Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial.

BACKGROUND: The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described. METHODS: We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial. RESULTS: TF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen. CONCLUSION: MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.

Percutaneous absorption of chemicals: developing an understanding for the treatment of disease in frogs.

The permeable nature of frog skin presents an alternative route for the delivery of therapeutic chemicals to treat disease in frogs. However, although therapeutic chemicals are often topically applied to the skin of frogs, their pharmacokinetics have rarely been reported. To provide evidence to guide both candidate drug and formulation selection, we highlight factors expected to influence percutaneous absorption through frog skin, including the anatomy and physiology of the skin and the physicochemical properties of applied therapeutic chemicals. Importantly, we also highlight the effects of the formulation on percutaneous absorption, especially the inclusion of potential penetration enhancers as excipients. Finally, we collate empirical data on the topical application of various therapeutic chemicals in postmetamorphic frogs and show that, in contrast to mammalian species, even large chemicals (i.e. >500 Da) and those with a wide range of log P values (-4 through +6) are likely to be absorbed percutaneously. Topical application in frogs thus promises a convenient and effective method for delivering systemic treatments of a diverse range of chemicals; however, further experimental quantification is required to ensure optimal outcomes.

Preservation of protein fluorescence in embedded human dendritic cells for targeted 3D light and electron microscopy.

In this study, we present a correlative microscopy workflow to combine detailed 3D fluorescence light microscopy data with ultrastructural information gained by 3D focused ion beam assisted scanning electron microscopy. The workflow is based on an optimized high pressure freezing/freeze substitution protocol that preserves good ultrastructural detail along with retaining the fluorescence signal in the resin embedded specimens. Consequently, cellular structures of interest can readily be identified and imaged by state of the art 3D confocal fluorescence microscopy and are precisely referenced with respect to an imprinted coordinate system on the surface of the resin block. This allows precise guidance of the focused ion beam assisted scanning electron microscopy and limits the volume to be imaged to the structure of interest. This, in turn, minimizes the total acquisition time necessary to conduct the time consuming ultrastructural scanning electron microscope imaging while eliminating the risk to miss parts of the target structure. We illustrate the value of this workflow for targeting virus compartments, which are formed in HIV-pulsed mature human dendritic cells.

Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

The Atacama Rover Astrobiology Drilling Studies (ARADS) Project.

With advances in commercial space launch capabilities and reduced costs to orbit, humans may arrive on Mars within a decade. Both to preserve any signs of past (and extant) martian life and to protect the health of human crews (and Earth's biosphere), it will be necessary to assess the risk of cross-contamination on the surface, in blown dust, and into the near-subsurface (where exploration and resource-harvesting can be reasonably anticipated). Thus, evaluating for the presence of life and biosignatures may become a critical-path Mars exploration precursor in the not-so-far future, circa 2030. This Special Collection of papers from the Atacama Rover Astrobiology Drilling Studies (ARADS) project describes many of the scientific, technological, and operational issues associated with searching for and identifying biosignatures in an extreme hyperarid region in Chile's Atacama Desert, a well-studied terrestrial Mars analog environment. This paper provides an overview of the ARADS project and discusses in context the five other papers in the ARADS Special Collection, as well as prior ARADS project results.

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) ± etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Structure and assembly of immature HIV.

The major structural components of HIV are synthesized as a 55-kDa polyprotein, Gag. Particle formation is driven by the self-assembly of Gag into a curved hexameric lattice, the structure of which is poorly understood. We used cryoelectron tomography and contrast-transfer-function corrected subtomogram averaging to study the structure of the assembled immature Gag lattice to approximately 17-A resolution. Gag is arranged in the immature virus as a single, continuous, but incomplete hexameric lattice whose curvature is mediated without a requirement for pentameric defects. The resolution of the structure allows positioning of individual protein domains. High-resolution crystal structures were fitted into the reconstruction to locate protein-protein interfaces involved in Gag assembly, and to identify the structural transformations associated with virus maturation. The results of this study suggest a concept for the formation of nonsymmetrical enveloped viruses of variable sizes.

Isotopic evolution of planetary crusts by hypervelocity impacts evidenced by Fe in microtektites.

