Are histomorphological patterns a predictor for survival in uveal melanoma patients with hepatic metastases undergoing hepatic artery infusion chemotherapy?

INTRODUCTION: In uveal melanoma (UM) patients with hepatic metastases, hepatic artery infusion chemotherapy (HAIC) is a viable, palliative treatment option. To evaluate the impact of two histomorphological patterns (spindle cell vs. epithelioid) of liver metastases on median overall survival (mOS) in UM patients undergoing HAIC. METHODS: A retrospective analysis with 60 UM patients (29 females, mean age: 61.6 ± 12.1 years) with hepatic metastases was performed. Histomorphological patterns in metastases were analysed and classified as either predominant spindle cell or epithelioid pattern. mOS between both patient groups was analysed using Kaplan-Meier curves and the log-rank test. RESULTS: In 73.3% (44/60) of the metastases, a predominant epithelioid pattern, in 21.7% (13/60) a predominant spindle cell pattern, and in 5% (3/60) other patterns were found. No significant differences between patients with an epithelioid (mOS: 14.2 months, 95% CI: 8.8-19.6) and a spindle cell pattern (mOS: 14.4 months, 95% CI: 4.3-24.5) were detected by the log-rank test, χ2(2) = 0.22, P = 0.881. CONCLUSION: Histomorphological patterns of UM metastases do not seem to be a predictor for mOS in UM patients undergoing HAIC.

Dose-Response Relationship in Patients with Liver Metastases from Neuroendocrine Neoplasms Undergoing Radioembolization with 90Y Glass Microspheres.

The benefit of multicompartment dosimetry in the radioembolization of neuroendocrine neoplasms is not firmly established. We retrospectively assessed its potential with patient outcome. Methods: Forty-three patients were eligible. The association of mean absorbed dose (MAD) for tumors and treatment response was tested per lesion with a receiver operating characteristic curve analysis, and the association of MAD with progression-free survival (PFS) and overall survival was tested per patient using uni- and multivariate Cox regression analyses. Results: The area under the curve for treatment response based on MAD was 0.79 (cutoff, 196.6 Gy; P < 0.0001). For global PFS, grade (grade 2 vs. 1: hazard ratio [HR], 2.51; P = 0.042; grade 3 vs. 1: HR, 62.44; P < 0.001), tumor origin (HR, 6.58; P < 0.001), and MAD (HR, 0.998; P = 0.003) were significant. For overall survival, no prognostic parameters were significant. Conclusion: In line with prior publications, a MAD of more than 200 Gy seemed to favor treatment response. MAD was also associated with PFS and may be of interest for radioembolization planning for neuroendocrine neoplasm patients.

Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab.

Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD.

Voxel-Based Dosimetry Predicts Hepatotoxicity in Hepatocellular Carcinoma Patients Undergoing Radioembolization with 90Y Glass Microspheres.

Personalized dosimetry holds promise to improve radioembolization treatment outcomes in hepatocellular carcinoma (HCC) patients. To this end, tolerance absorbed doses for nontumor liver tissue are assessed by calculating the mean absorbed dose to the whole nontumor liver tissue (AD-WNTLT), which may be limited by its neglect of nonuniform dose distribution. Thus, we analyzed whether voxel-based dosimetry could be more accurate in predicting hepatotoxicity in HCC patients undergoing radioembolization. Methods: In total, 176 HCC patients were available for this retrospective analysis; of these, 78 underwent partial- and 98 whole-liver treatment. Posttherapeutic changes in bilirubin were graded using the Common Terminology Criteria for Adverse Events. We performed voxel-based and multicompartment dosimetry using pretherapeutic 99mTc-labeled human serum albumin SPECT and contrast-enhanced CT/MRI and defined the following dosimetry parameters: AD-WNTLT; the nontumor liver tissue volume exposed to at least 20 Gy (V20), at least 30 Gy (V30), and at least 40 Gy (V40); and the threshold absorbed dose to the 20% (AD-20) and 30% (AD-30) of nontumor liver tissue with the lowest absorbed dose. Their impact on hepatotoxicity after 6 mo was analyzed using the area under the receiver-operating-characteristic curve; thresholds were identified using the Youden index. Results: The area under the curve for prediction of posttherapeutic grade 3+ increases in bilirubin was acceptable for V20 (0.77), V30 (0.78), and V40 (0.79), whereas it was low for AD-WNTLT (0.67). The predictive value could further be increased in the subanalysis of patients with whole-liver treatment, where a good discriminatory power was found for V20 (0.80), V30 (0.82), V40 (0.84), AD-20 (0.80), and AD-30 (0.82) and an acceptable discriminatory power was found for AD-WNTLT (0.63). The accuracies of V20 (P = 0.03), V30 (P = 0.009), V40 (P = 0.004), AD-20 (P = 0.04), and AD-30 (P = 0.02) were superior to that of AD-WNTLT but did not differ significantly from each other. The respective thresholds were 78% (V30), 72% (V40), and 43 Gy (AD-30). Statistical significance was not reached for partial-liver treatment. Conclusion: Voxel-based dosimetry may more accurately predict hepatotoxicity than multicompartment dosimetry in HCC patients undergoing radioembolization, which could enable dose escalation or deescalation with the intent to optimize treatment response. Our results indicate that a V40 of 72% may be particularly useful in whole-liver treatment. However, further research is warranted to validate these results.

