluded from the survival analysis, further divergence of survival curves was observed. In conclusion, LG can be safely performed in patients with locally advanced gastric cancer and accomplish the oncological standard with short ICU and overall hospital stay. Since postoperative complications could affect overall treatment results and diminish and blur the positive effect of the minimally invasive approach, further clinical investigations should be focused on the patients with no surgical complications and on clinical practice to cut down the prevalence of complications.

SMAD4-201 transcript as a putative biomarker in colorectal cancer.

BACKGROUND: Transcripts with alternative 5'-untranslated regions (UTRs) result from the activity of alternative promoters and they can determine gene expression by influencing its stability and translational efficiency, thus executing complex regulation of developmental, physiological and pathological processes. Transcriptional regulation of human SMAD4, a key tumor suppressor deregulated in most gastrointestinal cancers, entails four alternative promoters. These promoters and alternative transcripts they generate remain unexplored as contributors to the SMAD4 deregulation in cancer. The aim of this study was to investigate the relative abundance of the transcript SMAD4-201 in colorectal cell lines and tissues in order to establish if its fluctuations may be associated with colorectal cancer (CRC). METHODS: Relative abundance of SMAD4-201 in total SMAD4 mRNA was analyzed using quantitative PCR in a set of permanent human colon cell lines and tumor and corresponding healthy tissue samples from patients with CRC. RESULTS: The relative abundance of SMAD4-201 in analyzed cell lines varied between 16 and 47%. A similar relative abundance of SMAD4-201 transcript was found in the majority of analyzed human tumor tissue samples, and it was averagely 20% lower in non-malignant in comparison to malignant tissue samples (p = 0.001). Transcript SMAD4-202 was not detectable in any of the analyzed samples, so the observed fluctuations in the composition of SMAD4 transcripts can be attributed to transcripts other than SMAD4-201 and SMAD4-202. CONCLUSION: The expression profile of SMAD4-201 in human tumor and non-tumor tissue samples may indicate the translational potential of this molecule in CRC, but further research is needed to clarify its usability as a potential biomarker for early diagnosis.

Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models.

Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.

Minimally Invasive Esophagectomy for Cancer: Single Center Experience after 44 Consecutive Cases.

INTRODUCTION: At the Department of Minimally Invasive Upper Digestive Surgery of the Hospital for Digestive Surgery in Belgrade, hybrid minimally invasive esophagectomy (hMIE) has been a standard of care for patients with resectable esophageal cancer since 2009. As a next and final step in the change management, from January 2015 we utilized total minimally invasive esophagectomy (tMIE) as a standard of care. OBJECTIVE: The aim of the study was to report initial experiences in hMIE (laparoscopic approach) for cancer and analyze surgical technique, major morbidity and 30-day mortality. METHODS: A retrospective cohort study included 44 patients who underwent elective hMIE for esophageal cancer at the Department for Minimally Invasive Upper Digestive Surgery, Hospital for Digestive Surgery, Clinical Center of Serbia in Belgrade from April 2009 to December 2014. RESULTS: There were 16 (36%) middle thoracic esophagus tumors and 28 (64%) tumors of distal thoracic esophagus. Mean duration of the operation was 319 minutes (approximately five hours and 20 minutes). The average blood loss was 173.6 ml. A total of 12 (27%) of patients had postoperative complications and mean intensive care unit stay was 2.8 days. Mean hospital stay after surgery was 16 days. The average number of harvested lymph nodes during surgery was 31.9. The overall 30-day mortality rate within 30 days after surgery was 2%. CONCLUSION: As long as MIE is an oncological equivalent to open esophagectomy (OE), better relation between cost savings and potentially increased effectiveness will make MIE the preferred approach in high-volume esophageal centers that are experienced in minimally invasive procedures.

The use of autologous fascia lata graft in the laparoscopic reinforcement of large hiatal defect: initial observations of the surgical technique.

