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Background Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1). Methods After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival. Results The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26–0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis. Conclusions High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.

Background Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice. Methods A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival. Findings In 2012–2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Six-hundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80•4 months in R0/1-resected (HR 0•15; CI95% 0•12–0•19), 39•1 months in R2-resected/LAT (0•39; 0•29–0•53) patients, and 20•8 months in patients treated with “systemic therapy alone” (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively. Interpretation Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later. Funding The funders had no role in the study design, analysis, and interpretation of the data or writing of this report. Tiivistelmä Tausta Kolorektaalisyövän etäpesäkkeiden leikkaushoitoa käytetään todennäköisesti liian vähän tosielämän hoidoissa. Menetelmät RAXO on maanlaajuinen suomalainen tosielämän prospektiivinen interventiotutkimus, joka rekrytoi lääkehoitokuntoisia, levinnyttä suolistosyöpää sairastavia potilaita. Tutkimuksessa arvioitiin keskitetysti etäpesäkkeiden leikattavuutta levinneen syövän toteamisvaiheessa ja kahdesti ensilinjan hoidon aikana Helsingin yliopistollisen sairaalan moniammatillisessa hoitokokouksessa. Tulokset Vuosina 2012-2018 tutkimukseen otettiin 1086 potilasta. Mediaaniseuranta-aika oli 58 kuukautta. Usean elimen etäpesäkkeet todettiin 500:lla (46 %) levinneen syövän toteamisvaiheessa ja 820:lla (76 %) seurannan aikana. Moniammatillisessa arvioinnissa 447 luokiteltiin leikattavaksi 310 (29%) toteamisvaiheessa ja 137 (18%) konversiohoidon jälkeen. Kuusisataayhdeksänkymmentä etäpesäkekirurgista ja/tai paikallishoitotoimenpidettä tehtiin 399 potilaalle (89 % 447:sta), joista parantavalla tavoitteella R0/1-resektio 326 potilaalle ja R2-resektio ja/tai paikallistoimenpide 73:lle. Useita toimenpiteitä tehtiin 148 (37%) potilaalle useamman elimen etäpesäkkeiden tai uusien etäpesäkekohtien ilmentymisen takia. Kaiken kaikkiaan tehtiin 414 maksa-, 112 keuhko-, 57 peritoneaalikarsinoosi- ja 107 muuta toimenpidettä. Mediaanielinaika oli 80,4 kuukautta R0/1-resekoiduilla potilailla (HR 0,15; 95 % luottamusväli 0,12–0,19), 39,1 kuukautta R2-resekoiduilla/paikallishoidetuilla (0,39; 0,29–0,53), ja 20,8 kuukautta vain lääkehoitoa saaneilla (referenssi), ja vastaavat viiden vuoden elossaololuvut olivat 66%, 40% ja 6%. Merkitys Keskitetyllä, toistetulla moniammatillisella toiminnalla saavutetaan korkea arvio etäpesäkkeiden leikattavuudesta (41%). Etäpesäkkeiden leikkaus- ja/tai paikallishoito toteutuu 37 prosentilla erinomaisin tuloksin silloinkin, kun syöpä on levinnyt useaan elimeen sairauden toteamisvaiheessa tai sen aikana Tuki Tutkimuksen tukijat eivät osallistuneet tutkimussuunnitelman kirjoittamiseen, datan analysointiin tai tulkintaan, eivätkä tämän raportin kirjoittamiseen. Abstrakt Bakgrund Resektion av kolorektalcancermetastaser ger god överlevnad, men används troligen suboptimalt i normal praktik. Metod RAXO-studien är en prospektiv finsk studie som inkluderade behandlingsbara patienter med spridd kolorektalcancer. Studiens intervention utvärderade möjligheten till metastasoperation vid centraliserad multidisciplinär konferens (MDK) på Helsingfors universitetssjukhus vid behandlingsinitiering och två gånger under första linjens behandling. Det primära syftet var att undersöka resekabilitet och resektioner, samt överlevnad. Fynd 1086 patienter inkluderades 2012-2018. Medianuppföljningstiden var 58 månader. Multipel metastasering sågs hos 500 (46%) av patienterna vid metastasdiagnostidpunkten och hos 820 (76%) under uppföljningen. I MDK-utvärderingen klassificerades 447 (41%) som operabla, varav 310 (29%) vid metastastasdiagnos och 137 (18%) efter konversionsbehandling. Sexhundranittio åtgärder gjordes hos 399 patienter (89% av de 447 operabla), med R0/1-resektion hos 326 och R2-resektion eller lokalbehandling hos 73. Flera åtgärder gjordes hos 148 (37%) patienter med multipla metastasorgan eller nya metastaslokaler under uppföljningen; totalt 414 lever-, 112 lung-, 57 peritoneal-, och 107 andra åtgärder. Medianöverlevnaden var 80,4 månader hos R0/1-opererade (HR 0,15; 95% konfidensintervall 0,12–0,19), 39,1 månader hos R2-opererade/lokalbehandlade (0,39; 0,29–0,53) och 20,8 månader hos ”enbart systembehandlade” (referens), och femårsöverlevnaden var 66%, 40% och 6% i respektive grupp. Betydelse Upprepad centraliserad MDK-utvärdering vid spridd kolorektalcancer visar att 41% av metastaserna någon gång bedöms som resekabla och att operation och/eller lokalbehandling är möjlig i 37% av fallen. Imponerande överlevnad ses även i fall med multipla metastaslokaler vid diagnostillfället eller under uppföljningen. Finansiering Finansiärerna hade ingen roll i utformningen av denna studie, i dataanalys, tolkning av data eller i skrivandet av denna forskningsrapport. publishedVersion

