Adamo, Daniel A.

Motor-evoked potential (MEP) monitoring is an electrophysiologic technique useful for testing peripheral motor nerve integrity during cryoablation cases with risk of nerve injury. Previously, neuromonitoring within the magnetic resonance imaging (MRI) suite for cryoablation has not been performed as magnetic needles are used which could cause magnetic field interactions with neuromonitoring leads. We present the first report of a patient who underwent MEP monitoring during MRI-guided cryoablation of a vascular malformation adjacent to the brachial plexus. We demonstrate that MEPs may be safely and accurately performed by interleaving MRI and MEPs during treatment, reducing the risk of postprocedural complications.

2658 Background: Immune checkpoint inhibitors provide limited benefit in patients with immunologically cold tumors, characterized by a lack of T cells. This creates a niche for T cell-inducing agents such as TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFa-IRES-hIL2). While the 5/3 chimeric oncolytic adenovirus platform prompts potent immunogenic capacity per se, this virus has been armed with TNFa and IL-2 selected based on their ability to activate and attract T cells into tumors. TILT-123 capsid modification, and double selectivity devices for virus replication in cancer cells only, allow intravenous use of TILT-123. This is an important advantage over conventional oncolytic viruses whose widespread use has been hindered by the need for intratumoral injection. Methods: Here we report tumor transduction, pharmacokinetic and immune effects of a single intravenous administration of TILT-123 from three Phase 1 dose escalation clinical trials (TUNIMO-NCT04695327, TUNINTIL-NCT04217473, and PROTA-NCT05271318), with a total of 52 patients. Overall, the most common tumor types were melanoma (20), ovarian cancer (18) and sarcoma (7). In each of these trials, the first TILT-123 injection was performed intravenously, and a tumor biopsy collected 7 days later. Peripheral blood was collected before and after systemic TILT-123 treatment. No other therapy was administered concurrently. Presence of virus in blood was detected with qPCR, while presence of virus in tumor biopsies was measured with immunohistochemistry (IHC) for adenovirus proteins. Immune changes in tumors were evaluated by IHC. Results: TILT-123 was detected in the peripheral blood of all treated patients. Virus concentration was highest at 1 hour after administration, with lower levels seen 16 hours post-injection. Concurrently, IFN-γ levels increased in the patients´ serum. The lowest TILT-123 blood concentrations were observed with the lowest dose, with progressive increases in subsequent cohorts. At higher doses, TILT-123 was detected circulating in blood one week post-administration. Treatment was safe and no dose-limiting toxicity was encountered. Overall, signs of TILT-123 transduction in tumors were observed in 75% of patients evaluated in all three trials, 80% in TUNIMO patients, and 63.64% in TUNINTIL patients. Early results from PROTA suggest a positive effect of TILT-123 in tumors from all cohorts´ dosages studied. Conclusions: In summary, intravenous injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration. These data suggest that TILT-123 could be developed as an intravenous therapy. However, further increases in tumor transduction could be achieved by using multiple intravenous injections of TILT-123. Clinical trial information: NCT04695327 ; NCT04217473 ; NCT05271318 .

The purpose of this study is to investigate the potential of using ultrasound gel to mitigate the risks of skin burn at the insertion site during microwave ablation (MWA) using non-actively cooled applicators. Ex vivo experiments in porcine tissue were conducted using two identical MWA systems. Five MWA scenarios were tested at different applicator insertion depths with an ultrasound gel layer applied at the applicator insertion sites: 8 cm insertion depth with and without 4 cm thick gel, 10 cm insertion depth with and without 2 cm thick gel, and 12 cm insertion depth without gel (reference). In all experiments, temperature elevations at the applicator insertion site on the tissue surface were recorded using thermal sensors in all experiments during 10-min MWA. The application of ultrasound gel and increasing applicator insertion depths resulted in measurable reductions in temperature elevations at the applicator insertion sites. For an insertion depth of 8 cm, the temperature elevations were 39.9 ± 4.7°C and 23.2±6.5°C without and with gel, respectively (P < 0.001). For an insertion depth of 10 cm, the temperature elevations were 20.8 ± 1.5°C and 14.4 ± 1.5°C without and with gel, respectively (P < 0.001). The maximal temperature elevations corresponding to an 8 cm insertion depth with gel were comparable with those corresponding to a 10 cm insertion depth without gel. Similarly, the maximal temperature elevations (12.2 ± 1.8°C) corresponding to 12 cm insertion depth without gel were comparable to those corresponding to 10 cm insertion depth with gel. Applying ultrasound gel at the applicator insertion site can significantly reduce temperature elevations at the tissue surface during MWA procedures.

