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Yohan, Darren, Anthony Kim, Elina Korpela, Stanley Liu, Carolyn Niu, Brian C. Wilson e Lee CL Chin. "Quantitative monitoring of radiation induced skin toxicities in nude mice using optical biomarkers measured from diffuse optical reflectance spectroscopy". Biomedical Optics Express 5, n.º 5 (1 de abril de 2014): 1309. http://dx.doi.org/10.1364/boe.5.001309.
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Bradford, Chairman, Robert W., e Curriculum Oversight. "High Resolution Optical Microscopy Will Play a Major Role in Functional Assessments and the Prevention of Disease". Microscopy and Microanalysis 6, S2 (agosto de 2000): 834–35. http://dx.doi.org/10.1017/s1431927600036667.
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The typical aging processes can be characterized by a gradual alteration and essential breakdown of the functional systems of the body. Numerous factors play important roles in the alterations of these pathways from biochemical individuality and genetic predisposition to environmental insults and deficiency states.1 Clinical research, as but one example, has clearly documented the role of free radicals (ROS) or oxidative injury in disease and aging affecting the body's basic cellular structures.The objective of functional or health assessments is to be able to detect in vivo stresses and imbalances in the biological systems, while the patient is asymptomatic, so that early therapeutic intervention can resolve the problems prior to disease onset or accelerated aging. The ability to assess risk factors and treat the sub-clinical metabolic toxicities, deficiency states, hormonal imbalances, oxidative injury (ROS), immunodeficiencies, enzyme down regulations, antioxidant status, metal toxicities, cardiovascular stresses, organ reserves/stresses and detox systems in a low-complexity, cost-effective office procedure is true preventive medicine.
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Futra, Dedi, Lee Heng, Asmat Ahmad, Salmijah Surif e Tan Ling. "An Optical Biosensor from Green Fluorescent Escherichia coli for the Evaluation of Single and Combined Heavy Metal Toxicities". Sensors 15, n.º 6 (28 de maio de 2015): 12668–81. http://dx.doi.org/10.3390/s150612668.
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Colaço, Raul, Mariana Portela, Ilda Costa, Marta Guedes e António Mota. "Radiotherapy as Salvage Treatment in Intraocular Lymphoma: A Case Report". Case Reports in Oncology 14, n.º 1 (1 de março de 2021): 184–89. http://dx.doi.org/10.1159/000512216.
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A 67-year-old previously healthy woman presented with progressive visual impairment including bitemporal hemianopsia. A brain magnetic resonance imaging revealed a contrast-enhancing mass in the optic chiasm, spreading along the left optic tract. The patient underwent a transcranial biopsy of the left optical tract that yielded a diagnosis of diffuse large B-cell lymphoma. CT scans of the chest, abdomen, and pelvis, PET-CT, and bone marrow biopsy revealed no evidence of systemic lymphoma. Thus, the final diagnosis was of primary central nervous system lymphoma of the optic chiasm. Systemic treatment was initiated with full response. Six months after the end of the treatment, recurrence at cerebellum parenchyma and left tentorium was recorded. A new systemic treatment achieved full response. A second recurrence was noted in an optical coherence tomography of the right eye, 2 years after the initial diagnosis. The patient was treated with intravitreal methotrexate with initial success, but eventual failure after 10 months. Intravitreal rituximab was used with no effect. The patient was then referred to radiotherapy and underwent external beam radiotherapy with VMAT. There were no acute toxicities to report. After the radiotherapy treatment, at 1-year follow-up, the patient has no evidence of disease. Long-term toxicities were recorded and are considered manageable. The present case emphasizes the role of ocular irradiation as an option in the management of intraocular lymphoma patients, including in the salvage setting, with an acceptable ocular toxicity profile.
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Capitini, Claudia, Jayneil R. Patel, Antonino Natalello, Cristiano D’Andrea, Annalisa Relini, James A. Jarvis, Leila Birolo et al. "Structural differences between toxic and nontoxic HypF-N oligomers". Chemical Communications 54, n.º 62 (2018): 8637–40. http://dx.doi.org/10.1039/c8cc03446j.
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Xing, Lei, Jia-Liang Zhang, Tian-jiao Zhou, Yu-Jing He, Peng-Fei Cui, Jia-Hui Gong, Minjie Sun et al. "A novel design of a polynuclear co-delivery system for safe and efficient cancer therapy". Chemical Communications 54, n.º 63 (2018): 8737–40. http://dx.doi.org/10.1039/c8cc03720e.
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A polynuclear nanoparticle fabricated through a sequential hydrophobic and electrostatic interaction mechanism can circumvent the contradictory problem of siRNA binding capacity and toxicities of cationic vectors.
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Dang, Xiangnan, Li Gu, Jifa Qi, Santiago Correa, Geran Zhang, Angela M. Belcher e Paula T. Hammond. "Layer-by-layer assembled fluorescent probes in the second near-infrared window for systemic delivery and detection of ovarian cancer". Proceedings of the National Academy of Sciences 113, n.º 19 (25 de abril de 2016): 5179–84. http://dx.doi.org/10.1073/pnas.1521175113.
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Fluorescence imaging in the second near-infrared window (NIR-II, 1,000–1,700 nm) features deep tissue penetration, reduced tissue scattering, and diminishing tissue autofluorescence. Here, NIR-II fluorescent probes, including down-conversion nanoparticles, quantum dots, single-walled carbon nanotubes, and organic dyes, are constructed into biocompatible nanoparticles using the layer-by-layer (LbL) platform due to its modular and versatile nature. The LbL platform has previously been demonstrated to enable incorporation of diagnostic agents, drugs, and nucleic acids such as siRNA while providing enhanced blood plasma half-life and tumor targeting. This work carries out head-to-head comparisons of currently available NIR-II probes with identical LbL coatings with regard to their biodistribution, pharmacokinetics, and toxicities. Overall, rare-earth-based down-conversion nanoparticles demonstrate optimal biological and optical performance and are evaluated as a diagnostic probe for high-grade serous ovarian cancer, typically diagnosed at late stage. Successful detection of orthotopic ovarian tumors is achieved by in vivo NIR-II imaging and confirmed by ex vivo microscopic imaging. Collectively, these results indicate that LbL-based NIR-II probes can serve as a promising theranostic platform to effectively and noninvasively monitor the progression and treatment of serous ovarian cancer.
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Yang, Han Yu. "Lanthanide-Based Nanoprobes for Time-Resolved Luminescence Imaging on Various Ions and Molecules". Materials Science Forum 1075 (30 de novembro de 2022): 9–17. http://dx.doi.org/10.4028/p-76fds1.
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Lanthanide-doped upconversion nanoparticles (Ln-UCNPs) have been extensively explored in the biological field. In particular, Ln-UCNPs with near-infrared (NIR) fluorescence have tremendous potential for biological imaging because of their outstanding photo-and chemo-stability, extended photoluminescence lifetimes, low long-term toxicities and narrow photoluminescence bandwidths as well as minimal background interferences. Using predesigned energy transfer routes makes it possible to get upconversion luminescence from lanthanides' 4f-4f optical transitions. This article clarifies the key working principles and superiorities of Ln-UCNPs for bioimaging. A crucial overview of recent advances in biological detection adopting lanthanide-based luminescence resonance energy transfer (LRET) mechanisms is presented while emphasizing the importance of modifying Ln-UCNPs to obtain a more efficient energy transfer mechanism.
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Ray, Shariqsrijon Sinha, e Jayita Bandyopadhyay. "Nanotechnology-enabled biomedical engineering: Current trends, future scopes, and perspectives". Nanotechnology Reviews 10, n.º 1 (1 de janeiro de 2021): 728–43. http://dx.doi.org/10.1515/ntrev-2021-0052.
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Abstract Applications of nanotechnology in biomedical engineering are vast and span several interdisciplinary areas of nanomedicine, diagnostics, and nanotheranostics. Herein, we provide a brief perspective on nanotechnology as an enabling tool for the design of new functional materials and devices for medical applications. Semiconductor nanocrystals, also known as quantum dots, are commonly used in optical imaging to diagnose diseases such as cancer. Varieties of metal and metal oxide nanoparticles, and two-dimensional carbon-based nanostructures, are prospective therapeutics and may also be used in protective antiviral/antibacterial applications. Similarly, a number of nanomaterials have shown the potential to overcome the drawbacks of conventional antiviral drugs. However, assessing the adverse effects and toxicities of nanoparticles in medicine and therapeutics is becoming more critical. This article discusses the latest developments of nanomaterials in diagnosis, nanotheranostics, and nanomedicines, with particular emphasis on the importance of nanomaterials in fighting against coronavirus disease. Further, we considered the safety and toxicity of nanomaterials in the context of biomedical applications. Finally, we provided our perspective on the future of nanotechnology in emerging biomedical engineering fields.
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Jia, Qi, Nana Xu, Pengqian Mu, Bo Wang, Shuming Yang e Jing Qiu. "Stereoselective Separation and Acute Toxicity of Tau-Fluvalinate to Zebrafish". Journal of Chemistry 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/931908.
