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Monday, September 24, 2018

Iodine-125 Seed Strand Implantation in Combination with TACE for Treatment of HCC with Tumor Thrombus


Summary


A recent study from researchers in Shanghai, China published their findings on comparing Iodine-125 (I-125) seed strand implantation in conjunction with transarterial chemoembolization (TACE) versus TACE alone in treatment of patients with hepatocellular carcinoma (HCC) and tumor thrombus. This retrospective study included 76 patients (20 in the I-125 and TACE group, 56 in TACE alone group) with overall survival as the primary end-point. Inclusion criteria consisted of Childs-Pugh A and B patients with intrahepatic HCC single tumor > 5 cm or multiple tumors > 3 cm) with type II tumor thrombus (involvement of right or left portal vein but not main portal vein). TACE was performed with epirubicin and lipiodol. I-125 implantation was performed through a single, percutaneous portal venous access with deployment of the I-125 strand to span the portal vein tumor thrombus. The mean I-125 dose was 62.6 Gy. The authors demonstrated a longer overall survival in the I-125 seed strand implantation group (28.0 vs 8.7 months in a propensity score matched cohort, P = .001). Using modified Response Evaluation Criteria in Solid Tumors, intrahepatic disease control rate favored the combined therapy group (60% versus 28.6%, P = .012) while tumor thrombus disease control rate was significantly improved in the combination therapy group (90% vs 33.9%, p < .001). There were no serious adverse events. Of note, the combined therapy group also received more additional TACE treatments during the follow up period. The authors conclude that combined treatment of HCC with portal vein tumor thrombus with TACE and I-125 seed strand is safe and effective.



Figure 2. (a) The 125I seed strand prepared for implantation. (b) Portography of a 65-year-old man shows filling defects in the right portal vein (arrows). (c) The 125I seed strand is located at the target position (arrow) and delivered through the 5-F sheath. (d) The 5-F sheath is removed and the transhepatic puncture track is occluded with the use of 3 3 coils (arrow). (e) Hepatic angiography (arrows) is immediately performed after the 125I seed strand implantation.

Commentary


This paper evolves the limited prior research on usage of Iodine-125 seed implantation for treatment/control of tumoral thrombus in patients with HCC. The reported outcomes, specifically overall survival and disease control rates, are exciting and intriguing. Portal vein tumoral thrombus is an important diagnostic finding, limiting treatment options and purporting poor prognosis. Limitations of this study include the retrospective nature, small sample size (19 patients ultimately in the propensity-score matched analysis), homogeneous population (Chinese study, hepatitis B), and disparate number of future TACE procedures. Technical success rate and procedure duration may prove inhibiting in other patient populations. How this compares to other treatments directed at treating/controlling portal vein tumoral thrombus, such as radioembolization and SBRT, would be interesting for future research. Percutaneous implantation of I-125 seed strand could prove to be another weapon in our armamentarium against HCC. Ultimately, further research is required to determine if/where this falls in the treatment paradigm for HCC.

Zhang, ZH, Zhang W, Gu JY, et al. Treatment of Hepatocellular Carcinoma with Tumor Thrombus with the Use of Iodine-125 Seed Strand Implantation and Transarterial Chemoembolization: A Propensity-Score Analysis. J Vasc Interv Radiol. 2018; 29: 1085-1093.

Post Author:
David M Mauro, MD
Assistant Professor
Department of Radiology
Vascular and Interventional Radiology
University of North Carolina
@DavidMauroMD

Friday, September 21, 2018

Multicenter Phase II Clinical Trial of Sorafenib Combined with Transarterial Chemoembolization for Advanced Stage Hepatocellular Carcinomas (Barcelona Clinic Liver Cancer Stage C): STAB Study


Summary


A phase II non randomized open label multicenter study designed to evaluate the efficacy and safety of combining Sorafinib with conventional Trans arterial chemoembolization (TACE) in patients with Barcelona Clinic Liver Cancer Stage C hepatocellular cancer(HCC) is described in this paper. Primary end point was completion rate of the treatment protocol defined as 2 months of treatment with Sorafinib after TACE. Secondary end points of the study included objective response rate, disease control rate, overall survival, progression free survival and incidence of adverse effects. Sorafinib 400 mg daily was administered after 4 weeks of lobar/segmental/sub segmental conventional TACE with lipoidol combined with any of the following 5 drugs: epirubicin, doxorubicin, cisplatin, miraplatin, mitomycin C. Dose interruptions and reductions were allowed when drug toxicity developed. 32 patients were enrolled, 1 was excluded as tumor was cholangiohepatoma and not HCC. All 31 patients were followed for a year or until death. 28 (90.3%) patients completed the protocol, 1 refused treatment with Sorafinb, 2 dropped out due to intolerance/ drug toxicity. Median number of TACE were 2, Sorafinib interruptions was required in 77.4% and dose reduction in 67.7%. Complete, partial response, stable disease and progressive disease were noted in 9.7,67.7,12.9 and 9.7% respectively using the mRECIST criteria. Objective response rate was 77.4% and disease control rate was 90.3%. Median overall survival and progression free survival were 17.3 months and 5.4 months respectively. Tumor response rate by mRECIST (P=0.42) and serum AFP(P=0.01) were the only significant prognostic factors that affected survival in multivariate analysis. The most common grade 3 or 4 AEs were increased AST (54.8% 17/31), increased ALT (45.2%, 14/31), hypertension (22.6%, 7/31), thrombocytopenia(19.4%, 6/31), increased amylase (9.7%, 3/31), and hand-foot syndrome (9.7%; 3 of 31) during the entire period of combination therapy. 


Fig 1 Kaplan Meier curve showing overall survival of patients included in the study

Commentary

This was a much needed study evaluating combination therapy in advanced disease. While the primary end point was achieved in over 90%, the tolerability of Sorafinib after TACE was variable with only 9.7% of the patient sticking to the original dosage regime.

Subgroup analysis of the SHARP and Asia-Pacific trials showed a median overall survival of 5.6-9.7 months in advanced stage HCC with Sorafinib monotherapy. The present study demonstrates an overall survival of 17.3 months compared to these trials. However, it should be noted that SHARP and Asia-Pacific trials were much larger trials with a more advanced patient population and more advanced BCLC stage than the presented study. The authors attribute the improved survival to patient selection and exclusion of patients with first order portal vein thrombosis. Similar studies comparing overall survival for TACE plus Sorafinib versus TACE alone and Sofafinib alone have shown benefit of combination therapy (7-11 months vs 4.9-6.0 months vs 5.9 months). These findings are concordant to the results of this study and highlight the benefit of combination therapy in Child A population with BCLC C disease. 


Sato Y, Nishiofuku H, Yasumoto T, et al. Multicenter Phase II Clinical Trial of Sorafenib Combined with Transarterial Chemoembolization for Advanced Stage Hepatocellular Carcinomas (Barcelona Clinic Liver Cancer Stage C): STAB Study. J Vasc Interv Radiol 2018; 29:1061-7. 

Post Author:
Anil K Pillai, MD
Associate Professor and Section Chief,
University of Texas Health Science Center
Anil Pillai@AnkupiMD


Monday, September 17, 2018

Clinical Predictors of Port Infections in Adult Patients with Hematologic Malignancies


Summary


Infection is typically the most common long-term complication of port placement and is also the most common reason for premature removal of a port. In addition, patients with hematologic malignancies have been reported to have a higher risk of port infection relative to the solid tumor population. In this paper, the authors performed a single center retrospective review of 223 patients with hematologic malignancies who underwent port placement for chemotherapy. Prophylactic antibiotics were administered to every patient. Identification of risk factors for port infection were assessed by stratifying patients based on demographics, clinical history, medications, type of malignancy, port characteristics, and a host of laboratory values. The definition of infection was also specified according to CDC guidelines as early infection and overall infection. Early infection was defined as that occurring within 30 days of placement.

A total of 8 out of 223 (3.6%) patients had early infection. During the follow-up period 26 patients (11.7%) overall had port infections. After inclusion of variables into the final regression model, hypoalbuminemia at the time of port placement was the only independent risk factor for early port infection (p=.03). Lab values at the time of port placement were not analyzed in the context of overall infection. From a medication standpoint, steroid therapy was the only independent risk factor associated with port infection in the overall infection group (p=.002).





