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Peritonoid sensitivity to standard care chemotherapeutic regimens ex vivo.

Purpose:Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.Experimental Design:CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.Results:Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.Conclusions:Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Summary of drug panels and peritonoid genomic information

Supplementary Methods

Background Both wound infiltration (WI) with local anaesthetic and Erector Spinae Plane block (ESPB) have been described for post-operative analgesia after abdominal surgery. This study compared the efficacy of WI versus ESPB for post-operative analgesia after laparoscopic assisted colonic surgery. Methods Seventy-two patients between 18 and 85 years of age undergoing elective surgery were randomised to receive either WI or ESPB. In the WI group a 40 ml bolus of 0.5% Ropivacaine, infiltrated at the ports and minimally invasive wound at subcutaneous and fascia layers. In the ESPB group at T8 level, under ultrasound guidance, a 22-gauge nerve block needle was passed through the Erector Spinae muscle to reach its fascia. A dose up to 40 ml of 0.5% Ropivacaine, divided into two equal volumes, was injected at each side. Both groups had a multimodal analgesic regime, including regular Paracetamol, dexamethasone and patient-controlled analgesia (PCA) with Fentanyl. The primary end point was a post-operative pain score utilising a verbal Numerical Rating Score (NRS, 0–10) on rest and coughing in the post anaesthetic care unit (PACU) and in the first 24 h. Secondary outcomes measured were: opioid usage, length of stay and any clinical adverse events. Results There was no significant treatment difference in PACU NRS at rest and coughing (p-values 0. 382 and 0.595respectively). Similarly, there were no significant differences in first 24 h NRS at rest and coughing (p-values 0.285 and 0.431 respectively). There was no significant difference in Fentanyl use in PACU or in the first 24 h (p- values 0.900 and 0.783 respectively). Neither was there a significant difference found in mean total Fentanyl use between ESPB and WI groups (p-value 0.787). Conclusion Our observations found both interventions had an overall similar efficacy. Trial registration The study was registered with the Australian New Zealand Clinical Trial Registry (ACTRN: 12619000113156).

Objectives Gastric cancer remains one of the most fatal cancers, despite an intensive treatment regime of chemotherapy–surgery–chemotherapy. Peritoneal metastatic disease is commonly diagnosed post treatment regime and once established, patients are likely to die in 3–9 months. Systemic chemotherapy does not increase survival for these patients due to the poor vascularisation of this area. We are proposing the addition of pressurised intraperitoneal aerosol chemotherapy (PIPAC) to the treatment regime for curative patients as a preventive measure to reduce the risk of peritoneal metastases occurring. Methods This is a prospective, single centre, non-randomised, open-label pilot trial evaluating the addition of PIPAC to the standard multimodal treatment pathway. Patients will undergo standard neoadjuvant chemotherapy with four cycles of fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT), then PIPAC, followed by gastrectomy. Four cycles of FLOT will be administered post-surgery. Primary outcome is safety and feasibility, assessed by perioperative morbidity and possible interruptions of the standard multimodal treatment pathway.

Purpose Machine learning algorithms were hypothesized as being able to predict the quality of colonoscopy luminal images. This is to enhance training and quality indicators in endoscopy. Methods A separate study involving a randomized controlled trial of capped vs. un-capped colonoscopies provided the colonoscopy videos for this study. Videos were analyzed with an algorithm devised by the Australian Institute for Machine Learning. The image analysis validated focus measure, steerable filters-based metrics (SFIL), was used to assess luminal visualization quality and was compared with two independent clinician assessments (C1 and C2). Goodman and Kruskal's gamma (G) measure was used to assess rank correlation data using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY). Results A total of 500 random colonoscopy video clips were extracted and analyzed, 88 being excluded. SFIL scores matched with C1 in 45% and C2 in 42% of cases, respectively. There was a significant correlation between SFIL and C1 (G = 0.644, p0.005) and SFIL and C2 (G = 0.734, p0.005). Conclusion This study demonstrates that machine learning algorithms can recognize the quality of luminal visualization during colonoscopy. We intend to apply this in the future to enhance colonoscopy training and as a metric for quality assessment.

