Hug sign in intraprocedural cone-beam-CT to predict short-term response to combined treatment of hepatocellular carcinoma.

OBJECTIVES: Combined treatment of ablation and chemoembolization for hepatocellular carcinoma represents a promising therapy to increase treatment efficacy and improve patient survival. The "hug sign" is a recently introduced radiological sign consisting in deposition of beads/contrast agent during transarterial chemoembolization in the hyperemic area surrounding the post-ablation volume, seen during intraprocedural unenhanced cone-beam CT, that may indicate intraprocedural success. Aim of our retrospective study was to analyze the usefulness of the "hug sign" at the intraprocedural unenhanced cone-beam CT as an early predictor of response to combined treatment, based on the hug sign angle. MATERIALS AND METHODS: Between January 2017 and September 2021 all patients with hepatocellular carcinoma which underwent a combined treatment of thermal ablation followed by chemoembolization were enrolled. All treated patients underwent immediate post-procedural unenhanced cone-beam CT to evaluate the deposition of contrast agent, lipiodol or radiopaque beads and to assess the percentage of coverage of the ablated area with the contrast agent (hug sign angle). Patients with missing pre-procedural, intra-procedural and/or post-procedural data/imaging, or with poor-quality post-procedural cone-beam CT images were excluded. RESULTS: 128 patients (mean age, 69.3 years ± 1.1 [standard deviation]; 87 men) were evaluated. Our study evidenced that 84.4% (81/85) of patients with a hug sign angle of 360° had no residual tumor at the first 1-/3-months follow-up examination. A hug sign angle of 360° also showed to be an independent protective factor against residual tumor at multivariate analysis. CONCLUSION: Unenhanced cone-beam CT performed at the end of a combined treatment with ablation plus chemoembolization can effectively predict an early treatment response on radiological images, when a hug sign angle of 360° was detected.

Prediction of Protumorigenic Effects after Image-Guided Radiofrequency Ablation of Hepatocellular Carcinoma Using Biomarkers.

PURPOSE: To perform radiofrequency (RF) ablation of hepatocellular carcinoma (HCC) and to assess serological and histopathological markers of tumorigenesis in distant untreated tumors to determine whether these were associated with unfavorable outcomes such as early relapse and increased biological aggressiveness. MATERIALS AND METHODS: The study cohort comprised 13 patients from a prospective single-arm study. All patients underwent 2 ablation sessions of multifocal HCC nodules 14 days apart. Core biopsy samples of untreated tumors were acquired at baseline and at the time of the second ablation session. Samples were stained immunohistochemically with Ki-67 (proliferation) and CD34 (microvasculature). Blood plasma was obtained at baseline and 2 days after the initial ablation session and analyzed for hepatocyte growth factor (HGF), vascular endothelial growth factor C, and angiopoietin-2 using an enzyme-linked immunosorbent assay. The clinical follow-up period ranged from 7 to 25 months. Patients were stratified as responders (complete remission or limited and delayed recurrence at >6 months; n = 6) or nonresponders (any recurrence within 6 months or >3 new tumors or any new tumor of >3 cm thereafter; n = 7). RESULTS: In 3 of 7 nonresponders, the Ki-67 index markedly increased in untreated tumors, whereas Ki-67 was stable in all responders. Microvascular density strongly increased in a single nonresponder only. HGF and angiopoietin-2 increased by >30% in 3 of 7 and 4 of 7 nonresponders, respectively, whereas they were stable or decreased in responders. Overall, ≥2 biomarkers were elevated in 6 of 7 (85.7%) nonresponders, whereas 4 of 6 responders demonstrated no increased biomarker and 2 patients demonstrated increase in 1 biomarker only (P = .002). CONCLUSIONS: RF ablation of HCC can produce protumorigenic factors that induce effects in distant untreated tumors. These may potentially function as biomarkers of clinical outcome.

Interventional Oncology and Immuno-Oncology: Current Challenges and Future Trends.

