Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.

The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease.

Net protein anabolism with hypocaloric parenteral nutrition in obese stressed patients.

Thirteen obese patients requiring parenteral nutrition for postoperative complications were studied prospectively to evaluate the efficacy of hypocaloric, high-protein parenteral feeding. Nonprotein caloric intake averaged 881 kcal/d or 51.5% of the patients' measured resting energy expenditure. Protein intake averaged 2.13 +/- 0.59 g/kg IBW. Serum albumin and TIBC increased significantly (2.8 +/- 0.5 g/dL to 3.2 +/- 0.4 g/dL, p less than 0.01, and 196 +/- 39 micrograms/dL to 248 +/- 49 micrograms/dL, p less than 0.05, respectively), and subjects lost weight (120.0 +/- 60.0 kg to 109.7 +/- 32.5 kg, p less than 0.05). Nitrogen balance studies in eight subjects suggested nitrogen equilibrium or positive balance can be achieved (+2.4 +/- 1.9 g/d). All patients exhibited complete tissue healing of wounds and abscess cavities and closure of fistulae. In obese, protein-depleted surgical patients net protein anabolism and clinical efficacy can be achieved with hypocaloric, high-protein feeding. Abundant endogenous fat stores provide obligatory energy.

Effect of parenteral nutrition on protein synthesis in adult cancer patients.

The rate of whole body protein synthesis was measured with 15N glycine in three groups of subjects: 1) normal healthy adult controls, 2) semistarved adult patients with upper gastrointestinal tract malignancies and, 3) a group of patients similar to 2) except they were maintained parenterally on a regimen adequate in amino acids and glucose. By comparing the patient results with data obtained from rat studies with 15N glycine were concluded that the patients were protein rather than energy depleted.

Intestinal fatty acid esterification activity in jejunoileal bypass patients.

In four patients undergoing reversal of jejunoileal bypass we compared functional (in continuity) with bypassed intestine in order to determined the effects of luminal contents. Total mucosal thickness, villus height, and crypt depth, as well as in vitro fatty acid esterification activity were determined. Morphological studies in segments exposed to luminal contents revealed that the ileum had a greater mucosal thickness than the jejunum (p less than 0.001) and that the difference was reflected in both villus height and crypt depth (p less than 0.001). The functioning segments of both jejunum and ileum had a greater mucosal thickness than corresponding bypassed segments consequent to a difference in villus height (p less than 0.001) but not crypt depth. Despite similar exposure to luminal contents, total fatty acid esterification was significantly higher (p less than 0.001) in the functioning jejunum than in the ileum. Jejunum incontinuity possessed higher esterification activity than bypassed jejunum. These results indicate that 1) luminal contents are the most important modulator of intestinal fatty acid esterification activity and the absence of luminal contents in bypassed intestine leads to a significant reduction in esterification activity, 2) the jejunum and ileum possess intrinsic differences in esterification activity even when both are exposed to an identical luminal environment.

Adjuvant therapy of resected adenocarcinoma of the pancreas.

Seventy-two patients underwent resections of pancreatic carcinomas between 1981 and 1989 at the Hospital of the University of Pennsylvania and were evaluable for follow-up. There were three treatment groups as treatment policies evolved. Initially, patients were observed after surgery without adjuvant treatment (Group 1-33 patients). Beginning in 1984, patients were offered adjuvant radiation therapy postoperatively (Group 2-19 patients) and eight of these patients also received 5-FU as an IV bolus on the first 3 days of the first and fifth weeks of treatment. Twenty patients were treated with chemosensitized radiation therapy following surgery using 96-hour 5-FU infusions during the first and fifth weeks of treatment. There were four postoperative deaths, which are excluded from the analysis, and sites of failure could not be determined for five other patients. Among evaluable patients, local recurrences occurred in 85% of the patients in group 1, 55% of the patients in group 2, and 25% of the patients in group 3. The 2-year survival was 35% in group 1, 30% in group 2, and 43% in group 3. Patients with involved surgical margins had a poor survival; only 2 of these 16 patients survived longer than 18 months. Among patients with negative margins, the 2-year survival is 41% in group 1, 33% in group 2, and 59% in group 3. Although the number of patients is smaller, the 3-year survival is 22% in group 1, 11% in group 2, and 47% in group 3. Chemosensitized irradiation is well tolerated in these patients. The major challenge in this group of patients is nutritional maintenance. There was no other significant toxicity. The trend in these observations suggests that survival following pancreatic resection is substantially improved with the addition of adjuvant chemosensitized radiation therapy.

