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1.
Molecules ; 27(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2099669

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the betacoronavirus genus can cause severe respiratory illnesses, accompanied by pneumonia, multiorgan failure, and ultimately death. CoVs have the ability to transgress species barriers and spread swiftly into new host species, with human-to-human transmission causing epidemic diseases. Despite the severe public health threat of MERS-CoV, there are currently no vaccines or drugs available for its treatment. MERS-CoV papain-like protease (PLpro) is a key enzyme that plays an important role in its replication. In the present study, we evaluated the inhibitory activities of doxorubicin (DOX) against the recombinant MERS-CoV PLpro by employing protease inhibition assays. Hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of DOX showed an IC50 value of 1.67 µM at 30 min. Subsequently, we confirmed the interaction between DOX and MERS-CoV PLpro by thermal shift assay (TSA), and DOX increased ΔTm by ~20 °C, clearly indicating a coherent interaction between the MERS-CoV PL protease and DOX. The binding site of DOX on MERS-CoV PLpro was assessed using docking techniques and molecular dynamic (MD) simulations. DOX bound to the thumb region of the catalytic domain of the MERS-CoV PLpro. MD simulation results showed flexible BL2 loops, as well as other potential residues, such as R231, R233, and G276 of MERS-CoV PLpro. Development of drug repurposing is a remarkable opportunity to quickly examine the efficacy of different aspects of treating various diseases. Protease inhibitors have been found to be effective against MERS-CoV to date, and numerous candidates are currently undergoing clinical trials to prove this. Our effort follows a in similar direction.


Subject(s)
Middle East Respiratory Syndrome Coronavirus , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Papain/chemistry , Peptide Hydrolases/metabolism , Drug Repositioning , Doxorubicin/pharmacology , Doxorubicin/metabolism
2.
Am J Case Rep ; 23: e937500, 2022 Sep 24.
Article in English | MEDLINE | ID: covidwho-2056389

ABSTRACT

BACKGROUND Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). While bone marrow (BM) involvement is common in lymphoma, primary bone marrow (PBM) DLBCL is extremely rare. We present a case of PBM DLBCL discovered in a patient with COVID-19. CASE REPORT An 80-year-old man presented with generalized abdominal pain, weight loss, fever, fatigue, anorexia, and watery diarrhea over a 3-month period. Physical examination was unremarkable. Laboratory workup revealed anemia, thrombocytopenia, and elevated inflammation markers. SARS-COV-2 PCR was positive, while blood cultures were negative. A rapid decline in the white blood cell count in the following days prompted a BM biopsy, confirming the diagnosis of PBM DLBCL. Computed tomography (CT) did not show thoracic or abdominal lymphadenopathy. The patient received packed red blood cell and platelet transfusions, granulocyte colony-stimulating factor (G-CSF) for pancytopenia, and empirical antibiotics for suspected infection. Due to active COVID-19 and advanced age, cytotoxic chemotherapy was delayed. Rituximab and prednisone were initiated on day 9, followed by an infusion reaction, which led to treatment discontinuation. He died 2 days later. CONCLUSIONS Diagnosing PBM malignancy is challenging, especially with coexisting infection. It is essential to suspect underlying BM malignancy in patients with clinical deterioration and worsening pancytopenia despite adequate treatment. The diagnosis of PBM DLBCL requires the absence of lymphadenopathy, and the presence of histologically confirmed DLBCL. Prompt management with combination chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with/without hematopoietic stem cell transplant can improve the prognosis.


Subject(s)
COVID-19 , Lymphadenopathy , Lymphoma, Large B-Cell, Diffuse , Pancytopenia , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , COVID-19/complications , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Lymphadenopathy/pathology , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Pancytopenia/etiology , Prednisone/therapeutic use , Rituximab/therapeutic use , SARS-CoV-2 , Vincristine/therapeutic use
3.
J Clin Oncol ; 40(25): 2946-2956, 2022 09 01.
Article in English | MEDLINE | ID: covidwho-2043160

ABSTRACT

PURPOSE: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations. RESULTS: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.


Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/therapeutic use , Breast Neoplasms/pathology , Cyclophosphamide , Doxorubicin , Female , Humans , Neoadjuvant Therapy/adverse effects , Paclitaxel , Receptor, ErbB-2/metabolism , Trastuzumab , Treatment Outcome
4.
Chemosphere ; 306: 135578, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1914233

ABSTRACT

Overexpression of proteins/antigens and other gene-related sequences in the bodies could lead to significant mutations and refractory diseases. Detection and identification of assorted trace concentrations of such proteins/antigens and/or gene-related sequences remain challenging, affecting different pathogens and making viruses stronger. Correspondingly, coronavirus (SARS-CoV-2) mutations/alterations and spread could lead to overexpression of ssDNA and the related antigens in the population and brisk activity in gene-editing technologies in the treatment/detection may lead to the presence of pCRISPR in the blood. Therefore, the detection and evaluation of their trace concentrations are of critical importance. CaZnO-based nanoghosts (NGs) were synthesized with the assistance of a high-gravity technique at a 1,800 MHz field, capitalizing on the use of Rosmarinus officinalis leaf extract as the templating agent. A complete chemical, physical and biological investigation revealed that the synthesized NGs presented similar morphological features to the mesenchymal stem cells (MSCs), resulting in excellent biocompatibility, interaction with ssDNA- and/or pCRISPR-surface, through various chemical and physical mechanisms. This comprise the unprecedented synthesis of a fully inorganic nanostructure with behavior that is similar to MSCs. Furthermore, the endowed exceptional ability of inorganic NGs for detective sensing/folding of ssDNA and pCRISPR and recombinant SARS-CoV-2 spike antigen (RSCSA), along with in-situ hydrogen peroxide detection on the HEK-293 and HeLa cell lines, was discerned. On average, they displayed a high drug loading capacity of 55%, and the acceptable internalizations inside the HT-29 cell lines affirmed the anticipated MSCs-like behavior of these inorganic-NGs.


Subject(s)
DNA, Single-Stranded , Doxorubicin , Nanoparticle Drug Delivery System , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Calcium , DNA, Single-Stranded/analysis , Doxorubicin/administration & dosage , HEK293 Cells , HeLa Cells , Humans , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/genetics , Zinc Oxide
5.
Blood Adv ; 6(22): 5811-5820, 2022 11 22.
Article in English | MEDLINE | ID: covidwho-1846780

ABSTRACT

Patients with aggressive B-cell lymphoma and MYC rearrangement at fluorescence in situ hybridization exhibit poor outcome after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In the last decade, 68 patients with Burkitt lymphoma ([BL] n = 46) or high-grade B-cell lymphoma ([HGBCL] single, double, or triple hit; n = 22) were treated with a dose-dense, short-term therapy termed "CARMEN regimen" at 5 Italian centers. Forty-six (68%) patients were HIV+. CARMEN included a 36-day induction with sequential, single weekly doses of cyclophosphamide, vincristine, rituximab, methotrexate, etoposide, and doxorubicin plus intrathecal chemotherapy, followed by high-dose-cytarabine-based consolidation. Patients who did not achieve complete remission (CR) after induction received BEAM (carmustina, etoposide, cytarabine, melfalan)-conditioned autologous stem cell transplantation (ASCT) after consolidation. Sixty-one (90%) patients completed induction, and 59 (87%) completed consolidation. Seventeen patients received ASCT. Grade 4 hematological toxicity was common but did not cause treatment discontinuation; grade 4 nonhematological toxicity was recorded in 11 (16%) patients, with grade 4 infections in 6 (9%). Six (9%) patients died of toxicity (sepsis in 4, COVID-19, acute respiratory distress syndrome). CR rate after the whole treatment was 73% (95% confidence interval [CI], 55% to 91%) for patients with HGBCL and 78% (95% CI, 66% to 90%) for patients with BL. At a median follow-up of 65 (interquartile range, 40-109) months, 48 patients remain event free, with a 5-year progression-free survival of 63% (95% CI, 58% to 68%) for HGBCL and 72% (95% CI, 71% to 73%) for BL, with a 5-year overall survival (OS) of 63% (95% CI, 58% to 68%) and 76% (95% CI, 75% to 77%), respectively. HIV seropositivity did not have a detrimental effect on outcome. This retrospective study shows that CARMEN is a safe and active regimen both in HIV-negative and -positive patients with MYC-rearranged lymphomas. Encouraging survival figures, attained with a single dose of doxorubicin and cyclophosphamide, deserve further investigation in HGBCL and other aggressive lymphomas.


Subject(s)
Burkitt Lymphoma , COVID-19 , HIV Infections , Hematopoietic Stem Cell Transplantation , Lymphoma, B-Cell , Lymphoma , Humans , Rituximab/therapeutic use , Vincristine/adverse effects , Etoposide/adverse effects , Retrospective Studies , In Situ Hybridization, Fluorescence , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Transplantation, Autologous , Cyclophosphamide/adverse effects , Prednisone/therapeutic use , Cytarabine/adverse effects , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/genetics , Doxorubicin/adverse effects , Lymphoma, B-Cell/drug therapy , Lymphoma/drug therapy , HIV Infections/drug therapy
6.
Environ Int ; 164: 107230, 2022 06.
Article in English | MEDLINE | ID: covidwho-1778115

ABSTRACT

BACKGROUND: Widespread environmental contamination can directly interact with human immune system functions. Environmental effects on the immune system may influence human susceptibility to respiratory infections as well as the severity of infectious diseases, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, the efficacy of vaccines to respiratory diseases may be impacted by environmental exposures through immune perturbations. Given the quick pace of research about COVID-19 and associated risk factors, it is critical to identify and curate the streams of evidence quickly and effectively. OBJECTIVE: We developed this systematic evidence map protocol to identify and organize existing human and animal literature on high-priority environmental chemical classes (Per- and polyfluoroalkyl substances, pesticides, phthalates, quaternary ammonium compounds, and air pollutants) and their potential to influence three key outcomes: (1) susceptibility to respiratory infection, including SARS-CoV-2 (2) severity of the resultant disease progression, and (3) impact on vaccine efficacy. The result of this project will be an online, interactive database which will show what evidence is currently available between involuntary exposures to select environmental chemicals and immune health effects, data gaps that require further research, and data rich areas that may support further analysis. SEARCH AND STUDY ELIGIBILITY: We will search PubMed for epidemiological or toxicological literature on select toxicants from each of the chemical classes and each of the three outcomes listed above. STUDY APPRAISAL AND SYNTHESIS OF METHODS: For each study, two independent reviewers will conduct title and abstract screening as well as full text review for data extraction of study characteristics. Study quality will not be evaluated in this evidence mapping. The main findings from the systematic evidence map will be visualized using a publicly available and interactive database hosted on Tableau Public.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Doxorubicin , Environmental Exposure/adverse effects , Immunity , Mitomycin
7.
IET Nanobiotechnol ; 16(3): 85-91, 2022 May.
Article in English | MEDLINE | ID: covidwho-1758388

ABSTRACT

Mesoporous magnetic nanoparticles of haematite were synthesised using plant extracts according to bioethics principles. The structural, physical and chemical properties of mesoporous Fe2 O3 nanoparticles synthesised with the green chemistry approach were evaluated by XRD, SEM, EDAX, BET, VSM and HRTEM analysis. Then, their toxicity against normal HUVECs and MCF7 cancer cells was evaluated by MTT assay for 48 h. These biogenic mesoporous magnetic nanoparticles have over 71% of doxorubicin loading efficiency, resulting in a 50% reduction of cancer cells at a 0.5 µg.ml-1 concentration. Therefore, it is suggested that mesoporous magnetic nanoparticles be used as a multifunctional agent in medicine (therapeutic-diagnostic). The produced mesoporous magnetic nanoparticles with its inherent structural properties such as polygonal structure (increasing surface area to particle volume) and porosity with large pore volume became a suitable substrate for loading the anti-cancer drug doxorubicin.


