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1.
Medicina (Kaunas) ; 58(4)2022 Apr 03.
Article in English | MEDLINE | ID: covidwho-1810018

ABSTRACT

Dabrafenib and trametinib are two available molecules that have been approved for the treatment of metastatic melanoma with BRAF-V600E or V600K mutations. Their combined therapy has led to long-lasting survival benefits and substantially improved outcomes. Until now, only a few cases of severe hypersensitivity reactions to dabrafenib and vemurafenib have been reported, and even fewer desensitization protocols to these molecules have been documented. We report the case of a 71-year-old female patient with metastatic melanoma harboring a BRAF-V600E mutation undergoing targeted therapy with dabrafenib and trametinib. Two weeks after the initiation of the combined treatment, she developed a hypersensitivity reaction. The cause-effect relationship between dabrafenib and the hypersensitivity reaction was demonstrated twice, when symptoms recurred upon dabrafenib reintroduction. We started a rapid 3-day dabrafenib desensitization protocol, which was well tolerated. When the patient discontinued the drug administration, we decided on a longer protocol that included more steps and more days in order to prevent the occurrence of other hypersensitivity reactions. Our patient tolerated both rapid and slow-going schedules, the first one reaching the final dose within 3 days and the second one reaching the total daily dose within 14 days. Depending on the patient's needs, the severity of the hypersensitivity reaction and the hospital's availability, the doctor may choose either the rapid or slow-going desensitization protocol.


Subject(s)
Melanoma , Neoplasms, Second Primary , Skin Neoplasms , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Imidazoles , Melanoma/drug therapy , Melanoma/genetics , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Second Primary/etiology , Oximes , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/pathology
2.
Sci Rep ; 12(1): 3775, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1735272

ABSTRACT

Loop-mediated isothermal amplification is known for its high sensitivity, specificity and tolerance to inhibiting-substances. In this work, we developed a device for performing real-time colorimetric LAMP combining the accuracy of lab-based quantitative analysis with the simplicity of point-of-care testing. The device innovation lies on the use of a plastic tube anchored vertically on a hot surface while the side walls are exposed to a mini camera able to take snapshots of the colour change in real time during LAMP amplification. Competitive features are the rapid analysis (< 30 min), quantification over 9 log-units, crude sample-compatibility (saliva, tissue, swabs), low detection limit (< 5 copies/reaction), smartphone-operation, fast prototyping (3D-printing) and ability to select the dye of interest (Phenol red, HNB). The device's clinical utility is demonstrated in cancer mutations-analysis during the detection of 0.01% of BRAF-V600E-to-wild-type molecules from tissue samples and COVID-19 testing with 97% (Ct < 36.8) and 98% (Ct < 30) sensitivity when using extracted RNA and nasopharyngeal-swabs, respectively. The device high technology-readiness-level makes it a suitable platform for performing any colorimetric LAMP assay; moreover, its simple and inexpensive fabrication holds promise for fast deployment and application in global diagnostics.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing/instrumentation , Colorimetry , Humans , Limit of Detection , Molecular Diagnostic Techniques , Nasopharynx/virology , Neoplasms/diagnosis , Neoplasms/genetics , Neoplasms/pathology , Nucleic Acid Amplification Techniques , Point-of-Care Testing , Proto-Oncogene Proteins B-raf/genetics , RNA, Viral/analysis , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sensitivity and Specificity , Smartphone
3.
Exp Mol Pathol ; 120: 104634, 2021 06.
Article in English | MEDLINE | ID: covidwho-1152690

ABSTRACT

Lung and colorectal cancers (CRC) have two of the highest mortality rates among all cancer types, and their occurrence and the need for personalized diagnostics and subsequent therapy were not influenced by the COVID-19 pandemics. However, due to the disruption of established delivery chains, standard assays for in vitro diagnostics of those cancers were temporarily not available, forcing us to implement alternative testing methods that enabled at least basic therapy decision making. For this reason, we evaluated rapid testing on the Biocartis Idylla™ platform (Biocartis, Mechelen, Belgium) for four important genes commonly mutated in lung and colorectal cancers, namely EGFR, NRAS, KRAS, and BRAF. Clinical specimens from which the mutation status has previously been determined using Next Generation Sequencing (NGS), were retested to determine whether Idylla™ can offer accurate results. To compare the results, the sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) are calculated for each of the mutation types and then combined to determine the values of the Idylla™ system in total, while setting NGS as the gold-standard basis the assays were compared with. Idylla testing thereby displayed acceptable sensitivity and specificity and delivered reliable results for initial therapy decisions.