Table 5, 6. ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; BMI = body mass index; CI = confidence interval; CLL = chronic lymphocytic leukemia; HR = hazard ratio; NA = nonapplicable owing to small number of patients within the subgroup; PSHREG = proportional subdistribution hazard regression.
Incorporated in multivariate logistic regression.
Significance at .05 level.


Commentary


This article is elegant in its simplicity and ability to identify potentially implementable screening practice parameters. More than any other complication, infection tends to be the most perseverated upon in regards to port placements. This is even more paramount for patients with hematologic malignancies who will likely suffer severe leukopenia after initiation of chemotherapy. The results of this study suggest that initiation of pre-procedural screening for patients with hypoalbuminemic states may prove beneficial in minimizing early port infections although further prospective randomized trials may be needed. On the contrary, steroids were frequently (though not always) a component of chemotherapy regimens in this study and are likely non-modifiable parameters to minimize port infections. Port placements in these patients are an absolute necessity and delaying placement to discontinue steroid therapy is probably not in their best interest. These decisions will likely need to be made on a case by case basis. However, a concerted effort to improve nutrition and potentially increase albumin levels is an easily modifiable and low/no risk intervention that is probably overlooked in its significance.

Click here for abstract

Shunqing Zhang, MS, Katsuhiro Kobayashi, MD, Masoud Faridnia, MD, Philip Skummer, MPH, Dianbo Zhang, MD, Mitchel I. Karmel, MD. Clinical Predictors of Port Infections in Adult Patients with Hematologic Malignancies. J Vasc Interv Radiol 2018; 29: 1148-1155.

Post Author:
Cane Hoffman, MD, PGY-5
Department of Radiology
Wake Forest Baptist Medical Center
@WakeForest_IR

Thursday, September 13, 2018

Prostatic Artery Embolization with 250-μm Spherical Polyzene-Coated Hydrogel Microspheres for Lower Urinary Tract Symptoms with Follow-up MR Imaging


Summary


Investigators from the University of Jena, Germany, published their initial experience of prostatic artery embolization (PAE) with 250-μm spherical, Polyzene-coated hydrogel microspheres with a diameter of 250 μm (Embozene; Boston Scientific). 30 patients with moderate to severe lower urinary tract symptoms were included in this prospective, nonrandomized study. Clinical outcomes and possible MR imaging predictors of clinical success were analyzed. PAE was technically successful in 90% of patients (who had at least unilateral embolization). Clinical success measured by decreased IPSS and QOL scores and increased Qmax were accomplished in 59% (16 of 27), 63% (17 of 27), and 74% (20 of 27) after 1, 3, and 6 mo, respectively. IIEF scores did not differ significantly during follow-up. Adverse events included urethral burning (5 of 27), fever (2 of 27), and urethral bleeding, rectal bleeding, cystitis, and penile burning sensation (1 of 27 each). No initial MR imaging changes correlated statistically with clinical outcomes after 6 months (P values from .14 to .98). The authors concluded that PAE with 250-μm hydrogel microspheres led to good clinical success after 6 months with a low complication rate and MR imaging predictors of clinical success were not identified.



Figure. (a) Posterior–anterior view of the left hemiprostate after application of contrast material. The microcatheter is placed above the bifurcation of the left prostatic artery into a central branch (vertical arrow) and a lateral branch (horizontal arrow). (b) Image after PAE with 250-μm microspheres.

Commentary


This manuscript presents the results of a specific embolic agent, 250um Polyzene-coated hydrogel microspheres (Embozene; Boston Scientific), on PAE performed in a limited cohort of patients with symptomatic BPH. Effectiveness and safety results were comparable to the current literature. As PAE is becoming a common therapeutic approach in this patient population, the question of which embolic agent is the most appropriate starts to emerge. Recent meta-analysis including studies that used different types of particulate agents showed better clinical outcomes with smaller PVA (50-100um). However, to better answer this question large randomized control trials would be required. For now any additional evidence on different agents are welcomed to help interventionalists decide which material to use. Finally, defining predictor factors for better clinical outcomes on imaging can be extremely helpful, but this was not possible in the present study likely due to the small sample size, which is a limitation. Further investigation could aim to define predictor factors on pre-procedure imaging. These potential findings could really impact the decision making process and clinical management.

