Current trends in multiple myeloma management.

Treatment of multiple myeloma, a B-cell cancer, is usually palliative, however, as a result of intensive clinical research there are numerous new treatment options available today. The present review summarizes non-transplant treatment options for multiple myeloma on the basis of available publications. Treatment with new substances, such as immunomodulatory agents, farnesyl transferase inhibitors and apoptosis stimulators, and their mechanisms of action are discussed. In addition to this systematic review of the available evidence on multiple myeloma therapy we have also summarized current recommendations from national and international organizations on aspects of the treatment of multiple myeloma. This should enable readers to see different points of view at a glance and, hopefully, will provide a basis for translation of the available evidence into the best possible therapy.

Repetitive ozone exposure of young adults: evidence of persistent small airway dysfunction.

Earlier, we found that acute ozone (O3) exposure caused, along with inflammation, greater, more protracted changes in small airway function (isovolumetric V max at intermediate to low lung volumes) than in FVC or FEV1. To test if this distinction prevailed with repetitive O3 exposure, we exposed eight healthy adults on four consecutive days alternatively to filtered air (FA) and O3 (0.25 ppm x 2 h). Isovolumetric FEF25-75, Vmax50, and Vmax75, were grouped into a single value representing small airway function (SAW(grp)); respiratory frequency (f) and tidal volume (VT) were monitored during exercise. On Day 5, peripheral airway resistance (Rp) was measured followed by lavage. All daily spirometric and ventilatory changes declined in magnitude (adapted) after one or more days of O3 exposure. In addition, SAW(grp), f, and VT showed persistent changes beginning with Day 2, denoted either by depression of the preexposure baseline (SAW(grp)) or exaggerated tachypnea during exercise. O3-induced neutrophilia (p = 0.04) was present in lavage fluid. The possible relationship between these persistent changes in small airway function, measured in days, and the likelihood of cumulative injury in the same region if exposure is long term, is unknown.

[Improved results in the treatment of acute myeloid leukemia - Results of study AML-BFM-93 in East Germany with comparisons to the preceding studies AML-I-82 and AML-II-87]. / Verbesserte Ergebnisse in der Therapie der akuten myeloischen Leukämie - Ergebnisse der Therapiestudie AML-BFM-93 in den neuen Bundesländern im Vergleich mit den Vorgängerstudien AML-I/82 und AML-II/87 der DDR.

BACKGROUND: Three multicenter studies were conducted in East Germany on the treatment of acute myeloid leukaemia in children. The latest of the three studies (AML-BFM-93-OST) was part of the common German study AML-BFM-93. PATIENTS AND METHODS: The total number of registered patients was 262. The number and dosage of administered chemotherapeutic agents was elevated with each new study. RESULTS: Both the remission rate (85 %) and the likelihood of an event free survival (52 % after 5 years) could be improved significantly in study AML-BFM-93-OST. The results of the common German study AML-BFM-93 were identical to those of the East German part AML-BFM-93-OST. Compared with international studies it was one of the most successful treatment strategies in children with AML. Patients who showed toxic side effects to heart, liver, kidneys, skin or nervous system during the chemotherapy had a significantly lower risk of relapse, once they overcame the intensive therapy. During the five years of study AML-BFM-93-OST, treatment results could be improved despite an unchanged therapy strategy. This may partly be due to the modernisations and restorations that were carried out in many East German hospitals in this time. CONCLUSIONS: The therapy regimen of study AML-BFM-93 allowed a substantial improvement in the treatment of children with AML. Further intensification of chemotherapy should only be undertaken in accordance to the individual sensitivity of each patient.

Pulmonary artery catheterization and clinical outcomes: National Heart, Lung, and Blood Institute and Food and Drug Administration Workshop Report. Consensus Statement.