The purpose of this research was to investigate the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). We evaluated preoperative cSFRP5 levels in CRC patients and controls (n = 208). We found significantly higher cSFRP5 levels in CRC patients compared with non-CRC controls (p < 0.001). Levels of cSFRP5 were significantly lower in CRC patients with either vascular invasion (p = 0.001) or liver metastasis (p = 0.016). High cSFRP5 levels were associated with longer disease-free survival in both univariate (p = 0.024) and multivariate (p = 0.015) analyses. Analysis of an independent tissue cohort from The Cancer Genome Atlas database revealed significantly lower SFRP5 RNA expression in CRC tumor tissue compared with adjacent normal mucosa (n = 590 vs 47; p

BACKGROUND: Preoperative screening for coronavirus disease 2019 (COVID-19) aims to preserve surgical safety for both patients and surgical teams. This rapid review provides an evaluation of current evidence with input from clinical experts to produce guidance for screening for active COVID-19 in a low prevalence setting. METHODS: An initial search of PubMed (until 6 May 2020) was combined with targeted searches of both PubMed and Google Scholar until 1 July 2020. Findings were streamlined for clinical relevance through the advice of an expert working group that included seven senior surgeons and a senior medical virologist. RESULTS: Patient history should be examined for potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hyposmia and hypogeusia may present as early symptoms of COVID-19, and can potentially discriminate from other influenza-like illnesses. Reverse transcription-polymerase chain reaction is the gold standard diagnostic test to confirm SARS-CoV-2 infection, and although sensitivity can be improved with repeated testing, the decision to retest should incorporate clinical history and the local supply of diagnostic resources. At present, routine serological testing has little utility for diagnosing acute infection. To appropriately conduct preoperative testing, the temporal dynamics of SARS-CoV-2 must be considered. Relative to other thoracic imaging modalities, computed tomography has the greatest utility for characterizing pulmonary involvement in COVID-19 patients who have been diagnosed by reverse transcription-polymerase chain reaction. CONCLUSION: Through a rapid review of the literature and advice from a clinical expert working group, evidence-based recommendations have been produced for the preoperative screening of surgical patients with suspected COVID-19.

Background Long‐term effects after COVID‐19 may affect surgical safety. This study aimed to evaluate the literature and produce evidence‐based guidance regarding the period of delay necessary for adequate recovery of patients following COVID‐19 infection before undergoing surgery. Methods A rapid review was combined with advice from a working group of 10 clinical experts across Australia and New Zealand. MEDLINE, medRxiv and grey literature were searched to 4 October 2020. The level of evidence was stratified according to the National Health and Medical Research Council evidence hierarchy. Results A total of 1020 records were identified, from which 20 studies (12 peer‐reviewed) were included. None were randomized trials. The studies comprised one case–control study (level III‐2 evidence), one prospective cohort study (level III‐2) and 18 case‐series studies (level IV). Follow‐up periods containing observable clinical characteristics ranged from 3 to 16 weeks. New or excessive fatigue and breathlessness were the most frequently reported symptoms. SARS‐CoV‐2 may impact the immune system for multiple months after laboratory confirmation of infection. For patients with past COVID‐19 undergoing elective curative surgery for cancer, risks of pulmonary complications and mortality may be lowest at 4 weeks or later after a positive swab. Conclusion After laboratory confirmation of SARS‐CoV‐2 infection, minor surgery should be delayed for at least 4 weeks and major surgery for 8–12 weeks, if patient outcome is not compromised. Comprehensive preoperative and ongoing assessment must be carried out to ensure optimal clinical decision‐making., A rapid review was combined with advice from a working group of 10 clinical experts across Australia and New Zealand to produce evidence‐based guidance regarding the period of delay necessary for adequate recovery of patients following COVID‐19 infection before undergoing surgery. We found that follow‐up periods containing observable clinical characteristics ranged from 3 to 16 weeks and SARS‐CoV‐2 may impact the immune system for multiple months after laboratory confirmation of infection. Therefore, after laboratory confirmation of SARS‐CoV‐2 infection, minor surgery should be delayed for at least 4 weeks and major surgery for 8–12 weeks, if patient outcome is not compromised; additionally comprehensive preoperative and ongoing assessment must be carried out to ensure optimal clinical decision‐making.

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in KRAS and GNAS but are usually wild-type for BRAF, APC, and P53. Conversely, appendiceal adenocarcinomas are frequently found with mutations in KRAS, GNAS, P53, PIK3CA, and APC, and have significant nuclear expression of ��-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in P53 and chromatin-modifier genes, but they tend to be wild-type for KRAS, GNAS, APC, and PIK3CA. The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including APC, BRAF, SMAD4, and PIK3C. The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous CTNN��1, NOTCH1, and NOTCH4 germline mutations have recently been identified in low and high grades ANs.