An immune cell score (ICS) was introduced for predicting survival in pancreatic ductal adenocarcinoma (PDAC). Few studies have compared different methods of evaluating immune infiltrate. This study compared ICSs determined in whole sections or tissue microarray-like hotspots for predicting survival after PDAC surgery. We included in 79 consecutive patients from a single geographical area that underwent surgery for PDAC (R0/R1, stages I–III). We performed digital image analyses to evaluate CD3 and CD8 staining. ICSs were classified as low, moderate, or high, based on the numbers of immune cells in the tumour core and invasive margin. We compared ICS groups determined with the hotspot and whole-section techniques. Associations between ICS and survival were analysed with Cox regression models, adjusted for sex, age, tumour stage, differentiation grade, perineural invasion, and resection radicality. In hotspot ICS analysis, 5-year overall survival rates for low, moderate, and high groups were 12.1%, 26.3%, and 26.8%, respectively (p = 0.193). In whole-section analyses, overall survival rates were 5.3%, 26.4%, and 43.8%, respectively (p = 0.030). In the adjusted Cox model, whole-section ICS groups were inversely associated with the overall mortality hazard ratio (HR): low, moderate, and high ICS groups had HRs of 1.00, 0.42 (95% CI 0.20–0.88), and 0.27 (95% CI 0.11–0.67), respectively. The number of immune cells per square millimetre in the tumour core and the invasive margin were significantly higher and had a wider range in hotspots than in whole-tissue sections. Accordingly, ICS could predict survival in patients with PDAC after surgery. Whole tissue section ICSs exhibited better prognostic value than hotspot ICSs.

Simple Summary Metastasis is the main cause for cancer mortality. The most common metastatic sites of colorectal cancer (CRC) are the liver and lungs. Tumour-infiltrating lymphocytes are recognized as beneficial prognostic factors both in primary and metastatic CRC, but less is known about their reciprocal differences. The aim of our study was to evaluate immune microenvironment and its prognostic value in a series of mismatch proficient (pMMR) CRC with matched liver and lung metastases. The proportion of tumours with high immune cell infiltration together with PD-L1-positivity almost doubled in metastases compared to primary tumours. Our study confirmed the prognostic value of high ICS in least immune-infiltrated metastases in pMMR CRC patients. Major differences observed in immune contexture between primary tumours and metastases may have significance for treatment strategies for patients with advanced CRC. Purpose: To evaluate immune cell infiltration, the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) expression and their prognostic value in a series of mismatch proficient (pMMR) CRC with matched liver and lung metastases. Methods: Formalin-fixed paraffin-embedded tissue sections stained for CD3, CD8, PD-L1 and PD-1 from 113 primary CRC tumours with 105 liver and 59 lung metastases were analyzed. The amount of CD3 and CD8 positive lymphocytes were combined as immune cell score (ICS). Comparative analyses on immune contexture were performed both between the primary tumour and matched metastases and between the metastatic sites. Results: In liver metastases, immune cell infiltration was increased in general compared to primary tumours but did not correlate case by case. On the contrary, ICS between lung metastases and primary tumours correlated well, but the expression of PD-1/PD-L1 was increased in lung metastases. The proportion of tumours with high ICS together with PD-L1-positivity almost doubled in metastases (39%) compared to primary tumours (20%). High ICS (compared to lowest) in patient's least immune-infiltrated metastasis was an independent prognostic marker for disease-specific (HR 9.14, 95%CI 2.81-29.68) and overall survival (HR 6.95, 95%CI 2.30-21.00). Conclusions: Our study confirms the prognostic value of high ICS in least immune-infiltrated metastases in pMMR CRC patients. Major differences observed in immune contexture between primary tumours and metastases may have significance for treatment strategies for patients with advanced CRC.