Personalized cancer treatments help to deliver tailored and biologically driven therapies for cancer patients. Interventional oncology techniques are able to treat malignancies in a locoregional fashion, with a variety of mechanisms of action leading to tumor necrosis. Tumor destruction determines a great availability of tumor antigens that can be recognized by the immune system, potentially triggering an immune response. The advent of immunotherapy in cancer care, with the introduction of specific immune checkpoint inhibitors, has led to the investigation of the synergy of these drugs when used in combination with interventional oncology treatments. The aim of this paper is to review the most recent advances in the field of interventional oncology locoregional treatments and their interactions with immunotherapy.

Quantitative MRI for Assessment of Treatment Outcomes in a Rabbit VX2 Hepatic Tumor Model.

Globally, primary and secondary liver cancer is one of the most common cancer types, accounting 8.2% of deaths worldwide in 2018. One of the key strategies to improve the patient's prognosis is the early diagnosis, when liver function is still preserved. In hepatocellular carcinoma (HCC), the typical wash-in/wash-out pattern in conventional magnetic resonance imaging (MRI) reaches a sensitivity of 60% and specificity of 96-100%. However, in recent years functional MRI sequences such as hepatocellular-specific gadolinium-based dynamic-contrast enhanced MRI, diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) have been demonstrated to improve the evaluation of treatment success and thus the therapeutic decision-making and the patient's outcome. In the preclinical research setting, the VX2 liver rabbit tumor, which once originated from a virus-induced anaplastic squamous cell carcinoma, has played a longstanding role in experimental interventional oncology. Especially the high tumor vascularity allows assessing the treatment response of locoregional interventions such as radiofrequency ablation (RFA) and transcatheter arterial embolization (TACE). Functional MRI has been used to monitor the tumor growth and viability following interventional treatment. Besides promising results, a comprehensive overview of functional MRI sequences used so far in different treatment setting is lacking, thus lowering the comparability of study results. This review offers a comprehensive overview of study protocols, results, and limitations of quantitative MRI sequences applied to evaluate the treatment outcome of VX2 hepatic tumor models, thus generating a unique basis for future MRI studies and potential translation into the clinical setting. Level of Evidence: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2020;52:668-685.

US-guided laser treatment of parathyroid adenomas.

Objective: To determine the clinical efficacy of laser ablation for the tredatment of primary hyperparathyroidism (pHPT).Materials and methods: Twelve patients with pHPT were treated with laser ablation. Energy was administered by means of 1.5 m optical fibers percutaneously placed into the target via 21 G needles. A laser ablation unit (EchoLaser X4, Esaote) applied 3 W power for 400-600 s/fiber/insertion to a total 3600-9000 Joules of energy. Patient serum parathyroid hormone (PTH) and calcium levels were checked at baseline and thereafter every 6 months. Patients were followed-up for 2 years with serologic and contrast-enhanced ultrasound. Therapeutic success was defined as normal PTH and calcium levels together with disappearance of nodule-related symptoms.Results: All procedures were performed in single session. Immediately following ablation, contrast enhanced ultrasound confirmed that all but one target had become avascular (technical success rate 11/12; 92%), remaining avascular at all follow-up ultrasound examinations, thereafter. The mean volume of parathyroid nodules decreased from 0.54 cc to 0.36 cc (72.0%). Serum PTH and calcium levels were significantly lower at 1, 12 and 24 m compared to baseline (p < 0.01). By 6 m, PTH and calcium returned to normal and were stable until 24 m in all successfully treated patients. All cases of hyperparathyroid-related symptoms resolved by 6 m (ostealgia [n = 5], repeated renal colic [n = 5], vomiting [n = 3]). Only one patient (8%) reported transient dysphonia as a minor complication.Conclusion: Laser ablation of enlarged, symptomatic parathyroid glands is safe and well-tolerated and can produce long-term, sustained reduction of serum PTH and calcium levels.

In-cell determination of Lactate Dehydrogenase Activity in a Luminal Breast Cancer Model ⁻ ex vivo Investigation of Excised Xenograft Tumor Slices Using dDNP Hyperpolarized [1-13C]pyruvate.

