Timothy E. Newhook

Morbidity and mortality of hepatectomy for benign liver tumors

BACKGROUND This study compared the morbidity and mortality following hepatectomy for benign liver tumors and hepatic metastases. METHODS This retrospective cohort study compared patients who underwent hepatectomy for benign liver tumors and metastases reported to National Surgical Quality Improvement Program between 2005 and 2011. RESULTS A total of 5,542 patients underwent hepatectomy: 1,164 (21%) for benign and 4,378 (79%) for metastatic diseases. Patients with benign tumors were younger, predominantly female, and were less likely to have preoperative comorbidities (all P < .037). Rates of major complications including infections, embolism, renal failure, stroke, coma, cardiac arrest, reoperation, and ventilator dependence were similar between the 2 groups (all P ≥ .05). Thirty-day mortality was .9% among patients with benign tumors and 1.4% among patients with metastases (P = .128). After adjusting for significant effects of age and major complications (both P ≤ .007), benign vs malignant diagnosis and extent of hepatectomy was not associated with 30-day survival (both P ≥ .083). CONCLUSIONS Despite patients with benign disease being younger and healthier, risks of major complications are similar after hepatectomy for benign and metastatic disease. Hepatectomy should be offered selectively for patients with benign liver tumors.

Jejunal tube extensions via percutaneous endoscopic gastrostomy and delayed small-bowel perforations: a case series

In patients who cannot tolerate oral feedings or maintain adequate nutrition, supplemental enteric or intravenous nutrition must be provided. Enteric nutrition is the preferred method over total parenteral nutrition when the gastrointestinal tract is intact with functional motility and absorptive capabilities.1, 2 Enteric feeding maintains the bowel’s mucosal structure and integrity, maintains immune-secretory function, improves wound healing, and lowers infection rates and subsequent morbidity.3, 4 The first operation on the stomach, the gastrotomy, was initially performed to extract “bizarre and sundry objects” swallowed by the mentally deficient and circus performers.5 The concept of the gastrostomy followed soon thereafter as a portal of introduction, rather than extraction, and is credited to Dr. Egeberg, in 1837. A decade later, Sedillot performed the first successful gastrostomy and subsequently numerous surgeons including Stamm, Witzel, Dupage, and Janeway, improved various open operative techniques for gastrostomy creation.5, 6, 7 In 1980, the novel technique of percutaneous endoscopic gastrostomy (PEG), or the “sutureless gastrostomy”, was introduced.8 More than 215,000 PEGs are now placed annually for adult enteral nutrition with minimal associated morbidity and thus has become the preferred method for gastrostomy at our institution.9 Distal feeding, via a jejunostomy or jejunal tube extension, is used for patients with gastroparesis, gastric outlet obstruction, abnormal anatomy after esophagectomy or gastrectomy, and for patients with significant gastroesophageal reflux at high risk for aspiration.4, 10–13 Many techniques are used for minimally invasive distal enteric feeding, predominantly with jejunal tubes maneuvered endoscopically or fluoroscopically, with varying rates of success and complications. Herein, we present our institution’s most common technique for jejunal feeding tube advancement and three cases of associated small-bowel perforations.

Abstract A47: A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies

Abstracts: AACR Special Conference on Tumor Metastasis; November 30-December 3, 2015; Austin, TX Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies. Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumors distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured. Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p<0.001; Tumor 366: MS not achieved vs. 167 days, p=0.0488). In a randomized preclinical trial, sequential therapy with gemcitabine followed by trametinib provided a survival advantage and increased TTP when compared with control and single agent gemcitabine treatment. Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver. Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A47.

Abstract B21: In a patient-derived xenograft model of occult hepatic metastasis from pancreatic cancer the MEK inhibitor trametinib delays tumor outgrowth and prolongs survival

