Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma.

BACKGROUND: We sought to investigate the role of ErbB3-mediated signalling on the interaction between pancreatic cancer-associated fibroblasts (CAF) and carcinoma cells in an effort to disrupt tumourigenic pancreatic ductal adenocarcinoma (PDAC) stromal-epithelial cross-communication. METHODS: Primary CAF cultures were established from human PDAC surgical specimens. AsPC-1 pancreatic cancer cell murine subcutaneous xenografts were developed in the presence and absence of CAF and were subsequently treated with epidermal growth factor receptor (EGFR) inhibitors (erlotinib) and ErbB3 inhibitors (MM-121, monoclonal ErbB3 antibody). RESULTS: Cancer-associated fibroblasts were found to secrete neuregulin-1 (NRG-1), which promoted proliferation via phosphorylation of ErbB3 and AKT in AsPC-1 PDAC cells. This signalling cascade was effectively inhibited both in vitro and in vivo by specific ErbB3 blockade with MM-121, with greater degree of tumourigenesis inhibition when combined with erlotinib. The CAF-AsPC-1 pancreatic cancer xenografts reached significantly greater tumour volume than those xenografts lacking CAF and were resistant to the anti-tumour effects of EGFR inhibition with erlotinib. CONCLUSION: Cancer-associated fibroblasts-derived NRG-1 promote PDAC tumourigenesis via ErbB3-AKT signalling and overcomes single-agent EGFR inhibition. Disruption of this stromally mediated tumourigenic mechanism is best obtained through combined EGFR-ErbB3 inhibition with both erlotinib and MM-121. We have identified the NRG-1/ErbB3 axis as an attractive molecular target for the interruption of tumourigenic stromal-epithelial interactions within the PDAC microenvironment.

Preoperative anthropomorphic radiographic measurements can predict postoperative pancreatic fistula formation following pancreatoduodenectomy.

BACKGROUND: Postoperative pancreatic fistulae (POPF) are a major contributing factor to pancreatoduodenectomy-associated morbidity. Established risk calculators mostly rely on subjective or intraoperative assessments. We hypothesized that various objective preoperatively determined computed tomography (CT) measurements could predict POPF as well as validated models and allow for more informed operative consent in high-risk patients. METHODS: Patients undergoing elective pancreatoduodenectomies between January 2013 and April 2018 were identified in a prospective database. Comparative statistical analyses and multivariable logistic regression models were generated to predict POPF development. Model performance was tested with receiver operating characteristics (ROC) curves. Pancreatic neck attenuation (Hounsfield units) was measured in triplicate by pancreatic protocol CT (venous phase, coronal plane) anterior to the portal vein. A pancreatic density index (PDI) was created to adjust for differences in contrast timing by dividing the mean of these measurements by the portal vein attenuation. Total areas of subcutaneous fat and skeletal muscle were calculated at the L3 vertebral level on axial CT. Pancreatic duct (PD) diameter was determined by CT. RESULTS: In the study period 220 patients had elective pancreatoduodenectomies with 35 (16%) developing a POPF of any grade. Multivariable regression analysis revealed that demographics (age, sex, and race) were not associated with POPF, yet patients resected for pancreatic adenocarcinoma or chronic pancreatitis were less likely to develop a POPF (10 vs. 24%; p = 0.004). ROC curves were created using various combinations of gland texture, body mass index, skeletal muscle index, sarcopenia, PDI, PD diameter, and subcutaneous fat area indexed for height (SFI). A model replacing gland texture with SFI and PDI (AUC 0.844) had similar predictive performance as the established model (p = 0.169). CONCLUSION: A combination of preoperative objective CT measurements can adequately predict POPF and is comparable to established models relying on subjective intraoperative variables. Validation in a larger dataset would allow for better preoperative stratification of high-risk patients and improve informed consent among this patient population.

Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity.

Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.

Effect of systemic hyperinsulinemia in cancer patients.