OBJECTIVE: The efficacy and safety of the pulmonary artery catheter are under scrutiny because of its association with increased morbidity and mortality in observational studies. In response, the National Heart, Lung, and Blood Institute (NHLBI) and the US Food and Drug Administration (FDA) conducted the Pulmonary Artery Catheterization and Clinical Outcomes workshop in Alexandria, Va, on August 25 and 26, 1997, to develop recommendations regarding actions to improve pulmonary artery catheter utility and safety. PARTICIPANTS: The NHLBI and FDA planning task force selected a workshop chairperson, subcommittee chairs, and participants. Approximately 85 participants were selected for their collective expertise in critical care, pulmonary medicine, cardiovascular medicine and surgery, pediatrics, nursing, biostatistics, and medical economics. The meeting was open to industry representatives and other government and lay observers. This workshop was funded by the NHLBI and the FDA's Division of Devices. EVIDENCE: Published reports relating to the efficacy and safety of the pulmonary artery catheter, especially consensus documents developed by professional societies. CONSENSUS PROCESS: The planning task force disseminated materials, held teleconferences, and developed draft position papers prior to the workshop. These were modified during the workshop and thereafter in the course of several teleconferences, and presented to the entire group for final modifications and approval. CONCLUSIONS: A need exists for collaborative education of physicians and nurses in performing, obtaining, and interpreting information from the use of pulmonary artery catheters. This effort should be led by professional societies, in collaboration with federal agencies, with the purpose of developing and disseminating standardized educational programs. Areas given high priority for clinical trials were pulmonary artery catheter use in persistent/refractory congestive heart failure, acute respiratory distress syndrome, severe sepsis and septic shock, and low-risk coronary artery bypass graft surgery. JAMA. 2000;283:2568-2572

Race and gender differences in the effects of smoking on lung function.

STUDY OBJECTIVE: To assess the extent to which the relationship between smoking and lung function in adults varies by gender and race/ethnicity. DESIGN: A random-effects metaregression analysis to synthesize results from common cross-sectional regression models fit to participants in each of 10 gender-race strata in each of eight large population-based observational studies or clinical trials. SETTING: Source data collected as part of the most recently completed examination cycle for each of the participating studies. PARTICIPANTS: Participants ranged in age from 30 to 85 years, although the age, race, gender, and general health characteristics of each of the populations varied greatly. INTERVENTIONS: Most of the studies were observational in nature, although some did involve lifestyle interventions. All treatment assignments were ignored in the analysis. MEASUREMENTS AND RESULTS: All studies measured lung function using standardized methods with centrally trained and certified technicians. Study findings confirm statistically significant, dose-related smoking effects in all race-gender groups studied. Significant gender differences in the effects of cigarette smoking were seen only for blacks; black men who smoked had greater smoking-related declines in FEV(1) than did black women. This effect was present in only one of two smoking models, however. Significant racial differences in the effects of smoking were seen only for men, with Asian/Pacific Islanders having smaller smoking-related declines than white men in both models. CONCLUSIONS: In summary, this analysis generally failed to support the hypothesis of widespread differences in the effects of cigarette smoking on lung function between gender or racial subgroups.

Pulmonary function testing in population-based studies.

A wealth of information on pulmonary function is currently available in NHLBI-sponsored, population-based studies. These data can be used to address critically important questions in pulmonary and cardiovascular disease research, but their potential cannot be realized without the active collaboration of pulmonary- and cardiovascular-disease researchers. Investigators interested in analyzing these data in collaboration with the parent study investigators are invited to contact these investigators directly (see APPENDIX). Results of analyses recommended in the workshop should be used to identify hypotheses for future efforts in collecting data on the epidemiology of pulmonary diseases and their relationship to cardiovascular disease.

An update on air pollution.

Air pollution is associated with adverse health effects. Much of the recent literature, which is the focus of this review, has concentrated on identifying individuals at risk and on the health effects of mixed pollutants. For indoor air, new analyses continue to support the notion that the risk of residential radon exposure is low and that environmental tobacco smoke may cause respiratory symptoms and dysfunction in adults, especially asthmatic adults, as well as in children. For outdoor air, the long-term effects of ozone exposure remain unclear, despite evidence of inflammation and small airway dysfunction after acute exposure. Ozone may increase the sensitivity of asthmatic patients to allergens. Increased morbidity in association with increasing particulate matter levels gives coherence to the argument that the relationship between particulate matter and mortality is causal. However, other investigators note the tight associations among outdoor pollutants and consider particulate matter a marker of air pollution levels.

A method for assessing small airways independent of inspiratory capacity.

