Etay Ziv

Image-guided biopsy in the era of personalized cancer care: Proceedings from the society of interventional radiology research consensus panel

Alda L. Tam, M.D., Howard J. Lim, M.D., Ignacio I. Wistuba, M.D., Anobel Tamrazi, M.D., Ph.D., Michael D. Kuo, M.D., Etay Ziv, M.D., Ph.D., Stephen Wong, Ph.D., Albert J. Shih, Ph.D., Robert J. Webster III, Ph.D., Gregory S. Fischer, Ph.D., Sunitha Nagrath, Ph.D., Suzanne E. Davis, M.M.S., M.B.A., Sarah B. White, M.D., and Kamran Ahrar, M.D. Departments of Interventional Radiology (A.L.T., K.A.) and Translational Molecular Pathology (I.I.W.); and the Division of Cancer Medicine, Research Planning and Development (S.E.D.); The University of Texas M.D. Anderson Cancer Center, Houston, TX; the Division of Medical Oncology (H.J.L.), University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; the Division of Vascular and Interventional Radiology (A.T.), Johns Hopkins University School of Medicine, Baltimore, MD; the Department of Radiological Sciences (M.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, CA; the Departments of Interventional Radiology and Computational Biology (E.Z.), Memorial Sloan Kettering Cancer Center, NY, NY; the Houston Methodist Research Institute, Houston, TX and Weill Cornell Medical College of Cornell University, NY, NY (S.W.); the Departments of Mechanical and Biomechanical Engineering (A.J.S.) and the Departments of Chemical and Biomedical Engineering (S.N.), University of Michigan, Ann Arbor, MI; the Department of Mechanical Engineering (R.J.W. 3rd), Vanderbilt University, Nashville, TN; the Automation and Interventional Medicine (AIM) Robotics Lab (G.S.F.) in the Department of Mechanical Engineering, Worcester Polytechnic Institute, Worcester, MA; and, the Division of Vascular and Interventional Radiology (S.B.W.), Medical College of Wisconsin, Milwaukee, WI

Lung Adenocarcinoma: Predictive Value of KRAS Mutation Status in Assessing Local Recurrence in Patients Undergoing Image-guided Ablation

Purpose To establish the relationship between KRAS mutation status and local recurrence after image-guided ablation of lung adenocarcinoma. Materials and Methods This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of 56 primary lung adenocarcinomas in 54 patients (24 men, 30 women; median age, 72 years; range, 54-87 years) treated with percutaneous image-guided ablation and with available genetic mutational analysis. KRAS mutation status and additional clinical and technical variables-Eastern Cooperative Oncology Group (ECOG) status, smoking history, stage at diagnosis, status (new primary or not), history of radiation, history of surgery, prior systemic treatment, modality of ablation, size of nodule, ablation margin, and presence of ground-glass appearance-were recorded and evaluated in relation to time to local recurrence, which was calculated from the time of ablation to the first radiographic evidence of recurrence. Predictors of outcome were identified by using a proportional hazards model for both univariate and multivariate analysis, with death as a competing risk. Results Technical success was 100%. Of the 56 ablated tumors, 37 (66%) were wild type for KRAS and 19 (34%) were KRAS mutants. The 1-year and 3-year cumulative incidences of recurrence were 20% and 35% for wild-type KRAS compared with 40% and 63% for KRAS mutant tumors. KRAS mutation status was a significant predictor of local recurrence at both univariate (P = .05; subdistribution hazard ratio [sHR], 2.32) and multivariate (P = .006; sHR, 3.75) analysis. At multivariate analysis, size (P = .026; sHR, 2.54) and ECOG status (P = .012; sHR, 2.23) were also independent significant predictors, whereas minimum margin (P = .066) was not. Conclusion The results of this study show that there is a relationship between KRAS mutation status and local recurrence after image-guided ablation of lung adenocarcinoma. Specifically, KRAS mutation status of the ablated lesion is a significant predictor of time to local recurrence, independent of size and margin.

Kras mutation is a marker of worse oncologic outcomes after percutaneous radiofrequency ablation of colorectal liver metastases