Abstract Background TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a serotype chimeric dual safety device oncolytic adenovirus armed with tumor necrosis factor alpha and interleukin-2. It was designed to improve efficacy of T-cell therapies such as immune checkpoint blockade or adoptive cell transfer. We present biological and immunological endpoints from an open-label phase 1 dose escalation study of TILT-123 in combination with anti-PD-1 pembrolizumab in platinum resistant or refractory ovarian cancer patients. Experimental procedures In this dose escalation trial (NCT05271318), patients were first injected with an intravenous (i.v.) dose of TILT-123 ranging from 3x1011 to 4x1012 virus particles (VP), followed by five intratumoural (i.t.) or intraperitoneal (i.p.) injections ranging from 1x1011 to 5x1011 VP. Patients also received intravenous injections of 200 mg pembrolizumab every three weeks starting 36 days after the first dose of TILT-123. The primary endpoint was safety, while efficacy by RECIST1.1 was a secondary endpoint. Collection of tumor biopsies, circulating immune cells, serum, saliva, urine and feces enabled multi-omic evaluation of mechanism of action and identification of predictive biomarkers. Summary of data As of January 2nd 2024, 15 patients received trial therapy. No dose-limiting toxicities were observed and the most frequent AEs associated with therapy included chills and nausea (&gt;10% of patients). Stable disease by RECIST 1.1 was seen in 67% in 12 evaluable patients. TILT-123 replication was detected in both injected and non-injected tumors as assessed by qPCR and anti-hexon IHC. Multiplex immunofluorescence demonstrated induction of robust immunological activity in both injected and non-injected tumors, including significant increase in granzyme B+, PD-1+ CD4+ and CD8+ T cells as well as PD-1+ NK cells. Baseline intratumoral CD4+, FOXP3+ regulatory T cells were not associated with clinical response. Tertiary lymphoid structures and lymphoid aggregates were identified in patients showing long term disease control. Low to medium titers of neutralizing antibodies against 5/3 chimeric adenovirus were detected in 57% of patients at baseline and were not a predictive factor of disease control. No patients had high titers at baseline. Conclusion TILT-123 in combination with anti-PD-1 pembrolizumab was safe and resulted in disease control in both platinum resistant and refractory ovarian cancer patients. Analysis of biological samples revealed insights into mechanism of action, including an immune profile predictive of clinical response. These results, together with those from four other trials (NCT04695327, NCT04217473, NCT06125197 and NCT05222932) set the stage for continued clinical evaluation of TILT-123. Citation Format: James H. Clubb, Matthew S. Block, Johanna Mäenpää, Santeri Pakola, Lyna Haybout, Dafne C. Quixabeira, Tatiana Kudling, Mirte van der Heijden, Elise Jirovec, Tuomo Alanko, Daniel A. Adamo, Susan Ramadan, Jorma Sormunen, Juha Kononen, Julia W. Cohen, Nadena Singh, John Goldfinch, Suvi Sorsa, Riikka Havunen, Claudia Kistler, João M. Santos, Víctor Cervera-Carrascon, Akseli Hemminki. Immunological activity of oncolytic adenovirus encoding TNFα and IL-2 (TILT-123) in combination with pembrolizumab in platinum resistant or refractory ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT139.