Background Inconsistencies regarding the use of appropriate personal protective equipment (PPE) have raised concerns for the safety of surgical staff during the coronavirus disease 2019 (COVID‐19) pandemic. This rapid review synthesises the literature that includes input from clinical experts to provide evidence‐based guidance for surgical services. Methods The rapid review comprised of targeted searches in PubMed and grey literature. Pertinent findings were discussed by a working group of clinical experts, and consensus recommendations, consistent with Australian and New Zealand Government guidelines, were formulated. Results There was a paucity of high‐quality primary studies specifically investigating appropriate surgical PPE for healthcare workers treating patients possibly infected with COVID‐19. SARS‐CoV‐2 is capable of aerosol, droplet and fomite transmission, making it essential to augment standard infection control measures with appropriate PPE, especially during surgical emergencies and aerosol‐generating procedures. All biological material should be treated a potential source of SARS‐COV‐2. Staff must have formal training in the use of PPE and should be supervised by a colleague during donning and doffing. Patients with suspected or confirmed COVID‐19 should wear a surgical mask during transfer to and from theatre. Potential solutions exist in the literature to extend the use of surgical P2/N95 respirators in situations of limited supply. Conclusion PPE is advised for all high‐risk procedures and when a patient’s COVID‐19 status is unknown. Surgical departments should facilitate staggered rostering, remote meeting attendance, and self‐isolation of symptomatic staff. Vulnerable surgical staff should be identified and excluded from operations with a high risk of COVID‐19 infection.

BACKGROUND: The novel coronavirus, SARS-CoV-2, caused the COVID-19 global pandemic. In response, the Australian and New Zealand governments activated their respective emergency plans and hospital frameworks to deal with the potential increased demand on scarce resources. Surgical triage formed an important part of this response to protect the healthcare system's capacity to respond to COVID-19. METHOD: A rapid review methodology was adapted to search for all levels of evidence on triaging surgery during the current COVID-19 outbreak. Searches were limited to PubMed (inception to 10 April 2020) and supplemented with grey literature searches using the Google search engine. Further, relevant articles were also sourced through the Royal Australasian College of Surgeons COVID-19 Working Group. Recent government advice (May 2020) is also included. RESULTS: This rapid review is a summary of advice from Australian, New Zealand and international speciality groups regarding triaging of surgical cases, as well as the peer-reviewed literature. The key theme across all jurisdictions was to not compromise clinical judgement and to enable individualized, ethical and patient-centred care. The topics reported on include implications of COVID-19 on surgical triage, competing demands on healthcare resources (surgery versus COVID-19 cases), and the low incidence of COVID-19 resulting in a possibility to increase surgical caseloads over time. CONCLUSION: During the COVID-19 pandemic, urgent and emergency surgery must continue. A carefully staged return of elective surgery should align with a decrease in COVID-19 caseload. Combining evidence and expert opinion, schemas and recommendations have been proposed to guide this process in Australia and New Zealand.

Background Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has created a global pandemic. Surgical care has been impacted, with concerns raised around surgical safety, especially in terms of laparoscopic versus open surgery. Due to potential aerosol transmission of SARS‐CoV‐2, precautions during aerosol‐generating procedures and production of surgical plume are paramount for the safety of surgical teams. Methods A rapid review methodology was used with evidence sourced from PubMed, Departments of Health, surgical colleges and other health authorities. From this, a working group of expert surgeons developed recommendations for surgical safety in the current environment. Results Pre‐operative testing of surgical patients with reverse transcription‐polymerase chain reaction does not guarantee lack of infectivity due to a demonstrated false‐negative rate of up to 30%. All bodily tissues and fluids should therefore be treated as a potential source of COVID‐19 infection during operative management. Caution must be taken, especially when using an energy source that produces surgical plumes, and an appropriate capture device should also be used. Limiting the use of such devices or using lower energy devices is desirable. To reduce perceived risks association with desufflation of pneumoperitoneum during laparoscopic surgery, an appropriate suction irrigator system, attached to a high‐efficiency particulate air filter, should be used. Additionally, appropriate use of personal protective equipment by the surgical team is necessary during high‐risk aerosol‐generating procedures. Conclusions As a result of the rapid review, evidence‐based guidance has been produced to support safe surgical practice., Surgical care has been impacted by the coronavirus disease 2019 pandemic, with concerns raised around surgical safety, especially in terms of laparoscopic versus open surgery. Due to potential aerosol transmission of severe acute respiratory syndrome coronavirus 2, precautions during aerosol‐generating procedures and production of surgical plume are paramount for the safety of surgical teams. From a rapid review on the topic, a working group of expert surgeons developed evidence‐based guidance to support safe surgical practice in the current environment.

