Design of PI3K-mTOR Dual Inhibitors for Ovarian Cancer: Are We on the Right Track?

Ovarian cancer is one of the most familiar kinds of gynecological cancer seen in women. Though it is not as familiar as breast cancer, the survival rate for ovarian cancer is very low when compared with breast cancer. Even after being one among the familiar types, to date, there are no proper treatments available for ovarian cancer. All the treatments that are present currently show a high rate of recurrence after the treatment. Therefore, treating this silent killer from the roots is the need of the hour. PI3K/AKT/m- TOR pathway is one of the pathways that get altered during ovarian cancer. Studies are already going on for the inhibition of PI3K and mTOR separately. Efforts have been made to inhibit either PI3K or mTOR separately earlier. However, due to its side effects and resistance to the treatments available, current studies are based on the inhibition of PI3K and mTOR together. Inhibition of PI3K and mTOR simultaneously reduces the chances of negative feedback, thus decreasing the toxicity. This review contains the evolution of PI3K and mTOR drugs that are approved by the FDA and are in the trials for different cancer types, including Ovarian cancer. In this article, how a molecular targeted therapy can be made successful and free from toxicity for treating ovarian cancer is discussed. Therefore, this review paves the way for finding an effective scaffold rather than the clinical part. The scaffold thus selected can be further modified and synthesized in the future as dual PI3K/mTOR inhibitors specifically for OC.

Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients.

BACKGROUND AND AIM: Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram. METHODS: A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions. RESULTS: Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models. CONCLUSION: Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Oncofertility awareness among primary care physicians in India.

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.

Potential Drug-Drug Interactions Between Anti-Cancer Drugs and Other Medications in Lung Cancer Patients: A Retrospective Study.

BACKGROUND: Cancer patients are more vulnerable to developing drug-drug interactions as multiple medications are administered concomitantly with cytotoxic agents to treat the underlying comorbidities. These drug-drug interactions often receive less medical attention and consequently are associated with adverse clinical outcomes. OBJECTIVE: We intended to comprehensively characterize the drug-drug interactions among anticancer drugs and other concomitantly prescribed drugs in hospitalized lung cancer patients. METHODS: A retrospective, observational, single-centre study was conducted on lung cancer inpatients from the medical records department of Kasturba Hospital, Manipal, India. Drug-drug interactions were identified using the drug interaction checkers of two drug information databases, Micromedex and Epocrates. These drug-drug interactions were categorized based on the source from which they were identified, mechanism, severity/significance, adverse consequences, and management strategies required. RESULTS: Among 196 patients, 555 drug-drug interactions were identified in 185 patients using Micromedex and Epocrates. Based on the mechanism of action, 74% and 22% of the drug-drug interactions were classified as pharmacodynamic and pharmacokinetic respectively. 112 drug-drug interactions were recorded from Micromedex alone, while 549 interactions were found using Epocrates. The oral chemotherapeutic drug gefitinib was found to be associated with the highest number of drug-drug interactions. CONCLUSION: Drug-drug interactions were highly prevalent among hospitalized lung cancer patients. Structured screening and monitoring for these potentially clinically relevant drug-drug interactions by oncologists in collaboration with clinical pharmacists should be carried out prior to initiation and during anticancer treatment to prevent adverse clinical outcomes.

PENS approach for breaking bad news in the oncology outpatient setting: a real-world report.

PURPOSE: Breaking bad news (BBN) is a vital part of oncology practice. We conducted this study to assess an abbreviated PENS protocol [Patient preference, Explanation, Next appointment, and Support] for BBN in oncology outpatient (OP) settings. METHODS: This observational study was conducted in a university teaching hospital, including cancer patients who were unaware of their condition and willing to discuss their disease status. The duration of BBN was the primary outcome. After the BBN session, patients filled a validated questionnaire; response scores of ≤ 13 were classified as content with BBN. RESULTS: Fifty patients (mean age 53.7 years, range 28-76) were included in the study. The average duration of BBN was 6.1 (range 2-11) min. Assessed by the response score sum, 43 (86%) patients were satisfied with BBN. Only three (6%) of the discontented patients felt that the BBN duration was too short. Most (94%) of patients reported that they understood the information imparted during the BBN session. After the session, 36 (72%) patients admitted to either feeling the same or reassured compared to before the session. The oncologists also were comfortable with PENS. CONCLUSIONS: The PENS approach is a practical method for BBN, especially when the oncologists have higher OP workloads. More extensive trials are required to validate the protocol in other settings. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI/2021/07/034707).

A Case of Basal Cell Carcinoma With Metastasis to the Pelvic Bone.

Our patient initially presented in 2015 with an ulcerative lesion over the scalp. Fine needle aspiration cytology (FNAC) from a regional enlarged lymph node showed features of metastatic poorly differentiated carcinoma and he underwent wide local excision with functional neck dissection. His next visit was after five years in 2020 with pain in the left hip region. Bone marrow biopsy was reported as metastatic carcinoma morphologically consistent with the patient's known basal cell carcinoma. He received palliative radiotherapy for the same at the hip region followed by platinum-based chemotherapy.

