Video Consultations Between Patients and Clinicians in Diabetes, Cancer, and Heart Failure Services: Linguistic Ethnographic Study of Video-Mediated Interaction.

BACKGROUND: Video-mediated clinical consultations offer potential benefits over conventional face-to-face in terms of access, convenience, and sometimes cost. The improved technical quality and dependability of video-mediated consultations has opened up the possibility for more widespread use. However, questions remain regarding clinical quality and safety. Video-mediated consultations are sometimes criticized for being not as good as face-to-face, but there has been little previous in-depth research on their interactional dynamics, and no agreement on what a good video consultation looks like. OBJECTIVE: Using conversation analysis, this study aimed to identify and analyze the communication strategies through which video-mediated consultations are accomplished and to produce recommendations for patients and clinicians to improve the communicative quality of such consultations. METHODS: We conducted an in-depth analysis of the clinician-patient interaction in a sample of video-mediated consultations and a comparison sample of face-to-face consultations drawn from 4 clinical settings across 2 trusts (1 community and 1 acute care) in the UK National Health Service. The video dataset consisted of 37 recordings of video-mediated consultations (with diabetes, antenatal diabetes, cancer, and heart failure patients), 28 matched audio recordings of face-to-face consultations, and fieldnotes from before and after each consultation. We also conducted 37 interviews with staff and 26 interviews with patients. Using linguistic ethnography (combining analysis of communication with an appreciation of the context in which it takes place), we examined in detail how video interaction was mediated by 2 software platforms (Skype and FaceTime). RESULTS: Patients had been selected by their clinician as appropriate for video-mediated consultation. Most consultations in our sample were technically and clinically unproblematic. However, we identified 3 interactional challenges: (1) opening the video consultation, (2) dealing with disruption to conversational flow (eg, technical issues with audio and/or video), and (3) conducting an examination. Operational and technological issues were the exception rather than the norm. In all but 1 case, both clinicians and patients (deliberately or intuitively) used established communication strategies to successfully negotiate these challenges. Remote physical examinations required the patient (and, in some cases, a relative) to simultaneously follow instructions and manipulate technology (eg, camera) to make it possible for the clinician to see and hear adequately. CONCLUSIONS: A remote video link alters how patients and clinicians interact and may adversely affect the flow of conversation. However, our data suggest that when such problems occur, clinicians and patients can work collaboratively to find ways to overcome them. There is potential for a limited physical examination to be undertaken remotely with some patients and in some conditions, but this appears to need complex interactional work by the patient and/or their relatives. We offer preliminary guidance for patients and clinicians on what is and is not feasible when consulting via a video link. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/10913.

Factors affecting length of stay after percutaneous biliary interventions.

OBJECTIVE:: To evaluate the factors affecting the length of hospital stay (LOS) after percutaneous transhepatic biliary drainage (PTBD). METHODS:: A retrospective review of all patients who had undergone PTBD with or without stenting at a UK specialist centre between 2005 and 2016 was conducted. RESULTS:: 692 patients underwent 1976 procedures over 731 clinical episodes for which, the median age was 65 (range 18-100) years, and the median Charlson Index was 3. PTBD was performed for malignant (n = 563) and benign strictures (n = 60), stones (n = 62), and bile leaks (n = 46). The median LOS was 13 (range 0-157) days, and the median interprocedure duration was 9 (range 0-304) days. The median number of procedures per patient was 2 and the median number of days required to complete a set of procedures for a patient (TBID) ranged from 0 to 557 days, with a median of 16 (interquartile range: 8-32) days. Patients with biliary leak had the highest LOS. Biliary stents were mostly placed at the second stage at a median of 6 (range 0-120) days from the first procedure day. Placement of a biliary stent in the first stage of the procedure was associated with shorter LOS (p < 0.001). CONCLUSIONS:: Biliary stenting at index procedure reduces LOS, although it is not always technically possible. Patients with bile leak managed with PTBD have longer LOS. ADVANCES IN KNOWLEDGE:: This study provides data which can help in appropriate consenting, better planning, and efficient resource utilization for patients undergoing PTBD.