Purpose: Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown. Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. Conclusions: Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC). Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. Results: The median age of YOCRC cases was 44 years (18–54) and of controls was 45 years (18–54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0–9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen. Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate. Refereed/Peer-reviewed

IntroductionGastrointestinal recovery after surgery is of worldwide significance. Postoperative gastrointestinal dysfunction is multifaceted and known to represent a major source of postoperative morbidity, however, its significance to postoperative care across all surgical procedures is unknown. The complexity of postoperative gastrointestinal recovery is poorly defined within gastrointestinal surgery, and even less so outside this field. To inform the clinical care of surgical patients worldwide, this systematic review and meta-analysis will aim to characterise the duration of postoperative gastrointestinal recovery that can be expected across all surgical procedures and determine the associations between factors that may affect this.Methods and analysisMEDLINE, Embase, Cochrane Library and CINAHL will be searched for studies reporting the time to first postoperative passage of stool after any surgical procedure. We will screen records, extract data and assess risk of bias in duplicate. Forest plots will be constructed for time to postoperative gastrointestinal recovery, as assessed by various outcome measures. Because of potential heterogeneity, a random-effects model will be used throughout the meta-analysis. Funnel plots will be used to test for publication bias. Meta-regressions will be undertaken where the outcome is the mean time to first postoperative passage of stool, with potential predictors and confounders being patient characteristics, postoperative outcomes and surgical factors.Ethics and disseminationThis study will not involve human or animal subjects and, thus, does not require ethics approval. The outcomes will be disseminated via publication in peer-reviewed scientific journal(s) and presentations at scientific conferences.PROSPERO registration numberCRD42021256210.

BackgroundNeutropenia and thrombocytopenia are well-recognised complications of systemic chemotherapy. In cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC), the interplay between surgical factors and systemic toxicity of chemotherapeutics must be considered when considering post-operative haematological outcomes. We sought to quantify the incidence of these events in cytoreductive surgery and HIPEC at our institution.MethodsWe conducted a single centre, a retrospective cohort study of 50 consecutive patients who underwent cytoreductive surgery and HIPEC from 2002 to 2015. Routine haematological data were analysed and complications classified according to CTCAE 4.0. Subgroup analysis was undertaken to compare those who received or not perioperative systemic chemotherapy.ResultsThe rate of all-grade post-procedure neutropenia was 4 % (n=2/50); one grade 1, and one grade 4 neutropenia. The patient with grade 4 neutropenia died day 57 post-operatively, despite subsequent growth factor support. Eight percent (n=4/50) of patients had thrombocytopenia preoperatively. The overall rate of post-procedure thrombocytopenia was 46 % with grade 3–4 thrombocytopenia of 4 %. If not present preoperatively, thrombocytopenia onset was on day 1 or 2 post-operatively, with a median duration of 3 days.ConclusionsIntraperitoneal delivery of chemotherapy as HIPEC can cause haematological toxicity with potentially fatal outcomes. However, the incidence of neutropenia and thrombocytopenia after CRS and HIPEC is low.

Background: Colorectal cancer (CRC) diagnosed at

The expression of HLA-G by tumour cells is an established mechanism to escape recognition and immune mediated destruction, allowing tumour survival, growth and metastasis. However, the prognostic value of soluble HLA-G (sHLA-G) remains unknown. Mucinous carcinoma (MC) is a distinct form of colorectal cancer (CRC) found in 10 to 15% of patients, which has long been associated with poor response to treatment. To investigate the prognostic value of plasma sHLA-G levels in CRC patients, preoperative plasma sHLA-G levels were determined by ELISA in CRC patients (n = 133). In addition, the local expression of HLA-G in tumour biopsies was assessed using tissue microarray analysis (n = 255). Within the high 33rd percentile of sHLA-G levels (265-890 U/mL; n = 44) we observed higher frequency of MC patients (p = 0.012; Chi-square), and higher sHLA-G levels in patients with vascular invasion (p = 0.035; two-tailed t-test). Moreover, MC patients had significantly higher sHLA-G levels compared to those with adenocarcinoma not otherwise specified (p = 0.036; two-tailed t-test). Surprisingly, while stage II patients showed negative correlation between sHLA-G levels and liver metastasis free survival (LMFS) (p = 0.041; R = -0.321), in stage III patients high sHLA-G levels were associated with significantly longer LMFS (p = 0.002), and sHLA-G levels displayed positive correlation with LMFS (p = 0.006; R = 0.409). High HLA-G expression in tumours was associated with poor cancer specific overall survival in stage II to III (p = 0.01), and with shorter LMFS in stage II patients (p = 0.004). Our findings reveal that sHLA-G levels are associated with distinct progression patterns in consecutive disease stages, indicating a potential value as surrogate marker in the differential prognosis of CRC.

