Publications by authors named "Jonathan G Sham"

20 Publications

  • Page 1 of 1

Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft murine model of hepatocellular carcinoma.

J Nucl Med 2021 Nov 12. Epub 2021 Nov 12.

University of Washington, Department of Surgery, United States.

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a Th-labeled GPC3 targeting antibody conjugate (Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of Th. In vitro stability was evaluated by measuring percentage of protein-bound Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. Octapa-conjugated αGPC3 provided up to 70% Th labeling yield in 2 h at room temperature. In the presence of ascorbate, ≥97.8% of Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in mice receiving 500 kBq/kg Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.
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http://dx.doi.org/10.2967/jnumed.121.262562DOI Listing
November 2021

CT Radiomics-Based Preoperative Survival Prediction in Patients With Pancreatic Ductal Adenocarcinoma.

AJR Am J Roentgenol 2021 11 1;217(5):1104-1112. Epub 2021 Sep 1.

Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD 21287.

Pancreatic ductal adenocarcinoma (PDAC) is often a lethal malignancy with limited preoperative predictors of long-term survival. The purpose of this study was to evaluate the prognostic utility of preoperative CT radiomics features in predicting postoperative survival of patients with PDAC. A total of 153 patients with surgically resected PDAC who underwent preoperative CT between 2011 and 2017 were retrospectively identified. Demographic, clinical, and survival information was collected from the medical records. Survival time after the surgical resection was used to stratify patients into a low-risk group (survival time > 3 years) and a high-risk group (survival time < 1 year). The 3D volume of the whole pancreatic tumor and background pancreas were manually segmented. A total of 478 radiomics features were extracted from tumors and 11 extra features were computed from pancreas boundaries. The 10 most relevant features were selected by feature reduction. Survival analysis was performed on the basis of clinical parameters both with and without the addition of the selected features. Survival status and time were estimated by a random survival forest algorithm. Concordance index (C-index) was used to evaluate performance of the survival prediction model. The mean age of patients with PDAC was 67 ± 11 (SD) years. The mean tumor size was 3.31 ± 2.55 cm. The 10 most relevant radiomics features showed 82.2% accuracy in the classification of high-risk versus low-risk groups. The C-index of survival prediction with clinical parameters alone was 0.6785. The addition of CT radiomics features improved the C-index to 0.7414. Addition of CT radiomics features to standard clinical factors improves survival prediction in patients with PDAC.
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http://dx.doi.org/10.2214/AJR.20.23490DOI Listing
November 2021

Postoperative biliary anastomotic strictures after pancreaticoduodenectomy.

HPB (Oxford) 2021 Nov 27;23(11):1716-1721. Epub 2021 Apr 27.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Biliary anastomotic stricture (BAS) is an uncommon complication of pancreaticoduodenectomy (PD). As PDs are performed more frequently, BAS may become a more common pathologic entity requiring clinical engagement. The aim of this study was to report the incidence of BAS in the modern era of pancreatic surgery and identify risk factors associated with it.

Methods: Patients undergoing PD at the Johns Hopkins Hospital between 2007 and 2016 were identified using an institutional registry and clinicopathological features were analyzed to identify risk factors associated with BAS.

Results: Of 2125 patients identified, 103 (4.9%) developed BAS. Factors independently associated with BAS included laparoscopic approach (HR:2.83,95%CI:1.35-5.92, p = 0.006), postoperative pancreatic fistula (HR:2.45,95%CI:1.56-4.16,p < 0.001), postoperative bile leak (BL) (HR:5.26,95%CI:2.45-11.28,p < 0.001), and administration of adjuvant radiation therapy (HR:6.01,95%CI:3.19-11.34,p < 0.001). Malignant pathology was associated with lower rates of BAS (HR:0.52,95%CI:0.30-0.92, p = 0.025). BL was associated with higher rates of early-BAS (HR:16.49,95%CI:3.28-82.94, p = 0.001) while use of Vicryl suture for biliary enteric anastomosis was associated with lower rates of early-BAS (HR:0.20,95%CI:0.05-0.93, p = 0.041).

Conclusion: Approximately 5% of patients undergoing PD experience BAS. Multiple factors are associated with the development and timing of BAS.
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http://dx.doi.org/10.1016/j.hpb.2021.04.008DOI Listing
November 2021

IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections.

Surg Endosc 2021 Feb 19. Epub 2021 Feb 19.

Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Health Sciences Bldg. Room BB-442, Box 356410, Seattle, WA, 98195, USA.

Background: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution.

Methods: Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation).

Results: Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5-9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively.

Conclusion: In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.
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http://dx.doi.org/10.1007/s00464-021-08345-wDOI Listing
February 2021

Glypican-3 targeted delivery of Zr and Y as a theranostic radionuclide platform for hepatocellular carcinoma.

Sci Rep 2021 02 12;11(1):3731. Epub 2021 Feb 12.

Department of Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356410, Health Sciences Bldg. Room BB-442, Seattle, WA, 98195-6410, USA.

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (Zr) and yttrium-90 (Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUV by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R = 0.90). Serum AFP was significantly lower 30 days after RIT in Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R = 0.87), and GTV of animals treated with Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted Zr and Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.
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http://dx.doi.org/10.1038/s41598-021-82172-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881163PMC
February 2021

Radical antegrade modular pancreatosplenectomy versus standard distal pancreatosplenectomy for pancreatic cancer, a dual-institutional analysis.

Chin Clin Oncol 2020 Aug 16;9(4):54. Epub 2020 Jun 16.

Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.

Background: Radical antegrade modular pancreatosplenectomy (RAMPS) has been adopted by some surgeons in the treatment of left-sided pancreatic cancer (PDAC). Low disease incidence and heterogenous disease biology make robust prospective comparison of RAMPS and standard distal pancreatosplenectomy (DPS) difficult.

Methods: Consecutive cases of chemo-naïve patients undergoing open RAMPS and DPS for PDAC between 2010-2017 at two international high-volume pancreatectomy centers were compared. Cox proportional hazard modeling was utilized for multivariate analysis.

Results: We identified 193 DPS and 253 RAMPS during the study period. DPS was associated with higher rates of median estimated blood loss (500 vs. 300 cc, P<0.001), median total harvested lymph nodes (18 vs. 12, P<0.001) and R0 resection (94.3% vs. 88.9%, P=0.013). There were no differences in rates of postoperative pancreatic fistula (16.5% vs. 17.8%, P=1) or postoperative hemorrhage (5.9% vs. 3.6%, P=0.385) (DPS vs. RAMPS). After controlling for significant clinical pathological parameters, RAMPS was associated with non-superior recurrence-free survival (RFS) (HR 0.29; 95% CI, 0.07-1.27, P=0.101) and overall-survival (HR 1.03; 95% CI, 0.71-1.49, P=0.895) compared with DPS. Similar results were observed in node-positive patients.

Conclusions: RAMPS is safe and effective in the treatment of PDAC, but is not associated with an improvement in either RFS or overall-survival over DPS.
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http://dx.doi.org/10.21037/cco-20-6DOI Listing
August 2020

Adjuvant Transcatheter Arterial Infusion Therapy for Hepatocellular Carcinoma: Not Yet for Everybody.

Ann Surg Oncol 2020 Oct 4;27(11):4070-4072. Epub 2020 Jun 4.

Department of Surgery, University of Washington, Seattle, WA, USA.

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http://dx.doi.org/10.1245/s10434-020-08702-4DOI Listing
October 2020

Management of primary hepatic malignancies during the COVID-19 pandemic: recommendations for risk mitigation from a multidisciplinary perspective.

Lancet Gastroenterol Hepatol 2020 08 6;5(8):765-775. Epub 2020 Jun 6.

UCL Cancer Institute, University College London, London, UK; Department of Medical Physics and Biomedical Engineering, University College London, London, UK.

Around the world, recommendations for cancer treatment are being adapted in real time in response to the pandemic of COVID-19. We, as a multidisciplinary team, reviewed the standard management options, according to the Barcelona Clinic Liver Cancer classification system, for hepatocellular carcinoma. We propose treatment recommendations related to COVID-19 for the different stages of hepatocellular carcinoma (ie, 0, A, B, and C), specifically in relation to surgery, locoregional therapies, and systemic therapy. We suggest potential strategies to modify risk during the pandemic and aid multidisciplinary treatment decision making. We also review the multidisciplinary management of intrahepatic cholangiocarcinoma as a potentially curable and incurable diagnosis in the setting of COVID-19.
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http://dx.doi.org/10.1016/S2468-1253(20)30182-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274990PMC
August 2020

Spleen-preserving distal pancreatectomy with splenic vessel preservation: challenges in measuring the learning curve.

Laparosc Surg 2018 Oct 30;2. Epub 2018 Oct 30.

Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA.

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http://dx.doi.org/10.21037/ls.2018.10.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555427PMC
October 2018

Laparoscopic anatomical S3 segmentectomy by the glissonian approach.

Surg Oncol 2019 Mar 1;28:222. Epub 2019 Feb 1.

Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: In an attempt to preserve hepatic volume in cases of severe cirrhosis, isolated resection of segment 3 (Sg3) may be beneficial [1-3]. We describe a laparoscopic anatomical Sg3 segmentectomy via an extrahepatic Glissonian approach.

Video: First, the falciform and coronary ligament were dissected. The Glissonian pedicle to Sg3 was isolated via meticulous dissection with the laparoscopic CUSA and suction catheter. After temporary occlusion, the ischemic margin of Sg3 was confirmed and the transection was performed from the medial and lateral aspects of Sg3. After the transection planes meet, hepatic venous and portal pedicle branches are controlled, and ultimately the main s3 Glissonian pedicle is ligated.

Results: Operative time was 175 minutes and the estimated intraoperative blood loss was 30 mL. On postoperative day 3, the patient was discharged without any complications. Pathologic findings demonstrated a 2.1 × 1.5 × 1.0 cm hepatocellular carcinoma (pT2) with a 0.3 cm tumor-free resection margin.

Conclusions: The laparoscopic anatomic Sg3 segmentectomy is a feasible and safe procedure for hepatocellular carcinoma. This approach may be beneficial in cases where hepatic parenchymal preservation is desired.
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http://dx.doi.org/10.1016/j.suronc.2019.01.014DOI Listing
March 2019

Laparoscopic anatomical S7 segmentectomy by the intrahepatic glissonian approach.

Surg Oncol 2019 Mar 8;28:158. Epub 2019 Jan 8.

Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Laparoscopic anatomical liver resection for posterosuperior lesions is challenging [1,2] A technique of anatomical liver resection with intrahepatic Glissonian approach in open surgery has been published [3]. However, few articles report this technique via the laparoscopic approach [4]. We report a case of laparoscopic anatomical S7 segmentectomy using the Glissonian pedicle approach.

Video: A 76-year-old male was admitted for an incidentally detected hepatic mass in segment 7 (S7). Abdominal computed tomography (CT) showed a 5.5 cm solitary tumor. First, the major Glissonian pedicle of the right posterior section was dissected, followed by hepatic parenchymal dissection peripherally until the branches of the Glissonian pedicles of segment 6 and 7 were reached. The S7 Glissonian pedicle was temporarily clamped to confirm demarcation. Dissection was then performed until the right hepatic vein (RHV) was exposed. Further dissection was then continued along the RHV, up to its root.

Results: Operative time was 330 minutes. The estimated intraoperative blood loss was 300 mL without a requirement for intraoperative transfusion. On postoperative day 4, the abdominal CT was performed, which revealed no abnormal findings. The patient was discharged on postoperative day 5 without any complications. Pathologic findings demonstrated a 5.2 × 3.8 × 3.1 cm hepatocellular carcinoma (pT1b) with a 2.8-cm tumor-free resection margin.

Conclusion: Laparoscopic anatomical S7 segmentectomy via the intrahepatic Glissonian approach is a technically demanding procedure and should be adopted for selected patients. However, this technique is feasible with careful dissection and control of the intrahepatic Glissonian pedicle.
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http://dx.doi.org/10.1016/j.suronc.2019.01.004DOI Listing
March 2019

The Impact of Extent of Liver Resection Among Patients with Neuroendocrine Liver Metastasis: an International Multi-institutional Study.

J Gastrointest Surg 2019 03 6;23(3):484-491. Epub 2018 Jul 6.

Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 614, Baltimore, MD, 21287, USA.

Background: Liver resection in patients with neuroendocrine liver metastasis (NELM) provides a survival benefit, yet the optimal extent of resection remains unknown. We sought to examine outcomes of patients undergoing non-anatomic (NAR) versus anatomic liver resection (AR) for NELM using a large international cohort of patients.

Methods: Two hundred and fifty-eight patients who underwent curative intent liver resection from January 1990 to December 2016 were identified from eight institutions. Patients were excluded if they underwent concurrent ablation, had extrahepatic disease, underwent a debulking operation, or had mixed anatomic and non-anatomic resections. Overall (OS) and recurrence-free (RFS) survival were compared among patients based on the extent of liver resection (AR vs. NAR).

