Induction of delayed hypersensitivity reactions in cancer patients by cholesterol-hemisuccinate-treated autologous tumor cells.

Cholesterol-hemisuccinate (CHS) incorporated into tumor cells increases membrane lipid microviscosity and confers enhanced immunogenicity, which can be manifested by delayed hypersensitivity skin reactions. Skin testing was performed in 30 patients with various advanced malignant tumors. Patients were given intradermal injections of 10(6) autologous, irradiated, CHS-treated tumor cells. Control injections consisted of untreated irradiated tumor cells, CHS-treated autologous normal peripheral lymphocytes, or CHS-treated autologous normal tissues. For all patients tested, strongly positive skin reactions were observed when CHS-treated tumor cells were used. Untreated irradiated cells gave negative or very weakly positive reactions. In all cases, normal CHS-treated cells did not elicit any observable skin reactions. CHS-treated cells may have unmasked tumor-associated antigens to which patients may elicit immunologic responses.

Prospective evaluation of malignant neoplasms in cardiac transplant recipients uniformly treated with prophylactic antilymphocyte globulin.

Although there is convincing evidence that prophylactic administration of high doses of the monoclonal antibody OKT3 predisposes patients to an increased prevalence of early posttransplantation malignancy, particularly posttransplantation lymphoproliferative disease, it is indeterminate whether polyclonal antilymphocyte globulin poses a similar hazard. We reviewed the outcome of 112 consecutive cardiac transplant recipients who received uniform immunosuppression, including induction therapy with antilymphocyte globulin, and were prospectively followed-up for a median duration of 41.5 months (range 1 to 81 months). No patients had posttransplantation lymphoproliferative disease. Nine malignant neoplasms (8%) were detected from 6 to 70 months after transplantation. Four patients with cutaneous neoplasms were alive and well at the time this article was written. Three patients died of disseminated adenocarcinoma 6 months, 17 months, and 60 months after transplantation. One patient was undergoing treatment of Kaposi's sarcoma at the time this article was written, and another was undergoing treatment of transitional bladder cell carcinoma. Actuarial survival for all patients was 88% at 1 year and 79% at 5 years. Moderate doses of induction antilymphocyte globulin may facilitate rapid reduction of maintenance cyclosporine and steroid doses, thereby decreasing the duration of intense immunosuppression and lowering the risk of posttransplantation lymphoproliferative disease. Testing this hypothesis would require the development of reliable and reproducible in vivo assays to prospectively assess immune status.

Magnetic resonance imaging in ischemic injury after heart transplantation in rats.

Magnetic resonance imaging with and without gadolinium (Gd)-DTPA has been shown to enable detection of coronary occlusive ischemic injury and heart transplant rejection. This study was performed to examine findings on magnetic resonance images associated with ischemic injury after heart transplantation in rats. Magnetic resonance imaging was performed immediately before death in 22 rats, between 1 and 90 days after isogeneic (Lewis grafts, Lewis host; or Fischer graft, Fischer host) heterotopic heart transplantation. Ischemic injury, characterized histologically by cellular infiltration or myocyte necrosis, correlated inversely with graft duration. It was graded as moderate to severe in 5 of 5 rats killed at 1 to 2 days, and in 0 of 9 animals killed at greater than or equal to 30 days. T2-weighted myocardial signal intensity (TR = 2.3 seconds; TE = 90 milliseconds) correlated inversely with graft duration and was significantly greater in grafts with moderate or severe histologic abnormalities than in grafts with absent or minimal changes. GD-DTPA-induced myocardial enhancement was judged on T1-weighted images (TR = 0.5 seconds, TE = 25 milliseconds). Areas of intense enhancement were present in all seven grafts with severe histologic abnormalities, but in only 3 of 15 grafts with absent to moderate histologic abnormalities. In conclusion, after heart transplantation in rats, ischemic injury causes increased T2-weighted signal intensity and Gd-DTPA-induced T1-weighted signal enhancement--findings similar to those described in transient coronary occlusive ischemia and in graft rejection. Abnormalities seen on magnetic resonance images during the first few posttransplant weeks may represent ischemic injury rather than rejection.

Tracheoesophageal fistula associated with Barrett's ulcer: the importance of reflux control.

A benign tracheoesophageal fistula occurring as a complication of Barrett's ulcerative esophagitis is described. Surgical control of gastroesophageal reflux resulted in healing of the fistula, obviating the need for a resective procedure or esophageal exclusion. Although Barrett's ulcer has been reported as a cause of acquired esophagorespiratory fistula, to our knowledge, the important role of reflux control in the management of this difficult problem has not been discussed.

Efficacy of retrograde coronary sinus cardioplegia in patients undergoing myocardial revascularization: a prospective randomized trial.