[1-13C]pyruvate, the most widely used compound in dissolution-dynamic nuclear polarization (dDNP) magnetic resonance (MR), enables the visualization of lactate dehydrogenase (LDH) activity. This activity had been demonstrated in a wide variety of cancer models, ranging from cultured cells, to xenograft models, to human tumors in situ. Here we quantified the LDH activity in precision cut tumor slices (PCTS) of breast cancer xenografts. The Michigan Cancer Foundation-7 (MCF7) cell-line was chosen as a model for the luminal breast cancer type which is hormone responsive and is highly prevalent. The LDH activity, which was manifested as [1-13C]lactate production in the tumor slices, ranged between 3.8 and 6.1 nmole/nmole adenosine tri-phosphate (ATP) in 1 min (average 4.6 ± 1.0) on three different experimental set-ups consisting of arrested vs. continuous perfusion and non-selective and selective RF pulsation schemes and combinations thereof. This rate was converted to an expected LDH activity in a mass ranging between 3.3 and 5.2 µmole/g in 1 min, using the ATP level of these tumors. This indicated the likely utility of this approach in clinical dDNP of the human breast and may be useful as guidance for treatment response assessment in a large number of tumor types and therapies ex vivo.

CT-guided high dose rate brachytherapy can induce multiple systemic proteins of proliferation and angiogenesis predicting outcome in HCC.

BACKGROUND AND PURPOSE: To determine the potential prognostic value of proliferation and angiogenesis plasma proteins following CT-guided high dose rate brachytherapy (HDR-BT) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: For this prospective study, HDR-BT (1 × 15 Gy) was administered to 24 HCC patients. Plasma was obtained and analyzed using an Olink proteomics Target-96 immuno-oncology-panel that included multiple markers of angiogenesis and proliferation. Fold-change (FC) ratios were calculated by comparing baseline and 48 h post HDR-BT paired samples. Patients were classified as responders (n = 12) if they had no local progression within 6 months or systemic progression within 2 years. Non-responders (n = 12) had recurrence within 6 months and/or tumor progression or extrahepatic disease within 2 years. RESULTS: Proliferation marker EGF was significantly elevated in non-responders compared to responders (p = 0.0410) while FGF-2, HGF, and PlGF showed no significant differences. Angiogenesis markers Angiopoietin-1 and PDGF-B were likewise significantly elevated in non-responders compared to responders (p = 0.0171, p = 0.0462, respectively) while Angiopoietin-2, VEGF-A, and VEGFR-2 did not differ significantly. Kaplan-Meier analyses demonstrated significantly shorter time to systemic progression in patients with increased EGF and Angiopoietin-1 (p = 0.0185, both), but not in patients with one of the remaining proteins elevated (all p > 0.1). Pooled analysis for these 9 proteins showed significantly shorter time to systemic progression for FC ≥1.3 and ≥1.5 for at least 3 proteins elevated (p = 0.0415, p = 0.0193, respectively). CONCLUSION: Increased plasma levels of EGF and Angiopoietin-1 after HDR-BT for HCC are associated with poor response and may therefore function as predictive biomarkers of outcome.

Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy.