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Tau-fluvalinate (TFLV) is one of the most potent chiral synthetic pyrethroids to control a wide range of pests in agricultural fields, especially in apiary. In this study, two stereoisomers of TFLV were fully separated by high-performance liquid chromatography (HPLC) with a semipreparative chiral column using cellulose-tris(3,5-dimethylphenylcarbamate) as chiral stationary phase andn-hexane and 2-propanol (96/4, v/v) as mobile phase at a flow rate of 2.5 mL min−1. The (+)-stereoisomer was first eluted by detecting with an optical rotation detector. After obtaining pure single stereoisomer of TFLV, acute toxicities of each isomer and TFLV standard to zebrafish were evaluated. The results showed that the (+)-stereoisomer exhibited 273.4 times higher toxicity than the (−)-stereoisomer and 6.7 times higher than TFLV standard, according to their LC50values at 96 h after exposure. This indicates that the toxicity of TFLV mainly originates from (+)-stereoisomer. These results are very helpful to prepare single stereoisomer of chiral pesticides and evaluate their different toxicological effects to aquatic organisms.
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Kim, Sang Ho, Chanchal Sharma, Imran Khan e Sun Chul Kang. "Breeding of zebrafish in the laboratory environment for research development". Bangladesh Journal of Pharmacology 12, n.º 4 (30 de novembro de 2017): 434. http://dx.doi.org/10.3329/bjp.v12i4.34143.
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<p>The zebrafish (<em>Danio rerio</em>) has turn out to be an excellent vertebrate organism for analyzing developmental stages, disease modeling, and screening of drug toxicities due to their minuscule, high fecundity, optical transparency and there close parallels with the genome of human beings. Although maintenance of zebrafish is relatively easy, yet it is a complex process, greatly influenced by various factors including mating behavior, day-light cycle, age, and size of fish. This visual experiment will provide an overview of zebrafish care and maintenance in the laboratory environment. Additionally, the presentation will include information essential for improving the spawning habitat by recreating breeding settings in the lab. Collectively, this experimental memorandum of zebrafish environment can serve as a mean to understand the reproducibility, efficiency of use and its welfare for future research development.</p><p><strong>Video Clip of Methodology</strong>:</p><p>2 min 52 sec: <a href="https://www.youtube.com/v/-oqF4xvfIjg">Full Screen</a> <a href="https://www.youtube.com/watch?v=-oqF4xvfIjg">Alternate</a></p>
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Fasolino, Giuseppe, Laura Moschetta, Jacques De Grève, Pieter Nelis, Pierre Lefesvre e Marcel Ten Tusscher. "Choroidal and Choriocapillaris Morphology in Pan-FGFR Inhibitor-Associated Retinopathy: A Case Report". Diagnostics 12, n.º 2 (20 de janeiro de 2022): 249. http://dx.doi.org/10.3390/diagnostics12020249.
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Emerging anticancer agents such as the pan-FGFR Inhibitor have achieved remarkable improvements in the survival of patients with metastatic malignancies. Nevertheless they are still associated with specific ophthalmic toxicities. Understanding their pathophysiology can lead us to better clinical practice of life-threatening and vision-threatening circumstances. To investigate choroidal alterations as a potential pathophysiological mechanism of a serous detachment in bilateral pan-FGFR Inhibitor-Associated Retinopathy (FGFRAR), the morphology of the choroid and choriocapillaris were assessed. The choroidal thickness (ChT) and choriocapillaris flow void were measured by macular optical coherence tomography (OCT) and angiography (OCT-A), respectively. Data were collected at the baseline, then at one-month and two-months follow-ups after starting erdafitinib, in a single case of pulmonary angiosarcoma. Choroidal and choriocapillaris morphology showed stable ChT and choriocapillaris flow void at FGFRAR onset and relapse. To the best of our knowledge, this is the first analyzed case reported with flow-void OCT-angiography. Considering these results, FGFRAR in this patient does not seem to match the pachychoroid spectrum disorder definition; rather, an intracellular mechanism based on intracellular transduction pathways may be at work.
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Foulet, Amandine, Ouahid Ben Ghanem, Mohanad El-Harbawi, Jean-Marc Lévêque, M. I. Abdul Mutalib e Chun-Yang Yin. "Understanding the physical properties, toxicities and anti-microbial activities of choline-amino acid-based salts: Low-toxic variants of ionic liquids". Journal of Molecular Liquids 221 (setembro de 2016): 133–38. http://dx.doi.org/10.1016/j.molliq.2016.05.046.
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Di Nicola, Maura, Giulio Barteselli, Laura Dell’Arti, Roberto Ratiglia e Francesco Viola. "Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature". BioMed Research International 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/249617.
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Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease.
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Gootenberg, Joseph E., e Philip A. Pizzo. "Optimal Management of Acute Toxicities of Therapy". Pediatric Clinics of North America 38, n.º 2 (abril de 1991): 269–97. http://dx.doi.org/10.1016/s0031-3955(16)38078-6.
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Rahmani, Reyhaneh, Mohsen Gharanfoli, Mehran Gholamin, Majid Darroudi, Jamshidkhan Chamani, Kayvan Sadri e Alireza Hashemzadeh. "Plant-mediated synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) using aloe vera and flaxseed extracts and evaluation of their cellular toxicities". Ceramics International 46, n.º 3 (fevereiro de 2020): 3051–58. http://dx.doi.org/10.1016/j.ceramint.2019.10.005.
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Liu, Chusheng, Yanjing Wang, Gaofei Zhang, Xuebin Pang, Jiao Yan, Xiaoou Wu, Yingheng Qiu et al. "Dermal Toxicity Influence of Gold Nanomaterials after Embedment in Cosmetics". Toxics 10, n.º 6 (24 de maio de 2022): 276. http://dx.doi.org/10.3390/toxics10060276.
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Gold nanomaterials (Au NMs) have been widely used in cosmetic products for improving the brightening, and reducing the wrinkling of, skin, etc.; however, the dermal safety of Au NMs is rarely concerned. A previous study found that cosmetics could enhance the toxicity of Au nanosheets, but different physicochemical properties of Au NMs will induce different interaction modes with ingredients of cosmetics, potentially leading to different toxicity profiles. In the present study, spherical and rodlike Au NMs were first found in commercial cosmetics, and then Au nanospheres (NSs) with different sizes and Au nanorods (NRs) with different aspect ratios were prepared to simulate these Au NMs in cosmetics and further investigate their toxicity before and after embedment in cosmetics. It was found that the primary sizes, morphologies, and optical absorptions of these Au NSs and NRs before and after embedment were similar; however, their hydrodynamic sizes and zeta potentials were noticeably different. Then, these Au NSs and NRs presented weak or no cytotoxicity against HaCaT keratinocytes, while cosmetic cream could alleviate their cytotoxicity. Moreover, the cream could enhance the accumulation of Au NSs and NRs in the skin of hairless mice, but it also alleviated the toxicological responses of Au NSs and NRs in terms of superoxide dismutase (SOD) elevation and malondialdehyde (MDA) reduction. Therefore, the embedment of Au NSs and NRs into cosmetics can alleviate the in vitro and in vivo dermal toxicities of Au NSs and NRs.
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Mirandola, Alfredo, Stefania Russo, Maria Bonora, Barbara Vischioni, Anna Maria Camarda, Rossana Ingargiola, Silvia Molinelli et al. "A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients". Cancers 14, n.º 11 (28 de maio de 2022): 2678. http://dx.doi.org/10.3390/cancers14112678.
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(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the ΔNTCP and ΔDVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to ΔNTCP > 3% for at least one severe toxicity, 4 (18.2%) due to ΔNTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of ΔNTCP and ΔDVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.
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Shabir, Shabnam, Amit Sehgal, Joydeep Dutta, Inderpal Devgon, Sandeep K. Singh, Walaa F. Alsanie, Abdulhakeem S. Alamri et al. "Therapeutic Potential of Green-Engineered ZnO Nanoparticles on Rotenone-Exposed D. melanogaster (Oregon R+): Unveiling Ameliorated Biochemical, Cellular, and Behavioral Parameters". Antioxidants 12, n.º 9 (28 de agosto de 2023): 1679. http://dx.doi.org/10.3390/antiox12091679.
