Pharmaceutical drug promotion: perception and attitude of medical interns towards drug company interactions in a tertiary care teaching hospital

Background: Interactions of pharmaceutical industry with the physicians which are usually mediated through pharmaceutical representatives have a significant impact on physician decision-making. This interaction can start as early as medical school during their training and this is said to influence their prescribing behavior when they become physicians. Aims and objectives of the study was to evaluate the attitude of interns towards pharmaceutical companies interactions including accepting gifts, ethical issues and influence on clinical decisions and also to study perception of medical interns towards the accuracy of information provided by the medical representatives.Methods: This was a cross sectional questionnaire based study that was conducted among the medical interns of the teaching hospital attached to Mandya Institute of Medical Sciences, Mandya. The study was carried out between July and August 2016. A preformed structured questionnaire was distributed to the interns consenting to participate in the study. Completed questionnaires were collected, compiled and data was analyzed.Results: A total of 93 questionnaires were distributed and 90 interns responded (response rate 96.7%). About 44.4% respondents felt that accepting gifts from Drug Company would influence their own decision making. Only 26.6% of them were of the opinion that it is ethical to accept pharmaceutical company gifts. Majority of them felt that Medical Representatives exaggerate the benefits of medicines and downplay the risks and contraindications of medicine. About 32.2% of them were of the opinion that they would prefer to prescribe the drug from the companies offering them with gifts over those without. Majority of the respondents felt that the doctors should be offered with gifts by drug companies whenever their drugs are prescribed.Conclusions: Attitude of Medical Interns towards Drug Company interactions as observed suggests for training the budding doctors on appropriate drug company interactions to prevent the risks associated with promotional efforts of pharmaceutical companies.

A prospective study of drug utilization pattern in cardiac intensive care unit at a tertiary care teaching hospital

Background: Cardiovascular diseases remain the most common cause of sudden death. Appropriate drug therapy in cardiac intensive care unit (CICU) is crucial in managing cardiovascular emergencies and to decrease morbidity and mortality. The present study was conducted to observe the emergency cardiac diseases which are most frequently being treated and to study the prescribing prevalence among inpatients in CICU.Methods: A prospective, observational study was carried out among 102 patients admitted in CICU at a tertiary care teaching hospital, Karnataka, for a period of 3 months. Demographic data, clinical history, and complete drug therapy received during their stay in CICU was noted.Results: In our study, males (64.7%) had a higher incidence of cardiovascular emergencies than females (35.3%). Hypertension (32.4%) and Type 2 diabetes mellitus (28.4%) were the frequently associated co-morbid conditions. Antiplatelet drugs 80 (78.4%) was most commonly prescribed, followed by hypolipidemic drugs 75 (73.5%) and anticoagulants 65 (63.7%). The mean duration of stay in the hospital was 4.79±1.9 days. The average number of drugs per prescription was 7.8±2.2. Percentage of drugs prescribed by generic names was 52.9%. The percentage of drugs prescribed from essential drug list was 75.1%.Conclusions: Antiplatelet drugs were the most frequently prescribed drug group. Mean number of drugs per prescription were high. The prescribing pattern could be improved by reducing the number of drugs per prescription and by prescribing generic drugs to reduce the economic burden of the patients

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

: Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity

Primary central nervous system germ cell tumors in children and young adults: A review of controversies in diagnostic and treatment approach

Primary central nervous system (CNS) germ cell tumors (GCT) are a rare heterogenous group of cancers, arising most commonly in the second decade of life. Through several clinical trials conducted around the world by various groups, the treatment approach for CNS GCT has advanced substantially with generally improved overall outcomes. In recent years, the goal of clinical trials has been focused on reduction of the radiotherapy burden and minimization of long-term toxicity. This review summarizes the current diagnostic and treatment regimens for CNS GCT, examines the controversies associated with these approaches, gaps in contemporary knowledge, and underscores the challenges we face. We also explore future directions in the management of CNS GCT with the ultimate overall aim of preserving curative outcomes, identifying novel biomarkers, and mitigating neurocognitive, endocrine, and psychological toxicity through prospective clinical studies

Programmed Death-Ligand 1 Expression in a Large Cohort of Pediatric Patients With Solid Tumor and Association With Clinicopathologic Features in Neuroblastoma.

PURPOSE: Programmed death-ligand 1 (PD-L1) expression represents a potential predictive biomarker of immune checkpoint blockade response. However, literature about the prevalence of PD-L1 expression in the pediatric cancer setting is discordant. METHODS: PD-L1 expression was analyzed using immunohistochemistry in 500 pediatric tumors (including neuroblastoma, sarcomas, and brain cancers). Tumors with ≥ 1% cells showing PD-L1 membrane staining of any intensity were scored as positive. Positive cases were further characterized, with cases with weak intensity PD-L1 staining reported as having low PD-L1 expression and cases with a moderate or strong intensity of staining considered to have high PD-L1 expression. RESULTS: PD-L1-positive staining was identified in 13% of cases, whereas high PD-L1 expression was found in 3% of cases. Neuroblastoma (n = 254) showed PD-L1 expression of any intensity in 18.9% of cases and was associated with longer overall survival (P = .045). However, high PD-L1 expression in neuroblastoma (3.1%) was significantly associated with an increased risk of relapse (P = .002). Positive PD-L1 staining was observed more frequently in low- and intermediate-risk patients (P = .037) and in cases lacking MYCN amplification (P = .002). CONCLUSION: In summary, high PD-L1 expression in patients with neuroblastoma may represent an unfavorable prognostic factor associated with a higher risk of cancer relapse. This work proposes PD-L1 immunohistochemical assessment as a novel parameter for identifying patients with an increased likelihood of cancer recurrence

Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase (NTRK) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L-NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L-NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L-NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L-NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods

Supplementary Material for:A Paediatric Acute Promyelocytic Leukaemia Patient Harbouring a Cryptic PML-RARA Insertion due to a Complex Structural Chromosome 17 Rearrangement

Acute promyelocytic leukaemia with <i>PML-RARA</i> fusion is usually associated with the t(15;17)(q24.1;q21.1) translocation but may also arise from complex or cryptic rearrangements. The fusion usually resides on chromosome 15 but occasionally on others. We describe a cryptic <i>PML-RARA </i>fusion within a novel chromosome 17 rearrangement. We performed interphase fluorescence in situ hybridisation (FISH) using a dual-fusion <i>PML-RARA </i>probe, followed by reverse transcriptase-polymerase chain reaction (RT-PCR) for <i>PML-RARA</i>, karyotyping, and metaphase FISH using <i>RARA</i>break-apart, locus-specific, and subtelomere probes for chromosome 17. An 850K SNP microarray was also employed. Interphase and metaphase FISH showed atypical results involving a single <i>PML</i>-<i>RARA</i> fusion, no second fusion, but instead separate diminished <i>PML</i> and <i>RARA</i> signals. RT-PCR confirmed <i>PML-RARA </i>fusion; however, karyotyping detected only an altered chromosome 17. Metaphase FISH showed the single fusion and diminished 5′<i> RARA</i> signals located unexpectedly in the subtelomeric short-arm and long-arm regions of the rearranged chromosome 17, respectively. SNP microarray revealed no copy number abnormality. This paediatric patient with <i>PML-RARA</i> fusion reflects a cryptic insertion that resides within a complex and novel chromosome 17 rearrangement. This rearrangement likely arose via 7 chromosome breaks with the insertion occurring first followed by sequential paracentric and then pericentric inversions

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade & GE;1 were considered cases, and patients with grade 0 were controls. Variants with a p-value < 10(-5) were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 x 10(-7)). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity