Value of long-term administration of acyclovir and similar agents for protecting against AIDS-related lymphoma: case-control and historical cohort studies.

Acyclovir or similar agents with activity against Epstein-Barr virus (EBV) theoretically may prevent non-Hodgkin's lymphoma (NHL) in AIDS. A case-control study of 29 patients with AIDS-related NHL and 58 matched control subjects assessed the frequency with which daily acyclovir (>/=800 mg/d) or similar agents were used for > or =1 year. In a historical cohort of 304 patients with AIDS for > or =2 years, the prevalence of NHL was assessed among 3 groups of patients: those who received long-term treatment with high-dose acyclovir (or similar agents) or low-dose or intermittent acyclovir; those treated with ganciclovir/foscarnet for <1 year; and those who had not previously been treated with acyclovir, ganciclovir, or foscarnet. In the case-control study, 22 patients (72.4%) with NHL never received acyclovir or similar drugs versus 19 control subjects (32.8%; P=. 002); 2 patients (6.9%) with NHL received acyclovir (> or =800 mg/d) for > or =1 year versus 27 (46.6%) of control subjects (P=.0001). In the cohort study, 6 (6.8%) of 88 patients who received acyclovir (> or =800 mg/d) for > or =1 year developed NHL versus 15 (15.5%) of 97 patients who received intermittent or lower-dose acyclovir and 30 (25.2%) of 119 patients who never received these agents (P=.002). Long-term administration (>1 year) of high-dose acyclovir or similar agents with anti-EBV activity may prevent NHL in patients with AIDS. A prospective, randomized study is warranted to confirm these results.

Barriers to cancer pain relief: fear of tolerance and addiction.

The purposes of this study were to (a) test the feasibility of the Cancer Total Quality Pain Management (TQPM) Patient Assessment Tool in a population of oncology inpatient and outpatients; and (b) identify factors associated with poor pain relief. The Cancer TQPM Tool was adapted from the American Pain Society's Quality Assurance Standards on Acute Pain and Cancer Pain and was tested in a convenience sample of 200 patients. The majority of patients reported that the TQPM Tool was easy to understand and to use, providing evidence for the feasibility of the tool. Factors associated with higher pain intensity included the inpatient setting, the presence of metastatic disease, hesitancy in bothering the nurse, and concerns regarding tolerance and addiction. Although there was a strong relationship between concern about addiction and concern about tolerance, fear of tolerance appeared to have a greater effect on pain intensity scores than did fear of addiction. The findings from this study suggest that the Cancer TQPM Patient Assessment Tool can be used effectively in both inpatients and outpatients to determine outcomes and the quality of cancer pain management, as well identify factors associated with poor pain control. Clinical implications include more effective education of patients and caregivers, including equivalent emphasis on tolerance and addiction.

GM-CSF primes and modulates neonatal PMN motility: up-regulation of C3bi (Mo1) expression with alteration in PMN adherence and aggregation.

Neonatal polymorphonuclear leukocytes (PMNs) are deficient in the expression of the adherence protein C3bi (Mo1), and are associated with reduced physiological inflammatory responses. We evaluated the priming and direct stimulating effect of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on newborn PMN expression of C3bi (Mo1), PMN adherence and PMN aggregation. Cord PMNs were incubated with rhGM-CSF (Amgen 4 x 10(7) U/mg) for 0-15 min, and C3bi surface receptor expression measured by immunofluorescence with CD11b, adherence with nylon wool, and aggregation using a Payton aggregometer. RhGM-CSF (15 min) significantly induced Mo1 expression: 250 pM/L 129.4 +/- 5.3% of C (p less than 0.001) 500 pM/L 141.5 +/- 4.1% (p less than 0.001), 1,000 pM/L 150.2 +/- 1.3% (p less than 0.0001). RhGM-CSF (1,000 pM/L x 5 min) followed by A23187 also primed newborn PMNs for increased Mo1 expression 122 +/- 4.5% of C (p less than 0.001). Additionally, rhGM-CSF (10 min) induced significant PMN adherence 50 pM/L 117.9 +/- 8.3% and 100 pM/L 131.5 +/- 5.7% of C (p less than 0.04). RhGM-CSF additionally primed newborn PMNs (100 pM/L) for increased adherence following A23187 (107.9 +/- 0.6% of C), p less than 0.02. Lastly, rhGM-CSF primed newborn PMNs for increased aggregation following FMLP: 100 pM/L, 15 min, 138.1 +/- 14.1%, p less than 0.0001. Co-incubating murine-antihuman GM-CSF AB 100 micrograms/ml neutralized 86.8 +/- 7.0% of newborn PMN Mo1 up-regulation. These studies demonstrate that rhGM-CSF primes and directly stimulates newborn PMNs for increased in vitro expression of Mo1, adherence, and aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphokines: enhancement by granulocyte-macrophage and granulocyte colony-stimulating factors of neonatal myeloid kinetics and functional activation of polymorphonuclear leukocytes.

Colony-stimulating factors, such as the granulocyte-macrophage and the granulocyte colony-stimulating factors (GM-CSF and G-CSF), are glycoproteins with biologic specificity defined by their ability to support proliferation and differentiation of hematopoietic cells of various lineages. Their physiologic activities include stimulation and proliferation of early stem cell precursors and functional activation of mature peripheral effector cells. Recently produced recombinant human (rh) GM-CSF and G-CSF have been demonstrated to regulate hematopoietic neutrophil progenitor colony growth; to stimulate the release of bone marrow neutrophil storage pools; and to prime mature effector functions, including chemotaxis, oxidative metabolism, phagocytosis, C3bi receptor expression, and antibody-dependent cytotoxicity in adults. We examined the effects of rh-GM-CSF on priming superoxide release and chemotaxis of neonatal (cord) polymorphonuclear leukocytes (PMNs) and of rh-G-CSF and rh-GM-CSF on bone marrow neutrophil egress in the neonatal rat. A time-response evaluation of the effect of rh-GM-CSF revealed enhanced release of superoxide by PMNs. PMN chemotaxis also was enhanced by rh-GM-CSF, with a maximal response occurring earlier than enhanced superoxide release. Intraperitoneal administration of rh-G-CSF or rh-GM-CSF to 1-day-old rats resulted in significant increases in white blood cell counts and significant early neutrophilia. Bone marrow examination revealed that the neutrophilia was secondary to egress and mild depletion of the neutrophil storage pool but that the neutrophil storage pool later returned to normal. These preliminary studies suggest that rh-GM-CSF and rh-G-CSF prime neonatal effector function and induces significant PMN egress and neutrophilia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of idarubicin and epirubicin on in vitro polymorphonuclear function: diminished superoxide radical formation compared to their parent compounds daunorubicin and doxorubicin.

Anthracyclines are active against a variety of malignancies. The present study examined the effect of epirubicin and idarubicin on in vitro polymorphonuclear (PMN) function including chemotaxis, aggregation, bacteriocidal activity degranulation, and superoxide generation. We also studied the effects of cyclosporin (100 ng/ml) and verapamil (500 ng/ml), two membrane active biological response modifiers, on their potential role in modulating anthracycline-induced oxygen radical formation in the human PMN. Older anthracyclines (doxorubicin and daunorubicin) did not affect superoxide generation in the human PMN. However, the newer anthracyclines, both epirubicin and idarubicin, profoundly inhibited human superoxide generation (P less than .02) and (P less than .01), respectively. This inhibition was not agonist specific but occurred with multiple agonists including FMLP, PMA, A23187, and Zymosan-activated serum (ZAS). Last, cyclosporin and verapamil did not modulate the anthracycline effects of PMN superoxide generation. This study suggests that two of the newest anthracyclines, epirubicin and idarubicin, inhibit more PMN superoxide radical formation compared to their parent compounds. This reduction in oxyradical formation may account in part for their difference in anthracycline cellular cytotoxic activity.

