Expert opinion on the clinical utilization of high dose telmisartan in Indian patients with hypertension

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using ‘common terminology criteria for adverse events’ (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

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Thromboprophylaxis in Multiple Myeloma Patients Treated with Lenalidomide - a Systematic Review

Blood ◽

10.1182/blood.v126.23.2321.2321 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2321-2321 ◽

Cited By ~ 1

Author(s):

Fatimah Al-Ani ◽

Martha L Louzada ◽

Jose Maria Bastida Bermejo ◽

Maria Victoria Mateos

Keyword(s):

Systematic Review ◽

Multiple Myeloma ◽

Venous Thromboembolism ◽

Expert Opinion ◽

Advisory Board ◽

Risk Of Bias ◽

Phase Iii ◽

High Dose ◽

Pooled Data ◽

High Dose Dexamethasone

Abstract Background Lenalidomide in combination to steroid therapy, including high-dose dexamethasone (RD), low-dose dexamethasone (Rd) or triple therapy of melphalan, prednisolone, lenalidomide (MPR), has shown to be an effective and well-tolerated treatment for patients with newly diagnosed multiple myeloma (NDMM) and relapsed refractory multiple myeloma (RRMM). Lenalidomide is associated with an increased risk of venous thromboembolism, and studies have consistently demonstrated the need for venous thromboembolism (VTE) prophylaxis in patients receiving these combinations. However, the optimal approach to thromboprophylaxis has not yet been established. Objective In this systematic review we sought to compare the efficacy of aspirin (ASA) or low molecular weight heparin (LMWH) in the prevention of VTE in patients with myeloma using lenalidomide- based therapy. Methods A systematic literature search strategy was used to identify potential studies on MEDLINE, EMBASE, and CENTRAL using an OVID interface. The methodological quality of the selected cohort studies was assessed according to Newcastle-Ottawa Quality Assessment Scale, and risk of bias of randomised controlled trials (RCTs) was assessed according to risk of bias assessment tool from the Cochrane Handbook. The primary outcome measure was the incidence rate of VTE while using ASA or LMWH. Results Out of 247 studies, 6 met our inclusion criteria with a total of 1126 participants including a total of 5 phase III RCTs, and one retrospective study. Overall, all studies show high quality: In 4 of the 5 RCTs type of randomization was clearly reported, outcome assessment was blinded, and withdrawal rates were reported, and the remaining RCT was an abstract. In 4 RCTs the intervention and comparator arms were related to anti-myeloma treatment regimens. Pooled data of studies of NDMM treated with lenalidomide based regimen with ASA prophylaxis show a VTE rate of 98 of 915 (10.7%) [95% CI: 8.86-12.88] (Table1). In NDMM and RRMM patients treated with lenalidomide, VTE rate on LMWH prophylaxis was 3 of 211 (1.4%) [95% CI: 0.48-4.09] (Table2). The relative risk (RR) of VTE in patients receiving ASA compared to LMWH was 7.5 (95% CI: 2.41-23.53, p =0.0005). Overall, the rate of VTE was 1.4 (95% CI: 1.14 - 1.69) per 100 patient-cycles of anti-myeloma treatment. A subgroup analysis on patient using ASA showed a similar risk of 1.5 (95% CI: 1.24 - 1.84).The incidence of VTE in those using ASA while on RD was 52 of 195 (26.6%) [95% CI: 20.9-33.2], while VTE rate in those receiving Rd was 27 of 262 (10.3%) [95% CI: 7.18-14.58] demonstrating a statistically significant higher risk for patients on RD [RR=2.5 (95% CI: 1.68- 3.96), p <0.0001]. Furthermore, VTE rate with MPR therapy while on ASA was 19 of 458 (4.1%) [95% CI: 2.67-6.38]. Pooled data of studies revealed that patients who received lenalidomide and dexamethasone alone (RD+Rd) had a significantly higher risk of VTE compared to those on MPR while on ASA (RR=6.4 [(95% CI: 4.11- 9.91), p< 0.0001]). Conclusion The study showed that the most frequent thromboprophylaxis of choice for patients with myeloma on lenalidomide-based therapy is ASA. However, ASA may not confer appropriate protection against VTE, especially in patients using high dose dexamethasone. On the other hand, the risk of VTE in patients receiving MPR and ASA was low and ASA may be a safe option for these patients. More studies comparing the safety of ASA to other anticoagulants such as LMWH or direct oral anticoagulants are warranted. Table 1. Rate of VTE using ASA in NDMM with different lenalidomide based regimens. Rx: treatment; 95% CI: 95% confidence interval. Study Design Rx N VTE rate: N (%) 95% CI Zonder, 2010 Rajkumar, 2010 Phase III RCT RD 195 52 (26.6) 20.9-33.2 Larocca, 2011 Rajkumar, 2010 Phase III RCT Rd 262 27 (10.3) 7.18-14.58 Palumbo, 2012 Stewart, 2014 Phase III RCT MPR 458 19 (4.1) 2.67-6.38 Total 915 98 (10.7) 8.86-12.88 Table 2. Rate of VTE using LMWH in myeloma patients (NDMM or RRMM) on lenalidomide-based regimen. 95% CI: 95% confidence interval. Paper Design Induction Setting N VTE rate: N (%) 95% CI Klein, 2008 Retrospective cohort RD RRMM 45 1(2.2) 0.39-11.57 Larocca, 2011 Phase III RCT Rd NDMM 166 2(1.2) 0.33-4.28 Total 211 3(1.4) 0.48-4.09 Disclosures Louzada: pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion; Celegene: Consultancy, Other: advisory board and expert opinion.

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Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies

Rheumatology ◽

10.1093/rheumatology/keaa337 ◽

2020 ◽

Author(s):

Ryan M Close ◽

Laura M Close ◽

Patrick Galdun ◽

Stefanie Gerstberger ◽

Matthew Rydberg ◽

...

Keyword(s):

Risk Factors ◽

American Indian ◽

American Indians ◽

Rare Condition ◽

Recent Change ◽

Lipid Lowering ◽

High Dose ◽

Illustrative Case ◽

Indian Patients ◽

Autoimmune Myopathy

Abstract Objectives Statin-associated autoimmune myopathy is a rare condition associated with the formation of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Underlying environmental and genetic risk factors remain poorly understood. American Indians have high rates of cardiovascular disease and associated co-morbidities that require lipid-lowering therapies. We observed this autoimmune myopathy in a series of American Indian statin users in rural Arizona. Methods We reviewed the charts of six American Indian patients with statin-associated autoimmune myopathy. We provide an illustrative case in addition to summaries of clinical presentations and treatment courses. Results This is the first report of statin-associated autoimmune myopathy in American Indians. These cases were all identified at the same geographically isolated hospital that exclusively serves an American Indian population with only 1800 statin users. There is relatively low migration. Each case was consistent with the previously described classical presentations for the disease. All six of our cases had diabetes and developed myopathy on high-dose atorvastatin, often with a recent change in statin type or dose. Conclusion Providers serving American Indians need to be aware of the possibility of statin-associated autoimmune myopathy and familiar with its presentation. Larger, inclusive, population-based investigations are needed to elucidate risk factors for this condition, in particular the potential interactions between predisposing HLA alleles, diabetes and specific statin exposures. This is necessary to identify effective and safe lipid-lowering medications.

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Electron Beam Damage of Biomolecules Assessed by Energy Loss Spectroscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100069855 ◽

1978 ◽

Vol 36 (3) ◽

pp. 61-69

Author(s):

M. Isaacson ◽

M.L. Collins ◽

M. Listvan

Keyword(s):

Electron Microscopy ◽

Radiation Damage ◽

Structural Integrity ◽

Analytical Electron Microscopy ◽

High Dose ◽

Dose Rates ◽

Special Cases ◽

Analytical Electron ◽

Atom Migration ◽

Beam Damage

Over the past five years it has become evident that radiation damage provides the fundamental limit to the study of blomolecular structure by electron microscopy. In some special cases structural determinations at very low doses can be achieved through superposition techniques to study periodic (Unwin & Henderson, 1975) and nonperiodic (Saxton & Frank, 1977) specimens. In addition, protection methods such as glucose embedding (Unwin & Henderson, 1975) and maintenance of specimen hydration at low temperatures (Taylor & Glaeser, 1976) have also shown promise. Despite these successes, the basic nature of radiation damage in the electron microscope is far from clear. In general we cannot predict exactly how different structures will behave during electron Irradiation at high dose rates. Moreover, with the rapid rise of analytical electron microscopy over the last few years, nvicroscopists are becoming concerned with questions of compositional as well as structural integrity. It is important to measure changes in elemental composition arising from atom migration in or loss from the specimen as a result of electron bombardment.

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Electron-diffraction studies in synthetic polymer materials

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100075579 ◽

1983 ◽

Vol 41 ◽

pp. 362-365

Author(s):

D.T. Grubb

Keyword(s):

Electron Diffraction ◽

Synthetic Polymer ◽

Polymer Materials ◽

Crystallographic Structure ◽

High Dose ◽

Electron Dose ◽

Dose Rates ◽

First Case ◽

Diffraction Patterns ◽

The Many

Diffraction studies in polymeric and other beam sensitive materials may bring to mind the many experiments where diffracted intensity has been used as a measure of the electron dose required to destroy fine structure in the TEM. But this paper is concerned with a range of cases where the diffraction pattern itself contains the important information.In the first case, electron diffraction from paraffins, degraded polyethylene and polyethylene single crystals, all the samples are highly ordered, and their crystallographic structure is well known. The diffraction patterns fade on irradiation and may also change considerably in a-spacing, increasing the unit cell volume on irradiation. The effect is large and continuous far C94H190 paraffin and for PE, while for shorter chains to C 28H58 the change is less, levelling off at high dose, Fig.l. It is also found that the change in a-spacing increases at higher dose rates and at higher irradiation temperatures.

