Study of correlation between EGFR mutation status and P-AKT, TTF 1 in adenocarcinoma lung and to compare the quality of life between patients on TKI and Chemotherapy

BACK GROUND: Treatment of advanced carcinoma lung has been disappointing till last decade. The discovery of TKI’s has changed the natural history of this disease especially in patients who are EGFR mutation positive. Data regarding EGFR mutation testing and response to treatment depending on EGFR mutation status is limited from India. EGFR mutation testing by RT-PCR is expensive and time consuming. Surrogate tests which are less expensive and less time consuming, which can replace RT- PCR of EGFR mutation analysis will be of great importance especially in countries with limited resources. P-AKT and TTF-1 by IHC have shown some significant promise in detecting EGFR mutation. METHOD: This is a prospective single institution study where 73 patients with adenocarcinoma of lung were studied for EGFR mutation and treatment response, in which treatment was started on the basis of EGFR mutation status, that is in patients who were EGFR mutation positive were started on TKI and those who were negative were started on chemotherapy. 101 patients were included for analysis of correlation between EGFR mutation status and P-AKT and TTF-1. The quality of life (QOL) was also assessed in TKI and chemotherapy group by using questionnaire which was standardized to Indian population. RESULTS: EGFR mutation in our study population was 48.5%. The one year OS and PFS of study population was 72.6% and 51.1 % respectively. The patients in TKI group had better one year PFS and OS (61.2% and 80.7% respectively) compared chemotherapy group (42.4% and 55.9% respectively) even though it was statistically not significant. The major toxicity in TKI group was skin toxicity which was much higher with erlotinib compared to gefitinib. In the correlation study of EGFR mutation status and IHC, negative predictive value of TTF-1 and P-AKT was very high (>90%). In our study, QOL was better in TKI group compared to chemotherapy group. CONCLUSION: EGFR mutation based treatment approach resulted in improved survival in both TKI and chemotherapy group, which emphasis the impotence of doing EGFR mutation testing in upfront setting. TKI arm compared to chemotherapy group had increased PFS and OS, and also had better quality of life. TTF-1 and P-AKT has high negative predictive value in detection of EGFR mutation, indicating that in patients who are above IHC negative, EGFR mutation testing can be avoided and started on chemotherapy, if the treatment needs to be started urgently

BORTEZOMIB INDUCED SUBCONJUNCTIVAL HEMORRHAGE

Many drugs are used in the treatment of multiple myeloma but Thalidomide, Lenalidomide, Bortezomib, dexamethasone and their combination remains the main stay of treatment. The molecular formula of bortezomib is C19H25BN4O4 and its chemical IUPAC name is [3-methyl-1-(3-phenyl-2-pyrazin-2-ylcarbonylamino-propanoyl) amino-butyl] boronic acid. Mechanisms by which it acts is usually by 26 SProteasome inhibition leading to degradation of anti-apoptotic proteins. Bortezomib is known to cause many side effects. So hence we report a rare case of Bortezomib induced subconjunctival hemorrhage in our tertiary care hospital.KEYWORDS: Bortezomib, Adverse effect, Proteosome inhibition, Subconjunctival Hemorrhag

Phytochemical analysis, antimicrobial and antioxidant activity of Lophopetalum wightianum Arn. (Celastraceae)

Objectives: Lophopetalum wightianum Arn. (Celastraceae) is a lofty evergreen tree reaching around 40m in height. The present study was carried out to investigate antimicrobial and antioxidant activity of leaf and bark extract of L. wightianum. Methods: The shade dried and powdered leaf and bark were extracted by maceration process using methanol. Extracts were screened for phytoconstituents present by standard protocols. Antibacterial and antifungal activity of extracts was evaluated by agar well diffusion and poisoned food technique respectively. Antioxidant activity was determined by DPPH radical scavenging and ferric reducing assays. Results: Phytochemicals viz. alkaloids, flavonoids, sterols, saponins and triterpenoids were detected in both leaf and bark extracts. Inhibitory activity against test bacteria of bark extract was marked than leaf extract. Bark extract displayed more or less similar activity against test bacteria while leaf extract was more effective against Escherichia coli. In antifungal activity, leaf extract showed highest inhibitory against Bipolaris sp. than A. niger. Bark extract showed more or less similar antifungal activity against A. niger and Bipolaris sp. Bark extract scavenged DPPH radicals more efficiently with IC50 value 7.03µg/ml than leaf extract which scavenged radicals with IC50 value of 24.64µg/ml. Reducing potential exhibited by bark extract was higher when compared to leaf extract. Conclusion: Overall, bark extract displayed marked antimicrobial and antioxidant potential. The plant is shown to contain bioactive principles with activity against pathogenic microorganisms and free radicals that cause oxidative damage. Keywords: Lophopetalum wightianum, Maceration, Phytochemical, Antimicrobial, Antioxidan