Recombinant human granulocyte-macrophage colony-stimulating factor primes neonatal granulocytes for enhanced oxidative metabolism and chemotaxis.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) induces proliferation and differentiation of hematopoietic stem cells. Additionally, rhGM-CSF enhances the physiologic responses of adult polymorphonuclear leukocytes (PMN) especially with respect to oxidative metabolism and chemotaxis. Neonatal PMN are deficient in chemotaxis and have been demonstrated to have reduced oxidative responses in times of stress. We evaluated the priming effects of rhGM-CSF (1-100 pmol/L) on cord (neonatal) superoxide production and chemotaxis. Cord and adult PMN were incubated with 100 pmol/L rhGM-CSF (Amgen, 4 x 10(7) U/mg) for 0-120 min and stimulated with N-formyl-l-methionyl-l-leucyl-phenylalanine. RhGM-CSF enhanced O2- production at all time periods with maximal priming at 60 min (147.97 +/- 11.14% p less than or equal to 0.006) with less, but significant enhancement at 120 min (116.53 +/- 7.92% p less than or equal to 0.05). Maximal adult PMN O2- release occurred at 120 min (190.02 +/- 8.71% p less than or equal to 0.003) and was more pronounced than cord PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and laboratory experience in marrow harvesting in children for autologous bone marrow transplantation.

The laboratory and clinical experience of a single institution of 75 consecutive children undergoing bone marrow harvesting, 65 for subsequent autologous reinfusion and 10 for allogeneic infusion, was analysed and compared in detail with the adult literature. The median age was 9.3 years (range 6 months-20 years) with equal distribution between all childhood age groups. The median volume of marrow harvested was 15.94 ml/kg (range 4.94-27.7 ml/kg) and there was no significant difference within each age group. Fifty percent of autologous marrows (32/65) required Ficoll-Hypaque density separation and the other 50% (33/65) were separated by using the Cobe 2991 cell separator. Allogeneic harvests yielded 5.1 x 10(8) cells/kg vs 2.4 x 10(8) cells/kg for autologous harvests. Only 48% of children required red cell transfusions following this procedure (average volume 9.36 ml/kg). There were no episodes of postoperative fever or infection. There was only one episode of life-threatening morbidity (1.3%), a pulmonary embolus related to venous stasis from tumor obstruction. Lastly, the average time to engraftment following autologous reinfusion (n = 10) (neutrophils greater than or equal to greater than or equal to 500 x 10(6)/l for 2 days) was 19.8 +/- 5.3 (SD) days and time to platelet recovery (greater than or equal to 20 x 10(8)/l without transfusions) was 25.6 +/- 5.8 days. This study suggests that bone marrow harvesting in a large cohort of children with an active pediatric malignancy for a future autologous bone marrow transplantation is a safe and reliable procedure with a low incidence of serious morbidity.

Lymphokine-activated killer cytotoxicity in neonatal mononuclear cells: in vitro responses to tumor cell lines from pediatric solid tumors.

The presence of neonatal (cord) lymphokine-activated killer (LAK) cell activity toward natural killer cell resistant Raji and Daudi cell lines has recently been reported from our laboratory. We investigated the future therapeutic use of LAK adoptive immunotherapy by examining LAK in vitro cytotoxicity from both neonatal and adult mononuclear cells against solid tumor cell lines of relevance to pediatric oncology: SH-SY5Y (neuroblastoma), SK-NM-C (neuroblastoma-neuroepithelioma), NEP-1 (Wilms' tumor), SK-ES-1 (Ewing's sarcoma), and A-204 (rhabdomyosarcoma). Cord and adult mononuclear cells were activated by recombinant IL-2 (100 mu/ml) for 5-7 days and added in an effector:target ratio of 40:1 to 51Cr-labeled target cells. Specific cell lysis was determined after a 4-h incubation. There was a significantly high level of cord and adult LAK cytotoxicity against Wilms' (76.4 +/- 9.8 versus 77.3 +/- 6.8%) and Ewing's (84.2 +/- 5.5 versus 71.1 +/- 6.5%) cell lines and significant but moderate LAK activity against neuroepithelioma (52.0 +/- 6.6 versus 55.4 +/- 4.5%) and rhabdomyosarcoma (46.6 +/- 5.7 versus 43.9 +/- 5.2%) cell lines. There was no difference between cord and adult LAK activity toward these targets. However, a differential response toward the more classical neuroblastoma cell line, SH-SY5Y, was noted with significantly more LAK cytotoxicity from cord mononuclear cells than adult mononuclear cells (51.2 +/- 6.9 versus 28.5 +/- 8.2%) (p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Fluorescent cytometric analysis of polymorphonuclear leukocytes in Chediak-Higashi syndrome: diminished C3bi receptor expression (OKM1) with normal granular cell density.

