Propensity score-matched outcomes analysis of the liver-first approach for synchronous colorectal liver metastases.

BACKGROUND: Liver resection before primary cancer resection is a novel strategy advocated for selected patients with synchronous colorectal liver metastases (sCRLM). This study measured outcomes in patients with sCRLM following a liver-first or classical approach, and used a validated propensity score. METHODS: Clinical, pathological and follow-up data were collected prospectively from consecutive patients undergoing hepatic resection for sCRLM at a single centre (2004-2014). Cumulative disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were calculated by means of Kaplan-Meier analysis. Survival differences were analysed in the whole cohort and in subgroups matched according to Basingstoke Predictive Index (BPI). RESULTS: Of 582 patients, 98 had a liver-first and 467 a classical approach to treatment; 17 patients undergoing simultaneous bowel and liver resection were excluded. The median (i.q.r.) BPI was significantly higher in the liver-first compared with the classical group: 8·5 (5-10) versus 8 (4-9) (P = 0·030). Median follow-up was 34 months. The 5-year DFS rate was lower in the liver-first group than in the classical group (23 versus 45·6 per cent; P = 0·001), but there was no difference in 5-year CSS (51 versus 53·8 per cent; P = 0·379) or OS (44 versus 49·6 per cent; P = 0·305). After matching for preoperative BPI, there was no difference in 5-year DFS (37 versus 41·2 per cent for liver-first versus classical approach; P = 0·083), CSS (51 versus 53·2 per cent; P = 0·616) or OS (47 versus 49·1 per cent; P = 0·846) rates. CONCLUSION: Patients with sCRLM selected for a liver-first approach had more oncologically advanced disease and a poorer prognosis. They had inferior cumulative DFS than those undergoing a classical approach, a difference negated by matching preoperative BPI.

Patient-reported outcomes in long-term survivors of metastatic colorectal cancer needing liver resection.

BACKGROUND: Five-year survival after hepatic resection for colorectal cancer (CRC) liver metastases is good, but data on patient-reported outcomes are lacking. This study describes the long-term impact of liver surgery for CRC metastases on patient-reported outcomes. METHODS: The study used the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and the disease-specific module, EORTC QLQ-LMC21. For functional scales, mean scores out of 100 with 95 per cent c.i. were calculated; differences of 10 points or more were considered clinically significant. Responses to symptom scales and items were categorized as 'minimal' or 'severe'. Proportions and 95 per cent c.i. for symptoms were calculated. RESULTS: A total of 241 patients were recruited; nine (3·7 per cent) had unresectable disease and were excluded. Some 68 (42 men) of 80 long-term survivors participated; their mean age was 69·5 years and median follow-up was 8·0 (range 6·9-9·2) years. Values for baseline and 1-year patient-reported outcome data were similar. Scores for functional scales were excellent (emotional function: 92, 95 per cent c.i. 87 to 96; social function: 94, 89 to 99; role function: 94, 90 to 98), reflecting clinically significant improvements from baseline values of 17 (10 to 24), 12 (3 to 21) and 12 (3 to 20) respectively. Severe symptoms were uncommon (affected less than 5 per cent of patients) for most patient-reported outcome scales or items, but persistent severe symptoms were noted for sexual function (2 per cent increase from baseline), peripheral neuropathy (2 per cent increase), constipation (10 per cent increase) and diarrhoea (5 per cent increase). CONCLUSION: Long-term survivors of metastatic colorectal cancer who have undergone liver surgery have excellent global quality of life, high levels of function and few symptoms.

Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases.