BACKGROUND AND AIMS: Prognostic biomarkers identifying patients with early tumor progression after local ablative therapy remain an unmet clinical need. The aim of this study was to investigate circulating miR-21 and miR-210 levels as prognostic biomarkers of HCC treated by CT-guided high-dose rate brachytherapy (HDR-BT). MATERIALS AND METHODS: 24 consecutive HCC patients (BCLC A and B) treated with CT-guided HDR-BT (1 × 15 Gy) were included in this prospective IRB-approved study. RT-PCR was performed to quantify miR-21 and miR-210 levels in blood samples acquired prior to and 2 d after HDR-BT. Follow-up imaging (contrast-enhanced liver MRI and whole-body CT) was performed in 3 months follow-up intervals. Therapy response was assessed with patients classified as either responders or non-responders (12 each). Responders were defined as having no local or diffuse systemic progression within 6 months and no diffuse systemic progression exceeding 3 nodules/nodule diameter > 3 cm from 6 months to 2 years. Non-responders had recurrence within 6 months and/or tumor progression with > 3 nodules or individual lesion diameter > 3 cm or extrahepatic disease within two years, respectively. Biostatistics included parametric and non-parametric testing (Mann-Whitney-U-test), as well as Kaplan-Meier curve construction. RESULTS: The responder group demonstrated significantly decreasing miR-21 values 2 d post therapy compared to non-responders (median miR-21 2-ΔΔCт: responders 0.73 [IQR 0.34], non-responders 1.53 [IQR 1.48]; p = 0.0102). miR-210 did not show any significant difference between responders and non-responders (median miR-210 2-ΔΔCт: responders 0.74 [IQR 0.45], non-responders 0.99 [IQR 1.13]; p = 0.8399). Kaplan-Meier curves demonstrated significantly shorter time to systemic progression for increased miR-21 (p = 0.0095) but not miR-210 (p = 0.7412), with events accumulating > 1 year post therapy in non-responders (median time to systemic progression 397 days). CONCLUSION: Increasing circulating miR-21 levels are associated with poor response and shorter time to systemic progression in HDR-BT-treated HCC. This proof-of-concept study provides a basis for further investigation of miR-21 as a prognostic biomarker and potential stratifier in future clinical trials of interventional oncology therapies. TRIAL REGISTRATION: In this monocentric clinical study, we analyzed prospectively acquired data of 24 patients from the "ESTIMATE" patient cohort (Studiennummer: DRKS00010587, Deutsches Register Klinischer Studien). Ethical approval was provided by the ethics committee "Ethikkommission bei der LMU München" (reference number "17-346") on June 20, 2017 and August 26, 2020.

Early-Stage HCC Percutaneous Locoregional Management: East versus West Perspectives.

Hepatocellular carcinoma represents an important cause of death worldwide. Early-stage hepatocellular carcinoma patients not suitable for surgery can be treated with a variety of minimally invasive locoregional interventional oncology techniques. Various guidelines in different countries address the treatment of hepatocellular carcinoma, but the actual treatment is usually discussed by a multidisciplinary tumor board in a personalized manner, leading to potential treatment differences based on Western and Eastern perspectives. The aim of this paper is to integrate literature evidence with the eminent experiences collected during a focused session at the Mediterranean Interventional Oncology (MIO) Live Congress 2023.

Fibroblast growth factors induce hepatic tumorigenesis post radiofrequency ablation.

Image-guided radiofrequency ablation (RFA) is used to treat focal tumors in the liver and other organs. Despite potential advantages over surgery, hepatic RFA can promote local and distant tumor growth by activating pro-tumorigenic growth factor and cytokines. Thus, strategies to identify and suppress pro-oncogenic effects of RFA are urgently required to further improve the therapeutic effect. Here, the proliferative effect of plasma of Hepatocellular carcinoma or colorectal carcinoma patients 90 min post-RFA was tested on HCC cell lines, demonstrating significant cellular proliferation compared to baseline plasma. Multiplex ELISA screening demonstrated increased plasma pro-tumorigenic growth factors and cytokines including the FGF protein family which uniquely and selectively activated HepG2. Primary mouse and immortalized human hepatocytes were then subjected to moderate hyperthermia in-vitro, mimicking thermal stress induced during ablation in the peri-ablational normal tissue. Resultant culture medium induced proliferation of multiple cancer cell lines. Subsequent non-biased protein array revealed that these hepatocytes subjected to moderate hyperthermia also excrete a similar wide spectrum of growth factors. Recombinant FGF-2 activated multiple cell lines. FGFR inhibitor significantly reduced liver tumor load post-RFA in MDR2-KO inflammation-induced HCC mouse model. Thus, Liver RFA can induce tumorigenesis via the FGF signaling pathway, and its inhibition suppresses HCC development.

Lymphadenopathy Associated With the COVID-19 Vaccine.

