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Background: Our objective was to support the automated classification of Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) reports for their usefulness in assessing the possibility of a causal relationship between a drug product and an adverse event., Method: We used a data set of 326 redacted FAERS reports that was previously annotated using a modified version of the World Health Organization-Uppsala Monitoring Centre criteria for drug causality assessment by a group of SEs at the FDA and supported a similar study on the classification of reports using supervised machine learning and text engineering methods. We explored many potential features, including the incorporation of natural language processing on report text and information from external data sources, for supervised learning and developed models for predicting the classification status of reports. We then evaluated the models on a larger data set of previously unseen reports., Results: The best-performing models achieved recall and F1 scores on both data sets above 0.80 for the identification of assessable reports (i.e. those containing enough information to make an informed causality assessment) and above 0.75 for the identification of reports meeting at least a Possible causality threshold., Conclusions: Causal inference from FAERS reports depends on many components with complex logical relationships that are yet to be made fully computable. Efforts focused on readily addressable tasks, such as quickly eliminating unassessable reports, fit naturally in SE's thought processes to provide real enhancements for FDA workflows., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants., Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages., Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively., Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer., Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years., Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer., Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug-related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.

Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction., Patients and Methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients., Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study., Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Annual mean concentrations in air and annual total (wet plus dry) depositions to ground of 90Sr, 137Cs, 238Pu and (239,240)Pu decreased at Neuherberg, south Germany, in the period from July 1986 (i.e. after the end of the initial deposition phase from Chernobyl) to 1998 as follows: 90Sr from 0.77 to 0.05 microBq m(-3), and from 0.82 (1988) to 0.28 Bq m(-2) year(-1); 137Cs from 133 to 2.8 microBq m(-3), and from 116 to 3.8 Bq m(-2) year(-1); 238Pu from 0.95 to 0.063 nBq m(-3), and from 1.0 to 0.23 mBq m(-2) year(-1); (239,240)Pu from 8.1 to 0.53 nBq m(-3), and from 6.4 to 2.1 mBq m(-2) year(-1). The values for the non-caesium radionuclides are compared to the few available data from other stations. After an initial phase which is characterised for a given radionuclide by the varying ratio of the Chernobyl-derived inventory to the earlier, weapons fallout-derived inventory, the time courses of concentrations of 137Cs, 90Sr, 238Pu and (239,240)Pu in air become more or less parallel (from about 1990), despite the considerable differences in the physico-chemical properties of these elements. By contrast, the time series of radionuclide deposition rates show until about 1994 less similarity among each other and with the respective concentration series in air. From 1994, concentrations in air and depositions to ground become nearly constant, or decrease very slowly. At the end of the observation period, resuspension factors between 1.4 x 10(-10) m(-1) and 1.0 x 10(-11) m(-1) are observed for the various nuclides. The time courses of specific activities (Bq g(-1)) as well as the time courses of radionuclide ratios show characteristic differences between air and deposition. The data will be useful in predicting the post-accident behaviour of radionuclides a long time after a large-scale contamination event.

A health risk assessment of platinum (Pt) emitted from automotive catalytic converters is presented. Following a stepwise approach, the relevant literature is discussed in order to characterize Pt emissions as well as the toxic potential of Pt and its compounds. In an exposure assessment, ambient Pt concentrations in air are predicted to range from approximately 4 pg/m3 (street canyon, typical conditions) up to approximately 112 pg/m3 (express motorway, severe conditions). These values agree well with the few measured concentrations, which are also in the low pg/m3 range. Pt is emitted from catalytic converters in very small amounts (ng/km range), mainly in the (0)-oxidation state (elemental Pt). The nanocrystalline Pt particles are attached to microm-sized aluminum oxide particles. Whether free ultrafine Pt particles may be emitted and result in biological effects has not been studied sufficiently. Hence, risk assessment can only be based on the respiratory sensitizing potential of halogenated Pt salts. The presence of such compounds in automotive Pt emissions cannot definitely be excluded. From recent occupational studies conducted in catalytic converter production, a conservative no-effect level (NOEL) of 1.5 ng/m3 can be derived for the sensitizing effect of halogenated Pt salts. In a (reasonable) worst case approach, it is assumed that such compounds comprise 1% (0.1%) of the total Pt emissions. Applying a safety factor of 10 to account for interindividual variability, a guidance value of 15 (150) ng/m3 is derived for catalyst-borne Pt. The exposure to Pt in ambient air as measured or predicted is at least two orders of magnitude below this guidance range. Rhodium is also contained in automotive catalysts, palladium has increasingly substituted Pt, and iridium-based catalysts have recently been introduced. Although the database on these platinum group metals is rather small, there is no evidence that they pose a health risk to the general population.