Results: Most primary tumors were located in the pancreas (n = 117, 45.4%) or the small intestine (n = 65, 25.2%). Liver resection consisted of NAR (n = 126, 48.8%) or AR (n = 132, 51.2%) resection. The overwhelming majority of patients who underwent NAR had an estimated liver involvement of < 50% (NAR 109, 97.3% vs. AR n = 82, 65.6%; P < 0.001). Patients who underwent NAR also had higher rates of primary tumor lymph node metastasis (NAR n = 79, 71.2% vs. AR n = 37, 33.6%; P < 0.001) and microscopically positive margins (R1) (NAR n = 29, 25.7% vs. AR n = 16, 12.5%; P = 0.009). After a median follow-up of 47.7 months, 48 (18.6%) patients died and 37.0% (n = 95) had evidence of disease recurrence. Patients who underwent AR had both longer median OS (not reached) and RFS (not reached) versus patients who underwent NAR (median OS 138.3 months; median RFS 31.3 months) (both P < 0.01). After controlling for patient and disease-related factors, extent of liver resection was independently associated with an increased risk of recurrence (HR 2.39, 95% CI 1.04-5.48; P = 0.04) but not death (HR 1.92, 95% CI 0.40-9.28; P = 0.42).

Conclusion: NAR was independently associated with a higher incidence of recurrence versus patients who undergo a formal anatomic hepatectomy among patients with NELM.
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http://dx.doi.org/10.1007/s11605-018-3862-2DOI Listing
March 2019

A Large Animal Survival Model to Evaluate Bariatric Surgery Mechanisms.

Surg Sci 2015 Aug 24;6(8):337-345. Epub 2015 Jul 24.

Departments of Surgery, University of Washington, Seattle, USA ; Departments of Health Services, University of Washington, Seattle, USA.

Background: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part because of limitations in relevant bariatric-surgery animal models, specifically the lack of naturally insulin-resistant large animals. With overfeeding, Ossabaw swine develop a robust metabolic syndrome, and may be suitable for studying post-surgical physiology. Whether bariatric surgery is feasible in these animals with acceptable survival is unknown.

Methods: Thirty-two Ossabaws were fed a high-fat, high-cholesterol diet to induce obesity and insulin resistance. These animals were assigned to RYGB (n = 8), RYGB with vagotomy (RYGB-V, n = 5), gastrojejunostomy (GJ, n = 10), GJ with duodenal exclusion (GJD, n = 7), or sham operation (n = 2) and were euthanized 60 days post-operatively. Post-operative changes in weight and food intake are reported.

Results: Survival to scheduled necropsy among surgical groups was 77%, living an average of 57 days post-operatively. Cardiac arrest under anesthesia occurred in 4 pigs. Greatest weight loss (18.0% ± 6%) and food intake decrease (57.0% ± 20%) occurred following RYGB while animals undergoing RYGB-V showed only 6.6% ± 3% weight loss despite 50.8% ± 25% food intake decrease. GJ (12.7% ± 4%) and GJD (1.2% ± 1%) pigs gained weight, but less than sham controls (13.4% ± 10%).

Conclusions: A survival model of metabolic surgical procedures is feasible, leads to significant weight loss, and provides the opportunity to evaluate new interventions and subtle variations in surgical technique (e.g. vagus nerve sparing) that may provide new mechanistic insights.
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http://dx.doi.org/10.4236/ss.2015.68050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871691PMC
August 2015

Efficacy and cost of robotic hepatectomy: is the robot cost-prohibitive?

J Robot Surg 2016 Dec 6;10(4):307-313. Epub 2016 May 6.

Department of Surgery, Center for Advanced Minimally Invasive Liver Oncologic Therapies (CAMILOT), University of Washington, 1959 Pacific St NE, Seattle, WA, 98195, USA.

