Microwave Ablation, Radiofrequency Ablation, Irreversible Electroporation, and Stereotactic Ablative Body Radiotherapy for Intermediate Size (3-5 cm) Unresectable Colorectal Liver Metastases: a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Based on good local control rates and an excellent safety profile, guidelines consider thermal ablation the gold standard to eliminate small unresectable colorectal liver metastases (CRLM). However, efficacy decreases exponentially with increasing tumour size. The preferred treatment for intermediate-size unresectable CRLM remains uncertain. This systematic review and meta-analysis compare safety and efficacy of local ablative treatments for unresectable intermediate-size CRLM (3-5 cm). RECENT FINDINGS: We systematically searched for publications reporting treatment outcomes of unresectable intermediate-size CRLM treated with thermal ablation, irreversible electroporation (IRE) or stereotactic ablative body-radiotherapy (SABR). No comparative studies or randomized trials were found. Literature to assess effectiveness was limited and there was substantial heterogeneity in outcomes and study populations. Per-patient local control ranged 22-90% for all techniques; 22-89% (8 series) for thermal ablation, 44% (1 series) for IRE, and 67-90% (1 series) for SABR depending on radiation dose. Focal ablative therapy is safe and can induce long-term disease control, even for intermediate-size CRLM. Although SABR and tumuor-bracketing techniques such as IRE are suggested to be less susceptible to size, evidence to support any claims of superiority of one technique over the other is unsubstantiated by the available evidence. Future prospective comparative studies should address local-tumour-progression-free-survival, local control rate, overall survival, adverse events, and quality-of-life.

Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial.

Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.

Locally Advanced Pancreatic Cancer: Percutaneous Management Using Ablation, Brachytherapy, Intra-arterial Chemotherapy, and Intra-tumoral Immunotherapy.

PURPOSE OF REVIEW: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasms, bearing a terrible prognosis. Stage III tumors, also known as locally advanced pancreatic cancer (LAPC), are unresectable, and current palliative chemotherapy regimens have only modestly improved survival in these patients. At this stage of disease, interventional techniques may be of value and further prolong life. The aim of this review was to explore current literature on locoregional percutaneous management for LAPC. RECENT FINDINGS: Locoregional percutaneous interventional techniques such as ablation, brachytherapy, and intra-arterial chemotherapy possess cytoreductive abilities and have the potential to increase survival. In addition, recent research demonstrates the immunomodulatory capacities of these treatments. This immune response may be leveraged by combining the interventional techniques with intra-tumoral immunotherapy, possibly creating a durable anti-tumor effect. This multimodality treatment approach is currently being examined in several ongoing clinical trials. The use of certain interventional techniques appears to improve survival in LAPC patients and may work synergistically when combined with immunotherapy. However, definitive conclusions can only be made when large prospective (randomized controlled) trials confirm these results.

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study.

BACKGROUND: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation. METHODS: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery. RESULTS: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy. CONCLUSION: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.

Breast-conserving surgery following neoadjuvant therapy-a systematic review on surgical outcomes.

PURPOSE: Neoadjuvant chemotherapy (NACT) is increasingly used in breast cancer treatment. One of the main goals of NACT is to reduce the extent of local surgery of the breast and axilla. The aim of this study was to determine surgical outcomes for patients receiving breast-conserving therapy (BCT) after NACT, including margin status plus secondary surgeries, excision volumes, and cosmetic outcomes. METHODS: A systematic review was performed in accordance with PRISMA principles. Pubmed, MEDLINE, Embase, and the Cochrane Library were searched for studies investigating the results of BCT following NACT. The main study outcomes were margin status, additional local therapies, excision volumes, and cosmetic outcomes. Non-comparative studies on NACT were also included. Exclusion criteria were studies with less than 25 patients, and studies excluding secondary mastectomy patients. FINDINGS: Of the 1219 studies screened, 26 studies were deemed eligible for analysis, including data from 5379 patients treated with NACT and 10,110 patients treated without NACT. Included studies showed wide ranges of tumor-involved margins (2-39.8%), secondary surgeries (0-45.4%), and excision volumes (43.2-268 cm3) or specimen weight (26.4-233 g) after NACT. Most studies were retrospective, with a high heterogeneity and a high risk of bias. Cosmetic outcomes after NACT were reported in two single-center cohort studies. Both studies showed acceptable cosmetic outcomes. INTERPRETATION: There is currently insufficient evidence to suggest that NACT improves surgical outcomes of BCT. It is imperative that clinical trials include patient outcome measures in order to allow monitoring and meaningful comparison of treatment outcomes in breast cancer.

