Search

Splenic function as measured by number of vacuolated red blood cells (RBC) seen with phase contrast microscopy was studied in 44 patients with systemic lupus erythematosus (SLE). Two of 44 patients (4.6%) had increased percentages of vacuolated RBC (8.4% and 30.6%) indicative of hyposplenism. Both patients had inactive disease at the time, were on low doses of corticosteroids, and had persistence of vacuolated RBC when restudied 2 and 4 months later. The present study confirms the association of hyposplenism with SLE and indicates that the incidence of hyposplenism in SLE is about 5%.

The effect of thermotolerance and of polyhydroxy compounds on the cytotoxicity of bleomycin and cis-platinum was studied in cultured RIF tumor cells. Cell survival in response to drug-heat treatments was compared in cells not previously exposed to hyperthermia and in preheated cells that had developed thermotolerance. Since cellular accumulation of polyhydroxy compounds is a potential mechanistic basis of thermotolerance, we also compared cell survival of thermotolerant cells and chemically heat-protected cells. The cytotoxicity of bleomycin and cis-platinum in control cells treated with drug plus heat (43 degrees C, 1 h) was increased synergistically over the cytotoxicity of drug and heat alone. In thermotolerant cells, the synergistic interaction was largely reversed with the bleomycin-heat combination but retained with cis-platinum at 43 degrees C. In the absence of heat, bleomycin and cis-platinum showed similar cytotoxicity in control and thermotolerant cells. The addition of heat protectors (erythritol or galactose) modified the drug-heat cytotoxicity similar to thermotolerance. The synergistic interaction of bleomycin-43 degrees C, but not cis-platinum-43 degrees C, was reversed by the polyhydroxy compounds.

The in vivo effects of hyperthermia combined with bleomycin, cis-platinum, or BCNU were studied. C3H mice with RIF tumors implanted on the dorsal aspect of their feet were used in these experiments. Heat alone (45 degrees C, 30 min) had a minimal effect on mean tumor growth delay (TGD), the time required for the tumor to reach twice the original tumor volume. The maximum tolerated dose (MTD), approximately equivalent to an LD10, of BCNU (50 mg/kg) gave a mean TGD of 24 days, while 40 mg/kg of BCNU (MTD for BCNU with heat) alone resulted in a mean TGD of only 5.5 days. No tumors were cured when treated with heat or chemotherapy alone. However, BCNU (40 mg/kg) given with concomitant heat (45 degrees C, 30 min) resulted in 9/12 cures (tumor control to 120 days). In the three remaining mice, there was one tumor growth, one foot amputation response and one death. The combinations of bleomycin-heat and cis-platinum-heat were inferior to BCNU-heat. Even the combination of bleomycin and cis-platinum with heat resulted in only 4/18 cures, with 5 tumor regrowths, 4 foot amputations, and 5 deaths. Thus, the combination of BCNU-heat gave the best in vivo response rate (75% cure) with acceptable toxicity.

We have tested the reported ability of procaine to inhibit the induction and the development of thermotolerance in Chinese hamster ovary cells. Thermotolerance was induced either by hyperthermia alone (10 min, 45 degrees C) or by combining hyperthermia and procaine (5 min, 45 degrees C + 10 mM procaine) with heating times adjusted to yield similar cell survival after the conditioning treatments. Both the kinetics of thermotolerance development in fresh medium without procaine and the magnitude of thermotolerance 6 h after heat conditioning were similar for the two treatment groups. Development of thermotolerance in the presence of procaine was tested by adding the drug at 5 or 10 mM to culture medium between, but not during two fractionated heat treatments. Thermotolerance development was observed even in the presence of 10 mM procaine, but only if cell survival was corrected for the 37 degrees C-procaine toxicity. Complete survival curves of cells incubated for 6 h at 37 degrees C in 7.5 mM procaine between heat conditioning and test heating showed a D0 that was only 35 per cent lower than that of thermotolerant controls. The data are consistent with the reported sensitization to heat killing by procaine, but show that thermotolerance induction and development were only minimally perturbed by procaine.

A wide number of agents are now available for chemotherapeutic treatment of cancer. The agents fall into four categories: the alkylating agents, the antimetabolites, the anti-tumor antibiotics, and the mitotic inhibitors. Various combinations of the agents are used to gain greater treatment efficacy and reduce resistance, and chemotherapy used as an adjunct to surgery can give added benefit in some cases. Since successful chemotherapy depends on using active drugs, new assays to predict drug responsiveness are being developed. Toxicity of cytotoxic drugs remains a major problem, although attempts at modification hold promise. Clinical trials, the mainstay for evaluating efficacy and toxicity of chemotherapy, must be carefully analyzed to interpret results meaningfully.