Immune suppressing molecule CD73 is overexpressed in various cancers and associated with poor survival. Little is so far known about the predictive value of CD73 in pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the prognostic significance of CD73 in PDAC. The study material consisted of 110 radically treated patients for PDAC. Tissue microarray blocks were constructed and stained immunohistochemically using CD73 antibody. Staining intensity and numbers of stained tumour cells, inflammatory cells, stroma, and blood vessels were assessed. High-level CD73 expression in tumour cells was positively associated with PD-L1 expression, perineural invasion, and histopathological grade. CD73 positivity in tumour-infiltrating lymphocytes was significantly associated with lymph node metastasis. Lymphocytic CD73 positivity was also associated with staining positivity in both stroma and vascular structures. In addition, CD73 positivity in vascular structures and stroma were associated with each other. There were no significant associations between CD73 positive tumour cells and CD73 positivity in any other cell types. PD-L1 expression was associated with CD73 staining positivity in stroma (p = 0.007) and also with histopathological grade (p = 0.033) and T class (p = 0.016) of the primary tumour. CD73 positivity in tumour cells was significantly associated with poor disease-specific (p = 0.021) and overall survival (p = 0.016). In multivariate analysis, CD73 positivity in tumour cells was an independent negative prognostic factor together with histopathological grade, TNM stage, and low immune cell score. In conclusion, high CD73 expression in tumour cells is associated with poor survival in PDAC independently of the number of tumour-infiltrating lymphocytes or TNM stage.

Hyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

Purpose To compare laparoscopic non-CME colectomy with laparoscopic CME colectomy in two hospitals with similar experience in laparoscopic colorectal surgery. Methods Data was collected retrospectively from Päijät-Häme Central Hospital (PHCH, NCME group) and Central Finland Central Hospital (CFCH, CME group) records. Elective laparoscopic resections performed during 2007–2016 for UICC stage I–III adenocarcinoma were included to assess differences in short-term outcome and survival. Results There were 340 patients in the NCME group and 325 patients in the CME group. CME delivered longer specimens (p p p p = 0.528, NCME 93.2% vs CME 88.9%, p = 0.132, respectively). Thirty-day morbidity, mortality, and length of hospital stay were similar between the groups. Conversion to open surgery was associated with decreased survival. Discussion Complete mesocolic excision (CME) is reported to improve survival. Most previous studies have compared open CME with open non-CME (NCME) or open CME with laparoscopic CME. NCME populations have been historical or heterogeneous, potentially causing bias in the interpretation of results. Studies comparing laparoscopic CME with laparoscopic NCME are few and involve only small numbers of patients. In this study, diligently performed laparoscopic non-CME D2 resection delivered disease-free survival results comparable with laparoscopic CME but was not safer.

Background Hepatopancreatobiliary surgery is prone to complications. Methods are needed to monitor surgical outcomes and enable comparison between institutions. Methods Complications were collected prospectively and reviewed using the modified Accordion Severity Grading System (MASGS) and the Postoperative Morbidity Index (PMI). Results This study included 527 consecutive patients receiving either pancreatic or liver resection in 2000-2017 in Central Finland Central Hospital. The PMI was 0.177 for all patients, and 0.192, 0.094, 0.285, and 0.129 for patients receiving major pancreatic (n=218), minor pancreatic (n=93), major liver (n=73), and minor liver (n=143) resection, respectively. The rates of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomies (n=200) were 6.5% for grade B and 5.5% for grade C; rates for biliary leak were 1.0% (grade A), 2.5% (grade B), and 0.5% (grade C). Similarly, the rates for delayed gastric emptying (DGE) were 2.8% (grade A), 15.6% (grade B), and 3.7% (grade C). Postoperative hepatic dysfunction occurred in 2.3%, major surgical site bleeding in 2.3%, and biloma in 7.9% of patients after liver resection. Ninety-day mortality rates were 3.7% and 1.1% in major and minor pancreatic resections, and 8.2% and 0.7% in major and minor liver resections. Major complications occurred in 13.3% and 3.3% in pancreatic, and 19.2% and 6.3% in liver resections, respectively. Conclusions Major pancreatic and hepatic surgery are associated with significant morbidity and burden in our center, comparable with previous population-based studies. PMI is an informative way to monitor surgical outcomes and enable comparison between institutions.

Background Wait-and-see policy after endoscopic sphincterotomy (ES) for common bile duct (CBD) stones in patients with concomitant gallbladder stones may lead to recurrent biliary complications. The aim of this study was to assess the short and long-term results of wait-and-see policy in patients with intact gallbladder after endoscopic clearance of CBD stones. Materials and methods From January 1999 to December 2014 a total of 181 consecutive patients with intact gallbladder underwent ES for CBD stones. The main measures of outcome were long-term biliary complications, biliary related mortality, CBD stone recurrence and need for surgical interventions. Secondary outcomes were 30-day mortality and 30-day morbidity. Clinical data were retrospectively collected from hospital records and from the National Registry of Death. Results During the median follow-up of 3.9 years (IQR 1.6–6.6) late biliary complications were observed in 24 (13.8%) patients. Cumulative biliary related morbidity at 3 and 5 years was 7.6% and 10.8%, respectively. CBD stone recurrence was observed in 9 (5.2%) patients. On-demand cholecystectomy was performed in 6 (3.3%) patients. 30-day mortality was 3.9% and 30–day morbidity 9.4%. Overall cumulative mortality rate at 3 and 5 years after ES was 31.4% and 49.7%, respectively. Long-term biliary related mortality was 1.7%. No significant difference in long term complications or biliary mortality was observed between patients Conclusion Prophylactic cholecystectomy after ES has been shown to reduce mortality even in high-risk patients. In our series late biliary related mortality and morbidity were relatively low, because a considerable number of patients died from non-biliary related causes.However, most biliary-related events seem to occur evenly during the follow-up after ES. A prompt risk assesment and consideration of surgical treatment during index admission may prevent late biliary –related complications.