Technology-Enhanced Consultations in Diabetes, Cancer, and Heart Failure: Protocol for the Qualitative Analysis of Remote Consultations (QuARC) Project.

BACKGROUND: Remote videoconsulting is promoted by policy makers as a way of delivering health care efficiently to an aging population with rising rates of chronic illness. As a radically new service model, it brings operational and interactional challenges in using digital technologies. In-depth research on this dynamic is needed before remote consultations are introduced more widely. OBJECTIVE: The objective of this study will be to identify and analyze the communication strategies through which remote consultations are accomplished and to guide patients and clinicians to improve the communicative quality of remote consultations. METHODS: In previous research, we collected and analyzed two separate datasets of remote consultations in a National Institute for Health Research-funded study of clinics in East London using Skype and a Wellcome Trust-funded study of specialist community heart failure teams in Oxford using Skype or FaceTime. The Qualitative Analysis of Remote Consultations (QuARC) study will combine datasets and undertake detailed interactional microanalysis of up to 40 remote consultations undertaken by senior and junior doctors and nurse specialists, including consultations with adults with diabetes, women who have diabetes during pregnancy, people consulting for postoperative cancer surgery and community-based patients having routine heart failure reviews along with up to 25 comparable face-to-face consultations. Drawing on established techniques (eg, conversation analysis), analysis will examine the contextual features in remote consultations (eg, restricted visual field) combined with close analysis of different modes of communication (eg, speech, gesture, and gaze). RESULTS: Our findings will address the current gap in knowledge about how technology shapes the fine detail of communication in remote consultations. Alongside academic outputs, findings will inform the coproduction of information and guidance about communication strategies to support successful remote consultations. CONCLUSIONS: Identifying the communication strategies through which remote consultations are accomplished and producing guidance for patients and clinicians about how to use this kind of technology successfully in consultations is an important and timely goal because roll out of remote consultations is planned across the National Health Service. REGISTERED REPORT IDENTIFIER: RR1-10.2196/10913.

Predicting complications in hepatic resection for colorectal liver metastasis: the lymphocyte-to-monocyte ratio.

BACKGROUND: Colorectal cancer is one of the most common malignancies worldwide; whilst approximately 20% of patients have hepatic disease at presentation. Hepatic resection remains the gold standard of care; however, it is associated with significant morbidity. We sought to establish whether the lymphocyte-to-monocyte ratio (LMR) could help predict post-operative complications, thus improving patient outcomes. METHODS: We performed a retrospective cohort study of patients undergoing hepatic resection at a single centre. Baseline demographics and complications within 30 days following surgery were recorded. White blood cell counts and C-reactive protein (CRP) were recorded pre-operatively, and until post-operative day 7. RESULTS: A total of 188 operations were included. About 47.3% of resections had a complicated recovery, of which 31.46% were major. The median LMR was 1.29 across the cohort, 1.60 for uncomplicated procedures, 1.14 for those with complications and 0.85 in major complications. For detecting major complications versus an uncomplicated recovery, median LMR was the best parameter (area under the curve 0.78), whilst it was the only parameter to accurately predict such complications within 48 hours of surgery (area under the curve 0.72 on day 1). It was consistently the most accurate parameter at detecting uncomplicated versus complicated recovery, minor versus major complications, and major complications versus an uncomplicated recovery, at numerous timepoints over the post-operative period. CONCLUSION: The LMR appears better at predicting complications following hepatic resection for colorectal liver metastases, as opposed to conventionally measured parameters.

Neutrophil: Lymphocyte ratio as a method of predicting complications following hepatic resection for colorectal liver metastasis.

