Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

BACKGROUND: Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications. METHODS: CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories. RESULTS: Updated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing. CONCLUSIONS: The development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

Long-read genome sequencing resolves a complex 13q structural variant associated with syndromic anophthalmia.

Microphthalmia, anophthalmia, and coloboma (MAC) are a heterogeneous spectrum of anomalous eye development and degeneration with genetic and environmental etiologies. Structural and copy number variants of chromosome 13 have been implicated in MAC; however, the specific loci involved in disease pathogenesis have not been well-defined. Herein we report a newborn with syndromic degenerative anophthalmia and a complex de novo rearrangement of chromosome 13q. Long-read genome sequencing improved the resolution and clinical interpretation of a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) and terminal deletion. Sequence features at the breakpoint junctions suggested microhomology-mediated break-induced replication (MMBIR) of the maternal chromosome as the origin. Comparing this rearrangement to previously reported copy number alterations in 13q, we refine a putative dosage-sensitive critical region for MAC that might provide new insights into its molecular etiology.

An infant with congenital respiratory insufficiency and diaphragmatic paralysis: A novel BICD2 phenotype?

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cultural humility, working alliance, and Outcome Rating Scale in psychodynamic psychotherapy: Between-therapist, within-therapist, and within-client effects.

We examined how client working alliance (CWA) and therapist working alliance (TWA), and client-rated functioning (Outcome Rating Scale, ORS) related to client-perceived Cultural Humility (CH) of their therapist across the course of open-ended psychodynamic psychotherapy for 118 clients and 17 therapists. Clients and therapists completed measures of the WA after every session and clients completed the ORS prior to every session. Clients also judged their therapists' CH at Session 3, 8, and then every 8th session. CH data was partitioned into within-client, within-therapist, and between-therapists components and used to predict CWA, TWA, and ORS in a 4-level Hierarchical Linear Modeling (HLM) growth model. Between-therapist differences in CH were not related to next session CWA, TWA, or ORS, nor were these differences related to growth in CWA, TWA, and ORS. Within-therapist differences in CH were only related to the next session's CWA. At the within-client level, time-periods with higher CH, compared to clients' average CH, were associated with stronger next session (i.e., the immediate subsequent session) CWA and TWA, and time periods with lower CH, compared to clients' average CH, were associated with linear increase in CWA and TWA. Time-periods with high CH, compared to clients' average CH, were associated with significant increase in client functioning. Results suggest that lower CH weakens CWA and TWA in the next session but both CWA and TWA strengthen subsequently. By contrast, greater CH has no immediate effect on outcome but with greater CH psychological functioning increased over time. Implications for practice and research are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Do therapists improve in their ability to assess clients' satisfaction? A truth and bias model.

We used the truth and bias model to examine changes in tracking accuracy and under/overestimation (directional bias) on therapists' judgments about clients' satisfaction. We examined 3 factors of clinical experience that could moderate accuracy: (a) overall level of acquaintanceship with a client, operationalized as treatment length (i.e., less or more time seeing a client), (b) time point in therapy with a specific client, operationalized as session number (i.e., earlier or later in treatment with a client), and (c) order (1st client seen, 2nd client seen . . . last client seen across two years of training in a psychology clinic) in which clients were seen. We conducted a three-level hierarchical linear modeling using data on 6054 sessions, nested in 284 adult clients, nested in 41 doctoral student therapists providing open-ended psychodynamic individual psychotherapy. We found that therapists were able to accurately track client-rated session evaluations with less underestimation (i.e., lower tendency to estimate that clients were less satisfied than they actually were) as they gained experience (both treatment length and client order). Furthermore, therapists exhibited greater tracking accuracy gains over the span of shorter treatments and when working with clients earlier in their clinical training. In longer treatments and with clients seen later in training, tracking accuracy was stable and consistent. Implications for research and practice are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Feeling offended by clients: The experiences of doctoral student therapists.

Ten doctoral student therapists (8 White, 5 female) in 1 counseling psychology doctoral program located in the Mid-Atlantic United States were interviewed for approximately 1 hour each about their experiences of feeling offended by a client during an individual psychotherapy session. Interview data were analyzed with consensual qualitative research (CQR). Trainee therapists typically felt offended related to their sociocultural identities (e.g., being a woman, LGBTQ+, racial-ethnic minority), felt frozen after the events and uncertain about how to respond, wished they had handled the events differently, and struggled when clients expressed opinions or beliefs that ran counter to their own values. Trainees had difficulty maintaining an empathic, nonjudgmental therapeutic stance where they could both value the client and maintain their own sense of integrity and beliefs about social justice and multiculturalism. Implications for training, practice, and research are provided. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.