IMPORTANCE: Complex surgical interventions are inherently prone to variation yet they are not objectively measured. The reasons for outcome differences following cancer surgery are unclear. OBJECTIVE: To quantify surgical skill within advanced laparoscopic procedures and its association with histopathological and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: This analysis of data and video from the Australasian Laparoscopic Cancer of Rectum (ALaCaRT) and 2-dimensional/3-dimensional (2D3D) multicenter randomized laparoscopic total mesorectal excision trials, which were conducted at 28 centers in Australia, the United Kingdom, and New Zealand, was performed from 2018 to 2019 and included 176 patients with clinical T1 to T3 rectal adenocarcinoma 15 cm or less from the anal verge. Case videos underwent blinded objective analysis using a bespoke performance assessment tool developed with a 62–international expert Delphi exercise and workshop, interview, and pilot phases. INTERVENTIONS: Laparoscopic total mesorectal excision undertaken with curative intent by 34 credentialed surgeons. MAIN OUTCOMES AND MEASURES: Histopathological (plane of mesorectal dissection, ALaCaRT composite end point success [mesorectal fascial plane, circumferential margin, ≥1 mm; distal margin, ≥1 mm]) and 30-day morbidity. End points were analyzed using surgeon quartiles defined by tool scores. RESULTS: The laparoscopic total mesorectal excision performance tool was produced and shown to be reliable and valid for the specialist level (intraclass correlation coefficient, 0.889; 95% CI, 0.832-0.926; P

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.

Background In addition to technical expertise, surgical competence requires effective non-technical skills to ensure patient safety and maintenance of standards. Recently the Royal Australasian College of Surgeons implemented a new Surgical Education and Training (SET) curriculum that incorporated non-technical skills considered essential for a competent surgeon. This study sought to compare the non-technical skills of experienced surgeons who completed their training before the introduction of SET with the non-technical skills of more recent trainees. Methods Surgical trainees and experienced surgeons undertook a simulated scenario designed to challenge their non-technical skills. Scenarios were video recorded and participants were assessed using the Non-Technical Skills for Surgeons (NOTSS) scoring system. Participants were divided into subgroups according to years of experience and their NOTSS scores were compared. Results For most NOTSS elements, mean scores increased initially, peaking around the time of Fellowship, before decreasing roughly linearly over time. There was a significant downward trend in score with increasing years since being awarded Fellowship for six of the 12 NOTSS elements: considering options (score −0·015 units per year), implementing and reviewing decisions (−0·020 per year), establishing a shared understanding (−0·014 per year), setting and maintaining standards (−0·024 per year), supporting others (−0·031 per year) and coping with pressure (−0·015 per year). Conclusion The drop in NOTSS score was unexpected and highlights that even experienced surgeons are not immune to deficiencies in non-technical skills. Consideration should be given to continuing professional development programmes focusing on non-technical skills, regardless of the level of professional experience.

Background Simulation-based training assumes that skills are directly transferable to the patient-based setting, but few studies have correlated simulated performance with surgical performance. Methods A systematic search strategy was undertaken to find studies published since the last systematic review, published in 2007. Inclusion of articles was determined using a predetermined protocol, independent assessment by two reviewers and a final consensus decision. Studies that reported on the use of surgical simulation-based training and assessed the transferability of the acquired skills to a patient-based setting were included. Results Twenty-seven randomized clinical trials and seven non-randomized comparative studies were included. Fourteen studies investigated laparoscopic procedures, 13 endoscopic procedures and seven other procedures. These studies provided strong evidence that participants who reached proficiency in simulation-based training performed better in the patient-based setting than their counterparts who did not have simulation-based training. Simulation-based training was equally as effective as patient-based training for colonoscopy, laparoscopic camera navigation and endoscopic sinus surgery in the patient-based setting. Conclusion These studies strengthen the evidence that simulation-based training, as part of a structured programme and incorporating predetermined proficiency levels, results in skills transfer to the operative setting.

Background Training in basic laparoscopic skills can be undertaken using traditional methods, where trainees are educated by experienced surgeons through a process of graduated responsibility or by simulation-based training. This study aimed to assess whether simulation trained individuals reach the same level of proficiency in basic laparoscopic skills as traditional trained participants when assessed in a simulated environment. Methods A prospective study was undertaken. Participants were allocated to one of two cohorts according to surgical experience. Participants from the inexperienced cohort were randomized to receive training in basic laparoscopic skills on either a box trainer or a virtual reality simulator. They were then assessed on the simulator on which they did not receive training. Participants from the experienced cohort, considered to have received traditional training in basic laparoscopic skills, did not receive simulation training and were randomized to either the box trainer or virtual reality simulator for skills assessment. The assessment scores from different cohorts on either simulator were then compared. Results A total of 138 participants completed the assessment session, 101 in the inexperienced simulation-trained cohort and 37 on the experienced traditionally trained cohort. There was no statistically significant difference between the training outcomes of simulation and traditionally trained participants, irrespective of the simulator type used. Conclusions The results demonstrated that participants trained on either a box trainer or virtual reality simulator achieved a level of basic laparoscopic skills assessed in a simulated environment that was not significantly different from participants who had been traditionally trained in basic laparoscopic skills.

Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used.

Background A retrospective analysis of age-related postoperative morbidity in the Australia and New Zealand prospective randomized controlled trial comparing laparoscopic and open resection for right- and left-sided colonic cancer is presented. Methods A total of 592 eligible patients were entered and studied from 1998 to 2005. Results Data from 294 patients who underwent laparoscopic and 298 who had open colonic resection were analysed; 266 patients were aged less than 70 years and 326 were 70 years or older (mean(s.d.) 70·3(11·0) years). Forty-three laparoscopic operations (14·6 per cent) were converted to an open procedure. Fewer complications were reported for intention-to-treat laparoscopic resections compared with open procedures (P = 0·002), owing primarily to a lower rate in patients aged 70 years or more (P = 0·002). Fewer patients in the laparoscopic group experienced any complication (P = 0·035), especially patients aged 70 years or above (P = 0·019). Conclusion Treatment choices for colonic cancer depend principally upon disease-free survival; however, patients aged 70 years or over should have rigorous preoperative investigation to avoid conversion and should be considered for laparoscopic colonic resection. Registration number: NCT00202111 (http://www.clinicaltrials.gov).

Circulating tumor cells (CTC) may be defined as tumor- or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial-mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing "curative" resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years. Refereed/Peer-reviewed

Aim In colorectal cancer (CRC), adjuvant therapy is offered on the basis of stage and attempts to identify factors to better target treatment have not been successful. Recent work suggested that mismatch repair deficient CRCs may not benefit from 5FU adjuvant chemotherapy but studies remain conflicting. We aimed to determine if gender, tumor site, tumor pathological characteristics and microsatellite instability (MSI) predict survival benefit from adjuvant chemotherapy in stage C CRC. Methods Data were collated on ACPS (Australian Clinico-pathological Staging System) stage C CRC cases that underwent curative resection over a 23-year period. Pathology was reevaluated, DNA was extracted from the formalin-fixed paraffin specimen, and MSI status was established by BAT26 instability. Multivariate analysis was performed using Cox proportional hazard model and effects modification interaction testing. Results In total 814 unselected cases were included, of whom 37% received chemotherapy. Seventy-seven cases exhibited MSI. Overall, adjuvant chemotherapy produced a cancer-specific survival benefit (HR 0.52, 95% CI 0.39–0.70; P

Background The aim of this systematic review was to compare the safety and efficacy of dynamic graciloplasty with colostomy for the treatment of faecal incontinence. Methods Two search strategies were devised to retrieve literature from the Medline, Current Contents, Embase and Cochrane Library databases up until November 1999. Inclusion of papers depended on a predetermined protocol, independent assessments by two reviewers and a final consensus decision. English language papers were selected. Acceptable study designs included randomized controlled trials, controlled clinical trials and case series. Forty papers met the inclusion criteria. They were tabulated and critically appraised in terms of methodology and design, outcomes, and the possible influence of bias, confounding and chance. Results No high-level evidence was available and there were no comparative studies. Mortality rates were around 2 per cent for both graciloplasty and colostomy. Morbidity rates reported for graciloplasty appear to be higher than those for colostomy. Dynamic graciloplasty was clearly effective at restoring continence in between 42 and 85 per cent of patients, whereas colostomy is, by its design, incapable of restoring continence. However, dynamic graciloplasty is associated with a significant risk of reoperation. Conclusion While dynamic graciloplasty appears to be associated with a higher rate of complications than colostomy, it is clearly a superior intervention for restoring continence in some patients. It is recommended that a comparative, but non-randomized, study be undertaken to evaluate the safety of dynamic graciloplasty in comparison to colostomy, and that the procedure should be performed only in centres where it is carried out routinely.

