548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor... more 548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. A similar TKI, regorafenib, has efficacy as monotherapy in advanced mCRC. Demonstrating activity of this compound class with standard cytotoxic therapy represents a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2 PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity and quality of life. Sample size was based on a 50% impr...
e19152 Background: Cancer treatment is becoming more complex, necessitating subspecialty expertis... more e19152 Background: Cancer treatment is becoming more complex, necessitating subspecialty expertise and multidisciplinary approaches to treatment planning. Simultaneously, there is increasing demand to provide care as close to home as possible. While tumor boards have long been an institutional backbone to providing high-quality multidisciplinary care in tertiary facilities, connecting several hospitals and dozens of cancer specialists in a large integrated healthcare system is unique and potentially transformational for smaller facilities and communities. Methods: Using highly-secure, network firewall-protected Cisco Telepresence and WebEx capabilities, 11 disease specific tumor boards (Breast, GI, Sarcoma, GU, Thoracic, Head/Neck, Melanoma, Neuro, Heme, Hepatobiliary, Gyn) were organized across Intermountain Healthcare’s 24 geographically and medically diverse hospitals spanning over 500 miles. Meetings for each of these disease-specific tumor boards have been held at least every 1...
Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious... more Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious option for converting appropriately selected patients with borderline-resectable hepatocellular carcinoma (HCC) to surgical candidacy. In 2018 and 2019, a diverse multidisciplinary group of surgical and interventional experts with experience using 90Y for downstaging and bridging to liver transplant convened to review peer-reviewed literature and personal experience in the use of 90Y to convert borderline resectable liver cancer patients to surgical candidacy. The working group included surgical oncologists specializing in liver cancer, liver transplant surgeons with experience in complex hepatobiliary surgery, and interventional radiologists with experience using 90Y. This document presents expert recommendations based upon the group's experience and consensus. By combining related evidence from the literature with expert experiences with TARE in surgical candidates, these recommendations aim to demonstrate the safety, efficacy, and feasibility of TARE in converting borderline-resectable patients to surgical options. The document also addresses the concerns about potential complications associated with TARE during the surgical intervention.
Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation... more Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than ...
Mechanical obstruction, thrombus, intrinsic liver disease causing fibrosis or cirrhosis, or an ou... more Mechanical obstruction, thrombus, intrinsic liver disease causing fibrosis or cirrhosis, or an outflow obstruction at the level of the sinusoids or hepatic venous obstruction can cause an increase in pressure or resistance, or both, leading to portal hypertension (PH). Portosystemic shunts (PSS) are usually performed to relieve the congestion that inevitably occurs in the setting of PH. Since their introduction, surgical PSS were often the treatment of choice to prevent recurrent bleeding in patients with clinically significant PH. Development of novel pharmacological therapies, continuous improvement of endoscopic approaches, the introduction of transjugular intrahepatic portosystemic shunt, and advancements in transplantation has provided an evolution in the approach for PH and has precipitated the steady decrease in the proportion of patients needing surgical shunts. Despite this, PSS remain important tools in the surgeon's armamentarium, as they are often employed in the ped...
Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has... more Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has been associated with worse oncologic outcomes. However, limited data exist regarding the impact of PRBC donor factors. We hypothesized that PRBC donor age impacts survival after hepatectomy for non-hepatocellular malignancies. Patients who underwent hepatectomy for non-hepatocellular malignancy from 2005 to 2014 were retrospectively evaluated. Impact of clinicopathologic and PRBC factors on oncologic outcomes were assessed. Of 149 identified patients, 76 received a perioperative PRBC transfusion (median 2 units). Transfusion was associated with increased median length of stay (8 vs. 6 days; p < 0.01) and median operative blood loss (700 vs. 350 mL; p < 0.01) versus non-transfused, respectively. In transfused patients, receipt of PRBC from older donors compared to younger resulted in decreased RFS (0.94 vs. 2.63 years, respectively; p = 0.02) and OS (1.94 vs. 3.44 years, respective...
Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tum... more Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tumors that comprise about 5% of cystic masses of the liver in adults. These slow-growing lesions most commonly occur in middle-aged individuals, with a female sex predominance. Herein, we present a MCA in a 6-year-old male, one of only very few such cases described in the pediatric literature to date. Although MCAs are generally considered benign lesions, malignant transformation rarely occurs. The recurrence rate is high when partial cyst excision is performed. Therefore, complete surgical cyst resection with clinical follow-up, including imaging, is warranted.
To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (T... more To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) using variable radiodosimetry to identify imaging surrogates of histologic response. Twelve patients with HCC underwent ablative (≥ 190 Gy) and/or non-ablative (< 190 Gy) TARE delivered in a segmental, lobar, or combined fashion as a surgical neoadjuvant or bridge to transplantation. Both targeted tumor and treatment angiosome were analyzed before and after TARE utilizing hepatocyte-specific contrast-enhanced MRI or contrast-enhanced CT. Responses were graded using EASL and mRECIST criteria. Histologic findings including percent tumor necrosis and adjacent hepatic substrate effects were correlated with imaging features. Complete pathologic necrosis (CPN) was observed in 7/12 tumors post-TARE. Ablative and non-ablative dosing resulted in CPN in 5/6 and 2/6 tumors, respectively. Hyperintensity on T2-weighted imaging, the absence of hepatocyte-speci...
No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplanta... more No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation betwe...