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Nanotechnology holds significant ameliorative potential against neurodegenerative diseases, as it can protect the therapeutic substance and allow for its sustained release. In this study, the reducing and capping agents of Urtica dioica (UD), Matricaria chamomilla (MC), and Murraya koenigii (MK) extracts were used to synthesize bio-mediated zinc oxide nanoparticles (ZnO-NPs) against bacteria (Staphylococcus aureus and Escherichia coli) and against rotenone-induced toxicities in D. melanogaster for the first time. Their optical and structural properties were analyzed via FT-IR, DLS, XRD, EDS, SEM, UV–Vis, and zeta potential. The antioxidant and antimicrobial properties of the fabricated ZnO-NPs were evaluated employing cell-free models (DPPH and ABTS) and the well diffusion method, respectively. Rotenone (500 µM) was administered to Drosophila third instar larvae and freshly emerged flies for 24–120 h, either alone or in combination with plant extracts (UD, MC, an MK) and their biogenic ZnO-NPs. A comparative study on the protective effects of synthesized NPs was undertaken against rotenone-induced neurotoxic, cytotoxic, and behavioral alterations using an acetylcholinesterase inhibition assay, dye exclusion test, and locomotor parameters. The findings revealed that among the plant-derived ZnO-NPs, MK-ZnO NPs exhibit strong antimicrobial and antioxidant activities, followed by UD-ZnO NPs and MC-ZnO NPs. In this regard, ethno-nano medicinal therapeutic uses mimic similar effects in D. melanogaster by suppressing oxidative stress by restoring biochemical parameters (AchE and proteotoxicity activity) and lower cellular toxicity. These findings suggest that green-engineered ZnO-NPs have the potential to significantly enhance outcomes, with the promise of effective therapies for neurodegeneration, and could be used as a great alternative for clinical development.
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Biswal, Manas R., Ryan J. Paulson, Riddhi Vichare e Alfred S. Lewin. "Buspirone Enhances Cell Survival and Preserves Structural Integrity during Oxidative Injury to the Retinal Pigment Epithelium". Antioxidants 12, n.º 12 (17 de dezembro de 2023): 2129. http://dx.doi.org/10.3390/antiox12122129.
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Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO3)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone’s effect on protective gene expression, we performed RT–PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone’s impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO3 model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1, Cat, Sqstm1, Gstm1, and Sod2 genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.
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Williams, Wesley Allen, e Shyam Aravamudhan. "Micro-Nanoparticle Characterization: Establishing Underpinnings for Proper Identification and Nanotechnology-Enabled Remediation". Polymers 16, n.º 19 (8 de outubro de 2024): 2837. http://dx.doi.org/10.3390/polym16192837.
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Microplastics (MPLs) and nanoplastics (NPLs) are smaller particles derived from larger plastic material, polymerization, or refuse. In context to environmental health, they are separated into the industrially-created “primary” category or the degradation derivative “secondary” category where the particles exhibit different physiochemical characteristics that attenuate their toxicities. However, some particle types are more well documented in terms of their fate in the environment and potential toxicological effects (secondary) versus their industrial fabrication and chemical characterization (primary). Fourier Transform Infrared Spectroscopy (FTIR/µ-FTIR), Raman/µ-Raman, Proton Nuclear Magnetic Resonance (H-NMR), Curie Point-Gas Chromatography-Mass Spectrometry (CP-gc-MS), Induced Coupled Plasma-Mass Spectrometry (ICP-MS), Nanoparticle Tracking Analysis (NTA), Field Flow Fractionation-Multiple Angle Light Scattering (FFF-MALS), Differential Scanning Calorimetry (DSC), Thermogravimetry (TGA), Differential Mobility Particle [Sizing] (DMPS), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Scanning Transmission X-ray Microspectroscopy (STXM) are reviewed as part of a suite of characterization methods for physiochemical ascertainment and distinguishment. In addition, Optical-Photothermal Infrared Microspectroscopy (O-PTIR), Z-Stack Confocal Microscopy, Mueller Matrix Polarimetry, and Digital Holography (DH) are touched upon as a suite of cutting-edge modes of characterization. Organizations, like the water treatment or waste management industry, and those in groups that bring awareness to this issue, which are in direct contact with the hydrosphere, can utilize these techniques in order to sense and remediate this plastic polymer pollution. The primary goal of this review paper is to highlight the extent of plastic pollution in the environment as well as introduce its effect on the biodiversity of the planet while underscoring current characterization techniques in this field of research. The secondary goal involves illustrating current and theoretical avenues in which future research needs to address and optimize MPL/NPL remediation, utilizing nanotechnology, before this sleeping giant of a problem awakens.
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Qiu, Xudong, Seth T. Gammon, Carol Rasmussen, Federica Pisaneschi, Charlene B. Y. Kim, James Ver Hoeve, Steven W. Millward et al. "In vivo scanning laser fundus and high-resolution OCT imaging of retinal ganglion cell injury in a non-human primate model with an activatable fluorescent-labeled TAT peptide probe". PLOS ONE 19, n.º 12 (6 de dezembro de 2024): e0313579. https://doi.org/10.1371/journal.pone.0313579.
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The optical imaging agent TcapQ488 has enabled imaging of retinal ganglion cell (RGC) injury in vivo in rodents and has potential as an effective diagnostic probe for early detection and intervention monitoring in glaucoma patients. In the present study, we investigated TcapQ488 in non-human primates (NHPs) to identify labeling efficacy and early signals of injured RGC, to determine species-dependent changes in RGC probe uptake and clearance, and to determine dose-limiting toxicities. Doses of 3, 6, and 12 nmol of TcapQ488 were delivered intravitreally to normal healthy NHP eyes and eyes that had undergone hemiretinal endodiathermy axotomy (HEA) in the inferior retina. Post-injection fundus fluorescence imaging using a Spectralis imaging platform (Heidelberg Engineering) documented TcapQ488 activation in RGC cell bodies. Optical coherence tomography (OCT), slit-lamp examinations, intraocular pressure measurements, and visual electrophysiology testing were performed to monitor probe tolerability. For comparison, a negative control, non-cleavable, non-quenched probe (dTcap488, 6 nmol), was delivered intravitreally to a normal healthy eye. In normal healthy eyes, intravitreal injection of 3 nmol of TcapQ488 was well-tolerated, while 12 nmol of TcapQ488 to the healthy eye caused extensive probe activation in the ganglion cell layer (GCL) and eventual retinal nerve fiber layer thinning. In HEA eyes, the HEA procedure followed by intravitreal TcapQ488 (3 nmol) injection resulted in probe activation within cell bodies in the GCL, confined to the HEA-treated inferior retina, indicating cell injury and slow axonal transport in the GCL. However, in contrast to rodents, a vitreal haze that lasted 2–12 weeks obscured rapid high-resolution imaging of the fundus. By contrast, intravitreal TcapQ488 injection prior to the HEA procedure led to minimal probe labeling in the GCL. The results of the dTcap488 control experiments indicated that fast axonal transport carried the probe out of the retina after cell body uptake. No evidence of pan-retinal toxicity or loss of retino-cortical function was detected in any of the three NHPs tested. Overall, these data provide evidence of TcapQ488 activation, without toxicity, in NHP HEA eyes that had been intravitreally injected with 3 nmol of the probe. Compared to rodents, unexpectedly rapid axonal transport in the NHPs reduced the capacity to visualize RGC cell bodies and axons through the backdrop of an intravitreal haze. Nonetheless, although intravitreal clearance rates did not scale to NHPs, HEA-induced reductions in axonal transport enhanced probe visualization in the cell body.
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Zheng, Liyun, e Jiansong Ji. "Magnesium microspheres to enhance lipiodol-mediated transarterial chemo-embolization (TACE) of hepatocellular carcinoma: From bench to a pilot clinical study." Journal of Clinical Oncology 42, n.º 16_suppl (1 de junho de 2024): e16204-e16204. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e16204.
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e16204 Background: Transarterial chemoembolization (TACE) has been extensively used in clinic to treat unresectable hepatocellular carcinoma (HCC). However, arterial embolization would worsen the hostile physicochemical features in the tumor microenvironment (TME) by further reducing its pH and increasing hypoxia, leading to immunosuppressive TME and drug resistance. Methods: Magnesium microspheres (Mg MSs), acting as H2 donors and pH modulators, were prepared via gas atomization pulverization. Characterization included inverted optical microscopy, SEM, and XRD analysis. Their H2 generation and acid neutralization capabilities were confirmed. The Lip-Mg dispersion (Mg MSs dispersed in lipiodol) was tested for therapeutic efficacy in H22 murine liver tumor-bearing mice, 4T1, and CT26 subcutaneous tumor models, as well as in vivo interventional TAE therapy for rabbit orthotopic liver tumors. The modulated capacities of Lip-Mg in H2 gas generation, acid neutralization, and promotion of antitumor immune response were investigated in vivo. Finally, a single-center, single-arm, open-label trial (ChiCTR2200064999) evaluated the safety and efficacy of TACE treatment with Lip-Mg (M-TACE) in Chinese HCC patients. Results: Inverted optical microscopy and SEM images confirmed uniform, smooth Mg microspheres (~60 μm) with a grayish-white color. In acidic buffer (pH 6.4), Mg microspheres rapidly increased pH, as measured by pH meter or fluorescent probe. Lip-Mg treatment significantly inhibited tumor growth compared to controls, prolonging mouse survival by ~2-fold, validated in 4T1 and CT26 models. Ultrasonic and multispectral fluorescence imaging demonstrated Lip-Mg's ability to release H2 and neutralize pH in vivo, reversing the immunosuppressive tumor microenvironment. Clinical study showed manageable treatment-related adverse events, with no unexpected toxicities and negligible impact on serum magnesium levels, confirming the safety of Mg microspheres for M-TACE. According to mRECIST, M-TACE exhibited high CR (61.5%), PR (38.5%), and ORR (100%) rates, with an overall response rate and CR rate of 90% and 60%, respectively. Conclusions: Metallic Mg microspheres (~60 μm) were developed to enhance lipiodol-mediated TAE/TACE for HCC. When combined with lipiodol and injected, they neutralized the acidic TME, triggered hydrogen therapy, and reversed immunosuppression, effectively inhibiting tumor growth. Lip-Mg showed superior outcomes to lipiodol alone for TAE therapy, with M-TACE treatment exhibiting higher ORR and CR rates than cTACE. Post-M-TACE, adverse events were managed well without treatment discontinuations. Our study introduces Mg microspheres as a promising embolic device for M-TACE therapy, potentially improving TACE benefits. Clinical trial information: ChiCTR2100050327.
