Interferon-gamma or granulocyte-macrophage colony-stimulating factor administered as adjuvants with a vaccine of irradiated autologous tumor cells from short-term cell line cultures: a randomized phase 2 trial of the cancer biotherapy research group.

The objective was to study the effects of patient-specific vaccine immunotherapy administered with either interferon-gamma (IFNgamma) or granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with metastatic cancer. Short-term cell lines were established from cancer tissue resected from patients with metastatic cancer for use as autologous tumor cell vaccines. Successful cultures were expanded to 1 to 2 x 108 cells, irradiated, and cryopreserved in aliquots of 106 cells for intradermal testing of delayed tumor hypersensitivity and 107 cells for subcutaneous vaccinations. The study design was that of a randomized phase 2 trial. Patients were stratified by tumor type and by whether they had measurable disease at the time vaccination was to commence, and then randomized to receive either 100 MIU IFNgamma subcutaneously or 500 microg GM-CSF subcutaneously at the time of each tumor cell vaccination. Following a baseline test of delayed-type hypersensitivity (DTH) to an intradermal injection of 106 irradiated autologous tumor cells, patients received 3 weekly subcutaneous injections of 107 cells, had a repeat DTH test at week 4, then received monthly vaccinations for 5 months. A positive DTH test was defined as at least 10 mm of induration; survival was determined from the first DTH test. There were 98 patients enrolled with a median follow-up of over 4 years. The most prevalent diagnoses were melanoma (51), renal cell carcinoma (18), and soft-tissue sarcoma (14). There were 49 patients (26 men, 23 women, average age 50.4 years) randomized to IFNgamma and 49 (28 men, 21 women, average age 54.1 years) to GM-CSF. The average numbers of vaccine and adjuvant injections were 6.3 and 5.9, respectively. For the patients who received IFNgamma, the objective response rate was 0 of 21; for patients who received GM-CSF the response rate was 1 of 26. Only eight patients (four from each arm) had a positive baseline DTH reaction to autologous tumor. The tumor DTH test converted from negative to positive in 13 of 45 of the IFNgamma group and 11 of 43 of the GM-CSF group. With 29 patients deceased in the IFNgamma arm and 31 in the GM-CSF arm, the 2-year and 5-year survival rates were 45% and 29% for the IFNgamma arm and 41% and 23% for the GM-CSF arm (NSD). Both adjuvants were well tolerated and results were similar in both arms of the study. Both adjuvants were associated with a 25% to 30% rate of DTH conversion and a 25% 5-year survival rate. Immune recognition of autologous tumor can be induced with this approach.

Short-term autologous tumor cell lines for the active specific immunotherapy of patients with metastatic melanoma.

We established short-term cell lines for 108/170 (64%) patients with metastatic melanoma. Tumor cell numbers were expanded to 10(8), then cells were irradiated, aliquoted, and cryopreserved for clinical use. Vaccines have been used to treat 69 patients with clinical follow up for 33 who had measurable metastatic disease at the time vaccine therapy was initiated (METS), and 33 who had no evidence of disease (NED) at the time of vaccine therapy following surgical resection of metastases. The protocol called for a baseline test of delayed tumor hypersensitivity (DTH), three weekly injections, a repeat of the DTH test, then monthly injections for an additional 5 months. Objective tumor responses were noted in 3/26 (12%) patients who received a minimum of three vaccinations, one complete, and two partial, with survivals of 36, 46+, and 78+ months. Only 6/64 (9.4%) had a positive DTH (>10 mm) at baseline, including three METS, all of whom progressed within 4 months and died within a year, and three who are still NED after more than 5 years. Conversion of DTH from negative to positive was documented in 18/44 (41%) patients who were tested at week 0 and 4. At a median follow up of greater than 5 years, the median overall survival (OS) was 40 months for "NED" with a 5-year survival rate of 39%, and 8.6 months with a 5-year survival rate of 10% for "METS" The 18 patients who had conversion of their DTH had a median event-free survival (EFS) of 15.8 months and 5-year EFS of 32% compared to 4.2 months and 9% for the 26 non-converters (P=0.012, two-tailed, log-rank test). Among patients who were NED when treatment started, the 12 patients whose DTH converted had a median overall survival of 61.4 months with 5-year survival of 63% compared to 9.7 months and 0% for the 13 non-converters (P=0.0026). This treatment approach is feasible, produces minimal toxicity, and is associated with long-term survival in a significant subset of patients.

