Differences in alloimmune response between elderly and young mice.

OBJECTIVE: The upper age of renal transplant recipients is rising on the transplant wait list. Age-dependent immune responsiveness to new antigens has not been thoroughly studied. This study used a mouse model of alloantibody response to neoalloantigen to study age-related differences. METHODS: Transgenic huCD20-C57BL/6 mice were immunized intraperitoneally with BALB/c splenocytes (2.5 × 10(7)) at baseline and 1 month. Plasma samples were collected at baseline and 1 and 2 months after inoculation, frozen, and tested in a batch run (n = 22). Samples were tested by flow cytometric crossmatch for alloantibody with 2-fold serial dilution from neat to 1:640 using BALB/c splenocytes as targets. The sum of the median fluorescence intensity of the tested sample was calculated after subtracting that of an autologous serum control. Elderly mice (ELD; 42-103 weeks) at inoculation were compared with younger mice (YOU; 11-15 weeks). Statistical analysis was performed with 2-sample t test. RESULTS: Mean age (weeks) between the groups was significantly different (ELD 69.3 ± 9.6 vs YOU 13.4 ± 1.4; P < .001). There was no difference in alloantibody between groups at baseline (ELD 0.7 ± 3.1 vs YOU 0.6 ± 0.4; P = .93). There was a higher alloantibody response at 1 month for YOU (52.9 ± 31.78) compared with ELD (5.12 ± 8.18). There was a greater difference after the 2 month (YOU 109.38 ± 66.43 vs ELD 21.97 ± 27.14; P < .0024). CONCLUSIONS: There was a difference in response to new alloantigen in this animal model. Older animals had significantly decreased responses to new alloantigen stimulation 1 month after inoculation and even more profound decreases at 2 months compared with young animals. This model may be used to study differences in immune refractoriness to antigen signaling. It may be important to adapt clinical immunosuppression in the aged population to possible decreased responses to immune stimulation.

Contemporary treatment strategies for external pancreatic fistulas.

BACKGROUND: Optimal treatment strategies for patients with external pancreatic fistulas have evolved with improved radiographic imaging and the development of transpapillary pancreatic duct stents. The aim of this study was to examine factors affecting fistula closure and develop a classification scheme to guide therapeutic interventions. METHODS: Retrospective chart review was made of all patients with external pancreatic fistulas treated at our institution from January 1991 to January 1997. Side (partial) fistulas maintained continuity with the gastrointestinal tract; end (complete) fistulas had no continuity with the gastrointestinal tract. RESULTS: Postoperative side fistulas resolved with medical treatment in 13 (86%) of 15 patients after a mean of 11 weeks of conservative management. Inflammatory side fistulas resolved with medical treatment in only 8 (53%) of 15 patients after a mean of 22 weeks; those that did not close initially did so with transpapillary stenting. End pancreatic fistulas never closed with medical treatment and were unable to be stented; therefore internal drainage or pancreatic resection was necessary to achieve closure. There were no differences in sepsis rates, Acute Physiology and Chronic Health Evaluation II scores, fistula site, total parenteral nutrition, somatostatin treatment, or initial fistula output between groups. CONCLUSIONS: Classifying external pancreatic fistulas as to their pancreatic duct relationship and cause provides important prognostic and therapeutic information.

Percutaneous radiologic, surgical endoscopic, and percutaneous endoscopic gastrostomy/gastrojejunostomy: comparative study and cost analysis.

PURPOSE: To compare the results and costs of three different means of achieving direct percutaneous gastroenteric access. METHODS: Three groups of patients received the following procedures: fluoroscopically guided percutaneous gastrostomy/gastrojejunostomy (FPG, n = 42); percutaneous endoscopic gastrostomy/gastrojejunostomy (PEG, n = 45); and surgical endoscopic gastrostomy/gastrojejunostomy (SEG, n = 34). Retrospective review of the medical records was performed to evaluate indications for the procedure, procedure technical success, and outcome. Estimated costs were compared for each of the three procedures, using a combination of charges and materials costs. RESULTS: Technical success was greater for FPG and SEG (100% each) than for PEG (84%, p = 0.008 vs FPG and p = 0.02 vs SEG). All patients (n = 7) who failed PEG subsequently underwent successful FPG. Success in placing a gastrojejunostomy was 91% for FPG, and estimated at 43% for PEG and 0 for SEG. Complications did not differ in frequency among groups. For gastrostomy, the average cost per successful tube was lowest in the PEG group ($1862, p = 0.02); FPG averaged $1985, and SEG $3694. SEG costs significantly more than FPG or PEG (p = 0.0001). For gastrojejunostomy, FPG averaged $2201, PEG $3158, and SEG $3045. CONCLUSION: Technical success for gastrostomy is higher for FPG and SEG than PEG. Though PEG is the least costly procedure, the difference is modest compared with FPG. For gastrojejunostomy, FPG offers the highest technical success rate and lowest cost. Due to high costs associated with the operating room, SEG should be reserved for those patients undergoing a concurrent surgical procedure.

