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ABSTRACT: Steroids are a mainstay of treatment in orthotopic liver transplantation (OLT) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance.
Patients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy (n = 50) or complete steroids avoidance (n = 50). Analyses were performed on an intention-to-treat basis. The mean follow-up of all recipients was 2095 ± 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications.
Incidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1-year, 80% versus 86%; 3-year, 68% versus 76%; 5-year, 60% versus 72%; graft survival: 1-year, 76% versus 76%; 3-year, 64% versus 74%; 5-year, 56% versus 72%), but the differences were not statistically different.
Complete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation.
HPB 04/2013; 15(4):286-93. · 1.60 Impact Factor
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ABSTRACT: BACKGROUND AND OBJECTIVES: Hepatic arterial infusional (HAI) chemotherapy combined with systemic chemotherapy is effective palliative therapy for unresectable colorectal cancer liver metastases (CRLM). Some patients considered for HAI have evidence of minimal extrahepatic disease (EHD), and the role of HAI in these situations is unknown. METHODS: All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Survival of patients who were ultimately proven to have low-volume EHD was compared to those without EHD. RESULTS: Three hundred seventy-three patients were included in this study. Seventy-nine percent of patients were previously treated with chemotherapy. One hundred forty-five patients (39%) ultimately proved to have EHD. Median overall survival from HAI pump placement in patients without EHD was 32 months compared to 16 months for patients with EHD, P < 0.001. Median overall survival from HAI pump placement in patients with a single site of EHD was 18 months compared to 9 months for those with multiple sites of EHD, P = 0.01. CONCLUSIONS: In this study of heavily pre-treated patients, overall survival was favorable in patients who proved to have EHD at one site. J. Surg. Oncol © 2012 Wiley Periodicals, Inc.
Journal of Surgical Oncology 07/2012; · 2.10 Impact Factor
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ABSTRACT: To study the pathology, treatment, and outcome of patients with gastric remnant cancer (GRC) after resection for peptic ulcer disease (PUD).
Review of a prospective gastric cancer database identified patients with GRC after gastrectomy for PUD. Clinicopathologic and treatment-related variables were obtained. Multivariate analysis was performed for factors associated with disease-specific survival (DSS).
From January 1985 to April 2010, 4402 patients with gastric adenocarcinoma were treated at our institution and 105 patients (2.4%) had prior gastrectomy for PUD. Prior resections were most often Billroth II (N = 97, 92%). The median time from initial resection to development of GRC was 32 years (3-60 years), and the majority of tumors were located at the gastrointestinal anastomosis (N = 72, 69%). Median DSS was 1.3 years (0.6-2.1 years). Patients who had resection had a significantly better outcome than patients who did not have resection (median DSS 5 vs 0.35 years, P < .0001). Factors associated with DSS on multivariate analysis included advanced T-stage (HR 16.5 (CI 2.2-123.4), P = .0006) and lymph node metastasis (HR 1.1 (CI 1.0-1.2), P < .0001). Stage-specific survival following R0 resection was similar to patients with conventional gastric cancer.
Patients have a lifetime risk for the development of GRC following resection for PUD. As with conventional gastric cancer, determinants of survival of patients with GRC include advanced T stage and nodal metastasis. Patients with GRC amenable to curative resection exhibit the best DSS and have stage-specific outcomes similar to patients with conventional gastric cancer.
Annals of Surgical Oncology 11/2010; 18(3):670-6. · 4.17 Impact Factor
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ABSTRACT: Colorectal cancer metastases to the liver are primarily supplied by the hepatic artery. Therefore, delivery of regional chemotherapy via the hepatic artery is a viable treatment option. Chemotherapy can be delivered in high concentration to the liver with minimal systemic toxicity. Hepatic artery infusional (HAI) chemotherapy both alone and in combination with systemic chemotherapy in the treatment of isolated hepatic metastases from colorectal cancer has resulted in high response rates and increased resection rates for previously unresectable liver disease. Regional chemotherapy can also be used as adjuvant treatment after complete resection of liver metastases to reduce hepatic recurrences. The combination of HAI therapy with modern systemic chemotherapy has a role in the palliative, adjuvant, and neoadjuvant settings.