The efficacy of retrograde coronary sinus cardioplegia (RCSC) administered through the right atrium compared with aortic root cardioplegia (ARC) has not been examined critically in patients undergoing coronary artery bypass grafting (CABG). Twenty patients having elective CABG were randomized prospectively to receive cold blood ARC (Group I, 10 patients) or cold blood RCSC (Group II, 10 patients). Patient demographics were similar in both groups. Ventricular function was assessed preoperatively by radionuclide ventriculography and postoperatively by simultaneous hemodynamic and radionuclide ventriculographic studies with volume loading. There was no change in ejection fraction (EF) (preoperative versus postoperative value) in Group I (50 +/- 6% versus 53 +/- 6%) but in group II, at similar peak systolic pressure and similar left ventricular end-diastolic volume index (LVEDVI), LVEF improved significantly (49 +/- 6% versus 60 +/- 12%, p less than 0.05). Postoperative ventricular function (stroke work index versus EDVI) for the left ventricle and right ventricle were similar in both groups. Evaluation of postoperative LV systolic function (end-systolic blood pressure versus end-systolic volume index) and diastolic function (pulmonary capillary wedge pressure versus EDVI) were also similar in both groups. Retrograde coronary sinus cardioplegia is as effective as ARC for intraoperative myocardial protection, and provides excellent postoperative function in patients undergoing elective CABG.

Effects of atrial cardioplegia on the ischemic right ventricle after acute coronary artery occlusion and reperfusion.

Right atrial cardioplegia has been advocated as a simple method of delivering retrograde cardioplegia. Passive distention of the right heart inherent with right atrial cardioplegia has been shown to impair right ventricular function in a canine model of global ischemia. This study was designed to compare right ventricular performance after right atrial cardioplegia administered intermittently (n = 5) and continuously (n = 5) with coronary sinus retrograde cardioplegia (n = 5) and aortic root cardioplegia (n = 8) in a canine model of acute right ventricular ischemia and reperfusion. Right ventricular performance was assessed using the load-independent relationship of end-systolic pressure versus dimension (myocardial fiber length). Right ventricular performance was well preserved after reperfusion in those dogs protected with intermittent right atrial cardioplegia (95% of control). Results with continuous right atrial cardioplegia (66% of control) and coronary sinus retrograde cardioplegia (40% of control) demonstrated diminished postreperfusion right ventricular performance. Right ventricular performance in the group protected with aortic root cardioplegia was significantly impaired after reperfusion when compared with all retrograde groups (34% of control, p less than 0.05). In this model, postreperfusion right ventricular performance was preserved in the right atrial cardioplegia groups despite passive ventricular distention. All methods of retrograde cardioplegia resulted in superior preservation of right ventricular performance when compared with standard aortic root cardioplegia.

Technical considerations in aortocoronary bypass grafting.

Since the inception of aortocoronary bypass surgery, many technical advances have been rapidly achieved. Early experience was limited to reversed saphenous vein grafting of single vessel coronary artery disease. Multiple grafts to several vessels soon became commonplace and sequential grafting techniques were developed. Expanded use of the internal mammary artery resulted after analysis of superior patency rates achieved with this conduit. Use of alternative conduits such as upper extremity veins, allogenic veins, synthetic graft material (polytetrafluorethylene), radial artery, splenic artery, and gastroepiploic artery have been explored. Apart from the gastroepiploic vessel, none of these alternative conduits have been suitable. A grat deal of effort has been directed at the mechanisms of saphenous vein occlusion including technical considerations, early thrombosis, intimal hyperplasia and graft atherosclerosis. Platelet inhibition and lipid reduction have shown promise in improving patency rates. Further work in these areas should lead to even better results.

Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy.

We conducted a randomized prospective trial in 19 disease-free soft tissue sarcoma patients with doxorubicin-induced cardiomyopathy identified by ECG radionuclide angiography at rest and during exercise to determine the efficacy of the free radical scavenger, N-Acetyl Cysteine (NAC), in reversing the drug's cardiotoxic effect. Of the 19 patients, 11 received oral NAC (5.5 gm/m2 daily for 30 days) and eight patients served as controls. Patients were stratified for age less than greater than 45 years, time from final dose of doxorubicin to randomization less than greater than 8 months, and history of treatment with mediastinal irradiation. The two groups were well-matched for all parameters. Cumulative mean doxorubicin dose (523 mg/m2 and 532 mg/m2) and range 500-600 mg/m2 was comparable. Left ventricular (LV) ejection fraction before randomization was not significantly different between the two groups either at rest (39 +/- 10% control, 38 +/- 13% NAC) or during exercise (38 +/- 12% control, 35 +/- 11% NAC). Neither rest nor exercise ejection fraction values changed significantly in either group between prerandomization and 1-month postrandomization studies. Late studies performed in seven NAC patients 3-5 months after randomization revealed no difference in LV ejection fraction compared to 1-month postrandomization values. Clinical course in patients with overt congestive heart failure was similar in both groups. LV function did not return to normal in any patient in either group. We conclude that N-Acetyl Cysteine has no effect in reversing long standing doxorubicin-induced cardiomyopathy.

Reduced incidence and severity of accelerated graft atherosclerosis in cardiac transplant recipients treated with prophylactic antilymphocyte globulin.