BACKGROUND: Even though there is no consensus, many authors believe that in the cases of large hiatal defects, structurally altered crura and/or absence of peritoneal lining, a crural reinforcement should be performed. Reinforcement could be performed with different techniques and different type of mesh, either synthetic or biologic. The disadvantages of mesh repair include the possibility of serious complications and increased costs especially in the usage of composite or biologic mesh. METHODS: The study includes 10 cases of reinforced primary suture line of the pillars with autologous fascia lata, in elective laparoscopic repair of the giant PEH with a large hiatal defect and friable crura. After intraopreative confirmation of the large hiatal defect (hiatal surface area of more than 8 cm²) and friable crura, an autologous fascia lata graft was harvested in the usual manner and placed in on-lay fashion to reinforce the pillar suture line. We analyzed surgical technique, complications, and initial follow-up of the patients. RESULTS: Average hiatal surface area (HSA) in our series was 10.6 cm² (range 8.1 to 14.4 cm²). The average duration of operation was 203.9 min/3.4 hours (range 160-250 min). Except for a mild hematoma in the harvesting region that resolved spontaneously, there were no procedure related complications and 30 days mortality rate was zero. The average postoperative length of stay was 6.5 days (5-8 days). Out of 10 patients, 5 completed the annual follow-up visit, while 8 completed a 6- month follow-up visit. So far there is no hernia recurrence and/or problems with swallowing function. However, one patient has felt a mild discomfort in the harvested region that does not influence normal daily activities. CONCLUSIONS: Autologous fascia lata graft hiatal reinforcement represents a technically feasible, easy, and available option for the on-lay reinforcement of large hiatal defects with friable crura in the laparoscopic repair of giant PEHs.

The Burden of Gastroesophageal Reflux Disease on Patients' Daily Lives: A Cross-Sectional Study Conducted in a Primary Care Setting in Serbia.

INTRODUCTION: Recent data from the studies conducted in the Western countries have proved that patients with gastroesophageal reflux disease have significantly impaired health-related quality of life compared to general population. OBJECTIVE: The study is aimed at evaluating the burden of reflux symptoms on patients'health-related quality of life. METHODS: The study involved 1,593 patients with diagnosed gastroesophageal reflux disease.The Serbian version of a generic self-administered Centers for Disease Control and Prevention questionnaire was used. Statistical analyses included descriptive statistics, Pearson chi-square test and a multiple regression model. RESULTS: Among all participants, 43.9% reported fair or poor health. Mean value of unhealthy days during the past 30 days was 10.4 days, physically unhealthy days 6.4 days, mentally unhealthy days 5.3 days and activity limitation days 4.3 days. Furthermore, 24.8% participants reported having ≥ 14 unhealthy days, 14.9% had 14 physically unhealthy days, 11.8% reported 14 mentally unhealthy days, and 9.4% had ≥ 14 activity limitation days. CONCLUSION: This study addressed complex relationships between reflux symptoms and patients'impaired everyday lives.

Laparoscopic repair of hiatal hernias: experience after 200 consecutive cases.

INTRODUCTION: Repair of hiatal hernias has been performed traditionally via open laparotomy or thoracotomy. Since first laparoscopic hiatal hernia repair in 1992, this method had a growing popularity and today it is the standard approach in experienced centers specialized for minimally invasive surgery. OBJECTIVE: In the current study we present our experience after 200 consecutive laparoscopic hiatal hernia repairs. METHODS: A retrospective cohort study included 200 patients who underwent elective laparoscopic hiatal hernia repair at the Department for Minimally Invasive Upper Digestive Surgery, Clinic for Digestive Surgery, Clinical Center of Serbia in Belgrade from April 2004 to December 2013. RESULTS: Hiatal hernia types included 108(54%) patients with type 1, 30 (15%) with type III, 62 (31%) with giant paraesophageal hernia, while 27 (13.5%) patients presented with a chronic gastric volvulus. There were a total of 154 (77%) Nissen fundoplications. In 26 (13%) cases Nissen procedure was combined with esophageal lengthening procedure (Collis-Nissen), and in 17 (8.5%) Toupet fundoplications was performed. Primary retroesophageal crural repair was performed in 164 (82%) cases, Cleveland Clinic Foundation suture modification in 27 (13.5%), 4 (2%) patients underwent synthetic mesh hiatoplasty, 1 (0.5%) primary repair reinforced with pledgets, and 4 (2%) autologous fascia lata graft reinforcement. Poor result with anatomic and symptomatic recurrence (indication for revisional surgery) was detected in 5 patients (2.7%). CONCLUSION: Based on the result analysis, we found that laparoscopic hiatal hernia repair was a technically challenging but feasible technique, associated with good to excellent postoperative outcomes comparable to the best open surgery series.