Mucin-hypersecreting intraductal neoplasms of the pancreas: a precursor to cystic pancreatic malignancies.

BACKGROUND: Muncin-hypersecreting intraductal pancreatic neoplasms were first described in 1982 and have been observed in increasing numbers since. They are observed primarily by endoscopic retrograde cholangiopancreatography (ERCP) and are characterized by an intraductal papillary neoplasm that secretes thick mucin, causing pancreatic duct dilatation and obstructive pancreatitis. METHODS: Twenty patients are presented, 14 male and six female, with an average age of 59 +/- 11 years. All patients presented with abdominal pain, and most had nausea and vomiting, weight loss, and documented pancreatitis. Of the preoperative studies, ERCP was positive in all patients. Computed tomography scan, endoscopic ultrasonogram, and cytologic findings were less sensitive. Tumor markers were only positive in one patient. All 20 patients were treated surgically. Nine underwent Whipple procedure, one patient had a total pancreatectomy, and nine had distal pancreatic resections. The first patient in the series did not have a pancreatic resection, and his disease evolved into a lethal cystadenocarcinoma causing his death 99 months later. RESULTS: Histopathologic findings were interpreted as borderline malignant in 17 of the 20 patients, and three patients had evidence of invasive adenocarcinoma. Two of these three patients had nodal or distant metastases at the time of diagnosis, and all three died of adenocarcinoma. Seventeen of the patients are alive and well, although two of three with positive pancreatic margins have had recurrent symptoms and have been successfully reresected. CONCLUSIONS: The mucin-producing intraductal papillary tumor of the pancreas is a newly described variant of pancreatic cancer. It presents with symptoms of pancreatitis and has a progressive but more indolent course than the more lethal invasive ductal cancers. Patients with unexplained pancreatitis should undergo ERCP investigation, and aggressive surgical therapy should be carried out because the prognosis for this lesion, when appropriately treated, is more favorable than the usual pancreatic cancer.

An analysis of perioperative cholangiography in one thousand laparoscopic cholecystectomies.

BACKGROUND: We undertook this retrospective study to ascertain the proper role of perioperative cholangiography in the management of 1002 patients undergoing laparoscopic cholecystectomy for symptomatic cholelithiasis. METHODS: Nine hundred forty-one patients were categorized as being at high or low risk for choledocholithiasis according to the presence or absence of jaundice, pancreatitis, elevated bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase, or radiographic evidence of common bile duct stones (CBDSs). RESULTS: Intraoperative cholangiography (IOCG) and preoperative endoscopic retrograde cholangiopancreatography (ERCP) were equivalent in the detection of CBDSs, and laparoscopic common bile duct exploration (CBDE) was successful in 12 of the 21 patients (57%) in whom it was attempted. The ducts of the other 52 patients with CBDSs were successfully cleared by preoperative or postoperative ERCP. CONCLUSIONS: Laparoscopic IOCG is successful in detecting CBDS in high-risk patients and half of these ducts can be cleared laparoscopically. The incidence of CBDS in low-risk patients is 1.7%, a risk that does not warrant routine cholangiography. These data suggest ERCP should be reserved for those at-risk individuals in whom IOCG or laparoscopic duct clearance has been unsuccessful.

Value of helical computed tomography, angiography, and endoscopic ultrasound in determining resectability of periampullary carcinoma.