Adenocarcinoma of the esophagus and esophago-gastric junction: the effects of single and combined modalities on the survival and patterns of failure following treatment.

One hundred sixty-five patients with localized adenocarcinomas of the esophagus or esophago-gastric (EG) junction were treated with surgery alone, radiation therapy alone, chemotherapy alone, surgery followed by post-operative radiation therapy, chemotherapy, or chemosensitized radiation therapy, and chemosensitized radiation therapy alone. Patients were retrospectively evaluated for survival, control of tumor within the mediastinum, post-operative swallowing function, patterns of failure, and treatment-related morbidity. Follow-up of survivors ranges from 9-88 months (median 23 months). Chemotherapy and radiation therapy as single modalities were associated with a recurrence rate of 100%. Combined modality therapy significantly reduced the risk of local recurrence in all patient groups. Chemosensitized radiation therapy alone reduced the local recurrence rate to 48%, and surgery followed by radiation therapy reduced the local failure rate to 24%. When chemotherapy or chemosensitization was added to surgery plus radiation, the risk was further reduced to 15%. The use of combined modality therapy was also found to extend the survival of patients without excessive toxicity. Median survival was shortest among the group treated with radiation alone (5 months) and intermediate among patients following chemosensitized radiation alone (10 months) or complete surgical resection alone (15 months). Patients treated with all three modalities had the longest median survival (21 months). Based on this experience, the optimum treatment of these patients appears to include aggressive attempts at surgical resection with chemosensitized radiation therapy. Excellent palliation can also be achieved in unresectable patients with chemosensitized radiation therapy with a smaller chance for long term survival.

Outcome of pancreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinomas.

PURPOSE: To determine the clinical outcomes and potential impact of adjuvant chemoradiation in patients undergoing surgical resection of ampullary carcinoma. PATIENTS AND METHODS: Between 1988 and 1997, 39 patients underwent pancreaticoduodenectomy for ampullary adenocarcinomas. Clinical and pathologic factors, adjuvant therapy records, and disease status were obtained from chart review. Thirteen (33%) patients received adjuvant chemoradiation. Radiation therapy was delivered to the surgical bed and regional nodes to a median dose of 4,860 cGy with concurrent bolus or continuous infusion of 5-fluorouracil. Outcomes measures included locoregional control, disease-free survival, and overall survival. Univariate analysis was used to assess the impact of various patient- and tumor-related factors and the use of adjuvant therapy. Twenty (51%) patients with tumor invasion into the pancreas (T3) or node-positive disease were classified in a "high-risk" subgroup. RESULTS: After a median follow-up of 45 months for survivors, overall 3-year survival was 55%. Survival was significantly worse for patients with positive nodes (23% vs. 73%, p < 0.001) and high-risk status (30% vs. 80%, p = 0.002). Disease-free survival was 54% at 3 years. There were 3 postoperative deaths, and these patients (all high risk) are excluded from further analysis on adjuvant therapy. In univariate analysis, the use of adjuvant chemoradiation had no clear impact on local-regional control or overall survival. However, by controlling for risk status in multivariate analysis, the use of adjuvant therapy reached statistical significance for overall survival (p = 0. 03). Among the high-risk patients, 7 (77%) of 9 patients receiving adjuvant therapy remained disease-free during follow-up compared with only 1 (14%) of 7 patients not receiving adjuvant therapy (p = 0.012). CONCLUSION: Despite the relatively favorable prognosis of ampullary carcinomas compared with other pancreaticobiliary tumors, patients with nodal metastases or T3 disease are at high risk for disease relapse. The use of adjuvant chemoradiation may improve long-term disease control in these patients.

The role of mastectomy in patients with stage I-II breast cancer presenting with gross multifocal or multicentric disease or diffuse microcalcifications.

PURPOSE: Women with Stage I-II invasive breast cancer who present with gross multicentric disease or diffuse microcalcifications have a significant risk of breast recurrence when treated with conservative surgery and radiation. The purpose of this report is to present the results of mastectomy in this group of patients. METHODS AND MATERIALS: Between 1982 and 1989, 88 patients with clinical Stage I-II breast cancer who presented with clinical and mammographic evidence of gross multicentric disease or diffuse microcalcifications underwent modified radical mastectomy. Median followup was 4 years for the 57 patients with gross multicentric disease and 5.6 years for 31 patients with diffuse microcalcifications. At the time of mastectomy, 42% of patients were found to have positive axillary nodes. Following mastectomy, 15 patients received post mastectomy radiation and 35 patients received adjuvant systemic chemotherapy. RESULTS: When compared to a group of 1295 patients with unifocal, Stage I-II breast cancer, treated with conservative surgery and radiation during the same time period, patients with gross multicentric disease and diffuse microcalcifications had a significantly higher incidence of > or = 4 positive nodes, patients with gross multicentric disease had a lower incidence of positive resection margins following mastectomy and patients with diffuse microcalcifications were younger. The 5-year actuarial risk of an isolated local-regional recurrence was 8% for patients with gross multicentric disease or diffuse microcalcifications and 7% for patients with unifocal disease. Patients with gross multicentric disease or diffuse microcalcifications and > or = 4 positive axillary nodes who did not receive post mastectomy radiation had an increased risk for local regional recurrence. There were no significant differences in the 5-year actuarial overall or relapse-free survival (88% and 73% gross multicentric disease, 97% and 86% diffuse microcalcifications and 90% and 79% unifocal disease), freedom from distant metastasis (76% gross multicentric disease, 90% diffuse microcalcifications, 86% unifocal disease) or incidence of contralateral breast cancer (10% gross multicentric disease, 13% diffuse microcalcifications, 8% unifocal disease) among the three groups. CONCLUSION: The present study demonstrates no increased risk of local-regional recurrence in patients with gross multicentric disease or diffuse microcalcifications undergoing mastectomy in contrast to the increased risk of breast recurrence in patients with gross multicentric disease undergoing conservative surgery and radiation. Indications for post mastectomy radiation include > or = 4 positive nodes or close or positive surgical margins. Despite a significantly higher incidence of > or = 4 positive nodes, patients with gross multicentric disease and diffuse microcalcifications have a 5-year actuarial overall and relapse-free survival comparable to a group of patients with unifocal disease treated with conservative surgery and radiation.

Application of backpropagation neural networks to diagnosis of breast and ovarian cancer.

Neural network programs have been developed in an attempt to improve the diagnosis of breast and ovarian cancer using a group of laboratory tests and the age of the patient. The laboratory tests employed in this study include albumin, cholesterol, HDL-cholesterol, triglyceride, apolipoproteins A1 and B, NMR linewidth (the Fossel Index) and a tumor marker (i.e., CA 15-3 or CA 125). The breast cancer study involved 104 patients (45 malignant and 59 benign subjects). The ovarian cancer study involved 98 individuals (35 malignant, 36 benign and 27 control subjects). Methods are outlined for identification of the most influential input parameters and optimization of network structure and training. Network characteristics were contrasted with the test results of the appropriate serum tumor marker assay. For the breast cancer study, the best neural network program, using six input parameters, had a sensitivity of only 55.6% and a specificity of 72.9%. The tumor marker CA 15-3 alone gave results of 61.3% and 64.4%, respectively. For the ovarian cancer study, the best neural network program, using six input parameters, had a sensitivity of 80.6% and a specificity of 85.5%. The tumor marker CA 125 alone gave results of 77.8% and 82.3%, respectively. These methods provide an objective approach to neural network optimization and parameter selection applicable to other data bases of clinical and laboratory data.

Experience with the esophagogastric devascularization procedure.

Twenty-eight consecutive unselected patients were treated for esophageal varices by means of a modified Sugiura procedure between 1978 and 1985. In accordance with Child's classification, 59% were considered as class A, 11% as class B, and 30% as class C. The etiology of the cirrhosis included alcohol abuse (42%), hepatitis (33%), granulomatous disease (7%), and cryptogenic disease (18%). One patient had extrahepatic portal hypertension from unknown causes. The surgical treatment included esophageal and gastric devascularization in all cases. The average operative time was 4 1/2 hours. The average blood replacement during surgery was 8 units. The operative mortality was 32% (2/16 class A, 1/3 class B, and 6/9 class C). Morbidity occurred in 33% of the patients. Significant causes of morbidity and mortality were related to complications of the esophageal transection, which was omitted in the later series. Six of the eighteen patients who survived surgery died later, but only one death was due to presumed recurrent variceal hemorrhage. Significant bleeding occurred in four patients--two due to recurrent varices and two due to peptic ulcer disease. Encephalopathy, which was present preoperatively in two patients, is still manifest but is well controlled. Encephalopathy did not develop in any other patients. At present, the 12 surviving patients have stable liver function.

The effects of semistarvation and parenteral nutrition on the gastric mucosa of rats.

The effects of semistarvation and parenteral nutrition on the gastric mucosa were studied in 24 Wistar rats (250 to 350 grams). The animals were divided into three dietary regimens: Group I-standard rat chow ad libitum; Group II-50 cc. per day of a hyperalimentation solution containing 30% glucose + 5% amino acids; Group III-50 cc. per day of 5% glucose. The animals were fed for a period of 7 days. Gastric mucosal fluxes of Na+, Li+, and H+ then were measured after the gastric instillation of two gastric wash solutions, one primarily an HC1 solution, the other a solution of HC1 plus sodium taurocholate. Gross examination of the gastric mucosal surfaces were recorded. Compared to Group I (oral diet), Groups II and III demonstrated a decrease in volume in gastric secretion during the test period (p less than 0.005); and an increase in net negative hydrogen flux (p less than 0.005). Compared to Group II (hyperalimented), Group III (semistarved) demonstrated an increased net negative H+ flux (p less than 0.01), but no difference in volume of secretion. Only Group III demonstrated a difference in H+ flux after the addition of sodium taurocholate (p less than 0.05). Gastric lesions were significantly increased in Group III, as compared to Groups I and II. Semistarvation renders the gastric mucosa of the rat more susceptible to injury. Adequate intravenous nutrition alone protected against these effects.

Improved renal function and inhibition of renin and aldosterone secretion following peritoneovenous (LeVeen) shunt.

Twelve patients with cirrhosis, refractory ascites, and varying degrees of renal failure (creatinine clearance, 5 to 44 ml/min) were studied before and up to 2 weeks following peritoneovenous shunt. Creatinine clearance increased 60% or more in seven patients (group I) and 22% or less in five patients (group II). There were no significant differences in maximum urine output or sodium excretion between groups (group I, 4,272 ml/14 hr, 372 mEq/24 hr; group II, 3,722 ml/24 hr, 255 mEq/24 hr). Aldosterone and renin concentrations were higher in group I and showed a greater decrease after shunting. Renin substrate levels also were higher in group I and rose following shunt insertion, while group II remained low. Ascitic fluid was found to contain renin substrate in concentrations of approximately 25% to 50% of plasma concentrations. Patients with the greatest increase in creatinine clearance showed the largest rise in substrate concentration and fall in renin and aldosterone secretion, suggesting a dynamic relationship between these factors. That a diuresis could occur without significant change in these parameters in five of 12 patients suggests independent control mechanisms for renal salt and water excretion and glomerular filtration in the ascitic patient.

Laparoscopic-guided jejunostomy.

The proximal jejunum is the preferred site for long-term enteral access in the patient at risk for aspiration. Herein we describe a laparoscopic technique for the creation of a feeding tube jejunostomy. This minimally invasive approach is an alternative for patients requiring chronic postpyloric enteral feeding.