The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% (p

Background This population‐based study aimed to examine the incidence, patterns and results of multimodal management of metastatic colorectal cancer. Methods A retrospective population‐based study was conducted on patients with metastatic colorectal cancer in Central Finland in 2000–2015. Clinical and histopathological data were retrieved and descriptive analysis was conducted to determine the pattern of metastatic disease, defined as synchronous, early metachronous (within 12 months of diagnosis of primary disease) and late metachronous (more than 12 months after diagnosis). Subgroups were compared for resection and overall survival (OS) rates. Results Of 1671 patients, 296 (17·7 per cent) had synchronous metastases, and 255 (19·6 per cent) of 1302 patients with resected stage I–III tumours developed metachronous metastases (94 early and 161 late metastases). Liver, pulmonary and intraperitoneal metastases were the most common sites. The commonest metastatic patterns were a combination of liver and lung metastases. The overall metastasectomy rate for patients with synchronous metastases was 16·2 per cent; in this subgroup, 3‐ and 5‐year OS rates after any resection were 63 and 44 per cent respectively, compared with 7·1 and 3·3 per cent following no resection (P, In a study of the incidence and management of metastatic colorectal cancer in a population‐based cohort, 17·7 per cent of 1671 patients with colorectal cancer had synchronous metastases, and 19·6 per cent of 1302 patients who had resection of stage I–III tumours developed metachronous metastases. In the whole population, the proportion of patients with any metastasis was 33·0 per cent. Metastasis from colorectal cancer

Background One–stage laparoscopic common bile duct (CBD) stone clearance and laparoscopic cholecystectomy (LCBDE+LC) for cholecystocholedocholithiasis ( CCL) can be performed with similar short and long-term outcomes than two-stage endoscopic retrograde cholangiography followed by subsequent LC (ERCP+LC). This study examined retrospectively the outcome and hospital costs of one-stage versus two-stage treatment of CBD stones. Methods From January 1999 and December 2014, 217 consecutive, elective patients underwent one-stage (LCBDE + LC ) or two-stage (ERCP + subsequent LC ) treatment for CBD stones. The data from the one-stage management was collected prospectively, and from the two-stage management retrospectively. The main measure of outcome was hospital costs, with the success of one-stage versus two-stage management, postoperative morbidity and postoperative stay as secondary outcome measures. Results One-stage laparoscopic transcystic management was the least costly option compared to laparoscopic one-stage transductal approach (TC 5455€ versus TD 9364, p < 0.001) or two-stage management (6913 €, p = 0.02). Overall success rate of primary intervention (including conversions to open surgery) for CBD stone clearance was 96.9%, 97.0% and 98.3% after transcystic one-stage, transductal one-stage and two-stage approach, p = 0.79. Postoperative morbidity was 15.5% versus 7.5%, p = 0.64, and postoperative hospital stay median 2 days (IQR 2–5) versus 4.5 days ( IQR 3–7), p < 0.001 in the one-stage and two-stage management groups. Conclusions Our study shows that laparoscopic one-stage transcystic management of CCL results in high rate of CBD clearance, fewer procedures per patient, shorter hospital and lower costs than the two-stage management. Therefore the one-stage transcystic management seems to be an attractive strategy for the treatment of CCL depending on local resources and surgical expertise .

The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population‐based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5‐year disease‐free survival (DFS) rates were 59, 68, 78, 83 and 94% (p

Introduction Gastro-oesophageal reflux disease (GORD) is suggested to cause or aggravate several respiratory conditions. Studies with proton pump inhibitors have resulted in only minor improvements in pulmonary outcomes in patients with GORD. It has been speculated that operative treatment of GORD might be more efficient as it also diminishes non-acidic reflux. Objectives To compare the effects of esomeprazole 40 mg bid and fundoplication on airway responsiveness, forced expiratory volume in 1 s (FEV1), exhaled nitric oxide (NO) and respiratory symptoms in patients with moderate-to-severe GORD. Methods Sixty-nine GORD patients had methacholine inhalation challenge performed on them, and FEV1, exhaled NO and respiratory symptoms were measured at baseline, after a 3-month treatment with esomeprazole and 3 months after fundoplication. Primary outcome variable was dose-response slope (DRS), i.e. decline in FEV1 during methacholine challenge divided with the amount of methacholine administered (%/μmol). Pre-defined subgroup analysis was performed among those with concomitant asthma (n = 12). Results There was no improvement in DRS, FEV1 or exhaled NO after esomeprazole treatment or fundoplication. Cough and dyspnoea measured with visual analog scale improved with esomeprazole treatment (P