Correction to: Breast-conserving surgery following neoadjuvant therapy-a systematic review on surgical outcomes.

In the original publication of the article, Table 2 was published incorrectly. The corrected Table 2 is given in this erratum. The original article has been corrected.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

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.

Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS: Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. RESULTS: We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. DISCUSSION: The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node.

Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I-II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3(+) DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8(+) T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p = 0.04). These findings indicate that i.d. delivery of low-dose CpG ± GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs.

Is ultrasound-guided fine-needle aspiration cytology of adequate value in detecting breast cancer patients with three or more positive axillary lymph nodes?

This study evaluated the accuracy of ultrasound-guided fine-needle aspiration cytology of the sonographically most suspicious axillary lymph node (US/FNAC) to select early breast cancer patients with three or more tumour-positive axillary lymph nodes. Between 2004 and 2014, a total of 2130 patients with histologically proven early breast cancer were evaluated and treated in the Noordwest Clinics Alkmaar. US/FNAC was performed preoperatively in all these patients. We analysed the results of US/FNAC retrospectively. Pathological axillary node status (sentinel node biopsy and/or axillary lymph node dissection) was used as reference standard. A total of 634 (29.8 %) of 2130 patients had axillary lymph node metastases on final histology. 248 node positive patients (11.6 %) had three or more positive lymph nodes. The accuracy of US/FNAC to detect three or more positive lymph nodes was 89.8 %, sensitivity was 44.8 %, specificity was 95.7 %, PPV was 58.1 %, and NPV was 92.9 %. This study shows a more than adequate accuracy of preoperative US/FNAC to detect three or more positive lymph nodes (89.8 %). However, when US/FNAC was chosen as the only axillary staging method, 6.4 % of all patients (false negative group) would have been undertreated and 3.8 % of all patients (false positive group) would have been overtreated according to the ACOSOG Z0011 criteria.

Radiofrequency Ablation to Improve Survival After Conversion Chemotherapy for Colorectal Liver Metastases.

INTRODUCTION: Systemic chemotherapy is able to convert colorectal liver metastases (CRLM) that are initially unsuitable for local treatment into locally treatable disease. Surgical resection further improves survival in these patients. Our aim was to evaluate disease-free survival (DFS), overall survival, and morbidity for patients with CRLM treated with RFA following effective downstaging by chemotherapy, and to identify factors associated with recurrence and survival. MATERIALS AND METHODS: Included patients had liver-dominant CRLM initially unsuitable for local treatment but eligible for RFA or RFA with resection after downstaging by systemic chemotherapy. Chemotherapeutic regimens consisted predominantly of CapOx, with or without bevacizumab. Follow-up was conducted with PET-CT or thoraco-pelvic CT. RESULTS: Fifty-one patients had a total of 325 CRLM (median = 7). Following chemotherapy, 183 lesions were still visible on CT (median = 3). Twenty-six patients were treated with RFA combined with resection. During surgery, 309 CRLM were retrieved on intraoperative ultrasound (median = 5). Median survival was 49 months and was associated with extrahepatic disease at time of presentation and recurrences after treatment. Estimated cumulative survival at 1, 3 and 4 years was 90, 63 and 45 %, respectively. Median DFS was 6 months. Twelve patients remained free of recurrence after a mean follow-up of 32.6 months. CONCLUSION: RFA of CRLM after conversion chemotherapy provides potential local control and a good overall survival. To prevent undertreatment, the involvement of a multidisciplinary team in follow-up imaging and assessment of local treatment possibilities after palliative chemotherapy for liver-dominant CRLM should always be considered.