Data defining the isolated effect of insulin on whole body protein and glucose metabolism in cancer patients are limited. Ten normal volunteers (controls), age 55 +/- 3 years (mean +/- SEM); 8 cancer patients, age 61 +/- 3 years, weight loss 2 +/- 1% (CANWL); and 8 cancer patients, age 55 +/- 2 years, weight loss 18 +/- 2% (CAWL), were studied in the post-absorptive state. Whole body leucine kinetics were determined during a baseline and then a study period during which insulin was infused at 1.0 milliunits/kg/min to achieve a high physiological level of 71 +/- 6, 83 +/- 5, and 64 +/- 5 microunits/ml in controls, CANWL, and CAWL, respectively. Whole body net balance equals protein synthesis minus protein breakdown. Glucose disposal (mg/kg/min) is the rate of D30 infusion at steady state. Glucose disposal of CANWL and CAWL during the study period was significantly (P less than 0.05, analysis of variance) less than controls (3.91 +/- 0.6 in CANWL, 3.66 +/- 1.0 in CAWL, and 5.87 +/- 0.6 mg/kg/min in controls), suggesting resistance to insulin with respect to carbohydrate metabolism. Hyperinsulinemia, under euglycemic and near basal amino acid conditions, significantly reversed the negative postabsorptive leucine net balance (P less than 0.05, analysis of variance) by decreasing protein breakdown in controls as well as weight-stable and weight-losing cancer patients, suggesting that cancer patients are not resistant to the anti-catabolic effect of insulin with respect to whole body protein metabolism.

The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.

The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

Prognostic significance of a positive microscopic margin in high-risk extremity soft tissue sarcoma: implications for management.

PURPOSE: A positive microscopic margin (PMM) is a significant prognostic variable and leads to local recurrence (LR) in high-grade soft tissue sarcoma (STS) patients. Its effect on the rate of distant metastasis (DM) and tumor mortality (TM) remains controversial. PATIENTS AND METHODS: One hundred sixty-eight primary, high-risk (high-grade, deep, > or = 5 cm) extremity STS patients were identified from our data base, of which 42 had a PMM. Limb-sparing surgery (LSS) was the primary surgical therapy in 144 patients; 24 received amputation (AMP). Statistical analysis was by log-rank test and Cox model. Significance was defined as a P value less than .05. RESULTS: A PMM was a significant negative prognostic factor for both DM and TM (P = .002 and .002, respectively). However, those patients who received LSS with 28% PMMs showed no significant difference in the rate of DM or TM compared with patients who received AMP with only 8% PMMs (log-rank, P = .057 and .28, respectively). A PMM was significantly associated with > or = 1,000 mL blood loss and more than 3 hours of operating time (P < .006 and .001, respectively). CONCLUSION: The strong statistical significance that relates a PMM to DM and TM in high-risk STS of the extremity is likely related to biologically aggressive tumors and LSS. Residual microscopic disease is not a guarantee of LR. The main problem in this group of patients is not LR, but DM and subsequent death. Therefore, to increase a disability with further surgery or amputate a patient's limb without clear evidence of LR in this group at high risk for distant recurrence is not recommended.

Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management.

PURPOSE: Retroperitoneal soft tissue sarcomas are rare tumors. Studies characterizing long-term follow-up and patterns of recurrence are limited. The purpose of this analysis is to identify patterns of recurrence and prognostic factors associated with long-term survival after resection of retroperitoneal soft tissue sarcomas. METHODS: Between July 1, 1982, and June 30, 1990, 198 adult patients were identified from our prospective soft tissue sarcoma database carrying the diagnosis of retroperitoneal soft tissue sarcoma who were eligible for > or = 5 years of follow-up. Of these, 48 patients (25%) were documented to be alive > or = 5 years from the time of operation. Statistical analysis was by log-rank or Wilcoxon test for univariate analysis. Multivariate analysis was by the Cox model. RESULTS: The recurrence rate during the follow-up period was approximately 5% per year from the time of initial operation. Of the patients who were disease-free for > or = 5 years from initial surgery, 40% recurred by 10 years. Radiation therapy was the only factor significant (P = .02) for a reduction in the risk of local recurrence. Age < or = 50 years and high-grade tumors were significant factors (P = .003 and .009, respectively) for an increased risk of distant metastasis. Incomplete gross resection was the only factor significant for an increased risk of tumor mortality (P = .003). CONCLUSION: Complete surgical resection at the time of primary presentation is likely to afford the best chance for long-term survival. With long-term follow-up, it is clear that recurrence will continue to occur, and a 5-year disease-free interval is not a cure. Patients with an incomplete initial resection, age less than 50 years, and high-grade tumors are candidates for investigational adjuvant therapy.

Growth hormone and insulin combine to improve whole-body and skeletal muscle protein kinetics.

