Tissue Resistance Decrease during Irreversible Electroporation of Pancreatic Cancer as a Biomarker for the Adaptive Immune Response and Survival.

PURPOSE: To correlate irreversible electroporation (IRE) procedural resistance changes with survival outcomes and the IRE-induced systemic immune response in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Data on IRE procedural tissue resistance (R) features and survival outcomes were collected from patients with LAPC treated within the context of 2 prospective clinical trials in a single tertiary center. Preprocedural and postprocedural peripheral blood samples were prospectively collected for immune monitoring. The change (ie, decrease) in R during the first 10 test pulses (ΔR10p) and during the total procedure (ΔRtotal) were calculated. Patients were divided in 2 groups on the basis of the median change in R (large ΔR vs small ΔR) and compared for differences in overall survival (OS) and progression-free survival and immune cell subsets. RESULTS: A total of 54 patients were included; of these, 20 underwent immune monitoring. Linear regression modeling showed that the first 10 test pulses reflected the change in tissue resistance during the total procedure appropriately (P < .001; R2 = 0.91). A large change in tissue resistance significantly correlated with a better OS (P = .026) and longer time to disease progression (P = .045). Furthermore, a large change in tissue resistance was associated with CD8+ T cell activation through significant upregulation of Ki-67+ (P = .02) and PD-1+ (P = .047). Additionally, this subgroup demonstrated significantly increased expression of CD80 on conventional dendritic cells (cDC1; P = .027) and PD-L1 on immunosuppressive myeloid-derived suppressor cells (P = .039). CONCLUSIONS: IRE procedural resistance changes may serve as a biomarker for survival and IRE-induced systemic CD8+ T cell and cDC1 activation.

Practice variation and outcomes of minimally invasive minor liver resections in patients with colorectal liver metastases: a population-based study.

INTRODUCTION: In 2017, the Southampton guideline stated that minimally invasive liver resections (MILR) should considered standard practice for minor liver resections. This study aimed to assess recent implementation rates of minor MILR, factors associated with performing MILR, hospital variation, and outcomes in patients with colorectal liver metastases (CRLM). METHODS: This population-based study included all patients who underwent minor liver resection for CRLM in the Netherlands between 2014 and 2021. Factors associated with MILR and nationwide hospital variation were assessed using multilevel multivariable logistic regression. Propensity-score matching (PSM) was applied to compare outcomes between minor MILR and minor open liver resections. Overall survival (OS) was assessed with Kaplan-Meier analysis on patients operated until 2018. RESULTS: Of 4,488 patients included, 1,695 (37.8%) underwent MILR. PSM resulted in 1,338 patients in each group. Implementation of MILR increased to 51.2% in 2021. Factors associated with not performing MILR included treatment with preoperative chemotherapy (aOR 0.61 CI:0.50-0.75, p < 0.001), treatment in a tertiary referral hospital (aOR 0.57 CI:0.50-0.67, p < 0.001), and larger diameter and number of CRLM. Significant hospital variation was observed in use of MILR (7.5% to 93.0%). After case-mix correction, six hospitals performed fewer, and six hospitals performed more MILRs than expected. In the PSM cohort, MILR was associated with a decrease in blood loss (aOR 0.99 CI:0.99-0.99, p < 0.01), cardiac complications (aOR 0.29, CI:0.10-0.70, p = 0.009), IC admissions (aOR 0.66, CI:0.50-0.89, p = 0.005), and shorter hospital stay (aOR CI:0.94-0.99, p < 0.01). Five-year OS rates for MILR and OLR were 53.7% versus 48.6%, p = 0.21. CONCLUSION: Although uptake of MILR is increasing in the Netherlands, significant hospital variation remains. MILR benefits short-term outcomes, while overall survival is comparable to open liver surgery.

High-Voltage Electrical Pulses in Oncology: Irreversible Electroporation, Electrochemotherapy, Gene Electrotransfer, Electrofusion, and Electroimmunotherapy.

This review summarizes the use of high-voltage electrical pulses (HVEPs) in clinical oncology to treat solid tumors with irreversible electroporation (IRE) and electrochemotherapy (ECT). HVEPs increase the membrane permeability of cells, a phenomenon known as electroporation. Unlike alternative ablative therapies, electroporation does not affect the structural integrity of surrounding tissue, thereby enabling tumors in the vicinity of vital structures to be treated. IRE uses HVEPs to cause cell death by inducing membrane disruption, and it is primarily used as a radical ablative therapy in the treatment of soft-tissue tumors in the liver, kidney, prostate, and pancreas. ECT uses HVEPs to transiently increase membrane permeability, enhancing cellular cytotoxic drug uptake in tumors. IRE and ECT show immunogenic effects that could be augmented when combined with immunomodulatory drugs, a combination therapy the authors term electroimmunotherapy. Additional electroporation-based technologies that may reach clinical importance, such as gene electrotransfer, electrofusion, and electroimmunotherapy, are concisely reviewed. HVEPs represent a substantial advancement in cancer research, and continued improvement and implementation of these presented technologies will require close collaboration between engineers, interventional radiologists, medical oncologists, and immuno-oncologists.

Transcatheter CT Hepatic Arteriography Compared with Conventional CT Fluoroscopy Guidance in Percutaneous Thermal Ablation to Treat Colorectal Liver Metastases: A Single-Center Comparative Analysis of 2 Historical Cohorts.

PURPOSE: To evaluate safety and efficacy of CT hepatic arteriography compared with conventional CT fluoroscopy guidance in percutaneous radiofrequency (RF) and microwave (MW) ablation to treat colorectal liver metastases (CRLM). MATERIALS AND METHODS: This single-center comparative, retrospective study analyzed data of 108 patients treated with 156 percutaneous ablation procedures (42 CT fluoroscopy guidance [25 RF ablation, 17 MW ablation]; 114 CT hepatic arteriography guidance [18 RF ablation, 96 MW ablation]) for 260 CRLM between January 2009 and May 2019. Local tumor progression-free survival (LTPFS) was assessed using univariate and multivariate Cox proportional hazard regression analyses. LTPFS and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: There were no complications related to the transarterial catheter procedure. CT hepatic arteriography proved superior to CT fluoroscopy regarding 2-year LTPFS (18/202 [8.9%] vs 19/58 [32.8%]; P < .001, respectively). CT hepatic arteriography versus CT fluoroscopy (hazard ratio = 0.28; 95% confidence interval, 0.15-0.54; P < .001) and MW ablation versus RF ablation (hazard ratio = 0.52; 95% confidence interval, 0.24-1.12; P = .094) were positive predictors for longer LTPFS. Multivariate analysis revealed that CT hepatic arteriography versus CT fluoroscopy (hazard ratio = 0.41; 95% confidence interval, 0.19-0.90; P = .025) was associated with a significantly superior LTPFS. OS was similar between the 2 cohorts (P = .3). CONCLUSIONS: While adding procedure time and marginal patient burden, transcatheter CT hepatic arteriography-guided ablation was associated with increased local disease control and superior LTPFS compared with conventional CT fluoroscopy. CT hepatic arteriography represents a safe and valid alternative to CT fluoroscopy, as it reduces the number of repeat ablations required without adding risk or detrimental effect on survival.

Implementation and outcome of minor and major minimally invasive liver surgery in the Netherlands.