Click here for abstract

Franiel T, Aschenbach R, Trupp S, et al. Prostatic artery embolization with 250-μm spherical polyzene-coated hydrogel microspheres for lower urinary tract symptoms with follow-up MR imaging. J Vasc Interv Radiol. 2018; 29: 1127-1137.

Post Author:
Ricardo Yamada, MD
Assistant Professor
Department of Radiology
Division of Vascular and Interventional Radiology
Medical University of South Carolina

Monday, September 10, 2018

Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model study


Summary


The authors report the findings of a translational study using a Rabbit squamous cell tumor model implanted into the left hepatic lobe. The authors sought out to evaluate the necrotic and toxic effects of CDK-516, which is a Vascular Disrupting agent (VDA). VDA’s work by disrupting immature and proliferating endothelial cells by inducing apoptosis and breakdown of the cytoskeleton. Ten rabbits where allocated into each of the 4 different groups: Lipiodol alone, Lipiodol+ CDK-516, Lipiodol + Doxorubicin, Lipiodol + CDK-516+Doxorubicin. The chemotherapeutic regimen was then injected into the left hepatic artery. Post embolization non-contrast CT was obtained to evaluated lipiodol deposition. The authors then evaluated AST and ALT levels at day 1, 3 and 7. On day 7 the rabbit was sacrificed and histologic analysis was performed by evaluating percent of tumor necrosis in the histologic slide that presented the largest portion of tumor. Ischemic changes were also evaluated on the gross specimen.

The authors found 47.1% tumor viability in group A, 27.5% in group B, 14.4% in group C and 0.7% in group D. There was a statistical difference between the 4 groups, as well as when pairwise comparisons were performed. On gross specimen evaluation there was 0% infarction rate in group A, 20% in group B, 40% in group C and 80% in group D. AST and ALT levels showed significant differences on days 1 and 3, and between group B and D on days 1, 3 and 7.

It is important to highlight that VDAs and antiangiogenic agents such as Sorafenib VDAs target established tumor vascularity that results in ischemia and necrosis in the tumor center, while Sorafenib targets new vessel formation around the tumor. The reason for which CKD-516 infusion leads to central tumor necrosis is that it targets immature tumor vessels by targeting microtubules, which deprive the tumor from oxygen and nutrients. In the tumor periphery there are immature tumor vessels and normal vessels therefore CKD-516 does not work effectively which leads to tumor survival in the periphery. Therefore, the combination of cytotoxic agents (Doxorubicin) and VDAs would seem to offer a synergistic effect where both the tumor center and periphery are treated. On the other hand, CKD-516 also showed ischemic and toxic effects as seen by the 80% gross parenchymal infarction seen in group D and the elevation in AST and ALT which did not normalize to control level. The reason for this, the authors postulate, is that systemic doses were administered intra-arterially, which may be potentially a large dose for intra-arterial injection.

The authors identified important limitations. The adequate dosage for CKD-516 is unknown. The combination strategy of CKD-516 and doxorubicin is theoretical, however actual synergy and drug interaction between the agents has not been studied. The histologic evaluations were performed without blinding which may introduce bias. Toxicity was only evaluated by studying elevation of AST and ALT and gross pathologic inspection. VX2 tumors are squamous cell tumors that present a natural course of central necrosis. And finally, tumor necrosis assessment was done by evaluating the section with the largest tumor area, instead of a volumetric analysis.

The authors concluded that the intra-arterial injection of CKD-516 and Doxorubicin showed a therapeutic benefit in a rabbit liver tumor model, and that future studies need to be undertaken to optimize the pharmacologic characteristics of the regimen so that it can eventually be used in clinical trials.



Figure- Histopathologic analysis of the 4 groups. Areas of necrosis are marked by *, tumor area is delineated by the arrows. # denotes necrosis in the adjacent liver parenchyma.

Commentary


This manuscript draws a strong argument for the use of combination therapy in targeting different pathways in the treatment of liver tumors. By using cytotoxic agents and VDAs, tumors are not only treated by inhibiting tumor growth in the periphery (Doxorubicin) but also the tumor center (CKD-516). As the authors adequately identified, there are important differences between the rabbit liver tumor model and human HCC. Therefore, definitive assumptions cannot be made, however this is a step forward in creating stronger regimens that maybe be treated with catheter directed techniques. Important studies need to follow, such as adequate dosage evaluation, pharmacokinetics, drug interaction and toxicity. As it stands, the synergistic effect of these two drugs appear to lead to high tumor necrosis (0.7% tumor viability) and high toxicity (80% ischemic changes), therefore studies are required to identify the dosage that will allow high tumor necrosis and minimize the toxic side effects.

Click here for abstract

Lee IJ, Lee M, Kim SJ, Kim YK, Won JY, Chung JW. Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model Study. J Vasc Interv Radiol. 2018 Aug;29(8):1078-1084. doi: 10.1016/j.jvir.2018.03.016. Epub 2018 Jun 15. PubMed PMID: 29910164.

Post Author
Carlos J. Guevara, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Sciences, Houston
@UTHouston_IR
@CarlosGuevaraIR

Thursday, September 6, 2018

Anatomic Recanalization of Hepatic Vein and Inferior Vena Cava versus Direct Intrahepatic Portosystemic Shunt Creation in Budd-Chiari Syndrome: Overall Outcome and Midterm Transplant-Free Survival


Summary


Budd Chiari Syndrome (BCS) is a rare, devastating and potentially life-threatening condition related to significant hepatic venous outflow compromise. There are few studies that have robustly reviewed and compared outcomes of active interventions to reverse or by pass the underlying anatomical manifestation of the problem. Interventional radiology has been the lynch pin of these interventions.

Researchers from Institute of Liver and Biliary Sciences, D-1, Vasant Kunj in New Delhi, India recently published their clinical outcomes data for patients with BCS receiving either hepatic/inferior vena cava venous recanalization or DIPS (Direct intrahepatic porto-systemic shunt).

The retrospective study included 136 patients (92 venous recanalization and 44 DIPS) receiving endovascular treatment option based on a clearly defined clinical algorithm. They objectively evaluated Liver US elastography, biochemical markers, imaging pre and post intervention at defined periods. Patients were all followed up until either liver transplantation, death or last clinical visit prior to the end of the study period. In those patients with symptom recurrence and evidence of in-stent stenosis on imaging there was reintervention.

Both groups demonstrated significant clinical, biochemical and liver stiffness (elastography) improvement with intervention. There were lower number of reinterventions in the recanalization group (4%) vs DIPS group (7%) with the later attributed to mainly poor compliance to anticoagulation therapy.

There were no significant differences in the transplant free survival and overall survival between the two groups. The consistent predictor of death and poor clinical outcome in both groups was initial presentation in acute fulminant liver failure with encephalopathy, regardless of successful outflow restoration. They concluded that although DIPS was successful in flow restoration in that cohort, it needed to be considered carefully due to risk of exacerbating encephalopathy and those patients would be best served with liver transplant.



Commentary


The study adds to a growing body of evidence of the usefulness and durability of endovascular intervention in managing this rare but debilitating condition – BCS. The authors findings are largely consistent with the findings of other previous publications which had smaller samples hence adding further validity to the role of endovascular intervention.

One of the remarkable aspects about this study is the unique volume of cases (180 in 4 yrs) from this single institution for a generally uncommon condition - which emphasizes the level of experience and expertise with BCS from this institution. We learn from their experience and expertise that recanalization, wherever possible should be the primary endovascular approach vs DIPS/TIPS first approach. Not only does recanalization provide early treatment success; it is durable, has similar survival benefit to DIPS/TIPS and yet less risk of exacerbation or causing encephalopathy which is generally associated with poor outcomes. We also learn that patients presenting in acute fulminant BCS have a very poor prognosis and concerted efforts should be made towards early liver transplantation.

We also learn that biochemical changes and liver elastography changes appear to be closely linked to clinical improvement in the early period (< 3 months) and therefore could be useful surrogate markers of progress during the early post treatment phase. It is interesting to note that the etiology of the prothrombotic state appeared to not have a bearing on the outcomes of endovascular intervention. Although this may be a true finding, the sample may not be adequately powered to demonstrate that difference.

The study has a number of weaknesses which the authors acknowledge and discuss very well: Retrospective, likely operator bias in selecting patients for DIPS vs recanalization, regional variation in disease process hence variation in US elastography measurements and they do not have very long term follow up. Despite these limitations, the study contributes immensely to the growing evidence about the crucial role interventional radiology plays in the management of BCS.

With the other recently published studies on this issue about the role of IR in the management of BCS, it may be an opportunity for a pooled systematic review on this subject.

Click here for abstract

Mukund A, Mittal K, Mondal A, Sarin SK. Anatomic Recanalization of Hepatic Vein and Inferior Vena Cava versus Direct Intrahepatic Portosystemic Shunt Creation in Budd-Chiari Syndrome: Overall Outcome and Midterm Transplant-Free Survival. J Vasc Interv Radiol. 2018 Jun;29(6):790-799. doi:10.1016/j.jvir.2018.01.781. Epub 2018 Apr 25. PubMed PMID: 29705227.

Post Author:
Rodrick C Zvavanjanja MD, MSc, FRCR, DABR(VIR/DR)
Assistant Professor
Department of Diagnostic and Interventional Radiology
University of Texas at Houston McGovern Medical School
@RodZvavanjanja

Monday, September 3, 2018

Predicting treatment response for transarterial embolization in HCC by analyzing intraprocedural parenchymal blood volume 


Summary


It is difficult to predict which patients with hepatocellular carcinoma (HCC) will have optimal response to transarterial chemoembolization (TACE). While techniques for embolic delivery have evolved over time, identification of tumor factors allowing for quantification of the efficacy of the embolization procedure has not yet been realized. This study evaluated parenchymal blood volume (PBV) before and after embolization as a predictor of angiographic response to TACE of HCC. The authors reasoned that fluoroscopic-cone beam CT could provide semiquantitative assessment of tumoral vascular capacitance through the measurement of PBV. They looked at 40 consecutive patients who had a total of 52 tumors. 33 patients underwent embolization with drug-eluting microspheres, 6 patients underwent conventional chemoembolization, and 1 patient underwent bland embolization. PBV cone-beam CT was performed from the same catheter in the same position before and after embolization. Size measurements were obtained from preprocedural liver CT and tumor response to treatment assessed per mRECIST on posttreatment liver CT performed 3 months after embolization. Embolization was performed to the endpoint of angiographic stasis in all patients. Per mRECIST, 25 tumors (48%) exhibited complete response (CR), 13 (25%) exhibited partial response (PR), 3 (6%) exhibited stable disease (SD), and 11 (21%) exhibited progressive disease (PD). The greatest change in PBV was found in tumors that exhibited CR (200 mL/100 mL ± 99; P = .001) or PR (240 mL/100 mL ± 370; P = .003) to treatment on follow-up imaging. The tumors with lower change in PBVs exhibited SD (64mL/100mL±99;P= .30) or PD (88mL/100mL± 129; P = .06).



Commentary


This study addresses a vital question. How do we know how well a patient with HCC will respond to transarterial embolization? The authors show that change in PBV correlates to the level of response to treatment as seen on 3 month follow up. While these results may not immediately impact practice pattern or fundamentally change the method of TACE in the near-term, the assesment of dynamic changes in tumor perfusion intraprocedurally may help identify tumors that are unlikely to respond to traditional angiographic endpoints of stasis. Identifying these patients at the time of TACE would indicate which tumors are most likely to benefit from embolization adjuncts (balloon-occlusion delivery, antireflux catheters, etc.). The authors acknowledge limitations, including factors relating to generating and processing PBV maps, artifacts, and generalizability to the larger HCC population. However, this data is important to our understanding of HCC and lays the groundwork for further studies aimed at optimizing both assessment of prognosis and treatment.

Click here for abstract

De Korompay N, Alshammari M, Klass D, Chou FY, Chung J, Ho S, Liu DM. Intraprocedural parenchymal blood volume is a predictor of treatment response for chemoembolization in hepatocellular carcinoma: results of a prospective study. J Vasc Interv Radiol. 2018; 29: 928-935.

Post Author:
Zagum Bhatti, MD
Assistant Professor
Department of Radiology, Interventional Radiology Division
University of Texas Health Science Center at Houston, Houston, TX
@UTHouston_IR
@ZagumBhatti