BACKGROUND: A cooperative effect of exogenous insulin and recombinant human growth hormone (r-hGH) with respect to whole-body and skeletal muscle protein metabolism has not been demonstrated previously. This study examined the effect of r-hGH and insulin administration during euglycemic clamping and concurrent amino acid supplementation. METHODS: Twenty-three normal volunteers in the postabsorptive state were either treated with r-hGH for 3 consecutive days before a metabolic study (GH group; n = 10) or not treated (CTRL group; n = 13). The r-hGH dose was 0.2 mg/kg/day (n = 5) or 0.1 mg/kg/day (n = 5). All subjects then received an infusion of 14C-labeled leucine and tritiated phenylalanine, followed by measurement of baseline protein kinetics (GH and CTRL). Subsequently a euglycemic insulin infusion (1 mU/kg/min) with concurrent amino acid infusion was administered, and protein kinetic measurements were repeated at steady state. RESULTS: GH and insulin separately produced an increase in whole-body and skeletal muscle protein net balance. GH plus insulin was associated with a higher net balance of protein than was insulin alone. CONCLUSIONS: r-hGH and insulin in the presence of amino acids and glucose combine to improve whole-body and skeletal muscle protein kinetics.

The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm.

In vitro, insulin has been shown to increase skeletal muscle (SM) protein synthesis and decrease SM protein breakdown. Whether these same effects are found in vivo in man is less clear. The study of the effect of hyperinsulinemia (INS) on SM protein turnover (SMPT) is complicated by hypoaminoacidemia, which can obviate the true effect of insulin on SMPT. To prevent this, we studied the effect of INS on SMPT in the human forearm with amino acid (AA) infusion to ensure adequate substrate for full evaluation of insulin's effect. Twelve healthy volunteers (aged 53 +/- 3 years) were studied. Steady-state AA kinetics were measured across the forearm after a systemic 2-hour primed continuous infusion of 3H-phenylalanine (3H-Phe) and 14C-leucine (14C-Leu) in the postabsorptive (PA) state and in response to systemic INS (71 +/- 5 microU/mL). AAs were infused during INS as 10% Travasol (Travenol Laboratories, Deerfield, IL) at .011 mL/kg/min to maintain PA branched-chain AA (BCAA) levels, known regulators of SMPT, and to mildly elevate total AA levels. The negative PA net balance of both Phe and total Leu carbons (LeuC) became positive with INS + AA infusion (Phe from -16 +/- 2 to 12 +/- 3 nmol/min/100 g [P < .01]; LeuC from -26 +/- 6 to 24 +/- 7 nmol/min/100 g [P < .01]).(ABSTRACT TRUNCATED AT 250 WORDS)

Colorectal hepatic metastases: resection, local ablation, and hepatic artery infusion pump are associated with prolonged survival.

BACKGROUND: Treatment of metastatic colorectal cancer to the liver is not uniform. We describe the management of metastatic colorectal cancer of the liver at a single institution during a 10-year period. METHODS: From January 1, 1990, through December 31, 1999, 174 patients were identified from the tumor registry at the University of Alabama at Birmingham with a diagnosis of metastatic colorectal cancer to the liver. Patient, tumor, laboratory, operative, and adjuvant therapy factors were analyzed, with overall survival as the endpoint. Log-rank tests were used for univariate analysis, Cox-proportional hazards model for multivariate analysis, and Kaplan-Meier curves were used for graphical representation of survival. Significance was defined as P<.05. RESULTS: Median age was 60 years (age range, 18-92 years). Seventy-nine percent of patients had synchronous liver metastases at the time of diagnosis of the primary colorectal tumor. The primary tumor was in the colon and rectum 75% and 25% of the time, respectively. Of the 89 patients who underwent operation, 73 received definitive surgical treatment for their liver metastases. Fifty-two patients underwent lobectomy or wedge resection, 5 underwent cryotherapy, and 16 had a hepatic artery infusion pump (HAIP) inserted. Median follow-up duration of surgically treated patients was 26 months. Operative mortality was 1.3%. The 3-year actuarial survivals for patients who underwent resection, HAIP, or those with unresectable disease were 70 months, 32 months, and 3 months, respectively (P<.001). By multivariate analysis, surgical intervention, a carcinoembryonic antigen level less than 200 microg/L, or a low T stage of the primary tumor were associated with prolongation of survival. CONCLUSIONS: Surgical resection should be attempted for hepatic colorectal metastases, as this is associated with prolonged overall survival. Hepatic artery infusion pump insertion seems to prolong overall survival for those with unresectable hepatic metastases, but it is not equal to resection. Aggressive surgical management of patients with hepatic colorectal metastases is safe, may prolong overall survival, and therefore should be considered in all patients with metastases confined to the liver.

