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PubMed2000

Additivity of the proliferative effects of HGF/SF and EGF on hepatocytes.

The additivity of DNA synthesis induced by hepatocyte growth factor/scatter factor (HGF/SF) and epidermal growth factor (EGF) was revealed in periportal hepatocytes (PPH), perivenous hepatocytes (PVH), and primary hepatocytes. Furthermore, additivity of the signal transduction pathway of HGF/SF and EGF was investigated (i.e., the activity of mitogen-activated protein kinase (MAPK) induced by HGF/SF and EGF), but it was not seen in PPH, PVH, or primary hepatocytes, although wortomannin, a PI 3-kinase inhibitor, abolished the additivity. The additivity of DNA synthesis induced by HGF/SF and EGF was not related to hepatocyte heterogeneity, but to a difference in the signal transduction pathway, probably another pathway that is different from the classical MAPK (MAPK/ERK1,2) path.

Animals↗
PubMed2001

Vesicle Phases with Semipolar Additives.

We examined the influence of semipolar additives on the phase behavior of mixed zwitterionic surfactant/consurfactant systems. It is shown that in these systems with increasing concentration esters like hexylacetate (HA) and ketones like hexylmethylketone (HMK) can behave both like consurfactants and like hydrocarbons. In solutions of 200 mM tetradecyldimethylamineoxide (TDMAO)/cosurfactant the additives cause first a phase transformation from the micellar L(1) phase to a lamellar L(alpha) phase. Upon further increasing concentration, the L(alpha) phase is transformed into a microemulsion. The L(alpha) phase consists of densely packed multilamellar vesicles. The vesicles are shown by electron microscopy. The multilamellar character of the vesicles is also reflected in the conductivity of the phase. It is up to 10 times lower than the conductivity of the L(1) phase. In some systems the vesicles are transformed on rest into a multidomain stacked L(alpha) phase. It is furthermore demonstrated that the two-phase L(1)/L(alpha) region in these systems is very narrow. In situations where enough HA is added to be close to the boundary of the L(1) phase, it is shown that very small amounts of cosurfactant can transform the L(1) phase into the L(alpha) phase. In extreme situations 1 mM cosurfactant is sufficient for transforming the L(1) phase with 200 mM TDMAO into the L(alpha) phase. In the investigated systems the L(alpha) phase is a highly viscoelastic fluid in which the storage modulus is 1 order of magnitude larger than the loss modulus. Besides the conventional way to prepare samples by adding all ingredients and stirring the solution intensively, all investigated systems were additionally prepared without applying any shear forces. In a surfactant/cosurfactant solution the additive was brought into the sample by diffusion. The phase behavior of both types of samples showed fundamental differences in some cases, which give insight into the influence of shear forces on these systems. Copyright 2001 Academic Press.

Journal Article↗
PubMed1998

Effect of additional testosterone on purinergic responses in isolated rabbit corpus cavernosum strips.

Recently, it has been demonstrated that the endothelium of corpus cavernosum (CC) plays an important role on smooth muscle relaxation, which is crucial to initiate and maintain erection. We investigated the effect of long-lasting additional testosterone propionate (TP) therapy on endothelium-dependent and -independent relaxations of isolated rabbit CC. Isolated CC strips were mounted in organ baths and isometric tension was recorded. Addition of a specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginin methyl ester (L-NAME), into the organ bath had no effect on the relaxation responses to adenosine (ADO), adenosine 5'-triphosphate (ATP) and sodium nitroprusside (SNP) in isolated CC strips precontracted with phenylepherine, but completely inhibited relaxation responses produced by ADP. Adenosine and adenine nucleotides relaxed the phenylepherine-induced contractile response in control strips with the potency order: ADO (62.8 +/- 3.2%) > ATP (37.1 +/- 5.2%) > ADP (25.8 +/- 2.5%). The relaxation responses to ADO, ATP and SNP in isolated rabbit CC strips were not significantly altered by additional TP therapy. The relaxation responses produced by ADP were significantly enhanced following 1 and 2 months TP therapy as compared with controls. However, in the group treated with TP for 2 months followed by a 2 months drug-free period, relaxation responses were significantly reduced compared to 1 and 2 months treatment groups, and approached control values. Increased relaxation responses to ADP following 1 and 2 months additional TP therapy may be a result of increased endothelial purinergic receptor density, or it may be due to stimulation and/or release of endothelial nitric oxide (NO) by TP.

Adenosine↗
PubMed2001

Mixture effects of JP-8 additives on the dermal disposition of jet fuel components.

