Sidedness is not a prognostic factor in an unselected cohort of patients with colon cancer but prognosis for caecal carcinoma is worse - A multivariate analysis of a large single institution database.

PURPOSE: Sidedness has emerged as a prognostic factor for metastatic colorectal cancer treated with modern systemic therapies. This study investigates whether it is also relevant for an unselected patient cohort including all stages. METHODS: All consecutive patients admitted with colon cancer between 1995 and 2018 were retrieved from an institution-held database. Patients were divided into two cohorts. The first cohort included patients without distant metastases who were able to undergo curative resection. The second cohort presented with distant metastases (stage IV). Potentially prognostic factors were subjected to multivariate Cox Regression analysis. RESULTS: Overall, 1,606 patients met the inclusion and exclusion criteria. An R0-resection was achieved in 1,222 patients without distant metastases. Five-year cause-specific survival rate was 89.3% for this group. There was no difference between right- and left-sided cancers (88.2% vs. 90.1%, p = 0.220). However, prognosis of caecal carcinoma was significantly worse than that of all other sites combined (83.5% vs. 90.2%, p = 0.007). In multivariate analysis, pT-category, pN-category, grading, vascular invasion, emergency operation, adjuvant chemotherapy, and caecal carcinoma remained as independent prognostic factors. In the 384 patients with stage IV-disease, 3-year overall survival for right- vs. left-sided cancers differed only in univariate analysis (17.7% vs. 28.6%, p = 0.013). CONCLUSION: In non-metastatic colon cancer, location in the caecum is an independent prognostic factor. In unselected patients with stage IV colon cancer, sidedness was not found to be a prognostic factor. Differentiation into right- and left-sided tumors may be simplistic, and further studies on the biological behavior of different colonic sites are warranted.

Clinical impact of duodenal pancreatic heterotopia - Is there a need for surgical treatment?

BACKGROUND: Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. METHODS: A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich's classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). RESULTS: A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. CONCLUSIONS: PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

The microRNA-200 family--a potential diagnostic marker in hepatocellular carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) represents the main cause of death among patients with cirrhotic liver disease, but little is known about mechanisms of cirrhosis associated carcinogenesis. We investigated the diagnostic impact of microRNA-200 (miR-200) family members as important epigenetic regulators of epithelial-mesenchymal transition (EMT) to differentiate between patients with HCC and liver cirrhosis. METHODS: Expression of the miR-200 family was investigated by qRT-PCR in specimens of HCC patients with and without cirrhosis. Benign specimens with and without cirrhosis served as controls. Expression of the EMT markers ZEB-1, E-cadherin and vimentin was examined using immunohistochemistry. RESULTS: MiR-200a and miR-200b were significantly downregulated in HCC (miR-200a: -40.1% (P = 0.0002); miR-200b: -52.3% (P = 0.0002)), and in HCC cirrhotic tissue (miR-200a: -40.2% (P = 0.004); miR-200b: -51.1% (P = 0.007)) compared to liver cirrhosis. Spearman's Rho analysis revealed a significant negative correlation of miR-200a and miR-200b to the expression of the mesenchymal markers Vimentin (P < 0.007) and ZEB-1 (P < 0.0005) and a significant positive correlation to the epithelial marker E-cadherin (P < 0.0002). CONCLUSIONS: MiR-200 family members and their targets are significantly deregulated in HCC and liver cirrhosis. The miR-200 family is able to distinguish between cirrhotic and HCC tissue and could serve as an early marker for cirrhosis-associated HCC.

Laparoscopic simulation training: does timing impact the quality of skills acquisition?

BACKGROUND: Current surgical training involves integration of educational interventions together with service requirements during regular working hours. Studies have shown that voluntary training has a low acceptance among surgical trainees and obligatory simulation training during the regular working week leads to better skill acquisition and retention. We examined the difference in training effectiveness depending on the time of day. METHODS: Surgical novices underwent a curriculum consisting of nine basic laparoscopic tasks. The subjects were permitted to choose a training session between during regular working hours (8:00-16:00) or after hours (16:00-20:00). Each subject underwent baseline and post-training evaluation after completion of two 4-h sessions. Task completion was measured in time (s), with penalties for inaccurate performance. Statistical analysis included matched-pairs analysis (sex, age, and previous operative experience) with χ(2) und Mann-Whitney U test for between groups and Wilcoxon signed-rank test for testing within one group. RESULTS: There were no differences in demographic characteristics between the groups. Comparison of the individual baseline and post-training performance scores showed a significant (P < 0.05) improvement for all subjects in all exercises. No significant differences between groups were observed. CONCLUSION: All subjects improved in skill significantly throughout the week regardless of the timing of the training intervention. Simulation training can be offered outside of regular working hours with acceptable effectiveness.