Childhood maltreatment modifies the relationship of depression with hippocampal volume.

BACKGROUND: Childhood maltreatment (CM) may modify the relationship between major depressive disorder (MDD) and hippocampal volume reduction. To disentangle the impact of MDD and CM on hippocampal volume we investigated the association between MDD and hippocampal volume in persons with and without a history of CM in two independent cohorts. METHOD: We used data of 262 participants from the Netherlands Study of Depression and Anxiety (NESDA) (mean age 37 years, 32% male) and 636 participants from the SMART-Medea study (mean age 61 years, 81% male). In both studies a 12-month diagnosis of MDD and CM were assessed using a diagnostic interview. Hippocampal volume was measured in NESDA using FreeSurfer software on 3-T magnetic resonance (MR) images and in SMART it was manually outlined on 1.5-T MR images. With analysis of covariance adjusted for intracranial volume, age, gender and lifestyle factors we estimated the effects of MDD and CM on hippocampal volume. RESULTS: In both cohorts CM was not significantly associated with hippocampal volume. After pooling the data MDD was associated with smaller hippocampal volume (B = -138.90 mm(3), p = 0.05) and the interaction between MDD and CM reached significance (p = 0.04); in participants with CM, MDD was related to smaller hippocampal volume (NESDA: B = -316.8 mm(3), p = 0.02; SMART: B = -407.6, p = 0.046), but not in participants without CM (p > 0.05). CONCLUSIONS: Our study shows that in two independent cohorts, particularly in individuals with CM, a diagnosis of MDD is related to smaller hippocampal volume. Prospective studies are needed to further determine through which mechanism CM may amplify the relationship between MDD and hippocampal volume.

Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume.

BACKGROUND AND PURPOSE: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. METHODS: Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. RESULTS: Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. CONCLUSIONS: Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without dementia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dysfunction of ALS.

Local cortical thinning links to resting-state disconnectivity in major depressive disorder.

BACKGROUND: Local structural and metabolic as well as inter-regional connectivity abnormalities have been implicated in the neuropathology of major depressive disorder (MDD). How local tissue properties affect intrinsic functional connectivity is, however, unclear. Using a cross-sectional, multi-modal imaging approach, we investigated the relationship between local cortical tissue abnormalities and intrinsic resting-state functional connectivity (RSFC) in MDD. METHOD: A total of 20 MDD in-patients and 20 healthy controls underwent magnetic resonance imaging at 3 T for structural and functional imaging. Whole-brain cortical thickness was calculated and compared between groups. Regions with reduced cortical thickness defined seeds for subsequent whole-brain RSFC analyses. Contributions of structural tissue abnormalities on inter-regional RSFC were explicitly investigated. RESULTS: Lower cortical thickness was observed in MDD in the right dorsomedial prefrontal cortex (PFC), superior temporal gyrus/temporal pole, middle-posterior cingulate cortex, and dorsolateral PFC. No differences in local fractional amplitude of low-frequency fluctuations were observed. Lower thickness in patients' dorsomedial PFC further directly and selectively affected its RSFC with the precuneus, which was unaffected by symptom severity. No effects of cortical thickness in other regions showing abnormal thickness were observed to influence functional connectivity. CONCLUSIONS: Abnormal cortical thickness in the dorsomedial PFC in MDD patients was observed to selectively and directly affect its intrinsic connectivity with the precuneus in MDD patients independent of depression severity, thereby marking a potential vulnerability for maladaptive mood regulation. Future studies should include an unmedicated sample and replicate findings using independent component analysis to test for morphometric effects on network integrity.

Ablation of colorectal liver metastases by irreversible electroporation: results of the COLDFIRE-I ablate-and-resect study.