PURPOSE: Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing. METHODS: Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing. RESULTS: Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2. CONCLUSION: Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.

Insights into interplay between rexinoid signaling and myogenic regulatory factor-associated chromatin state in myogenic differentiation.

While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the specification and differentiation of skeletal muscle lineage. Here, we examine the genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between RXR signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.

What Are the Effects of Irreversible Electroporation on a Staphylococcus aureus Rabbit Model of Osteomyelitis?

BACKGROUND: The treatment of osteomyelitis can be challenging because of poor antibiotic penetration into the infected bone and toxicities associated with prolonged antibiotic regimens to control infection. Irreversible electroporation (IRE), a percutaneous image-guided ablation technology in which the targeted delivery of high-voltage electrical pulses permanently damages the cell membrane, has been shown to effectively control bacterial growth in various settings. However, IRE for the management of bone infections has yet to be evaluated. QUESTIONS/PURPOSES: We aimed to evaluate IRE for treating osteomyelitis by assessing (1) the efficacy of IRE to suppress the in vitro growth of a clinical isolate of S. aureus, alone or combined with cefazolin; and (2) the effects of IRE on the in vivo treatment of a rabbit model of osteomyelitis. METHODS: S. aureus strain UAMS-1 expanded in vitro to the log phase was subjected to an electric field of 2700 V/cm, which was delivered in increasing numbers of pulses. Immediately after electroporation, bacteria were plated on agar plates with or without cefazolin. The number of colony-forming units (CFUs) was scored the following day. ANOVA tests were used to analyze in vitro data. In a rabbit osteomyelitis model, we inoculated the same bacterial strain into the radius of adult male New Zealand White rabbits. Three weeks after inoculation, all animals (n = 32) underwent irrigation and débridement, as well as wound culture of the infected forelimb. Then, they were randomly assigned to one of four treatment groups (n = eight per group): untreated control, cefazolin only, IRE only, or combined IRE + cefazolin. Serial radiography was performed to assess disease progression using a semiquantitative grading scale. Bone and soft-tissue specimens from the infected and contralateral forelimbs were collected at 4 weeks after treatment for bacterial isolation and histologic assessment using a semiquantitative scale. RESULTS: The in vitro growth of S. aureus UAMS-1 was impaired by IRE in a pulse-dependent fashion; the number of CFUs/mL was different among seven pulse levels, namely 0, 10, 30, 60, 90, 120, and 150 pulses. With the number of CFUs/mL observed in untreated controls set as 100%, 10 pulses rendered a median of 50.2% (range 47.1% to 58.2%), 30 pulses rendered a median of 2.7% (range 2.5% to 2.8%), 60 pulses rendered a median of 0.014% (range 0.012% to 0.015%), 90 pulses rendered a median of 0.004% (range 0.002% to 0.004%), 120 pulses rendered a median of 0.001% (range 0.001% to 0.001%), and 150 pulses rendered a median of 0.001% (range 0.000% to 0.001%) (Kruskal-Wallis test: p = 0.003). There was an interaction between the effect of the number of pulses and the concentration of cefazolin (two-way ANOVA: F [8, 30] = 17.24; p < 0.001), indicating that combining IRE with cefazolin is more effective than either treatment alone at suppressing the growth of S. aureus UAMS-1. Likewise, the clinical response in the rabbit model (the percentage of animals without detectable residual bacteria in the bone and surrounding soft tissue after treatment) was better in the combination group than in the other groups: control, 12.5% (one of eight animals); IRE only, 12.5% (one of eight animals); cefazolin only, 25% (two of eight animals); and IRE + cefazolin, 75% (six of eight animals) (two-sided Fisher's exact test: p = 0.030). CONCLUSIONS: IRE effectively suppressed the growth of S. aureus UAMS-1 and enhanced the antibacterial effect of cefazolin in in vitro studies. When translated to a rabbit osteomyelitis model, the addition of IRE to conventional parenteral antibiotic treatment produced the strongest response, which supports the in vitro findings. CLINICAL RELEVANCE: Our results show that IRE may improve the results of standard parenteral antibiotic treatment, thus setting the stage for models with larger animals and perhaps trials in humans for validation.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.

The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.

Development of an Electroporation and Nanoparticle-based Therapeutic Platform for Bone Metastases.

Purpose To assess for nanopore formation in bone marrow cells after irreversible electroporation (IRE) and to evaluate the antitumoral effect of IRE, used alone or in combination with doxorubicin (DOX)-loaded superparamagnetic iron oxide (SPIO) nanoparticles (SPIO-DOX), in a VX2 rabbit tibial tumor model. Materials and Methods All experiments were approved by the institutional animal care and use committee. Five porcine vertebral bodies in one pig underwent intervention (IRE electrode placement without ablation [n = 1], nanoparticle injection only [n = 1], and nanoparticle injection followed by IRE [n = 3]). The animal was euthanized and the vertebrae were harvested and evaluated with scanning electron microscopy. Twelve rabbit VX2 tibial tumors were treated, three with IRE, three with SPIO-DOX, and six with SPIO-DOX plus IRE; five rabbit VX2 tibial tumors were untreated (control group). Dynamic T2*-weighted 4.7-T magnetic resonance (MR) images were obtained 9 days after inoculation and 2 hours and 5 days after treatment. Antitumor effect was expressed as the tumor growth ratio at T2*-weighted MR imaging and percentage necrosis at histologic examination. Mixed-effects linear models were used to analyze the data. Results Scanning electron microscopy demonstrated nanopores in bone marrow cells only after IRE (P , .01). Average volume of total tumor before treatment (503.1 mm3 ± 204.6) was not significantly different from those after treatment (P = .7). SPIO-DOX was identified as a reduction in signal intensity within the tumor on T2*-weighted images for up to 5 days after treatment and was related to the presence of iron. Average tumor growth ratios were 103.0% ± 75.8 with control treatment, 154.3% ± 79.7 with SPIO-DOX, 77% ± 30.8 with IRE, and -38.5% ± 24.8 with a combination of SPIO-DOX and IRE (P = .02). The percentage residual viable tumor in bone was significantly less for combination therapy compared with control (P = .02), SPIO-DOX (P , .001), and IRE (P = .03) treatment. The percentage residual viable tumor in soft tissue was significantly less with IRE (P = .005) and SPIO-DOX plus IRE (P = .005) than with SPIO-DOX. Conclusion IRE can induce nanopore formation in bone marrow cells. Tibial VX2 tumors treated with a combination of SPIO-DOX and IRE demonstrate enhanced antitumor effect as compared with individual treatments alone. © RSNA, 2017 Online supplemental material is available for this article.

Retinoid X Receptor-selective Signaling in the Regulation of Akt/Protein Kinase B Isoform-specific Expression.

The differentiation and fusion of myoblasts into mature myotubes are complex processes responding to multiple signaling pathways. The function of Akt/PKB is critical for myogenesis, but less is clear as to the regulation of its isoform-specific expression. Bexarotene is a drug already used clinically to treat cancer, and it has the ability to enhance the commitment of embryonic stem cells into skeletal muscle lineage. Whereas bexarotene regulates fundamental biological processes through retinoid X receptor (RXR)-mediated gene expression, molecular pathways underlying its positive effects on myogenesis remain unclear. In this study, we have examined the signaling pathways that transmit bexarotene action in the context of myoblast differentiation. We show that bexarotene promotes myoblast differentiation and fusion through the activation of RXR and the regulation of Akt/PKB isoform-specific expression. Interestingly, bexarotene signaling appears to correlate with residue-specific histone acetylation and is able to counteract the detrimental effects of cachectic factors on myogenic differentiation. We also signify an isoform-specific role for Akt/PKB in RXR-selective signaling to promote and to retain myoblast differentiation. Taken together, our findings establish the viability of applying bexarotene in the prevention and treatment of muscle-wasting disorders, particularly given the lack of drugs that promote myogenic differentiation available for potential clinical applications. Furthermore, the model of bexarotene-enhanced myogenic differentiation will provide an important avenue to identify additional genetic targets and specific molecular interactions that we can study and apply for the development of potential therapeutics in muscle regeneration and repair.