BACKGROUND AND OBJECTIVES: Approximately 30-50% of patients with colorectal cancer develop liver metastasis for which liver resection is the only hope for potential cure. However, hepatic resection is associated with considerable morbidity. The aim was to detect early complications by utilising the neutrophil: lymphocyte ratio (NLR). METHODS: We performed a retrospective cohort study of patients undergoing hepatic resection at a single institution between 2008 and 2016. Baseline demographics and complications within 30 days following surgery were recorded, with blood tests measured until day 7. Statistical analysis was performed using Mann Whitney and ROC analysis. RESULTS: One hundred eighty-eight operations were included. 47.3% had an associated complication, of which 31.46% were major. The median NLR was 6.31 across the cohort, 5.44 for uncomplicated procedures, 7.0 for complications and 10.65 in major complications. Median NLR was the best parameter for detecting major complications versus minor complications (AUC 0.74) as opposed to lymphocytes (AUC 0.65), neutrophils (AUC 0.60), and CRP (AUC 0.60). The diagnostic ability of NLR increased further when predicting major complications versus an uncomplicated recovery (AUC 0.78), and it was the only significant parameter in the early post-operative period on days 2, 3, and 4 (AUC 0.70, 0.72, and 0.75). CONCLUSIONS: The NLR may have a role in predicting complications following hepatic resection for CLM, and with earlier detection, potentially improving outcomes.

Solid pseudopapillary tumour of the pancreas: clinicopathological analysis.

BACKGROUND: We report on our experience of the surgical management and outcomes of 11 patients with solid pseudopapillary tumour of the pancreas (SPT). We sought to correlate the immunohistochemical staining of these tumours with that previously reported in the literature. METHODS: A retrospective analysis of the clinical presentation, radiological findings, surgical treatment, histopathological characteristics and outcomes for patients surgically managed with SPT at The Royal London Hospital. A literature search was performed to analyse the immunohistochemical stains commonly used to diagnose SPT. RESULTS: Between August 2006 and April 2016, 10 females and one male patient underwent surgery for SPT. The localization of the tumour was in the pancreatic head in two patients, one in the neck, three in the body and five in the tail. All 11 patients had localised disease. Six patients suffered post-surgical complications. Histopathology shows immunoreactivity for: ß-catenin, vimentin, CD-10, CD-56, α1-antitrypsin and negative staining for synaptophysin and chromogranin. At a median of 24 months of follow-up, the disease-free survival rate was 100% and no recurrence was noted. A literature review generated 38 suitable articles with 116 individual cases of SPT, with high expression of vimentin and neuron specific enolase throughout, and low rates of chromogranin and synatophysin positivity. CONCLUSION: SPT is rare and affects mostly young women. An accurate diagnosis is important as the relative indolent behaviour can be managed with surgical resection even when large in size, bringing excellent long-term outcomes.

Expression of polymeric immunoglobulin receptor and stromal activity in pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). Our aim was to assess the role of pIgR in human PDAC. METHODS: pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of 88 patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. RESULTS: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies. Down-regulation in pIgR expression in Capan1 cancer cell line resulted in reduction of cellular proliferation, adhesion and migration in 2D assays. In 3D physiomimetic organotypic models, pIgR downregulation resulted in reduced cancer cell invasion, alteration of apico-basal polarity and diminished stromal activity. In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. In combination with enhanced stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had a trend towards better survival. CONCLUSION: pIgR may be involved in PDAC progression and may be linked stromal activity. Further work on its precise role is mandated in in vivo models, to understand its influence on cancer progression.

The role of perioperative inflammatory-based prognostic systems in patients with colorectal liver metastases undergoing surgery. A cohort study.

BACKGROUND: We aim to evaluate the prognostic value of preoperative and postoperative inflammatory systems in patients who had undergone surgery for colorectal liver metastases, focusing our analysis on the role of C-reactive protein-to-albumin ratio (CAR) and Glasgow prognostic score (GPS). METHODS: A total of 194 patients were enrolled onto this study. Demographics, tumor-related variables, preoperative and postoperative (day 1) inflammatory variables were analyzed as potential prognostic factors. RESULTS: For the whole cohort three and 5-year survival were 68% and 53% respectively. Median follow up was 27 months (IQR 10-42). At multivariate analysis only preoperative GPS (HR 12.06, 95% CI 2.82-51.53; p = 0.0008) was an independent risk factor for poor survival. Patients with a preoperative GPS = 0 had a 3-years survival of 70% while it was 33% for those with GPS = 1 (p < 0.0001). In patients with preoperative GPS = 0 preoperative CAR (HR 1.19, 95%CI 1.05-1.35; p = 0.0059) could identify a sub-population at risk for reduced survival. The optimal cut-off for preoperative CAR (preCAR) was 0.133 (HR 7.11 95% CI 1.37-36.78, p = 0.0063). 3-years survival was 75% and 21% for patients with preCAR>0.133 and ≤ 0.133, respectively (p = 0.0005). The immediate postoperative inflammatory status did not have a significant impact on survival. CONCLUSION: GPS is a significant prognostic factor in patients with colorectal liver metastases undergoing surgery. CAR could be a valuable tool to further stratify patients with preoperative GPS = 0 according to their prognosis.