OBJECTIVES: Irreversible electroporation (IRE) is a new ablation technique that relies on high-voltage electrical pulses. This clinical study evaluates the pathological response of colorectal liver metastases (CRLM) treated with IRE and the clinical safety and feasibility. METHODS: Ten patients with resectable CRLM were included. During laparotomy, the metastases were treated with IRE and resected 60 min later. Safety and feasibility were assessed based on adverse events, laboratory values, technical success and intra-operative ultrasound findings. Tissue response was assessed using triphenyl tetrazolium chloride (TTC) vitality staining and (immuno)histochemical stainings (HE, complement-3d and caspase-3). RESULTS: Ten lesions with a mean diameter of 2.4 cm were successfully electroporated and resected, on average, 84 min later (range 51-153 min). One minor transient cardiac arrhythmia occurred during IRE. Ultrasound showed a sharply demarcated hypoechoic ablation zone around the tumour. TTC showed avitality of all lesions, covering the complete tumour in 8/10 lesions. Although immunohistochemistry proved heterogeneous and difficult to interpret within the tumours, it confirmed irreversible cell damage in the tumour-free margin of all specimens. CONCLUSIONS: This ablate-and-resect study demonstrated avitality caused by IRE of CRLM in humans. Further characterisation of tissue- and tumour-specific electrical properties is warranted to improve ablation protocols for maximised tissue ablation. KEY POINTS: • Irreversible electroporation induces cell death in colorectal liver metastases within 1 h. • The ablation zone shows a sharp demarcation between avital and vital tissue. • Apoptosis is involved in cell death of colorectal liver metastases after IRE. • Effects of IRE can be monitored real-time using intraoperative ultrasound. • Local electrical heterogeneities of tumour tissue may require tumour-specific ablation protocols.

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.

Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicentre, randomised controlled trial.

BACKGROUND: Breast-conserving surgery for palpable breast cancer is associated with tumour-involved margins in up to 41% of cases and excessively large excision volumes. Ultrasound-guided surgery has the potential to resolve both of these problems, thereby improving surgical accuracy for palpable breast cancer. We aimed to compare ultrasound-guided surgery with the standard for palpable breast cancer-palpation-guided surgery-with respect to margin status and extent of healthy breast tissue resection. METHODS: In this randomised controlled trial, patients with palpable T1-T2 invasive breast cancer were recruited from six medical centres in the Netherlands between October, 2010, and March, 2012. Eligible participants were randomly assigned to either ultrasound-guided surgery or palpation-guided surgery in a 1:1 ratio via a computer-generated random sequence and were stratified by study centre. Patients and investigators were aware of treatment assignments. Primary outcomes were surgical margin involvement, need for additional treatment, and excess healthy tissue resection (defined with a calculated resection ratio derived from excision volume and tumour diameter). Data were analysed by intention to treat. This trial is registered at http://www.TrialRegister.nl, number NTR2579. FINDINGS: 134 patients were eligible for random allocation. Two (3%) of 65 patients allocated ultrasound-guided surgery had tumour-involved margins compared with 12 (17%) of 69 who were assigned palpation-guided surgery (difference 14%, 95% CI 4-25; p=0·0093). Seven (11%) patients who received ultrasound-guided surgery and 19 (28%) of those who received palpation-guided surgery required additional treatment (17%, 3-30; p=0·015). Ultrasound-guided surgery also resulted in smaller excision volumes (38 [SD 26] vs 57 [41] cm(3); difference 19 cm(3), 95% CI 7-31; p=0·002) and a reduced calculated resection ratio (1·0 [SD 0·5] vs 1·7 [1·2]; difference 0·7, 95% CI 0·4-1·0; p=0·0001) compared with palpation-guided surgery. INTERPRETATION: Compared with palpation-guided surgery, ultrasound-guided surgery can significantly lower the proportion of tumour-involved resection margins, thus reducing the need for re-excision, mastectomy, and radiotherapy boost. By achieving optimum resection volumes, ultrasound-guided surgery reduces unnecessary resection of healthy breast tissue and could contribute to improved cosmetic results and quality of life. FUNDING: Dutch Pink Ribbon Foundation, Osinga-Kluis Foundation, Toshiba Medical Systems.