Colorectal cancer is one of the leading causes of death in older men and women. Therefore, this age-related cancer is of particular importance to geriatricians. The high incidence of this cancer may be decreased by dietary modifications recommended by the American Cancer Society. Early cancer detection is important to improve survival. When colorectal cancer is detected in the asymptomatic patient, there is a high likelihood of cure. Therefore, screening individuals at high risk is a major goal. Because age is the leading risk factor for colorectal cancer, the American Cancer Society has developed guidelines for screening individuals over age 40 years. Treatment decisions are based on stage of disease. For localized disease, surgical resection is the primary therapy. In advanced disease, palliative treatment may include the use of surgery, radiotherapy, chemotherapy, or a combination of these modalities. Because there is no evidence of an age effect, principles of treatment should be applied similarly in geriatric and younger patients.

Phenytoin sodium has been associated with the formation of altered T lymphocyte rosettes in vitro. To investigate the clinical relevance of this observation, the formation of T lymphocyte rosettes in nine patients was studied before treatment with phenytoin and after therapeutic concentrations of the drug in plasma were attained. The percentage of total rosette-forming cells found before treatment was not significantly different from the percentage found 24 hours after treatment. Likewise, the percentage of active rosette-forming cells before phenytoin therapy was not significantly less than after therapy. These results suggest that in vivo treatment with phenytoin does not acutely inhibit the formation of T lymphocyte rosettes.

The Clinical Oncology Assistantship Program has been offered to approximately 16 sophomore medical students each year at the University of Arkansas for Medical Sciences since 1975. This is an elective, 10-week program given during the summer recess. In the first week of the program, core lectures are given by a multidisciplinary team of cancer educators affiliated with the University of Arkansas. Following this, students spend nine weeks rotating through medical, surgical, and pediatric oncology services of the University of Arkansas for Medical Sciences. In addition, they spend several hours during the program participating in self-directed learning activities at the university's Cancer Teaching Center. The program has been well received by the students, and each year all of the available positions have been filled. Responses on a follow-up questionnaire sent in July 1983 to past participants showed that they continued to rate the program highly. Moreover, 78 percent of the respondents felt the program had influenced positively their attitude toward cancer patients.

Natural cell-mediated cytotoxicity was studied in 24 patients with cutaneous T-cell lymphomas and in 18 age- and sex-matched controls studied concomitantly. Percent cytotoxicity was determined by 4-h 51Cr release assay using K562 targets at effector to target ratios of 100:1, 50:1, and 25:1. Mean percent cytotoxicity was significantly lower in patients than in controls at an effector to target cell ration of 100:1. Likewise, decreased cytotoxicity was found at effector to target ratios of 50:1 and 25:1, although this difference was not significant. When natural killer activity was analyzed separately for males and females, cytotoxicity was lower in both, although the decrease was significant only for male patients. Impairment of natural killer activity did not correlate with blood zinc levels, but appeared to correlate with stage of disease.

Total lymphocyte counts and T and B lymphocytes were measured preoperatively in 19 patients with colorectal carcinoma. No correlation between lymphocyte levels and tumor stage was found. It is concluded that enumeration of T and B lymphocytes in adenocarcinoma of the colon or rectum would not be helpful in predicting disease status.

The numbers and percentages of active rosette-forming T cells were measured in two age groups, to assess the effects of aging. The study included 21 healthy persons in the 20--40 age group and 25 persons without major disease in the 60--85 age group. In the younger subjects the number of rosette-forming cells (RFC) averaged 1430 +/- 463/cu mm (mean and S.D.), a count not significantly different from that in the older subjects (1443 +/- 398/cu mm). Likewise, the active RFC count in the 20--40 age group (526 +/- 185/cu mm) and that in the 60--85 age group (558 +/- 197/cu mm) were not significantly different. There was no difference for the percentage total RFC (young 78 +/- 4%, elderly 78 +/- 6%) or the percentage active RFC (young 29 +/- 7%, elderly 30 +/- 6%). For the total lymphocyte count or the B lymphocyte count, there was no difference between the two groups of subjects. It is concluded that T lymphocytes, measured as total and active rosette-forming cells, are not decreased in healthy older persons.

