Marcus C. de Jong

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.

Trilateral retinoblastoma: a systematic review and meta-analysis

BACKGROUND About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma--intraocular retinoblastoma combined with a histologically similar brain tumour, most commonly in the pineal gland. We aimed to provide a systematic overview of published data for trilateral retinoblastoma, and to analyse how survival has changed. METHODS We searched Medline and Embase for scientific literature published between Jan 1, 1966, and April 14, 2014, that assessed trilateral retinoblastoma cases. We undertook a meta-analysis of survival with the Kaplan-Meier method and Cox proportional hazards regression, stratified on the basis of the original study, to account for between-study heterogeneity. FINDINGS We included 90 studies, with 174 patients with trilateral retinoblastoma. 5-year survival after pineal trilateral retinoblastoma increased from 6% (95% CI 2-15) in patients diagnosed before 1995, to 44% (26-61; p<0·0001) in those diagnosed from 1995 onwards. Before 1995, no patients with non-pineal trilateral retinoblastoma survived, but from 1995 onwards, 5-year survival was 57% (30-77; p=0·035). Hazard ratios (HR) adjusted for the presence of leptomeningeal metastases and trilateral retinoblastoma location, suggested that both conventional (HR 0·059, 95% CI 0·016-0·226; p<0·0001) and high-dose chemotherapy with stem-cell rescue (0·013, 0·002-0·064; p<0·0001) most strongly contributed to this improvement. Absence of leptomeningeal metastases (HR 2·13, 95% CI 0·98-4·60; p=0·055) were associated with improved survival. Non-pineal trilateral retinoblastomas were larger than pineal tumours (median 30 mm [range 6-100] vs 22 mm [7-60]; p=0·012), but both had similar outcomes since 1995. INTERPRETATION Our results suggest that improvements in overall survival are attributable to improved chemotherapy regimens and early detection of pineal trilateral retinoblastoma. As such, successful treatment of trilateral retinoblastoma should include screening at least at the time of retinoblastoma diagnosis and chemotherapy, which would preferably be a high-dose regimen with autologous stem-cell rescue. FUNDING None.

Diagnostic Performance of Magnetic Resonance Imaging and Computed Tomography for Advanced Retinoblastoma: A Systematic Review and Meta-analysis

PURPOSE To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard. DESIGN Systematic review and meta-analysis. PARTICIPANTS Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies. METHODS Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed. MAIN OUTCOME MEASURES Sensitivity and specificity of MRI and CT in detecting tumor extent. RESULTS Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses. CONCLUSIONS Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.

Thermal Energy during Irreversible Electroporation and the Influence of Different Ablation Parameters

PURPOSE Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE. MATERIALS AND METHODS IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated. RESULTS A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C). CONCLUSIONS Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.

Contrast-enhanced perfusion magnetic resonance imaging for head and neck squamous cell carcinoma: a systematic review.

This systematic review gives an extensive overview of the current state of perfusion-weighted magnetic resonance imaging (MRI) for head and neck squamous cell carcinoma (HNSCC). Pubmed and Embase were searched for literature until July 2014 assessing the diagnostic and prognostic performance of perfusion-weighted MRI in HNSCC. Twenty-one diagnostic and 12 prognostic studies were included for qualitative analysis. Four studies used a T2(∗) sequence for dynamic susceptibility (DSC)-MRI, 29 studies used T1-based sequences for dynamic contrast enhanced (DCE)-MRI. Included studies suffered from a great deal of heterogeneity in study methods showing a wide range of diagnostic and prognostic performance. Therefore we could not perform any useful meta-analysis. Perfusion-weighted MRI shows potential in some aspects of diagnosing HNSCC and predicting prognosis. Three studies reported significant correlations between hypoxia and tumor heterogeneity in perfusion parameters (absolute correlation coefficient |ρ|>0.6, P<0.05). Two studies reported synergy between perfusion-weighted MRI and positron emission tomography (PET) parameters. Four studies showed a promising role for response prediction early after the start of chemoradiotherapy. In two studies perfusion-weighted MRI was useful in the detection of residual disease. However more research with uniform study and analysis protocols with larger sample sizes is needed before perfusion-weighted MRI can be used in clinical practice.

Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression.

Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Research in context Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.

A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression.