Background Kras mutation has been associated with shorter overall survival and time to disease recurrence after resection of colorectal liver metastases (CLM). This study evaluated the prognostic value of Kras mutation in patients with CLM treated by percutaneous radiofrequency ablation (RFA). Methods This is an IRB waived retrospective analysis of the impact of KRAS mutation status on oncologic outcomes after CLM RFA. The endpoints were overall survival (OS), local tumor progression (LTP) rates, and incidence of new liver, lung, and peritoneal metastases. Survival times were calculated using Kaplan-Meier methodology from the time of RFA. Results The study enrolled 97 patients. Kras exon 2 mutation was detected in 39% (38/97) of patients. On univariate analysis, Kras mutation (P=0.016) (HR: 1.8; 95% CI: 1.1 – 2.9) was a significant predictor of OS and retained significance on multivariate analysis. Kras mutation was a significant predictor of new liver metastases (P=0.037) (SHR: 2.0; CI: 1.0-3.7) and peritoneal metastases (P=0.015) (sHR: 3.0; 95% CI: 1.2-7.2) on multivariate analysis. Kras mutation was a significant predictor of LTP after RFA of CLM ablated with margins of 1-5 mm (P=0.018) (SHR: 3.0; 95% CI: 1.2-7.7) with an LTP rate of 80% (12/15) versus 41% (11/27) for wild type. Conclusion Kras mutation is a significant predictor of overall survival, new liver, and peritoneal metastases after RFA of CLM. A minimal radiographic ablation margin ≥ 6 mm is essential for local tumor control especially for mutant CLM.

Metabolic tumor volume and total lesion glycolysis on FDG-PET/CT can predict overall survival after 90Y radioembolization of colorectal liver metastases: A comparison with SUVmax, SUVpeak, and RECIST 1.0

PURPOSE To compare the performance of 4 metrics of metabolic response on FDG-PET/CT against RECIST 1.0 for determining response and predicting overall survival (OS) following (90)Y resin microspheres radioembolization of colorectal liver metastases (CLM). METHODS We conducted an IRB-waived retrospective review of our radioembolization database to identify patients with unresectable CLM treated between December 2009 and December 2013. We included patients who had both PET/CT and contrast enhanced CT (CECT) available at baseline and on the first follow-up post-radioembolization. On baseline CECT up to five target tumors were chosen per patient according to RECIST 1.0. Four metrics of FDG-avidity (SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)) on PET/CT were measured for the same target tumors. Using RECIST 1.0, patients were classified as no progression (partial response or stable disease) and progression. For each PET metric, a cut-off point of ≥30% decrease was chosen to define response. OS was calculated from the time of radioembolization using Kaplan-Meier methodology. The log-rank test was used for univariate analysis to identify predictors of OS. RESULTS The study enrolled 49 patients with 119 target tumors; a median of 2 (range: 1-5) tumors were selected per patient. Median OS was 12.7 months (95%CI: 7.2-16.7). Response by MTV (P=0.035) and TLG (P=0.044) reached statistical significance in predicting OS. Response by SUVmax (P=0.21), SUVpeak (P=0.20) or no progression by RECIST 1.0 (P=0.44) did not predict OS. CONCLUSION Metabolic response based on changes in MTV and TLG can predict OS post-radioembolization of CLM.

PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases

Purpose To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization. Materials and Methods Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk. Results Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP. Conclusions PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

Therapeutic Application of Percutaneous Peritoneovenous (Denver) Shunt in Treating Chylous Ascites in Cancer Patients.

PURPOSE To evaluate the safety and efficacy of percutaneous peritoneovenous shunt (PPVS) placement in treating intractable chylous ascites (CA) in patients with cancer. MATERIALS AND METHODS Data from 28 patients with refractory CA treated with PPVS from April 2001 to June 2015 were reviewed. Demographic characteristics, technical success, efficacy, laboratory values, and complications were recorded. Univariate and multivariate logistic regression analysis was performed. RESULTS Technical success was 100%, and ascites resolved or symptoms were relieved in 92.3% (26 of 28) of patients. In 13 (46%) patients with urologic malignancies, whose ascites had resulted from retroperitoneal lymph node dissection, the ascites resolved, resulting in shunt removal within 128 days ± 84. The shunt provided palliation of symptoms in 13 of the remaining 15 patients (87%) for a mean duration of 198 days ± 214. Serum albumin levels increased significantly (21.4%) after PPVS placement from a mean of 2.98 g/dL ± 0.64 before the procedure to 3.62 g/dL ± 0.83 (P < .001). The complication rate was 37%, including shunt malfunction/occlusion (22%), venous thrombosis (7%), and subclinical disseminated intravascular coagulopathy (DIC) (7%). Smaller venous limb size (11.5 F) and the presence of peritoneal tumor were associated with a higher rate of shunt malfunction (P < .05). No patient developed overt DIC. CONCLUSIONS PPVS can safely and effectively treat CA in patients with cancer, resulting in significant improvement in serum albumin in addition to palliation of symptoms.