To examine the impact of day-care laparoscopic cholecystectomy (LC) with ultrasonic scissors dissection versus diathermy hook dissection method in a randomized setting. From April 2012 to September 2014, a total of 169 elective day-care patients were randomized to undergo either laparoscopic cholecystectomy with ultrasonic scissors using fundus-first approach (n = 88) or diathermy hook dissection starting from the triangle of Calot (n = 79). Main measures of outcome were operative time, same-day discharge and intraoperative complications. Secondary outcome measures were postoperative pain (numeric rating scale), postoperative nausea and vomiting (PONV), readmissions and 30-day morbidity. Median operative time was similar in the ultrasonic dissection and diathermy hook dissection groups (45 vs 45 min, p = 0.95). Same-day discharge was possible in 77 patients (87 %) in the ultrasonic dissection group and in 69 patients (87 %) in the diathermy group, p = 0.98. Intraoperative gallbladder perforations, mean intraoperative bleeding, postoperative pain and PONV at 1, 2 and 4 h (p = 0.78) did not differ significantly between the study groups. Day-care LC using either diathermy hook or ultrasonic dissection resulted in excellent same-day discharge in both groups (87 %). LC with ultrasonic dissection does not offer any clinical advantages compared to diathermy dissection.

To examine the quality of surgical care and long-term oncologic outcome after D2 gastrectomy for gastric cancer.From 1999 to 2008, a total of 109 consecutive patients underwent D2 gastrectomy without routine pancreaticosplenectomy in a multimodal setting at our institution. Oncologic outcomes together with clinical and histopathologic data were analyzed in relation to the type of surgery performed. Staging was carried out according to the Union for International Cancer Control criteria of 2002. Patients were followed-up for five years at the outpatient clinic. The primary measure of outcome was long-term survival with the quality of surgery as a secondary outcome measure. Clinical data were retrospectively collected from the patient records, and causes of death were obtained from national registries.A total of 109 patients (58 men) with a mean age of 67.4 ± 11.2 years underwent total gastrectomy or gastric resection with D2 lymph node dissection. The tumor stage distribution was as follows: stage I, (27/109) 24.8%; stage II, (31/109) 28.4%; stage III, (41/109) 37.6%; and stage IV, (10/109) 9.2%. Forty patients (36.7%) received chemotherapy or chemoradiotherapy. The five-year overall survival rate for all 109 patients was 45.0%, and was 47.1% for the 104 patients treated with curative R0 resection. The five-year disease-specific survival rates were 53.0% and 55.8%, respectively. In a multivariate analysis, body mass index and tumor stage were independent prognostic factors for overall survival (both P0.01), whereas body mass index, tumor stage, tumor site, Lauren classification, and lymph node invasion were prognostic factors for cancer-specific survival (all P0.05). Postoperative 30-d mortality was 1.8% and 30-d, surgical (including three anastomotic leaks, two of which were treated conservatively), and general morbidities were 26.6%, 12.8%, and 14.7%, respectively.D2 dissection is a safe surgical option for gastric cancer, providing quality surgical care and long-term oncologic outcomes that are in line with current Western standards.

Background: The objective of the study was to examine the role of microsatellite instability (MSI) and BRAFV600Emutation in colorectal cancer (CRC) by categorising patients into more detailed subtypes based on tumour characteristics. Methods: Tumour samples from 762 population-based patients with sporadic CRC were analysed for MSI and BRAFV600E by immunohistochemistry. Patient survival was followed-up for a median of 5.2 years. Results: Compared with microsatellite stable (MSS) CRC, MSI was prognostic for better disease-free survival (DFS; 5 years: 85.8% vs 75.3%, 10 years: 85.8% vs 72.9%, P=0.027; HR 0.49, CI 0.30–0.80, P=0.005) and disease-specific survival (DSS; 5 years: 83.2% vs 70.5% 10 years: 83.2 vs 65.0%, P=0.004). Compared with BRAF wild type, BRAFV600E was a risk for poor survival (overall survival; 5 years: 62.3% vs 51.6%, P=0.014; HR 1.43, CI 1.07–1.90, P=0.009), especially in rectal cancer (for DSS, HR: 10.60, CI: 3.04–36.92, P

Carbon dioxide (CO,) insufflation with increased intraabdominal pressure (IAP) has adverse hemodynamic, pulmonary, and renal effects. To avoid these problems, an abdominal wall lift method with a retractor was used to provide the surgical view without CO2 insufflation. Twenty-six patients undergoing elective laparoscopic cholecystectomy were randomly allocated to either the gasless, retractor group, or conventional CO, pneurnoperitoneum group (CPP). Hemodynamic data, ventilatory variables, urine output, urine oxygen tension, and blood samples for determining stress hormones were collected throughout the perioperative period. Patients in the retractor group had lower mean arterial pressure, heart rate, and central venous pressure (P < 0.001). They also had higher pulmonary dynamic compliance and needed a lower minute volume of ventilation to achieve normocarbia (P < 0.001). Urine output and oxygen tension in urine were higher (P < 0.05) with the retractor method than with CPP. Increase in plasma renin activity (P < 0.05) and decrease in core temperature (P < 0.001) were smaller with the gasless method than with CPP. The gasless method for laparoscopic cholecystectomy might be beneficial, especially in patients with compromised cardiorespiratory or renal function. Implications: Totally gasless laparoscopic cholecystectomy was compared with conventional pressure pneumoperitoneum with CO, insufflation. The gasless method resulted in more stable hemodynamics and pulmonary function, as well as higher urine, output than conventional pressure pneumoperitoneum. No changes in renal oxygenation was seen with the gasless method, compared with conventional pressure pneumoperitoneum.

In contrast to normal colorectal mucosa, peanut-agglutinin(PNA)-reactive glycoconjugates are commonly expressed in most colorectal carcinomas and in some pre-malignant conditions such as adenomas and ulcerative colitis. Since enzymatically detectable galactose-β1-3-N-acetyl-galactosamine residues are found in rectal mucus obtained from patients with carcinoma of the large bowel, it was investigated here whether PNA-reactive carbohydrate structures in rectal mucus can be exploited in the detection of colorectal neoplasia. Samples of rectal mucus obtained from 261 randomly selected patients with colorectal symptoms were applied on nitrocellulose filters. The presence of PNA-reactive glycoconjugates in mucus samples was determined by a peroxidase-conjugated PNA-overlay procedure. The results were correlated to findings from total colonoscopy/surgery and histopathology. PNA-reactive carbohydrate structures were detected in 76% of patients with carcinoma (p < 0.005), in 62% of patients with adenoma (p < 0.005), in 69% of patients with inflammatory bowel disease (p < 0.005), and in 38% of patients with hyperplastic polyps (NS), in contrast to 21% of the control subjects with macroscopically normal colorectal mucosa. These results show that PNA-reactive carbohydrate alterations in rectal mucus correlates with neoplastic and hyperproliferative conditions of the colorectal mucosa. The specificity of the PNA test for colorectal neoplasia was 76%. Therefore the use of more discriminate carbohydrate probes are needed for the pre-symptomatic detection of colorectal neoplasia. Int. J. Cancer 74:648–653, 1997.© 1997 Wiley-Liss, Inc.

Carbon dioxide (CO 2 ) pneumoperitoneum together with an increased intraabdominal pressure (IAP) induces a hemodynamic stress response, diminishes urine output, and may compromise splanchnic perfusion. A new retractor method may be less traumatic. Accordingly, 30 ASA physical status I or II patients undergoing laparoscopic cholecystectomy were randomly allocated to a CO 2 pneumoperitoneum (IAP 12-13 mm Hg) (control) or to a gasless abdominal wall lift method (retractor) group. Anesthesia and intravascular fluids were standardized. Direct mean arterial pressure (MAP), urine output, urine-N-acetyl-β-D-glucosaminidase (U-NAG), arterial blood gases, gastric mucosal Pco 2 , and intramucosal pH (pHi) were measured. Normoventilation was instituted in all patients. MAP increased (P < 0.001) only with CO 2 pneumoperitoneum. Minute volume of ventilation had to be increased by 35% with CO 2 insufflation. Paco 2 was significantly higher (P < 0.05) for 3 h postoperatively in the control group. Diuresis was less (P < 0.01) and U-NAG levels (P < 0.01) higher in the control group. The pHi decreased after induction of pneumoperitoneum up to three hours postoperatively and remained intact in the retractor group. We conclude that the retractor method for laparoscopic cholecystectomy ensures stable hemodynamics, prevents respiratory acidosis, and provides protection against biochemical effects, which reveal the renal and splanchic ischemia caused by CO 2 insufflation. Implications: A mechanical retractor method (gasless) was compared with conventional CO 2 pneumoperitoneum for laparoscopic cholestectomy. The gasless method ensured stable hemodynamics, prevented respiratory acidosis, and provided protection against the renal and splanchnic ischemia seen with CO 2 pneumoperitoneum.