Factors in older cadaveric organ donors impacting on renal allograft outcome.

Transplantation of renal allografts (RA) from older donors has become more common, despite conflicting data on outcome between reports from large series versus individual centres. Factors other than donor age per se may contribute to RA outcome. The outcome of RA procured from 114 older donors over 55 yr of age in NSW, between 1990 and 1997, was analysed. Corresponding donor factors, including demographics, medical history, inotrope use, major hypotension and findings at procurement, were also analysed. Of the potential RA, 8% were discarded and the remainder transplanted. Factors significantly associated with renal discard were pre-transplantation donation biopsy abnormality (p < 0.001) and a history of cardiovascular (CV) disease in the donor (p < 0.02). Donor aortorenal atherosclerosis (AS; p < 0.09) and a donor age of 65 yr or older (p < 0.08) were common in the discard group. The never function rate was 7.6% and was associated with a history of a discarded partner kidney (p < 0.05). The delayed graft function rate was 33% and was associated with a history of donor CV disease. At a median follow up of 5 yr, the death censored allograft failure rate was 24%. Allograft failure was associated with a history of donor hypertension (p < 0.05). Donor AS (p < 0.7) tended to have been more common in the allograft failure group. A number of cadaveric organ donor factors documented at procurement may be associated with inferior outcome of RA. These include biopsy abnormality, history of donor CV disease and history of donor hypertension. A donor age of 65 yr or older or significant visible aortorenal AS may also be factors. This retrospective review of kidneys procured from 114 older cadaveric organ donors identifies factors apart from donor age, which may have a negative impact on both allograft utilisation and outcome. Theses factors include renal biopsy abnormality, history of donor CV disease, discard of a partner kidney and donor hypertension. Visible AS in the donor aorta documented at renal procurement may also be a factor.

Minority cancer patients and their providers: pain management attitudes and practice.

BACKGROUND: The goals of the current studies were: 1) to determine the pain treatment needs of socioeconomically disadvantaged African-American and Hispanic patients with recurrent or metastatic cancer and 2) to assess the attitudes of health care professionals who treat them. METHODS: In the first study 108 African-American and Hispanic patients with metastatic or recurrent cancer and pain completed a survey about their pain intensity, pain interference, and attitudes toward analgesic medications. Physicians also rated their patients' pain and the adequacy of the patients' current analgesic prescriptions was assessed. In the second study 55 physicians and nurses who treat these patients completed a questionnaire regarding cancer pain and its management in their practice settings. RESULTS: Approximately 28% of the Hispanic and 31% of the African-American patients received analgesics of insufficient strength to manage their pain. Although the majority of patients received appropriate analgesics, 65% reported severe pain. Physicians underestimated pain severity for 64% of the Hispanic and 74% of the African-American patients. Physicians were more likely to underestimate the pain severity of female patients than male patients. Inadequate pain assessment, patient reluctance to report pain, and lack of staff time were perceived as barriers to pain management. CONCLUSIONS: Although the data suggest recent improvements in analgesic prescribing practices for African-American and Hispanic cancer patients, the majority of patients reported high levels of pain and limited pain relief from analgesic medications. Inadequate pain assessment remains a major barrier to optimal cancer pain treatment.

Dentists at high risk for hearing loss: protection with custom earplugs.

This article provides information on the effects of noise, especially to dentists. It gives information on how to protect one's hearing and furnishes a technique to fabricate custom earplugs.

