A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

This corrects the article DOI: 10.1038/leu.2016.303.

A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials.

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

Percutaneous transluminal atherectomy of the superficial femoral and popliteal arteries: long-term results in 48 patients.

PURPOSE: Evaluate retrospectively the long-term primary patency of directional atherectomy (DA) in the femoropopliteal arteries. MATERIALS AND METHODS: DA was used alone in 59 patients (47%) or in combination with predilatation to allow passage of the device (43%) or after thrombolysis (10%) to treat 127 (93%) excentric atherosclerotic stenoses and nine (7%) occlusions of the femoropopliteal arteries. Forty-eight patients were followed by telephone interview, scheduled outpatient visits, color-flow Doppler evaluation, and angiography for 1-36 months (mean 16.9 months). RESULTS: Technical success (reduction of the stenosis or occlusion to less than 30% luminal diameter) was achieved in 110 lesions (80.3%) during 48 procedures in 37 patients. Mean luminal diameter was increased 54% with a concomitant increase in mean ankle/brachial indices of 0.33. According to Kaplan-Meier survival curves, patency at 12 and 24 months was 88% and 75%, respectively. When patients who retained patency but developed restenosis were excluded, the probability of patency at 12, 24, and 36 months was 76%, 58%, and 32%, respectively. Major and minor complications occurred in 15 (21.4%) procedures each for a total complication rate of 42.8%. CONCLUSION: Based on our results, DA is an effective method for percutaneous treatment of atherosclerotic disease involving the femoropopliteal arteries. It has similar patency but a relatively high complication rate compared with PTA.

Interleukin-6 regulates expression of the syndecan-1 proteoglycan on B lymphoid cells.

Proteoglycans participate in hematopoiesis and immune responses by mediating cell adhesion and by binding and presenting growth factors to cells. However, the mechanisms that regulate proteoglycan expression on cells of the immune system have not been defined. Syndecan-1, a member of the syndecan family of integral membrane proteoglycans, is expressed by pre-B cells and plasma cells but is absent from circulating B cells. Because IL-6 is an important cytokine in both B cell differentiation and in the progression of B cell-related diseases, we examined the effect of IL-6 on syndecan-1 expression. Following growth of murine B lymphoid cells in medium containing IL-6, the level of syndecan-1 detected is dramatically reduced. This reduction in syndecan-1 expression is dependent on the concentration of IL-6 present in the medium, with syndecan-1 levels being 2.5- to 5-fold lower than those of controls when cells are grown in media containing 10 and 1000 U/ml of IL-6, respectively. The effect of IL-6 on syndecan-1 expression is time dependent, with syndecan-1 levels declining over the first 48 hr. This trend is reversible because following removal of exogenous IL-6, syndecan-1 levels increase within 24 hr to 80% of their control levels. The regulation of syndecan-1 expression by IL-6 appears to be via post-transcriptional mechanisms because syndecan-1 mRNA levels are not decreased following growth of cells in the presence of IL-6. Furthermore, IL-6 does not alter syndecan-1 structure and therefore its effect is different from that of TGF-beta which alters syndecan-1 glycosylation but not the number of syndecan-1 molecules at the cell surface. We conclude that IL-6 participates in the regulation of syndecan-1 expression on B lymphoid cells and, given its broad distribution, IL-6 may regulate proteoglycan expression on other cell types as well.

Adhesion of B lymphoid (MPC-11) cells to type I collagen is mediated by integral membrane proteoglycan, syndecan.

Differentiating B lymphocytes undergo changes in cell-cell and cell-matrix adhesion that control their movement through a series of distinct microenvironments. The integral membrane proteoglycan, syndecan, is a candidate for mediating B lymphocyte-matrix interactions because it is expressed on B lymphocytes only at times when they associate with matrix, and because syndecan is known to behave as a matrix receptor on simple epithelia. However, syndecan from B lymphocytes is significantly smaller in molecular mass than syndecan from simple epithelia (85 vs 160 kDa) suggesting that syndecan may have distinct functions on these two cell types. Our study was undertaken to determine if syndecan mediates adhesion of B lineage cells to extracellular matrix. The murine myeloma cell line MPC-11 was used because syndecan is the only major heparan sulfate proteoglycan detected on these cells and because they express a form of syndecan almost identical to that found on normal B lymphocytes. Cell binding assays demonstrate that syndecan binds MPC-11 cells to type I collagen. Binding is inhibited by heparin, by pretreatment of cells with heparitinase or by growth of cells before the assay in chlorate, an inhibitor of sulfation. Solid phase assays show that syndecan purified from MPC-11 cells binds to type I collagen but not type IV collagen, laminin, or fibronectin. The interaction of MPC-11-derived syndecan with type I collagen is of relatively high affinity (Kd app = 143 nM) as measured by affinity coelectrophoresis. However, the 160-kDa form of syndecan isolated from epithelial cells has a greater than fourfold higher affinity for type I collagen (Kd app = 31 nM) than does the MPC-11 syndecan, suggesting that different molecular forms of syndecan have distinct ligand binding properties. These results demonstrate that syndecan can mediate B lymphocyte interactions with matrix and suggest that changes in syndecan expression during B cell differentiation are a mechanism for controlling B cell localization within specific microenvironments.

Purification and properties of a distinct protamine kinase from the cytosol of bovine kidney cortex.

A protamine kinase has been purified to apparent homogeneity from extracts of the cytosol of bovine kidney cortex. This protamine kinase exhibited an apparent Mr = 43,000 as estimated by gel permeation chromatography on Sephacryl S-200 and an apparent Mr = 45,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified protamine kinase exhibited about 5% activity with casein, 8% with histone H2B, and less than 0.1% with histone H1, histone H4, glycogen synthase a from rabbit skeletal muscle, ovalbumin, bovine serum albumin, and phosvitin. The activity of the highly purified protamine kinase was unaffected by cyclic AMP (up to 0.1 mM), cyclic GMP (up to 0.1 mM), the heat-stable protein inhibitor of cyclic AMP-dependent protein kinase (up to 100 micrograms/ml), heparin (up to 100 micrograms/ml), EGTA (up to 1 mM), Ca2+ (up to 1 mM), calmodulin (up to 0.5 microM) in the absence or presence of Ca2+ (0.05 mM), and phosphatidylserine (up to 40 micrograms/ml) and/or diolein (up to 1 microgram/ml) in the absence or presence of Ca2+ (up to 0.5 mM). Experiments in which extracts of kidney cytosol were incubated with [gamma-32P]ATP and MgCl2 revealed that the phosphorylation of numerous polypeptides was markedly increased in the presence of the purified protamine kinase. The results indicate that this protamine kinase of kidney cytosol is a novel protein kinase.