A preoperative biliary stent is associated with increased complications after pancreatoduodenectomy.

BACKGROUND: A preoperative biliary stent is commonly used after the initial evaluation of the patient with a periampullary mass. OBJECTIVE: To evaluate the effect of a preoperative biliary stent on operative difficulty, postoperative complications, and length of hospital stay after a pancreatoduodenectomy. DESIGN: A retrospective review of a prospectively collected consecutive series. SETTING: The Memorial Sloan-Kettering Cancer Center's Surgical Service, New York, NY. PATIENTS AND METHODS: Seventy-four patients underwent pancreatoduodenectomy between March 1, 1994, and February 15, 1996. Thirty-five did not receive a biliary stent, and 39 received a biliary stent prior to medical evaluation. We analyzed patient, nutritional, laboratory, and operating room factors. Univariate analysis was by Student t test, chi2 test, and Fisher exact test; multivariate analysis was by logistic regression. Significance was defined at P<.05. MAIN OUTCOME MEASURES: Operative time, amount of blood loss, complications, and length of hospital stay. Wound complications were defined as cellulitis, superficial infections, and deep infections. Intra-abdominal complications were defined as intra-abdominal abscesses and pancreatic or biliary fistula. RESULTS: Groups were equivalent for tumor size, risk of comorbidity, time spent in the operating room, and amount of blood loss. There was 1 perioperative death. Patients with a stent had significantly lower bilirubin (P<.03) and aspartate aminotransferase (P<.04) levels and a significantly increased risk of nodal positivity (P<.05). The patients with a biliary stent had an increased risk of wound or abdominal complications on univariate (P<.003) and multivariate (P<.02) analysis and tended toward a prolonged hospital stay (P<.04, Wilcoxon signed rank test). CONCLUSIONS: A preoperative biliary stent was associated with an increased risk of wound or intra-abdominal complications; a stent may prolong the length of hospital stay. However, length of time under anesthesia, amount of blood loss, and transfusion requirements were not altered. A biliary stent should be used with a high degree of selectivity in the management of patients with resectable periampullary masses.

Preoperative identification and operative management of intraatrial extension of lung tumors.

Preoperative identification of intraatrial tumor is uncommon. A 23-year-old woman presented with local recurrence and pulmonary metastases after previous resection of a clavicular sarcoma. Evaluation by computed tomography revealed bilateral pulmonary masses. Due to the size and proximal location, magnetic resonance imaging and transesophageal echocardiography were performed, revealing a large intraatrial mass. She then underwent staged surgical excision without intraoperative complications. We summarize this case and review risk factors for intracardiac extension and prevention of tumor emboli.

The effect of insulin on glucose and protein metabolism in the forearm of cancer patients.

This study was designed to study the effect of systemic hyperinsulinaemia (INS) on glucose and protein metabolism in cancer patients. Sixteen cancer patients (8 > 10% weight loss (WL); 8 < 10% weight loss (NWL)) were compared with 12 healthy controls. Glucose uptake (GU) and phenylalanine (PHE) exchange kinetics were measured across the forearm in the postabsorptive state (PA) and in response to INS (71 +/- 5 microU ml-1). At steady state in response to INS, the negative PA PHE net balance became significantly positive, and GU significantly increased, for cancer and control groups, with no significant differences between the two groups. Subset analysis of NWL cancer vs. WL cancer found no difference between WL and NWL for the change in PHE balance from PA and INS, however GU increased significantly only for the NWL group between PA and INS. These data indicate that cancer patients are not resistant to the anabolic effect of INS on protein metabolism, regardless of weight loss, but are resistant to the effect of INS on glucose metabolism when further along in the disease process as evident by more significant weight loss. This differential response to the effect of INS can be exploited in an attempt to promote protein accrual in weight-losing cancer patients.

Concomitant sclerosing mesenteritis and bile duct fibrosis simulating Klatskin's tumor.

Sclerosing mesenteritis is an uncommon benign condition that should be included in the differential diagnosis of abdominal masses. We present the first reported case of this condition in association with idiopathic bile duct fibrosis simulating Klatskin's tumor. A review of the literature regarding both clinical entities is presented.

Multimodality treatment for patients with hepatocellular carcinoma: analysis of prognostic factors in a single Western institution series.

