Andrew X Zhu

Harvard University, Cambridge, Massachusetts, United States

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Publications (184)1130.23 Total impact

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    ABSTRACT: Many patients with primary hepatic malignancies present with advanced disease that is not suitable for surgical resection, orthotopic liver transplantation, or radiofrequency ablation. Outcomes are particularly dismal in patients with large, unresectable tumors and/or tumor venous thrombosis. Liver-directed radiotherapy, including stereotactic body radiotherapy (SBRT), is able to treat a variety of tumor sizes and tumors with venous involvement and has demonstrated excellent safety and control outcomes. SBRT should be considered a standard option in patients with early-stage hepatocellular carcinoma who are not candidates for surgical resection, orthotopic liver transplantation or radiofrequency ablation. SBRT should be strongly considered in patients with larger tumors and/or tumors with tumor venous thrombosis who have adequate liver function. Radiotherapy should remain a focus of hepatocellular carcinoma research.
    04/2015; DOI:10.2217/HEP.15.7
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    ABSTRACT: The purpose of this study was to evaluate the response of biliary tract cancer treated with multidrug chemotherapy using FDG PET in comparison with morphologic and density changes. In this phase II clinical trial, 28 patients with unresectable or metastatic biliary tract cancers treated with gemcitabine and oxaliplatin combined with bevacizumab (GEMOX-B) underwent FDG PET and contrast-enhanced CT at baseline and after the second cycle of the therapy (8 weeks). A single reviewer recorded tumor maximum standardized uptake value (SUVmax) along with size, volume (3D-sphere), and density. The percentage changes of the parameters were compared with progression-free survival at 7 months. Overall survival was compared with the percentage change of SUVmax. After 8 weeks, measurable reductions (± SD) in size (7.05 ± 4.19 to 5.52 ± 3.28 cm, -21.70%), volume (411.38 ± 540.08 to 212.41 ± 293.45 cm(3), -48.36%), and density (60.76 ± 20.65 to 50.68 ± 16.89 HU, -15.59%) were noted along with a substantial drop in SUVmax (5.95 ± 1.95 to 3.36 ± 1.28, -43.52%). The SUVmax change showed positive correlations with tumor size change (R(2) = 0.39, p = 0.0004) and volumetric change (R(2) = 0.34, p = 0.001). Patients who showed a larger drop in SUVmax at 8 weeks correlated with favorable progression-free survival (p = 0.02). ROC analysis showed that a 45% reduction in SUVmax was the best cutoff value to detect favorable progression-free survival patients. When we used this cutoff value, Kaplan-Meier analysis showed that patients with tumors showing greater reduction in SUVmax had favorable progression-free survival and overall survival (p = 0.0009, p = 0.03). In biliary tract cancers treated with GEMOX-B, the reduction of SUVmax after therapy is a better predictor for survival than morphologic and density changes.
    American Journal of Roentgenology 04/2015; 204(4):776-781. DOI:10.2214/AJR.14.13223 · 2.74 Impact Factor
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    ABSTRACT: Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyper-activation of mammalian target of rapamycin (mTOR) signaling plays a pivotal role in HCC tumorigenesis. Tuberous Sclerosis Complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the present study, we discovered that TSC2 loss of function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV+ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 02/2015; 14(5). DOI:10.1158/1535-7163.MCT-14-0768 · 6.11 Impact Factor
  • Dr. Andrew X. Zhu
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    ABSTRACT: Cholangiocarcinoma (CCA) comprises a heterogeneous group of cancers with pathologic features of biliary tract differentiation, and is best classified anatomically as intrahepatic CCA (ICC), perihilar (pCCA), or distal (dCCA) CCA. They represent a clinically and genetically diverse collection of cancers. Surgical resection represents the only curative modality for CCA, although there are encouraging data with liver transplantation for early stage pCCA. There is no established adjuvant therapy for CCA. Unfortunately, most patients with CCA will present with unresectable or metastatic disease with poor prognosis. Currently the combination of gemcitabine and cisplatin remains the standard therapy for advanced CCA. No second line therapy has definitely demonstrated improved survival benefits. Development of molecularly targeted therapies in advanced CCA remains challenging. However, recent efforts with targeted and whole exome sequencing have defined the landscape of mutations underlying CCA, particularly ICC. The identification of novel molecular signatures in CCA coupled with molecularly targeted therapy development provides the potential for developing novel therapeutic options in this intractable disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Best practice & research. Clinical gastroenterology 02/2015; 29(2). DOI:10.1016/j.bpg.2015.02.010 · 3.28 Impact Factor