Role of laparoscopy in hepatobiliary malignancies.

The many benefits of laparoscopy, including smaller incision, reduced length of hospital stay and more rapid return to normal function, have seen its popularity grow in recent years. With concurrent improvements in non-surgical cancer management the importance of accurate staging is becoming increasingly important. There are two main applications of laparoscopic surgery in managing hepato-pancreatico-biliary (HPB) malignancy: accurate staging of disease and resection. We aim to summarize the use of laparoscopy in these contexts. The role of staging laparoscopy has become routine in certain cancers, in particular T[2] staged, locally advanced gastric cancer, hilar cholangiocarcinoma and non-Hodgkin's lymphoma. For other cancers, in particular colorectal, laparoscopy has now become the gold standard management for resection such that there is no role for stand-alone staging laparoscopy. In HPB cancers, although staging laparoscopy may play a role, with ever improving radiology, its role remains controversial.

Inflammatory and Immune Responses to Surgery and Their Clinical Impact.

OBJECTIVE: The aim of this study was to describe current understanding of the local and systemic immune responses to surgery and their impact on clinical outcomes, predictive biomarkers, and potential treatment strategies. BACKGROUND: Patients undergoing major surgery are at risk of life-threatening inflammatory complications that include infection, the systemic inflammatory response syndrome (SIRS), or sepsis. Although improvements in surgical technique and peri-operative care have resulted in reduction in the rates of these complications, they remain high, especially in patients undergoing complex abdominal procedures. There are currently no drugs licensed specifically for the treatment of sepsis nor is it possible to identify those at highest risk, which would allow pre-emptive therapy that may improve outcomes. CONCLUSIONS: Local immune responses to surgery lead to systemic pro-inflammatory and immunosuppressive phases that are temporally related and proportionate in magnitude. Improved understanding of these mechanisms has implications for clinical study design and has led to the emergence of novel biomarkers such as Toll-like receptor expression. These can be used to stratify patient care pathways to maximize the benefit from current therapies or to select the right target at the right phase of illness for future drug development.

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.

OBJECTIVES: To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. BACKGROUND: Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. METHODS: Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. RESULTS: Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). CONCLUSIONS: These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.

Limited utility of inflammatory markers in the early detection of postoperative inflammatory complications after pancreatic resection: Cohort study and meta-analyses.

PURPOSE: To examine the diagnostic accuracy of systemic inflammatory markers in early prediction of inflammatory postoperative complications (IPC) and clinically-relevant pancreatic fistula (PF). METHODS: Preoperative and postoperative [until postoperative day (POD) 4)] measurements of hemoglobin, white blood cell counts (WBC), neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) were correlated with IPC and PF. Meta-analyses of biochemical predictors were performed. RESULTS: Ninety-two out of 378 patients developed IPC, PF occurred in 31. Preoperative WBC (OR 1.0001, 95% CI: 1.0001-1.0002, p = 0.02), NLR on POD2 (OR 1.05, 95% CI: 1.006-1.1, p = 0.02) and CRP on POD4 (OR 1.006, 95% CI: 1.002-1.01, p = 0.02) predicted IPC at multivariate analysis. The model including these three variables showed a diagnostic accuracy of 76.8% (sensitivity 20, specificity 97%.14; PPV 71.43, PPN 77.27) and, at logistic regression analysis an OR of 8.5 (95% CI: 2.5-28.6, p < 0.001). Only CRP >272 on POD3 (OR 3.32, 95% CI: 1.46-7.52, p = 0.003) was associated with PF with a diagnostic accuracy of 74% (sensitivity 54.5, specificity 78.5; PPV 16.88, NPV 94.25). Meta-analyses of available data suggested sensitivity of 75.3% (95% CI 66.7-82.6) and specificity of 75.5% (95% CI 61.3-85.7). However, these studies were significantly heterogeneous. CONCLUSIONS: Readily available, routine tests have limited utility in predicting IPC. Further research is required to develop novel biomarkers to aid management of these patients.

Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes.

Epithelial tissues have sparse stroma, in contrast to their corresponding tumours. The effect of cancer cells on stromal cells is well recognized. Increasingly, stromal components, such as endothelial and immune cells, are considered indispensable for cancer progression. The role of desmoplastic stroma, in contrast, is poorly understood. Targeting such cellular components within the tumour is attractive. Recent evidence strongly points towards a dynamic stromal cell participation in cancer progression that impacts patient prognosis. The role of specific desmoplastic stromal cells, such as stellate cells and myofibroblasts in pancreatic, oesophageal and skin cancers, was studied in bio-engineered, physiomimetic organotypic cultures and by regression analysis. For pancreatic cancer, the maximal effect on increasing cancer cell proliferation and invasion, as well as decreasing cancer cell apoptosis, occurs when stromal (pancreatic stellate cells) cells constitute the majority of the cellular population (maximal effect at a stromal cell proportion of 0.66-0.83), accompanied by change in expression of key molecules such as E-cadherin and ß-catenin. Gene-expression microarrays, across three tumour types, indicate that stromal cells consistently and significantly alter global cancer cell functions such as cell cycle, cell-cell signalling, cell movement, cell death and inflammatory response. However, these changes are mediated through cancer type-specific alteration of expression, with very few common targets across tumour types. As highlighted by these in vitro data, the reciprocal relationship of E-cadherin and polymeric immunoglobulin receptor (PIGR) expression in cancer cells could be shown, in vivo, to be dependent on the stromal content of human pancreatic cancer. These studies demonstrate that context-specific cancer-stroma crosstalk requires to be precisely defined for effective therapeutic targeting. These data may be relevant to non-malignant processes where epithelial cells interact with stromal cells, such as chronic inflammatory and fibrotic conditions.

A cross sectional study of colonic diverticulosis in the London Bangladeshi population.

BACKGROUND: Diverticular disease is the most common morphological abnormality of the colon and the fifth most important gastrointestinal disease in terms of cost in the Western world. Tower Hamlets is the poorest borough in London containing a large Bangladeshi community. We observed that emergency admissions with complications of colonic diverticulosis were minimal in the Bangladeshi community. The objective was to compare the background prevalence of colonic diverticulosis in Bangladeshis with other ethnicities in patients undergoing colonoscopy at a single centre in Tower Hamlets. METHODS: Four thousand four hundred and fifty-four consecutive colonoscopy reports over a 2-year period were retrospectively analysed. Patients under 40 years of age and repeat colonoscopies were excluded, leaving 3151 patients (mean age: 63 years; 48% male). Demographics including ethnicity and medical background were retrieved from the electronic patient record system and findings correlated with the prevalence of other 'Western' diseases in the cohort. RESULTS: Six hundred and thirty out of 3151 (20%) colonoscopies were performed on Bangladeshis. The prevalence of colonic diverticulosis was significantly lower in Bangladeshis (17/630: 2.7%) than Caucasians (673/1869: 36%), Indians/Pakistanis (16/161: 9.9%), Oriental (15/44: 34%) and Black (90/369: 24.4%) patient groups (χ(2) p < 0.0001 for all comparisons). The prevalence of classical sigmoid diverticulosis in the Bangladeshi cohort was only 1.0%, despite significantly more Bangladeshi patients undergoing colonoscopy for abdominal pain (p < 0.0001, χ(2)) and diarrhoea (p < 0.0034, χ(2)). There was also a significantly greater incidence of type 2 diabetes mellitus and ischaemic heart disease (p < 0.0001, χ(2)) in Bangladeshi patients. CONCLUSIONS: There is a negligible prevalence of colonic diverticulosis in the Bangladeshi population of London who undergo colonoscopy. This is in spite of a high incidence of type 2 diabetes and ischaemic heart disease. The effect of diet and genetics on the prevalence of colonic diverticulosis in Bangladeshis is not known and merits further investigation.