BACKGROUND: Obesity and tissue adiposity constitute a risk factor for several cancers. Whether tissue adiposity increases the risk of cancer recurrence after curative resection is not clear. The present study analysed the influence of hepatic steatosis on recurrence following resection of colorectal liver metastases. METHODS: A prospective cohort of patients who had primary resection of colorectal liver metastases in two major hepatobiliary units between 1987 and 2010 was studied. Hepatic steatosis was assessed in non-cancerous resected liver tissue. Patients were divided into two groups based on the presence of hepatic steatosis. The association between hepatic steatosis and local recurrence was analysed, adjusting for relevant patient, pathological and surgical factors using Cox regression and propensity score case-match analysis. RESULTS: A total of 2715 patients were included. The cumulative local (liver) disease-free survival rate was significantly better in the group without steatosis (hazard ratio (HR) 1·32, 95 per cent confidence interval 1·16 to 1·51; P < 0·001). On multivariable analysis, hepatic steatosis was an independent risk factor for local liver recurrence (HR 1·28, 1·11 to 1·47; P = 0·005). After one-to-one matching of cases (steatotic, 902) with controls (non-steatotic, 902), local (liver) disease-free survival remained significantly better in the group without steatosis (HR 1·27, 1·09 to 1·48; P = 0·002). Patients with steatosis had a greater risk of developing postoperative liver failure (P = 0·001). CONCLUSION: Hepatic steatosis was an independent predictor of local hepatic recurrence following resection with curative intent of colorectal liver metastases.

Resection of colorectal liver metastases in the elderly: does age matter?

AIM: Despite the incidence of colorectal cancer increasing with age the proportion of patients undergoing surgery for colorectal liver metastases decreases dramatically in the elderly. Is this referral or selection bias justified? METHOD: A prospective database of resection for colorectal liver metastases at a single centre was retrospectively analysed to compare the outcome in patients aged ≥75 years (group E) with those aged <75 years (group Y). Data were analysed using the Kaplan-Meier method with Cox regression modelling. RESULTS: Of 1443 resections, 151 (10.5%) in group E were compared with 1292 (89.5%) in group Y. The two groups were matched apart from higher American Society of Anesthesiology scores (P=0.001) and less use of chemotherapy (P=0.01) in the elderly. Perioperative morbidity and 90-day mortality were higher in the elderly compared with the younger group (32.5%vs 21.2%, P=0.02, and 7.3%vs 1.3%, P=0.001). In the last 5 years, mortality in the elderly improved and was no longer significantly different from that of the younger patients [n=2/76 (2.6%) vs n=9/559 (1.6%); P=0.063]. The 5-year survival was similar in groups E and Y for cancer-specific (41.4%vs 41.6%, P=0.917), overall (37.0%vs 38.2%) and median (44.1 months vs 43.6 months, P=0.697) survival respectively. CONCLUSION: In the elderly liver resection for metastatic disease can be performed with acceptable mortality and morbidity with as good a prospect of survival as for younger patients.

The incidence and outcome of brain metastases after liver resection for colorectal cancer metastases.

AIM: Brain metastases from colorectal cancer are rare, with an incidence of 0.6-4%. The risk and outcome of brain metastases after hepatic and pulmonary metastasectomy have not been previously described. This study aimed to determine the incidence, predictive factors, treatment and survival of patients developing colorectal brain metastases, who had previously undergone resection of hepatic metastases. METHOD: A retrospective review was carried out of a prospectively maintained database of patients undergoing liver resection for colorectal metastases. RESULTS: Fifty-two (4.0%) of 1304 patients were diagnosed with brain metastases. The annual incidence rate was 1.03% per person-year. In the majority of cases brain metastases were found as part of multifocal disease. Median survival was 3.2 months (95% CI: 2.3-4.1), but was best for six patients treated with potentially curative resection [median survival = 13.2 (range, 4.9-32.1) months]. Multivariate analysis showed that a lymph node-positive primary tumour [hazard ratio (HR) = 2.7, 95% CI: 1.8-6.19; P = 0.019], large liver metastases (> 6 cm) [HR = 2.23, 95% CI: 1.19-2.33; P = 0.012] and recurrent intrahepatic and extrahepatic disease [HR = 2.11, 95% CI: 1.2-4.62; P = 0.013] were independent predictors for the development of brain metastases. CONCLUSION: The annual risk of developing brain metastases following liver resection for colorectal metastases is low, but highest for patients presenting with a Dukes' C primary tumour, large liver metastases or who subsequently develop disseminated disease. The overall survival from colorectal brain metastases is poor, but resection with curative intent offers patients their best chance of medium-term survival.

Long-term survival following delayed presentation and resection of colorectal liver metastases.

BACKGROUND: Long-term survival from metastatic colorectal cancer is partly dependent on favourable tumour biology. Large case series have shown improved survival following hepatectomy for colorectal liver metastases (CRLM) in patients diagnosed with metastases more than 12 months after index colorectal surgery (metachronous), compared with those with synchronous metastases. This study investigated whether delayed hepatic resection for CRLM affects long-term survival. METHODS: Consecutive patients undergoing hepatic resection for CRLM in a single centre (1987-2007) were grouped according to the timing of hepatectomy relative to index bowel surgery: less than 12 months (synchronous; group 1), 12-36 months (group 2) and more than 36 months (group 3). Cancer-specific survival was calculated using Kaplan-Meier analysis. RESULTS: There were 577 patients (48·0 per cent) in group 1, 467 (38·9 per cent) in group 2 and 158 (13·1 per cent) in group 3. The overall 5-year cancer-specific survival rate after liver surgery was 42·3 per cent, with no difference between groups. However, when measured from the time of primary colorectal surgery, group 3 showed a survival advantage at both 5 and 10 years (94·1 and 47·6 per cent respectively) compared with groups 1 (46·3 and 24·9 per cent) and 2 (57·1 and 35·0 per cent) (P = 0·003). Survival graphs showed a steeper negative gradient from 5 to 10 years for group 3 compared with groups 1 and 2 (-0·80 versus - 0·34 and - 0·37), indicating an accelerated mortality rate. CONCLUSION: Patients undergoing delayed liver resection for CRLM have a survival advantage that is lost during long-term follow-up.

Elective intra-aortic balloon counterpulsation during a high risk liver resection.

SUMMARY: We present the case of a 65-year-old male with severe coronary artery disease and a single colorectal liver metastasis. An elective intra-aortic balloon pump (IABP) was inserted following induction of anaesthesia to reduce left ventricular workload during his liver resection. After an uneventful recovery he was discharged on day 5. We review the literature on the elective use of these devices in cardiac surgery in which it is becoming routine practice in high risk patients. However in non-cardiac surgery there have been only 15 published cases all in very high risk patients, with favourable outcomes. To our knowledge this is the first published case of the use of elective IABP during liver surgery.

Reversible impairment in monocyte major histocompatibility complex class II expression in malnourished surgical patients.

BACKGROUND: Upregulation of major histocompatibility complex (MHC) class II antigen in response to the T-cell lymphokine interferon-gamma (IFN-gamma) is central to T cell-macrophage cooperation and immune homeostasis. We evaluated this property in malnourished surgical patients and assessed the impact of nutrition repletion with total parenteral nutrition (TPN). METHODS: Sixty-two patients were studied: 37 malnourished and 25 controls. Whole blood was cultured with or without IFN-gamma (100 U mL-1), dual-labeled with anti-CD14 (monocyte) and anti-human leukocyte antigen-DR antibodies and analyzed by flow cytometry. Phagocytosis was measured by flow cytometry. In a second study, 10 severely malnourished patients received 5 days of TPN and MHC class II expression was measured at the end of this period. RESULTS: The magnitude of the increase in monocyte MHC class II expression in response to IFN-gamma was significantly increased in the control group compared with the malnourished group (107% vs 53%; p < .05). This impairment directly correlated with severity of malnutrition, but did not correlate with age or disease type. The number of bacteria phagocytozed per cell was significantly decreased (p < .05) in the malnourished group. In study 2, there was a significant increase in MHC class II induction with IFN-gamma after short-term TPN (58% before vs 173% after, p < .001). CONCLUSIONS: MHC class II induction in response to IFN-gamma is significantly impaired in malnourished patients, correlating with the severity of malnutrition. This defect is reversed by short-term TPN. These data identify the reversible loss of a key mechanism, fundamental to host defense, that may enhance the risk of infection in malnourished patients.

1997 Harry M. Vars Research Award. Does the route of feeding modify gut barrier function and clinical outcome in patients after major upper gastrointestinal surgery?

BACKGROUND: Direct experimental evidence suggests that total enteral nutrition (TEN) reduces septic morbidity compared with bowel rest and total parenteral nutrition (TPN) and that mucosal support and maintenance of gut barrier function is a key mechanism. This effect is supported indirectly by clinical studies, but this question has not previously been investigated directly in the postoperative patient. This study examined the hypothesis that early enteral feeding after major upper gastrointestinal surgery may modulate gut barrier function and decrease the risk of major infective complications compared with bowel rest and parenteral nutrition. METHODS: A randomized clinical trial of 67 patients (TPN = 34; TEN = 33) fed postoperatively for 7 days was performed. Thirty-day major morbidity and mortality were monitored. Intestinal permeability was measured using the lactulose/mannitol test preoperatively and on postoperative days 1 and 7. Systemic anti-endotoxin core immunoglobulin G and M antibodies and serum albumin and C-reactive protein were quantified at these time points. RESULTS: No clinical benefit was observed in patients fed enterally compared with the parenterally fed group. Intestinal permeability was increased on the 1st postoperative day in association with evidence of endotoxin exposure. By day 7, enteral feeding compared with parenteral feeding had failed to significantly influence any of the gut barrier or systemic parameters. CONCLUSIONS: This randomized controlled trial of TEN vs TPN after major upper gastrointestinal surgery failed to show a clinical benefit for the enteral route. Moreover, enteral nutrition did not modulate gut barrier function postoperatively.

Square pegs in round holes: has psychometric testing a place in choosing a surgical career? A preliminary report of work in progress.

Methods of selection of candidates for training in surgery has long been regarded as lacking explicit criteria and objectivity. Our purpose was to discover the aptitudes and personality types of applicants for surgical posts at the outset, in order to discover which were most likely to result in a satisfactory progression through training and which were associated with career difficulties. This longitudinal predictive validation study has been undertaken in a London Teaching Hospital since 1994. After short-listing, but immediately before interview, all candidates for senior house officer posts in basic surgical training and in geriatric medicine were asked to undertake psychometric tests of numerical (GMA) and spatial (SIT7) reasoning, personality type (MBTI), and self-rating of competency. There were no differences in ability scores between surgeons or geriatricians. Personality differences were revealed between the surgeons and the geriatricians, and between male and female surgeons. This study suggests that while there are no differences in ability between surgeons and geriatricians at the start of training, there are differences in personality. Long-term follow-up of the career development of this cohort of surgical SHOs is required to determine whether the psychometric measures described correlate with achievements of milestones in their surgical careers.

Accuracy of liver-specific magnetic resonance imaging as a predictor of chemotherapy-associated hepatic cellular injury prior to liver resection.

BACKGROUND/AIMS: To evaluate the diagnostic precision of chemical-shift imaging MRI and ferucarbotran-enhanced MRI for hepatic parenchymal injury prior to hepatic resection for colorectal metastases. METHODS: Preoperative MRI criteria were used to score 37 patients with colorectal liver metastases by two independent radiologists, blinded to outcomes, for signal drop-out on chemical-shift imaging MRI and ferucarbotran uptake and compared to blinded standardized histopathological endpoints of steatosis, steatohepatitis and sinusoidal dilatation. Sensitivity, specificity, predictive values and the area under the receiver operating characteristic curve (AUC) were calculated for the MRI sequences. RESULTS: On histology, severe steatosis, steatohepatitis and sinusoidal dilation were evident in 6 (16.2%), 4 (10.8%) and 9 (24.3%) patients respectively. Chemical-shift imaging MRI had a positive predictive value (PPV) of 100% for severe steatosis, 80% for steatohepatitis and zero for sinusoidal dilatation, with an AUC of 1.0, 0.99 and 0.36 respectively. Ferucarbotran-enhanced MRI had a 100% PPV for the detection of severe sinusoidal dilatation, with an AUC of 0.61. CONCLUSIONS: This study demonstrates that liver-specific MRI can accurately predict the severity of pre-existing hepatic injury. Moreover, it may play a key role in planning the timing and extent of chemotherapy and hepatic resection for colorectal metastases.