Background An important factor that may influence an individual's performance is self-efficacy, a personal judgement of capability to perform a particular task successfully. This prospective study explored newly qualified surgeons' and surgical trainees' self-efficacy in non-technical skills compared with their non-technical skills performance in simulated scenarios. Methods Participants undertook surgical scenarios challenging non-technical skills in two simulation sessions 6 weeks apart. Some participants attended a non-technical skills workshop between sessions. Participants completed pretraining and post-training surveys about their perceived self-efficacy in non-technical skills, which were analysed and compared with their performance in surgical scenarios in two simulation sessions. Change in performance between sessions was compared with any change in participants' perceived self-efficacy. Results There were 40 participants in all, 17 of whom attended the non-technical skills workshop. There was no significant difference in participants' self-efficacy regarding non-technical skills from the pretraining to the post-training survey. However, there was a tendency for participants with the highest reported self-efficacy to adjust their score downwards after training and for participants with the lowest self-efficacy to adjust their score upwards. Although there was significant improvement in non-technical skills performance from the first to second simulation sessions, a correlation between participants' self-efficacy and performance in scenarios in any of the comparisons was not found. Conclusion The results suggest that new surgeons and surgical trainees have poor insight into their non-technical skills. Although it was not possible to correlate participants' self-belief in their abilities directly with their performance in a simulation, in general they became more critical in appraisal of their abilities as a result of the intervention.

In colorectal cancer (CRC), a proportion of patients with early stage disease still die of metastatic or recurrent disease within 5 years of "curative" resection. Detection of carcinoma cells in the peripheral circulation at presentation may identify a subgroup of patients with micro-metastatic disease who may benefit from adjuvant chemotherapy or radiotherapy. Our aim was to determine the presence and clinical significance of colon carcinoma cells in peripheral blood at the time of surgery. Preoperative peripheral blood samples were collected from 94 patients with CRC and 64 patients undergoing bowel resection for benign conditions (adenoma, diverticular disease or Crohn's colitis). Blood was also obtained from 20 normal donors not undergoing bowel surgery. Immunomagnetic beads were used to isolate epithelial cells followed by reverse transcription-polymerase chain reaction (RT-PCR) analysis of expression of cytokeratin (CK) 19, CK 20, mucin (MUC) 1 and MUC 2. Nineteen of 94 (20%) CRC patients were positive for epithelial cells in preoperative blood, including 6 with early stage disease. Kaplan-Meier survival analysis showed that detection of epithelial cells in preoperative blood was associated with reduced disease-free and overall survival (log-rank test, p = 0.0001). Surprisingly, circulating epithelial cells were detected in 3/30 (10%) patients resected for adenoma, and in 4/34 (12%) patients resected for benign inflammatory conditions, suggesting that cells from nonmalignant colonic epithelium may also gain entry into the bloodstream in the presence of bowel pathology. All 20 normal control bloods were negative for epithelial cells.

Neostigmine is an acetylcholinesterase inhibitor that is increasingly used as a medical treatment in cases of pseudo-obstruction. It has a well-recognized side-effect profile that includes bradycardia and bronchospasm. We present a case of colonic perforation after administration of neostigmine in the treatment of pseudo-obstruction.

Importance Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. Objective To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. Design, Setting, and Participants Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. Interventions Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). Main Outcomes and Measures The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = −8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. Results A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of −7.0% [95% CI, −12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of −3.7% [95% CI, −7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of −0.4% [95% CI, −1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of −5.4% [95% CI, −10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. Conclusions and Relevance Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. Trial Registration anzctr.org Identifier:ACTRN12609000663257

Background Laparoscopic resection of intra-abdominal malignancies has yet to be widely adopted, partly because of concerns over the possible increase in the rate of port-site metastasis. The aetiology of these is unclear, but the laparoscopic instrumentation used may influence the deposition of tumour cells at the port sites during operation. An in vitro model to examine tumour cell adherence to laparoscopic ports and to port sites was developed to examine this hypothesis. Methods A pilot study (study 1) was performed in which six smooth plastic, six ribbed plastic and six metal ports were introduced through the shaved abdominal wall of a cadaveric sheep and suspended in a water-bath containing radiolabelled LIM 1215 human colonic cancer cells for 30 min. Radioactivity on both ports and port sites was measured and the number of cells adherent to each structure was calculated. The study was expanded to include a further 36 smooth plastic ports and 36 metal ports (study 2). Results In study 1 metal ports were found to have significantly more adherent cells than plastic ports (P = 0·004), as did ribbed ports when compared with smooth ports (P < 0·05). In study 2 increased numbers of cells were again detected on metal ports (P < 0·001) when compared with plastic ports. Significantly greater numbers of cells were also detected on the sites through which metal ports had passed than on sites through which plastic ports had passed (P = 0·03). Conclusion In this model, the use of metal ports as opposed to plastic ports resulted in increased deposition of tumour cells on both ports and port sites.