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    ABSTRACT: To compare the safety and efficacy of using 70-150 μm drug-eluting beads (DEBs) (LC BeadM1; Biocompatibles UK Ltd, Farnham, Surrey, United Kingdom) in addition to 100-300 μm DEBs with 100-300 μm DEBs alone in transarterial chemoembolization for treatment of hepatocellular carcinoma (HCC). A cohort of patients with HCC who underwent transarterial chemoembolization with two vials of 100-300 μm DEBs (group 1, 55 procedures among 42 patients, 33 men, average Model for End-Stage Liver Disease score 10 ± 0.6, 67% Child-Pugh A, 33% Child-Pugh B) was retrospectively compared with a cohort of patients who underwent transarterial chemoembolization with one vial of 70-150 μm DEBs followed by one vial of 100-300 μm DEBs (group 2, 51 procedures among 42 patients, 29 men, average Model for End-Stage Liver Disease score 9 ± 0.6, 73% Child-Pugh A, 27% Child-Pugh B) in regard to adverse events and response on 1-month follow-up imaging using modified Response Evaluation Criteria In Solid Tumors criteria. There was no difference in 1-month imaging response (P = .3). Patients in group 2 were readmitted more often within 1 month for hepatobiliary adverse events (group 2, 25%; group 1, 9%; P < .0001), including ascites, gastrointestinal hemorrhage, biliary dilatation, and cholecystitis. Despite similar efficacy based on short-term follow-up imaging, transarterial chemoembolization with smaller DEBs (70-150 μm) followed by larger DEBs (100-300 μm) may cause more hepatobiliary adverse events. Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.
    Journal of Vascular and Interventional Radiology 02/2015; 26(4). DOI:10.1016/j.jvir.2014.12.020 · 2.15 Impact Factor
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    ABSTRACT: The genetic abnormalities involved in the pathogenesis of gallbladder carcinoma (GBC) remain unclear. Microsatellite instability (MSI) has been described in many carcinomas, but little is known about the significance of mismatch repair in gallbladder carcinogenesis. Additionally, methylation status of long interspersed element-1 (LINE-1), a surrogate marker of global DNA methylation, has defined distinct subsets of other cancer types but has not been explored in GBC. Immunohistochemical expression of MSH2, MSH6, MLH1, and PMS2 and LINE-1 mRNA in situ hybridization was evaluated in 67 primary and 15 metastatic GBCs from 77 patients. Amplification of human epidermal growth factor receptor 2 (HER2) was evaluated by fluorescence in situ hybridization. Genotyping for 24 genes involved in carcinogenesis was performed using a multiplex PCR-based platform. MSI was present in 6 of 77 GBCs (7.8 %). Loss of MSH2/MSH6 was detected in five cases and loss of MLH1/PMS2 in one case. MSI status was not associated with Lynch syndrome, tumor grade, extracellular mucin, or tumor-infiltrating lymphocytes. There was no significant difference in mean overall survival of patients with and without MSI. Strong LINE-1 staining was identified in none of the GBC with MSI and in 36 of 69 (52 %) of those without MSI (p = 0.005), suggesting that LINE-1 in the former cohort was hypermethylated. All MSI tumors were negative for HER2 amplification, and TP53 and NRAS mutations were only found in GBC without MSI. MSI was identified in a minority of GBC cases. The strong correlation between global DNA methylation as measured by LINE-1 and loss of mismatch repair proteins suggests that methylation may account for the loss of these proteins. These hypermethylated tumors appear to represent a genetically unique cohort of gallbladder neoplasms, and the data suggests that demethylating agents may have a therapeutic value in this class of tumors.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2015; 466(4). DOI:10.1007/s00428-015-1720-0 · 2.56 Impact Factor
  • Journal of Vascular and Interventional Radiology 02/2015; 26(2):S106. DOI:10.1016/j.jvir.2014.12.285 · 2.15 Impact Factor
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    ABSTRACT: On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.
    Annals of Surgery 01/2015; 261(1):12-7. DOI:10.1097/SLA.0000000000000867 · 7.19 Impact Factor
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    ABSTRACT: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 12/2014; 33(6). DOI:10.1200/JCO.2013.53.7746 · 17.88 Impact Factor
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    ABSTRACT: Background Intrahepatic cholangiocarcinoma (ICC) often is a diagnosis determined by exclusion. Distinguishing ICC from other metastatic adenocarcinomas based on histopathologic or immunohistochemical analysis often is difficult and requires an extensive workup. This study aimed to determine whether albumin, whose expression is restricted to the liver, has potential as a biomarker for ICC using a novel and highly sensitive RNA in situ hybridization (ISH) platform. Methods Modified branched DNA probes were developed for albumin RNA ISH. The study evaluated 467 patient samples of primary and metastatic lesions. Results Of the 467 samples evaluated, 83 were ICCs, 42 were hepatocellular carcinomas (HCCs), and 332 were nonhepatic carcinomas including tumors arising from the perihilar region and bile duct, pancreas, stomach, esophagus, colon, breast, ovary, endometrium, kidney, and urinary bladder. Albumin RNA ISH was highly sensitive for cancers of liver origin, staining positive in 82 (99 %) of 83 ICCs and in 42 HCCs (100 %). Perihilar and distal bile duct carcinomas as well as carcinomas arising at other sites tested negative for albumin. Notably, 6 (22 %) of 27 intrahepatic tumors previously diagnosed as carcinomas of undetermined origin tested positive for albumin. Conclusions Albumin RNA ISH is a sensitive and highly specific diagnostic tool for distinguishing ICC from metastatic adenocarcinoma to the liver or carcinoma of unknown origin. Albumin RNA ISH could replace the extensive diagnostic workup, leading to timely confirmation of the ICC diagnosis. Additionally, the assay could serve as a guide to distinguish ICC from perihilar adenocarcinoma.