Allograft coronary artery disease (ACAD) is the major factor limiting long-term survival of cardiac transplant recipients (CTRs). Although cyclosporine based triple drug immunosuppression has not decreased the occurrence of ACAD, some preliminary data suggests that prophylactic antilymphocyte preparations may reduce the incidence of this problem. All CTRs at Henry Ford Hospital have uniformly received prophylactic Minnesota Antilymphocyte Globulin (ALG), thereby providing a unique opportunity to investigate this hypothesis. One hundred three CTRs were followed for a median duration of 34 months with annual angiograms begun one year after transplant. Patients who died without an angiogram were considered to have ACAD based on autopsy results or if their death was clinically suspicious. Ninety-two patients underwent at least one angiogram. Fourteen patients had abnormal angiograms. Nine patients were identified as having ACAD by non-angiographic criteria. Five had autopsy proven disease, 3 died suspiciously, and 1 underwent successful re-transplantation for ACAD. By Kaplan-Meier analysis, the risk of developing ACAD was 12% in 1 year, 16% in 2 years, 22% in 3 years, 26% in 4 years, and 29% in 5 years. Risk of ACAD increased with older recipient's age, higher triglyceride levels, and diabetes, but was not affected by active CMV infection, number of acute rejection episodes, and HLA mismatching. These results suggest that prophylactic ALG reduces the occurrence of ACAD.

Surgical treatment of acute myocardial infarction.

In recent years, advances in surgical techniques and perioperative management of cardiac surgical patients have facilitated more aggressive operative treatment of many serious and even catastrophic complications of acute myocardial infarction (MI). In addition, improved understanding of the natural history of these complications has helped to optimize the indications for and timing of surgical intervention. The role of emergency revascularization for postinfarction angina, evolving acute MI, cardiogenic shock after acute MI, and failed percutaneous transluminal angioplasty has expanded with overall satisfactory to excellent results. Surgical treatment of mechanical with overall satisfactory to excellent results. Surgical treatment of mechanical complications of acute MI such as free-wall rupture, acute ischemic mitral insufficiency, and ventricular septal defect also is undertaken earlier and more aggressively. Although the mortality rates for these conditions remain higher than desired, salvage of many previously doomed patients now is a reality.

Demonstration of tissue-specific antigens shared by normal pancreas and pancreatic neoplasms.

Xenoantiserum raised against extracts of normal hamster pancreas, after absorption with normal tissues, reacted specifically with normal hamster and human pancreas by immunodiffusion. Absorbed antiserum also reacted with hamster and human pancreatic carcinoma but not with other neoplasms. Immunization of hamsters with normal pancreas extracts prevented growth of transplantable pancreatic carcinomas.

Reduced infection in cardiac transplant recipients.

Despite the introduction of cyclosporine immunosuppression, infectious morbidity and mortality in cardiac transplant recipients has remained high. To decrease infectious complications, lower doses of cyclosporine and oral prednisone than previously reported were used for maintenance immunosuppression in 22 operative survivors of orthotopic cardiac transplantation. Twelve infections occurred in 10 patients followed 8 +/- 5 months. Fifty-five percent of patients had no infectious complications. There were no deaths. Seven infections required hospitalization for a mean of 12 days. Infection rate per patient for the first 3 months after transplantation was 0.23 compared with a range of 0.82 to 1.06 in series previously reported in which higher doses of steroids were used. Lowered doses of steroid can be used for maintenance immunosuppression and treatment of rejection with acceptable short-term results. With such a protocol, a low incidence of controllable infectious complications with no deaths has been observed.

Total lymphoid irradiation and discordant cardiac xenografts.

Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

Magnetic resonance imaging with gadolinium-DTPA for detecting cardiac transplant rejection in rats.

To date, no noninvasive tool has gained widespread acceptance as an adequate substitute for endomyocardial biopsy for the diagnosis and grading of cardiac transplant rejection. We examined the potential role of magnetic resonance imaging with gadolinium (Gd)-diethylenetriamine penta-acetic acid (DTPA) image enhancement for the diagnosis of cardiac graft rejection. We studied 15 rats with heterotopic cardiac transplants, nine of which received no immunosuppression, and six of which received cyclosporine, azathioprine, and methylprednisolone. The animals underwent magnetic resonance imaging, which was immediately followed by sacrifice (2-12 days after transplant). Myocardial image enhancement was assessed on T1-weighted images performed before and after administration of Gd-DTPA, 0.5 mmol/kg. Histological specimens were graded I, II, or III to indicate increasing severity of rejection. In the absence of rejection, Gd-DTPA induced mild homogeneous myocardial enhancement. Ten of 11 cases with Grade II or III rejection manifested one or more areas of intense myocardial enhancement. The extent and distribution of intense myocardial enhancement corresponded to the severity and distribution of histological rejection. Quantitative myocardial enhancement, expressed as the ratio of maximal signal intensity after Gd-DTPA to signal intensity before Gd-DTPA administration, separated Grade I animals (1.61 +/- 0.27; mean +/- SD) from Grades II (2.89 +/- 0.58) and III (3.10 +/- 0.77; p less than 0.01) animals. In conclusion, cardiac transplant rejection is characterized by intense T1-weighted image enhancement after administration of Gd-DTPA. Magnetic resonance imaging with Gd-DTPA thus has potential application in the clinical diagnosis of cardiac transplant rejection.