Effect of intravenous hyperalimentation on established delayed hypersensitivity in the cancer patient.

Forty-seven cancer patients were selected for study based on their candidacy for hyperalimentation. Each patient received selected skin test antigens intradermally in the forearm prior to the initiation of hyperalimentation, and at 7-day intervals throughout treatment with either chemotherapy, radiation therapy or surgery. Of 23 patients who received chemotherapy, 17 initially had negative skin tests. Thirteen of these patients had positive skin tests after an average of 11.4 +/- 5.5 days of hyperalimentation. Response to chemotherapy occurred only in hyperalimentation. Response to chemotherapy occurred only in those patients whose skin tests were positive, and conversion of skin test reactivity to positive occurred before clinical regression of metastatic disease. No patient who received radiation therapy developed or retained positive skin test reactivity, although nutritional repletion was considered satisfactory in each patient. Surgical patients whose skin tests converted to positive or remained positive preoperatively had an uncomplicated postoperative recovery, whereas 2 of 4 patients whose skin tests remained negative expired postoperatively. Absence of established delayed hypersensitivity in the cancer patient who is treated with chemotherapy or surgery is probably secondary to generalized malnutrition, and established cell-mediated immunity can be restored by proper nutritional repletion.     

The effect of intravenous hyperalimentation on cell mediated immunity.

The effect of intravenous hyperalimentation (IVH) on cell mediated immunity was examined in 22 patients. Each patient received PHA and PPD skin tests before and after the performance of IVH. In this study both PHA and PPD skin reactivity showed significant increase after IVH, and serum albumin levels had positive correlation with the PPD skin reaction changes. Absence of the established delayed hypersensitivity in the surgical patient, especially those with malignant diseases, is probably secondary to generalized malnutrition, and established cell mediated immunity can be restored by proper nutritional repletion.     

The effect of intravenous hyperalimentation on cell mediated immunity

The effect of intravenous hyperalimentation (IVH) on cell mediated immunity was examined in 22 patients. Each patient received PHA and PPD skin tests before and after the performance of IVH. In this study both PHA and PPD skin reactivity showed significant increase after IVH, and serum albumin levels had positive correlation with the PPD skin reaction changes. Absence of the established delayed hypersensitivity in the surgical patient, especially those with malignant diseases, is probably secondary to generalized malnutrition, and established cell mediated immunity can be restored by proper nutritional repletion.     

Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guerin

We evaluated the prognostic value of purified protein derivative skin test reactivity and a granulomatous response in intravesical bacillus Calmette-Guerin therapy. We treated 62 patients with intravesical bacillus Calmette-Guerin once a week for 6 weeks. Purified protein derivative skin tests were performed before and after therapy. Cold cup bladder biopsies were examined in a blind retrospective manner for the presence of granulomas 6 weeks after completion of therapy. A significant correlation between status free of tumor and the presence of either granulomas or positive purified protein derivative skin tests was observed for the total patient population. Of 25 patients whose purified protein derivative test was converted from negative to positive 19 (77 per cent) remained free of tumor, while only 11 of 32 (34 per cent) whose test did not convert to purified protein derivative positive remained free of tumor (p equals 0.0006, chi-square). Similarly, 28 of 37 patients (77 per cent) who had a granulomatous response remained free of tumor, while only 8 of 25 (32 per cent) without a granulomatous response remained free of tumor (p less than 0.003, chi-square). The correlation was similar for each parameter when the total patient population was subdivided into patients treated for carcinoma in situ, residual tumor or prophylaxis. Calculation of predictive values showed that neither purified protein derivative responsiveness, granuloma formation nor a combination of both provided a highly accurate predictive index of therapeutic response in individual patients. False positive or negative rates, ranging from 23 to 24 per cent and 32 to 39 per cent, respectively, were observed. These results suggest that a link between immunological responsiveness and response to therapy exists but that neither the purified protein derivative skin test nor the granulomatous response exhibits sufficient immunological specificity to serve as accurate prognostic indicators in individual patients.     