Safety and Efficacy of an Absorbable Filter in the Inferior Vena Cava to Prevent Pulmonary Embolism in Swine.

Purpose To evaluate the immediate and long-term safety as well as thrombus-capturing efficacy for 5 weeks after implantation of an absorbable inferior vena cava (IVC) filter in a swine model. Materials and Methods This study was approved by the institutional animal care and use committee. Eleven absorbable IVC filters made from polydioxanone suture were deployed via a catheter in the IVC of 11 swine. Filters remained in situ for 2 weeks (n = 2), 5 weeks (n = 2), 12 weeks (n = 2), 24 weeks (n = 2), and 32 weeks (n = 3). Autologous thrombus was administered from below the filter in seven swine from 0 to 35 days after filter placement. Fluoroscopy and computed tomography follow-up was performed after filter deployment from weeks 1-6 (weekly), weeks 7-20 (biweekly), and weeks 21-32 (monthly). The infrarenal IVC, lungs, heart, liver, kidneys, and spleen were harvested at necropsy. Continuous variables were evaluated with a Student t test. Results There was no evidence of IVC thrombosis, device migration, caval penetration, or pulmonary embolism. Gross pathologic analysis showed gradual device resorption until 32 weeks after deployment. Histologic assessment demonstrated neointimal hyperplasia around the IVC filter within 2 weeks after IVC filter deployment with residual microscopic fragments of polydioxanone suture within the caval wall at 32 weeks. Each iatrogenic-administered thrombus was successfully captured by the filter until resorbed (range, 1-4 weeks). Conclusion An absorbable IVC filter can be safely deployed in swine and resorbs gradually over the 32-week testing period. The device is effective for the prevention of pulmonary embolism for at least 5 weeks after placement in swine. © RSNA, 2017.

Irreversible Electroporation in the Epidural Space of the Porcine Spine: Effects on Adjacent Structures.

Purpose To determine the effects of irreversible electroporation (IRE) on the neural tissues after ablation in the epidural space of the porcine spine. Materials and Methods The institutional animal care and use committee approved this study. With the IRE electrode positioned in the right lateral recess of the spinal epidural space, 20 IRE ablations were performed with computed tomographic (CT) guidance by using different applied voltages in four animals that were euthanized immediately after magnetic resonance (MR) imaging of the spine, performed 6 hours after IRE (terminal group). Histopathologic characteristics of the neural tissues were assessed and used to select a voltage for a survival study. Sixteen CT-guided IRE ablations in the epidural space were performed by using 667 V in four animals that were survived for 7 days (survival group). Clinical characteristics, MR imaging findings (obtained 6 hours after IRE and before euthanasia), histopathologic characteristics, and simulated electric field strengths were assessed. A one-way analysis of variance was used to compare the simulated electric field strength to histologic findings. Results The mean distance between the IRE electrode and the spinal cord and nerve root was 1.71 mm ± 0.90 and 8.47 mm + 3.44, respectively. There was no clinical evidence of paraplegia after IRE ablation. MR imaging and histopathologic examination showed no neural tissue lesions within the spinal cord; however, five of 16 nerve roots (31.2%) demonstrated moderate wallerian degeneration in the survival group. The severity of histopathologic injury in the survival group was not significantly related to either the simulated electric field strength or the distance between the IRE electrode and the neural structure (P > .05). Conclusion Although the spinal cord appears resistant to the toxic effects of IRE, injury to the nerve roots may be a limiting factor for the use of IRE ablation in the epidural space. © RSNA, 2016 Online supplemental material is available for this article.

Interaction between vascularized lymph node transfer and recipient lymphatics after lymph node dissection-a pilot study in a canine model.