Fractionation effects related to evaporation and condensation had a major impact on the current elemental and isotopic composition of the Solar System. Although isotopic fractionation of moderately volatile elements has been observed in tektites due to impact heating, the exact nature of the processes taking place during hypervelocity impacts remains poorly understood. By studying Fe in microtektites, here we show that impact events do not simply lead to melting, melt expulsion and evaporation, but involve a convoluted sequence of processes including condensation, variable degrees of mixing between isotopically distinct reservoirs and ablative evaporation during atmospheric re-entry. Hypervelocity impacts can as such not only generate isotopically heavy, but also isotopically light ejecta, with δ56/54Fe spanning over nearly 5‰ and likely even larger variations for more volatile elements. The mechanisms demonstrated here for terrestrial impact ejecta modify our understanding of the effects of impact processing on the isotopic evolution of planetary crusts.

High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma.

BACKGROUND: We aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Patients aged 18-60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab. RESULTS: Overall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003). CONCLUSIONS: The addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.

High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

BACKGROUND: T-cell lymphomas (T-NHL) generally carry a poor prognosis. High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are increasingly used to treat younger patients. DESIGN AND METHODS: We treated patients <61 years with high-risk aggressive lymphoma with four to six courses of dose-escalated CHOP plus etoposide (MegaCHOEP) necessitating repeated ASCT. Outcomes of patients with mature T-NHL (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma) and aggressive B-NHL were compared using multivariate Cox regression analysis. RESULTS: Compared with 84.4% of B-NHL patients, 66.7% of T-NHL patients were able to receive all treatments; the rates of progressive disease were 27.3% in T-NHL and 16.3% in B-NHL patients. At 3 years, event-free survival (EFS) and overall survival were significantly worse for T-NHL [25.9% confidence interval (CI) 10.4% to 41.4% and 44.5% CI 26.5% to 62.5%) than for B-NHL patients (60.1% CI 52.1% to 68.1%; P < 0.001 and 63.4% CI 55.4% to 71.4%; P = 0.016). In multivariate analysis, T-NHL was a strongly significant adverse risk factor for EFS (relative risk 2.2, P = 0.001). CONCLUSIONS: MegaCHOEP for T-NHL patients was no better than other high-dose regimens and was unable to address the major problems of HDT/ASCT: neither early progressions nor early relapses were reduced. This study sheds some doubt on expectations that HDT/ASCT will significantly improve outcomes for patients with T-NHL.

The Japanese science education centers.

These six Japanese science education centers signify a sweeping reform of elementary and secondary school science teaching. They achieve their striking results because they are established on a permanent, local basis and are supported mainly by the local boards of education. They have avoided control by pedagogues and specialists in "education." Instead, they are operated by trained scientists and experienced school teachers who work together to devise programs specially suited to the needs of their teachers. With small and practicable steps, the teachers improve their understanding of methods which they can readily test in their own classrooms rooms and laboratories. The laboratory equipment in the science education centers is only slightly superior to that which the teachers have in their own schools, but superior enough to make them desire to improve their own facilities. Major facilities, such as x-ray machines, electron microscopes, telescopes (15-cm), and machine shops, as well as good working collections of minerals and fossils, and adequate greenhouses, permit the teachers to work with more expensive equipment, to gain a firsthand knowledge of its operation, and to bring groups of students to the center to observe what such instruments make possible. The use of American experimental course content improvement programs is widespread. Every science education center I visited is using PSSC, CHEMS, CBA, BSCS, or ESCP materials and studying the philosophy of these programs. Yet no center is entirely dependent on these programs, but uses them critically to supplement and improve its own courses. The emphasis is on good laboratory and field teaching as a basis for understanding scientific methods and concepts. Science as investigation and inquiry, instead of treatment solely as an authoritative body of facts, is coming into its own. The few defects of the science education centers of Japan inhere in the educational situation itself. The centers are at present inadequate to reach even a reasonable proportion of the science teachers within a 5-year, or even a 10-year cycle. The shortage of substitute teachers causes most of the courses to be far too brief for maximum effectiveness. Staff programming tends to be rather spotty instead of comprehensive. A major difficulty, frequently expressed, lies in the grim hold of the university entrance examination system over the science curricula of the lower schools. The university is the goal of every able student, for economic as well as intellectual reasons. To enter a university he must pass the examinations, which are established separately by each institution. The professor who makes out the examination questions therefore controls what must be taught and learned in the lower schools. This same rigorous control is in part reflected in the Ministry of Education syllabi, which must be followed by the teachers. Nevertheless, I found the men in the biological section of the Ministry of Education very enlightened and pressing for change. Many professors in the universities are also in the full current of modern biological thought, participate gladly in the programs of the science education centers, and would write examinations that emphasize interpreting data, applying tests to hypotheses, and drawing valid conclusions instead of merely memorizing and regurgitating facts. On the other hand, in many universities the upper positions are still filled by men to whom biology means classification rather than experimentation, morphology rather than biochemistry, organ physiology rather than cell biology. We cannot afford to discard taxonomy, morphology, or gross physiology-they are important parts of biology and will remain so. But they do not comprise all of biology-they are only a diminishing proportion of it. In Japan, as in the United States, the examination system must become more flexible. It must change with the development of science itself, must encourage scientific attitudes and cease defeating the introduction of new disciplines, new outlooks, new subject matter. The university and the examining boards in some educational systems indeed exhibit a rigor mortis. On balance, the science education centers in Japan may well represent the most significant educational experiment of our time. Their vitality, which springs from their local relationship to the prefectural schools and their permenent staffs, far exceeds in my own estimation that of most of the summer science institutes held in the United States, which lack that close relation to the local schools and which by their impermanency countenance ill-planned and ill-taught programs that are often little different from the usual summer school sessions. The best summer institutes in the United States are indeed very good, but far too few of them reach a passable standard. That is because, for the most part, their staffs are recruited quickly, teach their favorite subjects without much consideration of their appropriateness or suitability for improving science education in the lower schools, and depart without much contact with other members of the staff. What is needed is serious, continuous, prolonged, hard work devoted to the development of the right sorts of courses for renewing the training of science teachers. The Japanese seem to be achieving just that. We would do well, with our vast resources for the improvement of education, to emulate them. As they have profited by employing and improving upon our NSF supported programs in science education, we may likewise profit through the establishment of science education centers modeled on theirs.

Glassy Objects (Microtektites?) from Deep-Sea Sediments near the Ivory Coast.

Glassy objects of spherical, oval, dumbbell, teardrop, and irregular shapes have been found in a deep-sea sediment core taken off the Ivory Coast. They occur in a layer of sediment that was apparently deposited about 800,000 years ago. Their geographic location, appearance, and physical properties suggest that they are microtektites and that they are related to the tektite-strewn field of the Ivory Coast.

Silicate spherules from tunguska impact area: electron microprobe analysis.

The major oxide composition of four silicate spherules from the area of forest devastated by the explosion of the Tunguska meteorite has been determined by electron microprobe analysis. In general, the spherules have compositions similar to that of igneous glass except for the low iron and the high calcium oxide content of the three spherules that have a low content of silicon dioxide. None of the spherules seem to have compositions similar to the silicate portiof any major meteorite group.

Zircon and chromite crystals in a muong nong-type tektite.

Chromite, zircon, and quartz crystals (identified by x-ray diffraction) have been recovered from a 2.07-gram sample of Muong Nong-type tektite. The absence of eskolaite (Cr(2)O(3)) and baddeleyite (ZrO(2)) supports a previous conclusion that Muong Nong-type tektites were not heated as intensely as other tektite groups. X-ray asterism studies indicate that the crystals are shocked, which supports an impact origin. The presence of chromite and zircon together suggests that the Muong Nong-type tektite was produced from sedimentary material.

Lunar sample 14425: characterization and resemblance to high-magnesium microtektites.

Measurements by energy-dispersive x-ray analysis of the surface of lunar sample 14425, a large glass bead, yield a noritic composition enriched in aluminum and magnesium and, as compared with other norites, depleted in iron and especially calcium. The sample is close in composition to the most basic microtektites. Spherical inclusions of nickel-iron, flattened where they protrude, are found to be enriched in sulfur and phosphorus, at least at the surface. The inclusions form approximately 1 percent of the volume.

Paleomagnetic study of antarctic deep-sea cores.