BACKGROUND: While most of the evidence on minimally invasive liver surgery (MILS) is derived from expert centers, nationwide outcomes remain underreported. This study aimed to evaluate the implementation and outcome of MILS on a nationwide scale. METHODS: Electronic patient files were reviewed in all Dutch liver surgery centers and all patients undergoing MILS between 2011 and 2016 were selected. Operative outcomes were stratified based on extent of the resection and annual MILS volume. RESULTS: Overall, 6951 liver resections were included, with a median annual volume of 50 resections per center. The overall use of MILS was 13% (n = 916), which varied from 3% to 36% (P < 0.001) between centers. The nationwide use of MILS increased from 6% in 2011 to 23% in 2016 (P < 0.001). Outcomes of minor MILS were comparable with international studies (conversion 0-13%, mortality <1%). In centers which performed ≥20 MILS annually, major MILS was associated with less conversions (14 (11%) versus 41 (30%), P < 0.001), shorter operating time (184 (117-239) versus 200 (139-308) minutes, P = 0.010), and less overall complications (37 (30%) versus 58 (42%), P = 0.040). CONCLUSION: The nationwide use of MILS is increasing, although large variation remains between centers. Outcomes of major MILS are better in centers with higher volumes.

Colorectal liver metastases: surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial.

BACKGROUND: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. METHODS: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3 cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3 cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). DISCUSSION: If thermal ablation proves to be non-inferior in treating lesions ≤3 cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. TRIAL REGISTRATION: NCT03088150 , January 11th 2017.

Breast-specific factors determine cosmetic outcome and patient satisfaction after breast-conserving therapy: Results from the randomized COBALT study.

BACKGROUND AND OBJECTIVES: To identify breast-specific factors and the role of tumor, treatment, and patient-related items in influencing patient opinion on cosmesis and satisfaction after breast-conserving therapy (BCT). METHODS: Data from the randomized COBALT study was used. At 3, 12, and 36 months, 128 patients with T1-T2 breast cancer completed a questionnaire on breast-specific factors and overall cosmetic outcome and patient satisfaction, using a 4-point Likert scale. RESULTS: There was a strong positive correlation between breast-specific factors, overall cosmetic outcome,and satisfaction at all time-points. Excellent/good cosmetic outcomes and satisfaction decreased during follow-up. A shift was noted in the degree of influence of the various breast-specific factors. At 3 years, symmetry factors such as size, shape, and nipple position largely determined a patient's opinion on the final cosmesis, followed by firmness. The risk of an unacceptable outcome was associated with young age and large excision volumes. CONCLUSION: A questionnaire including breast-specific questions provides important information on final cosmetic results and satisfaction after BCT. These outcomes can also be of great value as quality indicators and pre-operative counseling. The major influence of breast-specific factors on asymmetry underlines the importance of achieving an optimal excision volume at the initial procedure.

Percutaneous Liver Tumour Ablation: Image Guidance, Endpoint Assessment, and Quality Control.

Liver tumour ablation nowadays represents a routine treatment option for patients with primary and secondary liver tumours. Radiofrequency ablation and microwave ablation are the most widely adopted methods, although novel techniques, such as irreversible electroporation, are quickly working their way up. The percutaneous approach is rapidly gaining popularity because of its minimally invasive character, low complication rate, good efficacy rate, and repeatability. However, matched to partial hepatectomy and open ablations, the issue of ablation site recurrences remains unresolved and necessitates further improvement. For percutaneous liver tumour ablation, several real-time imaging modalities are available to improve tumour visibility, detect surrounding critical structures, guide applicators, monitor treatment effect, and, if necessary, adapt or repeat energy delivery. Known predictors for success are tumour size, location, lesion conspicuity, tumour-free margin, and operator experience. The implementation of reliable endpoints to assess treatment efficacy allows for completion-procedures, either within the same session or within a couple of weeks after the procedure. Although the effect on overall survival may be trivial, (local) progression-free survival will indisputably improve with the implementation of reliable endpoints. This article reviews the available needle navigation techniques, evaluates potential treatment endpoints, and proposes an algorithm for quality control after the procedure.

Ablation of Locally Advanced Pancreatic Cancer with Percutaneous Irreversible Electroporation: Results of the Phase I/II PANFIRE Study.