The activity concentration in air and atmospheric deposition rate of the long-lived radon progeny 210Pb has been investigated at Munich-Neuherberg, south Germany, from 1972 (activity concentration) and from 1981 (atmospheric flux) to 1999. For these periods, the continuous measurements yielded an average 210Pb activity concentration at ground level of 0.57 mBq m(-3) and an average total 210Pb deposition rate to ground of 180 Bq m(-2) year(-1). The average total deposition velocity, which relates the total 210Pb deposition rate to the 210Pb activity concentration was calculated to be 1.0 cm s(-1). The variation of the data with time was studied by time-series analysis and distinct seasonal patterns were identified. Maximum 210Pb activity concentrations in air are observed in the autumn and winter months (October through February) of each year. By contrast, the maximum 210Pb deposition rate is observed during summer (June-August), i.e. in the months with the highest amount of rainfall at this site. Like the 210Pb deposition rate, the total deposition velocity exhibits a seasonal pattern with maximum values in summer. Due to the long observation period of 18 years, it was possible to observe for the first time a strong positive relationship between 210Pb deposition and precipitation, especially for the months May and June and to a smaller extent for several other months. In the long-term, variations of approximately a factor of 2 were observed in the annual average 210Pb activity concentrations, the annual deposition sums and the annual average deposition velocities. Since around 1981 210Pb concentrations in air steadily decreased while 210Pb depositions increased. As a consequence of these significant trends, the time series of the total deposition velocity exhibits a trend of the data from approximately 0.7 cm s(-1) in 1981 to 1.7 cm s(-1) in 1999.

Two hematopoietic colony-stimulating factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been shown to accelerate leukocyte and neutrophil recovery after high-dose chemotherapy and autologous bone marrow (BM) support. Despite their use, a prolonged period of absolute leukopenia persists during which infections and other complications of transplantation occur. We collected large numbers of peripheral blood (PB) progenitors after CSF administration using either G-CSF or GM-CSF and tested their ability to affect hematopoietic reconstitution and resource utilization in patients undergoing high-dose chemotherapy and autologous BM support. Patients with breast cancer or melanoma undergoing high-dose chemotherapy and autologous BM support were studied in sequential nonrandomized trials. After identical high-dose chemotherapy, patients received either BM alone, with no CSF; BM with either G-CSF or GM-CSF; or BM with G-CSF or GM-CSF and G-CSF or GM-CSF primed peripheral blood progenitor cells (PBPC). Hematopoietic reconstitution, as well as resource utilization, was monitored in these patients. The use of CSF-primed PBPC led to a highly significant reduction in the duration of leukopenia with a white blood cell (WBC) count under 100 and 200 cells/mL, and neutrophil count under 100 and 200 cells/mL with both GM- and G-CSF primed PB progenitor cells, compared with the use of the CSF with BM or with historical controls using BM alone. In addition, the use of CSF-primed PBPC resulted in a significant reduction in median number of antibiotics used, days in the Bone Marrow Transplant Unit, and hospital resources used. Patients receiving G-CSF primed PBPC also experienced a reduction in the median number of days in the hospital, red blood cell (RBC) transfusions, platelet transfusions, days on antibiotics, and discounted hospital charges. Phenotypic analysis of the CSF-primed PBPC indicated the presence of cells bearing antigens associated with both early and late hematopoietic progenitor cells. The use of CSF-primed PBPC can significantly improve hematopoietic recovery after high-dose chemotherapy and autologous BM support. In addition, the use of G-CSF-primed PBPC was associated with a significant reduction in hospital resource utilization, and a reduction in hospital charges.

The sources of Chernobyl-derived caesium concentrations in air and deposition samples collected from mid-1986 to the end of 1990 at Munich-Neuherberg, Germany, were investigated. Local resuspension has been found to be the main source. By comparison with deposition data from other locations it is estimated that within a range from 20 Bq m-2 to 60 kBq m-2 of initially deposited 137Cs activity approximately 2% is re-deposited by the process of local resuspension in Austria, Germany, Japan and the United Kingdom, while significantly higher total resuspension is to be expected for Denmark and Finland. Stratospheric contribution to the present concentrations is shown to be negligible. This is confirmed by cross correlation analysis between the time series of 137Cs in air and precipitation before and after the Chernobyl accident and the respective time series of cosmogenic 7Be, which is an indicator of stratospheric input. Seasonal variations of caesium concentrations with maxima in the winter months were observed.

The temporal variations of radionuclide ratios in air and deposition samples collected simultaneously at Munich-Neuherberg (F.R.G.) after the Chernobyl accident have been studied. Until 8 May 1986, the radionuclides investigated were 99Mo, 103Ru, 106Ru, 110mAg, 125Sb, 129mTe, 132Te, 131I, 134Cs, 137Cs, 140Ba, 141Ce and 144Ce. After 8 May, 99Mo, 110mAg, 125Sb, and the Ce isotopes were below the detection limits. Considerable temporal variations of the above radionuclides, relative to 137Cs, were observed in air as well as in deposition. In air the temporal variations reflect the arrival of different parts of the reactor plume with different elemental composition. In deposition, the temporal patterns were quite different from those in air for a given radionuclide. This is explained by varying contributions of dry and wet deposition. Until 8 May, the washout ratios of the above radionuclides covered a range from 240 to 5600, with smaller variations for all radionuclides within one event (e.g. 460-910), and larger variations from one event to another (e.g. 460-3300 for 137Cs). The dry deposition velocity of 137Cs was found to be 0.27 cm s-1, similar to that of 110mAg, aerosol 131I and 140Ba (0.37, 0.13 and 0.15 cm s-1). Another group of radionuclides includes 103Ru, 106Ru, 125Sb, total 131I and 132Te with dry deposition velocities of 0.08, 0.10, 0.07, 0.03 and 0.08 cm s-1 and with temporal variations in deposition which are quite different from those of the first group. From 8 May to the end of June, the washout ratios increased to values between 1500 and 24,000, with the exception of iodine, which had considerably lower washout ratios of between 37 and 4400. These later effects are explained by resuspension and, in the case of iodine, by remobilization of gaseous species.

Regional ischemia was induced in cats by occluding the middle cerebral artery. Evoked and spontaneous electrical activity as well as regional cerebral blood flow (rCBF) were recorded with platinum depth macroelectrodes in three primary cortical areas: the auditory cortex (A, middle ectosylvian gyrus) and the front and hind limb somatosensory cortex (SF and SH, lateral and medial posterior sigmoid gyrus). To distinguish among the various evoked potentials after click, median or tibial nerve stimulation, electrical field interactions had to be eliminated using a multiplex stimulation and analysis system. Spontaneous electrocortical activity was evaluated by power spectral analysis. In all areas, evoked potentials were abolished 10 min after arterial occlusion. However, rCBF behaved differently in these regions: it was severely reduced in A, decreased moderately in SF and remained unchanged in SH. The graded reduction of rCBF in the three cortical areas was related to changes in electrophysiological activity during the first minutes of ischemia. In A, auditory potentials were abolished within 3 min after occlusion, whereas in SH, the decrease of somatosensory responses started after about 5 min. In SF, two components of the EP changes were found: an early decrease immediately and a later decrease about 5 min after occlusion. The different rates of EP impairment possibly correspond to two types of ischemia. The fast EP abolishment seems to be caused by local cortical damage whereas the delayed EP decrease probably reflects impairment of subcortical white matter structures. Thus, this method may be useful for distinguishing between gray and white matter ischemia.

During the course of differentiation of early human myeloid cells toward monocytes and granulocytes, cell surface expression of the cell adhesion molecule, CD11b/CD18 (Mo1) increases dramatically and expression of myeloperoxidase (MPO), a bacteriocidal enzyme, decreases markedly. Using the inducible promyelocytic cell line HL-60 as a model, we studied the mRNA expression of these genes. Differentiation of these cells along both a monocytic and a granulocytic pathway demonstrated that the mRNA levels of the two subunits of CD11b/CD18 increased in a pattern temporally and quantitatively similar to the increase in cell surface expression of this heterodimer. In contrast, the expression of MPO mRNA decreased in a temporal and quantitative pattern similar to the known decrease in MPO protein during differentiation, suggesting that regulation of these myeloid-specific proteins may occur at the level of mRNA expression. These findings have important implications with regard to the nature of the block in differentiation in acute nonlymphocytic leukemia and the regulation of myeloid gene expression.