Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Consensus and controversies regarding follow-up after treatment with curative intent of nonmetastatic colorectal cancer: a synopsis of guidelines used in countries represented in the European Society of Coloproctology.

AIM: It is common clinical practice to follow patients for a period of years after treatment with curative intent of nonmetastatic colorectal cancer, but follow-up strategies vary widely. The aim of this systematic review was to provide an overview of recommendations on this topic in guidelines from member countries of the European Society of Coloproctology, with supporting evidence. METHOD: A systematic search of Medline, Embase and the guideline databases Trip database, BMJ Best Practice and Guidelines International Network was performed. Quality assessment included use of the AGREE-II tool. All topics with recommendations from included guidelines were identified and categorized. For each subtopic, a conclusion was made followed by the degree of consensus and the highest level of evidence. RESULTS: Twenty-one guidelines were included. The majority recommended that structured follow-up should be offered, except for patients in whom treatment of recurrence would be inappropriate. It was generally agreed that clinical visits, measurement of carcinoembryoinc antigen and liver imaging should be part of follow-up, based on a high level of evidence, although the frequency is controversial. There was also consensus on imaging of the chest and pelvis in rectal cancer, as well as endoscopy, based on lower levels of evidence and with a level of intensity that was contradictory. CONCLUSION: In available guidelines, multimodal follow-up after treatment with curative intent of colorectal cancer is widely recommended, but the exact content and intensity are highly controversial. International agreement on the optimal follow-up schedule is unlikely to be achieved on current evidence, and further research should refocus on individualized 'patient-driven' follow-up and new biomarkers.

Serum carcinoembryonic antigen trends for diagnosing colorectal cancer recurrence in the FACS randomized clinical trial.

BACKGROUND: Most guidelines recommend that patients who have undergone curative resection for primary colorectal cancer are followed up for 5 years with regular blood carcinoembryonic antigen (CEA) tests to trigger further investigation for recurrence. However, CEA may miss recurrences, or patients may have false alarms and undergo unnecessary investigation. METHODS: The diagnostic accuracy of trends in CEA measurements for recurrent colorectal cancer, taken as part of the FACS (Follow-up After Colorectal Surgery) trial (2003-2014), were analysed. Investigation to detect recurrence was triggered by clinical symptoms, scheduled CT or colonoscopy, or a CEA level of at least 7 µg/l above baseline. Time-dependent receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic accuracy of CEA trends with single measurements. CEA trends were estimated using linear regression. RESULTS: The area under the ROC curve (AUC) for CEA trend was at least 0·820 across all 5 years of follow-up. In comparison, the AUCs for single measurements ranged from 0·623 to 0·749. Improvement was most marked at the end of the first year of follow-up, with the AUC increasing from 0·623 (95 per cent c.i. 0·509 to 0·736) to 0·880 (0·814 to 0·947). However, no individual trend threshold achieved a sensitivity above 70 per cent (30 per cent missed recurrences). CONCLUSION: Interpreting trends in CEA measurements instead of single CEA test results improves diagnostic accuracy for recurrence, but not sufficiently to warrant it being used as a single surveillance strategy to trigger further investigation. In the absence of a more accurate biomarker, monitoring trends in CEA should be combined with clinical, endoscopic and imaging surveillance for improved accuracy.

A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer.

In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation.

Translational aspects in targeting the stromal tumour microenvironment: from bench to bedside.

Solid tumours comprise, not only malignant cells but also a variety of stromal cells and extracellular matrix proteins. These components interact via an array of signalling pathways to create an adaptable network that may act to promote or suppress cancer progression. To date, the majority of anti-tumour chemotherapeutic agents have principally sought to target the cancer cell. Consequently, resistance develops because of clonal evolution, as a result of selection pressure during tumour expansion. The concept of activating or inhibiting other cell types within the tumour microenvironment is relatively novel and has the advantage of targeting cells which are genetically stable and less likely to develop resistance. This review outlines key players in the stromal tumour microenvironment and discusses potential targeting strategies that may offer therapeutic benefit.

Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers. METHODS: Relevant articles were identified via Ovid medline 1946-2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis. RESULTS: A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15-3.79), CD3 (HR=0.51, 95% CI=0.32-0.70), CD8 (HR=0.55, CI=0.31-0.80) and EGFR (HR=1.65, 95% CI=1.14-2.16). DISCUSSION: Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good-quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers.

FOXO3 expression during colorectal cancer progression: biomarker potential reflects a tumour suppressor role.