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Weakland, Tina, e Henry Wagner. "Management of Toxicities of Combined Modality Therapy for Intrathoracic Malignancies". Cancer Control 3, n.º 4 (julho de 1996): 329–35. http://dx.doi.org/10.1177/107327489600300404.
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Background Combined radiation and chemotherapy for intrathoracic tumors can produce appreciable morbidity. Apprehension about the severity of these toxicities may inhibit optimal patient care. Methods The literature on recognition, diagnosis, prophylaxis, and management of these toxicities is reviewed and combined with the experiences of the authors to produce management recommendations. Results Toxicities include acute and chronic esophagitis, early and late pneumonitis with fibrosis, myelosuppression, and neurologic deficits. Measures are available to minimize their severity and to reduce their impact on the patient. Conclusions The morbidity of combined radiation and chemotherapy patients with intrathoracic tumors can be minimized by recognizing potential toxicities and by applying appropriate prophylactic and management measures.
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Lee, Shing M., Daniel Backenroth, Ying Kuen Ken Cheung, Dawn L. Hershman, Diana Vulih, Barry Anderson, Percy Ivy e Lori Minasian. "Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials". Journal of Clinical Oncology 34, n.º 12 (20 de abril de 2016): 1395–401. http://dx.doi.org/10.1200/jco.2015.66.0662.
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Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials.
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Howell, Matthew, Rebecca Lee, Samantha Bowyer, Alberto Fusi e Paul Lorigan. "Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer". Lung Cancer 88, n.º 2 (maio de 2015): 117–23. http://dx.doi.org/10.1016/j.lungcan.2015.02.007.
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Mucha, Simon R., e Prabalini Rajendram. "Management and Prevention of Cellular-Therapy-Related Toxicity: Early and Late Complications". Current Oncology 30, n.º 5 (15 de maio de 2023): 5003–23. http://dx.doi.org/10.3390/curroncol30050378.
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Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.
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Snider, Kelly L., e Michael L. Maitland. "Cardiovascular toxicities: clues to optimal administration of vascular endothelial growth factor signaling pathway inhibitors". Targeted Oncology 4, n.º 2 (17 de abril de 2009): 67–76. http://dx.doi.org/10.1007/s11523-009-0106-0.
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Gresham, Gillian, Jasleen Sidhu, Navraj Malhi e Winson Y. Cheung. "Predicting toxicities from adjuvant treatment in a population-based cohort of early colon cancer (CC) patients (pts): A strategy to improve use of curative chemotherapy." Journal of Clinical Oncology 32, n.º 3_suppl (20 de janeiro de 2014): 412. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.412.
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412 Background: CC pts treated with chemotherapy are at risk of experiencing a number of toxicities. The identification of pts who may be at a higher risk of developing toxicities allows clinicians to be more vigilant in preventing and managing side effects early, thus enabling more optimal delivery of chemotherapy. Our aim was to determine clinical factors associated with toxicities from adjuvant FOLFOX in early CC. Methods: Pts diagnosed with stage III CC from 2005 to 2008, seen at any 1 of 5 regional cancer centers of the British Columbia Cancer Agency, and treated with adjuvant FOLFOX chemotherapy were reviewed. We evaluated various toxicities, including gastrointestinal, hematologic, cardiovascular, and neurological side effects. Baseline and clinical factors were assessed in univariate and multivariate models to determine potential predictors for each of the different chemotherapy toxicities. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged >70 years, and 54.5% were men. In terms of function, the majority (90.1%) was ECOG 0/1. Time to adjuvant chemotherapy (TTAC) >8 weeks (OR 1.91, 95% CI 1.8-3.1, p=0.006) and renal dysfunction with a GFR <50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038) were significantly associated with higher odds of any GI toxicity. Likewise, TTAC >8weeks (OR 2.8, 95% CI 1.5-5.2, p=0.002), ECOG PS >1 (OR 2.86, 95% CI 1.2-6.7, p=0.016), and low white blood cell count <6.4 (OR 2.32, 95% CI 1.3-4.0, p=0.0043) were correlated with a greater risk of significant neutropenia. Multiple toxicities were more prevalent among those who waited >8 weeks to initiate adjuvant FOLFOX (OR 1.69, 95%CI 1.1-2.7, p=0.03). Further, advanced age >70 years was an indepenent risk factor for worse nausea and diarrhea. Conclusions: Consideration of important baseline characteristics such as TTAC, advanced age, renal function, and specific laboratory parameters when recommending adjuvant FOLFOX can be useful in identifying patients with increased likelihood of toxicities. This group of patients may benefit from increased monitoring in order to enable optimal doses of curative chemotherapy to be delivered.
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Martín, Antonio González. "Safety Profile of Trabectedin in Combination With Liposomal Pegylated Doxorrubicin in Relapsed Ovarian Carcinoma: Considerations for Optimal Management". International Journal of Gynecologic Cancer 21, Supp 1 (maio de 2011): S6—S8. http://dx.doi.org/10.1097/igc.0b013e318217b360.
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The toxicity profile of trabectedin in the OVA-301 trial, that combined trabectedin with pegylated liposomal doxorubicin for the treatment of patients with ovarian cancer, has shown to be predictable and manageable. No unexpected toxicities were found, with neutropenia and transient increase in transaminases as the most common adverse events reported. The elevation in transaminases appeared early and generally decreased in incidence and intensity over subsequent cycles, with no major clinical consequences. A similar safety profile was seen in the analysis of the older patients in the trial. There were no detrimental effects in quality of life with the combination. Moreover, the Global Health Status score was better for the combination arm in those patients with a PFI of 6 to 12 months that were in response after 5 cycles. Trabectedin with pegylated liposomal doxorubicin is not associated with cumulative end-organ toxicities (renal, cardiac, or neurological toxicities). The toxicity profile is different from other second-line strategies without the presence of inconvenient side effects, such as alopecia, hypersensitivity reactions, hand-foot syndrome, or mucositis.
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Dulong, Sandrine, Lucas Eduardo Botelho de Souza, Jean Machowiak, Benoit Peuteman, Gaelle Duvallet, Déborah Boyenval, Elise Roth et al. "Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities". Pharmaceutics 14, n.º 11 (15 de novembro de 2022): 2465. http://dx.doi.org/10.3390/pharmaceutics14112465.
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Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing-related determinants of oxaliplatin hematopoietic toxicities in mice. Body-weight loss (BWL), blood cell counts, bone marrow cellularity (BMC) and seven flow-cytometry-monitored hematopoietic progenitor populations were evaluated 72 h after oxaliplatin chronotherapy administration (5 mg/kg). In control animals, circadian rhythms of circulating white blood cells showed a peak at ZT5 in both sexes, whereas BMC was maximum at ZT20 in males and ZT13h40 in females. All BM progenitor counts presented robust rhythms with phases around ZT3h30 in females, whereas only three of them rhythmically cycled in males with a ≈ −6 h phase shift. In treated females, chronotoxicity rhythms occurred in BWL, WBC, BMC and all BM progenitors with the best timing at ZT15, ZT21, ZT15h15 and ZT14h45, respectively. In males, almost no endpoints showed circadian rhythms, BWL and WBC toxicity being minimal, albeit with a substantial drop in BM progenitors. Increasing dose (10 mg/kg) in males induced circadian rhythms in BWL and WBC but not in BM endpoints. Our results suggest complex and sex-specific clock-controlled regulation of the hematopoietic system and its response to oxaliplatin.
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Vanderburg, Sky Breeden, A. Lindsay Frazier e Jane Kim. "Determining optimal first-line chemotherapy for good and intermediate prognosis testicular germ cell tumors using decision analysis." Journal of Clinical Oncology 32, n.º 30_suppl (20 de outubro de 2014): 209. http://dx.doi.org/10.1200/jco.2014.32.30_suppl.209.