ZOLEDRONIC ACID: A MISCHIEVOUS SUSPECT FOR LIVER INJURY

ABSTRACTA 47-year-old male diagnosed as adenocarcinoma of the lung and received 8 cycles of chemotherapy comprising intravenous administration ofcisplatin 125 mg, pemetrexed 850 mg along with zoledronic acid 4 mg. After the completion of the 8 cycle, the liver enzymes were found to bemarkedly elevated, evincing zoledronic acid as the cause for hepatotoxicity. The case details were taken from the patient's medical record along withthe biochemical test reports and radiographic images. The causal association was confirmed using Naranjo's algorithm and Roussel Uclaf CausalityAssessment Method (RUCAM). After the uneventful chemotherapy, patient's liver function tests (LFT) were abnormal. There was an elevation in theaspartate aminotransferase, alanine transaminase, alkaline phosphatase, and direct bilirubin. The causal relationship was established using Naranjo'salgorithm (score-6) and RUCAM (score-5), displayed a probable†and possible†association. Hartwig's severity scale and Thornton's preventabilityscale displayed the adverse drug reaction to being moderately severe and not preventable, respectively. The zoledronic acid was stopped and neverreadministered. The LFTs assumed normal after a span of 2 months. The mechanism underlying hepatotoxicity due to zoledronic acid remains elusive.Zoledronic acid can induce acute phase response mediated by active production of interleukin-6, tumor necrosis factor alpha, and pro-inflammatorycytokines from the T-cells and macrophages. Vigilant monitoring along with timely assessment and management can prevent the occurrence ofirreversible liver damage. Henceforth, we would like to report the rare incidence of drug induced hepatic damage due to zoledronic acid. Henceforth,we would like to report the rare incidence of drug induced hepatic damage due to zoledronic acid.Keywords: Bisphosphonate, Dechallenge, Hepatotoxicity, Rechallenge.t

Integration of Liquid Biopsy and Pharmacogenomics for Precision Therapy of EGFR Mutant and Resistant Lung Cancers

The advent of molecular profiling has revolutionized the treatment of lung cancer by comprehensively delineating the genomic landscape of the epidermal growth factor receptor (EGFR) gene. Drug resistance caused by EGFR mutations and genetic polymorphisms of drug metabolizing enzymes and transporters impedes effective treatment of EGFR mutant and resistant lung cancer. This review appraises current literature, opportunities, and challenges associated with liquid biopsy and pharmacogenomic (PGx) testing as precision therapy tools in the management of EGFR mutant and resistant lung cancers. Liquid biopsy could play a potential role in selection of precise tyrosine kinase inhibitor (TKI) therapies during different phases of lung cancer treatment. This selection will be based on the driver EGFR mutational status, as well as monitoring the development of potential EGFR mutations arising during or after TKIs treatment, since some of these new mutations may be druggable targets for alternative TKIs. Several studies have identified the utility of liquid biopsy in the identification of EGFR driver and acquired resistance with good sensitivities for various blood-based biomarkers. With a plethora of sequencing technologies and platforms available currently, further evaluations using randomized controlled trials (RCTs) in multicentric, multiethnic and larger patient cohorts could enable optimization of liquid-based assays for the detection of EGFR mutations, and support testing of CYP450 enzymes and drug transporter polymorphisms to guide precise dosing of EGFR TKIs

Oncofertility awareness among primary care physicians in India [version 1; peer review: 2 approved, 1 not approved]

Background: Primary care physicians not only coordinate referrals to oncology services but can play a crucial role in successful fertility preservation referrals in cancer-diagnosed patients. Hence, it is important to assess their knowledge and attitudes towards fertility preservation. Methods: An eighteen-item oncofertility survey was administered to primary care physicians between May 2019 to September 2020.  Results: A total of forty-six responses were received and analysed. About 60% of primary care physicians did not have adequate knowledge about available fertility preservation options and only 26-32% were aware of international guidelines recommending fertility preservation in cancer patients.  Conclusions: Imparting awareness and knowledge of fertility preservation and its options to primary care physicians could enable an integrated cancer care model while also facilitating successful oncofertility referrals in countries like India

Oncofertility awareness among primary care physicians in India [version 2; peer review: 2 approved, 1 not approved]

Background: Primary care physicians not only coordinate referrals to oncology services but can play a crucial role in successful fertility preservation referrals in cancer-diagnosed patients. Hence, it is important to assess their knowledge and attitudes towards fertility preservation. Methods: An eighteen-item oncofertility survey was administered to primary care physicians between May 2019 to September 2020.  Results: A total of forty-six responses were received and analysed. About 60% of primary care physicians did not have adequate knowledge about available fertility preservation options and only 26-32% were aware of international guidelines recommending fertility preservation in cancer patients.  Conclusions: Imparting awareness and knowledge of fertility preservation and its options to primary care physicians could enable an integrated cancer care model while also facilitating successful oncofertility referrals in countries like India

High Performance Liquid Chromatographic Fluorescence Detection Method for the Quantification of Rivastigmine in Rat Plasma and Brain: Application to Preclinical Pharmacokinetic Studies in Rats

A highly sensitive and selective high performance liquid chromatographic fluorescence detection method has been developed and validated for the quantification of rivastigmine in rat plasma and brain. Protein precipitation and one-step liquid–liquid extraction techniques were utilized for the extraction of RSM from brain and plasma, respectively, along with an internal standard. The chromatographic separation was achieved with a column inertsil ODS-3V and a mobile phase consisting of ammonium acetate buffer (20 mM, pH 4.5) and acetonitrile (76:24, v/v) delivered at a flow rate of 1 ml/min. The lower limit of quantitation for the developed method was 10 ng/mL for both matrices. The method was found to be accurate and reproducible and was successfully used to quantify levels of RSM in plasma and brain following intravenous administration of RSM in rats

Liposomi rivastigmina za isporuku u mozak intranazalnim putem

The present study is mainly aimed at delivering a drug into the brain via the intranasal route using a liposomal formulation. For this purpose, rivastigmine, which is used in the management of Alzheimer’s disease, was selectd as a model drug. Conventional liposomes were formulated by lipid layer hydration method using cholesterol and soya lecithin as lipid components. The concentration of rivastigmine in brain and plasma was studied in rat models after intranasal and oral administration of liposomes and free drug. A significantly higher level of drug was found in the brain with intranasal liposomes of rivastigmine compared to the intranasal free drug and the oral route. Intranasal liposomes had a longer half-life in the brain than intranasally or orally administered free drug. Delivering rivastigmine liposomes through the intranasal route for the treatment of Alzheimer’s disease might be a new approach to the management of this condition.Glavni cilj rada je razvoj liposoma za intranazalnu primjenu za isporuku lijeka u mozak. U tu svrhu izabran je rivastigmin kao modelni lijek koji se upotrebljava u terapiji Alzheimerove bolesti. Liposomi su pripravljeni metodom hidratacije lipidnog sloja koristeći kolesterol i lecitin iz soje kao lipidne komponente. Praćena je koncentracija rivastigmina u mozgu i plazmi nakon intranazalne i peroralne primjene liposoma i slobodnog lijeka. S intranazalnim liposomima rivastigmina postignuta je značajno veća koncentracija lijeka u mozgu. Osim toga intranazalni liposomi imaju dulje vrijeme poluživota u mozgu. Intranazalna primjena liposoma rivastigmina mogla bi predstavljati novi pristup terapiji Alzheimerove bolesti

Factors Influencing Pharmacokinetics of Tamoxifen in Breast Cancer Patients: A Systematic Review of Population Pharmacokinetic Models

Background: Tamoxifen is useful in managing breast cancer and it is reported to have significant variability in its pharmacokinetics. This review aimed to summarize reported population pharmacokinetics studies of tamoxifen and to identify the factors affecting the pharmacokinetics of tamoxifen in adult breast cancer patients. Method: A systematic search was undertaken in Scopus, Web of Science, and PubMed for papers published in the English language from inception to 20 August 2022. Studies were included in the review if the population pharmacokinetic modeling was based on non-linear mixed-effects modeling with a parametric approach for tamoxifen in breast cancer patients. Results: After initial selection, 671 records were taken for screening. A total of five studies were selected from Scopus, Web of Science, PubMed, and by manual searching. The majority of the studies were two-compartment models with first-order absorption and elimination to describe tamoxifen and its metabolites’ disposition. The CYP2D6 phenotype and CYP3A4 genotype were the main covariates that affected the metabolism of tamoxifen and its metabolites. Other factors influencing the drug’s pharmacokinetics included age, co-medication, BMI, medication adherence, CYP2B6, and CYP2C19 genotype. Conclusion: The disposition of tamoxifen and its metabolites varies primarily due to the CYP2D6 phenotype and CYP3A4 genotype. However, other factors, such as anthropometric characteristics and menopausal status, should also be addressed when accounting for this variability. All these studies should be externally evaluated to assess their applicability in different populations and to use model-informed dosing in the clinical setting