Martin J. Heslin

A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy

OBJECTIVE The purpose of the study was to determine whether early postoperative enteral feeding with an immune-enhancing formula (IEF) decreases morbidity, mortality, and length of hospital stay in patients with upper gastrointestinal (GI) cancer. SUMMARY BACKGROUND DATA Early enteral feeding with an IEF has been associated with improved outcome in trauma and critical care patients. Evaluable data documenting reduced complications after major upper GI surgery for malignancy with early enteral feeding are limited. METHODS Between March 1994 and August 1996, 195 patients with a preoperative diagnosis of esophageal (n = 23), gastric (n = 75), peripancreatic (n = 86), or bile duct (n = 11) cancer underwent resection and were randomized to IEF via jejunostomy tube or control (CNTL). Tube feedings were supplemented with arginine, RNA, and omega-3 fatty acids, begun on postoperative 1, and advanced to a goal of 25 kcal/kg per day. The CNTL involved intravenous crystalloid solutions. Statistical analysis was by t test, chi square, or logistic regression. RESULTS Patient demographics, nutritional status, and operative factors were similar between the groups. Caloric intake was 61% and 22% of goal for the IEF and CNTL groups, respectively. The IEF group received significantly more protein, carbohydrate, lipids and immune-enhancing nutrients than did the CNTL group. There were no significant differences in the number of minor, major, or infectious wound complications between the groups. There was one bowel necrosis associated with IEF requiring reoperation. Hospital mortality was 2.5% and median length of hospital stay was 11 days, which was not different between the groups. CONCLUSION Early enteral feeding with an IEF was not beneficial and should not be used in a routine fashion after surgery for upper GI malignancies.

Association of local recurrence with subsequent survival in extremity soft tissue sarcoma.

PURPOSE The aim of this study was to analyze local recurrence in a large cohort of prospectively followed patients with primary extremity soft tissue sarcoma. In particular, we analyzed the correlation of local recurrence with subsequent metastasis and disease-specific survival. PATIENTS AND METHODS Patients who underwent treatment for primary extremity soft tissue sarcoma from July 1982 through July 1995 at Memorial Sloan-Kettering Cancer Center were the subject of this study. Local recurrence, distant metastasis, and disease-specific survival were used as end points of the study. The influence of local recurrence on subsequent distant metastasis and disease-specific survival were examined using the Cox proportional hazards model. RESULTS We treated 911 patients, of whom 297 (33%) developed recurrent disease. Local recurrence occurred in 116 patients (13%), metastasis in 167 (18%), and synchronous local recurrence and metastasis in 13 (2%). Of 116 patients who developed local recurrence, 38 subsequently developed metastasis and 34 died of disease. Metastasis after local recurrence was predicted in patients with initial high-grade (P = .005; risk = 3.5) or deep (P = .02; risk = 2.9) tumors. Tumor mortality after local recurrence was predicted in patients with initial high-grade (P = .007; risk = 3.7) or large (> 5 cm; P = .01; risk = 3.2) primary tumors. DISCUSSION These findings suggest that there is a strong association of local recurrence with the development of subsequent metastasis and tumor mortality, and that local recurrence is a poor prognostic factor. It would seem prudent to consider patients who develop local recurrence and have high-grade tumors as being at high risk for systemic disease and therefore eligible for investigational adjuvant systemic therapy.

Core needle biopsy for diagnosis of extremity soft tissue sarcoma.

AbstractBackground: Classic teaching has advocated the use of open biopsy to diagnose and grade extremity soft-tissue sarcoma. Reported advantages of core needle biopsy include the minimal morbidity, cost, and time. The perceived disadvantage has been diagnostic inaccuracy. The objective of this study was to compare the diagnostic accuracy of core needle biopsy to incisional or frozen section biopsy for primary extremity masses suspicious for soft-tissue sarcoma. Methods: Patients presenting with extremity masses were identified from our prospective soft-tissue sarcoma database (malignant) and from the clinical information center (benign) between January 1, 1990, and December 31, 1995. Biopsy and subsequent resection data were collected from the pathologic records. Results: During this time, 164 primary extremity soft-tissue masses were evaluated before any biopsy. As the initial diagnostic approach, there were 60 core needle, 44 incisional, 36 frozen section, and 26 excisional biopsies. Two patients underwent two biopsy procedures. Ninety-three percent of the specimens obtained at core needle biopsy were adequate to make a diagnosis. Of the adequate core needle biopsy specimens, 95%, 88% and 75% correlated with the final resection diagnosis for malignancy, grade, and histologic subtype, respectively. Of the frozen section biopsy specimens, 94% were adequate, and accurate diagnostic results of malignancy were obtained with 88%. However, only 62% and 47% were correct for grade and histologic subtype, respectively, which was significantly different than the results obtained with incisional biopsy. The false-negative and false-positive rates for core needle biopsy were 5% and 0% for malignancy. Two core needle biopsy specimens graded low were found to be high, and one core needle biopsy specimen graded high was subsequently found to be low on final resection. Conclusions: When read by an experienced pathologist, the results of core needle biopsy provide accurate diagnostic information for malignancy and grade. Adequate core needle biopsy obviates the need for open biopsy and can be used for rational treatment planning. In the absence of adequate tissue, open biopsy is required.