Contrast Agent Dose Reduction in MRI Utilizing a Generative Adversarial Network in an Exploratory Animal Study.

OBJECTIVES: The aim of this study is to use virtual contrast enhancement to reduce the amount of hepatobiliary gadolinium-based contrast agent in magnetic resonance imaging with generative adversarial networks (GANs) in a large animal model. METHODS: With 20 healthy Göttingen minipigs, a total of 120 magnetic resonance imaging examinations were performed on 6 different occasions, 50% with reduced (low-dose; 0.005 mmol/kg, gadoxetate) and 50% standard dose (normal-dose; 0.025 mmol/kg). These included arterial, portal venous, venous, and hepatobiliary contrast phases (20 minutes, 30 minutes). Because of incomplete examinations, one animal had to be excluded. Randomly, 3 of 19 animals were selected and withheld for validation (18 examinations). Subsequently, a GAN was trained for image-to-image conversion from low-dose to normal-dose (virtual normal-dose) with the remaining 16 animals (96 examinations). For validation, vascular and parenchymal contrast-to-noise ratio (CNR) was calculated using region of interest measurements of the abdominal aorta, inferior vena cava, portal vein, hepatic parenchyma, and autochthonous back muscles. In parallel, a visual Turing test was performed by presenting the normal-dose and virtual normal-dose data to 3 consultant radiologists, blinded for the type of examination. They had to decide whether they would consider both data sets as consistent in findings and which images were from the normal-dose study. RESULTS: The pooled dynamic phase vascular and parenchymal CNR increased significantly from low-dose to virtual normal-dose (pooled vascular: P < 0.0001, pooled parenchymal: P = 0.0002) and was found to be not significantly different between virtual normal-dose and normal-dose examinations (vascular CNR [mean ± SD]: low-dose 17.6 ± 6.0, virtual normal-dose 41.8 ± 9.7, and normal-dose 48.4 ± 12.2; parenchymal CNR [mean ± SD]: low-dose 20.2 ± 5.9, virtual normal-dose 28.3 ± 6.9, and normal-dose 29.5 ± 7.2). The pooled parenchymal CNR of the hepatobiliary contrast phases revealed a significant increase from the low-dose (22.8 ± 6.2) to the virtual normal-dose (33.2 ± 6.1; P < 0.0001) and normal-dose sequence (37.0 ± 9.1; P < 0.0001). In addition, there was no significant difference between the virtual normal-dose and normal-dose sequence. In the visual Turing test, on the median, the consultant radiologist reported that the sequences of the normal-dose and virtual normal-dose are consistent in findings in 100% of the examinations. Moreover, the consultants were able to identify the normal-dose series as such in a median 54.5% of the cases. CONCLUSIONS: In this feasibility study in healthy Göttingen minipigs, it could be shown that GAN-based virtual contrast enhancement can be used to recreate the image impression of normal-dose imaging in terms of CNR and subjective image similarity in both dynamic and hepatobiliary contrast phases from low-dose data with an 80% reduction in gadolinium-based contrast agent dose. Before clinical implementation, further studies with pathologies are needed to validate whether pathologies are correctly represented by the network.