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209 Background: Since 80-90% of testicular germ cell tumors (GCTs) are cured after first line therapy alone, minimizing toxicity should be an important consideration in the initial treatment decision between cisplatin and carboplatin. Cisplatin has been shown to be superior in 5-year disease-free survival, but cisplatin use confers a higher risk of key long-term toxicities. This study aims to quantify this trade-off between disease-free survival and toxicities using decision analysis. Methods: We developed a mathematical decision-analytic model that simulates competing strategies of initial treatment with cisplatin or carboplatin in terms of treatment response, long-term toxicity, and mortality associated with first, second, and third line therapies for patients with good and intermediate prognosis testicular GCTs and a median age of 20 years at diagnosis. Treatment toxicities included ototoxicity, neurotoxicity, and nephrotoxicity. Monthly probabilities were weighted means derived from a systematic review of total follow-up data reported in seminal clinical trials. The model projected life expectancies for each strategy. Sensitivity analysis was conducted to examine the impact of uncertain inputs and assumptions. Results: The life expectancies at diagnosis for cisplatin and carboplatin strategies were 436.1 months (36.3 years) and 663.2 months (55.3 years) respectively. Sensitivity analyses revealed life expectancy figures largely dependent on the risk of nephrotoxicity occurrence from first line therapy and death from nephrotoxicity. Unless these base monthly probabilities were reduced by 87% and 99% respectively, carboplatin consistently yielded higher life expectancy than cisplatin. Conclusions: Under the current model, first line carboplatin therapy yields longer life expectancy than cisplatin, but this difference is highly sensitive to variables concerning nephrotoxicity. These preliminary results suggest that first line carboplatin therapy could yield higher life expectancy, though this result may be mediated by inclusion of other factors in future analyses, including updated estimates of mortality from nephrotoxicity or other toxicities.
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Webb, Philip, Terry W. Rice e Timothy Cooksley. "Problem-based review: Immune-mediated complications of ‘Checkpoint Inhibitors’ for the Acute Physician". Acute Medicine Journal 16, n.º 1 (1 de janeiro de 2017): 21–24. http://dx.doi.org/10.52964/amja.0647.
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Immunotherapy with ’checkpoint-inhibitors‘ has significantly improved outcomes for patients with a range of malignancies. However, significant immune-mediated toxicities of these therapies are well-described. These immune-mediated toxicities can affect virtually all organ systems and are potentially fatal. The timing of onset of the adverse effects is dependent on the organ system affected and can occur after completion of the treatment. The increasing utilisation of ‘checkpoint-inhibitors’ means that Acute Physicians are likely to see a number of immune-mediated complications presenting to the AMU. The fundamental principles of management of immune-mediated toxicities are early recognition, supportive treatment, escalating steroid therapy (dependent on the severity of the toxicity), close liaison with Oncology and specialist organ team input. Research into the optimal strategies and pathways for the management of immune-mediated toxicity, as well as increased collaboration between Acute Physicians and Oncologists, will be necessary.
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Ribeiro, Andreza Alice Feitosa. "Follow–up beyond 1 month after autologous CAR T cell therapy". JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY 3, n.º 2 (23 de novembro de 2022): 181. http://dx.doi.org/10.46765/2675-374x.2022v3n2p181.
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The incidence of medium-term and long-term adverse events are critical factors determining the utility of CAR T-cell therapy and research of risk factors and timeline of late effects will be critical for optimal survivorship care. The most commonly reported toxicities during long-term follow-up after anti-CD19 CAR T-cell therapy are decreased blood B-cell counts, hypogammaglobulinemia, prolonged cytopenias and infections. Common determinants of late toxicities are age, underlying tumor type, previous therapy and CAR construct. Here we will provide some recommendations for patient monitoring during medium-term and long-term follow-up and management of the late adverse effects.
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Chitsazan, Mandana, Ahmad Amin, Luisa Ladel, Alyza Baig e Mitra Chitsazan. "Cardiovascular Toxicity Associated With Immune Checkpoint Inhibitor Therapy: A Comprehensive Review". Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine 22, n.º 3 (26 de junho de 2023): 69–82. http://dx.doi.org/10.1097/hpc.0000000000000327.
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Immune checkpoint inhibitors (ICIs), a significant breakthrough treatment of cancer, exert their function through enhancing the immune system’s ability to recognize and attack cancer cells. However, these revolutionary cancer treatments have been associated with a range of immune-related adverse effects, including cardiovascular toxicity. The most commonly reported cardiovascular toxicities associated with ICIs are myocarditis, pericarditis, arrhythmias, and vasculitis. These cardiovascular manifestations are often severe and can lead to life-threatening complications. Therefore, prompt identification and management of these toxicities is critical, and a multidisciplinary teamwork by cardiologists and oncologists are required to ensure optimal patient outcomes. In this review, we summarize the current knowledge on the mechanisms underlying ICI-associated cardiovascular toxicity, clinical presentations of these toxicities, potential risk factors, diagnosis, management, and surveillance strategies during ICI therapy. While ICIs have already transformed cancer treatment, further research is needed to better understand and manage their immune-related cardiovascular effects, and possibly, to identify biomarkers which can predict the occurrence of these cardiovascular complications.
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Sayed, Ahmed, Malak Munir, Sanam Ghazi, Mussammat Ferdousi, Satyam Krishan, Adnan Shaaban, Alma Habib et al. "Cardiovascular Toxicities Associated with Bispecific T-Cell Engagers". Blood 142, Supplement 1 (28 de novembro de 2023): 2882. http://dx.doi.org/10.1182/blood-2023-189603.
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Background: Bispecific T-cell engagers (BTEs) are a novel class of drugs used to treat hematological malignancies that link endogenous tumor antigens to CD3 on the T-cell receptor, priming circulating T-cells to effectively target tumor cells. Although chimeric antigen receptor T-cell therapies, a closely related class, have been associated with cardiovascular toxicity, little is known about the cardiovascular toxicity of BTEs. As early clinical trials may have been underpowered for the detection of cardiovascular adverse events (CVAEs), we conducted a large-scale post-marketing surveillance study to identify safety signals that may have been missed. Methods: Leveraging the US Food and Drug Administration's Adverse Events Reporting System (FAERS), we identified adverse event (AE) reports in patients who received BTEs from October 2014 to March 2023. Eligible therapies included Blinatumomab (CD3/CD19 bispecific antibody) and Teclistamab (CD3/BCMA bispecific antibody). The primary outcome of the study was the frequency and fatality rates of CVAEs associated with BTEs. CVAEs included bleeding, hypotension or shock, thromboembolic disease, heart failure, conduction abnormalities (including tachyarrhythmia, bradyarrhythmia, QT-prolongation, and premature contractions), myocarditis, pericarditis, sudden death, and vasculitis. Secondary outcomes included the frequency and fatality rates of cytokine release syndrome (CRS), neurotoxicity (seizures, altered mental status [AMS], speech disorders, gait disorders, and tremors), and infections. We used multivariable logistic regression models, adjusting for age, sex, and disease status, to calculate adjusted reporting odds ratios (RORs). RORs represent the likelihood of reporting a given AE with BTEs compared to reporting the same AE with all other drugs in the database. Mortality rates for each AE are also reported. Results: Overall, 1,181 cases were reported to FAERS for BTE-associated AEs. Among these, 148 (12.5%) involved CVAEs. The most common CVAEs (non-exclusive) were bleeding (70 events), hypotension or shock (56 events), thromboembolic disease (37 events), heart failure (23 events), and tachyarrhythmias (11 events). Less common CVAEs included myocarditis (3 events), pericarditis (1 event), sudden death (1 event), and vasculitis (1 event) (Figure 1A). Of these, BTEs as a class were disproportionately associated with shock or hypotension (ROR: 1.37 [95% CI: 1.03 to 1.80]). Blinatumomab was associated with disproportionately high rates of thromboembolic disease (ROR: 1.48 [95% CI: 1.05 to 2.08]), particularly disseminated intravascular coagulation (DIC; ROR: 4.67 [95% CI: 2.85 to 7.63]). Teclistamab was associated with disproportionately high rates of myocarditis (ROR: 35.79 [95% CI: 10.47 to 122.41]), QT prolongation (ROR: 9.85 [95% CI: 1.33 to 73.08]), and sudden death (ROR: 8.62 [95% CI: 1.16 to 63.99]). Compared to non-cardiovascular AEs, CVAEs were associated with a 92% relative increase in mortality (25.9% vs 50.7%; risk ratio: 1.92 [95% CI: 1.53 to 2.42]). Among CVAEs, the highest mortality rates were reported for heart failure (82.4%), myocarditis (66.7%), bleeding (61.5%), shock or hypotension (57.1%), thromboembolic disease (42.3%), and tachyarrhythmias (37.5%) (Figure 1B). Non-cardiovascular AEs such as neurotoxicity (322 events), infection (277 events), and CRS (190 events) were reported more frequently but had lower mortality rates (28.3%, 48.4%, and 40.0% respectively). Blinatumomab was associated with disproportionately high rates of CRS (ROR: 6.54 [95% CI: 5.41 to 7.92]) and neurotoxicity (ROR: 2.94 [95% CI: 2.56 to 3.39]). Neurotoxicity included AMS (ROR: 2.47 [95% CI: 2.01 to 3.04]), seizures (ROR: 2.81 [95% CI: 2.09 to 3.77]), speech disorders (ROR: 5.72 [95% CI: 4.16 to 7.85]), and tremors (ROR: 6.94 [95% CI: 5.15 to 9.34]). Teclistamab was associated with CRS (ROR: 134.35 [95% CI: 74.45 to 242.47]), infections (ROR: 6.83 [95% CI: 4.63 to 10.07]), and neurotoxicity (ROR: 2.75 [95% CI: 1.53 to 4.94]). Conclusion: In the first large-scale post-marketing surveillance study of BTEs, CVAEs were not uncommon and were more likely to be fatal compared to non-CVAE. Heart failure and myocarditis in particular may portend worse outcomes. These safety signals warrant clinical vigilance and further investigation of their mechanisms, optimal surveillance strategies, and treatment options.