Significant decrease of the pathological stage I rectal carcinoma in the era of neoadjuvant therapy-A matter of concern.

BACKGROUND: Neoadjuvant treatment (nTx) for rectal cancer is commonly reserved for UICC stages II/III. Patients with stage I tumours (T1-2N0M0) are not candidates for nTx. The accuracy of treatment allocation depends on the precision of clinical staging, which is liable to understaging and overstaging. The study aimed at exploring changes in the proportion of stage pI patients with the introduction of nTx over a 26-year period. MATERIALS AND METHODS: All consecutive patients with histologically proven rectal cancer excluding carcinoma in situ were retrieved from a prospective database of our colorectal unit. Time periods were defined as per the use of nTx: baseline phase 1994-1997; implementation phase 1998-2005 and guideline phase 2006-2019. Trends over time regarding proportion of applied nTx and stage pI tumours were investigated. RESULTS: Overall, 1468 patients met the inclusion criteria. There were no major differences in patients' characteristics, especially proportion of synchronous metastases (stage IV) over time. nTx was applied to 1.2% of patients without metastases in the baseline phase, to 29.6% in the implementation phase, and to 59.6% in the guideline phase (p < 0.001). Corresponding proportions for patients with stage pI were 31.0%, 26.3% and 14.2%, respectively (p < 0.001). CONCLUSION: With a stable proportion of stage IV carcinomas indicating no major changes in the patient cohorts, we could document a significant decrease of stage pI patients with increasing use of nTx. This trend clearly signals overtreatment caused by clinical T- and N-staging. More precise criteria are needed to better select patients with rectal cancer for nTx.

In vivo tumor cell adhesion in the pulmonary microvasculature is exclusively mediated by tumor cell--endothelial cell interaction.

BACKGROUND: Metastasis formation is the leading cause of death among colon cancer patients. We established a new in-situ model of in vivo microscopy of the lung to analyse initiating events of metastatic tumor cell adhesion within this typical metastatic target of colon cancer. METHODS: Anaesthetized CD rats were mechanically ventilated and 106 human HT-29LMM and T84 colon cancer cells were injected intracardially as single cell suspensions. Quantitative in vivo microscopy of the lung was performed in 10 minute intervals for a total of 40 minutes beginning with the time of injection. RESULTS: After vehicle treatment of HT-29LMM controls 15.2 +/- 5.3; 14.2 +/- 7.5; 11.4 +/- 5.5; and 15.4 +/- 6.5 cells/20 microscopic fields were found adherent within the pulmonary microvasculature in each 10 minute interval. Similar numbers were found after injection of the lung metastasis derived T84 cell line and after treatment of HT-29LMM with unspecific mouse control-IgG. Subsequently, HT-29LMM cells were treated with function blocking antibodies against beta1-, beta4-, and alphav-integrins wich also did not impair tumor cell adhesion in the lung. In contrast, after hydrolization of sialylated glycoproteins on the cells' surface by neuraminidase, we observed impairment of tumor cell adhesion by more than 50% (p < 0.05). The same degree of impairment was achieved by inhibition of P- and L-selectins via animal treatment with fucoidan (p < 0.05) and also by inhibition of the Thomson-Friedenreich (TF)-antigen (p < 0.05). CONCLUSIONS: These results demonstrate that the initial colon cancer cell adhesion in the capillaries of the lung is predominantly mediated by tumor cell - endothelial cell interactions, possibly supported by platelets. In contrast to reports of earlier studies that metastatic tumor cell adhesion occurs through integrin mediated binding of extracellular matrix proteins in liver, in the lung, the continuously lined endothelium appears to be specifically targeted by circulating tumor cells.

SERPINB5 and AKAP12 - expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinoma.

