Long-term survival in a patient with AL amyloidosis after cardiac transplantation followed by autologous stem cell transplantation.
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Adult↗
Biomedical subjects
H Goldschmidt
Publications and source records attributed to H Goldschmidt.
Preoperative elevation of serum C--reactive protein is predictive for prognosis in myeloma bone disease after surgery.
We investigated whether preoperative levels of serum C-reactive protein (CRP) and its correlation with tumour clinicopathological findings adds prognostic information beyond the time of diagnosis in patients with myeloma bone disease (MM) to facilitate the surgical decision-making process. Six hundred and fifty-eight myeloma patients were evaluated retrospectively for surgery. Clinicopathological variables of patients who underwent surgery (n=71) were compared between patients with preoperative CRP>or=6 mg l-1 and those with CRP<6 mg l-1. Univariate and multivariate analyses were performed to identify prognostic factors after surgery. Patients with an increase of CRP prior to surgery showed inferior survival compared to patients with normal levels. Patients with normal CRP levels at diagnosis but elevations prior to surgery do seem to have a similar unfavourable overall survival (OS) than patients with an increase both, at diagnosis and at surgery. Conversely, patients with normal CRP levels prior to surgery still have the best OS, irrespective of their basic values. Multivariate analysis revealed preoperative CRP levels above 6 mg l-1 Lactate dehydrogenase (LDH) above normal, and osteolyses in long weight bearing bones as independent predictors of survival. These findings suggest that in patients with MM serum levels of CRP increase during disease activity and might be significantly correlated with specific disease characteristics including adverse prognostic features such as osteolyses in long weight bearing bones. Thus, preoperative elevated CRP serum levels might be considered as independent predictor of prognosis and could provide additional prognostic information for the risk stratification before surgical treatment in patients with myeloma bone disease.
Adult↗
Clinical significance of cyclooxygenase-2 (COX-2) in multiple myeloma.
Several biological and clinical considerations suggest the involvement of cyclooxygenase-2 (COX-2), the key enzyme of prostaglandin (PG) synthesis, in the pathogenesis and progression of haematological malignancies. Despite the wealth of data concerning COX-2 expression, only limited information is available on multiple myeloma (MM). Using standard immunohistochemistry we therefore evaluated COX-2 protein expression in samples from 57 patients with a primary diagnosis of MM. Time to progression and a variety of clinicopathological features were evaluated by the Kaplan-Meier method and the Cox regression model. In addition, COX-2 expression was evaluated by staining bone marrow from healthy donors and 11 patients with MGUS. Overall, 31 MM samples (54%) expressed COX-2. Positivity for COX-2 was unrelated to stage or clinical or molecular features of the disease. However, patients with COX-2 positive tumours experienced a significantly shorter time to progression (17 vs 30 months, p = 0.037). In summary, COX-2 is frequently expressed in MM and correlates with shorter progression-free survival.
Adult↗
Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma.
The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) - neuregulin-1, amphiregulin, HB-EGF - promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10(5) molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.
B-Lymphocytes↗
[Targeted therapy in the treatment of solid tumors and in hematology-oncology. Advances and disappointments].
The development and clinical introduction of targeted therapies has resulted in significant progress for the treatment of malignant diseases. These forms of therapy supplement traditional methods of chemotherapy, radiation, and surgery. As new therapies increase the complexity of therapeutic options in oncology, the treatment costs steadily climb as well. Parameters need to be identified which will predict a response to new substances, and this effort is the subject of ongoing studies.
Antineoplastic Agents↗
Chromosomal aberrations in 130 patients with multiple myeloma studied by interphase FISH: diagnostic and prognostic relevance.
The study described the molecular cytogenetic characterization of myeloma cells in 130 patients via interphase fluorescence in situ hybridization. Nine repetitive DNA probes (for chromosomes 3, 7, 9, 11, 15, 17, 18, X, and Y) as well as seven single-copy DNA probes (for chromosomes 13, 17, 21, and two each for chromosomes 5 and 22) were used for the hybridizations. Using this panel of probes, we were able to show aberrations in 86% of patients. Most of them had one to three aberrations. There was a distinct correlation between the number of aberrations per patient and the tumor stage. Thus, the proportion of patients with 8-12 aberrations increased from 16% in stage II to 26% in stage III. There were marked differences among the chromosomes with respect to the prevalence of genomic losses and gains and deletions of gene loci. Chromosomes 3, 5, 7, 9, 11, 15, and 21 showed a preference for genomic gains. Losses were most often found for chromosomes 13 and 17 (locus specific) as well as for the X and Y chromosomes. The frequency of monosomies and trisomies were approximately the same for chromosomes 15 and 18, which indicates a skewed pattern of distribution. We found two specific aberrations that caused distinct changes in the survival rates of the patients: deletion 13q14 (28% of patients) and translocation of the IGH locus 14q32 (79% of 39 patients who were analyzed separately). The results obtained in this study yielded data of extremely relevant prognostic value.