To assess the quality of surgical care and outcome following multimodal treatment for low- and midrectal cancers, focusing on differences between low anterior and abdominoperineal resections. From 1999 to 2007, 179 patients underwent low anterior resection (LAR), abdominoperineal resection (APR), or proctocolectomy for low- or midrectal cancers. Preoperative (chemo)radiotherapy was given according to local guidelines and adjuvant postoperative chemotherapy in stage III disease. Outcome together with clinical and histopathological data were analyzed in relation to the type of surgery performed. The postoperative mortality was 2.2%; morbidity, 39.6%; reoperation rate, 8.4%; and readmission rate, 16.0%. Involved circumferential resection margin (CRM ≤ 1 mm) rate was 4.5% (APR 9.1% vs. LAR 2.6%, p = 0.046). Intraoperative bowel perforation occurred in 5.5% of APRs. Anastomotic leak rate was 15.3%. The 5-year overall survival of the 179 patients was 68.5 %; disease-specific survival, 82.2%; and local recurrence rate, 6.3%. The overall, disease-specific, and disease-free survival rates in the 162 patients treated for cure were 73.1%, 84.6%, and 78.3%, and local recurrence rate was 4.4% with no significant differences between LAR and APR. CRM was the only independent predictor of local recurrence and CRM, tumor stage, and level independent predictors of disease-free survival. Quality of surgical care was in line with the current international standards. CRM was an independent predictor for local recurrence and CRM, tumor stage, and level independent prognostic factors for disease-free survival. Neither the type of surgery (LAR vs. APR) nor the surgical approach (laparoscopic vs. open) influenced the oncologic outcome.

Carcinoembryonic antigen (CEA, ceacam5) is an important tumor-associated antigen with reported roles, e.g., in immunological defense, cell adhesion, cell survival and metastasis. Its overexpression in cancer cells is known to involve transcriptional activation of the CEA gene, but the underlying molecular details remain unclear. Here, we show that hypoxia and intracellular alkalinization, 2 factors commonly found in solid tumors, increase CEA protein expression in breast (MCF-7) and colorectal (CaCo-2 and HT-29) cancer cells. The increase was comparable (2-3-fold) to that observed in colorectal carcinomas in vivo. CEA promoter analyses further revealed that this upregulation involves a known binding site for HIF-1 transcription factor (5'-ACGTG-3') within one of the CEA promoter's positive regulatory elements (the FP1 site; the E-box). Accordingly, deletion or targeted mutagenesis of this motif rendered the CEA promoter unresponsive to hypoxia. Our chromatin immunoprecipitation data confirmed that endogenous HIF-1alpha binds to the CEA promoter in hypoxic cells but not in normoxic cells. Moreover, overexpression of the hypoxia-inducible factor (HIF-1alpha) was sufficient to increase CEA protein expression in the cells. In contrast, c-Myc, which is known to bind to the overlapping E-box, did not potentiate HIF-1alpha-induced CEA expression. CEA overexpression in vivo was also found to coincide with the expression of carbonic anhydrase IX, a well-known hypoxia marker. Collectively, these results define CEA as a hypoxia-inducible protein and suggest an important role for the tumor microenvironmental factors in CEA overexpression during tumorigenesis.

Preoperative radiotherapy (PRT) for rectal carcinoma has been shown to cause tumour regression and increase local control and patient survival. The aim of this study was to examine the usefulness of tumour regression grading (TRG) in quantifying the effect of PRT.Depending on the tumour stage (uT), as defined by preoperative endorectal ultrasound (ERUS), fixity and distance from the anal verge, 126 patients with rectal cancer underwent either surgery alone, or received short-course 25-Gy radiotherapy or long-course 50-Gy radiotherapy combined with 5-fluorouracil (5-FU) before surgery. TRG in each group was assessed and compared with the downstaging, defined as a change in preoperative uT stage and pathologic stage (pT).Complete response (no residual tumour, TRG 1) was seen in 7% of the patients (3/44) and total or major regression (TRG 1-3) in 73% of the patients (32/44) treated with 50-Gy chemoradiation. Of those treated with 25-Gy PRT, 21% (9/42) showed major tumour regression. Of the patients who underwent ERUS and PRT, 32% (26/83) were downstaged when comparing uT with pT, but 53% (14/26) of the downstaged tumours showed no response by TRG. In comparison, 50% (28/57) of the tumours with no downstaging showed a marked response by TRG (p=0.05).Tumour regression grading offers detailed information of the effect of PRT and shows that tumour regression is more marked after long-term chemoradiation than after short-course radiotherapy (p=0.02). In contrast, T-stage downstaging was similar in both groups and did not correlate with the TRG results (p=0.05).