[Laparoscopic myotomy in achalasia cardia treatment: experience after 36 operations].

INTRODUCTION: Laparoscopic Heller-Dor operation, a standard method in the treatment of achalasia, has been performed at the Center for Esophageal Surgery of the First Surgical Clinic since April 2006. OBJECTIVE: The aim of this study was to present this surgical procedure and initial experiences after 36 consecutive laparoscopic Heller-Dor operations. METHODS: This partly retrospective, partly prospective study presented our results after laparoscopic Heller-Dor operation (presentation of the treatment method). We performed a standard anterior esophagocardioymiotomy, without releasing the posterior aspect of the cardia, and anterior partial fundoplication. The type and severity of symptoms and their duration were evaluated based on questionnaires fulfilled by patients. The diagnosis was made based on radiological, endoscopic and manometric findings. Laparoscopic surgery as the method of treatment was evaluated based on the duration of surgery, intra- and postoperative complications, time interval until the initiation of oral feeding, length of hospital stay, need for additional therapeutic measures after the operation and effect of surgery on the severity of symptoms. RESULTS: Preopereratively, dysphagia was the predominant symptom in all patients, while regurgitation was much lower (44%). The average duration of operation was 127 minutes. Postoperative hospitalization lasted on the average 5.7 days. From 36 treated patients, 34 (94.4%) considered that the effect of treatment was good or excellent. Postoperative dysphagia was present in two patients (5.6%) and was successfully solved by balloon dilatation. CONCLUSION: Laparoscopic Heller-Dor operation is an effective and safe surgical procedure in resolving symptoms of achalasia and today presents the method of the first choice in the treatment of this disease.

Primary inflammatory myofibroblastic tumor of the stomach in an adult woman: a case report and review of the literature.

Inflammatory myofibroblastic tumor has been defined as a histologically distinctive lesion with uncertain behaviour. The term inflammatory myofibroblastic tumor more commonly referred to as "pseudostumor ", denotes a pseudosarcomatous inflammatory lesion that contains spindle cells, myofibroblasts, plasma cells, lymphocytes and histiocytes. It exhibits a variable biological behavior that ranges from frequently benign lesions to more aggressive variants. Inflammatory myofibroblastic tumor mostly occurs in the soft tissue of children and young adults, and the lungs are the most commonly affected site, but it has been recognized that any anatomic localization can be involved. Inflammatory myofibroblastic tumors in adults are very rare, especially in the stomach. We present a case of a 43-year old woman with primary inflammatory myofibiroblastic tumor in the stomach and a review of the literature.

[Neuroendocrine tumors of gastrointestinal tract: the paradigm that lasts].

Historically, the tumors that were morphologically different and clinically less agressive than the more common gastrointestinal adenocarcinomas were clasified under carcinoid tumors. However, the development of molecular biology tehniques revealed the heterogeneity of these tumors on cellular and subcellular level and ther different biological behaviour. Neuroendocrine tumors of gastrointestinal tract originated from neuroendocrine cells scaterred across the gastrointestinal mucosa. As a result these tumors were capable of secreting many different neurotransmiters, which may or may not be biologically active. The incidence of gastrointestinal NETs has been incresing over the last 2 to 3 decades. Patients often presented with vague, nonspecific symptoms which resulted in delayed diagnosis and adequate treatment. In this article, we discuss the nature of gastrointestinal NETs, clinical presentation, treatment options and prognosis.