Adult↗
Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial.
Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.
Acute Disease↗
Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma.
In this retrospective study, we evaluated donor lymphocyte infusions given for relapsed (n=48) or persistent (n=15) myeloma following non-myeloablative allogeneic stem cell transplantation (Allo-SCT). Twenty-four of 63 patients (38.1%) responded: 12 patients (19.0%) with a partial response (PR) and 12 patients (19.0%) with a complete response (CR). Overall survival after donor lymphocyte infusions (DLI) was 23.6 months (1.0-50.7+). Median overall survival for non-responding patients was 23.6 months and has not been reached for the patients responding to DLI. In responders, progression-free survival after DLI was 27.8 months (1.2-46.2+). Patients with a PR had a median progression-free survival of 7.0 months, whereas patients with a CR to DLI had a median progression-free survival of 27.8 months. Major toxicities were acute graft-versus-host disease (GVHD) (38.1%) and chronic GVHD (42.9%). Seven patients (11.1%) died from treatment-related mortality. The only significant prognostic factors for response to DLI were the occurrence of acute and chronic GVHD. There was a trend towards significance for time between transplantation and DLI, and response. Donor lymphocyte infusion following non-myeloablative Allo-SCT is a valuable strategy for relapsed or persistent disease.
Acute Disease↗
[Effects of a programme for structured outpatient follow-up care after inpatient rehabilitation of obese children and adolescents--a multicentre, randomized study].
INTRODUCTION: Inpatient rehabilitation is an important contributor to the treatment of child and adolescent obesity with comorbidity in Germany. Thus far outpatient follow-up care has not been subject to research. The main goal of this study is the development and longer-term evaluation of a programme for structured outpatient follow-up care by primary care physicians after inpatient rehabilitation of obese children and adolescents. METHODS: This multicentre, randomized, parallel controlled clinical trial enrolled 521 children and adolescents aged 9 - 16 (avg. 13.3) years in 7 cooperating specialized rehabilitation facilities. The patients were randomized at the end of their multimodal inpatient treatment that lasted for 5.9 (+/- 1.2) weeks. The intervention consisted of 12 half-hour outpatient consultations by the primary care physicians utilizing a modular consultation guideline and an internet-based training programme. The control group received standard care. Outcome variables included anthropometric measures, questionnaires on eating behaviour, physical activity, quality of life, self-efficacy and subjective rating of the intervention. Measurements were performed at the beginning (t1) and end (t2) of inpatient rehabilitation as well as 6 (t3) and 12 (t4) months after discharge. RESULTS: There was a highly significant improvement of BMI-z-score (standard deviation score of the Body Mass Index), relevant behaviour, quality of life and self-efficacy between t1 and t4. On intention to treat analysis no differences were detected between intervention and control groups. The intervention was utilized by only 50 % of entitled. The BMI-z-score reached a minimum at t3 (6-month follow-up). Predictors of longer-term BMI-z-score decline were psychological suffering, poor eating behaviour, low physical activity and high socio-economic status. In multivariate linear regression improvement of eating behaviour and physical activity correlated with the improvement of BMI-z-score. DISCUSSION: This low-level outpatient intervention did not improve the demonstrated longer-term effectiveness of inpatient rehabilitation. An interdisciplinary outpatient follow-up care in groups with inclusion of the parents is recommended.
Adolescent↗
Thalidomide in multiple myeloma.
Thalidomide (Thal) has antiangiogenic and immunomodulatory activity. Clinical research provided clear evidence that Thal is one of the most active drugs for the treatment of multiple myeloma leading to decrease of monoclonal protein of at least 50 % in 30 % of patients with relapsed or refractory multiple myeloma. Randomized trials based on a large body of evidence from phase II trials determined that Thal significantly increases total response rate in combination regimens (dexamethasone [Dex] and or chemotherapy) for relapsed as well as newly diagnosed patients. Thal also decreases time to response in combination therapy approaches. Thal has therefore been recognized by leading organizations as part of the treatment concept for patients with relapsed or refractory disease. Strict guidelines apply for the treatment and monitoring of Thal therapy to prevent the teratogenic effects of Thal and to monitor and prevent other potential adverse events as neuropathy and thrombosis. Additional randomized studies will now define the status of Thal for newly diagnosed patients and will be the basis for the approval in Europe and other countries world wide.
Angiogenesis Inhibitors↗
Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma -- CapRI: study protocol [ISRCTN62866759].
UNLABELLED: After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation. DESIGN: The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrollment. DISCUSSION: The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers.
Adenocarcinoma↗
Molecular monitoring of tumour load kinetics predicts disease progression after non-myeloablative allogeneic stem cell transplantation in multiple myeloma.
BACKGROUND: Non-myeloablative allogeneic stem cell transplantation followed by immunomodulatory therapies is considered a potentially curative approach in the treatment of multiple myeloma and most effective in a minimal residual disease setting. PATIENTS AND METHODS: The aim of this study was to find the most sensitive real-time PCR assay (TaqMan), based on the IGH rearrangement, to quantify the tumour load of 11 patients with multiple myeloma after non-myeloablative allogeneic transplantation. Patient-allele specific primers (ASO) and the TaqMan probe were derived from CDR2 and CDR3 hypervariable regions of IGH, while consensus primers were located within the FR3 and FR4/JH regions. Four different approaches of primer combinations were tested. RESULTS: ASO-forward and -reverse primers together with the clone-specific TaqMan probe were the most sensitive approach compared with the JH (P=0.071) or the FR3 consensus primer (P <0.001). The detection limit amounted to 1/10(4)-1/10(5) cells. Consecutively, 120 samples from 11 patients prior and post allogeneic transplantation were analysed. Three patients reached complete clinical remission accompanied by molecular remission. Disease progression or relapse was seen in six patients. In five, molecular progressive disease was detected prior to the clinical diagnosis of progression or relapse. CONCLUSION: Patient-specific real-time IGH-PCR provides the opportunity for earlier treatment intervention.
Adult↗
Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.
Conventional treatment or autologous transplantation has not been able to achieve long-term remission in patients with multiple myeloma (MM). Nonmyeloablative allogeneic transplantation might offer an option for cure without the high mortality associated with conventional conditioning. Here we present a retrospective analysis of patients with high-risk MM treated with nonmyeloablative allogeneic transplantation. In all, 52 patients with relapsed MM or high-risk features at diagnosis received 2 Gy TBI alone (n=3) or with fludarabine (n=49) as conditioning. Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. Regimen-related toxicity was low. Acute graft-versus-host disease II-IV occurred in 37% of patients, and 70% experienced chronic graft-versus-host disease (cGvHD). Median follow-up was 567 days, and transplant-related mortality was 17% in total. Estimated progression-free and overall survival at 18 months was 29.4 and 41.1%, respectively. Patients with cGvHD had a significantly higher progression-free survival, as did patients with up to eight cycles of pretreatment chemotherapy vs those with nine or more. In this highly pretreated patient group, disease control was unsatisfactory and our results suggest that a potential strategy might be to perform allogeneic transplant earlier in the course of the disease.
Adult↗
[Correlation of MRI and histopathology of bone marrow in patients with multiple myeloma].
PURPOSE: To compare MRI findings and histological plasmacellular infiltration of the bone marrow in patients with multiple myeloma (MM). MATERIAL AND METHODS: Twenty-four patients with different stages of MM underwent 1.5T MRI of the pelvic bone before iliac crest punch biopsy. Precontrast T1wSE and STIR and postcontrast (Gd-DTPA) T1wSE-fatsat were acquired using axial slices. Immediately after the biopsy, T1wSE was repeated to locate the biopsy canal. The corresponding region in the examination before punch biopsy was assessed for bone marrow involvement using a three-point score (0: negative, 1: suspect, 2: definite). RESULTS: Two patients were not included because the location of the biopsy canal was unclear. Of 7 patients without histological plasmacellular infiltration, MRI was false positive in one case (suspect). Of 15 patients with histological infiltration, MRI was positive in 10 cases (4 suspect, 6 definite). The T1wSE was positive in 9 cases, STIR in 8 cases, and postcontrast T1wSE-fatsat in 7 cases. In 10 of the 15 patients, the infiltration was histologically graded as low (5 - 20 % of bone marrow). In this group, MRI was only positive in 5 cases (3 suspect, 2 definite). Of five patients with the infiltration histologically graded as high (> 20 % of bone marrow), MRI was positive in all cases (1 suspect, 4 definite). CONCLUSION: Only advanced bone marrow infiltration in MM can be reliably detected by MRI. None of the used sequences proved to be significantly superior or inferior.
Aged↗
Long-term survival after surgical intervention for bone disease in multiple myeloma.
BACKGROUND: We describe the surgical treatment, outcome and long-term survival of patients with multiple myeloma (MM) in response to conventional (CC) or high-dose (HDT) chemotherapy. PATIENTS AND METHODS: Eighty-four patients diagnosed with MM were recruited for the study (51 male, 33 female; median age 62 years) and consecutively surgically treated in a single institution during a 12-year period. The main end point of the study was overall survival after surgery. Cox regression analysis was used to estimate the effect of factors that may predict survival. RESULTS: Spinal surgery was performed in 54 cases, and 30 patients were surgically treated at the extremities. The post-surgical complication rate was low (17%; 14/84 patients). The median overall survival time was 47 months. Patients receiving HDT had a longer 5-year overall survival rate than patients receiving CC (51% versus 33%). Univariate predictors of mortality included age >65 years [risk ratio (RR) 1.62; P=0.023], osteolyses in long weight-bearing bones (RR 2.23; P=0.007) and an elevated C-reactive protein level >5 mg/l (RR 1.82; P=0.016); the latter remained significant as a predictor in multivariate analysis (RR 2.66; P=0.0209). CONCLUSIONS: Given the high number of patients reaching 5-year overall survival and the low post-surgery complication rate, surgery should pursue a long-term stable reconstruction of the affected bone.
Adult↗
High-dose chemotherapy with autologous peripheral blood stem cell transplantation for bone and soft-tissue sarcomas.
The role of high-dose chemotherapy (HDCT) with PBSCT in the treatment of bone and soft-tissue sarcomas is not established. In total, 27 patients (15 female, median age at TPL 30.6 years (range: 13-59)) were analyzed (Ewing sarcoma family n=8, osteosarcoma n=6, MPNST (malignant peripheral nerve sheath tumor) n=4, synovial sarcoma n=3, liposarcoma n=2, leiomyosarcoma n=2, rhabdomyosarcoma n=1, meningosarcoma n=1). Following chemotherapy and surgery complete remission (CR) (n=9), partial remission (PR) (n=10), stable disease (SD) (n=2) and progressive disease (PD) (n=6) were reached prior HDCT. Different HDCT conditioning regimens were used. One patient died due to cardiac arrest after HDCT. Except hematologic side effects, no WHO grade III-IV complications were observed. Four patients died within 6 months due to PD, disease recurred in another seven patients and led to death, 15 patients are alive with/without disease. The median progression-free survival (PFS) is 12.0 months (range: 0-58), in nine CR patients median PFS is 25.8 months (range: 3-58). Although the role of HDCT in the treatment of sarcomas is not defined, a subgroup of patients who achieved CR before HDCT could benefit from this therapy.
Adolescent↗
Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy.
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Adolescent↗
[Dynamic MRI of the bone marrow for monitoring multiple myeloma during treatment with thalidomide as monotherapy or in combination with CED chemotherapy].
PURPOSE: To quantify changes of bone marrow microcirculation in multiple myeloma (MM) using contrast enhanced dynamic MRI (dMRI) during thalidomide as antiangiogenic monotherapy or in combination with chemotherapy (cyclophosphamide, etoposide, dexamethasone). MATERIALS AND METHODS: The study includes 63 patients with refractory or relapsed MM, who underwent dMRI with high temporal resolution (T1w-turboFLASH) of the lumbar spine before and following treatment. The contrast uptake was quantified using a two compartment model with the output parameters amplitude and k (ep) (exchange rate constant). The evaluation considered the initial dMRI finding (pathological or non-pathological) and the clinical therapeutic response (response or no response). RESULTS: During monotherapy with thalidomide (n = 38), no significant changes of the dMRI parameters were found, even when considering the initial dMRI finding (positive n = 22) and the therapeutic response (responder n = 14). The combination with chemotherapy (n = 25) had a significant reduction of k (ep) (p = 0.01) in 18 patients with positive initial dMRI finding and therapeutic response. Reduction of the amplitude was seen in most cases, but in the end without any significance (p = 0.09). CONCLUSION: dMRI can quantify significant changes of bone marrow microcirculation solely during treatment with thalidomide combined with chemotherapy, not with thalidomide alone.
Administration, Oral↗