Purpose To (a) investigate the safety of percutaneous irreversible electroporation (IRE) for locally advanced pancreatic cancer and (b) evaluate the quality of life (QOL), pain perception, and efficacy in terms of time to local progression, event-free survival, and overall survival (OS). Materials and Methods The study was approved by the local review board (NL42888.029.13). All patients provided written informed consent for study participation, the ablation procedure, and data usage. Between January 2014 and June 2015, 25 patients with histologically proved locally advanced pancreatic cancer 5 cm or smaller (13 women, 12 men; median age, 61 years; age range, 41-78 years) were prospectively included to undergo percutaneous computed tomographic-guided IRE. Patients with a metallic biliary Wallstent, epilepsy, or ventricular arrhythmias were excluded. Kaplan-Meier estimates were used to investigate time to local progression, event-free survival, and OS. Safety was assessed on the basis of adverse events, which were graded according to the Common Terminology Criteria for Adverse Events. Pain perception and QOL were evaluated by using specific questionnaires. Results All patients underwent IRE. The median largest tumor diameter was 4.0 cm (range, 3.3-5.0 cm). After a median follow-up of 12 months (interquartile range: 7-16 months), median event-free survival after IRE was 8 months (95% confidence interval [CI]: 4 months, 12 months); the median time to local progression after IRE was 12 months (95% CI: 8 months, 16 months). The median OS was 11 months from IRE (95% CI: 9 months, 13 months) and 17 months from diagnosis (95% CI: 10 months, 24 months). There were 12 minor complications (grade I or II) and 11 major complications (nine grade III, two grade IV) in 10 patients. There were no deaths within 90 days after IRE. Conclusion Percutaneous IRE for locally advanced pancreatic cancer is generally well tolerated, although major adverse events can occur. Preliminary survival data are encouraging and support the setup of larger phase II and III clinical trials to assess the efficacy of IRE plus chemotherapy in the neoadjuvant and adjuvant or second-line setting compared with more widely adopted regimens such as chemotherapy and/or radiation therapy. © RSNA, 2016 Online supplemental material is available for this article.

Cosmetic outcome and quality of life are inextricably linked in breast-conserving therapy.

INTRODUCTION: Cosmetic results and quality of life (QoL) are increasingly important in the treatment of breast cancer. This study was designed to determine the relationship between QoL and both subjectively and objectively measured cosmetic outcomes of breast-conserving therapy (BCT), and its course over time. METHODS: A total of 128 breast cancer patients who underwent BCT as part of a prospective randomized controlled trial were included. QoL was measured using the EORTC QLQ-C30 and QLQ-BR23 at baseline, 3, 6, 12, and 36 months. Cosmetic outcome was determined by patient self-evaluation, panel evaluation, and BCCT.core software. RESULTS: By 36 months, all QoL factors except arm symptoms had returned to baseline or improved. After adjustment for patient and tumor characteristics, a significantly better QoL in terms of body image, pain, and arm and breast symptoms was found for good/excellent cosmetic outcomes compared to fair/poor outcomes, as measured by both patient self-evaluation and panel evaluation. The BCCT.core showed no correlation with any QoL factors. CONCLUSION: There is a high correlation between poor cosmetic outcome and low scores on quality of life indicators, underlining the importance of achieving a good cosmetic outcome after BCT.

Intraoperative Ultrasound Guidance in Breast-Conserving Surgery Improves Cosmetic Outcomes and Patient Satisfaction: Results of a Multicenter Randomized Controlled Trial (COBALT).

