Predictive Dosimetry and Outcomes of Hepatocellular Carcinoma Treated by Yttrium-90 Resin Microsphere Radioembolization: A Retrospective Analysis Using Technetium-99m Macroaggregated Albumin SPECT/CT and Planning Software.

PURPOSE: To characterize estimated mean absorbed tumor dose (ADT), objective response (OR), and estimated target dose of hepatocellular carcinoma (HCC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors receiving 90Y radioembolization between October 2015 and June 2022 was performed using a commercial software package and pretreatment technetium-99m macroaggregated albumin single photon emission computed tomography (SPECT)/computed tomography (CT). In total, 101 patients with HCC underwent 102 treatments of 127 index tumors. Patients underwent imaging every 2-3 months after treatment to determine best response per modified Response Evaluation Criteria in Solid Tumors (mRECIST). Best response was defined as the greatest response category per mRECIST and categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and progression-free survival using ADT. RESULTS: The median follow-up period was 148 days (interquartile range [IQR], 92-273 days). The median ADT of OR was 141.9 Gy (IQR, 89.4-215.8 Gy) compared with the median ADT of NR treatments of 70.8 Gy (IQR, 42.0-135.3 Gy; P < .001). Only ADT was predictive of response (hazard ratio = 2.79 [95% confidence interval {CI}: 1.44-5.40]; P = .003). At 6 months, an ADT of 157 Gy predicted 90.0% (95% CI: 41.3%-98.3%) probability of OR. At 1 year, an ADT of 157 Gy predicted 91.6% (95% CI: 78.3%-100%) probability of progression-free survival. Partition modeling and delivered activity were predictive of progression (P = .021 and P = .003, respectively). CONCLUSIONS: For HCC treated with resin microspheres, tumors receiving higher ADT exhibited higher rates of OR. An ADT of 157 Gy predicted 90.0% OR at 6 months.

Partition Dosimetry and Outcomes of Metastatic Neuroendocrine Tumors after Yttrium-90 Resin Microsphere Radioembolization.

PURPOSE: To characterize estimated mean tumor-absorbed dose (ADT) and objective response of metastatic neuroendocrine tumor (NET) after resin microsphere yttrium-90 (90Y) hepatic radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors receiving 90Y radioembolization between 2013 and 2022 involved the use of Sureplan (MIM Software, Cleveland, Ohio) and technetium-99m macroaggregated albumin single photon emission computed tomography (SPECT) combined with computed tomography. Thirty-six patients with NET underwent treatment of 56 index tumors. Patients underwent imaging every 3-6 months after treatment to determine best response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) criteria. Responses were categorized as objective response (OR) or nonresponse (NR). Wilcoxon rank sum test evaluated differences in continuous variables, and Pearson χ2 test evaluated differences in categorical variables. RESULTS: Median follow-up was 582 days (IQR, 187-1,227 days). Per RECIST 1.1, 27 patients (75%) experienced OR and 9 patients experienced (25%) NR. Of the 36 patients, 33 (92%) showed hypervascular, mRECIST-evaluable tumors. Among them, 28 patients (85%) showed mRECIST OR and 5 patients (15%) showed NR. The mRECIST OR group received a higher ADT than the NR group (median, 107 Gy; IQR, 95.1-154 Gy vs median, 70.4 Gy; IQR, 62.9-87.6 Gy; P = .048). All tumors receiving at least 120 Gy showed mRECIST OR. CONCLUSIONS: In hypervascular metastatic NET treated by 90Y resin microsphere radioembolization, higher tumor dose was associated with better tumor response per mRECIST. Doses of ≥120 Gy led to OR.

Predictive Partition Dosimetry and Outcomes after Yttrium-90 Resin Microsphere Radioembolization of Colorectal Cancer Metastatic to the Liver: A Retrospective Analysis.

PURPOSE: To characterize estimated absorbed tumor dose (ADT), objective response (OR), and estimated target dose of liver metastatic colorectal cancer (mCRC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors undergoing 90Y radioembolization from October 2013 to July 2022 was performed using MIM SurePlan and pretreatment technetium-99m macroaggregated albumin infusion data. Thirty-eight patients with mCRC underwent treatments for 59 index tumors. Patients were imaged every 2-3 months after treatment and then every 3-6 months after disease control to determine the best response per Response Evaluation Criteria in Solid Tumors 1.1. Responses were categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and local progression-free survival (LPFS) based on ADT. RESULTS: Patients had a median follow-up of 116 days (interquartile range [IQR], 69-231 days). The ADT was higher for OR patients than for NR patients (median, 130.8 [IQR, 85.6-239.0] vs 40.6 [IQR, 26.0-66.3] Gy; P < .001). A greater percentage of OR than NR patients were treated with activities calculated by partition modeling (54% vs 12%; P = .005). Only ADT predicted response (P = .032). At 6 months, an ADT of 120 Gy predicted a 55% (95% CI, 0.0%-89%) probability of OR. Only ADT (P = .010) and female sex (P = .014) predicted LPFS. At 1 year, an ADT of 120 Gy predicted a 70% (95% CI, 35%-100%) probability of LPFS. CONCLUSIONS: Tumor dose was the strongest predictor of OR for mCRC. Administration of an estimated 120 Gy to mCRC predicted 55% OR with 90Y resin microspheres at 6 months.

Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo.

The CGL1 human hybrid cell system has been utilized for many decades as an excellent cellular tool for investigating neoplastic transformation. Substantial work has been done previously implicating genetic factors related to chromosome 11 to the alteration of tumorigenic phenotype in CGL1 cells. This includes candidate tumor suppressor gene FOSL1, a member of the AP-1 transcription factor complex which encodes for protein FRA1. Here we present novel evidence supporting the role of FOSL1 in the suppression of tumorigenicity in segregants of the CGL1 system. Gamma-induced mutant (GIM) and control (CON) cells were isolated from 7 Gy gamma-irradiated CGL1s. Western, Southern and Northern blot analysis were utilized to assess FOSL1/FRA1 expression as well as methylation studies. GIMs were transfected to re-express FRA1 and in vivo tumorigenicity studies were conducted. Global transcriptomic microarray and RT-qPCR analysis were used to further characterize these unique cell segregants. GIMs were found to be tumorigenic in vivo when injected into nude mice whereas CON cells were not. GIMs show loss of Fosl/FRA1 expression as confirmed by Western blot. Southern and Northern blot analysis further reveals that FRA1 reduction in tumorigenic CGL1 segregants is likely due to transcriptional suppression. Results suggest that radiation-induced neoplastic transformation of CGL1 is in part due to silencing of the FOSL1 tumor suppressor gene promoter by methylation. The radiation-induced tumorigenic GIMs transfected to re-express FRA1 resulted in suppression of subcutaneous tumor growth in nude mice in vivo. Global microarray analysis and RT-qPCR validation elucidated several hundred differentially expressed genes. Downstream analysis reveals a significant number of altered pathways and enriched Gene Ontology terms genes related to cellular adhesion, proliferation, and migration. Together these findings provide strong evidence that FRA1 is a tumor suppressor gene deleted and epigenetically silenced after ionizing radiation-induced neoplastic transformation in the CGL1 human hybrid cell system.

Six-Year Evaluation of Same-Day Discharge following Conventional Transarterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate whether same-day discharge increased the incidence of 30-day readmission (30dR) after conventional transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at a single institution. MATERIALS AND METHODS: In this retrospective study, 253 patients with HCC underwent 521 transarterial chemoembolization procedures between 2013 and 2020. TACE was performed with 50-mg doxorubicin/10-mg mitomycin C/5-10-mL ethiodized oil/particles. Patients not requiring intravenous pain medications were discharged after a 3-hour observation, and 30dR was tracked. The primary objective was to determine the incidence of 30dR in same-day discharge patients versus patients admitted for observation using the chi-square test. Secondary objectives assessed factors associated with overnight admission and factors predictive of 30dR using generalized estimated equation calculations and logistic regression. RESULTS: In the cohort, 24 readmissions occurred within 30 days (4.6%). Same-day discharge was completed after 331 TACE procedures with sixteen 30dRs (4.8%). Patients admitted overnight were readmitted 8 times after 190 TACE procedures (4.2%). This difference was not statistically significant (P = .4). Factors predicting overnight admission included female sex (58/190 [30.5%] vs 58/331 [17.5%], P < .001) and tumor size of ≥3.8 cm (104/190 [55%] vs 85/190 [45%]). Factors predicting 30dR included female sex (10/116 [8.6%] vs 14/405 [0.2%]) and younger age (median [interquartile range], 63 years [55-65 years] vs 65 years [59-71 years]). At regression, factors predictive of 30dR were Child-Pugh Class B/C (odds ratio [OR], 2.1; P = .04) and female sex (OR, 2.9; P = .004). CONCLUSIONS: Same-day discharge after conventional TACE is a safe and effective strategy with 30dR rate of <5%, similar to overnight observation.

Lobar Radioembolization for Intermediate and Advanced Hepatocellular Carcinoma: Retrospective and Prospective Data.

Historically, outcomes reporting for radioembolization with yttrium-90 ( 90 Y) of hepatocellular carcinoma has included patients across the range of Barcelona Clinic Liver Cancer (BCLC) stages. With the potential for curative radiation segmentectomy for BCLC 0/A patients and evolution of systemic therapy for BCLC C patients, focused review by group is of increasing interest. In this review, we report on efficacy of 90 Y in patients with intermediate (BCLC B) and advanced (BCLC C) hepatocellular carcinoma as well as expected toxicities. Additionally, we review existing trials comparing 90 Y to transarterial chemoembolization and systemic treatments in these patient groups and outline future studies.