Automated Microsurgical Tool Segmentation and Characterization in Intra-Operative Neurosurgical Videos.

Checklist based routine evaluation of surgical skills in any medical school demands quality time and effort from the supervising expert and is highly influenced by assessor bias. Alternatively, automated video based surgical skill assessment is a simple and viable method to analyse surgical dexterity offline without the need for acute presence of an expert surgeon throughout the surgery. In this paper, a novel approach and results for the automated segmentation of microsurgical instruments from the real-world neurosurgical video dataset was presented. The proposed tool segmentation model showcased mean average precision of 96.7% in detecting, and localizing five surgical instruments from the real-world neurosurgical videos. Accurate detection and characterization of motion features of the microsurgical tool from the novel annotated neurosurgical video dataset forms the key step towards automated surgical skill evaluation. Clinical Relevance- Tool segmentation, localization, and characterization in neurosurgical video, has several applications including assessing surgeons skills, training novice surgeons, understanding critical operating procedures post surgery, characterizing any critical anatomical response to the tool that leads to the success or failure of the surgery, and building models for conducting autonomous robotic surgery. Semantic segmentation, and characterization of the microsurgical tools forms the basis of the modern neurosurgery.

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.

Profile of patients with hepatocellular carcinoma: An experience from a tertiary care center in India.

BACKGROUND: The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide and it is now the third most common cause of cancer-related death. HCC is becoming a major health burden with steadily increasing incidence globally. METHODS: This is an observational study over a 3-year period in a tertiary care center in India. Three hundred and thirty-nine patients diagnosed to have HCC were included in this study. Patients' clinical, etiological, radiological and cytohistological data and therapy offered were recorded and analyzed. RESULTS: Cirrhosis of the liver was seen in 73.2% of the patients. 16.8% of patients were asymptomatic at the time of presentation. Ascites (57.2%) and jaundice (22.4%) were the most common signs of hepatic decompensation. The most common etiology of HCC was cryptogenic/non-alcoholic fatty liver disease (NAFLD) in 51% of the patients, while hepatitis B and C were seen in 17.4% and 5.8% of the patients, respectively. Advanced and end-stage disease with Barcelona Clinic Liver Cancer (BCLC) stages C and D were seen in 62.4% of patients. 56.6% had Albumin-bilirubin (ALBI) score of 2, while 62.8% had Okuda stage II disease. High alpha-fetoprotein (AFP) levels (>400 ng/mL) were seen in 48.9% of patients. Macrovascular invasion and metastases were seen in 45.9% and 22.2% of the patients, respectively. 17.6% of patients had evidence of tumor thrombus. 14.5% of biopsy specimens showed associated steatosis/steatohepatitis along with confirmation of HCC. Only 26.6% of the cirrhotic HCC patients were diagnosed during surveillance. CONCLUSIONS: HCC due to unknown cause/NAFLD appears to be overtaking hepatitis B as the commonest cause for HCC. Despite the advances in diagnostic methods and surveillance, most cases of HCC tend to be diagnosed at advanced stages.

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.

Oncofertility: Knowledge, Attitudes, and Barriers Among Indian Oncologists and Gynecologists.

Purpose: Recommendations from the American Society of Clinical Oncology (ASCO) emphasize the critical need to understand current trends in fertility preservation (FP) among the two sets of primary health care providers involved in oncofertility: the oncologists and the gynecologists. This study is aimed at understanding the health care providers' knowledge, attitudes, and barriers in oncofertility across India. Methods: An 18-item oncofertility survey was designed and directed to 77 oncologists and 214 gynecologists across India. The responses were analyzed by using descriptive statistical methods, and the oncofertility trends between the two groups were studied. Results: The total response rate was 34%, with 49 of 214 oncologists (23%) and 49 of 77 gynecologists (64%) participating in the survey. The awareness of ASCO FP guidelines among oncologists and gynecologists was 53% and 59.5%, respectively. About 48% of oncologists felt knowledgeable about sperm banking, whereas 52% knew about oocyte freezing but not about other options. On the other hand, among gynecologists, 38% reported inadequate knowledge of testicular or ovarian tissue cryopreservation. About 85% of oncologists reported routine referral of cancer diagnosed patients for FP, whereas 75% of gynecologists reported routine FP discussion with patients. Health care providers from both groups perceived the major barriers in oncofertility to be, "financial burden on the patient" (73%-86%) and, "lack of patient awareness" (71%-79.5%). Conclusion: Effective collaboration between oncologists and gynecologists is essential to establish a successful FP program. Economic burden on the patient and lack of patient and physician awareness are limiting factors that need to be overcome.

Liquid biopsy approaches for pleural effusion in lung cancer patients.