BACKGROUND: Vascularized lymph node transfer (VLNT) has become more widespread for surgical treatment of lymphedema. However, interaction between a transferred lymph node and the recipient lymphatic system in relieving lymphedema has not been identified. The aims of this study were to investigate anatomic changes in the lymphatic system in the forelimb of a canine after lymph node dissection and irradiation and to clarify the interaction between the transferred lymph node and recipient lymphatics. MATERIALS AND METHODS: Two adult female mongrel canines were used for this exploratory study. The unilateral axillary and lower neck node dissections were performed, and 15-Gy irradiation was applied on postoperative day 3. After 1 y, a VLNT flap was harvested from the lower abdominal region and inset in the axilla with vascular anastomoses. The girth of each forelimb was determined with a tape measure at different time points. Indocyanine green fluorescence lymphography and lymphangiography were performed before and after each surgery to evaluate morphologic changes in the lymphatics. RESULTS: Both canines revealed identical changes in the lymphatic system, but only one canine developed lymphedema. After lymph node dissection, a collateral lymphatic pathway formed a connection to the contralateral cervical node. After VLNT, an additional collateral pathway formed a connection to the internal mammary node via the transferred node in the axilla. CONCLUSIONS: The findings suggest that the lymphatic system has a homing mechanism, which allows the severed lymphatic vessels to detect and connect to adjacent lymph nodes. VLNT may create new collateral pathways to relieve lymphedema.

Irreversible electroporation of the lumbar vertebrae in a porcine model: is there clinical-pathologic evidence of neural toxicity?

PURPOSE: To evaluate the effects of irreversible electroporation (IRE) in the porcine spine. MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Twenty computed tomographically guided IRE ablations in either a transpedicular location or directly over the posterior cortex were performed in the lumbar vertebrae of 10 pigs by a single operator. T1- and T2-weighted magnetic resonance (MR) imaging was performed with and without contrast material 2 or 7 days after ablation. Mathematical modeling was performed to estimate the extent of ablation. Clinical, radiologic, pathologic, and simulation findings were analyzed. The Miller low-bias back transformation was used to construct 95% confidence intervals for the mean absolute percentage difference between the maximum length and width of the ablation zone on MR images and pathologic measurements by using square-root-transformed data. RESULTS: Bipolar IRE electrode placement and ablation were successful in all cases. The mean distances from the IRE electrode to the posterior wall of the vertebral body or the exiting nerve root were 2.93 mm ± 0.77 (standard deviation) and 7.87 mm ± 1.99, respectively. None of the animals had neurologic deficits. Well-delineated areas of necrosis of bone, bone marrow, and skeletal muscle adjacent to the vertebral body were present. Histopathologic changes showed outcomes that matched with simulation-estimated ablation zones. The percentage absolute differences in the ablation measurements between MR imaging and histopathologic examination showed the following average errors: 24.2% for length and 28.8% for width measurements on T2-weighted images, and 26.1% for length and 33.3% for width measurements on T1-weighted contrast material-enhanced images. CONCLUSION: IRE ablation in the porcine spine is feasible and safe and produces localized necrosis with minimal neural toxicity. Signal intensity changes on images acquired with standard MR imaging sequences demonstrate the ablation zone to be larger than that at histopathologic examination.

Rabbit hepatic arterial anatomy variations: implications on experimental design.

BACKGROUND: The VX2 rabbit model of liver cancer is commonly used to evaluate the efficacy of locoregional anticancer therapy and knowledge of the hepatic arterial anatomy in the rabbit is important for catheter-directed experiments. PURPOSE: To describe the normal anatomy and anatomic variations of the celiac axis and hepatic artery in the rabbit. MATERIAL AND METHODS: Angiograms of 222 rabbits were retrospectively reviewed. The branching pattern of the celiac axis was classified and the diameters of the major branches were measured. Paired t-tests were used to compare the difference between the average sizes of arteries. RESULTS: Variant celiac axis or hepatic artery anatomy was noted in 25.9% of angiograms, with the gastric branches arising from the proper hepatic artery in 23.3% of cases. The celiac axis could be successfully classified into one of five distinct branching patterns in 193 (86.9%) cases. The mean diameters of the right and left hepatic arteries were 0.67 mm (95% CI [0.64, 0.7]) and 1.25 mm (95% CI [1.19, 1.31]), respectively. The mean diameters of the medial and lateral branches of the left hepatic artery were 0.63 mm (95% CI [0.6, 0.67]) and 0.91 mm (95% CI [0.86, 0.96]), respectively. The right hepatic artery was significantly smaller than the left hepatic artery and the lateral branch of the left hepatic artery (all P values <0.0001). CONCLUSION: Arterial variants in the rabbit are not uncommon. The proper hepatic artery often gives origin to gastric artery branches. To facilitate superselective intra-arterial intervention, the left lateral lobe of the liver should be targeted for tumor implantation because of the significant size difference between the right and left hepatic arteries.