AbstractBackgroundComputed tomography (CT) is routinely used to guide cryoablation procedures. Notably, CT‐guidance provides 3D localization of cryoprobes and can be used to delineate frozen tissue during ablation. However, metal‐induced artifacts from ablation probes can make accurate probe placement challenging and degrade the ice ball conspicuity, which in combination could lead to undertreatment of potentially curable lesions.PurposeIn this work, we propose an image‐based neural network (CNN) model for metal artifact reduction for CT‐guided interventional procedures.MethodsAn image domain metal artifact simulation framework was developed and validated for deep‐learning‐based metal artifact reduction for interventional oncology (MARIO). CT scans were acquired for 19 different cryoablation probe configurations. The probe configurations varied in the number of probes and the relative orientations. A combination of intensity thresholding and masking based on maximum intensity projections (MIPs) was used to segment both the probes only and probes + artifact in each phantom image. Each of the probe and probe + artifact images were then inserted into 19 unique patient exams, in the image domain, to simulate metal artifact appearance for CT‐guided interventional oncology procedures. The resulting 361 pairs of simulated image volumes were partitioned into disjoint training and test datasets of 304 and 57 volumes, respectively. From the training partition, 116 600 image patches with a shape of 128 × 128 × 5 pixels were randomly extracted to be used for training data. The input images consisted of a superposition of the patient and probe + artifact images. The target images consisted of a superposition of the patient and probe only images. This dataset was used to optimize a U‐Net type model. The trained model was then applied to 50 independent, previously unseen CT images obtained during renal cryoablations. Three board‐certified radiologists with experience in CT‐guided ablations performed a blinded review of the MARIO images. A total of 100 images (50 original, 50 MARIO processed) were assessed across different aspects of image quality on a 4‐point likert‐type item. Statistical analyses were performed using Wilcoxon signed‐rank test for paired samples.ResultsReader scores were significantly higher for MARIO processed images compared to the original images across all metrics (all p < 0.001). The average scores of the overall image quality, iceball conspicuity, overall metal artifact, needle tip visualization, target region confidence, and worst metal artifact, needle tip visualization, iceball conspicuity, and target region confidence improved by 34.91%, 36.29%, 39.94%, 34.17%, 35.13%, and 45.70%, respectively.ConclusionsThe proposed method of image‐based metal artifact simulation can be used to train a MARIO algorithm to effectively reduce probe‐related metal artifacts in CT‐guided cryoablation procedures.

AbstractIntroduction/PurposePercutaneous core‐needle biopsy of the testicle has been shown to be a safe and effective method of obtaining tissue for histological analysis and can be considered in specific clinical scenarios. While the use of spermatic cord block has been shown to be effective in pain relief in the emergent setting and as an anaesthetic option for inguinal surgery, its use in percutaneous core‐needle biopsy has not been well described. Through this case series, we present our experience and technique of ultrasound‐guided percutaneous core‐needle biopsy using spermatic cord block in the setting of indeterminant testicular masses.MethodsOur departmental biopsy database was reviewed to identify patients who underwent percutaneous core‐needle biopsy of the testicle from March 2010 to July 2022 and who also received spermatic cord block during the procedure.ResultsThree patients were identified who met the search criteria. All three patients presented for the evaluation of indeterminant testicular mass and had a known non‐testicular primary cancer diagnosis at the time of biopsy. All three biopsies were performed using a combination of spermatic cord block, moderate sedation, and local anaesthetic. Biopsies were obtained using an 18‐gauge spring‐loaded device with 4‐5 core samples obtained during each procedure. All biopsies were well tolerated without significant pain or post‐procedure complications.DiscussionUltrasound‐guided percutaneous core‐needle testicular biopsy using spermatic cord block is a safe and effective option in sampling indeterminate testicular masses while maintaining patient comfort.ConclusionThe inclusion of a spermatic cord block in combination with local anaesthetic and moderate sedation has become standard practice in our institution, as we believe this maximises patient comfort and safety resulting in a better patient experience.

Background: Percutaneous image-guided thermal ablation has emerged as a treatment option for vascular malformations (VM). However, prospective data on intermediate to long-term effectiveness with uniform follow-up are lacking. Purpose: To prospectively evaluate the 12-month pain severity and pain interference outcomes following percutaneous MRI-guided laser ablation and cryoablation of focal painful, peripheral soft tissue VM. Materials and Methods: Participants undergoing clinically indicated MRI-guided laser ablation and cryoablation for focal painful (worst pain ≥4 out of 10 on Visual Analog Scale), peripheral soft tissue vascular malformations (VM) were enrolled in an IRB-approved prospective, observational study after giving informed consent. Participants completed the Brief Pain Inventory questionnaire prior to ablation and 1, 3, 6, and 12-month postablation. Differences in pain severity and interference outcomes from baseline on a 0 to 10 scale were compared using a paired t-test. Results: Seventeen participants (15 female; mean age 28.3 ± 9.3 years) underwent 24 MRI-guided and monitored ablation sessions including laser (n = 21), cryoablation (n = 2), or both (n = 1) for treatment of painful slow-flow (n = 16) or high-flow (n = 1) VM. Median maximal VM diameter was 5.7 cm (range 1.1 to 31.0 cm). Mean (±SD) preablation worst pain score was 7.9 ± 1.4. There was a significant decrease in worst pain at 1-month postablation (–3.5 ± 2.9; P = .0007) that was sustained at 3 (–3.4 ± 3.2; P = .0007), 6 (–4.2 ± 3.6; P = .0003), and 12 months (–3.6 ± 3.9; P = .002), with similar results for average, current, and least pain scores. There was a significant improvement in pain interference outcomes at 12-month postablation: general activity (P = .018), walking ability (P = .008), work (P = .003), sleep (P = .007), and enjoyment of life (P = .033). Conclusions: These data suggest that MRI-guided and monitored thermal ablation is safe and provides early and sustained significant improvements in pain severity and pain interference outcomes during the first year of follow-up in participants with focal painful peripheral soft tissue VM.