INFLUENCE OF HIGH CALORIC PARENTERAL NUTRITION ON CATABOLISM AND CELLULAR IMMUNE COMPETENCE IN CARCINOMA PATIENTS1

Urea production rate and cellular Immune reactivity measured by skin stamp tests were used to determine the extent of protein catabolism in 30 surgical patients with histologically diagnosed gastrointestinal carcinoma. All patients received high-caloric total parenteral nutrition (TPN) preoperatively. In those patients with an urea production rate of less than 15 g/day (according to definition a non-catabolic state) TPN was discontinued and the operation performed immediately, whereas the remaining 13 patients with an urea production rate exceeding 15 g/day (accordiong to definition a catabolic state) were given TPN a total of 10 days prior to operation. Nine of the 13 patients could be converted from a catabolic to a non-catabollc state. Only one of these patients died, whereas of the remaining 4 patients who – according to the definition – remained in a catabolic state, two died. The course of nutrition positively influenced the serum levels of IgG, IgA and IgM. The skin stamp test was positive in only three of the 13 patients. Obviously, a positive skin test reaction occurred only in those patients who could be returned to a non-catabolic state during the course of TPN. By means of preoperative TPN catabolic patients can be converted into a non-catabolic state which is associated with a reduction in morbidity and mortality. Moreover, high caloric parenteral nutrition rich in amino acids seems to improve the prognosis for patients with negative skin test reactivity.     

Influence of high caloric parenteral nutrition on catabolism and cellular immune competence in carcinoma patients

Urea production rate and cellular immune reactivity measured by skin stamp test were used to determine the extent of protein catabolism in 30 surgical patients with histologically diagnosed gastrointestinal carcinoma. All patients received high-caloric total parenteral nutrition (TPN) preoperatively. In those patients with an urea production rate of less than 15 g/day (according to definition of non-catabolic state) TPN was discontinued and the operation performed immediately, whereas the remaining 13 patients with an urea production rate exceeding 15 g/day (according to definition a catabolic state) were given TPN a total of 10 days prior to operation. Nine of the 13 patients could be converted from a catabolic to a non-catabolic state. Only one of these patients died, whereas of the remaining 4 patients who - according to the definition - remained in a catabolic state, two died. The course of nutrition positively influenced the serum levels of IgG, IgA and IgM. The skin stamp test was positive in only three of the 13 patients. Obviously, a positive skin test reaction occurred only in those patients who could be returned to a non-catabolic state during the course of TPN. By means of preoperative TPN catabolic patients can be converted into a non-catabolic state which is associated with a reduction in morbidity and mortality. Moreover, high caloric parenteral nutrition rich in amino acids seem to improve the prognosis for patients with negative skin test reactivity.     

Bacillus Calmette-Guerin immunotherapy for bladder cancer

Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer. While the optimal protocol for bacillus Calmette-Guerin remains to be determined, experience with 92 randomized and 30 nonrandomized (high risk) patients followed for up to 5 years provides information that may improve future protocols. Side effects of bacillus Calmette-Guerin are observed to increase with increasing frequency and duration of treatment. The protection from tumor recurrence has persisted: only 6 of 30 patients (20 per cent) treated with bacillus Calmette-Guerin have had recurrent tumor compared to 14 of 27 controls (52 per cent, p equals 0.008, chi-square test), and mean time to recurrence increased from 24 to 48 months (p less than 0.005, Savage). Skin test reactivity to purified protein derivative is particularly useful in predicting response to bacillus Calmette-Guerin immunotherapy. Currently, 60 patients have been randomized to receive bacillus Calmette-Guerin immunotherapy and only 1 of 22 patients (4.5 per cent) in whom the purified protein derivative skin test results converted from negative to positive has had recurrent tumor, compared to 12 recurrences (32 per cent) in patients whose skin tests were positive before treatment or failed to convert following treatment (p equals 0.014, chi-square). Seven recurrences (33 per cent) developed in 21 patients whose skin tests remained negative (p equals 0.015) and 5 recurrences (29 per cent) developed in 17 patients whose tests previously were positive (p equals 0.068, Fisher's test, not significant). The benefit of percutaneous bacillus Calmette-Guerin is suggested by the observations that the recurrence rate in patients treated with intravesical bacillus Calmette-Guerin alone is 40 per cent, and all 7 patients whose purified protein derivative skin tests were negative continued to have negative results when percutaneous bacillus Calmette-Guerin was omitted (p equals 0.003). Among high risk patients a marked decrease in or complete prevention of recurrent tumor was observed in 82 per cent of 22 patients treated previously with chemotherapy and 11 of 14 (78 per cent) with carcinoma in situ have had a complete response.     