Robotic technology is being utilized in multiple hepatobiliary procedures, including hepatic resections. The benefits of minimally invasive surgical approaches have been well documented; however, there is some concern that robotic liver surgery may be prohibitively costly and therefore should be limited on this basis. A single-institution, retrospective cohort study was performed of robotic and open liver resections performed for benign and malignant pathologies. Clinical and cost outcomes were analyzed using adjusted generalized linear regression models. Clinical and cost data for 71 robotic (RH) and 88 open (OH) hepatectomies were analyzed. Operative time was significantly longer in the RH group (303 vs. 253 min; p = 0.004). Length of stay was more than 2 days shorter in the RH group (4.2 vs. 6.5 days; p < 0.001). RH perioperative costs were higher ($6026 vs. $5479; p = 0.047); however, postoperative costs were significantly lower, resulting in lower total hospital direct costs compared with OH controls ($14,754 vs. $18,998; p = 0.001). Robotic assistance is safe and effective while performing major and minor liver resections. Despite increased perioperative costs, overall RH direct costs are not greater than OH, the current standard of care.
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http://dx.doi.org/10.1007/s11701-016-0598-4DOI Listing
December 2016

Iron-Oxide-Based Nanovector for Tumor Targeted siRNA Delivery in an Orthotopic Hepatocellular Carcinoma Xenograft Mouse Model.

Small 2016 Jan 7;12(4):477-87. Epub 2015 Dec 7.

Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Small interfering RNA (siRNA) holds promise as a new class of therapeutics for HCC, as it can achieve sequence-specific gene knockdown with low cytotoxicity. However, the main challenge in the clinical application of siRNA lies in the lack of effective delivery approaches that need to be highly specific and thus incur low or no systemic toxicity. Here, a nonviral nanoparticle-based gene carrier is presented that can specifically deliver siRNA to HCC. The nanovector (NP-siRNA-GPC3 Ab) is made of an iron oxide core coated with chitosan-polyethylene glycol (PEG) grafted polyethyleneimine copolymer, which is further functionalized with siRNA and conjugated with a monoclonal antibody (Ab) against human glypican-3 (GPC3) receptor highly expressed in HCC. A rat RH7777 HCC cell line that coexpresses human GPC3 and firefly luciferase (Luc) is established to evaluate the nanovector. The nanoparticle-mediated delivery of siRNA against Luc effectively suppresses Luc expression in vitro without notable cytotoxicity. Significantly, NP-siLuc-GPC3 Ab administered intravenously in an orthotopic model of HCC is able to specifically bound to tumor and induce remarkable inhibition of Luc expression. The findings demonstrate the potential of using this nanovector for targeted delivery of therapeutic siRNA to HCC.
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http://dx.doi.org/10.1002/smll.201501985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829640PMC
January 2016

Nanoparticle mediated silencing of DNA repair sensitizes pediatric brain tumor cells to γ-irradiation.

Mol Oncol 2015 Jun 29;9(6):1071-80. Epub 2015 Jan 29.

Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA; Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA; Department of Radiology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Medulloblastoma (MB) and ependymoma (EP) are the most common pediatric brain tumors, afflicting 3000 children annually. Radiotherapy (RT) is an integral component in the treatment of these tumors; however, the improvement in survival is often accompanied by radiation-induced adverse developmental and psychosocial sequelae. Therefore, there is an urgent need to develop strategies that can increase the sensitivity of brain tumors cells to RT while sparing adjacent healthy brain tissue. Apurinic endonuclease 1 (Ape1), an enzyme in the base excision repair pathway, has been implicated in radiation resistance in cancer. Pharmacological and specificity limitations inherent to small molecule inhibitors of Ape1 have hindered their clinical development. Here we report on a nanoparticle (NP) based siRNA delivery vehicle for knocking down Ape1 expression and sensitizing pediatric brain tumor cells to RT. The NP comprises a superparamagnetic iron oxide core coated with a biocompatible, biodegradable coating of chitosan, polyethylene glycol (PEG), and polyethyleneimine (PEI) that is able to bind and protect siRNA from degradation and to deliver siRNA to the perinuclear region of target cells. NPs loaded with siRNA against Ape1 (NP:siApe1) knocked down Ape1 expression over 75% in MB and EP cells, and reduced Ape1 activity by 80%. This reduction in Ape1 activity correlated with increased DNA damage post-irradiation, which resulted in decreased cell survival in clonogenic assays. The sensitization was specific to therapies generating abasic lesions as evidenced by NP:siRNA not increasing sensitivity to paclitaxel, a microtubule disrupting agent. Our results indicate NP-mediated delivery of siApe1 is a promising strategy for circumventing pediatric brain tumor resistance to RT.
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http://dx.doi.org/10.1016/j.molonc.2015.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439369PMC
June 2015

Glypican-3-targeting F(ab')2 for 89Zr PET of hepatocellular carcinoma.

J Nucl Med 2014 Dec 30;55(12):2032-7. Epub 2014 Oct 30.

