Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma.

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.

Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II. METHODS: This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria. RESULTS: Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m2 I.V. and 20 mg/m2 I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions. DISCUSSION: TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.

Endovascular management of traumatic pseudoaneurysms.

BACKGROUND: Pseudoaneurysms (PAs) caused by traumatic injury to the arterial vasculature have a high risk of rupture, leading to life-threatening hemorrhage and mortality, requiring urgent treatment. The purpose of this study was to determine the technical and clinical outcomes of endovascular treatment of visceral and extremity traumatic pseudoaneurysms. METHODS: Clinical data were retrospectively collected from all patients presenting for endovascular treatment of PAs between September 2012 and September 2018 at a single academic level one trauma center. Technical success was defined as successful treatment of the PA with no residual filling on post-embolization angiogram. Clinical success was defined as technical successful treatment with no rebleeding throughout the follow-up period and no reintervention for the PA. RESULTS: Thirty-five patients (10F/25M), average age (± stdev) 41.7 ± 20.1 years, presented with PAs secondary to blunt (n = 31) or penetrating (n = 4) trauma. Time from trauma to intervention ranged from 2 h - 75 days (median: 4.4 h, IQR: 3.5-17.1 h) with 27 (77%) of PAs identified and treated within 24 h of trauma. Average hospitalization was 13.78 ± 13.4 days. Ten patients underwent surgery prior to intervention. PA number per patient ranged from 1 to 5 (multiple diffuse). PAs were located on the splenic (n = 12, 34.3%), pelvic (n = 11, 31.4%), hepatic (n = 9, 25.7%), upper extremity/axilla (n = 2, 5.7%), and renal arteries (n = 1, 2.9%). Technical success was 85.7%. Clinical success was 71.4%, for technical failure (n = 5), repeat embolization (n = 1) or post-IR surgical intervention (n = 4). There was no PA rebleeding or reintervention for any patient after discharge over the reported follow-up periods. Three patients died during the trauma hospitalization for reasons unrelated to the PAs. CONCLUSIONS: Endovascular treatment of traumatic visceral and extremity PAs is efficacious with minimal complication rates and low reintervention requirements.

Intracystic Hemorrhage Complicating Polycystic Liver Disease in a 90-Year-Old Woman.

Nonparasitic hepatic cysts are common benign tumors that are often asymptomatic and incidentally discovered on imaging. Intracystic hemorrhage is a rare complication of hepatic cysts. We review the literature and discuss a case of intracystic hemorrhage in a 90-year-old woman with polycystic liver disease. The patient underwent cyst aspiration and percutaneous drain placement with subsequent resolution of symptoms. To our knowledge, we report the oldest patient to present with hemorrhage into a hepatic cyst. This case presents unique challenges in management, both because of the patient's age and because of her polycystic liver disease.

Demographic and facility volume related outcomes in radiofrequency ablation for early-stage hepatocellular carcinoma.

BACKGROUND: To evaluate outcomes related to disparities in facility volume and patient demographics in patients with early-stage hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA). METHODS: This is a retrospective study of patients with stage I/II HCC treated with RFA in the National Cancer Database. Independent contributors to overall survival were determined with Cox regression analysis. The Kaplan-Meier method and log-rank analyses were used to estimate overall survival and compare survival curves. A propensity score matched cohort analysis was performed. P-values < 0.05 were considered statistically significant. RESULTS: In total, 2911 patients were included. Stage II disease (p-value = 0.006), increasing alpha fetoprotein (p-value = 0.007), and increasing bilirubin (p-value < 0.001) were associated with worse survival. Improved survival was seen in patients treated at high-volume centers (p-value = 0.004), which persisted following propensity score adjustment (p-value = 0.003). Asian race was associated with significantly improved survival (p-value < 0.001), while governmental insurance was associated with a significant decrease in survival (p-value < 0.001). CONCLUSION: Treatment at a high-volume center and Asian race were significantly associated with improved survival following RFA for early-stage HCC. Governmental insurance, increasing alpha fetoprotein, increasing bilirubin, and higher disease stage were significantly associated with worse survival.

Patient and Facility Demographics Related Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated with Radiofrequency Ablation: A National Cancer Database Analysis.