Background While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. Methods We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). Results Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Interpretation Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

The potential of 3T high-resolution magnetic resonance imaging for diagnosis, staging, and follow-up of retinoblastoma

We demonstrate the value of high-resolution magnetic resonance imaging (MRI) in diagnosing, staging, and follow-up of retinoblastoma during eye-saving treatment. We have included informative retinoblastoma cases scanned on a 3T MRI system from a retrospective retinoblastoma cohort from 2009 through 2013. We show that high-resolution MRI has the potential to detect small intraocular seeds, hemorrhage, and metastatic risk factors not visible with fundoscopy (e.g., optic nerve invasion and choroidal invasion), and treatment response. Unfortunately, however, the diagnostic accuracy of high-resolution MRI is not perfect, especially for subtle intraocular seeds or minimal postlaminar optic nerve invasion. The most important application of MRI is the detection of metastatic risk factors, as these cannot be found by fundoscopy and ultrasound.

Diagnostic Accuracy of Intraocular Tumor Size Measured with MR Imaging in the Prediction of Postlaminar Optic Nerve Invasion and Massive Choroidal Invasion of Retinoblastoma

Purpose To assess the correlation of intraocular retinoblastoma tumor size measured with magnetic resonance (MR) imaging in the prediction of histopathologically determined metastatic risk factors (postlaminar optic nerve invasion and massive choroidal invasion). Materials and Methods The ethics committee approved this retrospective multicenter study with a waiver of informed consent. The study population included 370 consecutive patients with retinoblastoma (375 eyes) who underwent baseline MR imaging, followed by primary enucleation from 1993 through 2014. Tumor sizes (maximum diameter and volume) were measured independently by two observers and correlated with histopathologic risk factors. Receiver operating characteristic curves were used to analyze the diagnostic accuracy of tumor size, and areas under the curve were calculated. Logistic regression analysis was performed to evaluate potential confounders. Results Receiver operating characteristic analysis of volume and diameter, respectively, yielded areas under the curve of 0.77 (95% confidence interval [CI]: 0.70, 0.85; P < .0001) and 0.78 (95% CI: 0.71, 0.85; P < .0001) for postlaminar optic nerve invasion (n = 375) and 0.67 (95% CI: 0.57, 0.77; P = .0020) and 0.70 (95% CI: 0.59, 0.80; P = .0004) for massive choroidal tumor invasion (n = 219). For the detection of co-occurring massive choroidal invasion and postlaminar optic nerve invasion (n = 219), volume and diameter showed areas under the curve of 0.81 (95% CI: 0.70, 0.91; P = .0032) and 0.83 (95% CI: 0.73, 0.93; P = .0016), respectively. Conclusion Intraocular tumor size shows a strong association with postlaminar optic nerve invasion and a moderate association with massive choroidal invasion. These findings provide diagnostic accuracy measures at different size cutoff levels, which could potentially be useful in a clinical setting, especially within the scope of the increasing use of eye-salvage treatment strategies. (©) RSNA, 2015 Online supplemental material is available for this article.

From a Suspicious Cystic Pineal Gland to Pineoblastoma in a Patient with Familial Unilateral Retinoblastoma

Patients with hereditary retinoblastoma (Rb) have an increased risk of developing pineoblastoma. Unfortunately, most patients with concurrent pineoblastoma do not survive; Kivelä has shown that only patients who were diagnosed by screening and had a tumor smaller than 15 mm had a chance of survival. However, not all pineal lesions found with screening at the time of retinoblastoma diagnosis are pineoblastomas. Pineal cysts are a relatively common finding in the general population. In children up to 5 years of age the prevalence of pineal cysts diagnosed with magnetic resonance imaging (MRI) is 2.0%. Potentially, about 50% of pineoblastomas can be found at baseline screening and another 25% during the first year after Rb diagnosis. Therefore, baseline screening of the brain in newly diagnosed retinoblastoma is currently advised in imaging guidelines. In a recent study Rodjan and colleagues showed that the majority of pineoblastomas in Rb patients had a cystic appearance. Consequently baseline brain imaging with extended follow-up of pineal cysts might help early detection of pineoblastoma. We present a rare case of unilateral familial retinoblastoma and a suspicious cystic pineal gland on brain MR imaging that progressed into a pineoblastoma.