BACKGROUND: Ultrasound-guided breast-conserving surgery (USS) results in a significant reduction in both margin involvement and excision volumes (COBALT trial). Objective. The aim of the present study was to determine whether USS also leads to improvements in cosmetic outcome and patient satisfaction when compared with standard palpation-guided surgery (PGS). METHODS: A total of 134 patients with T1­T2 invasive breast cancer were included in the COBALT trial (NTR2579) and randomized to either USS (65 patients) or PGS (69 patients). Cosmetic outcomes were assessed by a three-member panel using computerized software Breast Cancer Conservative Treatment cosmetic results (BCCT.- core) and by patient self-evaluation, including patient satisfaction. Time points for follow-up were 3, 6, and 12 months after surgery. Overall cosmetic outcome and patient satisfaction were scored on a 4-point Likert scale (excellent, good, fair, or poor), and outcomes were analyzed using a multilevel, mixed effect, proportional odds model for ordinal responses. RESULTS: Ultrasound-guided breast-conserving surgery achieved better cosmetic outcomes, with 20 % excellence overall and only 6 % rated as poor, whereas 14 % of PGS outcomes were rated excellent and 13 % as poor. USS also had consistently lower odds for worse cosmetic outcomes (odds ratio 0.55, p = 0.067) than PGS. The chance of having a worse outcome was significantly increased by a larger lumpectomy volume (ptrend = 0.002); a volume [40 cc showed odds 2.78-fold higher for a worse outcome than a volume B40 cc. USS resulted in higher patient satisfaction compared with PGS. CONCLUSION: Ultrasound-guided breast-conserving surgery achieved better overall cosmetic outcomes and patient satisfaction than PGS. Lumpectomy volumes[40 cc resulted in significantly worse cosmetic outcomes.

Colorectal liver metastatic disease: efficacy of irreversible electroporation--a single-arm phase II clinical trial (COLDFIRE-2 trial).

BACKGROUND: Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique that has shown promise for the ablation of lesions in proximity to vital structures such as blood vessels and bile ducts. The primary aim of the COLDFIRE-2 trial is to investigate the efficacy of IRE for unresectable, centrally located colorectal liver metastases (CRLM). Secondary outcomes are safety, technical success, and the accuracy of contrast-enhanced (ce)CT and (18)F-FDG PET-CT in the detection of local tumor progression (LTP). METHODS/DESIGN: In this single-arm, multicenter phase II clinical trial, twenty-nine patients with (18)F-FDG PET-avid CRLM ≤ 3,5 cm will be prospectively included to undergo IRE of the respective lesion. All lesions must be unresectable and unsuitable for thermal ablation due to vicinity of vital structures. Technical success is based on ceMRI one day post-IRE. All complications related to the IRE procedure are registered. Follow-up consists of (18)F-FDG PET-CT and 4-phase liver CT at 3-monthly intervals during the first year of follow-up. Treatment efficacy is defined as the percentage of tumors successfully eradicated 12 months after the initial IRE procedure based on clinical follow-up using both imaging modalities, tumor marker and (if available) histopathology. To determine the accuracy of (18)F-FDG PET-CT and ceCT, both imaging modalities will be individually scored by two reviewers that are blinded for the final oncologic outcome. DISCUSSION: To date, patients with a central CRLM unsuitable for resection or thermal ablation have no curative treatment option and are given palliative chemotherapy. For these patients, IRE may prove a life-saving treatment option. The results of the proposed trial may represent an important step towards the implementation of IRE for central liver tumors in the clinical setting. TRIAL REGISTRATION NUMBER: NCT02082782.

Transcatheter CT hepatic arteriography-guided percutaneous ablation to treat ablation site recurrences of colorectal liver metastases: the incomplete ring sign.

Transcatheter computed tomography (CT) arterial portography-guided percutaneous liver tumor ablation has been proved to be feasible and accurate in treating liver metastases from colorectal origin that are obscure on ultrasound and unenhanced CT. However, distinguishing local recurrence from scars after ablation can still be difficult. This report describes nine patients with recurrences after ablation in whom transcatheter CT hepatic arteriography allowed differentiation of recurring and residual tumor tissue (incomplete ring enhancing lesion) from tumor-free nonenhancing scars. Using CT hepatic arteriography, it is possible to plan and guide percutaneous retreatment and confirm technical success without performing oversized repeat ablations or jeopardizing patients renal function.

Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy.