PURPOSE: To determine facility and patient demographics associated with survival in early-stage non-small cell lung cancer (NSCLC) treated with radiofrequency (RF) ablation. MATERIALS AND METHODS: The National Cancer Database was queried for cases of stage 1a NSCLC treated with RF ablation without chemotherapy or radiotherapy from 2004 to 2014. High-volume centers (HVCs) were defined as the top 95th percentile of facilities by number of procedures performed. Overall survival (OS) was estimated with the Kaplan-Meier method, and comparisons between survival curves were performed with the log-rank test. Propensity score-matched cohort analysis was performed. P values less than .05 were considered statistically significant. RESULTS: In the final cohort, 967 cases were included. Estimated median survival and follow-up were 33.1 and 62.5 months, respectively. Of 305 facilities, 15 were determined to be HVCs, treating 13 or more patients from 2004 to 2014. A total of 335 cases (34.6%) were treated at HVCs. On multivariate Cox regression analysis, treatment at an HVC was independently associated with improved OS (hazard ratio [HR] = 0.766; P = .006). After propensity score adjustment, 1-, 3-, and 5-year OS was 89.8%, 51.2%, and 27.7%, respectively, for patients treated at HVCs, compared to 85.2%, 41.5%, and 19.6%, respectively, for patients treated at non-HVCs (P = .015). Increasing age (HR = 1.012; P = .013) and higher T-classification (HR = 1.392; P < .001) were independently associated with worse OS. CONCLUSION: Patients with early-stage NSCLC treated with RF ablation at HVCs experienced a significant increase in OS, suggesting regionalization of lung cancer management as a means of improving outcomes.

A National Cancer Database Analysis of Radiofrequency Ablation versus Stereotactic Body Radiotherapy in Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: To compare overall survival (OS) after radiofrequency (RF) ablation and stereotactic body radiotherapy (SBRT) at high-volume centers in patients with early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Cases in the National Cancer Database of stage 1a and 1b NSCLC treated with primary RF ablation or SBRT from 2004 to 2014 were included. Patients treated at low-volume centers, defined as facilities below the 95th percentile in volume of cases performed, were excluded. Outcomes measured include OS and rate of 30-day readmission. The Kaplan-Meier method was used to estimate OS. The log-rank test was used to compare survival curves. Propensity score matched cohort analysis was performed. P < .05 was considered statistically significant. RESULTS: The final cohort comprised 4,454 cases of SBRT and 335 cases of RF ablation. Estimated median survival and follow-up were 38.8 months and 42.0 months, respectively. Patients treated with RF ablation had significantly more comorbidities (P < .001) and higher risk for an unplanned readmission within 30 days (hazard ratio = 11.536; P < .001). No difference in OS for the unmatched groups was found on multivariate Cox regression analysis (P = .285). No difference was found in the matched groups with 1-, 3-, and 5-year OS of 85.5%, 54.3%, and 31.9% in the SBRT group vs 89.3%, 52.7%, and 27.1% in the RF ablation group (P = .835). CONCLUSIONS: No significant difference in OS was seen between patients with early-stage NSCLC treated with RF ablation and SBRT.

Radiogenomics and IR.

Radiogenomics involves the integration of mineable data from imaging phenotypes with genomic and clinical data to establish predictive models using machine learning. As a noninvasive surrogate for a tumor's in vivo genetic profile, radiogenomics may potentially provide data for patient treatment stratification. Radiogenomics may also supersede the shortcomings associated with genomic research, such as the limited availability of high-quality tissue and restricted sampling of tumoral subpopulations. Interventional radiologists are well suited to circumvent these obstacles through advancements in image-guided tissue biopsies and intraprocedural imaging. Comprehensive understanding of the radiogenomic process is crucial for interventional radiologists to contribute to this evolving field.

Quality-of-life assessment after palliative interventions to manage malignant ureteral obstruction.

PURPOSE: Malignancies may cause urinary tract obstruction, which is often relieved with placement of a percutaneous nephrostomy tube, an internal double J nephro-ureteric stent (double J), or an internal external nephroureteral stent (NUS). We evaluated the affect of these palliative interventions on quality of life (QoL) using previously validated surveys. METHODS: Forty-six patients with malignancy related ureteral obstruction received nephrostomy tubes (n = 16), double J stents (n = 15), or NUS (n = 15) as determined by a multidisciplinary team. QoL surveys were administered at 7, 30, and 90 days after the palliative procedure to evaluate symptoms and physical, social, functional, and emotional well-being. Number of related procedures, fluoroscopy time, and complications were documented. Kruskal-Wallis and Friedman's test were used to compare patients at 7, 30, and 90 days. Spearman's rank correlation coefficient was used to assess correlations between clinical outcomes/symptoms and QoL. RESULTS: Responses to QoL surveys were not significantly different for patients receiving nephrostomies, double J stents, or NUS at 7, 30, or 90 days. At 30 and 90 days there were significantly higher reported urinary symptoms and pain in those receiving double J stents compared with nephrostomies (P = 0.0035 and P = 0.0189, respectively). Significantly greater fluoroscopy time was needed for double J stent-related procedures (P = 0.0054). Nephrostomy tubes were associated with more frequent minor complications requiring additional changes. CONCLUSION: QoL was not significantly different. However, a greater incidence of pain in those receiving double J stents and more frequent tube changes in those with nephrostomy tubes should be considered when choosing palliative approaches.