Changes in peripheral blood T-cell balance after percutaneous tumor ablation

Abstract Purpose: To evaluate the changes in T-cell balance in peripheral blood following percutaneous tumor ablation. Material and methods: Patients underwent thermal ablation including radiofrequency (n = 9) and microwave ablation (n = 5), or cryoablation (n = 5). Target tumors were located in the lung (n = 7), soft tissue (n = 5), liver (n = 4), and bone (n = 3). Patient peripheral blood samples were collected before and within 14 days after ablation. Peripheral blood populations of cytotoxic T-cells (CTL), type-1 (Th1) and type-2 helper T-cells (Th2), and regulatory T-cells (Treg) were measured using flow cytometry. Changes in CTL/Treg and Th1/Th2 ratios before and after ablation therapy were compared using paired t-tests. Results: Peripheral blood CTL population (27.5 ± 2.1% to 30.2 ± 2.5%, p < .03) and CTL/Treg ratios (18.8 ± 3.7% to 21.6 ± 3.6%, p < .05) increased significantly after ablation. Although a significant increase in CTL/Treg ratios was found after heat-based ablation (18.0 ± 4.4% to 21.6 ± 4.7%, p < .02), it remained unchanged after cryoablation (21.0 ± 7.0% to 21.5 ± 4.3%, p = .92). Th1/Th2 ratio (13.7 ± 3.0% to 17.2 ± 3.5%, p = .12) remained unchanged after ablation. Conclusion: Ablation therapy alters the T-cell balance by increasing the systemic CTL/Treg, ratio. Heat-based ablation might be a more effective approach than cryoablation to enhance systemic anti-tumor immunity.

The Importance of Biopsy in the Era of Molecular Medicine.

AbstractRecent advances in the molecular characterization of cancers have triggered interest in developing a new taxonomy of disease in oncology with the goal of using the molecular profile of a patient’s tumor to predict response to treatment. Image-guided needle biopsy is central to this “precision medicine” effort. In this review, we first discuss the current role of biopsy in relation to clinical examples of molecular medicine. We then outline important bottlenecks to the advancement of precision medicine and highlight the potential role of image-guided biopsy to address these challenges.

Gene Signature Associated with Upregulation of the Wnt/β-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization

PURPOSE To identify gene mutations in tumors undergoing transarterial embolization and explore the relationship between gene mutations and tumor response to embolization. MATERIALS AND METHODS This was a retrospective review that included 17 patients with primary or metastatic liver tumors treated with embolization and had specimens analyzed for a 341-gene panel next-generation sequence assay. Pathologic conditions included hepatocellular, carcinoid, pancreatic neuroendocrine, melanoma, medullary thyroid, and liver acinar-cell carcinoma. Disease, procedure data, and tumor response data were collected. Dimensionality reduction was performed by using principal component analysis. A linear support vector machine was used to learn a prediction rule and identify the genes most predictive of objective tumor response (partial or complete) per modified Response Evaluation Criteria In Solid Tumors. Cross-validation was used to test the prediction on the holdout set. Permutation testing was used to determine statistical significance of prediction accuracy. Recursive feature elimination was used to identify the most predictive genes. RESULTS At 4 months after embolization, 9 tumors showed a response and 8 did not. Using the top two principal components, prediction accuracy of the gene mutation signature was 70% (±11%), which was statistically significant (P < .05). The most predictive genes were CTNNB1, MEN1, and NCOR1: three genes associated with the Wnt/β-catenin and hypoxia signaling pathways. CONCLUSIONS This study identifies gene mutations in tumors treated with transarterial embolization. A gene-mutation signature obtained from the mutation data suggests that upregulation of the Wnt/β-catenin signaling pathway may be associated with sensitivity to embolization.

Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model

Background/Aim: The aim of this study was to determine whether the addition of bumetanide (BU), a glycolytic metabolism pathway inhibitor, to arterial embolization improves tumor necrosis of N1-S1 hepatocellular carcinoma in a rat model. Materials and Methods: N1-S1 tumors were surgically implanted in the liver of 14 Sprague-Dawley rats. The rats were divided into three groups: In control group (n = 5), 1 ml of normal saline was injected intra-arterially. The tumor in the transarterial embolization group (TAE, n = 4) was embolized using 10 mg of 50–150 μ polyvinyl alcohol (PVA) particles and embolization plus BU group (TAE + BU, n = 5) were embolized with 10 mg of PVA plus 0.04 mg/kg of BU. Tumor volume was measured using two-dimensional ultrasound before intervention and twice a week afterward. Relative tumor volume after the intervention was calculated as the percentage of preinterventional tumor volume. After 4 weeks of observation, the rats were sacrificed for histopathological evaluation. Results: No statistically significant difference was detected in the preintervention tumor sizes between the three groups (P > 0.05). In the control group, the relative tumor volume increased to 142.5% larger than baseline measurements. In the TAE group, the tumor volume decreased by 18.2 ± 12.2%. The tumor volume in the TAE + BU group decrease by 90.4 ± 10.2%, which was 72.2% more than in TAE only group (P < 0.0001). Histopathological evaluation demonstrated no residual tumor in the TAE + BU group. Conclusion: Tumor necrosis significantly increased in N1-S1 tumor that received BU at the time of TAE when compared to TAE alone.