Safe liver resection following chemotherapy for colorectal metastases is a matter of timing.

Neoadjuvant chemotherapy (NC) can improve the resectability of hepatic colorectal metastases (CRM). However, there is concern regarding its impact on operative risk. We reviewed 750 consecutive liver resections performed for CRM in a single unit (1996-2005) to evaluate whether NC affected morbidity and mortality. Redo hepatic resections or patients receiving adjuvant chemotherapy following primary resection were excluded. A total of 245 resections were performed in patients not requiring NC (control group) (mean age 63, 67% male) and 252 in patients who had NC (mean age 62, 67% male). The mean (s.d.) duration of surgery was less in the control group (241(64) vs 255(64)min, P=0.014) as was the mean blood loss (390(264) vs 449(424)ml, P=0.069). Postoperative mortality (2 vs 2%) and morbidity (27 vs 29%, P=0.34) was similar between groups. More NC patients developed septic (2.4%) or respiratory (10.3%) complications compared to controls (0 and 5.3%, P<0.03), with significantly more surgical complications if the interval between stopping NC and undergoing surgery was

Repeat hepatic resection for recurrent colorectal liver metastases is associated with favourable long-term survival.

BACKGROUND: The management of patients with recurrent colorectal liver metastases (RCLM) remains controversial. This study aimed to determine whether repeat liver resection for RCLM could be performed with acceptable morbidity, mortality and long-term survival. METHODS: Of 1121 consecutive liver resections performed and prospectively analysed between 1987 and 2005, 852 'curative' resections were performed on patients with colorectal liver metastases. Single liver resection was performed in 718 patients, and 71 repeat hepatic resections for RCLM were performed in 66 patients. RESULTS: There were no postoperative deaths following repeat hepatic resection compared with a postoperative mortality rate of 1.4 per cent after single hepatic resection. Postoperative morbidity was comparable following single and repeat hepatectomy (26.1 versus 18 per cent; P = 0.172), although median blood loss was greater during repeat resection (450 versus 350 ml; P = 0.006). Actuarial 1-, 3- and 5-year survival rates were 94, 68 and 44 per cent after repeat hepatic resection for RCLM, compared with 89.3, 51.7 and 29.5 per cent respectively following single hepatectomy. CONCLUSION: The beneficial outcomes observed after repeat liver resection in selected patients with RCLM confirm the experience of others and support its status as the preferred choice of treatment for such patients.

Refining the role of laparoscopy and laparoscopic ultrasound in the staging of presumed pancreatic head and ampullary tumours.

Laparoscopy and laparoscopic ultrasound have been validated previously as staging tools for pancreatic cancer. The aim of this study was to identify if assessment of vascular involvement with abdominal computed tomography (CT) would allow refinement of the selection criteria for laparoscopy and laparoscopic ultrasound (LUS). The details of patients staged with LUS and abdominal CT were obtained from the unit's pancreatic cancer database. A CT grade (O, A-F) of vascular involvement was recorded by a single radiologist. Of 152 patients, who underwent a LUS, 56 (37%) had unresectable disease. Three of 26 (12%) patients with CT grade O, 27 of 88 (31%) patients with CT grade A to D, 17 of 29 (59%) patients with CT grade E and all nine patients with CT grade F were found to have unresectable disease. In all, 24% of patients with tumours <3 cm were found to have unresectable disease. In those patients with tumours considered unresectable, local vascular involvement was found in 56% of patients and vascular involvement with metastatic disease in 17%, while 20% of patients had liver metastases alone and 5% had isolated peritoneal metastases. The remaining patient was deemed unfit for resection. Selective use of laparoscopic ultrasound is indicated in the staging of periampullary tumours with CT grades A to D.