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Farhadfar, Nosha, Jack W. Hsu, Brent R. Logan, Jennifer A. Sees, Pintip Chitphakdithai, Dennis L. Confer, Michael A. Pulsipher et al. "Weighty Choices: Selecting Optimal G-CSF Doses for Stem Cell Mobilization to Optimize Yield". Blood 132, Supplement 1 (29 de novembro de 2018): 193. http://dx.doi.org/10.1182/blood-2018-193.
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Abstract Introduction. There is little information on the effect of donor body mass index (BMI) on mobilization response to Filgrastim (G-CSF), especially in the unrelated donor setting. Obesity has been associated with chronic low-grade inflammation due to chronic activation of the innate immune system. Obesity-induced pro-inflammatory cytokines can interfere with bone marrow SDF1/CXCR4 axis and promote mobilization of progenitor cells leading to persistent leukocytosis and an increase in number of circulating progenitor cells. Given a higher number of circulatory progenitor cells in obese individuals compared to non-obese, a reduced G-CSF dose in obese donors may elicit adequate response, thus reducing the adverse events associated with peripheral blood stem cell (PBSC) collection. The aim of this study is to evaluate the impact of donor BMI on G-CSF mobilized peripheral blood progenitor cell yield in healthy donors. This study also examines whether there is a G-CSF dose threshold above which there is a significant increase in skeletal pain and other acute toxicities from mobilization without an appreciable increase in progenitor cell yield. Methods. The primary outcome was examination of CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF administration as a measure of collection yield. The secondary outcomes were the incidence of skeletal pain and highest toxicity level across selected body symptoms (fatigue, nausea, anorexia, insomnia, dizziness) at 24 hours after first G-CSF dose, day 1 to 5 of G-CSF administration, 2 days and 1-week post collection. The population studied was domestic unrelated G-CSF mobilized PBSC donors reported to the NMDP/CIBMTR between 2006 and 2016. G-CSF dosing was based on the NMDP weight-based dosing schema rounded to the nearest vial content. Donors were divided into normal, overweight, obese, and morbidly obese categories based on BMI. Multivariate analysis of collection yields between cohorts were done using linear regression analysis. Stepwise variable selection was used to add variables to the model: BMI group and G-CSF dose was forced into the final model as the variables of interest. Pain and acute toxicities at each time point were described using frequencies and compared between groups using chi-squared test or Fisher's exact test after adjusting for donor and baseline characteristics. Results. Examination of 20, 884 PBSC donors mobilized by G-CSF revealed a significant increase in collection yield in obese and morbidly obese compared to normal and overweight donors. Median CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF was 29.6, 36.4, 40.8 and 42.9 in normal, overweight, obese and morbidly obese donors, respectively (p<0.001). Based on the subgroup analyses evaluating impact of average daily dose of G-CSF on the collection yield for each BMI group, an increase in average daily G-CSF dose was associated with an increase in stem cell yield in normal and overweight BMI donors. In contrast, an increase in the average daily G-CSF dose beyond 780 mcg per day in obese and 900 mcg per day in morbidly obese did not increase the yield (Table 1). Figure 1 shows the time course and degree of toxicities in different BMI categories. Obese and morbidly obese were more likely to experience grade 2-4 pain and toxicities compared with normal or overweight in both the peri-collection and early post-donation recovery period but by one week after donation most toxicities abated and there was no difference. Donors with a higher BMI were more likely to experience grade 2 to 4 skeletal pain 24 hours post first G-CSF dose, 2 days post donation and at day 1 to 5 G-CSF administration. In addition, donors with higher BMI were more likely to have grade 2-4 toxicities (fatigue, anorexia, insomnia) at day 1 to 5 of G-CSF and 2 days after collection. However, within each BMI group, incremental increase in G-CSF dose was not associated with greater pain or other toxicities. Conclusions. Our data indicates a correlation between average daily G-CSF dose and CD34+ cell yield in normal and overweight donors. However, in obese and morbidly obese donors, there was no benefit in CD34+ yield with increasing average daily G-CSF dose above 780 mcg and 900 mcg respectively. Therefore, there appears to be a maximum effective G-CSF dose for mobilization in obese and morbidly obese donors where higher doses of G-CSF add no additional benefit and may result in additional complications. Disclosures Pulsipher: Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Adaptive Biotech: Consultancy, Research Funding; CSL Behring: Consultancy.
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Oza, Aabha, Patrick Grierson, Sean Glasgow, Katrina Pedersen, Stephen Barman, Thomas Westbrook, Matthew G. Mutch et al. "A phase I dose-escalation trial of intraperitoneal oxaliplatin with systemic capecitabine and bevacizumab following cytoreduction in patients with peritoneal carcinomatosis from appendiceal or colorectal cancer." Journal of Clinical Oncology 36, n.º 4_suppl (1 de fevereiro de 2018): 746. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.746.
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746 Background: Peritoneal carcinomatosis (PC) is the intraperitoneal spread of cancer. Optimal treatment for PC is controversial. Systemic chemotherapy offers limited benefit (Franko, 2011). Intraperitoneal (IP) chemotherapy following cytoreductive surgery (CRS) improves outcomes (Verwaal, 2008). Oxaliplatin (Ox), capecitabine, and bevacizumab are standard agents for the treatment of metastatic colorectal cancer (CRC). Evidence suggests benefit of IP Ox at high doses. However, the optimal dose of IP Ox combined with standard systemic therapy is unclear. Methods: We conducted an IRB-approved phase I dose-escalation study of IP Ox D1 at 25mg/m2-100mg/m2, with systemic bevacizumab D1 at 5mg/kg, and capecitabine 850mg/m2 BID for 7 days (cycle = 14 days), in patients with PC from appendiceal or CRC after CRS. The primary aim was to determine the recommended phase II dose (RP2D)/maximum tolerated dose (MTD) for this regimen. Dose limiting toxicities (DLTs) were assessed during cycle 1. DLTs included grade 3 or 4 non-hematological toxicities, or grade 4 hematological toxicities. Results: 18 patients (12 females, median age 56) were enrolled on the study. No DLTs were observed during cycle 1 in the first 4 cohorts. One DLT (abdominal pain) was observed in cohort 5. Another patient in cohort 5 experienced grade 3 abdominal pain soon after cycle 2, thus limiting repeated treatment for this cohort. Other toxicities included fatigue (72%), nausea (61%), peripheral neuropathy (50%), constipation (50%), mucositis (39%) and dizziness (39%). See table below for average # of cycles per cohort and responses. Conclusions: IP Ox combined with capecitabine and bevacizumab is feasible. Our recommended dose for IP Ox is 85 mg/m2 with systemic therapy (cohort 4). An expansion cohort is underway for this dose level. Based on these data, further investigation of IP Ox with systemic chemotherapy for PC is warranted. Clinical trial information: NCT01061515. [Table: see text]
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Advani, Anjali S. "Biology and Treatment of Acute Lymphocytic Leukemia in Adolescents and Young Adults". American Society of Clinical Oncology Educational Book, n.º 33 (maio de 2013): 285–89. http://dx.doi.org/10.14694/edbook_am.2013.33.285.
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The treatment of young adults (16 to 39 years of age) with acute lymphocytic leukemia (ALL) has been a focus of clinical research over the past decade. This review will focus on the biology, optimal treatment, treatment-related toxicities, and psychosocial issues in this patient population.
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Mercier, C., C. Brunet, C. Yang, C. Dupuis, D. Bagarry-Liegey, S. Duflo, A. Giovanni et al. "Pharmacoeconomic study in head and neck cancer patients: Impact of prospective DPD deficiency screening with 5-fluorouracil (5-FU) dose tailoring on toxicities-related costs". Journal of Clinical Oncology 27, n.º 15_suppl (20 de maio de 2009): 6515. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6515.