BACKGROUND: In previous studies, the Forkhead/winged-helix-box-class-O3 (FOXO3) transcription factor has displayed both tumour suppressive and metastasis-promoting properties.To clarify its role in human colorectal cancer (CRC) progression, we examined in vivo FOXO3 expression at key points of the metastatic cascade. METHODS: Formalin-fixed paraffin-embedded resection specimens from normal colon, adenomas, primary CRC specimens of different pathological stage and CRC specimens with matched liver metastases were used to generate three separate custom-designed tissue microarray (TMA) representations of metastatic progression. Triplicate cores, immunostained for FOXO3 were scored semiquantitatively by two investigators. RESULTS: The FOXO3 expression is significantly reduced in CRC specimens compared with normal tissue, and progressive FOXO3 downregulation is associated with advancing pathological stage. In addition, recurrent stage I/II primary tumours show a significantly lower FOXO3 expression compared with stage-matched non-recurrent tumours. When stratified according to high and low FOXO3 expression, mean disease-free survival in the low-expressing group was 28 months (95% CI 15.8-50.6) compared with 64 months (95% CI 52.9-75.4) in the high-expressing group. CONCLUSION: We have demonstrated an association between low FOXO3 expression and CRC progression in vivo using purpose-designed TMAs. Forkhead/winged-helix-box-class-O3 may represent a novel biomarker of nodal and distant disease spread with clinical utility in CRC.

Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression.

The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated α-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer.

The adaptive immune response to colorectal cancer: from the laboratory to clinical practice.

INTRODUCTION: Analysis of the adaptive immune system in the microenvironment of colorectal cancer is suggested to offer new insights into tumour biology and prognostic information independent of TNM staging. We aimed to review recent findings to investigate the potential for clinical use. METHODS: Relevant papers were identified through online searches regarding tumour infiltrating lymphocytes (TIL) in colorectal cancer. Identified papers were studied, focusing on clinically applicable uses for TIL data in the management of colorectal cancer. FINDINGS: The majority of identified studies were retrospective and observational in nature. The widest TIL investigation was in post resection prognosis but TIL subtypes, counts and methodology showed variability between studies. Recent reports explored TIL in predicting response to adjuvant and neoadjuvant treatments. CONCLUSION: An increasing body of evidence supports that visibility of colorectal cancer to immune attack is substantial and that it limits disease progression. Analysis of the adaptive immune infiltrate in resected colorectal cancer specimens offers prognostic information which is independent of conventionally measured parameters and potentially superior in predictive value.

Symptoms and signs in patients with colorectal cancer.

The symptoms and signs of colorectal cancer vary from the general population to primary care and in the referred population to secondary care. This review aims to address the diverse symptoms, signs and combinations with relevance to colorectal cancer at various points in the diagnostic pathway and tries to shed light on this complex and confusing area. A move towards a lower threshold for referral and increased use of diagnostics might be a more reliable option for early diagnosis.

Surgery for colorectal liver metastases.

In this review the surgery of colorectal liver metastases is discussed. It has long been known that liver surgery can cure metastatic colorectal cancer although in only a small proportion of the population with the disease. However with better understanding of the natural history of the condition and advances in technique more patients can have safe, potentially curative surgery. The multidiscipline management of patients with effective chemotherapy has led to more patients benefiting from surgery after reducing the size of the metastases and allowing operation on patients who were previously inoperable. Chemotherapy also improves at least the medium-term outcome in those who are operable at the outset. Minimally invasive techniques have been developed so that major hepatectomy may be accomplished in up to half of such cases with a very short hospital stay and limited interference with quality of life. Lastly, using portal vein embolisation to cause hypertrophy of the future liver remnant and on occasions combining it with staged liver resection allows potentially curative surgery on patients who previously could not have survived resection. These developments have led to more patients being cured of advanced colorectal cancer.

Hepatic splenosis mimicking HCC in a patient with hepatitis C liver cirrhosis and mildly raised alpha feto protein; the important role of explorative laparoscopy.

BACKGROUND: Splenosis is a heterotropic implantation of splenic fragments onto exposed vascularised peritoneal and intrathoracic surfaces, following splenic injury or elective splenectomy. CASE PRESENTATION: A 60 year old cirrhotic patient was referred to us with a hepatic mass, suspected to be HCC in a cirrhotic liver. A computerized tomography scan (CT) demonstrated a cirrhotic liver with a 2 x 2.7 cm focal hypervascular nodule, lying peripherally at the junction of segment 7 and 8. Diagnostic laparoscopy demonstrated a 3 cm exofitic dark brown splenunculus attached to the diaphragm and indenting the surface of segment 7 of the liver. The lesion was easily resected laparoscopically and shaved from the live surface with no need for a liver resection. The histopathological assessment confirmed the diagnosis of splenunculus, with no evidence of neoplasia. CONCLUSION: Hepatic splenosis is not a rare event and should be suspected in patients with a history of splenic trauma or splenectomy. Correct diagnosis is essential and will determine subsequent management plans. In doubtful cases laparoscopic investigation can offere essential information and should be part of the standard protocol for investigating suspected splenosis.