BACKGROUND: High-quality preoperative radiographic evaluation is crucial in selecting patients with periampullary carcinomas who are candidates for surgical exploration and tumor resection while minimizing the rate of unnecessary laparotomy. METHODS: Twenty-one consecutive patients were prospectively investigated using helical computed tomography (CT) scanning, endoscopic ultrasonography (EUS), and selective visceral angiography (SVA) to determine tumor resectability. All patients were explored and resectability determined. RESULTS: Helical CT had a sensitivity of 63%, a specificity of 100%, and an overall accuracy of 86%. EUS had a sensitivity of 75%, a specificity of 77%, and an overall accuracy of 76%. SVA had a sensitivity of 38%, a specificity of 92%, and an overall accuracy of 71%. CONCLUSIONS: Helical CT scanning is the best preoperative imaging test to determine tumor resectability. EUS is more sensitive than CT for tumor detection, but underestimates resectability. SVA is no longer helpful in the preoperative evaluation of these malignancies.

Antitumor activity and immunotherapeutic properties of Flt3-ligand in a murine breast cancer model.

Flt3-Ligand (Flt3-L) is a stimulatory cytokine for a variety of hematopoietic lineages, including dendritic cells and B cells. The antitumor properties of Flt3-L were evaluated in C3H/HeN mice challenged with the syngeneic C3L5 murine breast cancer cell line. Eighty % of animals receiving 500 microg/kg/day of Chinese hamster ovary-derived human Flt3-L for 10 days were protected from tumor growth, whether the tumor challenge was administered on the first or fourth days of Flt3-L administration. The protection provided by soluble Flt3-L was transient. All tumor-free animals rechallenged 4 weeks after the primary challenge developed tumor. Transduction of C3L5 with retroviral vectors expressing human or murine Flt3-L did not influence in vitro growth or MHC expression but decreased in vivo tumor development to 0 and 10% of mice, respectively. This compares with tumor growth of 52% with interleukin-2 transduced C3L5 and over 85% with untransduced and control vector-transduced C3L5. Unlike animals treated with soluble Flt3-L, administration of Flt3-L as a tumor vaccine protected mice from a subsequent challenge with untransduced C3L5 in 60-78% of mice, compared to 0% of controls. Our initial work used the most common Flt3-L isoform, which is membrane bound but can undergo proteolytic cleavage to generate a soluble form. To evaluate the role of the various Flt3-L isoforms in preventing tumor formation, retroviral vectors encoding only the membrane-bound form or only the soluble isoform were evaluated in the C3L5 model. Tumor formation was similar with either isoform, preventing tumor formation in 80-90% of mice after the primary challenge and 88-89% after the secondary challenge. Splenocytes obtained 4 weeks after the secondary challenge conferred adoptive immunity to naive mice in 60% of animals. This initial report of antitumor activity by Flt3-L is consistent with its known stimulatory effect on antigen-presenting cells and suggests it may enhance the development of tumor vaccines.

Nonfunctioning islet cell tumors of the pancreas: a difficult diagnosis but one worth the effort.

Islet cell tumors of the pancreas usually secrete gastroenteropancreatic peptides causing well-recognized clinical syndromes. Description of these syndromes and the identification of the responsible hormones by radioimmunoassay has led to a better understanding of neuroendocrine regulatory function. More recently, similar tumors have been seen that contain various peptides on immunohistochemical stain but do not secrete these substances sufficiently to cause clinical symptoms. Nonetheless, they have the same malignancy and metastatic rate as most of the functional tumors. Between 1972 and 1996, 44 patients with islet cell tumors have been treated at the Indiana University Medical Center Hospital, and of these 14 have been nonfunctional. Preoperative imaging studies, such as CT scan and endoscopic ultrasound, were able to visualize a lesion but not to make the specific diagnosis, even with fine-needle aspiration. Pancreatic ductal preservation on endoscopic retrograde cholangiopancreatography with CT evidence of a mass should arouse suspicion of an islet cell tumor. Once discovered, all but 1 of the 14 patients has under gone resective therapy, with only 1 postoperative death. Treatment has been aggressive, with 11 of the 13 resected patients undergoing pancreaticoduodenectomy, and 2 others distal pancreatectomy. Four of the seven patients with positive lymph node metastases are dead, while all patients with negative nodes are still alive. Thus far, 10 of the original 14 patients are alive, surviving an average of 32.7 months, with a median survival of 31.1 months. Because these tumors have a better overall prognosis, vigorous attempts at total or subtotal resection should be carried out, since the long-term survival is enhanced by tumor bulk reduction or curative resection when possible.

Effects of L-arginine supplementation on human lymphocyte proliferation in response to nonspecific and alloantigenic stimulation.

