Toxicity-reduced, myeloablative allograft followed by lenalidomide maintenance as salvage therapy for refractory/relapsed myeloma patients.

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.

Consensus guidelines for the optimal management of adverse events in newly diagnosed, transplant-ineligible patients receiving melphalan and prednisone in combination with thalidomide (MPT) for the treatment of multiple myeloma.

Thalidomide has received approval from the European Agency for the Evaluation of Medicinal Products for the treatment of newly diagnosed multiple myeloma (MM) patients older than 65 years or ineligible for transplant. The results of five phase III trials assessing thalidomide in combination with melphalan and prednisone (MPT) have demonstrated significantly improved response rates compared with melphalan and prednisone (MP) alone. Additionally, two of these studies showed that survival was extended by approximately 18 months in patients treated with MPT compared with MP alone. Thalidomide, in combination with MP, is associated with adverse events (AEs) including peripheral neuropathy and venous thromboembolism. In order to optimize the efficacy of MPT, a good awareness of these AEs is imperative. This manuscript outlines both evidence- and consensus-based recommendations discussed by a panel of experts, to provide a practical guide for physicians addressing the effective management of newly diagnosed, transplant-ineligible MM patients receiving thalidomide therapy.

Prognostic relevance of angiogenesis in stage III NSCLC receiving multimodality treatment.

Compelling evidence indicates that microvessel density (MVD) is a prognostic marker in early nonsmall cell lung cancer (NSCLC). However, its role in lymph node metastases in stage III NSCLC receiving multimodality treatment is unknown. Lymph nodes of 142 patients with stage III NSCLC, treated in a trial of the German Lung Cancer Cooperative group, were evaluated for MVD. Median follow-up was 7.39 yrs. MVD was correlated with demographic and tumour-related variables and survival. MVD (median 33.9) did not correlate with survival. However, in multimodality-treated stage IIIA patients receiving tumour resection with negative margins (R0), those with a high MVD had significantly prolonged overall survival with a median of 4.96 yrs compared with 1.99 yrs for those with low MVD (p = 0.041). Cox regression analysis revealed that MVD was a prognostic factor in R0-resected stage IIIA (hazard ratio 0.417). Furthermore, a significant correlation of MVD to stage was observed, with significantly lower MVD in stage IIIA than IIIB (p = 0.0062), and a significant correlation of MVD to histological subtype was observed, with adenocarcinoma revealing the highest scores (p = 0.0001). Increased angiogenesis within lymph node metastases is a prognostic indicator for better survival in NSCLC patients. Thus, measurement of MVD might be useful in selecting patients for future neoadjuvant treatment decisions.

High-dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment-related mortality in patients with multiple myeloma: results of a randomised study.

We conducted a randomised trial comparing an intensified versus a standard conditioning regimen for high-dose chemotherapy followed by autologous stem-cell transplantation in patients with multiple myeloma. In this study, 56 patients were randomly assigned for high-dose therapy with melphalan 200 mg/m2 or with idarubicin 42 mg/m2, melphalan 200 mg/m2 and cyclophosphamide 120 mg/kg. The primary objective was response rate. Acute toxicity, mainly because of infections, was higher in the intensified treatment arm with a treatment-related mortality of 20% versus 0% in the standard arm. This lead to the early discontinuation of the study. Response rates did not differ significantly between both treatment arms {intensified versus standard: complete response+near complete remission 50% [95% confidence interval (CI) 26-74%] vs. 33% (95% CI 17-55%), partial remission 35% (95% CI 16-61%) vs. 50% (95% CI 30-70%)}. After a follow-up of 5 years, the median time-to-progression and overall survival were not significantly different between both patient groups. Analysis restricted to patients surviving the first 100 d after transplant showed a better outcome for patients with >or=2 bad prognostic risk factors in the intensified treatment arm, however all treatment-related deaths occurred within this group of patients. In conclusion, intensified conditioning for high-dose therapy had intolerably high toxicity without improving outcome in patients with multiple myeloma.

Optimizing grain yields reduces CH4 emissions from rice paddy fields.

Microbial production in anoxic wetland rice soils is a major source of atmospheric CH4 the most important non-CO2 greenhouse gas. Much higher CH4 emissions from well managed irrigated rice fields in the wet than in the dry season could not be explained by seasonal differences in temperature. We hypothesized that high CH4 emissions in the wet season are caused by low grain to biomass ratios. In a screenhouse experiment, removing spikelets to reduce the plants' capacity to store photosynthetically fixed C in grains increased CH4 emissions, presumably via extra C inputs to the soil. Unfavorable conditions for spikelet formation in the wet season may similarly explain high methane emissions. The observed relationship between reduced grain filling and CH4 emission provides opportunities to mitigate CH4 emissions by optimizing rice productivity.

Coupling estimated effects of QTLs for physiological traits to a crop growth model: predicting yield variation among recombinant inbred lines in barley.

Advances in the use of molecular markers to elucidate the inheritance of quantitative traits enable the integration of genetic information on physiological traits into crop growth models. The objective of this study was to assess the ability of a crop growth model with QTL-based estimates of physiological input parameters to predict the yield of recombinant inbred lines (RILs) of barley. The model used predicts yield as spike biomass accumulated over the post-flowering period. We describe a two-stage procedure for predicting trait values from estimated additive and epistatic effects of QTLs. Values of physiological traits estimated by that procedure or measured in the field were used as input to the crop growth model. The output values (yield and shoot biomass) from the growth model using these two types of input values were highly correlated, indicating that QTL information can successfully replace measured input parameters. With the current crop growth model, however, both types of input values often resulted in large discrepancies between observed and predicted values. Improvement of performance may be achieved by incorporating physiological processes not yet included in the model. The prospects of using QTL-based predictions of model-input traits to identify new, high yielding barley genotypes are discussed.

Modelling field emergence patterns in arable weeds.

A model was developed to simulate weed emergence patterns after soil cultivation. In the model, the consecutive processes of dormancy release, germination and pre-emergence growth were modelled in separate modules. Input variables of the model were: date of soil cultivation, soil temperature and soil penetration resistance. Output variables of the model were: seedling density and timing of seedling emergence. The model was parameterized for Polygonum persicaria, Chenopodium album and Spergula arvensis with data from previous field and laboratory experiments. The model was evaluated with data from an experiment, in which emergence of P. persicaria, C. album and S. arvensis was monitored in field plots that were cultivated once only, at one of five dates in the spring. At the same time as the field observations on seedling emergence, seasonal changes in seed dormancy of the buried weed seeds were assessed by testing the germination of seed lots that were buried in envelopes. From a comparison between field observations and simulated data, it appeared that the model overestimated the rate of dormancy release in spring, whereas germination and pre-emergence growth were simulated well. In general, therefore, both the numbers of emerging seedlings and the timing of emergence could be predicted accurately, when dormancy was not simulated but introduced from experimental data. Improvement of predictions of field emergence of weeds should mainly focus on increasing the precision of the simulation of dormancy release. Close correlations were found between seedbed temperature and both the extent and rate of seedling emergence, but analysis with the simulation model revealed that they were only partly based on causal relationships, so that they have limited predictive value.

Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.

Vascular endothelial growth factor (VEGF), a multifunctional cytokine, potently stimulates angiogenesis including tumor neovascularization. Although well established in solid tumors, the role of VEGF in bone marrow neoangiogenesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marrow neovascularization parallels disease progression. This parallel prompted us to investigate the expression and secretion of VEGF by myeloma cells and its potential effects in myeloma-marrow stroma interactions. The biologically active splice variants VEGF165 and VEGF121 were expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM. As shown by immunocytochemistry or RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly expressed by marrow stromal cells. Therefore, we studied the effects of VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6), a potent growth factor for myeloma cells and an inhibitor of plasma cell apoptosis. Exposure of stromal and microvascular endothelial cells to recombinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P <.001). Conversely, rhIL-6 stimulated VEGF expression and secretion in myeloma cell lines (40%-60%; P <.05) and to a variable degree (up to 5.3-fold; P <.005) in plasma cells purified from the marrow of patients with MM. This mutual stimulation suggests paracrine interactions between myeloma and marrow stromal cells triggered by VEGF and IL-6. (Blood. 2000;95:2630-2636)

Community pharmacists' assessments and recommendations for treatment in four case scenarios.

OBJECTIVE: To evaluate community pharmacists' interpersonal skills, ability to make appropriate assessment of a patient' s drug-related problems, and ability to propose an appropriate therapeutic plan. DESIGN: A disguised shopper design was used. Four different case scenarios were designed, with input from a five-member community/primary care pharmacist advisory committee. Two different cases were assigned to each of two shoppers. One hundred and one pharmacies were shopped twice, totaling 202 shopping experiences. A three-member evaluation committee made up of clinical faculty members in ambulatory care and internal medicine assessed the appropriateness of the recommendations. SETTING: The study was conducted in 101 randomly selected community pharmacies in the Pittsburgh area, including both chain and independent pharmacies. MAIN OUTCOME MEASURES: Main outcome measures included the quality of the pharmacists' interpersonal skills, patient assessment skills, and recommendations. RESULTS: The majority of pharmacists demonstrated acceptable to good interpersonal skills. Overall, 31.7% of the recommendations were appropriate, while 39.1% were poor (i.e., recommendations that would likely worsen the patient's condition or potentially harm the patient). In 33.2% of the cases, recommendations were made without prior assessment of the patient's problems. CONCLUSIONS: A lack of clinical knowledge and skills should be considered as a barrier that must be overcome if the provision of pharmaceutical care is to become a reality in community practice.

Modelling for precision weed management.

Recently, the need for the development of weed management systems with a reduced dependency on herbicides has increased because of concern about environmental side-effects and cost. The development of such systems requires new strategies based on improvements with respect to (1) prevention, (2) decision making and (3) weed control technology. For the development of improvements in all three aspects, quantitative understanding of weed population dynamics and crop-weed interactions is needed. Models that integrate the available quantitative knowledge can be used to design preventive measures, to develop long-term and short-term strategies for weed management, to assist in decision making to determine if, when, where and how weeds should be controlled and to identify new opportunities for weed control. Ecophysiological simulation models for crop-weed competition simulate growth and production of species in mixtures, based on ecophysiological processes in plants and their response to the environment. Such models help improve insight into the crop-weed system and can be used for purposes such as the development of simple predictive yield-loss models, threshold levels or the design of competitive crop plant types. For strategic weed management decisions, preventive measures and the identification of new opportunities for weed control, quantitative insight into the dynamics and spatial patterns of weed populations is also required. The complexity of the process and the long-term character of weed population dynamics make the use of models necessary. Different modelling approaches have been developed and are described briefly. Opportunities to use the available knowledge and models to improve weed management are discussed. Weeds occur in patches and their sensitivity to herbicides changes strongly with developmental stage, making precision techniques for herbicide application in time and space an option for reducing herbicide use. Limitations related to insight in biological processes as well as the state of technological development are discussed.

DNA aneuploidy, increased proliferation and nuclear area of plasma cells in monoclonal gammopathy of undetermined significance and multiple myeloma.

DNA cytometric and morphometric parameters of plasma cells were determined in 73 multiple myelomas (MMs), 31 monoclonal gammopathies of undetermined significance (MGUS), 11 reactive plasmacytoses (RPs) and 33 cases of normal bone marrow (NBM) using a TV-based static cytometer combined with a computerized relocation stage. Neoplastic transformation was defined by either an aneuploid DNA profile, an increased proliferative fraction or an increased mean nuclear area of plasma cells. Using threshold values defined by mean values and variations of NBM and RP, 67/73 MMs were correctly classified as malignant (sensitivity, 92%), whereas all NBMs and RPs were classified as benign (specificity, 100%). In MGUS, cytometric parameters of malignancy were detected in 19/31 cases (61%). Six of these cases developed MM after a median time of 4.9 years (mean follow-up, 9.3 years). Another three cases with MGUS developed MMs without previous cytometric plasma cell aberrations. Cytometric data from repeated measurements in MGUS progressing to MM exhibited perfect consistency over time concerning the presence or absence of cytometrically detected neoplastic transformation. Cytometric aberrations seem to be frequently associated with neoplastic growth in monoclonal plasma cell proliferations but do not predict clinically malignant behavior.

DNA-image cytometry and clinical staging systems in multiple myeloma.

Clinical and hematological parameters, and three derived major staging systems were compared with DNA-cytometric parameters in 73 patients with newly diagnosed multiple myeloma (MM) and correlated in univariate analysis with survival to assess their predictive value. Regarding diagnostic validity, a multi-parameter system including STL, 5cER, PRF and MNA correctly classified 92% of MM as malignant (sensitivity 92%) at a 100% specificity. Regarding prognosis, the most powerful single clinical parameter was serum creatinine (p < 0.001, median survival [ms] 51 vs. 14 months) followed by platelet count (p < 0.01, ms 67 vs. 11 months). Mean nuclear area of plasma cells was the only cytometric parameter with prognostic relevance (p < 0.05, ms 43 vs. 14 months). Neither the original Salmon-Durie staging (p < 0.05 for I vs. II, p > 0.05 for II vs. III) nor the revised Salmon-Durie staging by Cavo et al were able to discriminate three patient groups at statistically significant levels. Only the staging system proposed by the British Medical Research Council (MRC) was found to be able to predict survival for all three groups significantly (p = 0.01 for A vs. B, p < 0.01 for B vs. C; ms A/B/C = 68/37/14 months, respectively).

Monitoring DNA cytometric parameters during the course of chronic myelogenous leukemia.

The prognostic value of three DNA cytometric parameters--stemline ploidy (STL), stemline shoulder fraction (SSF) and "proliferative" fraction (PRF)--for the prediction of disease transformation and survival was examined for 20 patients with chronic myelogenous leukemia (CML) during the course of their disease and compared with two commonly used hematologic parameters (degree of leukocytosis and percentage of circulating leukemic progenitor cells). With disease progression, STL and SSF increased significantly, whereas PRF showed a steady decrease from diagnosis to blast crisis. The most significant part of these changes took place during the chronic phase, before the clinical onset of disease transformation. Hematologic parameters, in comparison, revealed significant changes later, shortly before blast crisis. The remaining duration of the chronic phase diminished from 25.5 months at the time of diagnosis, when the median STL was 2.0c, to 19.6 months for patients showing an STL of 2.1c, to 15.0 months with an STL of 2.2c and to 1.0 months for those with an STL of greater than or equal to 2.3c. Prognostically relevant limits for SSF and PRF were at 20%. When the SSF passed this limit or the PRF fell below it, the mean remaining chronic phase of these patients amounted to only 14.1 and 10.1 months. Interactive cytometry allows analysis of the DNA cytometric equivalent of changes in leukemic progenitor cells, which are well known from cytogenetic and cell kinetic studies. These three DNA cytometric parameters reflect the "natural history" of CML with the development of a cytogenetically hyperdiploid clone during disease progression in most patients and a simultaneous loss of proliferative potential on the level of myelobasts.(ABSTRACT TRUNCATED AT 250 WORDS)

[Myocarditis caused by Toxoplasma gondii and Aspergillus fumigatus after orthotopic heart transplantation]. / Myokarditis durch Toxoplasma gondii und Aspergillus fumigatus nach orthotoper Herztransplantation.

This report describes the case of a 56-year-old patient, who died 53 days after orthotopic heart transplantation due to myocarditis caused by infection with Aspergillus fumigatus and Toxoplasma gondii. Aspergillosis was diagnosed by transthoracic needle aspiration of a pulmonary infiltration. Endomyocardial biopsy showed toxoplasma pseudocysts. Autopsy revealed myocardial infection with both infectious agents. Despite specific therapy, myocarditis determined the fatal outcome in this case. The value of invasive techniques for specific diagnosis of infectious diseases in immunocompromised patients is discussed.

Detection of high risk patients in chronic myelogenous leukemia by DNA-image cytometry.

Peripheral blood smears from the time of diagnosis of 64 patients with chronic myelogenous leukemia (CML) in chronic phase were restained according to Feulgen. Nuclear DNA content of at least 100 myeloblasts and promyelocytes was measured by interactive DNA-cytometry using a TV-image analysis system, combined with an automated microscope. From the resulting DNA values the DNA parameters stemline ploidy, stemline shoulder fraction and "proliferative" fraction, which reflect cytogenetic and cell kinetic characteristics of CML, were derived. Each of these DNA parameters identified subgroups with a significantly different survival time and duration of chronic phase. Indicators for a good prognosis were a near-diploid stemline ploidy (median survival time 49 v. 26 months), a low percentage of nuclei in the stemline shoulder fraction (45 v. 28 months) and a high "proliferative" fraction (45 v. 23 months). Independently of clinical and hematological features, the DNA-cytometric parameters yielded additional prognostic information both in the univariate and multivariate analysis.

[Bronchial endoprostheses (stents) in inoperable bronchial carcinoma]. / Bronchiale Endoprothesen (Stents) beim inoperablen Bronchialkarzinom.

Three patients suffering from bronchial carcinoma with severe bronchial obstruction have been successfully treated by implantation of metallic stents. Two of them suffered from peribronchial tumor growth while the third one complained about dyspnoea caused by the instability of the central airways. Stents were implanted into the left main bronchus or the intermediate bronchus either through a flexible bronchoscope under local anaesthesia and sedation or through a rigid bronchoscope under general anaesthesia. The successful dilatation of the stenosis could be demonstrated by bronchography. The patients tolerated the stents well. We found no dislocation, deformation or ulceration of the bronchial mucosa. The implantation of metallic stents thus seems to offer new possibilities for the palliative treatment of bronchial carcinoma.

[Importance of DNA-cytometric parameters in the prediction of blast crisis in the course of chronic myelogenous leukemia]. / Bedeutung DNA-zytometrischer Parameter zur Vorhersage eines Blastenschubs im Verlauf der chronisch-myeloischen Leukämie.

In a retrospective study the DNA-cytometric parameters stemline ploidy, stemline shoulder fraction and proliferative fraction were followed during the course of the disease in 20 patients with chronic myelogenous leukemia. Stemline ploidy and stemline shoulder fraction significantly increased whereas the proliferative fraction steadily decreased during the disease most of these changes taking place during chronic phase before the clinical onset of blast crisis. Prognostically relevant cutpoints indicating disease transformation during the next 12 months could be defined.

The effects of long-term open-air fumigation with SO2 on a field crop of broad bean (Vicia faba L.): III. Quantitative analysis of damage components.

Effects of SO2 on growth and production of broad bean, observed in three open-air fumigation experiments, were interpreted in terms of damage components with a mechanistic simulation model. The model consisted of an elementary model for crop growth, extended with submodels for the microclimate in the crop and with a submodel for uptake of SO2 by leaves and for effects on leaf photosynthesis. The major part of the observed reduction in total dry matter production could be explained by leaf injury observed in the oldest leaves of the fumigated plants at the end of the growing period. The effect consisted of dry matter loss through leaf abscission and a reduced growth rate at the end of the growth period due to reduction of the amount of absorbed radiation by the canopy. Direct effects of SO2 on leaf photosynthesis explained an extra 10% of the observed yield loss (losses ranged from 7 to 17% of control yield). This small effect was confirmed by field measurements which showed no detectable effects of SO2 on leaf and canopy photosynthesis. Increased leaf respiration, which was observed in the 1988 experiment, explained another 10% of the observed yield reduction. Total SO2 -sulphur uptake by the fumigated crop, which is an important component of dry deposition of SO2 , was accurately simulated by the model.