Chediak-Higashi Syndrome (CHS) has been associated with recurrent bacterial infections and defective polymorphonuclear (PMN) leukocyte function. Confirmation of the diagnosis of CHS and defective PMN function was established in a 2-month-old with accelerated phase CHS. The diagnosis was confirmed by demonstrating reduced PMN degranulation (beta-glucuronidase release 34.1 +/- 0.9% versus 5.1 +/- 4% and lysozyme release 17.6 +/- 1.2% versus 11.1 +/- 7% (control versus CHS) and staphylococcal bacterial killing at 15' 51.4 +/- 3.6% versus 24.9 +/- .4% (control versus CHS). Additional studies using fluorescent cytometric analysis were made to investigate other etiologies of PMN dysfunction in CHS. Total cell density and PMN granularity, as measured by fluorescent-activated cell sorter side scatter analysis, was no different from CHS and age-matched controls. Although CHS is characterized by large PMN granular inclusions, right angle light scatter analysis in this study suggests that the total cell density within the PMN of patients with CHS is normal (D less than .01). PMN granular release of surface receptors was also studied using antibody binding and fluorescent analysis. OKM1 antibody-binding demonstrated significantly reduced C3bi (MO-1) receptor expression (13% of control) p less than 0.001. Decreased surface reception expression of C3bi receptors may play an additional role in defective PMN mobility, chemotaxis, and bactericidal activity in patients with CHS.

Impaired neutrophil function in patients with AIDS or AIDS-related complex: a comprehensive evaluation.

We measured the neutrophil function of 6 patients with AIDS and Kaposi's sarcoma (KS); 22 patients with AIDS-related complex (ARC); and 28 healthy, heterosexual controls. Neutrophils from patients with ARC showed significantly less chemotaxis (P less than or equal to .025) than did those from patients with AIDS and KS or from controls. Serum from patients with AIDS and KS or with ARC significantly (P less than or equal to .05) inhibited chemotaxis of neutrophils from controls; heat treatment of the serum abolished this inhibitory effect. Bacterial killing by neutrophils from patients with AIDS and KS or with ARC was also significantly (P less than or equal to .05) less than for neutrophils from controls, as was neutrophil phagocytosis binding of Candida albicans (P less than or equal to .05). Expression of OKM1 antigen was increased in the patients studied. Enzyme degranulation, adherence, and aggregation were also examined. The defects found in neutrophil function are selective and may be important in the increased susceptibility of patients with human immunodeficiency virus infection to bacterial and fungal infections.

Therapy of genital herpes with topically applied interferon.

Ninety-four patients with recurrences of genital herpes were randomized in a double-blind trial to receive topical therapy for 5 days with either alpha-2a interferon at 30 X 10(6) IU/ml or 10 X 10(6) IU/ml or placebo six times daily. No differences were noted between either interferon dose and placebo with respect to the duration of viral shedding, the time to crusting, or the time to healing of herpetic lesions. Aqueous solutions of alpha-2a interferon applied topically to unroofed vesicles do not appear to be clinically useful in the treatment of recurrences of genital herpes.

Interferon in the prevention of genital herpes recurrence.

Patients with genital herpes were treated three times weekly for 12 weeks with 3 X 10(6) IU of alpha 2b interferon (20 patients) or placebo (17 patients) administered by subcutaneous injection in a double-blind trial. Interferon had minimal effects on the suppression of recurrences and moderate toxicity (chills, fever, fatigue, and leukopenia), suggesting that this route and dosage of interferon may not be clinically useful for this indication.