M.P. van den Tol

A comparison of three methods for nonpalpable breast cancer excision

AIMS To evaluate the efficacy of three methods of breast-conserving surgery (BCS) for nonpalpable invasive breast cancer in obtaining adequate resection margins and volumes of resection. MATERIALS AND METHODS A total of 201 consecutive patients undergoing BCS for nonpalpable invasive breast cancer between January 2006 and 2009 in four affiliated institutions was retrospectively analysed. Patients with pre-operatively diagnosed primary or associated ductal carcinoma in situ (DCIS), multifocal disease, or a history of breast surgery or neo-adjuvant treatment were excluded from the study. The resections were guided by wire localisation (WL), ultrasound (US), or radio-guided occult lesion localisation (ROLL). The pathology reports were reviewed to determine oncological margin status, as well as tumour and surgical specimen sizes. The optimal resection volume (ORV), defined as the spherical tumour volume with an added 1.0-cm margin, and the total resection volume (TRV), defined as the corresponding ellipsoid, were calculated. By dividing the TRV by the ORV, a calculated resection ratio (CRR) was determined to indicate the excess tissue resection. RESULTS Of all 201 excisions, 117 (58%) were guided by WL, 52 (26%) by US, and 32 (16%) by ROLL. The rate of focally positive and positive margins for invasive carcinoma was significantly lower in the US group (N = 2 (3.7%)) compared to the WL (N = 25 (21.3%)) and ROLL (N = 8 (25%)) groups (p = 0.023). The median CRRs were 3.2 (US), 2.8 (WL) and 3.8 (ROLL) (WL versus ROLL, p < 0.05), representing a median excess tissue resection of 3.1 times the optimal resection volume. CONCLUSION US-guided BCS for nonpalpable invasive breast cancer was more accurate than WL- and ROLL-guided surgery because it optimised the surgeons ability to obtain adequate margins. The excision volumes were large in all excision groups, especially in the ROLL group.

Anaesthetic management during open and percutaneous irreversible electroporation

BACKGROUND Irreversible electroporation (IRE) is a novel tumour ablation technique involving repetitive application of electrical energy around a tumour. The use of pulsed electrical gradients carries a risk of cardiac arrhythmias, severe muscle contractions, and seizures. We aimed to identify IRE-related risks and the appropriate precautions for anaesthetic management. METHODS All patients who were treated with IRE were prospectively included. Exclusion criteria were arrhythmias, congestive heart failure, active coronary artery disease, and epilepsy. All procedures were performed under general anaesthesia with complete muscle relaxation during ECG-synchronized pulsing. Adverse events, cardiovascular effects, blood samples, cerebral activity, and post-procedural pain were analysed. RESULTS Twenty-eight patients underwent 30 IRE sessions for tumours in the liver, pancreas, kidney, and lesser pelvis. No major adverse events occurred during IRE. Median systolic and diastolic blood pressure increased by 44 mm Hg (range -7 to 108 mm Hg) and 19 mm Hg (range 1-50 mm Hg), respectively. Two transient minor cardiac arrhythmias without haemodynamic consequences were observed. Muscle contractions were mild and IRE caused no reactive brain activity on a simplified EEG. Pain in the first 24 h after percutaneous IRE was generally mild, but higher pain scores were reported after pancreatic treatment (mean VAS score 3; range 0-9). CONCLUSIONS Side-effects during IRE on tumours in the liver, pancreas, kidney, and lesser pelvis seem mild and manageable when current recommendations for anaesthesia management, including deep muscle relaxation and ECG synchronized pulsing, are followed. Electrical pulses do not seem to cause reactive cerebral activity and evidence for pre-existing atrial fibrillation as an absolute contra-indication for IRE is questionable.

4-1BB-mediated expansion affords superior detection of in vivo primed effector memory CD8+ T cells from melanoma sentinel lymph nodes.