Reduced forced vital capacity may confound assessment of small-airway function. In 17 healthy and 16 asthmatic volunteers, we validated a method for measuring mean expiratory flow during the middle half of the forced vital capacity, mean expiratory flow during the third quarter of the forced vital capacity, instantaneous forced expiratory flow at 50% of forced vital capacity , and instantaneous expiratory flow at 75% of forced vital capacity. These measurements were conducted at the same absolute lung volume (isovolume) when forced vital capacity was reduced voluntarily to 100%, 85%, and 75% of maximum, and the variances, expressed as the coefficients of variations, were compared. Absolute lung volumes above residual volume were determined with two reference spirograms: 100% and 75% forced vital capacity. In normals, means of flow rates at the same absolute lung volume did not differ with the three forced vital capacities, regardless of whether the 100% or 75% forced vital capacity served as the reference spirogram. Reduced forced vital capacity among asthmatics was associated with modest increases in isovolume flow rates, an effect that may underestimate airway narrowing. Intrasubject variability was least among volume-averaged flow rates (e.g., mean expiratory flow during the middle half of the forced vital capacity). Volume-adjusted flow rates can be used to assess small-airways narrowing when forced vital capacity is reduced, and volume-averaged rates provide the least variability.

Ozone exposure in humans: inflammatory, small and peripheral airway responses.

We exposed eight normal adults to filtered air (FA) and 0.35 ppm ozone (O3) and compared responses in spirometry, including isovolume (isoV) flows at intermediate-to-low lung volumes, against levels of inflammatory markers in bronchoalveolar lavage fluid (BALF) and peripheral lung resistance (Rp) measured through a wedged bronchoscope. Spirometry was performed at the end, 25 min and 24 h after exposure, bronchoscopy at 24 h after exposure. The percentages of neutrophils, fibrinogen, albumin, PGE2, PGF2 alpha, and kinins were elevated in BALF after O3 compared with FA. The percentage reduction in (isoV) FEF25-75 at 25 min and 24 h after administration of O3 correlated closely with the rise in fibrinogen concentrations in BALF, a marker of altered vascular permeability. Rp, a measurement dominated by very small or peripheral airways, was unaffected in 7 of 8 subjects. The absence of change in Rp might have reflected insufficient penetration of O3 into these airways to produce or sustain an effect for 24 h; alternatively, the bronchoscopic procedure which included atropine and lidocaine pretreatment may have reversed an O3 effect. An unexpected finding was the significant association between baseline Rp (after FA) and the magnitude of the spirometric response to O3. Our results suggest that small airway dysfunction in the immediate post-O3 period is a marker of lung inflammation.

Evidence for ozone-induced small-airway dysfunction: lack of menstrual-cycle and gender effects.

Recently, we analyzed FEF25-75 isovolumetrically to assess the acute effects of ozone (O3) on small-airway function: the reduction in isovolumetric (isoV) FEF25-75 at end exposure progressed during the next 25 min even as FVC was recovering. To evaluate this effect over a longer period, we measured isovolumetric FEFs, helium-oxygen (He-O2) volume of isoflow (VisoV), the multiple breath nitrogen washout (MBNW) curve, FRC, and RV in 24 subjects 24 h after a 130-min exposure to filtered air (FA) and O3 (0.35 ppm). Men and women were studied to test for gender-based differences in response, after first determining that menstrual-cycle phase did not itself influence response. Isovolumetric FEF25-75, Vmax50, and Vmax75 were reduced about equally at 25 min after O3 exposure (p < or = 0.02) and showed no recovery at 24 h. FVC and FEV1, although still depressed after 24 h (p < 0.05), showed substantial recovery (p < 0.01). FRC, RV, and VisoV showed no effect of O3 exposure. No gender differences in O3 responsiveness were found. In summary, O3-induced reductions in isovolumetric flow rates, suggestive of small-airway dysfunction, may persist for 24 h following acute exposure to O3, a time-course consistent with inflammation.

Response to acute ozone exposure in healthy men. Results of a screening procedure.

We screened 64 healthy, nonsmoking men, 18 to 35 yr old, for their sensitivity to 0.35 ppm ozone (O3) administered for 130 to 150 min with intermittent exercise. The changes in FVC, FEV1, AND FEF25-75 (p < 0.0001) immediately after O3 exposure varied widely among subjects. Histograms of the percentage changes in FVC and FEV1 did not differ from a unimodal, skewed (gamma) distribution (p = 0.99 and p = 0.17, respectively); the changes in FEF25-75 tended to deviate from a gamma distribution (p = 0.055). To adjust FEF25-75 for the confounding effects of O3 on FVC, we used multiple linear regression analysis with contemporaneous FVC as a covariable, analysis of a subgroup of nine subjects whose O3-induced FVC changes were < or = 5%, and volume correction of FEF25-75 for any changes in FVC after exposure. These analyses showed reductions in FEF25-75 unexplained by and following a different time course than the O3-induced changes in FVC. In 26 subjects also exposed to filtered air, significant effects of O3 on respiratory frequency (p < 0.004) and tidal volume (p < 0.0007) correlated weakly with FVC changes. The results confirm the wide variability in spirometric responsiveness among individuals to O3 and suggest that intrinsic narrowing of the small airways may be a significant component of the functional response.