Background: Survival for patients with pancreatic ductal adenocarcinoma (PDAC) remains dismal and the majority of patients succumb to metastatic disease. Even for those with localized PDAC, most will die from metastatic disease despite margin-negative resection and adjuvant therapy. Therefore, these patients must harbor occult metastatic PDAC at presentation. There is a compelling need for the development of preclinical models that efficiently recapitulate occult metastatic liver PDAC to identify molecular and cellular pathways that drive metastatic cellular survival and growth. Towards this aim, we have developed a PDAC model of occult liver metastases using patient-derived xenografts (PDXs) to study the growth of PDAC within the metastatic environment and evaluated the effect of MEK inhibitor therapy on tumor progression. Methods and Results: Extensively characterized patient-derived KRAS-mutant (Tumors 608, 366, and 654) and wild-type (Tumors 738 and 215) PDAC cells were transduced with luciferase and injected into the spleens of athymic, nude mice, allowed to circulate for 10 minutes, after which a splenectomy was performed. To evaluate metastatic cell growth kinetics in the liver, tumor burden was monitored by sequential bioluminescent imaging. All mice exhibited defined phases of survival/dormancy and the proliferative outgrowth; however, differential kinetics were observed for each tumor cell line. To evaluate the effect of MEK inhibition of occult metastatic PDAC cells in the liver, Tumor 608 cells were injected and mice either received the MEK inhibitor trametinib (0.3 mg/kg, daily) or vehicle control beginning 48 hour post-injection. Trametinib significantly reduced metastatic tumor burden, delayed time to proliferative outgrowth, and greatly prolonged survival as compared to control (med. survival: 114 vs. 43 days, p<0.001). In contrast, in an orthotopic model with 250-500 mm3 tumors trametinib led to no inhibition in tumor growth for Tumor 608. To characterize metastatic PDAC cells within the liver after similar treatment conditions, we isolated cells from the liver 48 and 72 hours, 10 and 28 days after splenic injection. Tumor 608 cells were injected and metastatic PDAC cells were retrieved from the liver at the aforementioned timepoints post injection using magnetic column separation with human EpCAM (CD326)-targeted magnetically labeled microbeads. Flow cytometric analyses of retrieved cells revealed that decreased cellular markers of proliferation and increased caspase-3 cleavage correlated with decreased tumor burden observed at these timepoints in mice treated with trametinib. Conclusions: In a model of occult liver metastatic PDAC, patient-derived tumors exhibit different growth kinetics in the liver environment. Furthermore, MEK inhibition with trametinib decreased metastatic cellular proliferation, increased apoptosis, prolonged metastatic tumor outgrowth, and significantly increased survival of mice harboring occult hepatic metastases from PDAC. This efficacy of single agent trametinib is unique to occult metastatic disease and is not seen in orthotopic models of advanced, established pancreatic tumors. This finding illustrates the importance of using specific preclinical models that best recapitulate the clinical aspects of patients who will be evaluated in future clinical trials. Further investigation into the cellular and molecular factors promoting PDAC cell survival within the hepatic microenvironment utilizing this model will lead to development of rational therapeutic strategies for patients with occult metastatic disease. Citation Format: Timothy Newhook, James Lindberg, Sara Adair, J. Thomas Parsons, Todd W. Bauer. In a patient-derived xenograft model of occult hepatic metastasis from pancreatic cancer the MEK inhibitor trametinib delays tumor outgrowth and prolongs survival. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B21.

Preoperative bowel preparation for pancreaticoduodenectomy: Is it necessary?

279 Background: Preoperative bowel preparation (PBP) before pancreaticoduodenectomy (PD) is commonly performed; however, the effect of PBP on intraoperative fluid requirements and acute renal failu...

Targeting occult metastatic disease: A hematogenously derived xenograft model of human pancreatic tumor growth in the murine liver.

198 Background: Most pancreatic cancer patients will die following surgery due to recurrent metastatic disease. Thus, better systemic therapies are needed to treat occult metastases to improve survival. We have developed a model of occult liver metastasis from pancreatic cancer in order to evaluate novel treatment strategies. Methods: Pancreatic cancer cells (MAD 09-366, 08-608, MPanc96) transduced with green fluorescent protein (GFP) and luciferase were injected into the spleens of athymic, nude mice to generate hepatic metastases. Ninety-six hours after injection, tumor-bearing mice were treated with MEK1/2 inhibitor (trametinib, 0.3mg/kg, daily), gemcitabine (100mg/kg, twice weekly), or vehicle control. Sequential bioluminescence imaging, flow cytometry, and histologic evaluation were used to assess hepatic tumor growth and behavior. Results: All injected cell lines generated hepatic metastases. Different cell lines exhibited different growth kinetics. MPanc96 injected mice demonstrated a 64% decrease ...