Reliability of skin testing as a measure of nutritional state

The reliability of skin testing to assess the nutritional state was evaluated in 257 patients who received total parenteral nutrition (TPN). The nutritional state was assessed by determining body composition, by multiple-isotope dilution. Immunocompetence was simultaneously evaluated by skin testing with five recall antigens. These measurements were carried out before and at two-week intervals during TPN. A statistically significant relationship existed between the response to skin testing and the nutritional state. A body composition consistent with malnutrition was present in the anergic patients, while body composition was normal in the patients who reacted normally to skin testing. However, a considerable overlap existed as 43% of the reactive patients were malnourished, and 21% of the anergic patients were normally nourished. Thirty-seven (43%) of the 86 anergic patients converted and became reactive during TPN, and their body composition improved significantly. The remaining 49 anergic patients (57%) did not convert, and their body composition did not change despite similar nutritional support. The principal difference between the two groups of anergic patients was the nature of the therapy administered. In the anergic patients who converted, therapy was aggressive and appropriate, and clinical improvement occurred in 23 (62.2%) of the patients, with a mortality of 5.4%. In the 49 patients who remained anergic, therapy was often inappropriate or unsuccessful, with clinical improvement in only three (6.1%) of the patients and a mortality of 42.8%. The data demonstrated a significant relationship between the response to skin testing and the nutritional state. However, because of the wide overlap, skin testing does not accurately assess a person's nutritional state. The persistence of the anergic state is indicative of a lack of response to therapy.     

Nutritional concepts in the treatment of head and neck malignancies

Cancer cachexia should no longer be a contraindication to adequate antineoplastic treatment. Current methods of nutritional assessment allow one to identify malnutrition and to follow the nutritional status of the patient throughout the cancer-management program. Enteral nutritional repletion and maintenance remain the ideal course of action, but the gastrointestinal tract is not always readily available or advisable for use; in such circumstances, intravenous hyperalimentation (IVH) may be indicated. The properly nourished patient better tolerates cancer therapy, experiences fewer complications of malnutrition (e.g., sepsis and poor wound healing), and has a better-functioning immune system than does his malnourished counterpart. This article reviews methods of nutritional assessment, delineates indications and techniques for nutritional repletion, and summarizes the results obtained.     

Life-threatening anaphylactoid reactions to propofol (Diprivan)

Fourteen patients who had had a life-threatening reaction within a few minutes after receiving propofol (Diprivan) were investigated for anaphylaxis 4-6 weeks after the incident. Three kinds of immunologic tests were carried out: skin tests (prick tests and intradermal tests with the drugs used and Intralipid, the solvent for propofol), a leukocyte histamine release test, and a radioimmunoassay (RIA) of immunoglobulin E (IgE) against propofol and muscle relaxants, when they had been given with propofol. It had been previously shown that these were always negative in patients anesthetized with propofol without any complications. Thirteen of the 14 patients had at least one positive test supporting hypersensitivity to propofol; 2 patients had three tests positive; 4 had two tests positive; and 7 had one test positive. The skin tests with Intralipid were negative in 4 patients whose tests with propofol were positive. Two patients who had been given muscle relaxants at the same time as the propofol had positive IgE-RIA to both drugs. In one patient, results of all the tests remained negative, and the mechanism involved in the reaction remained unidentified. It is note-worthy that 9 patients of 14 had allergic histories that were known before the anesthetic (atopy; allergy to antibiotics, muscle relaxants, lidocaine, colloids) and that none of the patients had ever received propofol or Intralipid before. It is possible that the IgE that linked abnormally with the propofol had specific binding sites for the phenyl nucleus and the isopropyl groups, which are present in propofol and many other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nutritional Status and the Nonspecific Cellular and Humoral Immune Response in Esophageal Carcinoma