Subject(s)
Nanoparticles , Silicon Dioxide , Doxorubicin/chemistry , Doxorubicin/pharmacology , Drug Carriers/chemistry , Drug Delivery Systems/methods , Drug Liberation , Humans , Nanoparticles/chemistry , Porosity , Silicon Dioxide/chemistry
8.
Int J Hematol ; 115(1): 7-10, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1604920

ABSTRACT

We investigated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. Although T-cell-mediated immune responses were detected even in patients receiving R-CHOP treatment, the S1 antibody titer following BNT162b2 vaccination remained only marginally increased for more than 3 years after the final dose of anti-CD20 antibody. We found no relationship between the percent of B-cells and S1 antibody titer. The duration of this suppression was much longer than we anticipated. Further protection and treatment strategies against COVID-19 for these patients are warranted.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , COVID-19/prevention & control , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/drug therapy , Aged , Aged, 80 and over , Antibody Formation , Antigens, CD20/immunology , COVID-19/immunology , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , Humans , Lymphoma, B-Cell/immunology , Male , Middle Aged , Prednisone/therapeutic use , Rituximab/therapeutic use , Vincristine/therapeutic use
10.
J Control Release ; 337: 612-627, 2021 09 10.
Article in English | MEDLINE | ID: covidwho-1330947

ABSTRACT

Neutrophils, the most abundant leukocytes in human peripheral blood, are important effector cells that mediate the inflammatory response. During neutrophil dysfunction, excessive activation and uncontrolled infiltration are the core processes in the progression of inflammation-related diseases, including severe coronavirus disease-19 (COVID-19), sepsis, etc. Herein, we used sialic acid-modified liposomal doxorubicin (DOX-SAL) to selectively target inflammatory neutrophils in the peripheral blood and deliver DOX intracellularly, inducing neutrophil apoptosis, blocking neutrophil migration, and inhibiting the inflammatory response. Strong selectivity resulted from the specific affinity between SA and L-selectin, which is highly expressed on inflammatory neutrophil membranes. In inflammation models of acute lung inflammation/injury (ALI), sepsis, and rheumatoid arthritis (RA), DOX-SAL suppressed the inflammatory response, increased the survival of mice, and delayed disease progression, respectively. Moreover, DOX-SAL restored immune homeostasis in the body, without side effects. We have presented a targeted nanocarrier drug delivery system that can block the recruitment of inflammatory neutrophils, enabling specific inhibition of the core disease process and the potential to treat multiple diseases with a single drug. This represents a revolutionary treatment strategy for inflammatory diseases caused by inappropriate neutrophil activation.


Subject(s)
COVID-19 , Neutrophils , Animals , Doxorubicin , Humans , Inflammation/drug therapy , Mice , N-Acetylneuraminic Acid , SARS-CoV-2
11.
Blood ; 139(11): 1631-1641, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1309901