A method for revision of a foreshortened transjugular intrahepatic portosystemic shunt (TIPS) stent using transhepatic trans-stent access.

The high technical success rate of transjugular intrahepatic portosystemic shunt (TIPS) placement makes the procedure a popular treatment option for symptomatic portal hypertension. Among the major drawbacks of the procedure - hepatic encephalopathy, acute hepatic failure, hemorrhage, biliary injury - TIPS dysfunction is one of the most prevalent, often requiring endovascular reintervention. Conventional techniques for shunt revision rely on transjugular access to the stent; but in technically difficult cases of abnormal angulation or severe stenosis, transhepatic access may also be required. The pull-through method utilizes both transjugular and transhepatic access to achieve stable through-and-through access in order to advance a sheath into the stent and recannulate the shunt. In the case of TIPS foreshortening, however, the distal end of the stent may abut the wall of the hepatic vein, jailing it off and obviating the advancement of a wire out of that end. We present here a case of a modified pull-through method for TIPS revision whereby a transhepatic wire is passed through the interstices of the stent at the distal end to enter into the hepatic vein and IVC. Subsequent snaring of the wire at the transjugular end establishes through-and-through access, and balloon dilation through the interstices allows for insertion of a transjugular sheath into the TIPS stent for recanalization. Our case highlights how the modified pull-through method, using trans-stent access, can be safely performed in patients with a foreshortened TIPS that abuts against the hepatic and portal vessel walls.

Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis.

PURPOSE: To report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with χ2 tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after 90Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after 90Y radioembolization in patients with unresectable ICC.

Neutrophil/Lymphocyte Ratio Predicts Increased Risk of Immediate Progressive Disease following Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To demonstrate that patients with hepatocellular carcinoma (HCC) and elevated baseline neutrophil/lymphocyte ratio (NLR) have a significantly greater risk of progressive disease following initial transarterial chemoembolization. MATERIALS AND METHODS: A total of 190 HCC patients (149 male/41 female) treated with transarterial chemoembolization between July 2013 and July 2017 were reviewed. Mean patient age was 62. Child-Pugh grades were 132 A, 61 B, and 4 C. Tracked criteria included etiology of cirrhosis, tumor number, Barcelona Clinic Liver Cancer score, diameter of the largest 2 tumors, and presence of portal vein thrombosis. Complete blood count with differential before the procedure was used for NLR calculation. Follow-up imaging was performed 2 months after treatment. The modified response evaluation criteria in solid tumors were used to assess response. The association between baseline NLR and tumor response (ordinal modified response evaluation criteria in solid tumors categories) on 2-month follow-up imaging was evaluated using the proportional odds logistic regression model. RESULTS: A total of 194 patients (76.6%) patients had a preprocedural NLR <3.5, and 59 (23%) patients had a preprocedural NLR ≥3.5. There was a statistically significant association between baseline NLR and immediate progression on 2-month follow-up imaging (mean NLR 4.10, 2.76, 2.72, and 2.48 for progressive and stable disease and partial and complete response, respectively; odds ratio 2.1, P = .04). NLR (P = .021) and tumor multiplicity (P = .011) predicted progressive disease at 2-month imaging. CONCLUSIONS: Elevated baseline NLR is associated with higher rates of HCC tumor progression at 2-month follow-up imaging after transarterial chemoembolization.

Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis.

BACKGROUND: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. METHODS: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. RESULTS: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFß1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. CONCLUSIONS: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays.

We investigated the efficacy and mechanism of dimethylaminoparthenolide (DMAPT), an NF-κB inhibitor, to sensitize human lung cancer cells to X-ray killing in vitro and in vivo. We tested whether DMAPT increased the effectiveness of single and fractionated X-ray treatment through inhibition of NF-κB and/or DNA double-strand break (DSB) repair. Treatment with DMAPT decreased plating efficiency, inhibited constitutive and radiation-induced NF-κB binding activity, and enhanced radiation-induced cell killing by dose modification factors of 1.8 and 1.4 in vitro. X-ray fractionation demonstrated that DMAPT inhibited split-dose recovery/repair, and neutral DNA comet assays confirmed that DMAPT altered the fast and slow components of X-ray-induced DNA DSB repair. Knockdown of the NF-κB family member p65 by siRNA increased radiation sensitivity and completely inhibited split-dose recovery in a manner very similar to DMAPT treatment. The data suggest a link between inhibition of NF-κB and inhibition of DSB repair by DMAPT that leads to enhancement of X-ray-induced cell killing in vitro in non-small-cell lung cancer cells. Studies of A549 tumor xenografts in nude mice demonstrated that DMAPT enhanced X-ray-induced tumor growth delay in vivo.