Department of Surgery, University of Washington, Seattle, Washington

Unlabelled: Hepatocellular carcinoma (HCC) is an increasingly lethal malignancy for which management is critically dependent on accurate imaging. Glypican-3 (GPC3) is a cell surface receptor overexpressed in most HCCs and provides a unique target for molecular diagnostics. The use of monoclonal antibodies (mAbs) that target GPC3 (αGPC3) in PET imaging has shown promise but comes with inherent limitations associated with mAbs such as long circulation times. This study used (89)Zr-conjugated F(ab')2 fragments directed against GPC3 ((89)Zr-αGPC3-F(ab')2) to evaluate the feasibility of the fragments as a diagnostic immuno-PET imaging probe.

Methods: Immobilized ficin was used to digest αGPC3, creating αGPC3-F(ab')2 fragments subsequently conjugated to (89)Zr. In vivo biodistribution and PET studies were performed on GPC3-expressing HepG2 and GPC3-nonexpressing RH7777 orthotopic xenografts.

Results: Reliable αGPC3-F(ab')2 production via immobilized ficin digestion was verified by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. (89)Zr-αGPC3-F(ab')2 demonstrated F(ab')2-dependent, antigen-specific cell binding. HepG2 tumor uptake was higher than any other tissue, peaking at 100 ± 21 percentage injected dose per gram (%ID/g) 24 h after injection, a value 33- to 38-fold higher than GPC3-nonexpressing RH7777 tumors. The blood half-life of the (89)Zr-αGPC3-F(ab')2 conjugate was approximately 11 h, compared with approximately 115 h for historic mAb controls. This shorter half-life enabled clear tumor visualization on PET 4 h after administration, with a resultant peak tumor-to-liver contrast ratio of 23.3. Blocking antigen-expressing tumors with an excess of nonradiolabeled αGPC3 resulted in decreased tumor uptake similar to native liver. The kidneys exhibited high tissue uptake, peaking at 24 h with 83 ± 12 %ID/g. HepG2 tumors ranging from 1.5 to 7 mm were clearly visible on PET, whereas larger RH7777 tumors displayed signal lower than background liver tissue.

Conclusion: This study demonstrates the feasibility of using (89)Zr-αGPC3-F(ab')2 for intrahepatic tumor localization with small-animal PET. Faster blood clearance and lower background liver uptake enable excellent signal-to-noise ratios at early time points. Increased renal uptake is similar to that as has been seen with clinical radioactive peptide imaging. (89)Zr-αGPC3-F(ab')2 addresses some of the shortcomings of whole-antibody immuno-PET probes. Further optimization is warranted to maximize probe sensitivity and specificity in the process of clinical translation.
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http://dx.doi.org/10.2967/jnumed.114.145102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259878PMC
December 2014

Evaluating the mechanisms of improved glucose homeostasis after bariatric surgery in Ossabaw miniature swine.

J Diabetes Res 2014 24;2014:526972. Epub 2014 Aug 24.

Department of Surgery, University of Washington, Seattle, WA 98195, USA ; Department of Health Services, University of Washington, Seattle, WA 98195, USA.

Background: Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery.

Methods: Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs.

Results: High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasing AUCinsulin/AUCglucose.

Conclusions: Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increased AUCinsulin/AUCglucose, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis.
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http://dx.doi.org/10.1155/2014/526972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158302PMC
April 2015

Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment.

PLoS One 2014 2;9(5):e96565. Epub 2014 May 2.

Department of Surgery, University of Washington, Seattle, Washington, United States of America.

Objective: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA.

Design: We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood.

Results: In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg.

Conclusion: Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096565PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008589PMC
June 2015

Glypican-3-targeted 89Zr PET imaging of hepatocellular carcinoma.

J Nucl Med 2014 May 13;55(5):799-804. Epub 2014 Mar 13.

Department of Surgery, University of Washington, Seattle, Washington.

Unlabelled: Hepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-αGPC3) for intrahepatic tumor localization using PET.

Methods: Polymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts.

Results: (89)Zr-αGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 ± 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 ± 1.6 %ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 ± 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 ± 87.6 %ID/g) compared with control RH7777 tumors (3.9 ± 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr-αGPC3. HepG2 tumor treated with unlabeled αGPC3 or heat-denatured (89)Zr-αGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency.

Conclusion: This study demonstrated the feasibility of using (89)Zr-αGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.
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http://dx.doi.org/10.2967/jnumed.113.132118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116087PMC
May 2014
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