BACKGROUND: L-Arginine has been described as a potential immunostimulant in vitro and in vivo. Excessive arginine, however, may be counterproductive. Data support the concept of minimal arginine requirements for normal lymphocyte proliferation, but the results of supplementation with pharmacologic doses of arginine have been contradictory. We hypothesized that excessive arginine supplementation might result in a blunting of normal immune responses of human lymphocytes in vitro. MATERIALS AND METHODS: Peripheral blood mononuclear and T-cells were isolated from normal human donors. Cells were cultured in complete media with various concentrations of L-arginine, L-ornithine, and glycine. Lymphocytes were then stimulated with PHA or alloantigens, and proliferation was determined by measuring [3H]thymidine incorporation. RESULTS: Lymphocyte proliferation was inhibited by L-arginine at pharmacologic doses. The effects were completely reversible. This inhibition could not be prevented by lymphocyte stimulation with IL-2. Lymphocyte proliferation was more sensitive to inhibition by lower doses of arginine when alloantigens from irradiated fresh tumor cells or allogeneic lymphocytes were the stimuli. Finally, lymphocytes showed variable sensitivity to inhibition of proliferation in response to mitogen when treated with L-ornithine (little to no effect) or L-arginine (consistent inhibition at high doses). Pharmacologic doses of L-arginine result in reversible inhibition of normal lymphocyte proliferation in response to both mitogen and alloantigen. This inhibition could not be blocked by interleukin-2. CONCLUSIONS: We conclude that caution should be exercised when recommending aggressive L-arginine supplementation as a possible method to reverse clinical immunosuppression caused by cancer, malnutrition, or trauma.

The role of pancreatic resection in the treatment of pancreatic pseudocysts.

Complicated pancreatic pseudocysts, including multiple pseudocysts, those that have failed prior internal or external drainage, those with associated biliary or pancreatic duct strictures, and those where the diagnosis of cystic neoplasm cannot be excluded, pose unique problems in terms of treatment by standard internal or external drainage techniques. In the series reported herein, pancreatic resection (pylorus-sparing pancreaticoduodenectomy or distal pancreatectomy) was used to treat patients with these complicated pseudocysts resulting in a 59% morbidity rate, 3% mortality rate, and 6% recurrence rate. Results from a collective series of 152 patients from the literature support these findings. Although pancreatic resection has a limited role in the management of patients with uncomplicated pancreatic pseudocysts, it is the treatment of choice in patients with complicated pancreatic pseudocysts.

Cost-effective supply use in permanent central venous catheter operations.

A prospective, randomized trial was designed to determine whether a streamlined operating room supply pack was cost-effective in the placement of permanent central venous catheters. Over a 12-month period, 139 consecutive patients were randomized and evaluated. There were no differences found between the mean ages, sex, indication for catheter placement, mean operative time, or surgeon and nurse satisfaction between treatment groups. In addition, 30-day catheter infection rate, 30-day catheter malfunction rate, and 30-day catheter removal rate were similar between groups. Supply costs were $411.32 per patient operation in the control group and only $180.34 per patient operation in the study group, resulting in an average cost-effectiveness ratio of $230.98 per catheter placed. Based on these data, a streamlined operating room supply setup is cost-effective in the operative placement of permanent central venous catheters.

The role of flow cytometric DNA analysis in determining prognosis of resectable ductal adenocarcinoma of the pancreas.

Carcinoma of the pancreas is a leading cause of cancer mortality in the United States. Improvement in prediction of survival is needed. Flow cytometric analysis as a prognostic tool has produced conflicting results. We retrospectively analyzed the clinicopathologic features, operative factors, and outcome of 39 curative resections for ductal adenocarcinoma of the head of the pancreas performed at Indiana University Medical Center between 1989 and 1994. The group was composed of 20 females and 19 males. Procedures performed were Whipple without vagotomy (n = 5), Whipple with vagotomy (n = 19), pylorus-preserving Whipple (n = 12) and total pancreatectomy (n = 3). Thirty-two tumors were suitable for DNA analysis. Of the 32 patients with flow cytometric data, 33 per cent (3/9) of living patients and 39 per cent (9/23) of deceased patients had aneuploid tumors (P = 0.999). The average S-phase for living patients was 8.3 per cent +/- 3.8 per cent, and 16.1 per cent +/- 13.6 per cent for deceased patients (P = 0.115). In the multivariate analysis, only lymphatic invasion (P = 0.015) and alkaline phosphatase level (P = 0.024) predicted poor survival. Our data show no correlation between flow cytometric DNA ploidy, S-phase analysis, and prognosis in patients undergoing curative resection for ductal adenocarcinoma of the pancreatic head.