There are few Western studies evaluating prognostic factors for survival in patients with hepatocellular carcinoma (HCC) and the influence on survival of various therapeutic options including orthotopic liver transplantation (OLT). A retrospective analysis was performed of 122 patients with HCC treated at the University of Alabama at Birmingham from January 1990 through December 1999. Clinicopathologic and treatment factors were analyzed with overall survival as the main outcome variable. Median age was 62 years. Most patients were male (74%) and white (79%). Eighty patients (66%) had associated cirrhosis. Sixty-three percent of patients presented with American Joint Committee on Cancer (AJCC) stage III or IV tumors. The median follow-up for survivors was 22 months. The 1-, 3-, and 5-year actuarial survival rates for the entire cohort were 46%, 24%, and 17%, respectively. On multivariate analysis, ablative surgery (P = 0.003), AJCC stages I and II (P = 0.0012), and absence of vascular invasion (P = 0.0001) were found to be independent favorable characteristics. Forty-four patients underwent surgical resection (including OLT, n = 20) or a surgical ablative procedure. All but two nonsurgical patients died of disease. The actuarial 1-, 3-, and 5-year survival rates for this group were 80%, 71%, and 61%, respectively. On multivariate analysis of the surgical group, only vascular invasion was associated with poor prognosis (P = 0.001). OLT was associated with a favorable prognosis on univariate analysis (P = 0.02). Forty percent of patients who received transplants underwent local/regional treatment before transplantation and the outcome in these patients was no different from that in other transplant patients. Surgical treatment is the only potential curative option for HCC, and qualifying for liver transplantation may be a favorable prognostic factor in surgical patients. Local/regional therapy prior to transplantation may provide a bridge to OLT without an increase in tumor-related mortality.

Is intra-abdominal drainage necessary after pancreaticoduodenectomy?

Closed suction drains after pancreaticoduodenectomy are theoretically used to drain potential collections and anastomotic leaks. It is unknown whether such drains are effective, harmful, or affect the outcome after this operation. Eighty-nine consecutive patients underwent pancreaticoduodenectomy for presumed periampullary malignancy and were retrospectively reviewed. Thirty-eight had no intra-abdominal drains and 51 had drains placed at the conclusion of the operation. We analyzed patient, nutritional, laboratory, and operating room factors with end points being complications and length of hospital stay. Intra-abdominal complications were defined as intra-abdominal abscess and pancreatic or biliary fistula. Postoperative interventions were defined as CT-guided drainage and reoperation. Analysis was by Student's t test and chi-square test. Two of eight surgeons contributed 92% of the patients without drains. The groups were equivalent with respect to demographic, nutritional, and operative factors. Time under anesthesia was significantly shorter in the group without drains (P = 0.0001). There was no statistical difference in the rate of fistula, abscess, CT drainage, or length of hospital stay. Intra-abdominal drainage did not significantly alter the risk of fistula, abscess, or reoperation or the necessity for CT-guided intervention after pancreaticoduodenectomy. Routine use of drains after pancreaticoduodenectomy may not be necessary and should be subjected to a randomized trial.

Early postoperative enteral feeding improves whole body protein kinetics in upper gastrointestinal cancer patients.

BACKGROUND: Patients with upper gastrointestinal (GI) tract malignancies are at increased risk for malnutrition, as well as postoperative morbidity and mortality. As data clearly documenting the benefit of early postoperative enteral feeding in upper GI cancer patients as compared with no feeding are sparse, we examined the protein kinetic effects of early enteral feeding and compared it with standard postoperative care (ie, intravenous fluid). METHODS: Twenty-nine patients undergoing resection of an upper GI tract malignancy were prospectively randomized to either enteral feeding (FEED, n = 12) starting on postoperative day (POD) 1 via a jejunostomy tube or intravenous fluid (IVF, n = 17). On POD 5, all patients underwent resting energy expenditure determination and a protein metabolic study using the isotope 14C-leucine to determine whole body (WB, micromol leu/kg/min) protein kinetics. RESULTS: Respiratory quotient and insulin (microU/mL) levels were significantly increased in patients receiving enteral feeding (0.85 +/- 0.02, 19.8 +/- 4.5 versus 0.78 +/- 0.02, 9.3 +/- 0.8, FEED versus IVF, P < 0.05). Free fatty acids (meq/dL) were significantly lower in FEED group (0.36 +/- 0.04) as compared with IVF group (0.85 +/- 0.07, P < 0.0001). While there were no significant differences in WB protein oxidation (0.10 +/- 0.01 versus 0.10 +/- 0.02) or synthesis (0.81 +/- 0.09 versus 0.68 +/- 0.08, IVF versus FEED), WB protein catabolism was significantly less (0.91 +/- 0.10 versus 0.37 +/- 0.09, P = 0.002), and WB protein net balance was converted to positive in FEED group (-0.10 +/- 0.01 versus 0.30 +/- 0.03, IVF versus FEED, P < 0.001). CONCLUSIONS: Early enteral feeding decreases fat oxidation and whole body protein catabolism while improving net nitrogen balance. By significantly improving protein metabolism, enteral feeding may decrease postoperative morbidity and mortality in upper GI cancer patients.