Seminars in Oncology 04/2010; 37(2):139-48. · 3.50 Impact Factor
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ABSTRACT: The effects of intestinal inflammation on the central nervous system are unknown. The dorsal motor nucleus of the vagus (DMNV) integrates peripheral and central signals and sends efferent signals to the gastrointestinal system. The purpose of this study was to determine the effects of intestinal inflammation on the DMNV in an animal model and in vitro.
Carbocyanine dye (DiI) was injected into the stomach wall of rats to label retrogradely the neurons of the DMNV. Colitis was induced with trinitrobenzene sulfonic acid (TNBS). Tissue was examined under fluorescent microscopy. In vitro studies were performed using primary culture of DMNV neurons. Cell proliferation was measured by BrdU incorporation. Apoptosis was measured by an enzyme sandwich-linked immunosorbent assay. Single-cell cytoplasmic calcium transients were determined using the fluorescence dye fura-2-AM. Reverse transcriptase-polymerase chain reaction of glutamate receptor was performed.
Animals treated with TNBS ate less and lost weight compared with controls. Microscopic analysis demonstrated a 77% decrease in DiI labeling in the DMNV of TNBS animals compared with controls. Cell proliferation in DMNV neurons after 24-hour exposure to the cytokines interleukin- (IL)-1 beta, IL-6, or tumor necrosis factor- (TNF)-alpha was significantly decreased. Similarly, apoptosis of DMNV neurons after 24 hours of incubation with IL-1 beta or TNF-alpha was significantly increased, but no changes resulted with IL-6. Exposure to each cytokine resulted in decreased glutamate-induced intracellular calcium transients. Transcription of glutamate receptor was decreased after 24-hour exposure to TNF-alpha.
DMNV neurons projecting to the stomach are reduced in number after induction of colitis in rats. In vitro, proinflammatory cytokines diminish DMNV cellular proliferation, increase apoptosis, and alter calcium responses to glutamate. These results indicate that intestinal inflammation affects adversely neuronal survival and function in the DMNV.
Surgery 08/2008; 144(2):149-58. · 3.10 Impact Factor
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ABSTRACT: The effects of intestinal inflammation on the central neurons projecting to the enteric nervous system are unknown. The dorsal motor nucleus of the vagus signals to the gastrointestinal system. Ghrelin is elevated in patients with inflammatory bowel disease and has been implicated as an inflammatory mediator. The purpose of this study was to investigate the effects of gastrointestinal inflammation on the dorsal motor nucleus of the vagus in rats, as well as the effects of proinflammatory cytokines and ghrelin on neurons from the dorsal motor nucleus of the vagus in vitro.
DiI was injected into the stomach wall of rats to retrogradely label neurons of the dorsal motor nucleus of the vagus. Intestinal inflammation was induced with indomethacin injection. Serial serum ghrelin measurements were performed. Tissue was examined under fluorescent microscopy. In vitro studies using primary culture of neurons from the dorsal motor nucleus of the vagus were performed. Reverse transcriptase-polymerase chain reaction for cytokine transcripts and immunohistochemistry for cytokine receptors were performed. Cell proliferation and apoptosis were measured by enzyme-linked immunosorbent assay.
A significant decrease of DiI labeling was demonstrated in the dorsal motor nucleus of the vagus of animals injected with indomethacin. Serum levels of ghrelin were significantly elevated 2 days after induction of inflammation. In vitro, apoptosis and cell proliferation were measured after 24-hour exposure to experimental conditions. Ghrelin alone had no effect on apoptosis. Exposure to interleukin (IL)-1 beta or tumor necrosis factor (TNF)-alpha increased apoptosis. The addition of ghrelin to cytokine resulted in significant decreases in apoptosis compared to cytokine alone. Ghrelin significantly increased neuronal proliferation. Exposure to IL-1 beta, IL-6, or TNF-alpha significantly decreased proliferation. The addition of ghrelin to TNF-alpha or IL-6 significantly increased cellular proliferation compared to cytokine alone.
Neurons from the dorsal motor nucleus of the vagus that project to the stomach are reduced in number after induction of colitis in rats. In vitro, proinflammatory cytokines increase apoptosis and decrease cell proliferation of neurons from the dorsal motor nucleus of the vagus. These effects are attenuated by ghrelin.