Subject(s)
DNA Mutational Analysis/methods , GTP Phosphohydrolases/genetics , High-Throughput Nucleotide Sequencing/methods , Membrane Proteins/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , ErbB Receptors/genetics , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Pandemics , Reproducibility of Results , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Sensitivity and Specificity
4.
Anal Chem ; 93(9): 4149-4153, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1104413

ABSTRACT

Loop-mediated isothermal amplification (LAMP) holds great potential for point-of-care (POC) diagnostics due to its speed and sensitivity. However, differentiation between spurious amplification and amplification of the target sequence is a challenge. Herein, we develop the use of molecular beacon (MB) probes for the sequence-specific detection of LAMP on commercially available lateral flow immunoassay (LFIA) strips. The detection of three unique DNA sequences, including ORF1a from SARS-CoV-2, is demonstrated. In addition, the method is capable of detecting clinically relevant single-nucleotide polymorphisms (BRAF V600E). For all sequences tested, the LFIA method offers similar sensitivity to fluorescence detection using a qPCR instrument. We also demonstrate the coupling of the method with solid-phase microextraction to enable isolation and detection of the target sequences from human plasma, pond water, and artificial saliva. Lastly, a 3D printed device is designed and implemented to prevent contamination caused by opening the reaction containers after LAMP.


Subject(s)
Adhesins, Bacterial/genetics , COVID-19 Testing , Immunoassay , Molecular Diagnostic Techniques , Nucleic Acid Amplification Techniques , Proto-Oncogene Proteins B-raf/genetics , Viral Proteins/genetics , Humans , Polyproteins/genetics , Reagent Strips/chemistry , SARS-CoV-2/genetics , Sensitivity and Specificity , Sequence Analysis, DNA , Vibrio cholerae/genetics
5.
Arch Endocrinol Metab ; 65(2): 242-247, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1080888

ABSTRACT

Anaplastic thyroid carcinoma is the rarest tumor of the thyroid gland, representing less than 2% of clinically recognized thyroid cancers. Typically, it has an extremely rapid onset, fatal outcomes in most cases, and a median overall survival of 3 to 10 months despite aggressive multidisciplinary management. The presence of targetable mutations in anaplastic thyroid carcinoma patients is an opportunity for treatment when conventional therapeutics approaches are not effective, a frequent situation in the majority of patients. We present our experience in the management of a patient with unresectable anaplastic thyroid cancer who had a remarkable and rapid response to treatment with dabrafenib and trametinib during the COVID-19 pandemic. After four weeks of dabrafenib 150 mg twice daily plus trametinib 2 mg daily, he showed a dramatic reduction of the cervical mass around 90%. Nearly eight weeks under treatment with dabrafenib plus trametinib, the patient remains with minimal locoregional disease without distant metastases.


Subject(s)
COVID-19 , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Imidazoles , Male , Mutation , Oximes , Pandemics , Proto-Oncogene Proteins B-raf/genetics , Pyridones , Pyrimidinones , SARS-CoV-2 , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/genetics , Thyroid Neoplasms/drug therapy
6.
Anticancer Drugs ; 32(5): 589-591, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1082921

ABSTRACT

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.


Subject(s)
Carbamates , Drug Overdose , Liver Function Tests/methods , Long QT Syndrome , Medication Therapy Management/standards , Melanoma , Skin Neoplasms , Sulfonamides , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , COVID-19/epidemiology , Carbamates/administration & dosage , Carbamates/adverse effects , Carbamates/blood , Communicable Disease Control , Dose-Response Relationship, Drug , Drug Monitoring/methods , Drug Overdose/blood , Drug Overdose/diagnosis , Drug Overdose/etiology , Drug Overdose/physiopathology , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Male , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Middle Aged , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/blood , Vomiting/chemically induced , Vomiting/diagnosis
7.
Expert Rev Mol Diagn ; 21(1): 101-107, 2021 01.
Article in English | MEDLINE | ID: covidwho-962282

ABSTRACT

Background: The SARS-CoV-2 pandemic introduced a global distraction effect in cancer patients' care. The aim of this study was to explore the effect of the pandemic on the largest molecular diagnostics center for cancer patients and high-risk individuals in Serbia.Research design and methods: EGFR, KRAS/NRAS, BRAF, and BRCA1/2 mutation testing were performed by qPCR and NGS. NGS was used for panel testing of hereditary breast/ovarian cancer and cancers associated with Lynch syndrome. The analytical output during the state of emergency (SoE) was compared to the period before and after the outbreak using one-way ANOVA. Statistical significance was set at p < 0.05.Results: A 38% reduction in the number of analysis was detected during the SoE. After the SoE, a 19% reduction was noted compared to SoE and 50% compared to the period before the SoE (p = 0.038). Three of the 48 scheduled appointments for pretest genetic counseling were carried out during the SoE, but the number of NGS tests increased by 50%.Conclusions: The SARS-CoV-2 pandemic had a profound negative effect on the diagnostic output of our centralized molecular diagnostics center. The only positive effect was shortening of waiting lists for hereditary cancer patients and high-risk individuals.


Subject(s)
Breast Neoplasms/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Mutation , Ovarian Neoplasms/diagnosis , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , COVID-19 , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mutational Analysis , ErbB Receptors/genetics , Female , GTP Phosphohydrolases/genetics , Genetic Counseling , Genetic Predisposition to Disease , Humans , Liquid Biopsy , Membrane Proteins/genetics , Ovarian Neoplasms/genetics , Pandemics , Pathology, Molecular , Pharmacogenetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Serbia/epidemiology
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