Cord Langner

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program.

Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30–40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4‐bis‐[2‐(3,5‐dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone‐16α‐carbonitrile. Hepatic bile acid and bilirubin‐metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2‐4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse‐transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2‐4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid–hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid–sulfating Sult2a1 and bilirubin‐glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. (HEPATOLOGY 2005.)

Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

UNLABELLED This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence. MAIN RECOMMENDATIONS 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barretts esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).

Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy: A Multi-Institutional Analysis of 1249 Cases

BACKGROUND Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. OBJECTIVE We compared recurrence and cause-specific mortality rates of ONU and LNU. DESIGN, SETTING, AND PARTICIPANTS Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). MEASUREMENTS Univariable and multivariable survival models tested the effect of procedure type (ONU [n=979] vs LNU [n=270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment. RESULTS AND LIMITATIONS Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p<0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p<0.001] and 2.0 [p=0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p=0.1 for both). CONCLUSIONS Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

Impact of Lymph Node Dissection on Cancer Specific Survival in Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy

PURPOSE We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy. MATERIALS AND METHODS Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival. RESULTS Overall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only. CONCLUSIONS Nodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy

BACKGROUND There is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC). OBJECTIVE To investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS A retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC. INTERVENTION The 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007. MEASUREMENTS Data accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor. RESULTS AND LIMITATIONS The 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p<0.001), grade (p<0.02), and lymph node status (p<0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p=0.133) or cancer death (HR: 1.23; p=0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design. CONCLUSIONS There is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors.

Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders

aDepartment of Pharmacology and Therapeutics, University of Porto; MedInUP, Centre for Drug Discovery and Innovative Medicines; Centro Hospitalar São João, Porto, Portugal bIBD Unit, DIMEC, University of Bologna, Bologna, Italy cDepartment of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel dGastrointestinal Unit ASST Fatebenefratelli Sacco—University of Milan—Milan, Italy eIBD Unit Complesso Integrato Columbus, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli Universita’ Cattolica del Sacro Cuore, Rome, Italy fDepartment of Gastroenterology, IBD Unit, University Hospital Santiago De Compostela (CHUS), A Coruña, Spain gDepartment of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark hFirst Department of Medicine, Semmelweis University, Budapest, Hungary iIBD Unit, St Mark’s Hospital, Middlesex, UK jDepartment of Gastroenterology, University Hospital of Ghent, Ghent, Belgium kInstitute of Pathology, Medical University of Graz, Graz, Austria lDepartment of Gastroenterology, Pennine Acute Hospitals NHS Trust; Institute of Inflammation and Repair, University of Manchester, Manchester, UK mUnit of General Surgery, Second University of Naples, Napoli, Italy nMaria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Oncological Gastroenterology Warsaw; Medical Centre for Postgraduate Education, Department of Gastroenterology, Hepatology and Clinical Oncology, Warsaw, Poland oDepartment of Medicine, University of Cambridge, Cambridge, UK pImperial College London; Chelsea and Westminster Hospital, London, UK qDepartment of Pathobiology /NC22, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition/A3, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed?

BACKGROUND The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. OBJECTIVE To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. INTERVENTION Patients were treated with RNU and lymphadenectomy. MEASUREMENTS Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. RESULTS AND LIMITATIONS In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001). CONCLUSIONS The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Predicting Clinical Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

BACKGROUND Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. OBJECTIVE We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. DESIGN, SETTING, AND PARTICIPANTS Our study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971). INTERVENTIONS All patients underwent RNU. MEASUREMENTS Univariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping. RESULTS AND LIMITATIONS At a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. CONCLUSIONS Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

Tumour Necrosis Is an Indicator of Aggressive Biology in Patients with Urothelial Carcinoma of the Upper Urinary Tract

BACKGROUND Prognostic factors after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) are inconclusive, because most data in the literature have been obtained from small series. OBJECTIVE To assess the association of tumour necrosis with cancer recurrence and survival in a large international series of patients treated with RNU. DESIGN, SETTING, AND PARTICIPANTS Data were collected from 1425 patients treated with RNU at 13 centres and combined into a relational database. Pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria. Extensive tumour necrosis was scored as >10% of the tumour area. INTERVENTION Patients underwent either open or laparoscopic RNU. Lymph node dissection was performed in the presence of enlarged nodes. MEASUREMENTS Recurrence was defined as tumour relapse in the operative field, lymph node (LN) metastasis, and/or distant metastases. Bladder recurrences were not considered. Associations of extensive tumour necrosis with recurrence-free survival and cancer-specific survival were evaluated by univariate and multivariate analyses. RESULTS AND LIMITATIONS Extensive tumour necrosis was observed in 364 patients (25.5%) and was associated with advanced tumour stage, high tumour grade, sessile architecture, lymphovascular invasion (LVI), concomitant carcinoma in situ, and LN metastasis (p<0.0001 each). Extensive tumour necrosis was independently associated with disease recurrence and survival (p=0.037 and p=0.046, respectively) after adjusting for the effects of pathologic stage, grade, LVI, and LN status. The addition of extensive tumour necrosis to a base model comprising standard pathologic predictors marginally improved its predictive accuracy for both cancer-specific recurrence (1.5%) and survival (1.4%). CONCLUSIONS Extensive tumour necrosis is an independent predictor of clinical outcomes in patients who undergo RNU for UTUC. Assessment of tumour necrosis may help to identify patients who could benefit from multimodal therapy after RNU in the future. Evaluation of extensive tumour necrosis should be part of standard pathologic reporting.