Prediction of left lobe hypertrophy after right lobe radioembolization of the liver using a clinical data model with external validation.

In cirrhotic patients with hepatocellular carcinoma (HCC), right-sided radioembolization (RE) with Yttrium-90-loaded microspheres is an established palliative therapy and can be considered a "curative intention" treatment when aiming for sequential tumor resection. To become surgical candidate, hypertrophy of the left liver lobe to > 40% (future liver remnant, FLR) is mandatory, which can develop after RE. The amount of radiation-induced shrinkage of the right lobe and compensatory hypertrophy of the left lobe is difficult for clinicians to predict. This study aimed to utilize machine learning to predict left lobe liver hypertrophy in patients with HCC and cirrhosis scheduled for right lobe RE, with external validation. The results revealed that machine learning can accurately predict relative and absolute volume changes of the left liver lobe after right lobe RE. This prediction algorithm could help to estimate the chances of conversion from palliative RE to curative major hepatectomy following significant FLR hypertrophy.

LiMAx Prior to Radioembolization for Hepatocellular Carcinoma as an Additional Tool for Patient Selection in Patients with Liver Cirrhosis.

BACKGROUND AND AIMS: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. PATIENTS AND METHODS: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. RESULTS: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child-Pugh score B 28 days after RE or with a deterioration in Child-Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child-Pugh score A or with stable Child-Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. CONCLUSION: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child-Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

Radiation dose aspects and establishment of diagnostic reference levels for90Y radioembolisation during angiographic procedure.

90Y radioembolisation (RE) is an angiographic procedure used in patients with both primary and secondary hepatic malignancies. Local tumour control can be achieved by short range tumour irradiation by the regional intra-arterial administration of glass or resin microspheres loaded with 90yttrium that accumulate in the tumorous tissue. The aim of this study was to investigate the radiation exposure of RE and to establish a local diagnostic reference level (DRL). In this retrospective study, dose data from 397 procedures in 306 patients (mean age 67.4 ± 10.6 years, 82 female) who underwent RE between 06/2017 and 01/2022 using one of two different angiography systems were analysed. DRL was set as the 75th percentile of the dose distribution. In the overall population, dose area product (DAP) (median (interquartile range, IQR)) was 26 Gy cm2(IQR 12-50) with a median fluoroscopy time (FT) of 4.5 min (IQR 2.9-8.0). FT and DAP increased significantly with the number of infusion positions (median, IQR): one position 23 Gy cm2(12-46), two positions 33 Gy cm2(14-60), three positions 50 Gy cm2(24-82) (p< 0.0001). Local DRL is 47 Gy cm2for RE and 111 Gy cm2for RE with additional embolisation. Radiation exposure and FT are significantly higher with increasing number of infusion positions as well as additional embolisation. Our established DRLs for RE may serve as a benchmark for dose optimisation.

Radiation Dose Aspects of Hepatic Artery Infusion Chemotherapy in Uveal Melanoma Patients with Liver Metastases.

PURPOSE: In uveal melanoma patients, liver metastases can be treated by hepatic artery infusion chemotherapy (HAIC). During this procedure, melphalan or, less frequently, fotemustine is infused into the hepatic artery or the hepatic lobe arteries in regularly repeated interventions to achieve local tumor control. The aim of this study was to investigate the radiation exposure of HAIC. MATERIAL AND METHODS: In this retrospective study, dose data from 841 procedures in 140 patients (mean age 65.3 ± 9.9 years, 74 female) who underwent HAIC between 06/2017 and 10/2021 at one of three different angiography systems were analyzed. RESULTS: In the overall population, dose area product (DAP) (median (IQR)) was 1773 cGy·cm2 (884-3688). DAP was significantly higher in the first intervention, where a complete diagnostic workup of the vasculature was performed, than in follow-up interventions: 5765 cGy·cm2 (3160-8804) versus 1502 cGy·cm2 (807-2712) (p < 0.0001). DAP also increased significantly with the number of infusion positions (median, (IQR)): one position 1301 cGy·cm2 (633-2717), two positions 1985 cGy·cm2 (1118-4074), three positions 6407 cGy·cm2 (2616-11590) (p < 0.0001). CONCLUSION: In uveal melanoma patients with liver metastases undergoing HAIC, radiation exposure is significantly higher both at the first intervention compared to follow-up interventions, but also with increasing number of infusion positions.