Background Port-site metastases after laparoscopic surgery may occur with greater frequency than would be expected following open resection of intra-abdominal malignancies, but the causal mechanism for this is incompletely understood. The possibility that insufflation may increase peritoneal blood flow producing a wound environment conducive to the formation of metastases was investigated. Methods The effects of insufflation gas type and pressure were studied in 30-kg female pigs. Pigs were divided into five groups, which were subjected to insufflation at 12 mmHg pressure with helium, insufflation at 12, 8 or 4 mmHg pressure with carbon dioxide, or laparotomy. A microsphere technique utilizing two distinct radiotracers, 99mTc-labelled macroaggregated albumin (MAA) and 51Cr-labelled MAA, was used to study blood flow to the peritoneum, liver and kidneys. Results Insufflation with carbon dioxide or helium gases had no effect on renal (P < 0·09) or hepatic blood flow (P = 0·54). However, insufflation significantly increased peritoneal blood flow when carbon dioxide (P < 0·05), but not when helium (P = 0·99), was used as the insufflating gas. Conclusion These data suggest that blood flow within the peritoneum is influenced by insufflation with carbon dioxide. It is conceivable that such hyperaemia could increase the propensity for implanted tumour cells to metastasize in these sites following laparoscopy.

Expression of Fas, an apoptosis-inducing receptor, in colonic epithelium is progressively reduced during malignant transformation. We have examined the human Fas gene for loss of heterozygosity (LOH) and gross rearrangements in colon tumours and matched normal mucosa. Polymerase chain reaction (PCR) primers were designed to span a DraI restriction fragment length polymorphic site in the gene. Heterozygosity was detected in normal DNA samples by PCR amplification of the polymorphic site and restriction enzyme digestion. Thirty-eight of 88 patients (43%) with colon carcinomas were informative for the assay, and LOH was detected in 6 of the 38 (16%) corresponding tumours. Tumours from three patients with LOH did not express detectable Fas mRNA, and Fas expression was reduced or absent in 7 of 11 tumours from informative patients without LOH. Southern blotting of tumour DNA samples was used to detect rearrangement of the Fas gene, but no altered hybridization patterns were observed in 64 tumours analysed. These findings indicate that disruption of the Fas gene is not primarily responsible for the loss of Fas protein expression reported in colon cancer. We have also shown that loss of Fas gene transcription is common in these tumours, which may be due to epigenetic gene silencing. Images Figure 1 Figure 2 Figure 3 Figure 4

AIM: To compare the results from computed tomography (CT) colonography with conventional colonoscopy in symptomatic patients referred for colonoscopy. METHODS: The study included 227 adult outpatients, mean age 60 years, with appropriate indications for colonoscopy. CT colonography and colonoscopy were performed on the same day in a metropolitan teaching hospital. Colonoscopists were initially blinded to the results of CT colonography but there was segmental unblinding during the procedure. The primary outcome measures were the sensitivity and specificity of CT colonography for the identification of polyps seen at colonoscopy (i.e. analysis by polyp). Secondary outcome measures included an analysis by patient, extracolonic findings at CT colonography, adverse events with both procedures and patient acceptance and preference. RESULTS: Twenty-five patients (11%) were excluded from the analysis because of incomplete colonoscopy or poor bowel preparation that affected either CT colonography, colonoscopy or both procedures. Polyps and masses (usually cancers) were detected at colonoscopy and CT colonography in 35% and 42% of patients, respectively. Of nine patients with a final diagnosis of cancer, eight (89%) were identified by CT colonography as masses (5) or polyps (3). For polyps analyzed according to polyp, the overall sensitivity of CT colonography was 50% (95% CI, 39%-61%) but this increased to 71% (95% CI, 52%-85%) for polyps ≥ 6 mm in size. Similarly, specificity for all polyps was 48% (95% CI, 39%-58%) increasing to 67% (95% CI, 56%-76%) for polyps ≥ 6 mm. Adverse events were uncommon but included one colonic perforation at colonoscopy. Patient acceptance was high for both procedures but preference favoured CT colonography. CONCLUSION: Although CT colonography was more sensitive in this study than in some previous studies, the procedure is not yet sensitive enough for widespread application in symptomatic patients.

We have used commercially available cDNA arrays to identify EphB4 as a gene that is up-regulated in colon cancer tissue when compared with matched normal tissue from the same patient. Quantitative RT-PCR analysis of the expression of the EphB4 gene has shown that its expression is increased in 82% of tumour samples when compared with the matched normal tissue from the same patient. Using immunohistochemistry and Western analysis techniques with an EphB4-specific antibody, we also show that this receptor is expressed in the epithelial cells of the tumour tissue and either not at all, or in only low levels, in the normal tissue. The results presented here supports the emerging idea that Eph receptors play a role in tumour formation and suggests that further elucidation of this signalling pathway may identify useful targets for cancer treatment therapies.