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 intraabdominal 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.

Growth hormone and insulin reverse net whole body and skeletal muscle protein catabolism in cancer patients.

The authors examined the effect of recombinant-human growth hormone (r-hGH) and insulin (INS) administration on protein kinetics in cancer patients. Twenty-eight cancer patients either received r-hGH for 3 days (GH group, n = 12, weight loss = 6 +/- 2%) or were not treated (control [CTL] group, n = 16, weight loss = 11 +/- 2%) before metabolic study. Recombinant-human growth hormone dose was 0.1 mg/kg/day (n = 6) or 0.2 mg/kg/day (n = 6). Patients then underwent measurement of baseline protein kinetics (GH/B, CTL/B) followed by a 2-hour euglycemic insulin infusion (1 mU/kg/minute) and repeat kinetic measurements (GH/INS,CTL/INS). Whole-body protein net balance (mumol leucine/kg/minute) was higher (p less than 0.05) in GH/INS (0.20 +/- 0.06) than in CTL/INS (0.06 +/- 0.03) or GH/B (-0.19 +/- 0.03). Skeletal muscle protein net balance (nmol phenylalanine/100 g/minute) in GH/INS (25 +/- 6) and CTL/INS (19 +/- 5) was higher than CTL/B (-18 +/- 3). Recombinant-human growth hormone and insulin reduce whole-body and skeletal muscle protein loss in cancer patients. Simultaneous use of these agents during nutritional therapy may benefit the cancer patient.

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.

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 insulins 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)

Neovascularity and clinical outcome in high-grade extremity soft tissue sarcomas

AbstractBackground: Increased tumor neovascularity has been shown to correlate with poor prognosis in solid tumors. Methods: Microvessels were identified by factor VIII immunohistochemical staining. Analysis of microvessel counts, tumor characteristics, and resection details was performed on 119 primary, high-grade extremity soft tissue sarcomas (STS) and correlated with clinical outcome. Results: Tumor characteristics and resection details were analyzed and patient outcome was examined with respect to local recurrence, distant metastasis, and disease-specific survival. Factors found to be significant on univariate analysis for all outcome variables were positive microscopic margin and tumor size. A positive microscopic margin was found to be a significant risk factor for local recurrence (P=.03), distant metastasis (P=.006), and disease-specific survival (P=.004). A primary tumor greater than 10 cm in diameter was a poor prognostic factor for distant metastasis (P=.03) and disease-specific survival (P=.006) when compared to tumors smaller than 10 cm. Microvessel count did not correlate with survival nor did it predict distant metastasis or local recurrence. Histologic subtypes of STS that have a prominent vascular pattern as a diagnostic criterion (i.e., angiosarcoma, liposarcoma, hemangiopericytoma) form a subgroup of all STS. Neovascularity in these subtypes showed no relationship to clinical outcome. Conclusions: These data confirm the prognostic importance of microscopic margin and tumor size in high-grade extremity STS. Neovascularity measured by factor VIII staining had no prognostic significance in these mesenchymal tumors, in contradistinction to carcinomas. Alternatively, microvessel counts may not accurately represent the angiogenic capacity of STS. Therefore, patients with STS who are eligible for anti-angiogenesis clinical trials cannot be identified solely by microvessel count.

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.

Superficial extremity soft tissue sarcoma: An analysis of prognostic factors

AbstractBackground: Experience with soft tissue sarcoma has suggested that superficial tumors have a favorable prognosis. We evaluated the prognostic features of this subset of sarcoma. Methods: Prospective data on 215 patients presenting to Memorial Sloan-Kettering Cancer Center with primary extremity superficial soft tissue sarcomas between July 1, 1982 and July 1, 1996 were analyzed. Superficial sarcomas were defined as subcutaneous tumors not invading the investing fascia of the muscle. Analysis was by univariate and multivariate tests for local recurrence, metastasis, and tumor mortality. Results: Ninety (42%) patients were over 50 years of age, 115 (53%) had high-grade tumors, 53 (25%) had tumors ⩾5 cm, and 18 (8%) had positive margins following definitive resection. Median follow-up was 45 months (range 2 days to 151 months), 31 (14%) patients had local recurrences, 20 (9%) had distant metastases, and 15 (7%) died of disease. Five- and 10-year actuarial disease-specific survivals were 91% and 85%, respectively. On multivariate analysis, age >50 years predicted local recurrence (RR 5.7; 95% CI, 2.4–13.3;p<0.0001). High grade (RR 4.2; 95% CI, 1.4–12.7;p<0.006), and size ⩾5 cm (RR 4.4; 95% CI, 1.8–11;p<0.002) predicted distant metastases. High grade (RR 7; 95% CI, 1.5–31.4;p<0.003), size ⩾5 cm (RR 6.9; 95% CI, 2.3–20.8;p<0.0006), and positive margins (RR 3.8; 95% CI, 1.2–12.4;p<0.006) predicted tumor mortality. Conclusion: Primary superficial extremity soft tissue sarcomas have a favorable prognosis. Size and grade of superficial tumors are the strongest factors in predicting survival.