Sorafenib Versus Lenvatinib-Based Sequential Systemic Therapy for Advanced Hepatocellular Carcinoma: A Real-World Analysis.

The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.

Contrast Media Reduction in Computed Tomography With Deep Learning Using a Generative Adversarial Network in an Experimental Animal Study.

OBJECTIVE: This feasibility study aimed to use optimized virtual contrast enhancement through generative adversarial networks (GAN) to reduce the dose of iodine-based contrast medium (CM) during abdominal computed tomography (CT) in a large animal model. METHODS: Multiphasic abdominal low-kilovolt CTs (90 kV) with low (low CM, 105 mgl/kg) and normal contrast media doses (normal CM, 350 mgl/kg) were performed with 20 healthy Göttingen minipigs on 3 separate occasions for a total of 120 examinations. These included an early arterial, late arterial, portal venous, and venous contrast phase. One animal had to be excluded because of incomplete examinations. Three of the 19 animals were randomly selected and withheld for validation (18 studies). Subsequently, the GAN was trained for image-to-image conversion from low CM to normal CM (virtual CM) with the remaining 16 animals (96 examinations). For validation, region of interest measurements were performed in the abdominal aorta, inferior vena cava, portal vein, liver parenchyma, and autochthonous back muscles, and the contrast-to-noise ratio (CNR) was calculated. In addition, the normal CM and virtual CM data were presented in a visual Turing test to 3 radiology consultants. On the one hand, they had to decide which images were derived from the normal CM examination. On the other hand, they had to evaluate whether both images are pathological consistent. RESULTS: Average vascular CNR (low CM 6.9 ± 7.0 vs virtual CM 28.7 ± 23.8, P < 0.0001) and parenchymal (low CM 1.5 ± 0.7 vs virtual CM 3.8 ± 2.0, P < 0.0001) CNR increased significantly by GAN-based contrast enhancement in all contrast phases and was not significantly different from normal CM examinations (vascular: virtual CM 28.7 ± 23.8 vs normal CM 34.2 ± 28.8; parenchymal: virtual CM 3.8 ± 2.0 vs normal CM 3.7 ± 2.6). During the visual Turing testing, the radiology consultants reported that images from normal CM and virtual CM were pathologically consistent in median in 96.5% of the examinations. Furthermore, it was possible for the examiners to identify the normal CM data as such in median in 91% of the cases. CONCLUSIONS: In this feasibility study, it could be demonstrated in an experimental setting with healthy Göttingen minipigs that the amount of CM for abdominal CT can be reduced by approximately 70% by GAN-based contrast enhancement with satisfactory image quality.

Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience.

Objective: Evaluation of the efficacy and safety of atezolizumab/bevacizumab in a real-world HCC cohort, including patients with impaired liver function and prior systemic therapy. Methods: Retrospective analysis of 147 HCC patients treated with atezolizumab/bevacizumab at six sites in Germany and Austria. Results: The overall response rate and disease control rate were 20.4% and 51.7%, respectively. Seventy-three patients (49.7%) met at least one major exclusion criterion of the IMbrave150 trial (IMbrave-OUT), whereas 74 patients (50.3%) were eligible (IMbrave-IN). Median overall survival (mOS) as well as median progression-free survival (mPFS) was significantly longer in IMbrave-IN versus IMbrave-OUT patients [mOS: 15.0 months (95% confidence interval (CI): 10.7-19.3] versus 6.0 months (95% CI: 3.2-8.9; p < 0.001) and mPFS: 8.7 months (95% CI: 5.9-11.5) versus 3.7 months (95% CI: 2.7-4.7; p < 0.001)]. Prior systemic treatment did not significantly affect mOS [hazard ratio (HR): 1.32 (95% CI: 0.78-2.23; p = 0.305)]. mOS according to ALBI grades 1/2/3 were 15.0 months (95% CI: not estimable), 8.6 months (95% CI: 5.4-11.7), and 3.2 months (95% CI: 0.3-6.1), respectively. ALBI grade and ECOG score were identified as independent prognostic factors [ALBI grade 2 versus 1; HR: 2.40 (95% CI: 1.34 - 4.30; p = 0.003), ALBI grade 3 versus 1; HR: 7.28 (95% CI: 3.30-16.08; p < 0.001), and ECOG ⩾2 versus 0; HR: 2.09 (95% CI: 1.03 - 4.23; p = 0.042)], respectively. Sixty-seven patients (45.6%) experienced an adverse event classified as CTCAE grade ⩾3. Patients in the IMbrave-OUT group were at increased risk of hepatic decompensation with encephalopathy (13.7% versus 1.4%, p = 0.004) and/or ascites (39.7% versus 9.5%; p < 0.001). Conclusion: In this real-world cohort, efficacy was comparable to the results of the IMbrave150 study and not affected by prior systemic treatment. ALBI grade and ECOG score were independently associated with survival. IMbrave-OUT patients were more likely to experience hepatic decompensation.

