The European Organization for Research and Treatment for Cancer (EORTC) strategy for quality assurance in surgical clinical research: Assessment of the past and moving towards the future.

AIMS: Quality assurance (QA) in a surgical trial must be planned and implemented from study development to completion. Elements of quality must be consistently described in a protocols, case report forms (CRFs) and reported in publications. The purpose of this review was to evaluate the most common surgical parameters and how consistently they were described in EORTC study documents where surgery was included. This was the preliminary step in mapping out the challenges of developing a surgical QA strategy in EORTC. METHODS: A systematic review of EORTC surgical protocols from 1980 to 2013 was performed. Two independent reviewers selected and reviewed the protocols. Data extraction was done using a questionnaire developed by EORTC QA committee. The results were compared across the time period. RESULTS: The most common quality parameters described in protocols were surgical technique, definition of resectability, surgical margins and methods of assessing adverse events using the Common Terminology Criteria for Adverse Event (CTCAE). However, these were not consistently reported in publications. A general improvement in the method of protocol development was observed since year 2000 after standardization measures by EORTC. A new surgical chapter template has been proposed. CONCLUSION: There is a need to consistently define and report surgical parameters from protocol development to publication as a first step to QA. A standard surgical chapter in the EORTC protocol template can help address this need. A framework to consistently implement QA for future surgical trials is needed and the rationale for this is described in this review.

Real-time in vivo assessment of radiofrequency ablation of human colorectal liver metastases using diffuse reflectance spectroscopy.

BACKGROUND: The success of radiofrequency (RF) ablation is limited by the inability to assess thermal tissue damage achieved during or immediately after the procedure. The goal of this proof-of-principle study was to investigate whether diffuse reflectance (DR) spectroscopy during and after RF ablation of liver tumours could aid in detecting complete tissue ablation. MATERIAL AND METHODS: DR spectra were acquired in vivo in eight patients undergoing RF ablation for unresectable colorectal liver metastases, using a disposable spectroscopy needle. Intraoperative ultrasound imaging was used for accurate positioning of the RF electrode and the spectroscopy needle. Spectral changes were quantified and correlated to tissue histopathology and follow-up CT imaging. RESULTS: For the lesions in which ablation was monitored by DR spectroscopy (N = 8), median tumour size was 1.6 cm (range 0.8-3.3 cm). We found an excellent correlation (97-99%) between thermal damage suggested by spectral changes and histology. DR spectroscopy allowed discrimination between non-ablated and ablated tissue, regardless whether the needle was placed in tumour tissue or in surrounding liver tissue. Additional measurements performed continuously during ablation confirmed that the magnitude of spectral change correlates with the histochemical degree of thermal damage. CONCLUSIONS: Diffuse reflectance spectroscopy allows accurate quantification of thermal tissue damage during and after RF ablation. Real-time feedback by DR spectroscopy could improve the accuracy and quality of the RF procedures by lowering incomplete ablation rates.

Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983.

AIM: The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies. BACKGROUND: Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM. METHODS: The CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ≤4 cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55). RESULTS: Local recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30 mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease. CONCLUSIONS: LR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.

Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer.

INTRODUCTION: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval. METHOD: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival. RESULTS: In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10 years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p ≤ 0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001). CONCLUSION: This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease.

A comparison of short-term outcome after laparoscopic, transverse, and midline right-sided colectomy.

AIM: The aim of the present study was to compare the laparoscopy, transverse, and midline laparotomy in right-sided colectomies with respect to short- and long-term outcome. METHODS: The short- and long-term results of all patients who had an elective right-sided hemicolectomy, from January 2006 to April 2009 for malignant or benign disease, were evaluated according to the surgical technique: laparoscopic, midline, or transverse incision laparotomy. RESULTS: The 75 included patients (41% male) had laparoscopy (n = 30), midline (n = 22), or transverse incision laparotomy (n = 23). Median operating time in the laparoscopy group was significantly longer in comparison to the midline and transverse incision groups (129, 105, and 101 min respectively, p < 0.001). Short-term follow-up revealed a longer median total length of stay in the midline laparotomy group compared to the other groups (9 vs. 7 days, p = 0.026). Thirty-day morbidity was less in the laparoscopy and transverse incision groups compared to the midline laparotomy group (15%, 20%, and 41%; p = 0.06). After excluding patients who had a previous midline incision, an earlier return of bowel function was seen for laparoscopy and transverse hemicolectomy (3 vs. 5 days, p = 0.017). At a median follow-up of 40 months (21-58), four incisional hernias occurred, two in the midline laparotomy group (one operatively corrected) and two in the laparoscopy group. CONCLUSIONS: Although the results of this study need to be interpreted with care, our study shows that laparoscopic and transverse right hemicolectomy are equivalent and have a significant better short-term outcome compared to an open midline approach. In particular, laparoscopy and transverse laparotomy result in >50% reduction in 30-day morbidity, no reoperations, and a shorter median total hospital stay of 2 days.