Conversion of laparoscopic to open cholecystectomy. An analysis of risk factors.

BACKGROUND: Identifying patients who are at risk for conversion from laparoscopic (LC) to open cholecystectomy (OC) has proven to be difficult. The purpose of this review was to identify factors that may be predictive of cases which will require conversion to laparotomy for completion of cholecystectomy. METHODS: We reviewed 581 LCs initiated between July 1990 and August 1993 at a university medical center and recorded reasons for conversion to OC. Statistical analysis was then performed to identify factors predictive of increased risk for conversion. RESULTS: Of the 581 LC initiated, 45 (8%) required OC for completion. Reasons for conversion included technical and mandatory reasons and equipment failure. By multivariate analysis, statistically significant risk factors for conversion included increasing age, acute cholecystitis, a history of previous upper abdominal surgery, and being a patient at the Veterans Affairs Medical Center (VAMC). Factors not increasing risk of conversion included gender and operating surgeon. CONCLUSIONS: We conclude that no factor alone can reliably predict unsuccessful LC, but that combinations of increasing age, acute cholecystitis, previous upper abdominal surgery, and VAMC patient result in high conversion rates. Patients with the defined risk factors may be counseled on the increased likelihood of conversion. However, LC can be safely initiated for gallbladder removal with no excess morbidity or mortality should conversion be required.

Nonocclusive mesenteric ischemia remains a diagnostic dilemma.

BACKGROUND: Despite reports of low mortality and high bowel-salvage rates in nonocclusive mesenteric ischemia (NOMI), our experience has been much less favorable. This study analyzes our experience with NOMI. PATIENTS AND METHODS: A retrospective chart review (1979 to 1992) identified 113 patients with acute mesenteric ischemia, of whom 13 (12%) met our criteria for NOMI. RESULTS: Patients were grouped into early and late presenters. The 5 early presenters were women, younger (mean age [+/- SD] 50 +/- 5.8 years), with no risk factors, and had vague symptoms leading to a delay in diagnosis. The 7 late presenters were older (mean age [+/- SD] 63 +/- 5.3 years) with identifiable risk factors; all had bowel infarction at the time of initial diagnosis. CONCLUSIONS: Vague symptoms and a wide range of patients at risk make early diagnosis of NOMI uncommon. In the absence of early diagnosis, bowel resection with its high morbidity and mortality remains the only applicable treatment option in the vast majority of patients.

Surgical treatment of obstructive pancreatitis.

BACKGROUND: Unlike chronic calcific pancreatitis, obstructive pancreatitis occurs as a consequence of an obstruction or stricture in the main pancreatic duct. The purpose of this paper is to identify the best method of surgical treatment for patients with obstructive pancreatitis. METHODS: Retrospective analysis of 224 patients surgically treated for chronic pancreatitis during a 7-year period (1988 through 1994) identified 23 patients with obstructive pancreatitis. Patients were classified by surgical treatment into pancreaticoduodenectomy (five patients), side-to-side pancreaticojejunostomy (nine patients), or distal pancreatectomy (nine patients) groups and analyzed. RESULTS: Despite similar demographics, patients treated with distal pancreatectomy had significantly better outcomes (seven of nine) than those treated with either pancreaticoduodenectomy (zero of four) or side-to-side pancreaticojejunostomy (two of eight) at a mean follow-up of 26 months (chi-squared, p = 0.009). Multivariate analysis revealed stricture location, cause of pancreatitis, maximal duct dilatation, exocrine insufficiency, or continued alcohol intake had no influence on surgical outcome in this series (p = 0.698, logistic regression analysis). CONCLUSIONS: At 2 years of follow-up, distal pancreatectomy provided superior relief from pain and recurrent pancreatitis compared with pancreaticoduodenectomy or side-to-side pancreaticojejunostomy. Obstructive pancreatitis is best treated by distal rather than proximal pancreatic resection or drainage.

Classification and treatment of local septic complications in acute pancreatitis.

