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Background: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models. Methods: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. Results: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. Conclusion: High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects.

Introduction: Endotoxins, in the form of lipopolysaccharides (LPS), are potent inducers of biliary injury. However the mechanism by which injury develops remains unclear. We hypothesized that hepatic macrophages are pivotal in the development of endotoxin-induced biliary injury and that no injury would occur in their absence.Material and methods: Clodronate liposomes were used to deplete macrophages from the liver. Forty-eight rats were equally divided across six study groups: sham operation (sham), liposome treatment and sham operation (liposomes + sham), 1 mg/kg LPS i.p. (LPS), liposome treatment and LPS administration (liposomes + LPS), hepatic ischaemia-reperfusion injury with LPS administration (IRI + LPS) and liposome treatment followed by IRI + LPS (liposomes + IRI + LPS). Following 6 h of reperfusion, blood, bile, and liver tissue was collected for further analysis. Small bile duct injury was assessed, serum liver tests were performed and bile composition was evaluated. The permeability of the blood-biliary barrier (BBB) was assessed using intravenously administered horseradish peroxidase (HRP).Results: The presence of hepatic macrophages was reduced by 90% in LPS and IRI + LPS groups pre-treated with clodronate liposomes (P <0.001). Severe small bile duct injury was not affected by macrophage depletion, and persisted in the liposomes + IRI + LPS group (50% of animals) and liposomes + LPS group (75% of animals). Likewise, BBB impairment persisted following macrophage depletion. LPS-induced elevation of the chemokine Mcp-1 in bile was not affected by macrophage depletion.Conclusions: Depletion of hepatic macrophages did not prevent development of biliary injury following LPS of LPS-enhanced IRI. Cholangiocyte activation rather than macrophage activation may underlie this injury. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marcc Marzioni, Nicholas LaRusso and Peter Ja

BACKGROUND: The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres.METHODS: PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals.RESULTS: A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001).CONCLUSION: An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.

BACKGROUND: The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres.METHODS: PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals.RESULTS: A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001).CONCLUSION: An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.

BACKGROUND: The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres.METHODS: PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals.RESULTS: A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001).CONCLUSION: An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.

BACKGROUND: Postoperative outcomes were studied in relation to adverse nutritional risk (body mass index (BMI) below 20 kg/m(2)), advanced age (80 years or more) and co-morbidity (American Society of Anesthesiologists (ASA) grade III-IV) in patients undergoing colorectal resection within an enhanced recovery after surgery programme. METHODS: Outcomes were audited prospectively in 1035 patients. Morbidity and mortality were compared with those predicted using the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity, and a multivariable model was used to determine independent predictors of outcome. RESULTS: Postoperative morbidity was lower than predicted (observed to expected 0.68; P < 0.001). Independent predictors of delayed mobilization were ASA III-IV (P < 0.001) and advanced age (P = 0.025). Prolonged hospital stay was related to advanced age (P = 0.002), ASA III-IV (P < 0.001), male sex (P = 0.037) and rectal surgery (P < 0.001). Morbidity was related to ASA III-IV (P = 0.004), male sex (P = 0.023) and rectal surgery (P = 0.002). None of the factors predicted 30-day mortality. CONCLUSION: Age and nutritional status were not independent determinants of morbidity or mortality. Pre-existing co-morbidity was an independent predictor of several outcomes.

Background: Single-centre studies have suggested that enhanced recovery can be achieved with multimodal perioperative care protocols. This international observational study evaluated the implementation of an enhanced recovery programme in five European centres and examined the determinants affecting recovery and length of hospital stay. Methods: Four hundred and twenty-five consecutive patients undergoing elective open colorectal resection above the peritoneal reflection between January 2001 and January 2004 were enrolled in a protocol that defined multiple perioperative care elements. One centre had been developing multimodal perioperative care for 10 years, whereas the other four had previously undertaken traditional care. Results: The case mix was similar between centres. Protocol compliance before and during the surgical procedure was high, but it was low in the immediate postoperative phase. Patients fulfilled predetermined recovery criteria a median of 3 days after operation but were actually discharged a median of 5 days after surgery. Delay in discharge and the development of major complications prolonged length of stay. Previous experience with fast-track surgery was associated with a shorter hospital stay. Conclusion: Functional recovery in 3 days after colorectal resection could be achieved in daily practice. A protocol is not enough to enable discharge of patients on the day of functional recovery; more experience and better organization of care may be required.