548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor... more 548 Background: Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF, and PDGF pathways. A similar TKI, regorafenib, has efficacy as monotherapy in advanced mCRC. Demonstrating activity of this compound class with standard cytotoxic therapy represents a clinical unmet need. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2 PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity and quality of life. Sample size was based on a 50% impr...
e19152 Background: Cancer treatment is becoming more complex, necessitating subspecialty expertis... more e19152 Background: Cancer treatment is becoming more complex, necessitating subspecialty expertise and multidisciplinary approaches to treatment planning. Simultaneously, there is increasing demand to provide care as close to home as possible. While tumor boards have long been an institutional backbone to providing high-quality multidisciplinary care in tertiary facilities, connecting several hospitals and dozens of cancer specialists in a large integrated healthcare system is unique and potentially transformational for smaller facilities and communities. Methods: Using highly-secure, network firewall-protected Cisco Telepresence and WebEx capabilities, 11 disease specific tumor boards (Breast, GI, Sarcoma, GU, Thoracic, Head/Neck, Melanoma, Neuro, Heme, Hepatobiliary, Gyn) were organized across Intermountain Healthcare’s 24 geographically and medically diverse hospitals spanning over 500 miles. Meetings for each of these disease-specific tumor boards have been held at least every 1...
Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious... more Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious option for converting appropriately selected patients with borderline-resectable hepatocellular carcinoma (HCC) to surgical candidacy. In 2018 and 2019, a diverse multidisciplinary group of surgical and interventional experts with experience using 90Y for downstaging and bridging to liver transplant convened to review peer-reviewed literature and personal experience in the use of 90Y to convert borderline resectable liver cancer patients to surgical candidacy. The working group included surgical oncologists specializing in liver cancer, liver transplant surgeons with experience in complex hepatobiliary surgery, and interventional radiologists with experience using 90Y. This document presents expert recommendations based upon the group's experience and consensus. By combining related evidence from the literature with expert experiences with TARE in surgical candidates, these recommendations aim to demonstrate the safety, efficacy, and feasibility of TARE in converting borderline-resectable patients to surgical options. The document also addresses the concerns about potential complications associated with TARE during the surgical intervention.
Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation... more Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than ...
Mechanical obstruction, thrombus, intrinsic liver disease causing fibrosis or cirrhosis, or an ou... more Mechanical obstruction, thrombus, intrinsic liver disease causing fibrosis or cirrhosis, or an outflow obstruction at the level of the sinusoids or hepatic venous obstruction can cause an increase in pressure or resistance, or both, leading to portal hypertension (PH). Portosystemic shunts (PSS) are usually performed to relieve the congestion that inevitably occurs in the setting of PH. Since their introduction, surgical PSS were often the treatment of choice to prevent recurrent bleeding in patients with clinically significant PH. Development of novel pharmacological therapies, continuous improvement of endoscopic approaches, the introduction of transjugular intrahepatic portosystemic shunt, and advancements in transplantation has provided an evolution in the approach for PH and has precipitated the steady decrease in the proportion of patients needing surgical shunts. Despite this, PSS remain important tools in the surgeon's armamentarium, as they are often employed in the ped...
Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has... more Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has been associated with worse oncologic outcomes. However, limited data exist regarding the impact of PRBC donor factors. We hypothesized that PRBC donor age impacts survival after hepatectomy for non-hepatocellular malignancies. Patients who underwent hepatectomy for non-hepatocellular malignancy from 2005 to 2014 were retrospectively evaluated. Impact of clinicopathologic and PRBC factors on oncologic outcomes were assessed. Of 149 identified patients, 76 received a perioperative PRBC transfusion (median 2 units). Transfusion was associated with increased median length of stay (8 vs. 6 days; p < 0.01) and median operative blood loss (700 vs. 350 mL; p < 0.01) versus non-transfused, respectively. In transfused patients, receipt of PRBC from older donors compared to younger resulted in decreased RFS (0.94 vs. 2.63 years, respectively; p = 0.02) and OS (1.94 vs. 3.44 years, respective...
Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tum... more Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tumors that comprise about 5% of cystic masses of the liver in adults. These slow-growing lesions most commonly occur in middle-aged individuals, with a female sex predominance. Herein, we present a MCA in a 6-year-old male, one of only very few such cases described in the pediatric literature to date. Although MCAs are generally considered benign lesions, malignant transformation rarely occurs. The recurrence rate is high when partial cyst excision is performed. Therefore, complete surgical cyst resection with clinical follow-up, including imaging, is warranted.
To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (T... more To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) using variable radiodosimetry to identify imaging surrogates of histologic response. Twelve patients with HCC underwent ablative (≥ 190 Gy) and/or non-ablative (< 190 Gy) TARE delivered in a segmental, lobar, or combined fashion as a surgical neoadjuvant or bridge to transplantation. Both targeted tumor and treatment angiosome were analyzed before and after TARE utilizing hepatocyte-specific contrast-enhanced MRI or contrast-enhanced CT. Responses were graded using EASL and mRECIST criteria. Histologic findings including percent tumor necrosis and adjacent hepatic substrate effects were correlated with imaging features. Complete pathologic necrosis (CPN) was observed in 7/12 tumors post-TARE. Ablative and non-ablative dosing resulted in CPN in 5/6 and 2/6 tumors, respectively. Hyperintensity on T2-weighted imaging, the absence of hepatocyte-speci...
No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplanta... more No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation betwe...
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