BACKGROUND: An international symposium on acute pancreatitis recently developed a clinical classification system for severe acute pancreatitis that classifies all local septic complications into three groups: infected necrosis (IN), sterile necrosis (SN), and pancreatic abscess (PA). Despite the appeal of having three distinct, well-defined labels for this complex process, the clinical utility of this schema has yet to be determined. The purpose of this study was to investigate the prognostic and therapeutic utility of applying this clinical classification system to a large group of surgical patients with local septic complication from acute pancreatitis. PATIENTS AND METHODS: We reviewed the cases of 62 patients with complicated pancreatitis, classifying them into IN (n = 20), SN (n = 14), or PA (n = 28) groups. Ranson's score, APACHE II score, and computed tomography grading were calculated within the first 48 hours of admission. Information on patient demographics, etiology of pancreatitis, operative procedures, timing of intervention, bacteriology, blood loss, intensive care unit days, ventilator days, and morbidity and mortality were also accrued and analyzed. RESULTS: Despite similar demographics and etiology of pancreatitis, patients with necrosis, both IN and SN, were more critically ill than were patients with PA (APACHE II score > 15, 21% versus 0%, respectively), required earlier operative intervention (mean 14 days versus 29 days, P = 0.02), required necrosectomy with drainage (65% versus 4%, P < 0.001) rather than simple drainage (3% versus 86%, P < 0.001), more reoperations (2.3 versus 1.1, P < 0.05), and had a significantly higher mortality rate (35% versus 4%, P < 0.05). In addition, patients with IN required significantly more hospital days, ventilator days, and blood transfusions than either patients with SN or PA (P < 0.05). CONCLUSIONS: We conclude that this classification system allows for the stratification of patients into three distinct groups--infected necrosis, sterile necrosis, and pancreatic abscess--and has both therapeutic and prognostic usefulness.

Cystic neoplasms of the pancreas.

Cystic neoplasms of the pancreas are interesting, but rare. We reviewed the Indiana University experience with these tumors over a 15-year period to study preoperative evaluation and long-term outcome. Twenty-one patients (18 females and three males, mean age 59 years) were treated between 1977 and 1992. The lesions included mucinous cystic neoplasm-benign (6), mucinous cystic neoplasm-malignant (6), serous cystadenoma (5), ductal adenocarcinoma with cystic degeneration (2), papillary cystic neoplasm (1), and intra-ductal mucin hypersecreting neoplasm (1). The most common symptoms were abdominal pain, back pain, and weight loss. All eight patients with malignant tumors had symptoms; however, only seven of 13 patients with benign lesions had symptoms (P = 0.046, Fisher exact test). Patients were evaluated with computed tomography of the abdomen (20), endoscopic retrograde cholangiopancreatography (12), ultrasound (5), fine needle aspiration (4), and other studies (6). Six lesions were found incidentally. A correct preoperative diagnosis was made in only two cases. Operations performed included 14 distal pancreatectomies, five pancreaticoduodenectomies, and one total pancreatectomy. Fifteen of 21 patients are alive and well, with follow-up ranging from 4 months to 16 years. Five deaths occurred in patients with malignant mucinous cystic neoplasms, while only one death occurred in the patients with benign cystic neoplasms. Although computed tomography and other diagnostic modalities can identify cystic neoplasms of the pancreas, it is often difficult to make a definitive diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of immunologic antitumor therapy: lessons from the laboratory and clinical applications.

The use of interleukin 2-based immunotherapies for cancer has been associated with significant responses in tumor models in both mouse and humans. Further definition of the elements responsible for response is now possible. It appears that the response is associated with T-cell infiltration of the tumor, and transfer of tumor-infiltrating lymphocytes expanded in tissue culture with interleukin 2 is associated with significant antitumor effects. Further expansion of cultured human melanoma tumor-infiltrating lymphocytes with suppression of lymphokine-activated killer activity as well as the modulation of monocyte activity by interleukin 4 suggests that this cytokine may be clinically useful alone or in combination with interleukin 2. Other means of enhancing the activity of interleukin 2-based immunotherapy are suggested by the finding that tumor cell susceptibility to lysis by natural killer cells is depressed following treatment with interferon gamma and tumor necrosis factor, but susceptibility to lysis by tumor-infiltrating lymphocytes is markedly enhanced. Further development of these therapies will require innovative interpretation and application of findings related to the processing and presentation of human tumor antigens and the nature of tumor antigens and careful analysis of the T-cell receptor in antitumor effectors.