In carcinoma of the esophagus, two major factors are operative, both of which are capable of suppressing the immune response, namely starvation and the presence of a malignant tumor. Twenty patients who were treated by palliative intubation for unresectable carcinoma of the esophagus were investigated. All patients were suffering from protein-calorie malnutrition and were shown to be in negative nitrogen balance. Lymphocyte counts and the nonspecific cellular and humoral immune response were evaluated before and after correction of the nutritional deficit. No attempt was made to reduce tumor bulk. The cellular immune response was compromised in all patients. The DNCB skin test was negative, absolute lymphocyte counts and T-lymphocyte numbers were significantly depressed, and the mitogenic response to phytohaemagglutinin (PHA) stimulation also significantly depressed. Immunoglobulin A levels were significantly elevated but serum complement concentrations were normal. Reversal of the negative nitrogen balance resulted in a significant increase in absolute and T-lymphocyte numbers, and a significant increase in the mitogenic response to PHA. The DNCB skin test, however, remained nonreactive. Nutritional repletion also significantly increased serum C(3), C(4) and C(3)PA concentrations. Reversal of negative nitrogen balance may reverse in vitro evidence of immunoparesis and produce an increase in complement concentrations, without therapeutic reduction in the tumor load.     

Skin testing for chymopapain allergy in chemonucleolysis

Chemonucleolysis with chymopapain (Chymodiactin, Discase) bears the risk of unpredictable anaphylactic reactions. The rate of anaphylaxis is reported to be between 0.35% and 1.5%. Serological in vitro tests such as RAST (radio-allergo-sorbent test) or ChymoFAST (fluorescent allergo-sorbent test) are used to determine increased specific immunoglobulin E antibody titers against chymopapain in patients submitted to chemonucleolysis. Alternatively, skin prick tests have also been applied in clinical trials. A skin prick test including Discase, Chymodiactin, and Solutrast 250 M, which is a radiopaque dye, has been performed in a total of 257 patients; 222 patients were tested before, and 35 patients were tested after chemonucleolysis with chymopapain. From the group tested before chemonucleolysis, 2.3%-3.3% had positive skin tests. After chemonucleolysis, the overall allergy rate to chymopapain increased to 42.9%. Positive skin reactions seem to be time-dependent--between the 3rd and 12th weeks after chemonucleolysis, more than 70% of the patients had positive skin tests. There was no correlation between a history of previous allergy and the skin test result. Patients with positive skin tests should be excluded from chemonucleolysis. This procedure increases the safety for patients submitted to chemonucleolysis. No anaphylactic reaction has been observed hitherto in more than 350 patients who were treated with the intradiskal injection of chymopapain after a negative skin prick test.     

PPD, PHA and Su-PS skin tests in genitourinary malignancies

PPA, PHA and Su-PS skin tests were performed on 152 urogenital malignancy patients and the results obtained were analysed in terms of clinical course. The survival rate of 86 patients showing a positive response to the PPD skin test was significantly higher (P less than 0.005) than that of 65 patients showing a negative response to the PPD skin test. Among the 33 renal tumor patients, the positive rate of the 10 patients with stage I tumors to PPD skin test was significantly higher (P less than 0.05) than that of the 13 patients with stage IV tumors. In 68 bladder tumor patients, the response rate to PPD skin test in 47 patients with a low stage tumor was significantly high (P less than 0.05) compared with that in 21 patients with a high stage tumor. Out of 47 patients who died during the 84-month observation period, 10 (21.7%) and 3 (13.3%) showed a response change from negative to positive, in the PPD test and Su-PS test, respectively. It was assumed that 32 of the 46 patients (69.6%), 4 of the 6 patients (66.7%) and 17 of the 23 patients (73.9%) submitted to the PPD, PHA and Su-PS tests, respectively, showed a negative response at the time of their death.     