Evaluation of hearing preservation in adults with a slim perimodiolar electrode.

PURPOSE: Numerous endeavors have been undertaken to preserve hearing in cochlear implant (CI) patients. Particularly, optimization of electrode array design aims at preservation of residual hearing (RH). This study examines whether a slim perimodiolar (PM) electrode array could bear the capability to preserve hearing. METHODS: A total of 47 patients underwent cochlear implantation receiving the PM electrode. (i) Patients with pure tone audiogram (PTA) thresholds better than 85 dB and/or hearing loss for Freiburg speech test numbers less than 60 dB and more than 50% maximum monosyllabic understanding were assigned to the RH group (n = 17), while all others belonged to the noRH group (n = 30). (ii) Another group implanted with a slim straight, lateral wall (LW) electrode was recruited for comparison. RESULTS: We compared 17 RH-30 noRH patients all receiving the PM electrode. RH in PM recipients decreased faster than in LW recipients. No significant differences were observed between both (RH v/s noRH) groups in NRT thresholds, Freiburg speech test and A§E® phonemes. Analogous satisfaction levels were indicated through the questionnaires in terms of sound quality, hearing in silence, noise and directional hearing in both groups. CONCLUSIONS: The results suggest that hearing preservation is influenced not only by electrode shape but various factors. This study opens an avenue for further investigations to elucidate and enumerate the causes for progressive hearing loss.

New chemistries and enzymes for synthetic genetics.

Beyond the natural nucleic acids DNA and RNA, nucleic acid chemistry has unlocked a whole universe of modifications to their canonical chemical structure, which can in various ways modify and enhance nucleic acid function and utility for applications in biotechnology and medicine. Unlike the natural modifications of tRNA and rRNA or the epigenetic modifications in mRNA and genomic DNA, these altered chemistries are not found in nature and therefore these molecules are referred to as xeno-nucleic acids (XNAs). In this review we aim to focus specifically on recent progress in a subsection of this vast field-synthetic genetics-concerned with encoded synthesis, reverse transcription, and evolution of XNAs.

Transimpedance Matrix Measurements Reliably Detect Electrode Tip Fold-over in Cochlear Implantation.

OBJECTIVE: During cochlear implantation, electrophysiological tests are performed to document safe technical functioning of implant and electrodes. In rare cases, the apical part of the electrode folds over during insertion. The data from transimpedance matrix (TIM) measurements enable the generation of a heat map or TIM profile measuring the spatial distribution of voltage. The aim of this study was to determine the accuracy of heat-map TIM profiles and compare them with spread of excitation (SOE) measurements and intraoperative imaging for prediction of electrode malposition. STUDY DESIGN: Non-randomized study. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: One hundred patients who underwent cochlear implantation with completed TIM measurements, SOE data and perioperative imaging met the inclusion criteria and were enrolled. MAIN OUTCOME MEASURE: The electrophysiological data on the electrode array positioning was compared with temporal bone imaging. RESULTS: In seven cases, TIM measurements showed irregular results. In two cases, irregular TIM profiles were registered, but SOE data and 3D x-ray of the temporal bone didn't display deviated electrode positioning. A 3D x-ray of the skull displayed electrode tip fold-over in four cases and electrode buckling in one case. Sensitivity of TIM measurements and SOE data was 100%, specificity of TIM measurements was 97.89%, and specificity of SOE data was 98.93%. CONCLUSION: Out of 100 patients using TIM measurements for detection of electrode malpositioning, no false negative cases were detected. TIM measurements successfully detect electrode malposition in an intraoperative setting. Different heat map patterns may be observed depending on location and type of malposition.