Surgery 08/2008; 144(2):159-67. · 3.10 Impact Factor
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ABSTRACT: Surgical complications following pediatric liver transplantation are common and expensive. We examined the incremental costs of surgical complications and determined who pays for these complications (center or payer). We reviewed the records of 36 pediatric liver transplant patients aged <or=12 yr transplanted between July 1, 2002 and December 31, 2005. The association of recipient and financial data points was assessed. On univariate analysis, total hospital costs were significantly increased in patients with ACR, PNF, HAT, biliary complications, and ARF. Reimbursement by the payer was significantly increased in patients with PNF, HAT, biliary complications, and ARF. Hospital profits were significantly decreased in recipients with ACR and pneumonia. Multiple linear regression models (controlling for recipient factors) revealed that ARF and HAT were independently associated with a significant increase in median hospital costs (incremental costs of $238,990 and $125,650, respectively). ARF and HAT were also independently associated with a significant increase in median reimbursements (incremental costs of $231,611 and $125,287, respectively). No complications were independently associated with hospital margins. All parties (patient and families, physician, payer, and medical center) should benefit from quality improvement efforts, with payers having the largest financial interest.
Pediatric Transplantation 03/2008; 12(2):174-9. · 1.48 Impact Factor
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ABSTRACT: Complications after liver transplantation are common and expensive. The incremental costs of adult posttransplantation liver transplantation complications and who pays for these complications (center or payor) is unknown.
We reviewed the medical and financial records (first 90 postoperative days) of all adult liver transplant recipients at our center between July 1, 2002, and October 30, 2005 (N = 214). The association of donor, recipient, and financial data points (total costs, reimbursements, and profits) was assessed using standard univariable analyses. The incremental costs of complications were determined with multiple linear regression models to control for the costs inherent to donor and recipient characteristics.
Univariate analyses demonstrated that both total hospital costs and reimbursements were substantially increased in patients with several different complications. Multiple linear regression analysis, controlling for recipient (age, gender, race, and laboratory Model for End-Stage Liver Disease [MELD]) and donor factors (donor risk index), noted that increased hospital costs and hospital reimbursements were independently associated with laboratory MELD (incremental costs of $3,368 and $2,787, respectively, per MELD point) and pneumonia ($83,718 and $68,214, respectively). A negative profit margin for the medical center was independently associated with peritonitis ($21,760). Commercial insurance was associated with no changes in total costs when compared with public insurer, but it was associated with decreased reimbursement and profit.
The incremental costs of complications in liver transplantation are high for both the medical center and payor, but medical center profits are not affected substantially. The payor bears the financial burden for post-liver transplantation complications.
Journal of the American College of Surgeons 02/2008; 206(1):89-95. · 4.55 Impact Factor
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ABSTRACT: The dorsal motor nucleus of the vagus (DMNV) integrates peripheral and central signals and sends efferent output to the gastrointestinal system. Glutamate, the major excitatory neurotransmitter of the central nervous system, causes increases in intracellular calcium in DMNV neurons. The mechanisms by which glutamate activates calcium signaling in the DMNV were examined. DMNV neurons were isolated from neonatal rat brainstem using microdissection and enzymatic digestion. Exposure to glutamate caused intracellular Ca(2+) increments in greater than 80% of cells. Removal of extracellular Ca(2+) abolished intracellular Ca(2+) transients. Kynurenic acid, a nonspecific glutamate receptor antagonist, abolished intracellular Ca(2+) transients. Exposure to glutamate while blocking AMPA receptors with GYKI 52466 abolished the Ca(2+) response. Exposure to (S)AMPA, an AMPA receptor agonist, caused intracellular Ca(2+) increments in 97% of cells. Activation and antagonism of NMDA and kainate receptors produced no changes compared to control experiments. NiCl, a nonspecific Ca(2+) channel blocker, abolished intracellular Ca(2+) transients. Blocking T-type Ca(2+) channels with mibefradil abolished the Ca(2+) response in 76% of cells. Blockade of L-type and N-type Ca(2+) channels did not affect the Ca(2+) response. Glutamate mediates intracellular Ca(2+) currents in DMNV neurons via the AMPA receptor and T-type Ca(2+) channels, allowing influx of extracellular Ca(2+).