AbstractObjectiveThe objective of this study was to evaluate the role of adrenal venous sampling (AVS) in guiding the management of patients with corticotropin (ACTH)‐independent glucocorticoid secretory autonomy and bilateral adrenal masses.Design and PatientsA cohort with 25 patients underwent AVS and surgical management.MeasurementsCortisol was measured from the adrenal veins (AVs) and inferior vena cava (IVC). AV/IVC cortisol ratio and cortisol lateralization ratio (CLR) (dominant AV cortisol concentration divided by the nondominant AV cortisol concentration) were calculated. Posthoc receiver‐operating characteristic curves were generated to determine the specificity of revised AV/IVC cortisol ratio and CLR in differentiating unilateral from bilateral disease.ResultsPatients underwent unilateral (n = 21) or bilateral (n = 4) adrenalectomy. The mean AV/IVC cortisol ratio for unilateral adrenalectomy was 12.1 ± 9.6 (dominant) and 4.7 ± 3.8 (contralateral) with a mean CLR of 3.6 ± 3.5. The mean AV/IVC cortisol ratio for bilateral adrenalectomy was 7.5 ± 2.1, with a mean CLR of 1.1 ± 0.6. At a mean follow‐up of 22 months, one patient who underwent unilateral adrenalectomy for the predicted bilateral disease developed recurrent mild autonomous cortisol secretion. Posthoc analyses demonstrated a specificity of 95%–100% for unilateral disease with AV/IVC cortisol ratio >9 for one side, <2.0 for the opposite side and a CLR > 2.3. The specificity was 80%–90% for bilateral disease with AV/IVC cortisol ratio >5.1 bilaterally and a CLR < 1.1.ConclusionsAmong patients with bilateral adrenal masses and ACTH‐independent autonomous cortisol secretion, AVS can distinguish between unilateral and bilateral disease with high specificity and may guide surgical management.

Abstract Background and study aims Management of malignant gastrointestinal obstruction (MGIO) is more challenging in the presence of peritoneal carcinomatosis (PC). Outcomes data to guide the management of MGIO with PC are lacking. We aimed to compare the clinical outcomes and adverse events between endoscopic and surgical palliation and identify predictors of stent success in patients with MGIO with PC. Patients and methods Consecutive inpatients with MGIO with PC between 2000 and 2018 who underwent palliative surgery or enteral stenting were included. Clinical success was defined as relief of obstructive symptoms. Results Fifty-seven patients with enteral stenting and 40 with palliative surgery were compared. The two groups did not differ in rates of technical success, 30-day mortality, or recurrence. Clinical success from a single intervention (63.2 % versus 95 %), luminal patency duration (27 days vs. 145 days), and survival length (148 days vs. 336 days) favored palliative surgery (all P < 0.05) but the patients in the surgery group had a trend toward better Eastern Cooperative Oncology Group (ECOG) status. The rate of adverse events (AEs) (10.5 % vs. 50 %), the severity of AEs, and length of hospital stay (4.5 days vs. 9 days) favored enteral stenting (P < 0.05). The need for more than one stent was associated with a higher likelihood of stent failure. Conclusions Our study suggests that enteral stenting is safer and associated with a shorter hospital stay than palliative surgery, although unlike other MGIOs, clinical success is lower in MGIO with PC. Identification of the right candidates and potential predictors of clinical success in ECOG-matched large-scale studies is needed to validate these results.