Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.

Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation

Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has achieved success only in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In the study described here, we investigated the functional importance of autophagy in APL cell differentiation. We found that autophagy is increased during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of the APL cell line NB4 and that this is associated with increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we found that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.

Only Neochordoplasty Achieves Physiological Trans-valvular Pressure Gradients After Repair Of Acute Posterior Leaflet Prolapse In Porcine Mitral Valves

Objective: Minimizing resection and preserving leaflet tissue has been previously shown to be beneficial for mitral valve function and leaflet kinematics after repair of acute posterior leaflet prolapse in porcine valves. We examined the effects of different additional methods of mitral valve repair (neochordoplasty, ring annuloplasty, edge-to-edge repair and triangular resection) on hemodynamics at different heart rates in an experimental model. Methods: Severe acute P2 prolapse was created in eight porcine mitral valves by resecting the posterior marginal chordae. Valve hemodynamics was quantified under pulsatile conditions in an in vitro heart simulator before and after surgical manipulation. Mitral regurgitation was corrected using four different methods of repair on the same valve: neochordoplasty with expanded polytetrafluoroethylene sutures alone and together with ring annuloplasty, edge-to-edge repair and triangular resection, both with non-restrictive annuloplasty. Residual mitral valve leak, trans-valvular pressure gradients, flow and cardiac output were measured at 60 and 80 beats/min. A validated statistical linear mixed model was used to analyze the effect of treatment. The p values were calculated using a two-sided Wald test. Results: Only neochordoplasty with expanded polytetrafluoroethylene sutures but without ring annuloplasty achieved similar hemodynamics compared to those of the native mitral valve (p range 0.071-0.901). Trans-valvular diastolic pressure gradients were within a physiologic range but significantly higher than those of the native valve following neochordoplasty with ring annuloplasty (p=0.000), triangular resection (p=0.000) and edge-to-edge repair (p=0.000). Neochordoplasty alone was significantly better in terms of hemodynamic than neochordoplasty with a ring annuloplasty (p=0.000). These values were stable regardless of heart rate or ring size. Conclusions: Neochordoplasty without ring annuloplasty is the only repair technique able to achieve almost native physiological hemodynamics after correction of leaflet prolapse in a porcine experimental model of acute chordal rupture.

Liposome -mediated delivery of all-{\it trans\/}-retinoic acid

Because of its antiproliferative and differentiation-inducing properties, all-trans-retinoic acid (ATRA) has been used as a chemopreventive and therapeutic agent, for treatment various cancers including squamous cell carcinomas (SCCs). Long-term treatment with ATRA is associated with toxic effects in patients leading to acute or chronic hypervitaminosis syndrome. Moreover, prolonged treatment with oral ATRA leads to acquired resistance to the differentiation-inducing effects of the drug. This resistance is attributed to the induction of cytochrome P-450-dependent catabolic enzymes that lead to accelerated ATRA metabolism and decline in circulating levels. Most of these problems could be circumvented by incorporating ATRA in liposomes (L-ATRA) which results in sustained drug release, decrease in drug-associated toxicity, and protection of the drug from metabolism in the host. Liposomes also function as a solubilization matrix enabling lipophilic drugs like ATRA to be aerosolized and delivered directly to target areas in the aerodigestive tract and lungs. Of the 14 formulations tested, the positively-charged liposome, DPPC:SA (9:1, w/w) was found to be most effective in interacting with SCC cell lines. This, L-ATRA formulation was stable in the presence of serum proteins and buffered the toxic effects of the drug against several normal and malignant cell lines. The positive charge attributed by the presence of SA was critical for increased uptake and retention of L-ATRA by SCC cell lines and tumor spheroids. L-ATRA was highly effective in mediating differentiation in normal and transformed epithelial cells. Moreover, liposomal incorporation significantly reduced the rate of ATRA metabolism by cells and isolated liver microsomes. In vivo studies revealed that aerosol delivery is an effective way of administering L-ATRA, in terms of its safety and retention by lung tissue. The drug so delivered, is biologically active and had no toxic effects in mice. From these results, we conclude that liposome-incorporation is an excellent way of delivering ATRA to target tissues. The results obtained may have important clinical implications in treating patients with SCCs of the aerodigestive tract. ^

Planktonic foraminifera in the trans-tropical Pacific Ocean

Cores from four Ocean Drilling Program (ODP) sites were examined for planktonic foraminifers. One sample per core (from core-catchers in Holes 806B and 807B and from Section 4 in Holes 847B and 852B) was examined through the interval representing the last 5.8 m.y. Sites 806 (0°19.1'N; 159°21.7'E) and 847 (0o12.1'N; 95°19.2'W) are beneath the equatorial divergence zone. Sites 807 (3°36.4'N; 156°37.5'E) and 852 (5°19.6'N; 110°4.6'W) are located north of the equator in the convergence zone created by the interaction of the westward-flowing South Equatorial Current (SEC) and the eastward-flowing North Equatorial Countercurrent (NECC). Specimens were identified to species and then grouped according to depth habitat and trophic level. Species richness and diversity were also calculated. Tropical neogloboquadrinids have been more abundant in the eastern than in the western equatorial Pacific Ocean throughout the last 5.8 m.y. During the mid-Pliocene (3.8-3.2 Ma), their abundance increased at all sites, while during the Pleistocene (after ~ 1.6 Ma), they expanded in the east and declined in the west. This suggests an increase in surface-water productivity across the Pacific Ocean during the closing of the Central American seaway and an exacerbation of the productivity asymmetry between the eastern and western equatorial regions during the Pleistocene. This faunal evidence agrees with eolian grain-size data (Hovan, 1995) and diatom flux data (Iwai, this volume), which suggest increases in tradewind strength in the eastern equatorial Pacific that centered around 3.5 and 0.5 Ma. The present longitudinal zonation of thermocline dwelling species, a response to the piling of warm surface water in the western equatorial region of the Pacific, seems to have developed after 2.4 Ma, not directly after the closing of the Panama seaway (3.2 Ma). Apparently, after 2.4 Ma, the piling warm water in the west overwhelmed the upwelling of nutrients into the photic zone in that region, creating the Oceanographic asymmetry that exists in the modern tropical Pacific and is reflected in the microfossil record. In the upper Miocene and lower Pliocene sediments, the ratio of thermocline-dwelling species to mixed-layer dwellers is 60%:40%. During the mid-Pliocene, the western sites became 40% thermocline and 60% mixed-layer dwellers. Subsequent to -2.4 Ma, the asymmetry increased to 20%: 80% in the west and the reverse in the east. This documents the gradual thickening of the warm-water layer piled up in the western tropical Pacific over the last 5.8 m.y. and reveals two "steps" in the biotic trend that can be associated with specific events in the physical environment.

Geology, geochemistry, and mineralogy of sediments from the Trans Indian Ocean Geotraverse

The monograph is devoted to the main results of research on the Trans Indian Ocean Geotraverse from the Maskarene Basin to the north-western margin of Australia. These results were obtained by Russian specialists and together with Indian specialists during 15 years of cooperation in investigation of geological structure and mineral resources of the Indian Ocean. The monograph includes materials on information support of marine geological and geophysical studies, composition and structure of information resources on the Indian Ocean, bathymetry and geomorphology, structure and geological nature of the magnetic field, gravity field, plate tectonics, crustal structure and sedimentary cover, seismic stratigraphy, perspectives for detecting oil and gas, solid minerals, sediment composition, composition and properties of clay minerals, stratigraphy and sediment age, chemical composition of sediments, composition of and prospects for solid minerals.