The incidence of cancer increases progressively with age. Rearrangements of genomes have been found to accompany cellular aging. These factors, in concert with age-dependent alterations in immune function and host defense, may help to explain the increased risk of malignant disease in aged persons. The clinical presentation and natural history of neoplasia are also affected by aging. This conference reviews recent developments in these areas, examines the effects of drug use in the elderly and implications for management, and discusses current information on how age may influence the response of cancer to therapy.

Twenty-nine patients with heavily pretreated acute leukemia in relapse were treated with bisantrene (maximum dose 120 mg/m2/day x 5) in a phase II study. Twenty-seven of the 29 patients were evaluable for response, receiving a total of 53 courses of treatment. There were three complete remissions (11%) lasting 27, 107, and 115 days. One brief partial remission of 43 days was also seen for a total response rate of 15%. Toxicity was mainly limited to the expected myelotoxicity with minimal nonhematologic toxicity seen. Although the complete remission rate is low, an antileukemic effect was seen in the majority of the patients treated. Sixty-one percent of the patients had at least a 50% decrease in the circulating blast count and 32% had at least a 50% decrease in the number of bone marrow blasts. We conclude that bisantrene does have an antileukemic effect, but that the optimal starting dose is not yet established.

The ability of lymphocytes to form rosettes with sheep erythrocytes was studied in the acute burn period to quantitate T lymphocytes. Seventeen adult patients with burns of greater than 15% body surface area were studied serially and compared to normal controls. The absolute number of total rosette-forming cells (RFC) averaged 1,229.1 +/- 92.8/cu mm (SEM) for controls. In patients, a comspicuous decrease in absolute number of total RFC occurred at days 3 to 5 postburn (578.0 +/- 144.2/cu mm) (P less than .001) and during days 6 to 10 (799.8 +/- 106.1/cu mm) (P less than .01). Similarly, the percentage total RFC in patients at days 6 to 10 (48.9% +/- 3.3%) was significantly lower than controls (73.9% +/- 0.7%) (P less than .01). The decrease in total RFC did not correlate with the total lymphocyte count or the cortisol level. These findings suggest that T lymphocytes are decreased or have altered rosette-forming ability in the early postburn period and are in accordance with other reports of impaired cellular immunity following burns.

Splenic antibody-dependent, cell-mediated cytotoxicity against chicken red blood cell targets [ADCC (CRBC)] and natural killer cell-mediated cytotoxicity (NKMC) were determined in C57BL/6 mice given 1300 ppm lead acetate (827 ppm lead) in their drinking water for 8 weeks. ADCC in lead exposed mice was significantly lower than controls at effector to target cell ratios of 100:1, 50:1, and 25:1. In contrast, no significant difference in unstimulated NKMC was seen in lead exposed mice and control mice at effector to target cell ratios of 200:1, 100:1, and 50:1. Moreover, in vivo poly I:C-enhanced NKMC in lead-treated mice was similar to controls at an effector to target cell ratio of 200:1. Blood lead levels averaged 40.5 +/- 1.2 micrograms% in lead-exposed mice and 1.9 +/- 0.3 micrograms% in controls. These findings suggest that chronic low-level lead exposure in mice results in significant suppression of ADCC (CRBC) but does not alter natural killer activity.

Actual determination of the position of the oxygen-hemoglobin dissociation curve (P50) was compared to three methods of estimating P50 in 20 patients with erythrocytosis. There was a significant correlation between determined and estimated P50 values for each of the methods studied. Furthermore, four patients with high affinity hemoglobins were readily distinguished from the other patients by estimating P50. The data suggest that calculating P50 is reliable and may replace the need for actual measurement.

Cancer is one of the most serious illnesses of the elderly. Screening programs focusing on its early detection in this age-group are needed to allow maximum opportunity for cure. Also important is convincing the older patients who smoke that stopping is still worthwhile. Compared with younger patients, the elderly have more intercurrent medical illnesses and are more likely to suffer from financial difficulties and loss of family support. These factors must be considered when managing these patients. Although age-imposed compromises in treatment are often made, available data suggest that a priori dose reduction of chemotherapy on the basis of age alone is not indicated in patients with solid tumors. Prospective clinical trials are needed to further address the issue of responsiveness to chemotherapy as a function of age. Such trials should include assessment of physiologic age and quality of life.