    Annals of Surgical Oncology 12/2014; DOI:10.1245/s10434-014-4247-8 · 3.94 Impact Factor
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    ABSTRACT: Sorafenib—a broad tyrosine kinase inhibitor—is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC), but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8+ T-lymphocyte infiltration in both murine and human tumors. Moreover, we have shown in mouse models that after sorafenib treatment, intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death-ligand 1 (PD-L1) and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of the immunosuppressive cells is mediated in part by hypoxia-induced upregulation of stromal cell-derived 1 alpha (SDF1α). Inhibition of the SDF1α receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8+ T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the PD-L1 receptor PD-1 showed anti-tumor effects in treatment-naïve tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional anti-tumor activity only when combined with sorafenib and AMD3100, and not when combined with sorafenib alone. Conclusion: Anti-PD-1 treatment can boost anti-tumor immune responses in HCC models. When used in combination with sorafenib, this immunotherapy approach shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors. This article is protected by copyright. All rights reserved.
    Hepatology 12/2014; 61(5). DOI:10.1002/hep.27665 · 11.19 Impact Factor
  • Richard L Hesketh, Andrew X Zhu, Rahmi Oklu
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    ABSTRACT: Personalized care in oncology is expected to significantly improve morbidity and mortality, facilitated by our increasing understanding of the molecular mechanisms driving tumors and the ability to target those drivers. Hepatocellular carcinoma has a very high mortality to incidence ratio despite localized disease being curable, emphasizing the importance of early diagnosis. Radiomics, the use of imaging technology to extrapolate molecular tumor data, and the detection of circulating tumor cells (CTCs) are two new technologies that could be incorporated into the clinical setting with relative ease. Here we discuss the molecular mechanisms leading to the development of hepatocellular carcinoma focusing on the latest developments in liver magnetic resonance imaging, CTC, and radiomic technology and their potential to improve diagnosis, staging, and therapy.
    Diagnostic and interventional radiology (Ankara, Turkey) 11/2014; 21(1). DOI:10.5152/dir.2014.14237 · 1.43 Impact Factor
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    ABSTRACT: Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review, we summarize the current knowledge on HCC immunology, and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives. (Hepatology 2014;).
    Hepatology 11/2014; 60(5). DOI:10.1002/hep.27246 · 11.19 Impact Factor
  • Amy R Deipolyi, Andrew X Zhu, Rahmi Oklu
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    ABSTRACT: Predicting which patients will benefit from radioembolization remains a challenge, as reliable prognostic indicators are not defined. Abnormal tumor vascular anatomy could not only impact the ability of cancer therapies to penetrate tumors, but may also contribute to a lesion's metastatic potential. Specifically, intratumoral vascular shunts could allow circulating tumor cells to initiate metastases by allowing them to gain access to distant sites in the body, bypassing capillary beds. Here, we describe how tumoral angiogenesis occurs and how intratumoral vascular shunts may form.
    American Journal of Clinical Oncology 10/2014; DOI:10.1097/COC.0000000000000145 · 2.61 Impact Factor
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    ABSTRACT: Purpose To demonstrate the clinical translation of optical molecular imaging ( OMI optical molecular imaging ) for the localization of focal hepatic lesions during percutaneous hepatic interventions. Materials and Methods Institutional review board approval was obtained for this prospective, single-center, HIPAA-compliant trial. Patients who were suspected of having hepatocellular carcinoma or liver metastases from colorectal cancer and were scheduled for percutaneous liver biopsy or thermal ablation were eligible for this study. Patients (n = 5) received 0.5 mg per kilogram of body weight of indocyanine green ( ICG indocyanine green ) intravenously 24 hours prior to their scheduled procedure in this study. Intraprocedurally, a handheld device composed of an endoscope that fits coaxially through a standard 17-gauge introducer needle was advanced into the liver, and real-time measurements of ICG indocyanine green fluorescence were obtained. A point-of-care fluorescence imaging system was used to image ICG indocyanine green fluorescence in biopsy samples. Target-to-background ratios ( TBR target-to-background ratio s) were calculated by dividing the mean fluorescence intensity in the lesion by the mean fluorescence intensity in the adjacent liver parenchyma. The reference standard for determination of proper needle positioning in patients undergoing biopsy was final pathologic analysis of biopsy specimens or follow-up imaging. Results