Clinical experience with autologous tumor cell lines for patient-specific vaccine therapy in metastatic melanoma.

Because of their patient specificity and proliferative capacity, tumor cell lines established from autologous metastatic melanoma tumor samples may be an excellent immunogen for patient-specific vaccine therapy. Between October 1990 and July 1996, the Hoag Cancer Center cell biology laboratory received 136 fresh metastatic melanoma samples from 122 different patients. Tumor cell lines were successfully established for 92 of 136 samples (68%), for 87 of 122 patients (71%). Successful cultures were expanded to 10(8) cells (total culture time about 8 weeks), confirmed to be sterile, irradiated, and stored frozen in aliquots of 10(7) cells. Vaccines were prepared from 72 lines, and 62 vaccines were used in 57 different patients. Subcutaneous vaccination took place on weeks 1, 2 and 3, and then monthly for a total of 6 months. A delayed tumor hypersensitivity skin test (DTH) was administered at week zero and week 4. Various adjuvants were co-administered including BCG, alpha- or gamma-interferon, and GM-CSF. Patients were monitored for failure-free survival (FFS) and overall survival (OS) from the date of the first vaccination. Follow-up data is available for 52 patients, 27 who had no evident disease (NED) at the time of vaccination and 25 who had metastatic disease at the time of treatment. There were two partial responses which persisted 11.9 and 39.8+ months among the 25 patients who had detectable metastatic disease whün treatment was initiated (8%, 1 to 26%, 95%-Ci). Twenty patients had negative skin tests at week 0 and week 4; six were positive both times, and 13 converted their DTH from negative to positive, for a conversion rate of 13 of 33 (39%). Patients who received interferon-gamma and/or GM-CSF as an adjuvant had a higher rate of DTH conversion compared to patients who received other adjuvants (13 of 20 v 2 of 13, P = 0.003). For patients who were NED, nine of 19 (47%) converted their DTH test compared to four of 14 (29%) patients with metastatic disease (p = 0.33). For patients whose DTH converted from negative to positive after 3 weeks of vaccination, median FFS and OS were superior compared to patients whose DTH remained negative (19.4 v 4.0 months FFS, p = 0.0052 and 39.6 v 18.3 months OS, p = 0.0602). The autologous cell line approach to active specific immunotherapy is feasible for patients who have resectable foci of metastatic disease. Administration of such patient-specific vaccines improves survival for those patients who are NED at the time of vaccination and convert their DTH skin test, compared to those whose DTH test remains negative.

Voices from an Afghan community.

A major role of the community health nurse is advocating to meet the needs of population groups. This article describes how community health nurses utilized two assessment tools, a windshield survey, a semi-structured interview protocol, and the Healthy People 2000 National Health Objectives to collect pertinent information and recommend program strategies at the primary, secondary and tertiary prevention levels to reduce the prevalence of domestic violence in an Afghan community.

High-dose chemotherapy with autologous stem cell rescue in breast cancer.