PURPOSE: To provide an overview of current clinical results of irreversible electroporation (IRE), a novel, nonthermal tumor ablation technique that uses electric pulses to induce cell death, while preserving structural integrity of bile ducts and vessels. METHODS: All in-human literature on IRE reporting safety or efficacy or both was included. All adverse events were recorded. Tumor response on follow-up imaging from 3 months onward was evaluated. RESULTS: In 16 studies, 221 patients had 325 tumors treated in liver (n = 129), pancreas (n = 69), kidney (n = 14), lung (n = 6), lesser pelvis (n = 1), and lymph node (n = 2). No major adverse events during IRE were reported. IRE caused only minor complications in the liver; however, three major complications were reported in the pancreas (bile leak [n = 2], portal vein thrombosis [n = 1]). Complete response at 3 months was 67%-100% for hepatic tumors (93%-100% for tumors o 3 cm). Pancreatic IRE combined with surgery led to prolonged survival compared with control patients (20 mo vs 13 mo) and significant pain reduction. CONCLUSIONS: In cases where other techniques are unsuitable, IRE is a promising modality for the ablation of tumors near bile ducts and blood vessels. This articles gives an extensive overview of the available evidence, which is limited in terms of quality and quantity. With the limitations of the evidence in mind, IRE of central liver tumors seems relatively safe without major complications, whereas complications after pancreatic IRE appear more severe. The available limited results for tumor control are generally good. Overall, the future of IRE for difficult-to-reach tumors appears promising.

Transcatheter CT arterial portography and CT hepatic arteriography for liver tumor visualization during percutaneous ablation.

PURPOSE: To evaluate the feasibility of combining transcatheter computed tomography (CT) arterial portography or transcatheter CT hepatic arteriography with percutaneous liver ablation for optimized and repeated tumor exposure. MATERIALS AND METHODS: Study participants were 20 patients (13 men and 7 women; mean age, 59.4 y; range, 40-76 y) with unresectable liver-only malignancies--14 with colorectal liver metastases (29 lesions), 5 with hepatocellular carcinoma (7 lesions), and 1 with intrahepatic cholangiocarcinoma (2 lesions)--that were obscure on nonenhanced CT. A catheter was placed within the superior mesenteric artery (CT arterial portography) or in the hepatic artery (CT hepatic arteriography). CT arterial portography or CT hepatic arteriography was repeatedly performed after injecting 30-60 mL 1:2 diluted contrast material to plan, guide, and evaluate ablation. The operator confidence levels and the liver-to-lesion attenuation differences were assessed as well as needle-to-target mismatch distance, technical success, and technique effectiveness after 3 months. RESULTS: Technical success rate was 100%; there were no major complications. Compared with conventional unenhanced CT, operator confidence increased significantly for CT arterial portography or CT hepatic arteriography cases (P < .001). The liver-to-lesion attenuation differences between unenhanced CT, contrast-enhanced CT, and CT arterial portography or CT hepatic arteriography were statistically significant (mean attenuation difference, 5 HU vs 28 HU vs 70 HU; P < .001). Mean needle-to-target mismatch distance was 2.4 mm ± 1.2 (range, 0-12.0 mm). Primary technique effectiveness at 3 months was 87% (33 of 38 lesions). CONCLUSIONS: In patients with technically unresectable liver-only malignancies, single-session CT arterial portography-guided or CT hepatic arteriography-guided percutaneous tumor ablation enables repeated contrast-enhanced imaging and real-time contrast-enhanced CT fluoroscopy and improves lesion conspicuity.

The use of PET-MRI in the follow-up after radiofrequency- and microwave ablation of colorectal liver metastases.