The magnetic inclinations and inten sities of about 650 samples from seven deepsea cores taken in the Antarctic were measured on a spinner magnetometer. This series of measurements provided a magnetic stratigraphy, based on zones of normally or reversally polar ized specimens for each core, which was then correlated with the magnetic stra tigraphy of Cox et al. (1). One core (V16-134) gave a continuous record of the paleomagnetic field back to about 3.5 million years. When selected samples were subject ed to alternatingfield demagnetization, most were found to have an unstable component that was removed by fields of 150 oersteds; all samples from two cores were partially demagnetized in a field of 150 oersteds. The average inclination in these two cores was then in good agreement with the average inclination of the ambient field for the latitude of the core site. It was also found that the intensities of the samples decreased at the points of reversal; this finding is to be expected if, as has been postulated by the dynamo theory, the intensity of the dipole field decreases to zero and builds again with opposite polarity. We believe that the magnetiza tion of the cores results from the pres ence of detrital magnetite, although other magnetic minerals also may be present. Four faunal zones (, X, , and ) have been recognized in these Antarctic cores on the basis of upward sequential disappearance of Radiolaria. The faunal boundaries and reversals consistently have the same relations to one another, indicating that they are both timedependent phenomena. Using previously determined times of reversal, one may date the following events in the cores: 1) Radiolarian faunal boundaries:-X, 2 million years; X-, 0.7 million years; -, 0.4 to 0.5 million years. These dates are in good agreement with ages previously extrapolated from radio metric dates. 2) Initiation of Antarctic diatom ooze deposition, approximately 2.0 mil-lion years ago. 3) First occurrence of ice- rafted detritus, approximately 2.5 million years ago. One can also calculate rates of sedi mentation, which vary in the cores studied from 1.1 to about 8.0 millimeters per 1000 years. Sedimentation rates for the Indian Ocean cores are higher than for the Bellingshausen Sea cores. The near coincidence of faunal changes and reversals in the cores suggests but does not prove a causal relation. We conclude from this study that paleomagnetic stratigraphy is a unique method for correlating and dating deep sea cores, and that future work with such cores may provide a complete or nearly complete record of the history of the earth's magnetic field beyond 4 million years.

Fission track ages and ages of deposition of deep-sea microtektites.

The Australasian and Ivory Coast deep-sea microtektites have fission track ages of 0.71 and 1.09 million years, respectively. These ages are in good agreement with the ages of deposition of the microtektites determined from paleomagnetic data. Both the fission track ages and ages of deposition of the microtektites agree with the potassium/ argon and fission track ages of tektites from the respective tektite strewn fields.

Electron microprobe analysis of lunar samples.

Plagioclase feldspar, clinopyroxene, and ilmenite in a polished thin section of a type A crystalline rock were analyzed. The clinopyroxene grains are compositionally variable, and both high Ca and low Ca phases are present. The plagioclase is compositionally homogeneous. The ilmenite is chemically homogeneous except for occasional, small areas of high local chromium concentration. Accessory minerals are: apatite (containing Cl, F, Y, and Ce), troilite, and metallic iron. Glassy spherules from the lunar soil are for the most part similar in composition to the crystalline rocks; however, some appear to have been monomineralic. The crystalline rock has apparently formed by relatively rapid cooling of a silicate melt under conditions of low oxygen partial pressure. Many components of the soil appear to have formed by meteoritic impact.

Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality?

BACKGROUND AND OBJECTIVE: Patients are increasingly requiring their medications to be repackaged into dose administration aids because of the positive outcomes associated with reduction in medication related hospitalization and adverse effects due to improved medicines management. Since the stability of these repackaged medications is not the responsibility of manufacturer, it is important that drug substances with potential stability issues be identified. Thus the objective of this study was to evaluate the stability of prochlorperazine, a light sensitive drug repackaged into dose administration aids (DAAs), in order to provide guidelines to the pharmacist and advice to the patient on appropriate storage. METHODS: Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging for 8 weeks at ambient (25 +/- 1 degrees C; 60 +/- 1.5% RH), accelerated (40 +/- 1 degrees C; 75 +/- 1.5% RH) and in-use conditions encountered in situ both in a pharmacy and the patients' home. They were assessed for both chemical (using a validated HPLC method) and physical stability according to British Pharmacopoeial (BP) standards. In addition, photostability testing was undertaken under ICH conditions. RESULTS AND DISCUSSION: Chemical and physical stability was confirmed to be within BP Limits. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. CONCLUSION: Despite the confirmation of physical and chemical stability within BP limits, the discoloration and the potential for photodegradants to cause adverse effects in patients must lead us to draw the conclusion that the quality of this medication has been compromised. Pharmacists thus need to take this into account in repackaging and storage of prochlorperazine in DAAs and advise patients to store their DAA protected from light, heat and humidity.