Prognostic factors in patients treated with intravesical bacillus Calmette-Guerin for superficial bladder cancer

Several factors were evaluated for prognostic significance in 104 patients with a history of recurrent superficial bladder cancer treated with a 6-week course of intravesical bacillus Calmette-Guerin. Purified protein derivative skin test reactivity, tumor stage, tumor grade and number of previous tumor recurrences were evaluated in all patients. In addition, the prognostic value of a granulomatous response in the bladder was evaluated in 62 of the 104 patients. A significant correlation was reconfirmed between purified protein derivative reactivity and status free of tumor (p equals 0.041) after additional followup on 62 patients from a previous report. A significant correlation also was observed in the total patient population (p equals 0.054). Over-all, 60 per cent of the 62 patients and 52 per cent of the 104 patients whose purified protein derivative test converted from negative to positive remained free of tumor, compared to only 28 per cent of the 62 patients and 28 per cent of the 104 whose test failed to convert to positive. Mean followup was 29.3 +/- 5.7 months in the 62 patient subgroup and 23.5 +/- 5.8 months in the total 104 patients. Bladder granuloma data were available only for the 62 patient subgroup in the previous report. With extended followup, the significant correlation previously reported between status free of tumor and granulomatous response on bladder biopsy was lost. Over-all, 29 of 37 patients (51 per cent) with granulomas compared to 8 of 25 (32 per cent) without granulomas remained free of tumor (p equals 0.132). Tumor stage and grade, and number of previous tumor recurrences failed to show a significant correlation to status free of tumor. These results show that with extended followup, granulomatous response in the bladder lost its statistical correlation with status free of tumor, while a significant correlation was maintained for purified protein derivative responsiveness. This level of statistical significance was borderline and the purified protein derivative skin test response should not be considered useful as a prognostic indicator in individual patients.     

Purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus Calmette-Guérin therapy

Objectives

To investigate the relationship between purified protein derivative (PPD) skin test reactions before bacillus Calmette-Guérin (BCG) therapy and the clinical outcomes of BCG-naïve nonmuscle invasive bladder cancer patients treated with adjuvant BCG therapy.

Use of serum CPK-MM to monitor response to nutritional intervention in catabolic surgical patients

Nutritional status of surgical patients is widely assessed using anthropometrics, visceral proteins, and urinary nitrogen losses. Since assay of muscle-specific marker 3-methylhistidine (3MH) is currently limited to research laboratories, routine use of serum creatinine phosphokinase (CPK) and myoglobin is potentially useful in monitoring nutritional repletion of stressed patients. An acute and a temporal phase human studies were done to test this hypothesis. After an overnight fast, nondiabetic, noncardiac patients were given an IVGTT (0.5 g/kg) 3 days after a standard abdominal midline operation. Glucose, insulin, total CPK, myoglobin, and 3-methylhistidine were measured serially. Baseline CPK was elevated threefold above normal range of upper limits, whereas myoglobin was at the upper limit of normality. After the IVGTT insulin rose, (P less than 0.005) and CPK and 3MH fell (P less than 0.005) whereas myoglobin rose and remained elevated throughout the study (P less than 0.05). As long as insulin levels remained elevated, CPK remained depressed. With sufficient TPN to induce positive nitrogen balance (35 kcal and 0.2 g N/kg/day), elevated CPK levels fell and remained depressed in direct correlation with elevated insulin. Greater than 95% of total serum CPK consisted of the isoenzyme CPK-MM. These initial studies indicate that total serum CPK is useful in monitoring the short-term responses of postoperative catabolic patients who receive nutritional repletion.     