A new promoter-binding site in the PB1 subunit of the influenza A virus polymerase.

The influenza A virus RNA-dependent RNA polymerase consists of three subunits PB1, PB2 and PA. The 5' and 3' terminal sequences of the viral RNA (vRNA) form the viral promoter and are bound by the PB1 subunit. The putative promoter-binding sites of the PB1 subunit have been mapped in previous studies but with contradictory results. The aim of the current study was to investigate the function of two evolutionary conserved regions in PB1 - from aa 233 to 249 and 269 to 281, which lie immediately N- and C-terminal, respectively, of a previously proposed binding site for the 3' end of the vRNA promoter. The previously proposed binding site extended from aa 249 to 256 and centred on two phenylalanine residues (F251 and F254). However, the fact that F251 is required for polymerase activity was not confirmed here. Instead, it was proposed that the 233-249 region contains a new 5' vRNA promoter-binding site, and arginine residues crucial for this activity were characterized. However, residues 269-281 were unlikely to be directly involved in promoter binding. These results are discussed in relation to the previous studies and a new model for vRNA promoter binding to the influenza RNA polymerase is presented.

Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates.

The RNA-dependent RNA polymerase of influenza A virus is responsible for both transcription and replication of negative-sense viral RNA. It is thought that a "switching" mechanism regulates the transition between these activities. We demonstrate that, in the presence of preexisting viral RNA polymerase and nucleoprotein (NP), influenza A virus synthesizes both mRNA (transcription) and cRNA (replication) early in infection. We suggest that there may be no switch regulating the initiation of RNA synthesis and present a model suggesting that nascent cRNA is degraded by host cell nucleases unless it is stabilized by newly synthesized viral RNA polymerase and NP.

Pulmonary release and coronary and peripheral consumption of big endothelin and endothelin-1 in severe heart failure: acute effects of vasodilator therapy.

BACKGROUND: We investigated plasma endothelin (ET) levels in patients with congestive heart failure (CHF) during treatment for acute decompensation; we also measured imbalances in ET peptides across the pulmonary, coronary, and peripheral circulation. Methods and Results-In patients with severe CHF (n=21; cardiac index [CI], 1.9+/-0.2 L. min(-1). m(-2); pulmonary capillary wedge pressure [PCWP], 31+/-1 mm Hg), vasodilation was achieved with the nitric oxide donor sodium nitroprusside (n=11) or with the alpha(1)-antagonist urapidil (nitric oxide-independent, n=10). ET concentrations were determined from arterial blood and blood from the pulmonary artery, coronary sinus, and antecubital vein. Depending on sites of measurement, baseline big ET and ET-1 levels were, respectively, 12 to 16 times and 5 to 11 times higher than in controls (n=11), and 4 to 6 times and 2 to 3 times higher than in patients with moderate CHF (n=10; CI, 2.7+/-0.3 L. min(-1). m(-2); PCWP, 14+/-2 mm Hg). Patients with severe CHF demonstrated pulmonary net release and coronary and peripheral net consumption of both peptides (ie, arterial levels [big ET, 7.3+/-1.3 pmol/L; ET-1, 1.8+/-0.1 pmol/L] were higher than levels in the pulmonary artery [6.7+/-1.2 pmol/L; 1. 3+/-0.1 pmol/L], coronary sinus [6.4+/-1.0 pmol/L; 1.4+/-0.1 pmol/L], and antecubital vein [6.6+/-1.1 pmol/L; 1.3+/-0.1 pmol/L]). In these patients, sodium nitroprusside (SNP) and urapidil resulted in comparable hemodynamic improvement after 6 hours (CI: SNP, 63+/-2%; urapidil, 72+/-3%; PCWP: SNP, -50+/-2%; urapidil, -47+/-2%) and a maximum decrease in ET peptides by >50%. After 3 hours, pulmonary net release and coronary and peripheral net consumption were no longer detectable. CONCLUSIONS: In patients with severe CHF, the lungs act as a producer and the heart and the periphery act as consumers of elevated circulating ETs. Short-term vasodilator therapy decreases ETs and restores their pulmonary, coronary, and peripheral balance.