BACKGROUND: Thermal ablation of colorectal liver metastases (CRLM) may result in local progression, which generally appear within a year of treatment. As the timely diagnosis of this progression allows potentially curative local treatment, an optimal follow-up imaging strategy is essential. PET-MRI is a one potential imaging modality, combining the advantages of PET and MRI. The aim of this study is evaluate fluorine-18 deoxyglucose positron emission tomography (FDG) PET-MRI as a modality for detection of local tumor progression during the first year following thermal ablation, as compared to the current standard, FDG PET-CT. The ability of FDG PET-MRI to detect new intrahepatic lesions, and the extent to which FDG PET-MRI alters clinical management, inter-observer variability and patient preference will also be included as secondary outcomes. METHODS/DESIGN: Twenty patients undergoing treatment with radiofrequency or microwave ablation for (recurrent) CRLM will be included in this prospective trial. During the first year of follow-up, patients will be scanned at the VU University Medical Center at 3-monthly intervals using a 4-phase liver CT, FDG PET-CT and FDG PET-MRI. Patients treated with chemotherapy <6 weeks prior to scanning or with a contra-indication for MRI will be excluded. MRI will be performed using both whole body imaging (mDixon) and dedicated liver sequences, including diffusion-weighted imaging, T1 in-phase and opposed-phase, T2 and dynamic contrast-enhanced imaging. The results of all modalities will be scored by 4 individual reviewers and inter-observer agreement will be determined. The reference standard will be histology or clinical follow-up. A questionnaire regarding patients' experience with both modalities will also be completed at the end of the follow-up year. DISCUSSION: Improved treatment options for local site recurrences following CRLM ablation mean that accurate post-ablation staging is becoming increasingly important. The combination of the sensitivity of MRI as a detection method for small intrahepatic lesions with the ability of FDG PET to visualize enhanced metabolism at the ablation site suggests that FDG PET-MRI could potentially improve the accuracy of (early) detection of progressive disease, and thus allow swifter and more effective decision-making regarding appropriate treatment. TRIAL REGISTRATION NUMBER: NCT01895673.

MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial.

BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal prognosis. Stage III locally advanced pancreatic cancer is considered unresectable and current palliative chemotherapy regimens only modestly improve survival. Guidelines suggest chemoradiation or stereotactic ablative body radiotherapy (SABR) could be beneficial in certain circumstances. Other local treatments such as irreversible electroporation could enhance patient outcomes by extending survival while preserving quality of life. We aimed to compare the efficacy and safety of MRI-guided SABR versus CT-guided percutaneous irreversible electroporation following standard FOLFIRINOX chemotherapy. METHODS: CROSSFIRE was an open-label, randomised phase 2 superiority trial conducted at the Amsterdam University Medical Centre (Amsterdam, Netherlands). Eligible patients were aged 18 years or older with confirmed histological and radiological stage III locally advanced pancreatic cancer. The maximum tumour diameter was 5 cm and patients had to be pretreated with three to eight cycles of FOLFIRINOX. Patients were randomly assigned (1:1) to MRI-guided SABR (five fractions of 8 Gy delivered on non-consecutive days) or CT-guided percutaneous irreversible electroporation using a computer-generated variable block randomisation model. The primary endpoint was overall survival from randomisation, assessed in the intention-to-treat population. Safety was assessed in the per-protocol population. A prespecified interim futility analysis was done after inclusion of half the original sample size, with a conditional probability of less than 0·2 resulting in halting of the study. The trial was registered at ClinicalTrials.gov, NCT02791503. FINDINGS: Between May 1, 2016, and March 31, 2022, 68 patients were enrolled and randomly assigned to SABR (n=34) or irreversible electroporation (n=34), of whom 64 were treated according to protocol. Of the 68 participants, 36 (53%) were male and 32 (47%) were female, with a median age of 65 years (IQR 57-70). Median overall survival from randomisation was 16·1 months (95% CI 12·1-19·4) in the SABR group versus 12·5 months (10·9-17·0) in the irreversible electroporation group (hazard ratio [HR] 1·39 [95% CI 0·84-2·30]; p=0·21). The conditional probability to demonstrate superiority of either technique was 0·13; patient accrual was therefore stopped early for futility. 20 (63%) of 32 patients in the SABR group versus 19 (59%) of 32 patients in the irreversible electroporation group had adverse events (p=0·8) and five (16%) patients in the SABR group versus eight (25%) in the irreversible electroporation group had grade 3-5 adverse events (p=0·35). The most common grade 3-4 adverse events were cholangitis (two [6%] in the SABR group vs one [3%] in the irreversible electroporation group), abdominal pain (one [3%] vs two [6%]), and pancreatitis (none vs two [6%]). One (3%) patient in the SABR group and one (3%) in the irreversible electroporation group died from a treatment-related adverse event. INTERPRETATION: CROSSFIRE did not identify a difference in overall survival or incidence of adverse events between MRI-guided SABR and CT-guided percutaneous irreversible electroporation after FOLFIRINOX. Future studies should further assess the added value of local ablative treatment over chemotherapy alone. FUNDING: Adessium Foundation, AngioDynamics.