Health effects and exposure assessment of aerosolized pentamidine handlers.

Nurses administering aerosolized pentamidine (AP) were studied to determine any effect AP may be having on their health. Exposure was determined by each nurse's self-report of treatment given as recorded in a daily log and personal and area pentamidine sampling. Outcome measures were self-reported symptoms recorded in a daily log and peak expiratory flow rates (PEFR) and cross-shift and cross-week pulmonary function tests (PFTs). Results revealed no dose-response effect of pentamidine exposure on cross-shift and cross-week PFTs. However, declines in cross-shift PEFRs, diffusion capacities, and increased symptom complaints were observed for a subset of the study population. This suggested that outcomes were modulated by host factors (history of hay fever and allergy) as well as exposure doses. Treatment both efficacy in containing fugitive AP aerosol was also corroborated as a means of minimizing worker exposure.

Use of collateral airways to assess airway reactivity.

We investigated the correlation between collateral airway reactivity and other indexes of lung reactivity in response to aerosol and intravenous (iv) challenges. In four anesthetized mongrel dogs, we measured the peripheral airway resistance (Rp) to gas flow out of a wedged lung segment in different lobes on multiple occasions. We obtained dose-response curves of peripheral airways challenged with iv histamine or aerosols through the bronchoscope. During the same iv bolus challenge, whole lung airway pressure (Paw) responses to histamine were also measured. On separate occasions, changes in lung resistance (RL) were measured after the whole lung was challenged with a histamine aerosol. Reactivity was assessed from the dose-response curves for Rp and RL as the PD50 (dose required to produce a 50% increase); for changes in Paw we calculated the PD15 (dose required to produce a 15% increase over baseline). Results for Rp showed considerably more variability among different lobes in a given animal with the aerosol challenge through the bronchoscope than with the iv challenge. With aerosol challenge there were no significant differences in the mean PD50 for Rp among any of the animals. However, with the iv challenge two of the dogs showed significant differences from the others in reactivity assessed with Rp (P less than 0.01). Moreover, the differences found in the peripheral airways with iv challenge reflected differences found in whole lung reactivity assessed with either iv challenge (Paw vs. Rp, r2 = 0.96) or whole lung aerosol challenge (RL vs. Rp, r2 = 0.84). We conclude that the measurement of the collateral resistance response to iv challenge may provide a sensitive method for assessing airway reactivity.

Succinylcholine potentiates responses to intravenous acetylcholine in the canine lung periphery.

Using the wedged bronchoscope technique to measure collateral resistance (Rcs), we evaluated the effect of succinylcholine (SCh) on the response to acetylcholine (ACh) and methacholine (MCh) in the lung periphery in six mongrel dogs. Dogs were anesthetized, intubated, and mechanically ventilated. After a stable baseline Rcs was obtained, responses to intravenous ACh (25-200 micrograms), intravenous MCh (3-30 micrograms), and aerosolized ACh (30-100 micrograms/ml for 15 s) were measured. We compared the Rcs responses with 1) ACh alone, 2) ACh 2 min after SCh (0.5 mg/kg), 3) ACh 2 min after SCh and during hexamethonium infusion (5 mg/kg + 10 mg.kg-1.h-1), 4) MCh 2 min after SCh, and 5) ACh aerosol 2 min after SCh. SCh did not significantly alter baseline airway tone. SCh increased the Rcs response to ACh by 48 +/- 17% (SE) (P less than 0.01). SCh in the presence of hexamethonium increased the Rcs response by 10 +/- 3% (P less than 0.05), while hexamethonium itself increased the response to ACh by 69 +/- 27%. Because SCh did not increase the Rcs response to intravenous MCh or to aerosolized ACh, SCh probably enhances airway reactivity to intravenous ACh by competing for pseudocholinesterase in plasma. We conclude that the level of muscle relaxant must be taken into account in interpreting studies of airway reactivity when intravenous ACh is employed.