BACKGROUND: Because metastatic breast cancer is a lethal disease despite some responsiveness to systemic chemotherapy, high-dose chemotherapy with autologous stem cell rescue is being utilized with increasing frequency. This analysis was undertaken to determine the outcome for such patients treated with intensive chemotherapy between 1989-1994, at the Hoag Cancer Center in Newport Beach, CA. METHODS: During 1989, only patients with metastatic disease who had failed more than two standard breast cancer chemotherapy regimens were considered eligible for such treatment. They received high-dose BCNU/cyclophosphamide/cisplatinum chemotherapy with autologous bone marrow rescue. After January 1990, patients with metastatic disease were eligible only if they had received limited prior chemotherapy and demonstrated responsiveness to induction chemotherapy. Beginning June 1990, patients with metastatic disease were to receive mitoxantrone and thiotepa (MiTepa) followed by peripheral blood stem cell rescue, then ifosfamide, carboplatin and etoposide (ICE) chemotherapy followed by peripheral blood stem cell rescue. High-risk adjuvant patients were to receive one course of ICE followed by rescue. RESULTS: Between 1/89-12/94, 48 breast cancer patients underwent 65 intensive chemotherapy treatments followed by autologous stem cell rescue. During 1989, three of the eight patients with metastatic disease died within 60 days because of therapy-related complications. The longest failure-free survival (FFS) of these eight was 12.2 months, and the longest overall survival (OS) 20.5 months. Since 1/90, one physician has treated 24 patients with metastatic breast cancer, 17 of whom actually underwent two successive transplants with MiTepa/ICE. For the latter group, median FFS is 23.2 months; median OS is 39.7 months. There were no acute deaths, but two patients died > 60 days after initial transplant from therapy-related complications, veno-occlusive disease (5.2 months) and myelodysplastic syndrome (30.5 months), while five died of progressive disease at 22.5, 32.8, 39.4, 46.3, and 51.3 months. For the 24 metastatic patients treated 1990-1994, 1-, 2-, and 3-year FFS rates are 86%, 40%, and 17%, respectively, while OS rates are 91%, 80%, and 65%. Of 11 patients treated in the adjuvant setting, only one has relapsed (9.8 months) with follow-up from 3-61 months. CONCLUSIONS: Modifications made in the program, including selection of patients responsive to induction chemotherapy, transfusion of peripheral blood stem cells, implementation of hematopoietic colony stimulating factors, and use of tandem intensive treatments has been associated with a low rate of acute morbidity and encouraging survival rates.

Etiology and severity of community acquired pneumonia in children from Uruguay: a 4-year study.

The 4-year study (1987-1990) covered the major clinical-epidemiological characteristics of pneumonia in children as diagnosed at the emergency service of the Children's Hospital, as well as etiologies, and factors involved in the most severe cases. Etiology was determined in 47.7% of the 541 pneumonia cases, involving 283 pathogens of which 38.6% were viruses and 12.6% bacteria. Viral and mixed etiologies were more frequent in children under 12 months of age. Bacteria predominated in ages between 6 and 23 months. Among the viruses, respiratory syncytial virus predominated (66%). The bacterial pneumonias accounted for 12.2% of the recognized etiologies. The most important bacterial agents were S. pneumoniae (64%) and H. influenzae (19%). H. influenzae and mixed infections had a relevant participation during the 1988 season, pointing to annual variations in the relative participation of pathogens and its possible implication in severity of diseases. Correlation of severity and increased percentage of etiological diagnosis was assessed: patients with respiratory rates over 70 rpm, or pleural effusion and/or extensive pulmonary parenchyma compromise yielded higher positive laboratory results. Various individual and family risk factors were recognized when comparing pneumonia children with healthy controls.

Uptake of the noncytotoxic transport probe procainamide in the Chinese hamster ovary model of multidrug resistance.

Many of the cytotoxic substrates of the multidrug transporter are organic cations. Cimetidine, procainamide, and tetraethylammonium bromide were used in a Chinese hamster ovary model of multidrug resistance, to study handling of noncytotoxic cationic transport probes. Cimetidine and procainamide, but not tetraethylammonium, accumulated to a greater extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the resistant CHRC5 (C5) cell line. Accumulation of both cimetidine and procainamide was significantly increased by verapamil in C5 but not AB. Procainamide accumulation in both AB and C5 was temperature dependent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, tamoxifen, rhodamine, and ethidium also increased procainamide accumulation in C5 but not AB. Azide in glucose-free medium increased procainamide accumulation in C5, and this was reversed when glucose, but not 3-O-methylglucose, was added. Procainamide efflux rates were similar in AB and C5 and not affected by verapamil or azide. The initial rate of procainamide uptake was higher in AB than in C5, and both verapamil and azide increased the initial rate of procainamide uptake in C5. Thus, differences in accumulation of the noncytotoxic transport probe procainamide in the colchicine-sensitive and colchicine-resistant components of the Chinese hamster ovary cell line mimic the accumulation of known cytotoxic substrates for the multidrug transporter, such as colchicine, vinblastine, and doxorubicin. The differential accumulation of procainamide is due to differences in rates of drug influx, rather than efflux. Since procainamide influx is passive and decreased accumulation in the resistant line appears to parallel M(r) 170,000 glycoprotein presence and activity, we would speculate that decreased procainamide accumulation may be due to an indirect effect of the M(r) 170,000 glycoprotein, such as its effect on intracellular pH.