BACKGROUND: For colorectal surgery, evidence suggests that optimal management includes: no pre-operative fasting, a thoracic epidural analgesia continued for 2 days post-operatively, and avoidance of fluid overload. In addition, no long-acting benzodiazepines on the day of surgery and use of short-acting anaesthetic medication may be beneficial. We examined whether these strategies have been adopted in five northern-European countries. METHODS: In 2003, a questionnaire concerning peri-operative anaesthetic routines in elective, open colonic cancer resection was sent to the chief anaesthesiologist in 258 digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: The response rate was 74% (n = 191). Although periods of pre-operative fasting up to 48 h were reported, most (> 85%) responders in all countries declared to adhere to guidelines for pre-operative fasting and oral clear liquids were permitted until 2-3 h before anaesthesia. Solid food was permitted up to 6-8 h prior to anaesthesia. In all countries more than 85% of the responders indicated that epidural anaesthesia was routinely used. Except for Denmark, long-acting benzodiazepines were still widely used. Short-acting anaesthetics were used in all countries except Scotland where isoflurane is the anaesthetic of choice. With the exception of Denmark, intravenous fluids were used unrestrictedly. CONCLUSION: In northern Europe, most anaesthesiologists adhere to evidence-based optimal management strategies on pre-operative fasting, thoracic epidurals and short-acting anaesthetics. However, premedication with longer-acting agents is still common. Avoidance of fluid overload has not yet found its way into daily practice. This may leave patients undergoing elective colonic surgery at risk of oversedation and excessive fluid administration with potential adverse effects on surgical outcome.

BACKGROUND: For colorectal surgery, evidence suggests that optimal management includes: no pre-operative fasting, a thoracic epidural analgesia continued for 2 days post-operatively, and avoidance of fluid overload. In addition, no long-acting benzodiazepines on the day of surgery and use of short-acting anaesthetic medication may be beneficial. We examined whether these strategies have been adopted in five northern-European countries. METHODS: In 2003, a questionnaire concerning peri-operative anaesthetic routines in elective, open colonic cancer resection was sent to the chief anaesthesiologist in 258 digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: The response rate was 74% (n = 191). Although periods of pre-operative fasting up to 48 h were reported, most (> 85%) responders in all countries declared to adhere to guidelines for pre-operative fasting and oral clear liquids were permitted until 2-3 h before anaesthesia. Solid food was permitted up to 6-8 h prior to anaesthesia. In all countries more than 85% of the responders indicated that epidural anaesthesia was routinely used. Except for Denmark, long-acting benzodiazepines were still widely used. Short-acting anaesthetics were used in all countries except Scotland where isoflurane is the anaesthetic of choice. With the exception of Denmark, intravenous fluids were used unrestrictedly. CONCLUSION: In northern Europe, most anaesthesiologists adhere to evidence-based optimal management strategies on pre-operative fasting, thoracic epidurals and short-acting anaesthetics. However, premedication with longer-acting agents is still common. Avoidance of fluid overload has not yet found its way into daily practice. This may leave patients undergoing elective colonic surgery at risk of oversedation and excessive fluid administration with potential adverse effects on surgical outcome.

BACKGROUND: For colorectal surgery, evidence suggests that optimal management includes: no pre-operative fasting, a thoracic epidural analgesia continued for 2 days post-operatively, and avoidance of fluid overload. In addition, no long-acting benzodiazepines on the day of surgery and use of short-acting anaesthetic medication may be beneficial. We examined whether these strategies have been adopted in five northern-European countries. METHODS: In 2003, a questionnaire concerning peri-operative anaesthetic routines in elective, open colonic cancer resection was sent to the chief anaesthesiologist in 258 digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: The response rate was 74% (n = 191). Although periods of pre-operative fasting up to 48 h were reported, most (> 85%) responders in all countries declared to adhere to guidelines for pre-operative fasting and oral clear liquids were permitted until 2-3 h before anaesthesia. Solid food was permitted up to 6-8 h prior to anaesthesia. In all countries more than 85% of the responders indicated that epidural anaesthesia was routinely used. Except for Denmark, long-acting benzodiazepines were still widely used. Short-acting anaesthetics were used in all countries except Scotland where isoflurane is the anaesthetic of choice. With the exception of Denmark, intravenous fluids were used unrestrictedly. CONCLUSION: In northern Europe, most anaesthesiologists adhere to evidence-based optimal management strategies on pre-operative fasting, thoracic epidurals and short-acting anaesthetics. However, premedication with longer-acting agents is still common. Avoidance of fluid overload has not yet found its way into daily practice. This may leave patients undergoing elective colonic surgery at risk of oversedation and excessive fluid administration with potential adverse effects on surgical outcome.

Background: For colorectal surgery, evidence suggests that optimal management includes: no pre-operative fasting, a thoracic epidural analgesia continued for 2 days post-operatively, and avoidance of fluid overload. In addition, no long-acting benzodiazepines on the day of surgery and use of short-acting anaesthetic medication may be beneficial. We examined whether these strategies have been adopted in five northern-European countries. Methods: In 2003, a questionnaire concerning peri-operative anaesthetic routines in elective, open colonic cancer resection was sent to the chief anaesthesiologist in 258 digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. Results: The response rate was 74% (n = 191). Although periods of pre-operative fasting up to 48 h were reported, most (> 85%) responders in all countries declared to adhere to guidelines for pre-operative fasting and oral clear liquids were permitted until 2-3 h before anaesthesia. Solid food was permitted up to 6-8 h prior to anaesthesia. In all countries more than 85% of the responders indicated that epidural anaesthesia was routinely used. Except for Denmark, long-acting benzodiazepines were still widely used. Short-acting anaesthetics were used in all countries except Scotland where isoflurane is the anaesthetic of choice. With the exception of Denmark, intravenous fluids were used unrestrictedly. Conclusion: In northern Europe, most anaesthesiologists adhere to evidence-based optimal management strategies on pre-operative fasting, thoracic epidurals and short-acting anaesthetics. However, premedication with longer-acting agents is still common. Avoidance of fluid overload has not yet found its way into daily practice. This may leave patients undergoing elective colonic surgery at risk of oversedation and excessive fluid administration with potential adverse effects on surgical outcome.