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Microprobe analysis of inclusion bodies related to two benzofuran derivatives

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127785 ◽

1987 ◽

Vol 45 ◽

pp. 672-673

Author(s):

T. L. Benning ◽

P. Ingram ◽

J. D. Shelburne

Keyword(s):

Inclusion Bodies ◽

Uranyl Acetate ◽

Multiple Organ ◽

High Dose ◽

En Bloc ◽

Tissue Samples ◽

Transmission Electron ◽

Organ Systems ◽

Dense Inclusion ◽

Melanin Complex

Two benzofuran derivatives, chlorpromazine and amiodarone, are known to produce inclusion bodies in human tissues. Prolonged high dose chlorpromazine therapy causes hyperpigmentation of the skin with electron-dense inclusion bodies present in dermal histiocytes and endothelial cells ultrastructurally. The nature of the deposits is not known although a drug-melanin complex has been hypothesized. Amiodarone may also cause cutaneous hyperpigmentation and lamellar lysosomal inclusion bodies have been demonstrated within the cells of multiple organ systems. These lamellar bodies are believed to be the product of an amiodarone-induced phospholipid storage disorder. We performed transmission electron microscopy (TEM) and energy dispersive x-ray microanalysis (EDXA) on tissue samples from patients treated with these drugs, attempting to detect the sulfur atom of chlorpromazine and the iodine atom of amiodarone within their respective inclusion bodies.A skin biopsy from a patient with hyperpigmentation due to prolonged chlorpromazine therapy was fixed in 4% glutaraldehyde and processed without osmium tetroxide or en bloc uranyl acetate for Epon embedding.

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Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127906 ◽

1987 ◽

Vol 45 ◽

pp. 718-719

Author(s):

G.A. Miranda ◽

M.A. Arroyo ◽

C.A. Lucio ◽

M. Mongeotti ◽

S.S. Poolsawat

Keyword(s):

Low Dose ◽

Fetal Liver ◽

Late Pregnancy ◽

Toxic Chemicals ◽

Control Group ◽

High Dose ◽

Over The Counter ◽

Liver And Kidney ◽

Neonatal Liver ◽

Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

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Analysis of Silicon-On-Insulator Structures Formed By Oxygen Ion Implantation

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100118370 ◽

1985 ◽

Vol 43 ◽

pp. 300-301

Author(s):

N. Lewis ◽

E. L. Hall ◽

A. Mogro-Campero ◽

R. P. Love

Keyword(s):

Ion Implantation ◽

Single Crystal ◽

Single Crystal Silicon ◽

Silicon Layer ◽

Device Fabrication ◽

Silicon On Insulator ◽

High Dose ◽

Crystal Silicon ◽

Oxygen Ion ◽

Oxygen Ion Implantation

The formation of buried oxide structures in single crystal silicon by high-dose oxygen ion implantation has received considerable attention recently for applications in advanced electronic device fabrication. This process is performed in a vacuum, and under the proper implantation conditions results in a silicon-on-insulator (SOI) structure with a top single crystal silicon layer on an amorphous silicon dioxide layer. The top Si layer has the same orientation as the silicon substrate. The quality of the outermost portion of the Si top layer is important in device fabrication since it either can be used directly to build devices, or epitaxial Si may be grown on this layer. Therefore, careful characterization of the results of the ion implantation process is essential.

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Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100159539 ◽

1990 ◽

Vol 48 (3) ◽

pp. 398-399

Author(s):

A.M. Andrews ◽

S.W. Wilson ◽

A.C. Scallet ◽

S.F. Ali ◽

J. Bailey ◽

...

Keyword(s):

Synaptic Vesicles ◽

Rhesus Monkeys ◽

Low Dose ◽

Inhalation Exposure ◽

Synaptic Cleft ◽

High Dose ◽

Withdrawal Time ◽

Treatment Groups ◽

Ultrastructural Evidence ◽

Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

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Defect reduction in oxygen implanted silicon-on-insulator material during high-temperature annealing

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100154998 ◽

1989 ◽

Vol 47 ◽

pp. 604-605

Author(s):

P. Roitman ◽

B. Cordts ◽

S. Visitserngtrakul ◽

S.J. Krause

Keyword(s):

High Temperature ◽

Annealing Temperature ◽

Silicon On Insulator ◽

High Dose ◽

High Temperature Annealing ◽

High Current ◽

Defect Reduction ◽

Annealing Step ◽

Multiple Cycle ◽

Defect Densities

Synthesis of a thin, buried dielectric layer to form a silicon-on-insulator (SOI) material by high dose oxygen implantation (SIMOX – Separation by IMplanted Oxygen) is becoming an important technology due to the advent of high current (200 mA) oxygen implanters. Recently, reductions in defect densities from 109 cm−2 down to 107 cm−2 or less have been reported. They were achieved with a final high temperature annealing step (1300°C – 1400°C) in conjunction with: a) high temperature implantation or; b) channeling implantation or; c) multiple cycle implantation. However, the processes and conditions for reduction and elimination of precipitates and defects during high temperature annealing are not well understood. In this work we have studied the effect of annealing temperature on defect and precipitate reduction for SIMOX samples which were processed first with high temperature, high current implantation followed by high temperature annealing.

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