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Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma. [ABSTRACT FROM AUTHOR]

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. [ABSTRACT FROM AUTHOR]

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (20%) and absolute number (2 × 109/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. [ABSTRACT FROM AUTHOR]

The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions. [ABSTRACT FROM AUTHOR]

This study was conducted to audit maternal seafood intake awareness during pregnancy and to determine whether there is an association between fish consumption and various pregnancy outcomes. In total, 553 low-risk and healthy pregnant women were given a questionnaire concerning fish consumption. Pregnant women who developed gestational diabetes mellitus, pre-term labour-birth, macrosomia, low birth weight and small for gestational age were analysed. Fatty fish consumers tended to have higher birth weight infants than lean fish consumers. Low fish consumption was significantly correlated with low birth weight and small for gestational age (SGA) infants. The more fatty fish that the low fish consumers consumed, the more likely they were to have SGA infants. Fish consumption did not have an impact on the development of gestational diabetes mellitus, macrosomia or pre-term labour-birth. Low fish consumption during pregnancy may be associated with the development of low birth weight and SGA infants in a Turkish population. [ABSTRACT FROM AUTHOR]

Background: Quality of life measurement in cholangiocarcinoma and gallbladder cancer involves the assessment of patient-reported issues related to the symptoms, disease and treatment of these tumours. This study describes the development of the disease-specific quality of life (QoL) questionnaire for patients with cholangiocarcinoma and gallbladder cancer to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30 core cancer questionnaire.Methods: Phases 1-3 of the guidelines for module development published by the EORTC were followed, with adaptations for incorporation of questions from existing modules.Results: A total of 47 QoL issues (questions) were identified; 44 questions from the two related validated questionnaires, the EORTC QLQ-PAN26 (pancreatic module) and the EORTC QLQ-LMC21 (liver metastases module), two from the Functional Assessment of Cancer Therapy hepatobiliary module questionnaire in the literature search and one from healthcare professional interviews. Following phase 1 and 2 interviews with patients (n=101) and health care professionals (n=6), a 23-question provisional questionnaire was formulated. There were five questions from PAN26, 15 from LMC21 and three extra questions. In phase 3, the provisional item list was pre-tested in 52 patients in four languages and this resulted in a 21-item module.Conclusion: This is the only disease-specific QoL questionnaire for patients with cholangiocarcinoma and gallbladder cancer, and initial assessments show it to be accurate and acceptable to patients in reflecting QoL in these diseases. [ABSTRACT FROM AUTHOR]

Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future. [ABSTRACT FROM AUTHOR]

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM. [ABSTRACT FROM AUTHOR]

Cellular immune response and delayed-type hypersensitivity reactions are considered to play a major role in the immunopathogenesis of pulmonary tuberculosis (PTB). But the exact mechanism is still to be clarified. Th1 cells are mainly involved in cellular immune responses in PTB and provide a normal healing process with minimal or no sequela whereas Th2 cell and CD8+ T lymphocyte responses may lead to more severe type of disease. In this study, we investigated the peripheral blood immune responses in PTB. The study group consisted of acid fast positive young male soldiers with PTB and a negative HIV serology. The control group included healthy young volunteer male soldiers without a history of PTB. Intracytoplasmic cytokine content of CD8+ T cells and lymphocytes, including IL-2, IL-4, IL-5, IL-10 and IFN-γ were determined by flow cytometry, and IL-2, IL-4, IL-5, IL-10, IFN-γ and TNF-α serum levels were measured by cytometric bead array (CBA). No difference was observed between the percentages of T, B, NK cells and HLA-DR expression in both groups, however, the number of CD3+HLA-DR+ activated T cell percentages was higher in PTB group as compared to healthy subjects. IL-2, IL-4, IL-5, IL-10 contents of lymphocytes and IFN-γ+CD8+ T cells were found to be significantly lower in PTB patients when compared with healthy subjects, and in parallel, serum IL-2, IL-4, IL-5 and TNF-α levels were also significantly lower in PTB patients. In conclusion we suggest that, CD8+ T cells producing both Th1 and Th2 type cytokines, may play important role in the peripheral immune response to mycobacteria. [ABSTRACT FROM AUTHOR]

Several imaging technologies are used for the diagnosis and management of patients with multiple myeloma (MM). Conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging are all used in an attempt to better clarify the extent of bone disease and soft tissue disease in MM. This review summarizes all available data in the literature and provides recommendations for the use of each of the technologies. Conventional radiography still remains the ‘gold standard’ of the staging procedure of newly diagnosed and relapsed myeloma patients. MRI gives information complementary to skeletal survey and is recommended in MM patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. Urgent MRI or CT (if MRI is not available) is the diagnostic procedure of choice to assess suspected cord compression. Bone scintigraphy has no place in the routine staging of myeloma, whereas sequential dual-energy X-ray absorptiometry scans are not recommended. Positron emission tomography/CT or MIBI imaging are also not recommended for routine use in the management of myeloma patients, although both techniques may be useful in selected cases that warrant clarification of previous imaging findings, but such an approach should ideally be made within the context of a clinical trial. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the validity and reliability of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire liver module (QLQ-LMC21) for patients with liver metastases from colon cancer. The study revealed that EORTC QLQ-LMC21, with core questionnaire (QLQ-C30), is an effective assessment tool for patient-reported outcomes (PROs). An overview of the questionnaire module is also provided.

A letter to the editor in response to the article "Cotransplantation of mesenchymal cells and a higher relapse rate: a role for HLA-G molecules?" published online on June 5, 2008 is presented.

Several prognostic markers, including parameters of tumor burden and cytogenetics, were adopted to identify high-risk patients in multiple myeloma (MM). Recently, the International Staging System (ISS), including β2-microglobulin (β2M) and albumin, was introduced for patients with symptomatic MM. As bone disease is a hallmark of MM, we investigated the prognostic impact of the bone resorption marker carboxy-terminal telopeptide of type-1 collagen (ICTP) in combination with ISS, β2M, albumin, deletion of chromosome 13 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. β2M alone, albumin alone, ISS, HDT, del(13q14) and ICTP were significant prognostic factors for overall survival (OS). In a multivariate analysis, ICTP was the most powerful prognostic factor (log-rank P<0.001, hazard ratio: ninefold increase). ICTP clearly separated two subgroups with a good and a worse prognosis within each of the three ISS stages (ISS I: P=0.027, ISS II: P=0.022, ISS III: P=0.013). Incorporation of ICTP in a combined ICTP-ISS score significantly (P<0.001) separated four risk groups with a 5-year OS rate of 95, 65, 46 and 32%, respectively. These data demonstrate for the first time that the inclusion of the collagen-I degradation product ICTP, as a biomarker of bone resorption, adds to the prognostic value of ISS.Leukemia (2008) 22, 1767–1772; doi:10.1038/leu.2008.159; published online 26 June 2008 [ABSTRACT FROM AUTHOR]

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose 70 mg/m2 had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.Clinical Pharmacology & Therapeutics (2008); 83, 5, 749–757. doi:10.1038/sj.clpt.6100336 [ABSTRACT FROM AUTHOR]

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2–3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.Leukemia (2008) 22, 414–423; doi:10.1038/sj.leu.2405062; published online 20 December 2007 [ABSTRACT FROM AUTHOR]

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) leads to the induction of NF-κB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-κB inhibition using bortezomib (PS-341) and I-κB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-κB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.Leukemia (2007) 21, 2025–2034; doi:10.1038/sj.leu.2404806; published online 21 June 2007 [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.Leukemia (2007) 21, 1875–1884; doi:10.1038/sj.leu.2404843; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

Peripheral primitive neuroectodermal tumors (PNET) are usually located in bone or soft tissue in children or young adults but can also appear at a more advanced age. Case Report: A 60-year-old woman was admitted to our hospital presenting with a tumor of the right breast. Imaging studies led to the diagnosis of suspected benign lesion. Cytologic examination showed atypical cells. The biopsy showed a tumor composed of medium-sized tumor cells with round and ovoid vesicular nuclei and ill-defined cellular margins. The growth pattern was mainly solid in cell clusters. Focally sinusoidal, blood-filled spaces were present. Cytogenetic examination of 20 metaphases showed the karyotype 46,XX,t(11;22)(q24,q12)/46,XX. Mastectomy was performed, and adjuvant chemotherapy and radiotherapy were given. After a follow-up of 72 month, the patient is alive without evidence of disease. Conclusion: The adjuvant therapy (VACA regime) seems to lead, independently from tumor localization and patient age, to longer disease- free survival. [ABSTRACT FROM AUTHOR]

Objective To assess the effect of nifedipine tocolysis on Doppler parameters of the uterine, umbilical and fetal middle cerebral arteries and atrioventricular valves in the first 48 h of therapy. Methods Doppler waveforms of uterine, umbilical and middle cerebral arteries and both atrioventricular valves were measured from 28 pregnant women and fetuses prior to and during nifedipine therapy for preterm labor. Maternal and fetal heart rates (FHR), maternal systolic and diastolic blood pressure, and the Doppler pulsatility index (PI) of the uterine, umbilical and middle cerebral arteries were measured. The cerebroplacental ratio (middle cerebral artery PI/umbilical artery PI) was calculated. The total time velocity integrals (TVIs) of tricuspid and mitral valves and their E- and A-wave peak velocity ratio (E/A) were measured. Friedman repeated-measures analysis of variance was used to compare the variables before and after nifedipine therapy. If significant differences were found, Wilcoxon's signed ranks test was used to analyze the difference between the two variables. A P-value of < 0.05 was considered significant. Results Nifedipine maintenance was associated with a significant decline in maternal systolic and diastolic blood pressure after 24 h, while maternal heart rate and FHR were unaffected. The uterine artery PI had decreased significantly at 24 and 48 h, while the umbilical artery PI did not change significantly. The middle cerebral artery PI had decreased significantly at 24 and again at 48 h. A significant fall in the cerebroplacental Doppler ratio was maintained beyond 24 h. The mean E/A values, TVIs and TVI × FHR values at 24 and 48 h were unchanged from the baseline values. Conclusions Nifedipine maintenance tocolysis is associated with a significant decline in uterine artery and middle cerebral artery Doppler indices 24 h after the first dose. Fetal cardiac diastolic function is unaffected and the significant redistribution observed after 24 h is likely to be attributable to altered cerebral blood flow. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by 31P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses 1000 mg/m2, whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (±SD) CP elimination constants ke (h−1) were 0.109±0.025 in 44 CYP2C19*1/*1 subjects, 0.088±0.018 in 13 CYP2C19*1/*2, and 0.076±0.014 in three inactive CYP2C19*2/*2 carriers (P=0.009). At CP doses higher than 1000 mg/m2, a significantly increase of elimination was observed (P=0.001), possibly due to CYP induction. Further studies should link these findings with the clinical outcome.The Pharmacogenomics Journal (2005) 5, 365–373. doi:10.1038/sj.tpj.6500330; published online 23 August 2005 [ABSTRACT FROM AUTHOR]

Cytostatic chemotherapy of hematological malignancies is often complicated by neutropenia, which increases the risk of infections, especially if the neutrophil count is below 500/μl. Frequently, fever is the first, and in most patients the only, sign of an infection. Unexplained fever is defined as follows: temperature of ≥38.3°C or ≥38.0°C for at least 1 h, or measured twice within 12 h, if the neutrophil count is <500/μl or <1000/μl with predicted decline to 500/μl. Different risk categories can be identified according to the duration of neutropenia: low risk ≤5 days, intermediate risk 6–9 days, high risk ≥10 days. An empirical mono- or duotherapy with antipseudomonal and antistreptococcal agents should be initiated immediately. In the low risk patient group, oral therapy with cipro-, levo-, or ofloxacin combined with amoxicillin/clavulanic acid is permissible. For standard and high risk patients, monotherapy can be carried out with either ceftazidime, cefepime, piperacillin with tazobactam or a carbapenem. In duotherapy, a single dose of an aminoglycoside is combined with acylaminopenicillin or a cephalosporin of the third or fourth generation. The addition of glycopeptides in empirical therapy should only be considered in the presence of severe mucositis, or if a catheter-associated infection is suspected. If fever persists after 72–96 h of first-line therapy with antibiotics, the regimen should be modified (with the exception of e.g. coagulase-negative staphylococci infections, because these infections take longer to respond). Intermediate risk patients should additionally receive an aminoglycoside after monotherapy (penicillin or a cephalosporin). If a carbapenem was administered for monotherapy, this can be followed by a quinolone and/or a glycopeptide. In the high risk group, the same modifications should be made as in the intermediate risk group but with additional systemic antifungal treatment. In the presence of unexplained fever, fluconazole can be administered at first, but if this fails, amphotericin B (conventional or liposomal), itraconazole, voriconazole or caspofungin should be started. After defervescence to <38°C, treatment should be continued for 7 days if the neutrophil count is <1000/μl, and for 2 days if the neutrophil count is >1000/μl. [ABSTRACT FROM AUTHOR]

HMGI-C belongs to the high-mobility-group-protein (HMG) family of architectural transcription factors and considerable interest has recently been shown in its expression in neoplastic tissues and apparent involvement in tumorigenesis. We could previously demonstrate an expression of HMGI-C mRNA in the peripheral blood of breast cancer patients for the first time. In this prospective study, we evaluated the independent prognostic power of HMGI-C mRNA expression in the peripheral blood of an unselected cohort of 69 patients with metastatic breast cancer using a hemi-nested reverse transcriptase polymerase chain reaction (RT-PCR) followed by sequence analysis of the resulting PCR products. Multivariate analysis was performed using the Cox regression model. HMGI-C mRNA was detected in peripheral blood from 21 out of 69 (30%) patients with metastatic breast cancer. Median survival was 15.9 months in patients expressing HMGI-C, while in the group of patients without HMGI-C expression the median survival had not been reached yet after a median follow-up of 24.7 months and 85.4% were still alive in this group. Disease-specific survival was significantly worse for patients positive for HMGI-C in comparison to those not expressing HMGI-C (P=0.0001). In a multivariate regression analysis, HMGI-C remained an independent prognostic factor for overall survival (P=0.001) besides oestrogen receptor status (P=0.024) and presence of metastases in liver and lungs (P=0.029). HMGI-C expression in the peripheral blood of patients with metastatic breast cancer is a powerful independent indicator for poor overall survival and this is the first study to demonstrate its prognostic relevance in univariate and multivariate analysis. [ABSTRACT FROM AUTHOR]

Prediction of outcome and individualization of therapeutic strategies are challenging problems in oncology. Predictive parameters for response to hormonal treatment include the expression of hormone receptor, the extent and location of metastatic spread, disease-free interval, patient age, response to prior hormonal therapy, grading, and more recently, some molecular markers like the expression of HER-2/neu. The use of conventional statistics for prediction of response to hormonal treatment is limited by non-linearities and complex interactions between predictive factors. Modern computational mathematical models like artificial neural networks, entropy-based inductive algorithms or χ[sup 2] interaction detection algorithms can describe these interactions and generate classification models and decision structures. They can be used to predict the clinical outcome for individual patients. In contrast to conventional methods, the level of confidence for the predictions can reach 90% and more. This might be an important step towards further individualization of therapeutic strategies.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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There is growing evidence that angiogenesis is important not only in solid tumors but also in hematological malignancies. Recently, we found that bone marrow angiogenesis is a prognostic factor for disease-related survival in patients with multiple myeloma. In this report, we addressed the question of whether the microvessel density in bone marrow biopsies is correlated to other myeloma parameters, e.g., serum beta2-microglobulin (beta2-MG) and plasma cell infiltration in the bone marrow. In 22 multiple myeloma patients, immunohistochemical, CD34-stained, paraffin-embedded bone marrow biopsies before and after chemotherapy were studied. Microvessels were counted in 400x magnification, and the mean number of vessels per area in each sample was noted as the microvessel density (MVD). Pretreatment bone marrow MVD (median: 44, range: 11-175 vessels/mm2) correlated significantly with the bone marrow plasma cell infiltration (median: 30%, range: 5-90%, r = 0.642, P=0.001) and beta2-MG (median: 2.74, range: 1.4-26.1 mg/l, r = 0.749, P < 0.0005). In contrast, there was no correlation between posttreatment MVD and plasma cell infiltration or beta2-MG (median: MVD 31, range: 0-221 vessels/mm2, median plasma cell infiltration: 15%, range: 5-80%, r = 0.229, P = 0.306 and median beta2-MG: 2.65, range: 1-27.6 mg/l, r = -0.042, P = 0.853). These findings show that the strong correlations between bone marrow MVD and plasma cell infiltration as well as serum beta2-MG levels disappear after chemotherapy. The underlying mechanisms need further investigations. [ABSTRACT FROM AUTHOR]

Abstract: The impact of angiogenesis is well known for the growth and viability of solid tumors. Fewer studies have been published relating angiogenesis to clinical or pathological parameters in hematological malignancies. In this report, we have estimated the bone marrow microvessel density (MVD) before and after conventional-dose or high-dose chemotherapy with autologous stem cell transplantation. Immunohistochemical CD34-stained paraffin-embedded bone marrow biopsies of 21 patients with stage III multiple myeloma were studied. Microvessels were counted at 400× magnification, and the mean number of vessels per area in each sample was noted as the MVD. The median MVD of all patients was 53.1 vessels/mm2 (range 15.5–174.7 vessels/mm2) before treatment and 29.3 vessels/mm2 (range 0–221.1 vessels/mm2) after chemotherapy. The post-treatment MVD in the two groups of patients with and without remission was significantly different (p=0.001), whereas the pretreatment MVD was not. Responders but not nonresponders showed a significant decrease of MVD after therapy in comparison to their pretreatment levels. The progression-free survival in patients who achieved a reduction in MVD after chemotherapy was significantly longer than in patients without a decrease in MVD (P=0.006). Furthermore, we compared the MVD of patients after achievement of a remission to MVD of 15 untreated stage I myeloma patients. The MVD of patients in remission was not statistically different from the MVD in stage I myeloma. These results underscore the impact of angiogenesis in myeloma and give the first report that effective chemotherapy is accompanied by a significant decrease in bone marrow angiogenesis in this disease. [ABSTRACT FROM AUTHOR]

The influence of underlying disease on documented infections has rarely been addressed in patients treated with high-dose chemotherapy (HDCT) and subsequent autologous peripheral blood stem cell transplantation (PBSCT). Because autografting has been used most frequently for malignant lymphomas and breast cancer, we analyzed in a retrospective study the data of 100 consecutive adult patients with either malignant lymphomas (group A, n = 50) or breast cancer (group B, n = 50) treated with HDCT at a single institution. The number of autografted CD34+ cells was not statistically different in either group. In this paper, we show for the first time that there is a significant difference in clinically or microbiologically documented infections in these groups of patients: documented infections occurred in 30% of malignant lymphoma patients but only in 4% of breast cancer patients (P=0.001). Of all isolated microorganisms, 78% were gram-positive. Because most of the documented infections were due to staphylococci, further studies should prospectively evaluate preventive measures to reduce the high incidence of these infections. This is especially important for lymphoma patients, who can be regarded as a high-risk group concerning gram-positive bacteremia. [ABSTRACT FROM AUTHOR]

The importance of neoangiogenesis for the progressive growth and viability of solid tumors is well established. Recently, there has been growing evidence that angiogenesis might also be important in hematological malignancies, but only few data are available. In this report, we have studied the impact of bone marrow microvessel density and survival in patients with multiple myeloma (MM). Immunohistochemical CD34 stained paraffin-embedded bone marrow biopsies of 44 patients with newly diagnosed MM were studied. Microvessels were counted in 400 x magnification and the mean number of vessels per area in each sample was noted as the microvessel density (MVD). The median MVD was 48 vessels/mm2, the range was 0-125 vessels/mm2. Using a cut-off value of the median MVD in the Kaplan-Meier analysis, the median survival was 22.2 months in the group with the higher MVD and was not reached in the group with the lower MVD (P< 0.01). In a multivariate Cox regression analysis, using previously identified prognostic factors beta2-microglobulin, C-reactive protein (CRP), and age, MVD remained significant as a prognostic factor (P< 0.03). [ABSTRACT FROM AUTHOR]

An 18-year-old woman was admitted to hospital because of subcutaneous hematoma and fever of unknown origin. Acute myeloid leukemia was diagnosed and empirical antimicrobial treatment and induction chemotherapy were started. After initial defervescence, fever relapsed 2 days after the onset of neutropenia. The CT scan of the lung was consistent with an invasive fungal infection. Treatment with amphotericin B was started and antimicrobial treatment was continued with liposomal amphotericin B because of an increase in creatinine later. The fever persisted and the patient suddenly developed progressive neurological symptoms. CT scan of the head suggested cerebral infarction and angiography of the extra- and intracranial arteries showed signs of vasculitis. Six days after the onset of neurological symptoms cerebral death was diagnosed. Autopsy revealed non-septate, irregularly branched hyphae in various histologic sections including brain. Absidia corymbifera could be isolated from lung tissue confirming the diagnosis of disseminated mucormycosis. In this case, angiographic findings suggested severe cerebral vasculitis which was in fact caused by thromboembolic dissemination of fungal hyphae. This case underlines the fact that cerebral symptoms in febrile neutropenic patients are highly indicative for fungal infections of the brain. [ABSTRACT FROM AUTHOR]

Primary systemic AL (amyloid light-chain) amyloidosis is a plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure. The prognosis of primary amyloidosis is generally poor, with a median survival of 1-2 years. There is no available treatment which improves impaired organ function by induction of amyloid mobilization. Since amyloidosis is a dynamic process, measures that reduce the supply of the amyloid fibril precursor protein can result in a major regression of the deposits. Conventional-dose melphalan can prolong the median duration of survival from 8.5 to 18 months, but the clinical response rates with improvement of impaired organ function are low and the response is slow. Preliminary data suggest that VAD is effective in AL amyloidosis. Up-front high-dose chemotherapy with autologous peripheral blood stem cell transplantation can result in an improvement of the patient's clinical condition, but the treatment-related toxicity can be high, owing to impaired organ function. The use of VAD followed by high-dose chemotherapy is the concept of a German trial. The improvement of the patient's condition prior to high-dose chemotherapy by induction of a remission with VAD might reduce the transplantation-related morbidity and mortality in amyloidosis. [ABSTRACT FROM AUTHOR]

The pyruvate-stimulated adenylate cyclase from Brevibacterium liquefaciens produces up to 450 µM cyclic AMP in the culture medium when the bacterium is grown on glucose and alanine. In this paper we report the cloning, expression and sequencing of the gene for this enzyme. Residues were identified, within the C-terminal domain, which are conserved in adenylate and guanylate cyclase sequences from eukaryotes and in the adenylate cyclase of the prokaryote Rhizobium meliloti. We have also identified a sequence of 30 residues near the N-terminus of the protein which is homologous to part of the regulatory domain of the cellular homologues of the oncogenes fes and fps; this sequence is also present in the avian Fujinami sarcoma virus fps gene. [ABSTRACT FROM AUTHOR]

The adenylate cyclase toxin of the prokaryote Bordetella pertussis is stimulated by the eukaryotic regulatory protein, calmodulin. A general strategy, using the adenylate-cyclase-calmodulin interaction as a tool, has permitted cloning and expression of the toxin in Escherichia coli in the absence of any S. pertussis trans-activating factor. We show that the protein is synthesized in a large precursor form composed of 1706 amino acids. The calmodulin-stimulated catalytic activity resides in the amino-terminal 450 amino acids of the adenylate cyclase. The enzyme expressed in E. coli is recognized in Western blots by antibodies directed against purified B. pertussis adenylate cyclase, and its activity is inhibited by these antibodies. [ABSTRACT FROM AUTHOR]

The effects of various long-chain acyl-carnitines (AC) on mitochondrial functions and red cell membrane stability were studied. Lower concentrations slightly stimulate respiration-dependent functions such as phosphorylation rate and Ca uptake velocity, whereas higher concentrations inhibit these functions with concomitant depression of the ATP/O ratio. The order of effectiveness among the AC is very similar for different mitochondrial function. The differences among AC in their actions on red cell stability in hypotonic media and their differences in influence on mitochondiral functions exhibit less resemblance. The relative order of erythrolytic concentrations of AC follows the order of their critical micellar concentration. Model calculations indicate that the concentrations of AC found in ischemic hearts are below those which exhibit inhibitory effects in vitro. Ultrastructural changes in mitochondria incubated with AC are different from those found in ischemic tissue. From this, it seems questionable whether the elevated AC levels in ischemic hearts are indeed as importan for the development of membrane damage as is often supposed. [ABSTRACT FROM AUTHOR]

In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits. Monoclonal λ light chains were identified in serum and urine. A low percentage of monoclonal plasma cells was detected in the bone marrow. The patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT) with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell transplantation. Proteinuria rapidly diminished during chemotherapy. Three months after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are currently detectable. Using VAD before starting HDCT may improve the condition of patients with amyloidosis and reduce transplantation-related morbidity and mortality. [ABSTRACT FROM AUTHOR]

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9x10(9)/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 29-year-old woman, who achieved pregnancy of twins by intrauterine insemination. The first-trimester screening test revealed visible fetal bladders, and a low risk of Down's syndrome. Moreover, the woman undergone vesicoamniotic shunt treatment for late onset lower urinary tract obstruction.

A response by E. Terpos and O. Sezer to a letter to the editor about their article "The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma" is presented.

A correction to the article "Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma" is presented.