Pre-operative short-course radiotherapy is associated with faecal incontinence after anterior resection.

OBJECTIVE: To determine the contribution of total mesorectal excision (TME), short-course pre-operative radiotherapy (SCRT), the level of the anastomosis and other putative contributory factors to the incidence and degree of faecal incontinence after anterior resection of the rectum. PATIENTS AND METHODS: Survivors of anterior resection of the rectum performed between February 1996 and February 2001, with a functioning anastomosis, were asked to complete a telephone questionnaire regarding their current bowel habit. Faecal incontinence was scored using the St. Mark's Incontinence Score. RESULTS: The median age of 124 patients who completed the questionnaire was 76 years. Of these, 104 patients had neoplastic disease, 66 (53%) patients exhibited some degree of incontinence, median St. Marks' Score 6, interquartile range 3-10. There was a significant association between the anastomotic level, and the St. Mark's Score (P < 0.0001, linear regression). Male sex (P = 0.047), SCRT (P = 0.0014) and an anastomotic leak (P = 0.038) were associated with significantly higher incontinence scores. Age, splenic flexure mobilization, TME, anastomotic configuration or use of a temporary stoma had no detectable independent effect on incontinence scores. CONCLUSIONS: Poor functional outcome following anterior resection was associated with a low anastomosis, SCRT or an anastomotic leak. The finding that SCRT was a predictor of postoperative incontinence emphasizes the need for stringent patient selection for this treatment modality.

Avulsion of the gallbladder following trivial injury.

Traumatic cholecystectomy is a rare condition that has always been described in the context of major trauma and associated liver or biliary injuries. We present a case of isolated traumatic cholecystectomy following a trivial injury which resulted in both a delayed presentation and a difficult diagnosis.

Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice.

OBJECTIVE: To examine the effects of cholestatic jaundice on gut barrier function. SUMMARY BACKGROUND DATA: Gut barrier failure occurs in animal models of jaundice. In humans, the presence of endotoxemia indirectly implicates failure of this host defense, but this has not previously been investigated in jaundiced patients. METHODS: Twenty-seven patients with extrahepatic obstructive jaundice and 27 nonicteric subjects were studied. Intestinal permeability was measured using the lactulose-mannitol test. Small intestinal morphology and the presence of mucosal immunologic activation were examined in endoscopic biopsies of the second part of the duodenum. Systemic antiendotoxin core IgG antibodies and serum interleukin-6 and C-reactive protein were also quantified. Intestinal permeability was remeasured in 9 patients 5 weeks after internal biliary drainage. RESULTS: The median lactulose-mannitol ratio was significantly increased in the jaundiced patients. This was accompanied by upregulation of HLA-DR expression on enterocytes and gut-associated lymphoid tissue, suggesting immune activation. A significant increase in the acute phase response and circulating antiendotoxin core antibodies was also observed in the jaundiced patients. After internal biliary drainage, intestinal permeability returned toward normal levels. CONCLUSIONS: A reversible impairment in gut barrier function occurs in patients with cholestatic jaundice. Increased intestinal permeability is associated with local immune cell and enterocyte activation. In view of the role of gut defenses in the modern paradigm of sepsis, these data may directly identify an important underlying mechanism contributing to the high risk of sepsis in jaundiced patients.

Gut barrier function in malnourished patients.

BACKGROUND: The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown. AIMS: To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients. PATIENTS: Malnourished and well nourished hospitalised patients. METHODS: Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay. RESULTS: There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response. CONCLUSIONS: Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.