Microbial agents associated with pneumonia in children from Uruguay.

The etiology of severe pneumonia, not frequently encountered in a community-based study, was determined in 204 hospitalized children less than 5 years of age. Potential pathogens were identified in 41% of episodes. Viruses were isolated or antigen was detected in 36.3% of cases; 82.4% of these cases were due to respiratory syncytial virus. Bacteria or bacterial antigens were identified in 13.2% of cases; Streptococcus pneumoniae and Haemophilus influenzae were the most frequently identified bacterial pathogens isolated from blood and/or pleural effusions. Mixed infections were identified in 4.9% of the episodes. Among the 17 patients with pleural effusion whose pleural space was drained, the etiology was suggested for 10 (58.8%). A clear-cut seasonal variation was seen, with the highest prevalence between May and October. Viral infections were more common in the first 6 months of life, although viral and bacterial infections were distributed throughout the first 5 years of life.

Organic cation uptake by a cultured renal epithelium.

Several organic cations are actively transported by proximal renal tubules by mediated processes across both the apical and basolateral cell membranes. In order to evaluate this transport system in a cultured renal epithelium, uptake of 3H-tetraethylammonium (TEA) across the apical membrane was measured in LLCPK1 cells, a cell line with several characteristics of proximal tubules. 3H-TEA progressively entered these cells and reached a near-steady state by 30 min. Three-minute uptake was saturable with an apparent Vmax of 1,669 +/- 129 fmoles/micrograms DNA and apparent Km of 34.0 +/- 3.4 microM. 3H-TEA uptake was inhibited by an excess of nonradioactive TEA, other organic cations, sodium azide, and hypothermia. An alkaline external pH was associated with greater 3H-TEA uptake than an acid pH. However, efflux of 3H-TEA from cells was not appreciably affected by changes in external pH. Preincubation of cells in acid or alkaline media did not affect uptake. Alteration of cell pH by ammonium chloride addition or removal had little effect on 3H-TEA uptake. Finally, uptake of 3H-TEA was not accelerated by preloading cells with an excess of nonradioactive TEA. These results indicate that intact LLCPK1 cells possess a mechanism(s) in their apical membranes for the mediated transport of a prototypic organic cation. The mechanism(s) involved in this transport is uncertain. However, neither organic cation/proton nor organic cation/organic cation exchange appears to be the predominant process.

Feasibility of extended wear lens use in chlorinated swimming pools.

A group of 14 active swimmers was studied to evaluate corneal and conjunctival health immediately after extended wear contact lenses were worn in a chlorinated swimming pool. Two different lenses, a high (70%) and a low (38%) water content, were used for each subject in order to compare the corneal response to the high and low water content lenses. No significant difference in corneal and conjunctival response was found between the two lenses. Statistically significant differences were seen in corneal thickness and halo size between swimming with and without contact lenses. Corneal superficial erosion was of greater concern under both the control and test conditions, but this is believed to be due to unforeseen experimental design errors. The frequency of contact lens loss in this study was 3.57%. Hence, the conclusion that the rate of loss of hydrophilic lenses in a swimming situation is not the only concern in regard to lens wear during swimming, but there are other important factors such as lens adherence to the cornea and bacterial contamination of the lenses that need to be studied further.