Background & aims: Clinical care of patients undergoing colonic surgery differs between hospitals and countries. In addition, there is considerable variation in rates of recovery and length of hospital stay following major abdominal surgery. There is a need to develop a consensus on key elements of perioperative care for inclusion in enhanced recovery programmes so that these can be widely adopted and refined further in future clinical trials. Methods: Medline database was searched for all clinical studies/trials relating to enhanced recovery after colorectal resection. Relevant papers from the reference lists of these articles and from the authors' personal collections were also reviewed. A combination of evidence-based and consensus methodology was used to develop the resulting enhanced recovery after surgery (ERAS) clinical care protocol. Results and conclusions: Within traditional perioperative practice there is considerable evidence supporting a range of manoeuvres which, in isolation, may improve individual aspects of recovery after colonic surgery. The present manuscript reviews these issues in detail. There is also growing evidence that an integrated multimodal approach to perioperative care can result in an overall enhancement of recovery. However, effects on major morbidity and mortality remain to be determined. A protocol is presented which is in current use by the ERAS Group and may provide a standard of care against which either current or future novel elements of an enhanced recovery approach can be tested for their effect on outcome.

Evidence for optimal perioperative care in colorectal surgery is abundant. By avoiding fasting, intravenous fluid overload, and activation of the neuroendocrine stress response, postoperative catabolism is reduced and recovery enhanced. The specific measures that can be used routinely include no bowel preparation, epidural anaesthesia/analgesia continued for one to two days postoperatively, no nasogastric decompression tube postoperatively, intravenous fluid/saline restriction, and free oral intake from postoperative day one.5 This survey aimed to characterise perioperative practice in colorectal cancer surgery in five northern European countries: Scotland, the Netherlands, Denmark, Sweden, and Norway.

BACKGROUND: A comprehensive evidence base for perioperative care in upper gastrointestinal (GI) surgery is lacking. Little is known about the routines currently practiced in the absence of such evidence. We describe postoperative practice after gastric resections in five northern European countries. METHOD AND SETTING: Questionnaire survey in all major digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: 76% of all centres (n = 200/263) responded. Routines varied extensively both nationally and between countries. No uniformity was traced although a conservative trend was noticeable in the use of nasogastric decompression tubes and 'nil-by-mouth' regimens. Nutritional support during the first 5 days is generally offered in Denmark, but not in Scotland. Drinking at will is generally allowed in Denmark and Norway by the first postoperative day. Eating at will is uniformly restricted. CONCLUSION: The paucity of evidence is reflected by the marked heterogeneity in practice. Large groups of patients may be treated suboptimally. Best perioperative care for these patients must be defined and documented. Especially, the role of early oral intake at will in upper GI surgery needs to be clarified by sufficiently powered trials. Copyright (c) 2005 S. Karger AG, Basel.Discussion 352

Evidence for optimal perioperative care in colorectal surgery is abundant. By avoiding fasting, intravenous fluid overload, and activation of the neuroendocrine stress response, postoperative catabolism is reduced and recovery enhanced. The specific measures that can be used routinely include no bowel preparation, epidural anaesthesia/analgesia continued for one to two days postoperatively, no nasogastric decompression tube postoperatively, intravenous fluid/saline restriction, and free oral intake from postoperative day one.5 This survey aimed to characterise perioperative practice in colorectal cancer surgery in five northern European countries: Scotland, the Netherlands, Denmark, Sweden, and Norway.

BACKGROUND: A comprehensive evidence base for perioperative care in upper gastrointestinal (GI) surgery is lacking. Little is known about the routines currently practiced in the absence of such evidence. We describe postoperative practice after gastric resections in five northern European countries. METHOD AND SETTING: Questionnaire survey in all major digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: 76% of all centres (n = 200/263) responded. Routines varied extensively both nationally and between countries. No uniformity was traced although a conservative trend was noticeable in the use of nasogastric decompression tubes and 'nil-by-mouth' regimens. Nutritional support during the first 5 days is generally offered in Denmark, but not in Scotland. Drinking at will is generally allowed in Denmark and Norway by the first postoperative day. Eating at will is uniformly restricted. CONCLUSION: The paucity of evidence is reflected by the marked heterogeneity in practice. Large groups of patients may be treated suboptimally. Best perioperative care for these patients must be defined and documented. Especially, the role of early oral intake at will in upper GI surgery needs to be clarified by sufficiently powered trials. Copyright (c) 2005 S. Karger AG, Basel.Discussion 352