Chloramines, compounds made up of chlorine and ammonia, when present in tap water used for dialysis cause methemoglobinemia and hemolysis. Ascorbic acid addition has been reported to effectively neutralize chloramines in vitro and in patients dialyzed with the single batch dialysis delivery system. We extended these observations to patients dialyzed with the proportioning dialysis delivery system where exposure time of ascorbic acid to chloramines is shorter. This may be important since we found that the half time of the reaction between ascorbic acid and chloramines is 4 minutes. Red cell oxidant sensitivity in 15 patients was assessed by incubating red cells with ascorbate-cyanide and measuring methemoglobin which averaged 2.17 +/- 0.42 g/100 ml (SEM) before dialysis and 2.87 +/- 0.52 g/100 ml after dialysis (NS). Reduced glutathione (GSH) levels were also measured as an index of red cell oxidant damage. GSH decreased from a mean of 7.40 +/- 0.59 micromoles/g Hb before dialysis to 6.98 +/- 0.52 micronmoles/g Hb after dialysis (P less than 0.01). In 2 patients there was no change in 51Cr red cell survival when dialyzed on either the proportioning system or other chloramine free systems. We conclude that addition of ascorbic acid to neutralize chloramines in tap water is also effective when using the proportioning dialysis delivery system.

The interactions of BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea) with low pH, glucose and hyperthermia were studied in cultured RIF tumor cells. The effect of a mild heat treatment of 43 degrees C, 1 h at pH 7.4 on cell killing [surviving fraction (S) = 0.27 +/- 0.05, standard error of the mean (S.E.)] was significantly enhanced by pH 6.5 (S = 0.11 +/- 0.02, S.E.) and 50 mM D-glucose (S = 0.14 +/- 0.01, S.E.). When heat (43 degrees C, 1 h) was added to BCNU, cytotoxicity was increased approximately 14-fold over BCNU alone. Moreover, pH 6.5 increased killing with BCNU and heat by an additional factor of 28. The presence of glucose at 37 degrees C at either pH 6.5 or 7.4 reduced BCNU toxicity in a dose dependent fashion. However, the presence of glucose did not reduce cell killing by BCNU at 43 degrees C. As a result BCNU cytotoxicity was enhanced by approximately 2 orders of magnitude when tumor cell acidification (glucose and low pH) was combined with BCNU and heat.

Children undergoing splenectomy after trauma commonly have few vacuolated RBCs, suggesting a recurrence of splenic activity. We assayed RBCs with vacuoles in 17 adults who had splenectomies for trauma and 15 adults who underwent splenectomy for nontraumatic indications. Vacuolated cells averaged 29.0% +/- 1.0% (SE) in adults having emergency splenectomies and 32.3% +/- 2.0% in those having elective splenectomies. One adult who had a splenectomy for trauma had few RBCs with vacuoles, and a technetium Tc 99m sulfur colloid spleen scan showed one accessory spleen. These findings suggest that recurrence of splenic activity in adults, unlike in children, is an uncommon sequela of splenic rupture.

AZQ, an alkylating agent with lipophilic characteristics allowing CNS penetration was studied in patients with primary CNS malignancies refractory to surgical and radiotherapeutic modalities. Responses were evaluated by three criteria: neurologic examination, performance status and CT scan of the brain. Improvement in all three parameters with stable or decreasing doses of decadron was required for a partial response. Thirty-six poor risk (prior chemotherapy) patients with Grades III and IV astrocytomas were treated with 30 mg/m2. Three patients had a partial response (14, 17, 60 weeks duration). Two patients had mixed responses (worsening of one disease parameter with improvement in another), four had stable disease and one patient had improvement in neurologic parameters with a stable CT scan. Twenty-six patients had increasing disease. Fifteen good risk patients (no prior chemotherapy) with recurrent grades III and IV astrocytomas were treated at a dose of 40 mg/m2 intravenously every three weeks. There were no objective responses in this group of patients. Three patients with nonastrocytomas were treated and no responses observed. The drug was well tolerated. Myelosuppression in the form of leukopenia and thrombocytopenia was the major toxicity. Myelosuppression required dose reductions in eight patients and discontinuation of therapy due to repeated treatment delays in two patients. AZQ at doses of 30 and 40 mg/m2 given on an intermittent bolus schedule is inactive in patients with Grades III and IV recurrent astrocytoma.