European Multicenter Study on Degradable Starch Microsphere TACE: The Digestible Way to Conquer HCC in Patients with High Tumor Burden.

To evaluate the safety and efficacy of transarterial chemoembolization with degradable starch microspheres (DSM-TACE) for the treatment of hepatocellular carcinoma (HCC) with a high tumor burden ineligible for or failing other palliative therapies, 121 patients from three European centers were included. Kaplan-Meier analysis was used for median overall survival (OS) and time to progression (TTP, mRECIST criteria) in months with a 95% confidence interval (95% CI). Uni- (UVA) and multivariate (MVA) analyses were performed using the Cox Proportional Hazard Model. The median OS of the study cohort was 15.5 (13.3-18.7) months. The UVA identified HCC lesions ≤10 cm, unilobar involvement, lower Child-Pugh class and Barcelona Clinic Liver Cancer (BCLC) stage, absence of vascular invasion, and extrahepatic metastases as factors for prolonged survival. MVA confirmed lesions of ≤10 cm and unilobar disease as independent OS factors. Median TTP was 9.5 (7.6-10.3) months. The best response was achieved after a median of 3 (range: 1-6) treatments with CR/PR/SD/PD in 13.5%/44.5%/25.2%/16.8%, respectively. DSM-TACE was well tolerated with no major clinical adverse events and only limited major laboratory events. Preserved liver function was observed after repetitive DSM-TACE treatments. Repetitive DSM-TACE is a safe, well-tolerated and effective treatment option for HCC patients with high tumor burden ineligible or failing other palliative therapies.

PET Imaging of CD8 via SMART for Monitoring the Immunotherapy Response.

Imaging of CD8 receptors on T-cells by positron emission tomography (PET) has been considered a promising strategy for monitoring the treatment response to immunotherapy. In this study, a trial of imaging CD8 with our newly developed sequential multiple-agent receptor targeting (SMART) technology was conducted. Mice bearing a subcutaneous colorectal CT26 tumor received three times different immunotherapy treatments (PD1 or CTLA4 or combined). On either day 7 or day 14 after the first time treatment, the PET imaging study was performed with sequentially administered TCO-modified anti-CD8 antibody and 64Cu-labeled MeTz-NOTA-RGD. However, no positive response was detected, probably due to (1) inappropriate selection of biomarkers for the SMART strategy, (2) limited TCO modification on the anti-CD8 antibody, and (3) inadequate response of the CT26 tumor to the selected immunotherapies. Therefore, the potential of applying SMART in imaging CD8 was not demonstrated in this study, and further optimization will be necessary before it can be applied in imaging CD8.

The effect of chronic viral hepatitis on prognostic value of inflammatory biomarkers in hepatocellular carcinoma.

BACKGROUND: Inflammation and the immune system significantly impact the development, progression, and treatment response of hepatocellular carcinoma (HCC). This retrospective study investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in Western patients with HCC in the setting of chronic viral hepatitis. METHODS: Patients diagnosed with HCC from 2005 to 2016 were selected from a tertiary care institution. NLR was calculated within 30 days prior to treatment and dichotomized at the median. Kaplan-Meier overall survival (OS) curves and Cox hazard proportional models were utilized. Tumor and liver reserve parameters were included in multivariable analyses (MVA). RESULTS: A total of 581 patients met inclusion criteria (median age 61.0 yr; 78.3% male; 66.3% Caucasian) with median OS = 34.9 mo. 371 patients (63.9%) had viral hepatitis, of which 350 had hepatitis C (94.3%). The low-NLR group (

Predictive impact of the inflammation-based indices in uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.

BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.

Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.

Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.