Intraprocedural OMI optical molecular imaging was successfully performed in six lesions (two lesions in patient 3) in five patients. The median size of the targeted lesions was 16 mm (range, 10-21 mm). Four of five biopsies (80%) yielded an accurate pathologic diagnosis, and one biopsy specimen showed benign liver parenchyma; both ablated lesions showed no residual disease 1 month after the procedure. The median overall added procedure time to perform OMI optical molecular imaging was 2 minutes. ICG indocyanine green was found to localize with TBR target-to-background ratio s greater than 2.0 (median, 7.9; range, 2.4-13.4) in all target lesions. No trial-related adverse events were reported. Conclusion The clinical translation of OMI optical molecular imaging to percutaneous hepatic interventions was demonstrated. © RSNA, 2014 Online supplemental material is available for this article.
    Radiology 10/2014; 274(3):141308. DOI:10.1148/radiol.14141308 · 6.21 Impact Factor
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    ABSTRACT: Background Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. Methods Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. Results Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. Conclusion Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.
    Investigational New Drugs 09/2014; 33(1). DOI:10.1007/s10637-014-0164-8 · 2.93 Impact Factor
  • Richard L Hesketh, Andrew X Zhu, Rahmi Oklu
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    ABSTRACT: The 'omics revolution is facilitating a personalized approach to improving outcome by refining diagnosis, staging, treatment, and monitoring of hepatocellular carcinoma. Furthermore, the promise of being able to target a range of specific tumor drivers at a molecular level offers exciting new therapy prospects for a disease that is notoriously difficult to treat. We provide a unique perspective combining our understanding of the molecular mechanisms of hepatocellular carcinoma development with the potential of circulating tumor cells and radiogenomics to change the drivers of decision-making used in current practice.
    American Journal of Clinical Oncology 09/2014; DOI:10.1097/COC.0000000000000123 · 2.61 Impact Factor
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    ABSTRACT: Previous texture analysis studies of liver CT images have shown the potential to achieve hepatic malignancy or predict overall survival (OS). However, to date, most studies have mainly focused on assessing texture features of the noncontrast CT or portal-phase image in the dynamic contrast-enhanced CT sequence. The aim of this study was to quantify texture features of physiologically-based kinetic parametric images, and to develop prognostic kinetic textural biomarkers for 1-year survival (1YS) and OS in patients with advanced hepatocellular carcinoma (HCC) following antiangiogenic therapy in comparison among five different tracer kinetic models. Mean, standard deviation, coefficient of variation, skewness, and kurtosis of the pixel distribution histogram within HCC were derived from baseline first-pass perfusion CT parameters. Results suggest that texture analysis of kinetic parametric images can provide better chances of finding effective prognostic biomarkers for the prediction of survival than a mean value analysis alone.
    6th MICCAI Workshop on Abdominal Imaging: Computational and Clinical Applications; 09/2014
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    ABSTRACT: Dynamic contrast-enhanced MRI (DCE-MRI) data have often been analyzed using classic standard tracer kinetic models that assume a fast-exchange limit (FXL) of water. Recently, it has been demonstrated that deviations from the FXL model occurs when contrast agent arrives at the target tissue. However, no systematic analysis has been reported for the liver tumor with dual blood supply. In this study, we compared kinetic parameter estimates from DCE-MRI in advanced hepatocellular carcinoma that have the same physiological meaning between five different FXL standard dual-input tracer kinetic models and their corresponding water-exchange-modified (WX) versions. Kinetic parameters were estimated by fitting data to analytic solutions of five different FXL models and their WX versions based on a full two-site-exchange model for transcytolemmal water exchange or a full three-site-two-exchange model for transendothelial and transcytolemmal water exchange. Results suggest that parameter values differ substantially between the FXL standard and WX tracer kinetic models, indicating that DCE-MRI data are water-exchange-sensitive.
    6th MICCAI Workshop on Abdominal Imaging: Computational and Clinical Applications; 09/2014

Publication Stats

7k Citations
1,130.23 Total Impact Points

Institutions

  • 2004–2015
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • • Division of Hematology and Medical Oncology
      • • Department of Radiology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2014
    • University of Toronto
      • Department of Radiation Oncology
      Toronto, Ontario, Canada
  • 2003–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2010
    • The University of Calgary
      • Department of Medicine
      Calgary, Alberta, Canada
  • 2009
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States
  • 2006–2007
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • Rutgers, The State University of New Jersey
      Нью-Брансуик, New Jersey, United States