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6515 Background: Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the detoxification of 5-FU. We studied the impact of screening DPD impairment in head and neck cancer (HNC) patients, both on reduction of drug-related toxicities and as a pharmacoeconomic endpoint. Methods: A total of 148 consecutive patients with HNC treated with 5-FU+platinum were monitored. Seventy-four patients (Arm A - before 2006) were treated with standard dosage, whereas 74 other patients (Arm B - after 2006) had their DPD status phenotypically evaluated prior to receiving 5-FU, with subsequent dose reduction if DPD deficiency were suspected. Severe toxicities and response were compared. Additionally, direct and indirect costs required to manage the treatment-related toxicities and to establish DPD status were calculated. Results: Sepsis was observed in 16.2% of patients treated with standard dosage. In Arm B, DPD deficiency was suspected in 35% of the patients and 5-FU dosage was subsequently reduced. Consequently, only 1.8% of them experienced sepsis. Of note, response rates were comparable between Arm A and B (62 vs 61%, p>0.05), thus demonstrating that 5-FU dose tailoring did not negatively impact on treatment efficacy, while reducing the occurrence of severe toxicities. Managing toxicities required an average 23-days of extra-hospitalization (4–96 days), including an average 1.6-day stay in ICU. No patients from Arm B had to stay in ICU. Drugs required for managing toxicities cost an average of $339 per patient (Arm A) and was reduced down to $38 per patient (Arm B). Similarly, mean extra-hospitalization cost was $5,940/patient in Arm A and $245/patient in Arm B. Testing DPD cost $49/patient in Arm B. Conclusions: Developing an adaptative dosing strategy based upon DPD status evaluation led to a dramatic reduction of the incidence of 5-FU-related severe toxicities, while maintaining optimal efficacy. Subsequently, extra-cost (medication + hospitalization costs) required to manage the toxicities fell down from $6,279 to $294/patient. Overall, this study advocates that systematic screening for DPD deficiency could be cost-efficient in the setting of 5-FU-based chemotherapies, with a reduction of 95% of the extra-costs. No significant financial relationships to disclose.
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Zhou, Heng, Cong Chen, Linda Sun e Zhen Zeng. "A novel framework of Bayesian optimal interval design for phase I trials with late-onset toxicities". Contemporary Clinical Trials 105 (junho de 2021): 106404. http://dx.doi.org/10.1016/j.cct.2021.106404.
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Wang, W., Y. Zhang, Z. Gu, F. Zhang, C. Wang, K. Hu, J. Tang e P. Peng. "Daily Online Adaptive Radiotherapy for Rectal Cancer Utilizing CT-Linac: Assessing Feasibility, Toxicities and Optimal Margins". International Journal of Radiation Oncology*Biology*Physics 120, n.º 2 (outubro de 2024): e595-e596. http://dx.doi.org/10.1016/j.ijrobp.2024.07.1312.
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Mueller, Joerg P., Nils O'Brien, Franz Osl, Frank Herting, Christian Klein, Pablo Umana, Sara Colombetti, Thomas Poeschinger e Andreas Beilhack. "Abstract 1876: ROCKETS Science: A novel processing toolbox for light sheet microscopy reveals unknown binding sites for EpCAM-targeted antibodies". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 1876. http://dx.doi.org/10.1158/1538-7445.am2022-1876.
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Abstract Summary: We present a novel light sheet fluorescence microscopy (LSFM)-based imaging platform and corresponding set of procedures for greatly improved preclinical investigation of the biodistribution of novel drug candidates by the example of an EpCAM-targeting antibody. Methods: An anti-EpCAM antibody (G.8.8R) was applied intravenously to mice. Whole mice or individual organs were optically cleared following novel protocols, which we termed Rapid Optical Clearing Kit for Enhanced Tissue Scanning (ROCKETS). The procedures enabled processing of mouse organs and entire bodies for LSFM. For the GI tract, we developed 3D-Swiss rolls, a method that enables fixation, clearing and imaging of intestines in a compact form as a whole. The new procedures allowed us to investigate the biodistribution of G.8.8R in the entire mouse body and highly detailed in individual organs. Results: The ROCKETS concept achieved full transparency of any mouse organ, the entire GI tract and whole mouse bodies. All positive organs were easily identified in scans of whole mice, thereby providing excellent guidance for scanning of positive individual organs at higher magnifications. We detected G8.8R bound to all normal cuboidal and columnar epithelia, as well as in lymphoid organs and were able to reproducibly score binding levels. All reported EpCAM+ tissues in mice were accessed by G8.8R after intravenous application and binding was restricted to basolateral membranes of epithelia, as expected from published expression analyses. Moreover, we detected G8.8R in tissues that were reported EpCAM- or were not investigated, e.g. gustatory papillae of the tongue, choroid plexi in the brain or lingual mucous salivary glands. 3D-Swiss rolls of the GI tract revealed a highly heterogeneous binding pattern in the stomach, while the pattern along the small intestine was overall homogeneous. All binding was restricted to basolateral membranes of epithelial cells. We detected a general gradient of signals, decreasing from the bottom of the crypts to differentiated cells in all tissues, corresponding to described EpCAM downregulation with progressing differentiation. Furthermore, we first describe significantly increased signals at the common bile duct, major and minor duodenal papillae, as well as the mucosa in proximity of Peyer's patches (PP). Conclusions: The developed ROCKETS toolbox allowed for simple preparation of mouse organs and bodies for high-quality LSFM imaging. Our investigations of the highly heterogeneous biodistribution of G8.8R revealed previously unknown EpCAM binding locations, which may have far-reaching implications for EpCAM-targeting therapeutics in general, many of which failed in clinical studies due to dose limiting toxicities. In the future, the developed LSFM-imaging platform may contribute valuable data to preclinical drug development studies of any targeted therapeutic. Citation Format: Joerg P. Mueller, Nils O'Brien, Franz Osl, Frank Herting, Christian Klein, Pablo Umana, Sara Colombetti, Thomas Poeschinger, Andreas Beilhack. ROCKETS Science: A novel processing toolbox for light sheet microscopy reveals unknown binding sites for EpCAM-targeted antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1876.
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Xu, Zichun, e Xiaolei Lin. "Probability-of-decision interval 3+3 (POD-i3+3) design for phase I dose finding trials with late-onset toxicity". Statistical Methods in Medical Research 31, n.º 3 (22 de novembro de 2021): 534–48. http://dx.doi.org/10.1177/09622802211052746.
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Late-onset toxicities often occur in phase I trials investigating novel immunotherapy and molecular targeted therapies. For trials with cohort based designs (such as modified toxicity probability interval, Bayesian optimal interval, and i3+3), patients are often turned away since the current cohort are still being followed without definite dose-limiting toxicities, which results in prolonged trial duration and waste of patient resources. In this paper, we incorporate a probability-of-decision framework into the i3+3 design and allow real-time dosing inference when the next patient becomes available. Both follow-up time for the pending patients and time to dose-limiting toxicities for the observed patients are used in calculating the posterior probability of each possible dosing decision. An intensive simulation study is conducted to evaluate the operating characteristics of the newly proposed probability-of-decision-i3+3 design under various dosing scenarios and patient accrual settings. Results show that the probability-of-decision-i3+3 design achieves comparable safety and reliability performances but much shorter trial duration compared to the complete designs.
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Grunberg, Steven M. "Chemotherapy-Induced Nausea and Vomiting Incidence and Prevalence". American Society of Clinical Oncology Educational Book, n.º 32 (junho de 2012): 541–43. http://dx.doi.org/10.14694/edbook_am.2012.32.45.
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Overview: Although chemotherapy-induced nausea and vomiting is recognized as having been an important problem during the initial introduction of chemotherapy into the antineoplastic armamentarium, the assumption that this problem has already been solved can restrict optimal management and further advances. Underestimation of nausea and vomiting may have many causes. If these toxicities are assumed to be necessary properties of chemotherapy, then their incidence may be taken for granted. If nausea and vomiting appear after discharge from the clinic several days after chemotherapy, these toxicities may not be reported because of poor recall or because of efforts by patients to avoid unnecessary complaints. Physician education may be compromised if physicians see nausea and vomiting as population problems but not problems for their own patients. Failure to recognize nausea and vomiting as two distinct entities that may appear independently of each other can also limit understanding of the prevalence of these problems and efforts at effective management. Continued attention to the impact of nausea and vomiting on the patient experience will be necessary to insure optimal maintenance of quality of life.
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Wu, Di, Wenlan Chen, Zhichao Chen e Qiubai Li. "Venetoclax Combined with Hypomethylating Agents for Treatment-Naïve B/Myeloid Mixed Phenotype Acute Leukemia". Case Reports in Hematology 2021 (12 de janeiro de 2021): 1–4. http://dx.doi.org/10.1155/2021/6661109.
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Mixed phenotype acute leukemia (MPAL) is a rare hematological malignancy that lacks consensus on optimal management. We report for the first time two cases of treatment-naïve B/myeloid MPAL patients treated with a novel chemo-free regimen using venetoclax combined with hypomethylating agents, which successfully induced complete remission with tolerable toxicities.
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Przybylski, Daniel J., Jason J. Bergsbaken e Jennifer K. Piccolo. "Unleashing the power of immunotherapy and targeted therapy combinations: Advancing cancer care or discovering unknown toxicities?" Journal of Oncology Pharmacy Practice 27, n.º 4 (6 de janeiro de 2021): 930–38. http://dx.doi.org/10.1177/1078155220984235.