ABSTRACT

18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is now established as the gold-standard imaging modality for both staging and response assessment in follicular lymphoma (FL). In this Perspective, we propose where PET can, and cannot, guide clinicians in their therapeutic approach. PET at diagnosis and pretreatment is important for staging, with greater sensitivity compared with standard CT, and consequent improved outcomes in truly limited-stage FL. Small data sets suggesting that a high baseline standardized uptake value (SUVmax) identifies de novo histologic transformation (HT) have not been corroborated by data from GALLIUM, the largest prospective study to examine modern therapies for FL. Nonetheless, the role of baseline quantitative PET measures requires further clarification. The median survival of patients with newly diagnosed FL is now potentially >20 years. Treatment of symptomatic FL aims to achieve remission and optimize quality of life for as long as possible, with many patients achieving a "functional cure" at the cost of unwanted treatment effects. Several studies have identified end-of-induction (EOI) PET after initial chemoimmunotherapy in patients with a high tumor burden as strongly predictive of both progression-free and overall survival, and EOI PET is being evaluated as a platform for response-adapted treatment. Unmet needs remain: improving the inferior survival for patients remaining PET positive and quantifying the progression-free survival and time to next treatment advantage, and additional toxicity of anti-CD20 maintenance in patients who achieve complete metabolic remission. In the absence of an overall survival advantage for frontline antibody maintenance, the question of using PET to guide the therapeutic approach is more important than ever in the context of the COVID-19 pandemic.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorodeoxyglucose F18 , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/drug therapy , Positron Emission Tomography Computed Tomography/methods , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Humans , Kaplan-Meier Estimate , Outcome Assessment, Health Care/methods , Pandemics , Prednisone/administration & dosage , Prospective Studies , Rituximab/administration & dosage , SARS-CoV-2/physiology , Vincristine/administration & dosage
12.
J Allergy Clin Immunol ; 148(1): 91-95, 2021 07.
Article in English | MEDLINE | ID: covidwho-1291943

ABSTRACT

BACKGROUND: The mechanisms underpinning allergic reactions to the BNT162b2 (Pfizer) COVID-19 vaccine remain unknown, with polyethylene glycol (PEG) contained in the lipid nanoparticle suspected as being the cause. OBJECTIVE: Our aim was to evaluate the performance of skin testing and basophil activation testing to PEG, polysorbate 80, and the BNT162b2 (Pfizer) and AZD1222 (AstraZeneca) COVID-19 vaccines in patients with a history of PEG allergy. METHODS: Three known individuals with PEG allergy and 3 healthy controls were recruited and evaluated for hypersensitivity to the BNT162b2 and AZD1222 vaccines, and to related compounds by skin testing and basophil activation, as measured by CD63 upregulation using flow cytometry. RESULTS: We found that the BNT162b2 vaccine induced positive skin test results in patients with PEG allergy, whereas the result of traditional PEG skin testing was negative in 2 of 3 patients. One patient was found to be cosensitized to both the BNT162b2 and AZD1222 vaccines because of cross-reactive PEG and polysorbate allergy. The BNT162b2 vaccine, but not PEG alone, induced dose-dependent activation of all patients' basophils ex vivo. Similar basophil activation could be induced by PEGylated liposomal doxorubicin, suggesting that PEGylated lipids within nanoparticles, but not PEG in its native state, are able to efficiently induce degranulation. CONCLUSIONS: Our findings implicate PEG, as covalently modified and arranged on the vaccine lipid nanoparticle, as a potential trigger of anaphylaxis in response to BNT162b2, and highlight shortcomings of current skin testing protocols for allergy to PEGylated liposomal drugs.


Subject(s)
Anaphylaxis/immunology , Basophils/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Doxorubicin/analogs & derivatives , Drug Hypersensitivity/immunology , Nanoparticles/adverse effects , Polyethylene Glycols/adverse effects , SARS-CoV-2/physiology , Adult , Cell Degranulation , Cells, Cultured , Doxorubicin/adverse effects , Doxorubicin/chemistry , Female , Humans , Lipids/chemistry , Male , Middle Aged , Nanoparticles/chemistry , Polyethylene Glycols/chemistry , Skin Tests , Young Adult
13.
Eur J Pharmacol ; 896: 173922, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1252813

ABSTRACT

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19 , Doxorubicin/analogs & derivatives , Lopinavir/pharmacology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Internalization/drug effects , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Doxorubicin/pharmacology , Drug Repositioning , Enzyme Inhibitors/classification , Enzyme Inhibitors/pharmacology , Humans , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Topoisomerase II Inhibitors/pharmacology
14.
Curr Probl Cancer ; 45(6): 100739, 2021 12.
Article in English | MEDLINE | ID: covidwho-1163605