Ethylene oxide allergy in a dialysis center: prevalence in hemodialysis and peritoneal dialysis populations

Chronic hemodialysis (HD) and peritoneal dialysis (PD) patients in one dialysis center were examined for (EO)-related sensitization. Five of 56 (8.9%) HD patients and 0 of 30 PD patients skin tested with a conjugate of human serum albumin (HSA) and EO had positive skin prick tests. The sera of 13 of 107 (12.1%) HD patients including sera from 5 patients with negative skin tests were positive in an EO-HSA radioallergosorbent test (RAST). Sensitized patients in this population did not experience allergic-type reactions during hemodialysis. There were no positive EO-HSA RAST results which could be ascribed to PD. Non-specific cutaneous responsiveness of the renal failure patients was compared with that of normal adult subjects by the use of skin prick tests with codeine phosphate and histamine phosphate. A significantly reduced responsiveness is present in chronic renal failure patients which would be expected to lower the sensitivity of the diagnostic skin test by comparison with the RAST.     

Fat emulsion adversely affects lymphocyte reactivity

Although nutritional repletion of malnourished individuals may improve tests of cell-mediated immunity, the effects of intravenous nutrient solutions themselves on the immune system are largely unknown. This study examined the effects of five parenteral nutrition solutions on in vitro lymphocyte reactivity and measured lymphocyte responsiveness in patients receiving parenteral nutrition. Normal human lymphocytes were incubated with dilutions of an amino acid/dextrose solution, an amino acid/dextrose/fat solution, an amino acid solution, dextrose, and a fat emulsion, and lymphocyte responsiveness to antigenic (PPD) and mitogenic (PHA) stimulation was measured using an in vitro electrophoretic test of cell-mediated immunity. Lymphocyte reactivity was measured in 15 postoperative patients allocated randomly to receive either simple electrolyte solutions or isocaloric parenteral regimes with or without a fat emulsion. In vitro lymphocyte responses were significantly depressed (P less than 0.001) by the fat emulsion at concentrations similar to those achieved in clinical practice but were unaffected by dextrose or amino acid solutions. Lymphocyte reactivity was significantly depressed in patients during infusion of the fat emulsion in comparison with controls (P less than 0.05). The results show that fat emulsion impairs lymphocyte reactivity and suggest that careful consideration should be given before using fat emulsions in patients in whom cell-mediated immunity is impaired already.     

Prevention of chymopapain anaphylaxis by screening chemonucleolysis candidates with cutaneous chymopapain testing

With chymopapain at a concentration of 10 mg/ml, the authors skin tested 540 chemonucleolysis candidates; six were positive, and 534 were negative. None of the positive patients received therapeutic injections of chymopapain. There were no instances of unequivocal anaphylaxis to chymopapain in the patients with negative skin tests treated with chymopapain. When this 0% incidence of systemic reactions in skin test negative patients is compared with the historical rate of 1%, this difference is statistically significant (p less than 0.05). Restriction of chymopapain treatment to patients with negative prick tests can reduce the incidence of systemic reactions.     

The anergic state as a predictor of pancreatic sepsis

From 1984 to 1987, 187 patients with acute pancreatitis (AP) were studied. All patients were stratified according to Ranson's criteria upon admission and were followed up by performing a CT scan weekly. One hundred and thirty-eight patients had 3 or less Ranson's criteria (non-severe acute pancreatitis = NSAP) and 49 presented 4 or more (severe acute pancreatitis = SAP). Ninety-six percent of the patients with (p less than 0.0001). Of the 49 patients with SAP, 39 developed pancreatic or peripancreatic NSAP were reactive to skin tests on the third week, while 4% remained anergic necrosis and were operated. Twenty-two of these patients had positive cultures demonstrating the presence of bacteria in the tissue samples. One hundred percent of the infected patients remained anergic until surgery, while only 40% of those with negative cultures remained anergic (p less than 0.05). Mortality rate correlated well with skin test responses, being 31% in anergic patients while only 5% in reactive subjects. Sustained anergic state (AS), sequentially checked, is associated with a high incidence of pancreatic sepsis.