Aliphatic and aromatic components in formulated jet fuels can cause occupational dermatitis. However, the influence of JP-8 performance additives (DIEGME, 8Q21, and Stadis450) on the dermal disposition of fuel components is not well understood. These additives are formulated with commercial Jet-A to form military JP-8 fuel. The purpose of this study is to assess the influence of these additives on the dermal disposition of marker aromatic and aliphatic components, naphthalene and dodecane, respectively. Porcine skin sections in an in vitro system were used to characterize chemical-biological interactions that modulate diffusion of jet fuel components and isolated perfused porcine skin flaps (IPPSFs) were used to evaluate diffusion in a viable skin model with an intact microvasculature. In these 5-h studies, Jet-A, Jet-A + DIEGME, Jet-A + 8Q21, and Jet-A + Stadis450, Jet-A + DIEGME + 8Q21, Jet-A + DIEGME + Stadis450, Jet-A + 8Q21 + Stadis450, and JP-8 mixtures were tested. In general, naphthalene absorption (0.76-2.39% dose) was greater than dodecane absorption (0.10-0.84% dose), while the IPPSFs alone demonstrated that dodecane absorption was significantly greater in JP-8 than in Jet-A. Synergistic interactions with 8Q21 + Stadis450 appear to enhance systemic absorption of either naphthalene or dodecane, while DIEGME + Stadis450 increased naphthalene (1.88% dose) and dodecane (2.02% dose) penetration into the skin and fat tissues of IPPSFs. These findings were supported by the fact that 8Q21 + Stadis450 significantly increased dodecane flux and permeability in porcine skin sections, but 8Q21 alone reduced marker diffusion in both membrane systems. Furthermore, dodecane is more likely than naphthalene to remain in the stratum corneum and skin surface at 5 h, and DIEGME mixtures played a significant role in skin and surface retention of both markers. In summary, the data suggest that various combinations of these three performance additives in JP-8 can potentially alter the dermal disposition of aromatic and aliphatic fuel components in skin. More importantly, products of two-factor interactions were not predictable from single-factor exposures and, by extension, cannot be extrapolated to three-factor interactions.

Alkanes↗
PubMed1995

The various shapes of the paries jugularis and the frequency of additional ducts in the fossa jugularis as further factors influencing the spread of pathological processes.

We investigated 100 skulls and found in 8 cases a dehiscence of the paries jugularis. In 7 cases this was on the left side and in 1 case on the right. Thickness of the paries jugularis was estimated by means of a diaphanoscopic technique. We classified data according to four degrees of diaphaneity: 0 (hardly translucent), 1 (translucent), 2 (brightly translucent) and 3 (nearly transparent). The frequencies of these degrees were: 0, 38 cases (19%); 1, 122 cases (61%); 2, 35 cases (17.5%); and 3, 5 cases (2.5%). In investigating the frequency of additional ducts in the paries jugularis, we distinguished between three types of solum tympani: type I, no additional canals (18 cases); type II, 1-10 additional canals (172 cases); and type III, more than 10 additional canals (10 cases).

Adult↗
PubMed1992

DNA markers closely linked to nematode resistance genes in sugar beet (Beta vulgaris L.) mapped using chromosome additions and translocations originating from wild beets of the Procumbentes section.

Genes conferring resistance to the beet cyst nematode (Heterodera schachtii Schm.) have been transferred to sugar beet (Beta vulgaris L.) from three wild species of the Procumbentes section using monosomic addition and translocation lines, because no meiotic recombination occurs between chromosomes of cultured and wild species. In the course of a project to isolate the nematode resistance genes by strategies of reverse genetics, probes were cloned from DNA of a fragmented B. procumbens chromosome carrying a resistance gene, which had been isolated by pulsed-field gel electrophoresis. One probe (pRK643) hybridized with a short dispersed repetitive DNA element, which was found only in wild beets, and thus may be used as a molecular marker for nematode resistance to progeneis of monosomic addition lines segregating resistant and susceptible individuals. Additional probes for the resistance gene region were obtained with a polymerase chain reaction (PCR)-based strategy using repetitive primers to amplify DNA located between repetitive elements. One of these probes established the existence of at least six different chromosomes from wild beet species, each conferring resistance independently of the others. A strict correlation between the length of the wild beet chromatin introduced in fragment addition and translocation lines and the repeat copy number has been used physically to map the region conferring resistance to a chromosome segment of 0.5-3 Mb.

Animals↗
PubMed1994

Determination of epidermal growth factor receptor provides additional prognostic information to measuring tumor angiogenesis in breast carcinoma patients.

Recent studies have shown that women with invasive breast carcinoma having high microvessel density (MVD) (a measure of tumor angiogenesis) or epidermal growth factor receptor (EGFR) expression have increased risk for metastasis and/or decreased survival. To determine if MVD and EGFR expression provide additive prognostic information, we analyzed these two prognostic indicators in the primary invasive breast carcinomas from 165 consecutive patients, who were followed for a median of 51 months. Univariate analysis showed a highly significant (p < 0.001) association of MVD with overall and relapse-free survival in all patients, including both node-negative and node-positive groups (see JNCI 84:1875-1887, 1992). For EGFR, although univariate analysis suggested that women with tumors showing EGFR expression relapsed earlier and, perhaps, died earlier, the differences were not statistically significant. Multivariate analysis, in contrast, revealed that determination of EGFR did provide significant additional information to that already provided by MVD for predicting relapse-free survival in all women (p = 0.001) and in the subset of node-positive women (p = 0.007). Among node-negative women, however, the contribution of EGFR expression in predicting relapse-free survival was not significant (p = 0.12). Likewise, EGFR measurement did not provide significant additional information beyond that of MVD alone for predicting overall survival. Thus, EGFR provides additional prognostic information to determination of MVD, but only for relapse-free survival in node-positive women with invasive breast carcinoma.

Adult↗
PubMed1993

Analyzing preventive trials with generalized additive models.

Described a new class of nonparametric regression procedures called generalized additive models (Hastie and Tibshirani, 1991) for assessing intervention effects in mental health preventive field trials. Such models are often better than analysis of covariance models for examining intervention effects adjusted for one or more baseline characteristics and for assessing potential interactions between the intervention and baseline characteristics. Because of these advantages, generalized additive models are important tools analysts should consider in evaluating preventive field trials. We apply generalized additive models as well as more standard linear models to data from a preventive trial aimed at improving mental health and school performance outcomes through a universal intervention in first and second grades. Practical guidance is given to researchers regarding when generalized additive models would be beneficial.

Community Mental Health Services↗
PubMed1989

Weak hierarchies associated with similarity measures--an additive clustering technique.

A new and apparently rather useful and natural concept in cluster analysis is studied: given a similarity measure on a set of objects, a sub-set is regarded as a cluster if any two objects a, b inside this sub-set have greater similarity than any third object outside has to at least one of a, b. These clusters then form a closure system which can be described as a hypergraph without triangles. Conversely, given such a system, one may attach some weight to each cluster and then compose a similarity measure additively, by letting the similarity of a pair be the sum of weights of the clusters containing that particular pair. The original clusters can be reconstructed from the obtained similarity measure. This clustering model is thus located between the general additive clustering model of Shepard and Arabie (1979) and the standard hierarchical model. Potential applications include fitting dendrograms with few additional nonnested clusters and simultaneous representation of some families of multiple dendrograms (in particular, two-dendrogram solutions), as well as assisting the search for phylogenetic relationships by proposing a somewhat larger system of possibly relevant "family groups", from which an appropriate choice (based on additional insight or individual preferences) remains to be made.

Algorithms↗
PubMed2000

Additional chromosome aberrations in acute promyelocytic leukemia: characteristics and prognostic influence.

Patients with acute promyelocytic leukemia (APL) show other chromosome aberrations in addition to t(15;17) but their influence on the clinical outcome is still unclear. We have cytogeneticaly analyzed 43 APL patients with t(15;17)(q22;q21), treated with all-trans-retinoic acid (ATRA) according to the recommendations of the European APL 91 Group. Additional chromosome aberrations were observed in 14/43 patients (33%) studied at initial diagnosis. These patients were designed as 'complex' karyotype group and were compared to patients with t(15;17) asa sole cytogenetic abnormality ('simple' karyotype group). The 'complex' group had significantly lower platelet count and fibrinogen level and fewer cases without significant DIC at diagnosis than the 'simple' group. Comparison of 'simple' and 'complex' groups showed significant difference in complete remission rate (76% vs 35.7%, P = 0.0148) and early death rate (24% vs 64.3%, P = 0.0141). Survival analysis showed that the presence of additional chromosome abnormalities and significant DIC had an adverse effects on prognosis (P = 0.036 and P = 0.041, respectively), independent on other prognostic factors. These data indicate more aggressive biological nature of leukemic cells in patients with additional chromosome aberrations. Supplementary therapeutic strategies may be required for this subgroup of APL patients.

Adolescent↗
PubMed2000

Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer.

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m2 every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m2, while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m2) was administered i.v. before carboplatin and GM-CSF (480 microg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50 mg/m2 of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2-4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4-12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60 mg/m2 and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m2) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.

Adult↗
PubMed1999

Addition of opioids alters the density and spread of intrathecal local anesthetics? An in vitro study.

PURPOSE: To determine whether the addition of opioids alters the density and spread of intrathecal local anesthetics in vitro. METHODS: In Part I, the densities of hyperbaric bupivacaine 0.75% (HB), hyperbaric lidocaine 5% (HL) and isobaric bupivacaine 0.5% (IB) with and without morphine (M), and fentanyl (F) were measured at 22 degrees C. In Part II a model was constructed utilizing a column containing a solution similar in composition to cerebrospinal fluid (CSF) at 37 degrees C. The various local anesthetic-opioid solutions, coloured with crystalline methylene blue dye, were injected at 22 degrees C into the column at a controlled rate through a spinal needle. The direction and extent of spread of the injectates were compared. RESULTS: The relative densities of the five solutions were: HB = HL > IB > M > F. The addition of fentanyl to IB reduced the density of the final solution (P < 0.05). In the model, IB alone and IB with morphine showed mainly downward spread, with the addition of fentanyl to IB resulting in upward movement (P = 0.004). The hyperbaric local anesthetics moved downward with or without opioids. CONCLUSION: The addition of fentanyl reduces the density of IB in vitro and alters its movement in simulated CSF. This may prove to be important in predicting the level of spinal block in clinical practice.

Analgesics, Opioid↗
PubMed2005

An additive-dominance model to determine chromosomal effects in chromosome substitution lines and other gemplasms.

When using chromosome substitution (CS) lines in a crop breeding improvement program, one needs to separate the effects of the substituted chromosome from the remaining chromosomes. This cannot be done with the traditional additive-dominance (AD) model where CS lines, recurrent parent, and their hybrids are used. In this study, we develop a new genetic model and software, called a modified AD model with genotype x environment interactions, which can predict additive and dominance genetic effects attributed to a substituted alien chromosome in a CS line as well as the overall genetic effects of the non-substituted chromosomes. In addition, this model will predict the additive and dominance effects of the same chromosome of interest (i.e. chromosome 25 of cotton in this study) in an inbred line, as well as the effects of the remaining chromosomes in the inbred line. The model requires a CS line, its recurrent parent and their F(1) and/or F(2) hybrids between the substitution lines and several inbred lines. Monte Carlo simulation results showed that genetic variance components were estimated with no or slight bias when we considered this modified AD model as random. The correlation coefficient between predicted effects and true effects due to the chromosomes of interest varied from zero to greater than 0.90 and it was positively relative to the difference between the CS line and the recurrent line. To illustrate the use of this new genetic model, an upland cotton, Gossypium hirsusum L, CS line (CS-B25), TM-1 (the recurrent parent), five elite cultivars, and the F(2) hybrids from test-crossing these two lines with the five elite cultivars were grown in two environments in Mississippi. Agronomic and fiber data were collected and analyzed. The results showed that the CS line, CS-B25, which has chromosome 25 from line 3 to 79, Gossypium barbadense substituted into TM-1, had positive genetic associations with several fiber traits. We also determined that Chromosome 25 from FiberMax 966 had significantly positive associations with fiber length and strength; whereas, chromosome 25 from TM-1 and SureGrow 747 had detectable negative genetic effects on fiber strength. The new model will be useful to determine effects of the chromosomes of interest in various inbred lines in any diploid or amphidiploid crop for which CS lines are available.

Chromosomes, Plant↗
PubMed2003

Analysis of additive metals in fuel and emission aerosols of diesel vehicles with and without particle traps.

Fuel additives used in particle traps have to comply with environmental directives and should not support the formation of additional toxic substances. The emission of metal additives from diesel engines with downstream particle traps has been studied. Aspects of the optimisation of sampling procedure, sample preparation and analysis are described. Exemplary results in form of a mass balance calculation are presented. The results demonstrate the high retention rate of the studied filter system but also possible deposition of additive metals in the engine.

Journal Article↗
PubMed2000

The effects of instability and additional hand support on anticipatory postural adjustments in leg, trunk, and arm muscles during standing.

We investigated the role of additional perceptual information (finger touch) and additional mechanical support (hand grasp) on the anticipatory postural adjustments (APAs) associated with fast arm movements performed by standing subjects. The subjects performed fast, unilateral shoulder ante-flexion movements while standing on a stable force platform or on an unstable board with instability in a sagittal or in a frontal plane. Changes in the background activity of leg, trunk, and arm muscles and displacements of the center of pressure were quantified within time intervals typical for APAs. Leg and trunk muscles showed a significant drop in APAs with added finger touch and no further changes when the touch was substituted with hand grasp. Arm muscles showed no changes or a small drop in APAs with touch and a significant increase in APAs with grasp. These changes were seen during both stable and unstable standing. We conclude that APAs can show changes associated not only with mechanical aspects of a task, but also with its perceptual aspects. Based on the equilibrium-point hypothesis of motor control, an additional analysis of APAs was performed. With additional support, we observed a significant modulation of an index related to the co-activation of agonist-antagonist muscle pairs, while no changes in reciprocal activation were found. A similar analysis performed across all the leg and trunk muscles with respect to control of the center of mass lead to similar results. We conclude that the central nervous system seems to simplify adjustments of control patterns to changes in task parameters by modulation of only one of the two major central commands.

Adult↗
PubMed1999

Effect of Crude Oil and Chemical Additives on Metabolic Activity of Mixed Microbial Populations in Fresh Marsh Soils.

> Abstract Hydrocarbons increase abundance of hydrocarbon-degrading microorganisms, but also decrease microbial diversity. This could disrupt ecosystem dynamics by altering soil organic matter mineralization and resultant nutrient remineralization rates. Crude oil, which is known to contain toxins and reduce microbial diversity, was hypothesized to reduce gross metabolic activity of mixed microbial populations in wetland soils. Soil respiration and Eh were compared, for 6 months, among microcosms containing marsh soils that differed in soil organic matter (Panicum hemitomon Shult. or Sagittaria lancifolia L. dominated marshes), crude oil (Arabian crude, Louisiana crude, or no oil), and additives (a cleaner, a dispersant, fertilizer, or no additive). No treatment slowed activity; instead, Louisiana plus fertilizer and all Arabian treatments temporarily accelerated activity. Additional C respired from oiled microcosms exceeded C added as crude oil by 1.4 to 3.5 times. Thus, much additional C originated from soil organic matter rather than crude oil. Crude oils temporarily lowered soil Eh, which is consistent with accelerated metabolism and demand for electron acceptors. The lack of inhibition observed at the community level does not necessarily indicate an absence of toxicity. Instead, tolerant species with metabolic versatility probably maintained activity. Stimulation probably resulted from removal of micronutrient limitation, rather than removal of grazing pressure or macronutrient limitation. Regardless, accelerated soil organic matter mineralization surely accelerated nutrient remineralization. This might explain some reports of crude oil stimulating plant growth. These results are not inconsistent with theoretical and experimental conclusions regarding effects of biodiversity on ecosystem stability and productivity, nor are they inconsistent with conclusions that crude oils contain components that are toxic to microbes, vegetation, and fauna. However, these data do indicate that crude oils also contain components that temporarily stimulate metabolic activity of surviving microbes.

Journal Article↗
PubMed2000

Stability in Natural Bacterial Communities: I. Nutrient Addition Effects on Rhizosphere Diazotroph Assemblage Composition.

The ability of rhizosphere diazotrophs to remain competitive during increased nitrogen availability in situ was tested in a salt marsh grass stand. Nitrogen (16.3 g m(-2)) or nitrogen (16.3 g m(-2)) and phosphorus (18.0 g m(-2)) were added to plots of short form Spartina alterniflora for either 2 weeks or 8 weeks. The diazotroph assemblage composition was monitored via the polymerase chain reaction using nifH specific primers followed by denaturing gradient gel electrophoresis (DGGE) analysis. DGGE profiles from the short-term experiments (2 and 8 weeks) were compared to profiles from control (no additions) and from long-term (>10 y) nutrient addition plots. Nitrogen fixation activity was assayed in each short-term treatment and control plot using an acetylene reduction technique. The control and nutrient addition DGGE profiles were very similar throughout the short-term experiments. One DGGE band that was prominent in the control plots was not found in the long-term nutrient addition plots. Diazotrophy may provide a competitive advantage for some species in this system, as indicated by results from the long-term nutrient amended plots. However, the rhizosphere environment in situ appears to limit the immediate impacts of increased nutrient availability on the diazotroph assemblage composition. Results from the short-term nutrient amended plots showed no measurable effect on the diazotroph assemblage. These results indicate substantial short-term stability of the diazotroph assemblage composition, but the potential for change in the face of long-term changes in nutrient availability. </hea

Journal Article↗
PubMed2001

Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

PURPOSE: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III. METHODS: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model. RESULTS: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms). CONCLUSION: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

Administration, Oral↗