We have been studying the re-activation of tumor-associated antigen (TAA)-specific CD8(+) T cells in sentinel lymph nodes (SLN) of melanoma patients upon intradermal administration of the CpG-B oligodeoxynucleotide PF-3512676. To facilitate functional testing of T cells from small SLN samples, high-efficiency polyclonal T cell expansion is required. In this study, SLN cells were expanded via classic methodologies with plate- or bead-bound anti-CD3/CD28 antibodies and with the K562/CD32/4-1BBL artificial APC system (K32/4-1BBL aAPC) and analyzed for responsiveness to common recall or TAA-derived peptides. K32/4-1BBL-expanded T cell populations contained significantly more effector/memory CD8(+) T cells. Moreover, recall and melanoma antigen-specific CD8(+) T cells were more frequently detected in K32/4-1BBL-expanded samples as compared with anti-CD3/CD28-expanded samples. We conclude that K32/4-1BBL aAPC are superior to anti-CD3/CD28 antibodies for the expansion of in vivo-primed specific CD8(+) T cells and that their use facilitates the sensitive monitoring of functional anti-tumor T cell immunity in SLN.

Surgery-induced reactive oxygen species enhance colon carcinoma cell binding by disrupting the liver endothelial cell lining

Objective Resection of primary colorectal cancer is associated with enhanced risk of development of liver metastases. It was previously demonstrated that surgery initiated an early inflammatory response resulting in elevated tumour cell adhesion in the liver. Because reactive oxygen species (ROS) are shown to be produced and released during surgery, the effects of ROS on the liver vascular lining and tumour cell adhesion were investigated. Methods Human endothelial cell monolayers (human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells of the lung (HMEC-1s)) were exposed to ROS production, after which electrical impedance, cellular integrity and tumour cell adhesion were investigated. Furthermore, surgery-induced tumour cell adhesion as well as the role of ROS and liver macrophages (Kupffer cells) in this process were studied in vivo. Results Production of ROS decreased cellular impedance of endothelial monolayers dramatically. Moreover, formation of intercellular gaps in endothelial monolayers was observed, exposing subendothelial extracellular matrix (ECM) on which colon carcinoma cells adhered via integrin molecules. Endothelial damage was, however, prevented in the presence of ROS-scavenging enzymes. Additionally, surgery induced downregulation of both rat and human liver tight junction molecules. Treatment of rats with the ROS scavenger edaravone prevented surgery-induced tumour cell adhesion and downregulation of tight junction proteins in the liver. Interestingly, depletion of Kupffer cells prior to surgery significantly reduced the numbers of adhered tumour cells and prevented disruption of expression of tight junction proteins. Conclusions In this study it is shown that surgery-induced ROS production by macrophages damages the vascular lining by downregulating tight junction proteins. This leads to exposure of ECM, to which circulating tumour cells bind. In light of this, perioperative therapeutic intervention, preventing surgery-induced inflammatory reactions, may reduce the risk of developing liver metastases, thereby improving the clinical outcome of patients with colorectal cancer.

Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases.

Background:Resection of colorectal cancer liver metastasis (CRCLM) with curative intent has long-term benefit in ∼40% of cases. Prognostic biomarkers are needed to improve clinical management and reduce futile surgeries. Expression of epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2) has been associated with carcinogenesis and survival. We investigated the prognostic value of EGFR and PTGS2 expression in patients with resected CRCLM.Methods:Formalin-fixed paraffin-embedded CRCLM tissue and corresponding primary tumour specimens from a multi-institutional cohort of patients who underwent liver resection between 1990 and 2010 were incorporated into tissue microarrays (TMAs). TMAs were stained for EGFR and PTGS2 by immunohistochemistry. The hazard rate ratio (HRR) for the association between expression in CRCLM and overall survival was calculated using a 500-fold cross-validation procedure.Results:EGFR and PTGS2 expression could be evaluated in 323 and 351 patients, respectively. EGFR expression in CRCLM was associated with poor prognosis (HRR 1.54; P<0.01) with a cross-validated HRR of 1.47 (P=0.03). PTGS2 expression was also associated with poor prognosis (HRR 1.60; P<0.01) with a cross-validated HRR of 1.63 (P<0.01). Expression of EGFR and PTGS2 remained prognostic after multivariate analysis with standard clinicopathological variables (cross-validated HRR 1.51; P=0.02 and cross-validated HRR 1.59; P=0.01, respectively). Stratification for the commonly applied systemic therapy regimens demonstrated prognostic value for EGFR and PTGS2 only in the subgroup of patients who were not treated with systemic therapy (HRR 1.78; P<0.01 and HRR 1.64; P=0.04, respectively), with worst prognosis when both EGFR and PTGS2 were highly expressed (HRR 3.08; P<0.01). Expression of PTGS2 in CRCLM was correlated to expression in patient-matched primary tumours (P=0.02, 69.2% concordance).Conclusions:EGFR and PTGS2 expressions are prognostic molecular biomarkers with added value to standard clinicopathological variables for patients with resectable CRCLM.

