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1.
World J Clin Cases ; 10(20): 7171-7177, 2022 Jul 16.
Article in English | MEDLINE | ID: mdl-36051107

ABSTRACT

BACKGROUND: Procalcitonin (Pct) is a common biomarker in clinical practice, especially in the era of coronavirus disease 2019 (COVID-19) infection. Although it is frequently used for the diagnosis and prognostication of bacterial infections or sepsis, it is also elevated in a few other conditions, including medullary thyroid carcinoma (MTC). CASE SUMMARY: A 43-year-old female presented with moderately severe COVID-19 pneumonia in April 2021. She gradually recovered clinically; however, despite normalization of other inflammatory markers, Pct levels remained persistently elevated. Further workup identified the cause as left lobe MTC with locoregional metastasis. Calcitonin levels were high, and carcinoembryonic antigen levels were normal. The patient underwent total thyroidectomy and neck dissection, which was followed by another radical neck dissection due to residual disease. Currently, she is doing well, nearly having completed her course of external beam radiotherapy with no recurrence. Pct is well documented as a screening tool for MTC, especially because of its stable nature compared to calcitonin in the community settings. It is important to keep in mind the differential diagnosis of MTC in patients with persistently elevated Pct levels despite normal levels of other acute phase reactants. To the best of our knowledge, this is the first report from Asia of such an incidental diagnosis of MTC due to persistently elevated Pct levels in a patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CONCLUSION: Persistently elevated Pct levels can occur in any pro-inflammatory state including infections, sepsis, or acute respiratory distress syndrome. In the current setting, SARS-CoV-2 infection is one such clinical scenario, and in rare situations of persistent elevation, MTC may need to be ruled out.

2.
Orphanet J Rare Dis ; 17(1): 176, 2022 04 27.
Article in English | MEDLINE | ID: mdl-35477461

ABSTRACT

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families. RESULTS: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS. CONCLUSION: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.


Subject(s)
Birt-Hogg-Dube Syndrome , Kidney Neoplasms , Birt-Hogg-Dube Syndrome/genetics , Female , Humans , Male , Molecular Docking Simulation , Mutation/genetics , Nucleotides , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
3.
Expert Opin Biol Ther ; 22(2): 299-311, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33896318

ABSTRACT

BACKGROUND: MYL-1401O; trastuzumab-dkst (Ogivri™; Mylan Inc.) is a biosimilar to the trastuzumab reference product (Herceptin®; Genentech, USA). Assessment of physicochemical stability and biological activity for the non-reconstituted, reconstituted, and infused solution over an extended, clinically relevant duration is critical for ensuring optimal patient outcomes and health resource utilization. METHODS: The physicochemical and biological stability of MYL-1401O was assessed in non-reconstituted vials stored at 25 °C ± 2 °C/60% ± 5% relative humidity (RH) for 6 months, reconstituted 21 mg/mL solution in vials stored at 2 °C to 8 °C for 10 days, and diluted in 0.9% saline-containing infusion bags at 0.3 mg/mL and 4.0 mg/mL stored for 77 days at 2 °C to 8 °C, plus an additional 2 days at 25 °C ± 2 °C/60% ± 5% RH. RESULTS: At all storage conditions tested, MYL-1401O was physicochemically and biologically stable for extended duration and under various temperature and humidity conditions. CONCLUSIONS: MYL-1401O retained its physicochemical and biological stability under different storage conditions, which supports advanced preparation of MYL-1401O, better efficiency, less wastage, and cost-savings for better patient management.


Subject(s)
Biosimilar Pharmaceuticals , Saline Solution , Biosimilar Pharmaceuticals/chemistry , Drug Stability , Drug Storage , Humans , Trastuzumab/chemistry
4.
Expert Opin Biol Ther ; 22(2): 271-298, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34465264

ABSTRACT

BACKGROUND: Bevacizumab (BEV) is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to vascular endothelial growth factor (VEGF)-A and acts as an antiangiogenic agent. It is approved for treatment of many cancer indications, including metastatic colorectal cancer and nonsquamous non-small cell lung cancer. RESEARCH DESIGN AND METHODS: The analytical similarity of the BEV biosimilar MYL-1402O to reference BEV sourced from the European Union and United States was assessed using physicochemical and functional tests to support the clinical development of MYL-1402O. Assessment of physicochemical and analytical similarity showed that MYL-1402O has the same amino acid sequence and similar posttranslational modification profile as the reference BEV products. RESULTS: The functional and biologic activity of MYL-1402O assessed using inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells, inhibition of VEGF-induced VEGF receptor 2 phosphorylation, and fragment antigen and fragment crystallizable receptor binding, was comparable to reference BEV products. CONCLUSIONS: The totality of the data assessment confirms the high degree of similarity of MYL-1402O to reference BEV with respect to physicochemical and in vitro functional properties. The product quality data presented here, along with data from phase 1 clinical studies, demonstrate the similarity of MYL-1402O to reference BEV products, supporting further clinical development of this BEV biosimilar.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Human Umbilical Vein Endothelial Cells , Humans , Lung Neoplasms/drug therapy , Vascular Endothelial Growth Factor A
5.
Future Med Chem ; 13(18): 1531-1557, 2021 09.
Article in English | MEDLINE | ID: mdl-34289749

ABSTRACT

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.


Subject(s)
Antineoplastic Agents, Immunological/pharmacokinetics , Biosimilar Pharmaceuticals/pharmacokinetics , Breast Neoplasms/drug therapy , Polysaccharides/chemistry , Trastuzumab/pharmacokinetics , Animals , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Apoptosis/drug effects , Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/adverse effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disulfides/chemistry , Dose-Response Relationship, Drug , Drug Discovery , Female , Haplorhini , Humans , Protein Binding , Protein Conformation , Receptor, ErbB-2/metabolism , Structure-Activity Relationship , Tandem Mass Spectrometry , Trastuzumab/administration & dosage , Trastuzumab/adverse effects
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