Viable tumor tissue adherent to needle applicators after local ablation: a risk factor for local tumor progression.

BACKGROUND: Local tumor progression (LTP) is a serious complication after local ablation of malignant liver tumors, negatively influencing patient survival. LTP may be the result of incomplete ablation of the treated tumor. In this study, we determined whether viable tumor cells attached to the needle applicator after ablation was associated with LTP and disease-free survival. METHODS: In this prospective study, tissue was collected of 96 consecutive patients who underwent local liver ablations for 130 liver malignancies. Cells and tissue attached to the needle applicators were analyzed for viability using glucose-6-phosphate-dehydrogenase staining and autofluorescence intensity levels of H&E stained sections. Patients were followed-up until disease progression. RESULTS: Viable tumor cells were found on the needle applicators after local ablation in 26.7% of patients. The type of needle applicator used, an open approach, and the omission of track ablation were significantly correlated with viable tumor tissue adherent to the needle applicator. The presence of viable cells was an independent predictor of LTP. The attachment of viable cells to the needle applicators was associated with a shorter time to LTP. CONCLUSIONS: Viable tumor cells adherent to the needle applicators were found after ablation of 26.7% of patients. An independent risk factor for viable cells adherent to the needle applicators is the omission of track ablation. We recommend using only RFA devices that have track ablation functionality. Adherence of viable tumor cells to the needle applicator after local ablation was an independent risk factor for LTP.

Excessive resections in breast-conserving surgery: a retrospective multicentre study.

The main determinant of cosmetic outcomes following breast-conserving surgery (BCS) for breast cancer is the volume of resection. The importance of achieving optimal oncological control may lead to an unnecessarily large resection of breast tissue. The aim of this study is to evaluate excess resection volume in BCS for cancer by determining a calculated resection ratio (CRR). This retrospective study was conducted in four affiliated institutions and involved 726 consecutive patients with T1-T2 invasive breast cancer treated by BCS between January 2006 and 2009. The pathology reports were reviewed for tumor palpability, tumor size, surgical specimen size, and oncological margin status. The optimal resection volume (ORV) was defined as the spherical tumor volume with an added 1.0 cm margin of healthy breast tissue. The total resection volume (TRV) was defined as the ellipsoid volume of the surgical specimen. CRR was determined by dividing the TRV by the ORV. Of all tumors, 72% (525/726) were palpable, and 28% (201/726) were nonpalpable. The tumor stage was T1 in 492 patients (67.8%) and T2 in 234 patients (32.2%). The median CRR was 2.5 (0.01-42.93). Margin status was positive or focally positive in 153 patients (21.1%). Lower tumor stage was associated with a higher CRR (factor 0.61 [p < 0.0001] and a lower positive margin rate [p = 0.064]). Accordingly, the median CRR of the nonpalpable lesions was higher than that of the palpable lesions (3.1 and 2.2, respectively; p < 0.01), and the involved margin rate was lower (17.4% and 22.5%, respectively; p = 0.13). Of patients with a CRR >4.0, 10.7% still had tumor involved margins. This study clearly shows that BCS is associated with excessive resection of healthy breast tissue while clear margins are not assured. Surgical factors should be modified to improve surgical accuracy.

Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial).

BACKGROUND: Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life. METHODS/DESIGN: In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described. CONCLUSION: The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR): NTR2579.