Early postoperative enteral nutrition improves peripheral protein kinetics in upper gastrointestinal cancer patients undergoing complete resection: a randomized trial.

BACKGROUND: Patients with upper gastrointestinal (GI) tract malignancies are at risk for malnutrition and postoperative morbidity and mortality. We examined the protein kinetic effects of early enteral feeding in this population and compared it with results in patients receiving IV fluid. METHODS: Twenty-nine patients undergoing resection of an upper GI tract malignancy were prospectively randomized to either enteral feeding starting on postoperative day (POD) 1 via a jejunostomy tube (FEED, n = 12) or IV fluid (IVF, n = 17). On POD5, all patients underwent a protein metabolic study using [3H]phenylalanine to determine forearm skeletal muscle (nmol phenylalanine/100 g/min) protein net balance. Free fatty acids (FFA, mEq/dL) and insulin levels (mU/mL) were measured. RESULTS: Protein net balance was significantly less negative in the FEED group compared with the IVF group (-1.4 +/- 0.8 vs -5.0 +/- 1.4, p < .05). Respiratory quotient was significantly increased in patients receiving enteral feeding (0.85 +/- 0.02 vs 0.78 +/- 0.02 FEED vs IVF, p < .05). FFA levels were significantly decreased in the FEED group (0.36 +/- 0.04 vs 0.85 +/- 0.07, p < .05). Insulin levels were significantly elevated in the FEED group (19.8 +/- 4.5 vs 9.3 +/- 0.8, p < .05). Insulin levels correlated with amino acid fluxes. CONCLUSIONS: Postoperative enteral nutrition in upper GI cancer patients results in an improvement in protein kinetic net balance and amino acid flux across peripheral tissue. In addition, insulin levels are elevated, and this elevation correlates with amino fluxes across the forearm. By improving peripheral protein kinetics, early postoperative enteral nutrition may potentially contribute to a decrease in postoperative morbidity and mortality in upper gastrointestinal cancer patients.

Intestinal permeability after early postoperative enteral nutrition in patients with upper gastrointestinal malignancy.

BACKGROUND: Increased intestinal permeability may lead to sepsis in resected upper gastrointestinal (GI) cancer patients. This study sought to determine whether these patients demonstrated increased intestinal permeability and if early postoperative enteral nutrition would alter this result. METHODS: Nineteen patients undergoing complete resection of upper GI malignancy were randomized into two groups: the nonfed group received IV crystalloid, and the fed group started enteral nutrition by jejunostomy on postoperative day (POD) 1. Six nonoperative volunteers were controls. The lactulose/mannitol test was performed on PODs 1 and 5. Ten grams of lactulose and 5 g of mannitol were given, and urine was collected for 6 hours. RESULTS: All patients (nonfed, 1.895+/-0.34; fed, 0.893+/-0.24) had elevated lactulose/mannitol ratios on POD 1 vs controls (0.262+/-0.1; p < .008 and p = .05). These elevated levels returned toward control levels in both groups by day 5 (nonfed, 0.533+/-0.1, p = .06; fed, 0.606+/-0.12, p = .08). CONCLUSIONS: Major upper GI surgery for malignancy resulted in a significant increase in intestinal permeability on POD 1. With or without enteral nutrition, this measure of intestinal permeability returned to normal on POD 5 in well-nourished patients.

Imaging of soft tissue sarcomas.

Imaging of soft tissue sarcomas is critically important in the management of these patients. Whether CT scanning or MR imaging is the best test remains controversial; studies to support either modality exist and are reviewed. An integrated approach using clinical algorithms and radiologic studies to preoperatively stage and follow these patients seems to provide optimal care.