Irreversible Electroporation in Hepatopancreaticobiliary Tumours

Hepatopancreaticobiliary tumours are often diagnosed at an advanced disease stage, in which encasement or invasion of local biliary or vascular structures has already occurred. Irreversible electroporation (IRE) is an image-guided tumour ablation technique that induces cell death by exposing the tumour to high-voltage electrical pulses. The cellular membrane is disrupted, while sparing the extracellular matrix of critical tubular structures. The preservation of tissue integrity makes IRE an attractive treatment option for tumours in the vicinity of vital structures such as splanchnic blood vessels and major bile ducts. This article reviews current data and discusses future trends of IRE for hepatopancreaticobiliary tumours.

Minimally invasive intraoperative estimation of left-ventricular end-systolic elastance with phenylephrine as loading intervention

BACKGROUND Left-ventricular end-systolic elastance (Ees) is an index of cardiac contractility, but the invasive nature of its assessment has limited perioperative application. We explored the feasibility of a minimally invasive method of Ees estimation for perioperative assessment of cardiac function and evaluated the suitability of phenylephrine as a loading intervention. METHODS In 17 surgical patients, Ees was determined as the slope of the end-systolic pressure-volume relation, which was obtained from non-invasive or invasive continuous arterial pressure measurements and left-ventricular volume determinations using transoesophageal echocardiography (TOE). Ees was determined using as loading interventions preload reduction by inferior vena cava compression (IVCC) and afterload increase by phenylephrine administration. RESULTS Median invasive Ees determined with phenylephrine estimated 1.05 (0.59-1.21) mm Hg ml(-1) and with IVCC 0.58 (0.31-1.13) mm Hg ml(-1). Bland-Altman analysis to evaluate the level of agreement between minimally invasive and invasive Ees estimation revealed a bias of -0.03 (0.12) mm Hg ml(-1) with limits of agreement from -0.27 to 0.21 mm Hg ml(-1) and the percentage error was 33%. Agreement between Ees obtained with phenylephrine and IVCC revealed a bias of 0.15 (0.69) mm Hg ml(-1) with limits of agreement from -1.21 to 1.51 mm Hg ml(-1) and a percentage error of 149%. CONCLUSIONS It is feasible to determine Ees combining continuous non-invasive arterial pressure measurements and left-ventricular volume determinations with TOE. However, administration of phenylephrine cannot substitute IVCC as a loading intervention, indicating that estimation of Ees in the intraoperative setting remains a challenge.

Response to “The CUBE Technique: Continuous Ultrasound-Guided Breast Excision,” Published in August 2014 by Tummel et al. Amsterdam, 28th January 2015

We read the article ‘‘The CUBE technique: continuous ultrasound-guided breast excision,’’ published in August 2014 by Tummel et al. We congratulate the authors on their study and the positive results concerning intraoperative ultrasonography for breast cancer surgery. However, if the authors had performed a review of the literature on this subject, they would have realized that the described technique is actually not as ‘‘novel’’ as they opine. Over the past years, our study group has extensively published on this subject, resulting in a multicenter, randomized controlled trial including 134 patients. Although the term ‘‘CUBE’’ is indeed novel, the technique itself is an exact copy of the technique we—among other authors—have repeatedly described. Needless to say, it would have been appropriate for the authors to refer to these studies while presenting their results, and we are somewhat disappointed that the journal did not revise the literature list on behalf of the authors. We recommend that the authors repeat our randomized controlled trial on use of intraoperative ultrasound, so we can convince all surgical oncologists to use this excellent technique in the operating theater. It would be highly appreciated if the authors could respond to our letter, and we await their reply. REFERENCES