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Objective The purpose of this review was to summarize the triumphs and pitfalls of tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combinations. Data sources: A literature review of PubMed was conducted and studies were included if they were classified as a clinical trial and assessed TKI and ICI combinations for solid tumor malignancies. Dates of literature search included January 1, 1988 through September 22, 2019. Data summary: In the past decade, TKI and ICI monotherapy strategies have changed the management of many advanced solid tumors through their unique mechanisms of action. Preclinical data suggests that TKIs may be able to sensitize tumors to ICI therapy via direct and indirect pathways; however, optimal mechanisms to support various TKI and ICI combinations have yet to be determined. The FDA recently approved TKI and ICI combinations for renal cell carcinoma, endometrial carcinoma, and melanoma. Several other tumor types currently have TKI and immunotherapy combinations under investigation with mixed results. Dual therapy with TKIs and immunotherapy have the potential to be synergistic and improve patient outcomes; however, careful consideration will need to be taken in regard to what TKI and immunotherapy are combined. Conclusions Future research will be needed to determine appropriate sequencing of TKIs and ICIs after progression on combination therapy. Continued research is necessary to determine optimal dual TKI and immunotherapy options.
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Chen, Lily, Ang Gao, Bhavani S. Gannavarapu, Aurelie Garant, Neil Bipinchandra Desai, Michael Ryan Folkert, Chul Ahn et al. "Safety and outcome of stereotactic body radiation therapy (SBRT) with rectal hydrogel spacer for prostate cancer." Journal of Clinical Oncology 38, n.º 6_suppl (20 de fevereiro de 2020): 76. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.76.
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76 Background: Ultra-hypofractionated radiotherapy delivered using stereotactic body radiotherapy (SBRT) is a cost-effective treatment for localized prostate cancer. Optimal dosing remains unclear, as commonly used 30-40Gy/5fx regimens appear to overestimate hypofractionation’s control benefits. Here, we report the largest experience of 45Gy/5Fx of SBRT for prostate cancer patients treated with hydrogel peri-rectal spacer (‘hydrogel’). Methods: An IRB-approved retrospective protocol was used to conduct a registry search identifying all patients with prostate cancer who received 45Gy/5Fx between 2015-2019 with hydrogel. Genitourinary (GU) and gastrointestinal (GI) toxicities were defined using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. The ASTRO-Phoenix failure definition of Nadir+2 ng/mL was used for biochemical failure. Results: We analyzed 250 low (9.2%), intermediate (85.2%), and high-risk (5.6%) prostate cancer patients with a median follow-up of 9.9 months (range: 0-45.7 months). Acute GU and GI grade ≥ II toxicities were noted in 15.2% and 7.2% of patients, respectively. Late GU grade II and III toxicities occurred in 24.0% and 1.2% of patients, respectively, while late GI grade II and III toxicities occurred in 4.0% and 0.4% of patients, respectively. In patients (N=44) with follow-up >2 years, late GU and GI grade III toxicities occurred in 4.55% and 2.27% of patients, respectively. A significant correlation was noted for acute GI and GU toxicity predicting the respective late GI and GU toxicity (p-value < 0.001 for both). Physician-reported Grade ≥ II new onset erectile dysfunction was 17.2%. A gradual decline in prostate-specific antigen with a mean nadir of 0.04 (95% CI: [0.018, 0.067]) at 36 months was noted. The actuarial freedom from biochemical failure was 96.33% at 3 years. Overall survival was 94.09% at 3 years with no deaths attributed to prostate cancer. Conclusions: SBRT treatment of 45Gy/5Fx with hydrogel is well tolerated with GU/GI toxicities comparable to those reported for conventional fractionation. Although short, the 3-year biochemical control rate is encouraging. Longer follow-up and prospective evaluation are warranted.
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Rawlins, Yasmin, Jemily Malvar, Richard Sposto, Etan Orgel e Deepa Bhojwani. "Investigating Ethnic Differences in Toxicities of Childhood ALL Therapy". Blood 128, n.º 22 (2 de dezembro de 2016): 5989. http://dx.doi.org/10.1182/blood.v128.22.5989.5989.
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Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with an excellent survival rate due to advancements in therapy. However, significant chemotherapy treatment-related toxicities (TRTs) are associated with the intensity of such treatments, which can affect quality of life, preclude the ability to provide optimal therapy, and impact survival. Further, outcomes are worse among certain minority populations, including Hispanic patients. At this single institution with a predominately Hispanic population, we sought to review several TRTs and determine whether Hispanic ethnicity may be a risk factor for increased severe, short-term TRTs and to explore the effects of TRTs on event-free survival (EFS). Methods This study is a retrospective chart-review of patients diagnosed with ALL at Children's Hospital Los Angeles from January 2008 to December 2010. Infants, patients with Down's syndrome and those who transferred to another institution during therapy were excluded from this study. Demographic and TRT information were collected from the electronic medical record, from the start of treatment until 30 days after the end of primary therapy, relapse, transplant, or death. TRTs were graded per the Common Terminology Criteria for Adverse Events version 4.0; only toxicities severe enough to negatively effect patients' quality of life, chemotherapy continuation, and survival were included. The specific TRTs were fractures, osteonecrosis, and peripheral neuropathy of ≥ grade 2, fungal and culture-positive bacterial infections, thrombosis, pancreatitis, and hyperbilirubinemia ≥ grade 3, and hepatic transaminitis ≥ grade 4. The X2 test was used to compare the proportions of Hispanic and non-Hispanic patients with and without the selected TRTs. Univariable and multivariable Cox regression models were used to examine the association of patient demographics with EFS and time to TRT. All analyses were performed using a 2-sided test and completed using the statistical software Stata. Results Of the 172 patients diagnosed with ALL between 2008 and 2010, 138 patients are included in this study, 124 with B-cell ALL and 14 with T-cell ALL. Among the 138 patients, 57.2% were male, 24.6% were obese, 76.1% were Hispanic, and 58% were classified as high-risk by the NCI Rome criteria. The median age at diagnosis was 7.9 years (range 1.1 to 20). All patients were treated according to ongoing Children's Oncology Group therapeutic studies. During the course of therapy, 23 patients relapsed, 3 developed secondary malignancy, and 2 patients died from infection. There were 156 TRTs observed in 85 patients, with 61.6% of patients experiencing one or more of the selected TRTs. The most common TRTs were infectious and gastrointestinal/hepatobiliary events. While Hispanic patients had 2.2 times higher frequency of pancreatitis than non-Hispanic patients and 1.8 times more hyperbilirubinemia, there were no statistically significant differences in the incidence of any TRTs by ethnicity. NCI high risk and older age were the only significant predictors of any TRT (p<0.001). Obesity was significantly associated with the development of pancreatitis and hyperbilirubinemia (p=0.01). Ethnicity, NCI risk, and ages were all predictive of EFS in the univariable analysis, with Hispanic ethnicity associated with 3.4-fold increase in risk of relapse and death when compared to non-Hispanics (p = 0.047). In the multivariable setting, NCI risk was the only significant predictor of EFS, although there was a trend in increased risk of relapse and death among Hispanic patients. Discussion In this relatively small cohort of patients, we did not identify ethnicity as a risk factor for increased TRTs during therapy for ALL, although certain TRTs such as pancreatitis and hyperbilirubinemia may be more common among Hispanic patients. As expected, Hispanic ethnicity, NCI risk, and age at diagnosis were risk factors for increased relapse and death. These results may suggest that additional factors, such as genetics, disease biology, or medication compliance, may play a more significant role in worse outcomes for Hispanic patients, rather than difference in tolerance of the treatment itself. Analyses of a larger cohort of patients are ongoing to confirm these results and to comprehensively analyze the determinants of pancreatitis and hepatic toxicity, and their interaction with obesity in Hispanic patients with ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015.
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Burton, Leeann B., Mahsa Eskian, Amanda C. Guidon e Kerry L. Reynolds. "A review of neurotoxicities associated with immunotherapy and a framework for evaluation". Neuro-Oncology Advances 3, Supplement_5 (1 de novembro de 2021): v108—v120. http://dx.doi.org/10.1093/noajnl/vdab107.
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Abstract Immuno-oncology agents, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapies, are increasing in use for a growing list of oncologic indications. While harnessing the immune system against cancer cells has a potent anti-tumor effect, it can also cause widespread autoimmune toxicities that limit therapeutic potential. Neurologic toxicities have unique presentations and can progress rapidly, necessitating prompt recognition. In this article, we review the spectrum of central and peripheral neurologic immune-related adverse events (irAEs) associated with ICI therapies, emphasizing a diagnostic framework that includes consideration of the therapy regimen, timing of symptom onset, presence of non-neurologic irAEs, pre-existing neurologic disease, and syndrome specific features. In addition, we review the immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CAR-T cell therapy and address diagnostic challenges specific to patients with brain metastases. As immunotherapy use grows, so too will the number of patients affected by neurotoxicity. There is an urgent need to understand pathogenic mechanisms, predictors, and optimal treatments of these toxicities, so that we can manage them without sacrificing anti-tumor efficacy.