MicroRNAs: key players in carcinogenesis and novel therapeutic targets.

MicroRNAs (miRNAs) represent a recently uncovered class of small and endogenous non-coding RNAs. MiRNA function is critical to normal cellular processes such as differentiation and apoptosis, and recent studies have demonstrated that deregulated miRNA expression contributes to the malignant phenotype. The purpose of this review is to summarise these findings in relation to the most common human malignancies, and to analyse the clinical and therapeutic opportunities they provide.

Surgical resection versus radiofrequency ablation in the treatment of small unifocal hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high worldwide prevalence and mortality. While surgical resection and transplantation offers curative potential, donor availability and patient liver status and comorbidities may disallow either. Interventional radiological techniques such as radiofrequency ablation (RFA) may offer acceptable overall and disease-free survival rates. MATERIALS AND METHODS: Sixty-eight cirrhotic patients matched for age, sex, tumor size, and Child-Pugh grade with small (1-5 cm) unifocal HCC were studied retrospectively to find determinants of overall and disease-free survival in those treated with surgical resection and RFA between 1991 and 2003. RESULTS: Multivariate analysis using Cox proportional regression modeling showed that overall survival was related to tumor recurrence (p = 0.010), tumor diameter (p = 0.002), and treatment modality (p = 0.014); overall p = 0.008. Recurrence was independently related to the use of RFA over surgery (p = 0.023) on multivariate analysis; overall p = 0.034. CONCLUSION: Surgical resection offers longer disease-free survival and potentially longer overall survival than RFA in patients with small unifocal HCC.

Laparoscopic versus open left lateral hepatic sectionectomy: A comparative study.

BACKGROUND: Laparoscopic liver surgery has been difficult to popularize. High volume liver centres have identified left lateral sectionectomy (LLS) as a procedure with potential for transformation into a primarily laparoscopic procedure where surgeons can safely gain proficiency. METHODS: Forty-four patients underwent either laparoscopic (LLLS) or open (OLLS) left lateral sectionectomy (of segments II/III) for focal lesions at Southampton General Hospital. RESULTS: OLLS and LLLS groups were matched for age, sex and tumour types resected. Median operative time in the LLLS group was 180 (40-340) min and 155 (110-330) min in the OLLS group (p=0.885) with median intra-operative blood loss in the LLLS group 80 (25-800) ml versus a larger 470 (100-3000) ml; p=0.002 for patients receiving OLLS. Post-operative stay was also shorter in the LLLS group (3.5 (1-6) days) compared to the OLLS group (7 (3-12) days; p<0.001). Resection margin was not different in the two groups (11 (1.5-30) mm (LLLS) versus 12 (4-40) mm (OLLS); p=1) and neither was the complication rate (13% for LLLS versus 25% for OLLS; p=0.541). There were no conversions to open in the LLLS group and no deaths in either group at 90 days. Between the first and second 12 LLLS the median operative time fell from 240 (70-340) min to 120 (40-120) min; p=0.005 as well as median post-operative hospital stay from 4.5 (2-6) days to 2 (1-4) days, p=0.001. CONCLUSION: LLLS is a viable alternative to OLLS with potential improvements in intra-operative blood loss and shorter hospital stay without adversely affecting successful resection or complication rates. Larger prospective studies are required to explore this new avenue in laparoscopic liver surgery.

Validation of the lower gastrointestinal electronic referral protocol.

BACKGROUND: Recognition of people presenting to the general practitioner with symptoms suggestive of colorectal cancer varies considerably, as do the subsequent patterns of referral and treatment. The Lower Gastrointestinal Electronic Referral Protocol (e-RP) was developed to be used alongside the national Choose and Book programme. This paper addresses the validation of the e-RP. METHODS: The e-RP was validated using three datasets: 100 consecutive patients with colorectal cancer, 100 2-week wait (TWW) suspected cancer referrals and 100 routine referrals. The actual destination of referred patients, their clinical diagnosis and referral urgency were compared with destination and referral urgency assigned by the e-RP. RESULTS: Some 43.0 per cent of patients with colorectal cancer were actually referred through the TWW system and the e-RP successfully upgraded 85.0 per cent of these patients as TWW referrals (Pearson chi(2) = 9.76, 1 d.f., P = 0.002). The e-RP also redirected three of four patients with colorectal cancer in routine referrals to TWW clinics. Right-sided cancers were appropriately directed to colonoscopy as the first contact in secondary care or to outpatients for investigation of a palpable mass. Most patients with left-sided cancers were directed to flexible sigmoidoscopy clinics. CONCLUSION: A dedicated referral protocol addressing all colorectal symptoms would significantly improve the overall yield of colorectal cancers through the TWW route and reduce delays in patient pathways with 'straight to test' in secondary care.