Portal vein embolisation for extended hepatectomy: single-centre experience.

BACKGROUND: Portal vein embolisation (PVE) induces contra-lateral liver hypertrophy to facilitate an extended hepatectomy. AIM: This paper aims to analyse our data on PVE and extended hepatectomy. Outcome measures included success of PVE, feasibility of resections, operative morbidity and survival. METHODS: A retrospective analysis of data collected prospectively on 33 patients (2004-2008) was performed. Survival curves were estimated by the Kaplan-Meier (Breslow) method. Significance was defined as p < 0.05. RESULTS: A total of 31 patients had successful PVE. There were 24 patients who underwent surgery. Significant hypertrophy of residual liver was noted from 230.15 (pre-embolisation) to 428.50 ml (post-embolisation) (median, p < 0.0001). A total of 16 patients had hepatectomy (14: R0; 2: R1) with a single mortality (6.25%) and 56.25% morbidity, and a median length of stay of 17 days. Median overall survival was 14 (95% CI 7.8-20.2) months. Patients who underwent resection had a median disease-specific survival of 33 (95% CI 4-62) months compared with 8.6 (95% CI 0-19.9) months for patients without resection (p = 0.14). For patients with primary hepato-biliary tumours, the median disease-specific survival was 7.9 (95% CI 4.5-11.3) months compared with a median survival of 19.7 (95% CI 0-42.2) months for patients with metastases (p = 0.07). CONCLUSIONS: PVE is safe, facilitates R0 resection and offers the best chance of cure, especially for liver metastases.

Colorectal liver metastases.

BACKGROUND: Despite major advances in therapies for liver metastases, colorectal cancer remains one of the commonest causes of cancer-related deaths in the UK. SOURCES OF DATA: The international literature on the management of colorectal liver metastases (CLM) was reviewed. AREAS OF AGREEMENT: Due to a combination of highly active systemic agents and low perioperative mortality achieved by high-volume centres, a growing number of patients are being offered liver resection with curative intent. Patients with bilobar and/or extrahepatic disease who would previously have received palliative treatment only, are undergoing major surgery with good results. This review focuses on preoperative evaluation, surgical planning and the role of adjuvant therapies in the management of patients with CLM. AREAS OF CONTROVERSY: Can ablative therapies match the outcomes of surgical resection? How can even more patients be rendered resectable? GROWING POINTS: The use of other therapies, such as radiofrequency ablation and selective internal radiation therapy. AREAS TIMELY FOR DEVELOPING RESEARCH: New chemotherapy regimens for neo-adjuvant therapy and the development of new modalities of liver tumour ablation.

A methodological approach to tracing cell lineage in human epithelial tissues.

Methods for lineage tracing of stem cell progeny in human tissues are currently not available. We describe a technique for detecting the expansion of a single cell's progeny that contain clonal mitochondrial DNA (mtDNA) mutations affecting the expression of mtDNA-encoded cytochrome c oxidase (COX). Because such mutations take up to 40 years to become phenotypically apparent, we believe these clonal patches originate in stem cells. Dual-color enzyme histochemistry was used to identify COX-deficient cells, and mutations were confirmed by microdissection of single cells with polymerase chain reaction sequencing of the entire mtDNA genome. These techniques have been applied to human intestine, liver, pancreas, and skin. Our results suggest that the stem cell niche is located at the base of colonic crypts and above the Paneth cell region in the small intestine, in accord with dynamic cell kinetic studies in animals. In the pancreas, exocrine tissue progenitors appeared to be located in or close to interlobular ducts, and, in the liver, we propose that stem cells are located in the periportal region. In the skin, the origin of a basal cell carcinoma appeared to be from the outer root sheath of the hair follicle. We propose that this is a general method for detecting clonal cell populations from which the location of the niche can be inferred, also affording the generation of cell fate maps, all in human tissues. In addition, the technique allows analysis of the origin of human tumors from specific tissue sites.

Locating the stem cell niche and tracing hepatocyte lineages in human liver.

UNLABELLED: We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase-deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic. CONCLUSION: These data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins.