Renal disease in POEMS syndrome: report on a case and review of the literature

POEMS syndrome is a multisystem disorder associated with plasmacell dyscrasias. This report describes a patient with POEMS-associatedrenal disease and reviews the literature on biopsy-proven renalinvolvement in POEMS syndrome. Our patient had glomerulonephritiswith membranoproliferative features on light-microscopy withoutcharacteristic findings on immunofluorescence, and with ultra-structural evidence of glomerular microangiopathy. Ultrastructuralevidence of microangiopathy was also found in vasa nervorum.In 20 other cases of POEMS- associated renal disease, 16 hadglomerular disease. Light-microscopy showed membranoproliferative-likeglomerulopathy in 14 patients and glomerular microan giopathyin two. Ultrastructural evidence of microangi opathy was presentin all 15 patients in whom electron- microscopy was done. Thus,in most patients with POEMS-associated glomerular disease acharacteristic lesion is present with evidence of endothelialinjury. As endothelial damage is also found in endoneural vessels,generalized endothelial injury may play a role in non-renalmanifestations of POEMS syndrome. In previous reviews manifestationsof the POEMS syndrome were similar for patients with or withoutmyeloma. Among patients with biopsy-proven glomerular disease,however, myeloma patients are underrepres ented. Whether thisrepresents a sampling error or has true pathophysiological significanceremains to be established.     

The significance of the aminoterminal propeptide of type III procollagen in paroxysmal nocturnal haemoglobinuria and myelofibrosis

The level of the aminoterminal propeptide Col 1–3 of type III procollagen (PC-III) was determined in patients with paroxysmal nocturnal haemoglobinuria (PNH) and primary myelofibrosis (PMF), to study whether PC-III can be used as a parameter for the rate and/or degree of bone marrow replacement with collagen. Normal PC-III levels were found in PNH (6.6±1.1 g/l; N: 8.6±1.8 g/l), while significantly increased levels were found in PMF (24.8±2.2 g/l).During a follow-up of 1 year, a slight increase of 2 g/l occurred in three patients with a stable fibrosis, while one patient with more active disease demonstrated an increase of 25 g/l. Treatment with acetylsalicylic acid led to a decline of PC-III as well as -thromboglobulin level, although normalization did not occur. It was demonstrated by means of gel filtration that the antigens related to the PC-III peptide were heterogenous, and that in PMF at least two main peaks were present, with molecular masses equal to and smaller than PC-III peptide.These data demonstrate that the radioimmunoassay cannot be used for the quantitative determination of PC-III; nevertheless it gives some insight in the process of bone marrow fibrosis.     

Radioquimioterapia de la enfermedad limitada del carcinoma pulmonar de célula pequeña. ¿Tratamiento concomitante en protocolos asistenciales?

Purpose We retrospectively reviewed our institution’s database to investigate the outcome and impact of combined radiochemotherapy (RT/CT; concomitant or in sequence) in localised small-cell lung cancer (L-SCLC). Material and methods Between January 1995 to November 1999, 79 patients with L-SCLC received combined RT/CT at our Institution. RT was delivered concurrently or sequentially following the CT. Patients with treatment response received additional prophylactic cranial irradiation (PCI). Results Of the patients treated, 54% had received concurrent CT/RT compared to 46% receiving RT following the CT. PCI was administered to 80% of the patients. Complete response was observed in 66% of patients. With a median follow up of 30 months, median overall survival was 15.9 months; 14.3 months for patients who received RT following CT and 21.6 months for those receiving concurrent CT/RT. The type of schedule of combined radiochemotherapy was an independent prognostic factor for survival free of local recurrence, as was additional PCI for distant metastasis-free survival. Conclusions Our results are similar to those reported previously in the literature. The main point of interest is that our patients were non-selected. We strongly support the use of concurrent CT/RT so as to achieve results comparable to the best in the literature.

     

The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.     

Decrease in visceral fat following diet-induced weight loss in upper body compared to lower body obese premenopausal women

BACKGROUND: Obesity is associated with numerous metabolic disturbances, such as insulin resistance, diabetes mellitus type 2, dyslipidemia, and hypertension. An excess of fat within the abdomen, so-called visceral adiposity, confers a greater and independent health risk of metabolic and cardiovascular complications than does adipose tissue accumulation elsewhere. The present study aimed to investigate a possible differential effect of diet-induced weight loss in visceral fat mass and metabolic parameters in obese individuals with the upper body (UBO) and lower body (LBO) obese phenotype. METHODS: The obese subjects were prescribed a liquid, very-low calorie diet to reduce 50% of their overweight (15% body weight loss). Specific body fat measurements (MRI, BIA), anthropometrics, and fasting metabolic parameters were obtained in control subjects and two groups of obese subjects (UBO and LBO) before and after weight loss. RESULTS: Weight loss was accompanied by significant decreases in total, subcutaneous, and visceral fat in both UBO and LBO women. The largest reduction in visceral fat mass was found in the UBO women (absolute decrease 223+/-32 cm(2) vs 122+/-91 cm(2) in LBO women; P=0.01), while the amount of visceral fat was reduced to normal levels in LBO women (155+/-25 cm(2) after weight loss vs 143+/-17 cm(2) in controls; P=NS). Furthermore, weight loss significantly lowered fasting glucose, total cholesterol, and LDL cholesterol concentrations in UBO women. CONCLUSION: The obese phenotype is preserved after body weight loss. UBO women have to lose a larger amount of overweight in order to bring the amount of fat in the visceral depot down to normal levels and to obtain normalization of their cardiovascular risk profile.     

Progression of a solitary plasmacytoma to multiple myeloma. A population‐based registry of the northern Netherlands

Plasmacytoma is characterized by a local accumulation of monoclonal plasma cells without criteria for multiple myeloma (MM). The current treatment regimen is local radiotherapy. However, more than 50% of patients develop MM within 2 years after treatment. A population‐based registry was consulted for the diagnosis of solitary plasmacytoma between 1988 and 2011. Progression to MM and prognostic features for progression to MM were scored, including hypoxia inducible factors (HIF), vascular endothelial growth factor (VEGF, also termed VEGFA) and micro‐vessel density (MVD) expression in biopsy material. A total of 76 patients were included, 34% having extramedullary plasmacytoma (EMP) while 66% had a solitary plasmacytoma of the bone (SBP). Median follow‐up was 89 months, (7–293 months). In Seventy per cent of SBP patients developed MM with a median time to progression of 19 months (5–293). Three patients (12%) with EMP developed MM. High expression of VEGF and HIF‐2α (also termed EPAS1) was demonstrated in conjunction with an increased MVD in 66% of the patients. No association could be shown between angiogenesis parameters and progression to MM. In conclusion, this population‐based study demonstrates that SBP patients have a higher risk of developing MM following local radiotherapy, indicating that this group might benefit from added systemic chemotherapy.     

Genomic array as compared to karyotyping in myelodysplastic syndromes in a prospective clinical trial

Karyotyping is considered as the gold standard in the genetic subclassification of myelodysplastic syndrome (MDS). Oligo/SNP‐based genomic array profiling is a high‐resolution tool that also enables genome wide analysis. We compared karyotyping with oligo/SNP‐based array profiling in 104 MDS patients from the HOVON‐89 study. Oligo/SNP‐array identified all cytogenetically defined genomic lesions, except for subclones in two cases and balanced translocations in three cases. Conversely, oligo/SNP‐based genomic array profiling had a higher success rate, showing 55 abnormal cases, while an abnormal karyotype was found in only 35 patients. In nine patients whose karyotyping was unsuccessful because of insufficient metaphases or failure, oligo/SNP‐based array analysis was successful. Based on cytogenetic visible abnormalities as identified by oligo/SNP‐based genomic array prognostic scores based on IPSS/‐R were assigned. These prognostic scores were identical to the IPSS/‐R scores as obtained with karyotyping in 95%‐96% of the patients. In addition to the detection of cytogenetically defined lesions, oligo/SNP‐based genomic profiling identified focal copy number abnormalities or regions of copy neutral loss of heterozygosity that were out of the scope of karyotyping and fluorescence in situ hybridization. Of interest, in 26 patients we demonstrated such cytogenetic invisible abnormalities. These abnormalities often involved regions that are recurrently affected in hematological malignancies, and may therefore be of clinical relevance. Our findings indicate that oligo/SNP‐based genomic array can be used to identify the vast majority of recurrent cytogenetic abnormalities in MDS. Furthermore, oligo/SNP‐based array profiling yields additional genetic abnormalities that may be of clinical importance.     

Disturbed granulocyte macrophage-colony stimulating factor priming of phosphatidylinositol 3,4,5-trisphosphate accumulation and Rac activation in fMLP-stimulated neutrophils from patients with myelodysplasia

The production of reactive oxygen species (ROS) by human neutrophils is imperative for their bactericidal activity. Proinflammatory agents such as granulocyte macrophage-colony stimulating factor (GM-CSF) can prime ROS production in response to chemoattractants such as N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). In neutrophils from patients suffering from Myelodysplastic syndromes (MDS), a clonal, hematological disorder characterized by recurrent bacterial infections, this GM-CSF priming is severely impaired. In this study, we set out to further delineate the defects in neutrophils from MDS patients. We examined the effect of GM-CSF priming on fMLP-triggered activation of Rac, a small GTPase implicated in neutrophil ROS production. In contrast to healthy neutrophils, activation of Rac in response to fMLP was not enhanced by GM-CSF pretreatment in MDS neutrophils. Furthermore, activation of Rac was attenuated by pretreatment of neutrophils with the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. Unlike healthy neutrophils, fMLP-induced accumulation of the PI-3K lipid product PI(3,4,5)trisphosphate was not increased by GM-CSF pretreatment in MDS neutrophils. The disturbed Rac and PI-3K activation observed in MDS neutrophils did not appear to reflect a general GM-CSF or fMLP receptor-signaling defect, as fMLP-triggered Ras activation could be primed by GM-CSF in MDS and healthy neutrophils. Moreover, fMLP-induced activation of the GTPase Ral was also normal in neutrophils from MDS patients. Taken together, our data suggest that in neutrophils from MDS patients, a defect in priming of the PI-3K-Rac signaling pathway, located at the level of PI-3K, results in a decreased GM-CSF priming of ROS production.