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

AIM: To investigate the quality of life following laparoscopic Nissen fundoplication by assessing short-term and long-term outcomes. METHODS: From 1992 to 2005, 249 patients underwent laparoscopic Nissen fundoplication. Short-term outcome data including symptom response, side effects of surgery, endoscopy, and patient’s perception of overall success were collected prospectively. Long-term outcomes were investigated retrospectively in patients with a median follow-up of 10 years by assessment of reflux symptoms, side effects of surgery, durability of antireflux surgery, need for additional treatment, patient’s perception of success, and quality of life. Antireflux surgery was considered a failure based on the following criteria: moderate to severe heartburn or regurgitation; moderate to severe dysphagia reported in combination with heartburn or regurgitation; regular proton pump inhibitor medication use; endoscopic evidence of erosive esophagitis Savary-Miller grade 1-4; pathological 24-h pH monitoring; or necessity to undergo an additional surgery. The main outcome measures were short- and long-term cure rates and quality of life, with patient satisfaction as a secondary outcome measure. RESULTS: Conversion from laparoscopy to open surgery was necessary in 2.4% of patients. Mortality was zero and the 30-d morbidity was 7.6% (95%CI: 4.7%-11.7%). The median postoperative hospital stay was 2 d [interquartile range (IQR) 2-3 d]. Two hundred and forty-seven patients were interviewed for short-term analysis following endoscopy. Gastroesophageal reflux disease was cured in 98.4% (95%CI: 95.9%-99.6%) of patients three months after surgery. New-onset dysphagia was encountered postoperatively in 13 patients (6.7%); 95% reported that the outcome was better after antireflux surgery than with preoperative medical treatment. One hundred and thirty-nine patients with a median follow-up of 10.2 years (IQR 7.2-11.6 years) were available for a long-term evaluation. Cumulative long-term cure rates were 87.7% (81.0%-92.2%) at 5 years and 72.9% (64.0%-79.9%) at 10 years. Gastrointestinal symptom rating scores and RAND-36 quality of life scores of patients with treatment success were similar to those of the general population but significantly lower in those with failed antireflux surgery. Of the patients available for long-term follow-up, 83% rated their operation a success. CONCLUSION: For the long-term, our results indicate decreasing effectiveness of laparoscopic antireflux surgery, although most of the patients seem to have an overall quality of life similar to that of the general population.

Objective To compare the results of open and laparoscopic fundoplication. Design Nonrandomized controlled study with a 3-year follow-up. Patients and Methods Fifty-seven consecutive patients with erosive reflux esophagitis underwent laparoscopic (30 patients) or open (27 patients) fundoplication. Interventions Interview by an independent person. In addition, 52 patients (91%) underwent postoperative endoscopy, and 38 patients (67%) underwent esophageal 24-hour pH recording. Results Temporary dysphagia was reported by 20 patients (67%) after laparoscopic and by 11 (41%) after open fundoplication ( P =.05). There were no differences between groups concerning incidence of persistent dysphagia (20% vs 18%, respectively) and mild to no reflux symptoms (97% vs 100%, respectively). In addition, bloating (50% vs 63%, respectively) and increased flatus (77% vs 78%, respectively) were equally common. Visual analog scale scores for dysphagia, bloating, and increased flatus were 0.6, 2.4, and 4.3, respectively, in the laparoscopic and 0.6, 3.5, and 3.4, respectively, in the open groups. Normal belching ability was reported by 12 patients (40%) after laparoscopic and by 20 (74%) after open fundoplication ( P =.01). Visick grade 1 or 2 was reported by 21 patients (70%) after laparoscopic and by 24 (89%) after open fundoplication ( P =.08). Defective fundic wrap was detected in 4 patients (13%) in the laparoscopic and in none in the open group. In addition, abnormal results of 24-hour pH recording were found in 4 patients (22%) after laparoscopic and in 2 (10.5%) after open fundoplication. Conclusion From a functional point of view, both techniques were equally effective except concerning belching ability and temporary dysphagia.

Many tumour-specific antigens in gastrointestinal cancers have carbohydrate immuno-determinants. These epitopes can be identified by lectins and monoclonal antibodies. By using fluorescein-isothiocyanate (FITC)-conjugated peanut agglutinin (PNA) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) we have investigated glycoproteins carrying altered carbohydrate epitopes in normal and carcinomatous human colorectal mucosa. In normal mucosa PNA stained goblet cell glycoconjugates in the supranuclear (Golgi) distribution. After neuraminidase pretreatment PNA stained actual mucin goblet itself at all levels of the crypts. Colorectal carcinomas displayed a strong and direct binding of PNA to apical cell membranes of carcinomatous cells and intraluminal secretions. Analysis of the glycoproteins by SDS-PAGE and PNA-labelling revealed four carcinoma-associated glycoproteins (26kD, 32kD, 35kD and 50kD). In addition, four glycoproteins (29kD, 30kD, 33kD and 36kD) common to normal and carcinomatous colorectal mucosa could be identified. All of these glycoproteins differed in their molecular weight from those in red cell controls which bind PNA only after desialylation. The study shows that the expression of PNA-binding sites in colorectal carcinomas signifies a cancer-associated carbohydrate alteration. Four carcinoma-associated glycoprotein antigens could be detected by this lectin. The antigens we have identified might be useful in the isolation and purification of more selective reagents for the serologic detection of colorectal cancer. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5