Journal of Gastrointestinal Surgery 09/2007; 11(8):1016-24. · 2.83 Impact Factor
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ABSTRACT: Asb-4 is a gene that is specifically expressed in the hypothalamic energy homeostasis-associated areas and is down-regulated in the arcuate nucleus of fasted Sprague Dawley and obese Zucker rats. It has two functional domains, the ankyrin repeat and the SOCS box. The function of Asb-4 is unclear. We used yeast two hybridization to search for protein(s) that interact with Asb-4. With Asb-4 minus its SOCS box (Asb-4/Deltasb) as a bait, we screened mouse testis and arcuate nucleus cDNA libraries and identified G-protein pathway suppressor 1 (GPS1, also known as CSN1) as an Asb-4 interacting protein. GPS1 co-immunoprecipitated with Asb-4 both in vitro and in human HEK293 cells. When Asb-4 and GPS1 were co-transfected into HEK293 cells, expression of Asb-4 reduced the protein level of GPS1. Deletion of the SOCS box (Asb4/Deltasb) did not abolish the inhibitory effect of Asb-4 on GPS1, indicating that the SOCS box was not needed for its inhibitory effect. In NIH 3T3 L1 cells, expression of GPS1 enhanced c-Jun NH2-terminal kinase (JNK) activity. Co-expression of Asb-4 with GPS1 inhibited JNK activity. Treatment of the cells with insulin (20 nM) stimulated JNK activity. Expression of GPS1 potentiated the stimulatory effect of insulin, whereas co-expression of Asb-4 along with GPS1 inhibited JNK activity. In HEK293 cells expression of GPS1 elevated phosphorylation of insulin receptor substrate 1 (IRS-1) at serine307, co-expression of Asb-4 with GPS1 reduced the IRS-1ser307 phosphorylation. The present study demonstrates that Asb-4 interacts with GPS1 and inhibits JNK activity.
Cellular Signalling 07/2007; 19(6):1185-92. · 4.06 Impact Factor
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ABSTRACT: Intensive blood glucose management has been shown to decrease mortality and infections for intensive care patients. The effect of intraoperative strict glucose control on surgical outcomes, including liver transplantation, has not been well evaluated.
A retrospective review of all adult liver recipients transplanted between January 1, 2004 and July 6, 2006 was performed. Donor and recipient demographics, intraoperative variables, and outcomes were collected. Intraoperative glucose measurements were performed by the anesthesiology team and treated with intravenous insulin bolus or continuous infusion. Patients with strict glycemic control (mean blood glucose <150 mg/dL) were compared with those with poor control (mean blood glucose >or=150 mg/dL).
During the study period, a total of 184 patients met criteria for analysis. Recipients with strict glycemic control (n=60) had a mean glucose of 135 mg/dL compared with 184 mg/dL in the poorly controlled group (n=124). Other than recipient age (strict versus poor control, 47 +/- 2 y versus 53 +/- 1 y; P<0.01), both groups had similar donor and recipient characteristics. Although the incidence of most postoperative complications were similar, poor glycemic control was associated with a significantly increased infection rate at 30 d posttransplant (48% versus 30%; P=0.02), and also an increased 1 y mortality (21.9% versus 8.8%; P=0.05).
Intraoperative hyperglycemia during liver transplantation was associated with an increased risk of postoperative infection and mortality. Strict intraoperative glycemic control, possibly using insulin infusions, may improve outcomes following liver transplantation.
Journal of Surgical Research 06/2007; 140(2):227-33. · 2.25 Impact Factor
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ABSTRACT: HEK 293 cells stably expressing human melanocortin-3 receptor (MC3R) were exposed to melanocortin receptor agonist, NDP-MSH (10(-)(10)-10(-)(6) M). ERK1/2 was phosphorylated in a dose-dependent manner with an EC(50) of 3.3+/-1.5 x 10(-)(9) M, similar to the IC(50) of NDP-MSH binding to the MC3R. ERK1/2 phosphorylation was blocked by the melanocortin receptor antagonists SHU9119. NDP-MSH-induced ERK1/2 phosphorylation was sensitive to pertussis toxin and the PI3K inhibitor, wortmannin. Rp-cAMPS, BAPTA-AM and Myr-PKC did not inhibit the NDP-MSH-induced ERK1/2 phosphorylation. NDP-MSH stimulated cellular proliferation in a dose-dependent manner with a similar EC(50) to ERK1/2 phosphorylation, 2.1+/-0.6 x 10(-)(9) M. Cellular proliferation was blocked by AGRP (86-132) and by the MEK inhibitor, PD98059. The NDP-MSH did not inhibit serum deprivation-induced apoptosis. MC3R activation induces ERK1/2 phosphorylation via PI3K and this pathway is involved in cellular proliferation in HEK cells expressing MC3R.