ABSTRACT

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Hodgkin Disease/complications , Hodgkin Disease/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Alanine/analogs & derivatives , Alanine/therapeutic use , Amides/therapeutic use , Brentuximab Vedotin/therapeutic use , COVID-19/diagnosis , COVID-19 Nucleic Acid Testing , Dacarbazine/therapeutic use , Disease Progression , Doxorubicin/therapeutic use , Humans , Male , Pregnenediones/therapeutic use , Pyrazines/therapeutic use , Time Factors , Vinblastine/therapeutic use
15.
BMJ Open ; 10(11): e040162, 2020 11 26.
Article in English | MEDLINE | ID: covidwho-1166469

ABSTRACT

INTRODUCTION: In breast cancer, local tumour control is thought to be optimised by administering higher local levels of cytotoxic chemotherapy, in particular doxorubicin. However, systemic administration of higher dosages of doxorubicin is hampered by its toxic side effects. In this study, we aim to increase doxorubicin deposition in the primary breast tumour without changing systemic doxorubicin concentration and thus without interfering with systemic efficacy and toxicity. This is to be achieved by combining Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox, Celsion Corporation, Lawrenceville, NJ, USA) with mild local hyperthermia, induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated above 39.5°C, LTLD releases a high concentration of doxorubicin intravascularly within seconds. In the absence of hyperthermia, LTLD leads to a similar biodistribution and antitumour efficacy compared with conventional doxorubicin. METHODS AND ANALYSIS: This is a single-arm phase I study in 12 chemotherapy-naïve patients with de novo stage IV HER2-negative breast cancer. Previous endocrine treatment is allowed. Study treatment consists of up to six cycles of LTLD at 21-day intervals, administered during MR-HIFU-induced hyperthermia to the primary tumour. We will aim for 60 min of hyperthermia at 40°C-42°C using a dedicated MR-HIFU breast system (Profound Medical, Mississauga, Canada). Afterwards, intravenous cyclophosphamide will be administered. Primary endpoints are safety, tolerability and feasibility. The secondary endpoint is efficacy, assessed by radiological response.This approach could lead to optimal loco-regional control with less extensive or even no surgery, in de novo stage IV patients and in stage II/III patients allocated to receive neoadjuvant chemotherapy. ETHICS AND DISSEMINATION: This study has obtained ethical approval by the Medical Research Ethics Committee Utrecht (Protocol NL67422.041.18, METC number 18-702). Informed consent will be obtained from all patients before study participation. Results will be published in an academic peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT03749850, EudraCT 2015-005582-23.


Subject(s)
Breast Neoplasms , Breast Neoplasms/drug therapy , COVID-19 , Canada , Cyclophosphamide , Doxorubicin/analogs & derivatives , Feasibility Studies , Humans , Hyperthermia , Magnetic Resonance Spectroscopy , Polyethylene Glycols , SARS-CoV-2 , Tissue Distribution
17.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-746148

ABSTRACT

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Boron Compounds/administration & dosage , Glycine/analogs & derivatives , Multiple Myeloma/drug therapy , Peripheral Nervous System Diseases/chemically induced , Adolescent , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boron Compounds/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Glycine/administration & dosage , Glycine/adverse effects , Humans , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Neoplasm Staging , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Remission Induction , Survival Analysis , Thalidomide/administration & dosage , Thalidomide/adverse effects , Treatment Outcome
18.
Br J Haematol ; 191(3): 386-389, 2020 11.
Article in English | MEDLINE | ID: covidwho-697165

ABSTRACT

The COVID-19 pandemic has dramatically challenged care for cancer patients, especially those with active treatment who represent a vulnerable population for SARS-CoV-2 infection. Aggressive lymphoid neoplasms, such as diffuse large B cell lymphoma and high-grade B cell lymphoma, need to be treated without delay in order to get the best disease outcome. Because of that, our clinical practice was changed to minimise the risk of SARS-CoV-2 infection while continuing haematological treatment. In this report, we analyse the management of front-line therapy in 18 patients during the COVID-19 outbreak, as well as the results of the implemented measures in their outcome.