BACKGROUND: Early metastasis and infiltration are survival limiting characteristics of pancreatic ductal adenocarcinoma (PDAC). Thus, PDAC is likely to harbor alterations in metastasis suppressor genes that may provide novel diagnostic and therapeutic opportunities. This study investigates a panel of metastasis suppressor genes in correlation to PDAC phenotype and examines promoter methylation for regulatory influence on metastasis suppressor gene expression and for its potential as a diagnostic tool. METHODS: Metastatic and invasive potential of 16 PDAC cell lines were quantified in an orthotopic mouse model and mRNA expression of 11 metastasis suppressor genes determined by quantitative RT-PCR. Analysis for promoter methylation was performed using methylation specific PCR and bisulfite sequencing PCR. Protein expression was determined by Western blot. RESULTS: In general, higher metastasis suppressor gene mRNA expression was not consistent with less aggressive phenotypes of PDAC. Instead, mRNA overexpression of several metastasis suppressor genes was found in PDAC cell lines vs. normal pancreatic RNA. Of the investigated metastasis suppressor genes, only higher AKAP12 mRNA expression was correlated with decreased metastasis (P < 0.05) and invasion scores (P < 0.01) while higher SERPINB5 mRNA expression was correlated with increased metastasis scores (P < 0.05). Both genes' promoters showed methylation, but only increased SERPINB5 methylation was associated with loss of mRNA and protein expression (P < 0.05). SERPINB5 methylation was also directly correlated to decreased metastasis scores (P < 0.05). CONCLUSIONS: AKAP12 mRNA expression was correlated to attenuated invasive and metastatic potential and may be associated with less aggressive phenotypes of PDAC while no such evidence was obtained for the remaining metastasis suppressor genes. Increased SERPINB5 mRNA expression was correlated to increased metastasis and mRNA expression was regulated by methylation. Thus, SERPINB5 methylation was directly correlated to metastasis scores and may provide a diagnostic tool for PDAC.

The Hunger Games: Laparoscopic Performance in Novice Surgeons is Not Altered by Food Deprivation but Influenced by the Degree of Appetite - A Randomized Controlled Trial.

OBJECTIVES: Food deprivation is a common condition for visceral surgeons and especially laparoscopic approaches require high levels of concentration. The current literature does not provide adequate answers whether intraoperative breaks, especially food intake, might influence the quality of the surgical skills. Thus, the primary aim of this trial was to analyze the influence of food deprivation on the laparoscopic performance. DESIGN SETTING AND PARTICIPANTS: 37 laparoscopic novices participated from 10/2017 to 04/2018 in this single center, prospective-randomized trial and were trained during laparoscopic training sessions until they reached a predefined level of proficiency. Subsequently, participants were randomized into 3 different groups: food deprivation of 8 hours, 4 hours, or carbohydrate loading directly prior to the laparoscopic exam. The exam comprised PEG-transfer, precise cutting, gallbladder resection and surgical knot. MAIN FINDINGS: Completion time for PEG-transfer, precise cutting, gallbladder resection and surgical knot was 63s, 139s, 192s and 272s respectively. Participants starving for 8 hours performed 3 of 4 tasks more slowly whilst participants starving for 4 hours performed 3 of 4 tasks faster than the average. Analyzing self-reported level of appetite revealed: Students with an intermediate level were significantly faster (p <0.05) during complex procedures compared to participants that reported hunger prior to performing these tasks (192s vs. 307s). Additionally, hungry students had been more inaccurate during the surgical knot (p <0.05) whilst students with intermediate appetite level tend to be most accurate (p - value 0.012). CONCLUSIONS: The subjective level of appetite rather than the absolute number of fasting hours influences the laparoscopic performance most. Thus, any extreme level of appetite may be avoided and surgeons may achieve the best performance when they have an intermediate level of appetite. In consequence, heavy meals may be omitted immediately prior to demanding laparoscopic procedures and surgeons may have access to mini-breaks and refreshers during major procedures.

Laparoscopic simulation training: Testing for skill acquisition and retention.

BACKGROUND: Simulation in laparoscopy leads to skill acquisition. Although many curricula for simulation training have been described, the nature of skill deterioration remains unclear. We evaluated skill acquisition and retention after laparoscopic simulation training. METHODS: Thirty-six novices in surgery (medical students) underwent a 5-day curriculum consisting of 9 skills of increasing complexity. Each subject underwent baseline and post-training evaluation after completion of the course. Skill retention testing was measured after 6 weeks (group 1; n = 18) and after 11 weeks (group 2; n = 18). Neither group had access to a training facility during this interval. Task completion was measured in time (s) with penalties for inaccurate performance. RESULTS: Comparison of the baseline and post-training values revealed a significant learning outcome for all exercises in both groups (P < .001). In group 1, skill retention testing found no significant decrease in skill level when compared to post-training values in all but 1 task (extracorporeal knot tying; P = .007). In group 2, differences between skill retention and post-training evaluation were observed for 5 of the 9 tasks (transfer task, positioning, loop tie, extracorporeal knot, and intracorporeal knot; P ≤ .05 for each). CONCLUSION: Basic laparoscopic skills can be learned successfully by novices in surgery using a compact curriculum. These skills are retained for at least 6 weeks. Eleven weeks after initial training, skill deterioration is likely, and therefore an opportunity for practice and repetition is desirable.