Regulatory Peptides 04/2007; 139(1-3):115-21. · 2.11 Impact Factor
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ABSTRACT: Thoracic duct injury resulting in chylothorax is a well-known and documented complication of thoracic surgery. However, chylothorax under tension is a rarely reported complication that results in respiratory and hemodynamic collapse. Early recognition and treatment of this entity are essential for optimal patient outcome. Herein we present two cases of postoperative tension chylothorax followed by a review of the diagnostic work-up and therapy for this complication.
The Annals of thoracic surgery 09/2006; 82(2):729-30. · 3.74 Impact Factor
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ABSTRACT: At least 4% of childhood obesity is due to mutations in the hypothalamic melanocortin-4 receptor. The melanocortin-4 receptor, a seven transmembrane G-protein-coupled receptor, is important in the regulation of feeding behavior and body weight. The specific pathways of intracellular signaling remain in investigative stages. To further understand its function, we hypothesized that the melanocortin-4 receptor activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1) neurons.
Changes in intracellular calcium were measured after loading GT1-1 cells with fura-2-AM. Cells were treated with NDP-alphaMSH, an alpha-melanocortin stimulating hormone analogue, and intracellular calcium changes were recorded. Cells treated with NDP-alpha-MSH were also treated with the melanocortin-4 receptor antagonist, SHU-9119. To assess the specific G-protein subunit involved, GT1-1 neurons were treated with the phospholipase C inhibitor U73122 and its inactive analogue, U73433. Experiments were also performed after inhibition of IP3 receptors with 2-aminoethoxydiphenylborate (2APB). Additional experiments were conducted in a calcium-depleted buffer environment. Data were analyzed by ANOVA with statistical significance of P < 0.05.
Agonist treatment (0.01-1000 nm) of GT1-1 neurons resulted in dose-dependent increases in intracellular calcium. SHU-9119 (0.01-1000 nm) abolished the calcium response. Treatment with U73122 (10 microm) attenuated the calcium response, while U73433 (10 microm) had minimal effect. 2APB (200 microm) inhibited the calcium transient, and the use of calcium-free buffer did not affect the amplitude of the calcium spike.
Our study demonstrates that, upon agonist binding, the melanocortin-4 receptor mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway. Understanding the physiological importance of calcium signaling by the melanocortin-4 receptor may be important for future development of therapeutic targets.
Journal of Surgical Research 06/2006; 132(2):201-7. · 2.25 Impact Factor
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ABSTRACT: The combination of gemcitabine with concurrent radiation therapy (Gem/RT) is a promising new approach that is being investigated in patients with unresectable pancreatic cancer. However, substantial toxicity with this combination has also been observed. This review was conducted to determine whether Gem/RT could be safely delivered in the neoadjuvant setting, based on our experience with this combined therapy in a cohort of patients with previously unresectable pancreatic cancer, who subsequently underwent surgical resection. Between July 1996 and June 2001, a total of 67 patients with locally unresectable pancreatic cancer, without distant metastatic disease, received Gem/RT at our institution. Seventeen patients (25%) underwent exploratory surgery following Gem/RT, and nine underwent standard Whipple resection. Thus 9 (52%) of 17 patients who had exploratory operations or 9 (13%) of 67 patients, underwent surgical resection. Thirty-day mortality after resection was 0%, and there were no major surgical complications. Median length of hospital stay was 14 days (range 11 to 19 days). With a median follow-up of 32 months, median survival for the resected patients was 17.6 months (95% confidence interval 12.6 to 37.3 months). Median survival for the remaining 58 patients was 11.9 months (95% confidence interval 9.6 to 14.7 months, P=0.013). We conclude that surgical resection may be safely performed after Gem/RT in a select group of patients initially considered to have unresectable pancreatic cancer. The use of Gem/RT in a neoadjuvant setting is currently being investigated in a multi-institutional phase II trial.
Journal of Gastrointestinal Surgery 7(6):766-72. · 2.83 Impact Factor