Protein synthesis dynamics in human gastrointestinal malignancies.

The malnourishing effects of cancer and its treatments haveprovided a strong clinical incentive for the nutritional support of cancer patients with intravenous hyperalimentation (IVH), but potential enhancement of tumor growth by additional substrate provision has generated concern. Twenty-five patients undergoing surgical treatment for gastrointestinal cancer were studied on one of two preoperative dietary regimens: ad libitum oral diet or intravenous hyperalimentation. Using a stable isotope tracer, N-glycine, in vivo tissue fractional protein synthesis rates were determined from operative specimens of tumor and normal gastrointestinal tissue. Despite substantial advantage in caloric and protein intake, and nitrogen retention, tumors in IVH-fed patients were synthesizing protein no faster (14.2%/day) than those in orally fed patients (15.1/day). Tumor fractional protein synthesis rates (PSRs) correlated (r = + 0.708, P less than 0.005) with the PSR of the tissues from which they arose. IVH maintained gut PSR at the level occurring in the orally fed patients. Parenteral nutritional support in cancer patients does not maintain protein synthesis rates at levels greater than those present with regular oral diets. Although not a direct measure of tumor growth, these data provide preliminary evidence that optimal nutritional support of the cancer patient may be possible without undesirable stimulation of tumor growth.

Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome.

The individual nutrients arginine, RNA, and omega-3 fatty acids improve immune function, but prospective trials have not demonstrated their effects on clinical outcome. Patients (n = 85) who underwent operation for upper gastrointestinal malignancies were randomized to receive the supplemental diet or a standard enteral diet after surgery. Clinical patient characteristics were similar between the two groups. Mean caloric intakes (1421 vs 1285 kcal/day) were similar between groups. Mean nitrogen intakes (15.6 vs 9.0 gm/day) and nitrogen balances (-2.2 vs -6.6 gm/day) measured in the first 20 patients were significantly greater in the supplemented group than in the standard group (p = 0.05). In vitro lymphocyte mitogenesis was measured in the first 31 patients and was decreased on postoperative day 1 in both groups, but normal levels were regained only in the supplemented group. In the cohort of 77 eligible patients, infectious and wound complications occurred significantly less often (11% vs 37%) in the supplemented group than in the standard group (p = 0.02). Linear logistic models for infectious/wound complications with control for the amount of nitrogen suggested (p = 0.10) dietary treatment as the major factor. Mean length of stay in the hospital was significantly shorter (p = 0.01) for the supplemented group (15.8 +/- 5.1 days) than for the standard group (20.2 +/- 9.4 days). These results suggest that postoperative enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids instead of a standard enteral diet significantly improved immunologic, metabolic, and clinical outcomes in patients with upper gastrointestinal malignancies who were undergoing major elective surgery.

Influence of antrectomy on gastrin release and gastric secretion in conscious monkeys.

The plasma-gastrin response to feeding and to insulin stimulation was determined before and after precise antrectomy in conscious rhesus monkeys (Macaca mulatta). Feeding resulted in a significant increase above basal gastrin levels (107 plus or minus 13 to 276 plus or minus 22 pg. per milliliter), as did stimulation with insulin (93 plus or minus 8 to 182 plus or minus 23 pg. per milliliter). Antrectomy reduced basal gastrin concentrations and abolished the gastrin response to both feeding and insulin. Antrectomy abolished the acid secretory response to histamine and insulin. In order to eliminate the problems of reflux gastritis and to study the time course of reduced acid secretory capacity, three monkeys were antrectomized and maintained by duodenal feedings. The histamine acid secretory response virtually was abolished within 24 hours and was not recovered over a 4 week period. Parietal cell architecture remained intact. In the monkey a major portion of basal circulating gastrin is antral in origin and the gastrin response to feeding and insulin is from the antrum exclusively. Loss of antral gastrin results in a virtual abolition of the acid secretory response to insulin and histamine. This decline is immediate in onset and is not related to parietal cell atrophy.

Preliminary characterization of the procoagulant material in human ascites.