In vitro tracheal responses from mice chosen for in vivo lung cholinergic sensitivity.

We selected two inbred strains of mice based on their different in vivo lung responses to intravenous acetylcholine for studies on the in vitro tracheal responses to contractile and relaxing agents. In addition, we studied the role of cyclooxygenase products on the in vitro responses. Tracheal rings were contracted with increasing concentrations of carbachol and KCl and relaxed with increasing concentrations of isoproterenol after contraction with carbachol at the concentration that produced 30, 50, and 70% of the maximal contraction (EC30, EC50, and EC70, respectively) and KCl at the EC50. Half the tracheae simultaneously underwent the same protocols after pretreatment with indomethacin (3 X 10(-6) M). Despite a severalfold difference in the maximal response to cholinergic agents in vivo, there were no significant differences between the strains in the tracheal responses to carbachol (P = 0.78) or KCl (P = 0.13) in vitro. Both strains showed inhibition of the isoproterenol relaxation by carbachol (P less than 0.0001). Multiple linear regression analysis showed that the strain that was more sensitive to carbachol in vivo was also more sensitive to isoproterenol in vitro after carbachol contraction (P = 0.014). The greater isoproterenol sensitivity of the tracheae from this strain was not present after contraction with KCl, nor were these tracheae more sensitive to relaxation with sodium nitroprusside. Indomethacin pretreatment of the tissues in vitro augmented the maximal response and the sensitivity to carbachol (P less than 0.001) and KCl (P = 0.0006), and this effect was similar in both strains. Evaluation of isoproterenol relaxation after indomethacin pretreatment was confounded by the lower concentrations of carbachol needed for contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral lung resistance in normal and asthmatic subjects.

In obstructive lung disease, peripheral airways are a major site of pathologic abnormalities. However, resistance to airflow in small airways in the periphery of the lung accounts for only a small fraction of total airway resistance. Consequently, abnormalities of small airway function may not be readily detected using routine pulmonary function testing. In the present study, resistance of the peripheral lung was examined directly in six normal subjects and nine mildly asthmatic subjects. There were no significant differences between the normal and asthmatic groups in pulmonary function assessed by spirometry (FEV1, FVC) and body plethysmography (specific airway conductance). Direct measurements of peripheral lung function were made using a fiberoptic bronchoscope wedged into a subsegmental, right upper lobe bronchus. Using a double-lumen catheter inserted into the instrument channel of the bronchoscope, pressures (PB) produced by three or more different levels of gas flow (V) (5% CO2 in air) between 50 and 500 ml/min were measured. All pressure measurements were made at a constant lung volume (i.e., functional residual capacity) confirmed by monitoring transpulmonary pressure with an esophageal balloon. The pressure-flow relationship in both normal and asthmatic subjects could be approximated by a straight line through the origin, demonstrating these airways to be relatively nondistensible. Peripheral lung resistance (Rp) was defined by PB/V and averaged for three or more levels of flow.(ABSTRACT TRUNCATED AT 250 WORDS)

[Immunologic findings in the newborn infant. II. Studies of humoral immunity, reference values of immunologic studies in the newborn infant]. / Immunologïsche Befunde des Neugeborenen. II. Untersuchungen zur humoralen Immunität, Referenzwerte immunologischer Untersuchungen beim Neugeborenen.

After dealing with cellular immune aspects in the first part of the paper the authors describe in the second part the state of humoral immunity in healthy full-term newborns aged one to three days. The number of complementreceptor lymphocytes was 17.0 +/- 8.9% or 0.75 +/- 0.51 (mean +/- S.D.) respectively, with the EAC-rosette method. The percentage value equalled that of adults but the absolute count is higher. Using the immunodiffusion method IgA was detectable in 4 out of 132 newborns only 8.86 +/- 2.52 g/l (mean +/- S.D.) was measured as an average IgG concentration. With regard to the IgM content the values often exceeded 0.30 g/l in newborns of mothers who had been suffering from pre-eclampsia. Their mean value of 0.35 +/- 0.21 g/l, too, was significantly higher than 0.13 +/- 0.08 in the resting infants. Raised IgM values frequently coincided with high spontaneous transformation activities in lymphocyte cultures. The possible causes are discussed. Complement C3-component was measured on average with 0.78 +/- 0.18 g/l and C4-component with 0.34 +/- 0.11 g/l. When calculating reference values for newborns the results of infants with maternal pre-eclampsia have been omitted.