The coronavirus disease 2019 (COVID-19) pandemic has dominated nearly everyone's life since its initial outbreak in the Hubei province of China in December 2019. The disease had spread quickly throughout the world causing extensive, widespread morbidity, over two million deaths, and economical and social devastation over the entire world. Researchers and pharmaceutical companies around the globe have been racing to develop potent and safe vaccines for the disease. Pfizer-BioNTech COVID-19 vaccine followed by Moderna COVID-19 mRNA-1273 vaccine were the first to receive FDA approval. These vaccines are based on messenger RNA novel technology and considered efficient in preventing contagion ensuring safety. Known side effects for this vaccine have been reported as very similar to those known for other vaccines. Specifically, lymphadenopathy has not been considered a common manifestation of COVID-19 vaccination. Israel has been cited as leading in the introduction of these vaccines, which are available for every citizen older than 16 years. Here, we present the cases of three patients who developed lymphadenopathy after the first dose of Pfizer-BioNTech COVID-19 vaccine. Time elapsed from the injection until the appearance of the enlarged nodes, clinical symptoms, and sonographic features differed between the patients, but in all cases gradual regression was noted in the enlarged nodes until complete resolution. Accordingly, to our knowledge, this is the first report describing post-COVID-19 vaccine lymphadenopathy detailing the clinical aspects, sonographic features, and outcomes.

Image-Guided Thyroid Ablation: Proposal for Standardization of Terminology and Reporting Criteria.

Background: Image-guided tumor ablation is commonly performed in clinical practice. Trying to standardize terminology and data collection to enable a more reliable comparison among the different studies, in 2003, a document entitled "Image-Guided Tumor Ablation: Proposal for Standardization of Terms and Reporting Criteria" was published by the International Working Group on Image-Guided Tumor Ablation. Since then, ablations have evolved significantly, with the development of new technology and techniques and applications. This has included benign thyroid nodules, and their ablation has become increasingly accessible, not only among radiologists but also among other specialists involved in thyroid care, including endocrinologists and surgeons. This has resulted in further inhomogeneity in how data are presented and reported among different studies, resulting in a need for standardization to homogenize language and data reporting on the topic. Summary: In February 2018 in Milano, Italy, a meeting involving specialists concerned with minimally invasive treatments of thyroid lesions was organized, and the Italian Working Group on Minimally Invasive Treatments of the Thyroid was founded with the aim of establishing a collaborative network among all clinicians working in this field. The first work of this group is to present a proposal for standardization of terminology and reporting criteria on image-guided ablations to treat benign thyroid nodules. Conclusion: This proposal was drafted with the goal of providing guidance for standardized reporting of results in studies regarding image-guided thyroid ablations. We encourage adoption of this terminology worldwide, anticipating that this will facilitate improved communication and understanding within the field and stimulate further discussion on the topic over the next years.

Treatment of Metastatic Lymph Nodes in the Neck from Papillary Thyroid Carcinoma with Percutaneous Laser Ablation.

PURPOSE: To assess the effectiveness of percutaneous laser ablation (PLA) of cervical lymph node metastases from papillary thyroid carcinoma. MATERIALS AND METHODS: 24 patients (62.3 ± 13.2 year; range 32-80) previously treated with thyroidectomy, neck dissection, and radioiodine ablation underwent ultrasound-guided PLA of 46 (18)FDG-PET/CT-positive metachronous nodal metastases. All patients were at high surgical risk or refused surgery and were unsuitable for additional radioiodine ablation. A 300 µm quartz fiber and a continuous-wave Nd-YAG laser operating at 1.064 mm were used. Technical success, rate of complications, rate of serological conversion, and local control at follow-up were derived. Fisher's exact test and Mann-Whitney U test were used and Kaplan-Meier curve calculated. RESULTS: Technical success was obtained in all 46 lymph nodes (100 %). There were no major complications. Thyroglobulin levels decreased from 8.40 ± 9.25 ng/ml before treatment to 2.73 ± 4.0 ng/ml after treatment (p = 0.011), with serological conversion in 11/24 (45.8 %) patients. Overall, local control was obtained in 40/46 (86.9 %) lymph nodes over 30 ± 11 month follow-up, with no residual disease seen at imaging in 19/24 (79.1 %) patients. Local control was achieved in 40/46 (86.9 %) lymph nodes at 1 year and in all of the 25 nodes (100 %) followed for 3 years. Estimated mean time to progression was 38.6 ± 2.7 m. CONCLUSION: Ultrasound-guided PLA is a feasible, safe, and effective therapy for the treatment of cervical lymph node metastases from papillary thyroid carcinoma.