Disseminated intravascular coagulation invariably accompanies placement of peritoneovenous (LeVeen) shunts, which suggests that ascitic fluid contains procoagulant material capable of activating blood coagulation. In this study, we identified thrombogenic activity in human ascites and the hemostatic pathway by which it acts. Peritoneal fluid was removed percutaneously from patients with ascites due to various causes. Four fractions were prepared by centrifugation: cells, a low-speed, cell-free fluid, a high-speed supernatant, and the precipitate from the high-speed centrifugation. Cellular fractions from all ascitic fluids shortened a one-stage clotting time of normal pooled plasma by 68% in comparison with saline solution and endotoxin controls. Similarly, the cell-free fluids also shortened the clotting time of normal pooled plasma by 41%. The cellular and cell-free fractions shortened the clotting time of factor VIII-deficient plasma but failed to demonstrate procoagulant activity in factor VII-deficient plasma. These fractions had no effect on platelet aggregation or the platelet release reaction. The high-speed precipitate was dissociated by ethylenediaminetetra-acetate (EDTA) into fluid phase and precipitate, both of which demonstrated procoagulant activity. Furthermore, high-speed precipitate contained protein, phospholipid, and sterol in proportions similar to those of plasma membranes and contained membrane-bound vesicles as identified by means of electron microscopy. This material could be rendered inactive by heating to 100 degrees C for 2 minutes or by incubation with phospholipase C for 15 minutes. Finally, the ability of the high-speed precipitate to shorten the clotting time was prevented by preincubation with a monoclonal antibody, which is known to inhibit the procoagulant activity of human tissue factor. We suggest that several entities contribute to the procoagulant properties of human ascites, with procoagulant material deriving at least in part from peritoneal cells. The sedimentable procoagulant factor appears to be associated with cellular membranes or membrane fragments and is thromboplastin-like in its chemical composition, immunoreactivity, and substrate specificity.

The slipping rib syndrome.

The slipping rib syndrome is a cause of upper abdominal pain that is not widely known, possibly because of failure of recognition rather than infrequent occurrence. The syndrome should be suspected when pain can be reproduced by a rib-hooking maneuver. However, a thorough evaluation including intercostal nerve blocks is necessary both to eliminate coexistent gastrointestinal and psychiatric disorders as a cause of pain and to assure adequate treatment and a good prognosis. Patients with obvious slipping ribs appear to benefit from surgical excision.

Peritoneovenous shunt for hydrothorax associated with ascites.

Two patients with massive hydrothorax associated with ascites resistant to intensive long-term medical management were treated by insertion of a peritoneovenous (LeVeen) shunt. In each case the effusion was resolved within one month after insertion. With one revision each, the two shunts have remained clear for nine and 18 months. The peritoneovenous shunt is an alternative to medical therapy for large effusions. Its effectiveness in resolving them supports the idea that diaphragmatic defects help cause their formation.

Implications of malnutrition in the surgical patient.

The substantial prevalence of malnutrition in the hospitalized patient population has only been recently recognized. Preoperative nutritional and immunological assessment was performed prospectively on admission in 64 consecutive surgical patients. Factors measured included weight loss, triceps skinfold, midarm muscle circumference, creatinine-height index, serum albumin level, serum transferrin level, total lymphocyte count, serum complement level, serum immunoelectrophoresis, lymphocyte T rosettes formation, neutrophil migration, and delayed hypersensitivity. Using these criteria for malnutrition, 97% of the patients had at least one abnormal measurement and 35% had at least three abnormal measurements. Patients were monitored for complications during their hospital course. Serum albumin level, serum transferrin level, and delayed hypersensitivity reactions were the only accurate prognostic indicators of postoperative morbidity and mortality. Substantial unrecognized malnutrition exists in the surgical patient population. An isolated indicator of malnutrition should be interpreted with caution. The visceral protein compartment (serum albumin and serum transferrin levels and delayed hypersensitivity) is the most accurate prognostic indicator of postoperative morbidity and mortality. Perioperative nutritional support may reduce operative morbidity and mortality in the malnourished operative candidate.