Subject(s)
COVID-19/epidemiology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Pandemics , Plasmablastic Lymphoma/drug therapy , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Bacterial Infections/complications , Bacterial Infections/drug therapy , COVID-19/complications , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Testing , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Febrile Neutropenia/chemically induced , Febrile Neutropenia/prevention & control , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Infection Control/methods , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Rituximab/administration & dosage , Spain/epidemiology , Superinfection/drug therapy , Vincristine/administration & dosage , Vincristine/adverse effects
19.
BMJ Case Rep ; 13(7)2020 Jul 08.
Article in English | MEDLINE | ID: covidwho-640059

ABSTRACT

A 17-year-old man with osteosarcoma of the proximal humerus was planned for possible limb salvage surgery after standard neoadjuvant chemotherapy. However, during the surgical phase of treatment, the COVID-19 or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) outbreak occurred changing the healthcare landscape due to uncertainty regarding the virus, risk of COVID-19 infection and complications, and implementation of an enhanced community quarantine restricting movement of people within cities. Instead of limb salvage surgery, the patient underwent a forequarter amputation. Exposure to the virus in a high-risk hospital setting was minimised with patient discharge after a short hospital stay and home convalescence monitored by video conferencing. Multidisciplinary sarcoma team meetings with family members and a sarcoma navigator nurse were crucial in managing expectations and deciding on appropriate treatment in the setting of a novel infectious disease causing a pandemic.


Subject(s)
Amputation/methods , Bone Neoplasms , Cisplatin/administration & dosage , Coronavirus Infections , Doxorubicin/administration & dosage , Humerus , Limb Salvage/methods , Osteosarcoma , Pandemics , Pneumonia, Viral , Adolescent , Antineoplastic Agents , Betacoronavirus , Bone Neoplasms/pathology , Bone Neoplasms/therapy , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Humans , Humerus/diagnostic imaging , Humerus/surgery , Magnetic Resonance Imaging/methods , Male , Neoplasm Staging , Osteosarcoma/pathology , Osteosarcoma/therapy , Pandemics/prevention & control , Patient Selection , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , SARS-CoV-2
20.
Transpl Infect Dis ; 22(6): e13367, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-596059

ABSTRACT

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.


Subject(s)
COVID-19/immunology , Cardiomyopathy, Dilated/surgery , Heart Transplantation , Immunocompromised Host/immunology , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/surgery , Kidney Transplantation , Malnutrition/immunology , Opportunistic Infections/immunology , Antibiotics, Antineoplastic/adverse effects , BK Virus , Bacteremia/complications , Bacteremia/immunology , COVID-19/complications , COVID-19 Nucleic Acid Testing , Cardiomyopathy, Dilated/chemically induced , Cardiomyopathy, Dilated/complications , Cardiotoxicity , Doxorubicin/adverse effects , Graft Rejection/prevention & control , Gram-Positive Bacterial Infections/complications , Gram-Positive Bacterial Infections/immunology , Humans , Incidental Findings , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Male , Malnutrition/complications , Methicillin-Resistant Staphylococcus aureus , Middle Aged , Mycophenolic Acid/therapeutic use , Opportunistic Infections/complications , Polyomavirus Infections/complications , Polyomavirus Infections/immunology , Postoperative Complications/therapy , Prednisone/therapeutic use , Renal Dialysis , SARS-CoV-2 , Staphylococcal Infections/complications , Staphylococcal Infections/immunology , Surgical Wound Infection/complications , Surgical Wound Infection/immunology , Tacrolimus/therapeutic use , Tracheostomy , Tumor Virus Infections/complications , Tumor Virus Infections/immunology , Vancomycin-Resistant Enterococci , Viremia/complications , Viremia/immunology , Water-Electrolyte Imbalance/complications , Water-Electrolyte Imbalance/therapy
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