Genomic profiling of tumors has become the mainstay for diagnosis, treatment monitoring and a guide to precision medicine. However, in clinical practice, the detection of driver mutations in tumors has several procedural limitations owing to progressive disease and tumor heterogeneity. The current era of liquid biopsy promises a better solution. This diagnostic utility of liquid biopsy has been demonstrated by numerous studies for the detection of cell-free DNA (cfDNA) in plasma for disease diagnosis, prognosis, and prediction. However, cfDNAs are limited in blood circulation and still hurdles to achieve promising precision medicine. Malignant pleural effusion (MPE) is usually detected in advanced lung malignancy, which is rich in tumor cells. Extracellular vesicles and cfDNAs are the two major targets currently explored using MPE. Therefore, MPE can be used as a source of biomarkers in liquid biopsy for investigating tumor mutations. This review focuses on the liquid biopsy approaches for pleural effusion which may be explored as an alternative source for liquid biopsy in lung cancer patients to diagnose early disease progression.

Cytogenetics and Revised International Staging System (R-ISS): Risk Stratification in Multiple myeloma - A Retrospective Study in Indian Population.

BACKGROUND & OBJECTIVE: Cytogenetic abnormalities in Multiple myeloma (MM) has emerged as the most important factor that determine the prognosis and survival. Fluorescence in situ hybridization (FISH) can detect a greater number of cytogenetic abnormalities as compared to conventional karyotyping and hence has become the standard test in determining genetic abnormalities in MM. The present study was planned as there is an unmet need to find out various cytogenetic abnormalities and to implement them in prognostic stratification by Revised International Staging System (R-ISS) among Indian population. METHODS: A single institution retrospective study was conducted among a total of 117 patients newly diagnosed as Multiple Myeloma. They were analyzed for various cytogenetic abnormalities by using interphase FISH (iFISH) and were staged according to Revised International Staging System (R- ISS). RESULTS: Out of the 117 patients studied, deletion 17p13 (p53) was present in 16 patients (13.67%). Thirty patients (25.64%) showed deletion 13q14.3. Three patients (2.56%) were detected to have t(4:14).Two patients (1.7%) had t(11:14) and t(14:16), respectively. Total of 19 patients (16.23%) in our study exhibited high risk cytogenetics and two among them had more than one high risk cytogenetic abnormalities. There was a 66.4% moderate correlation between ISS-III and high-risk cytogenetics which was statistically insignificant. Of the total 117 patients, 37 (31.62%) were staged R-ISS III. CONCLUSION: High risk cytogenetics was found in 16.23 % of our study population and del 17p13 was the most common high-risk cytogenetic abnormality. Of the studied subjects, 31.62% had R-ISS III, which is significantly higher compared to western population.

Association of health literacy and cognition levels with severity of adverse drug reactions in cancer patients: a South Asian experience.

Background The occurrence of adverse drug reactions with chemotherapy among cancer patients is a well-documented phenomenon. However, the understanding of contributoring factors and their influence on the severity of adverse drug reactions is incomplete without the psychosocial factors affecting them. Objective The present study was done to understand if factors like Health literacy and cognition levels have an association with the severity of adverse drug reactions of cancer chemotherapy. Setting This study was done in the Department of Medical Oncology in a tertiary care hospital in India. Method Two hundred and twenty-four patients meeting the study inclusion and exclusion criteria took part in the study. Details of adverse drug reactions were collected as per the central drugs standard control organization format and severity of adverse drug reactions assessed with National Cancer Institute common terminology criteria of adverse events, version 5.0. Health Literacy and Cognition Levels of patients were assessed using standardized questionnaires, i.e., Short test of functional health literacy in adults and short portable mental status questionnaire, respectively. Data were anonymized and analyzed using Statistical Package for Social Sciences version 16.0 software. Pearson's Chi square test (p value ≤ 0.05 was considered statistically significant) was used to study the associations. Main outcome measure The associations of Health Literacy and Cognition Levels with the severity of adverse drug reactions. Result We found that both Health Literacy and Cognition Levels had a statistically significant association with Grade 3 and above adverse drug reactions in cancer patients receiving chemotherapy. Conclusion An initial assessment of Health Literacy and Cognition Levels in cancer patients by cancer care providers can help identify patients at high risk of developing severe adverse drug reactions. Interventional measures for improving Health Literacy by healthcare providers can help reduce the overall burden of disease on the patient due to adverse drug reactions.

Barriers and Opportunities of Oncofertility Practice in Nine Developing Countries and the Emerging Oncofertility Professional Engagement Network.

PURPOSE: Oncofertility practice continues to grow in developing countries despite the lack of health care services, especially those related to cancer care. The purpose of this study is to further explore oncofertility practice in these countries and identify opportunities for field-wide coalescence. METHODS: We generated a survey to learn more about oncofertility practice in nine developing countries within our Oncofertility Consortium Global Partners Network-Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India. Their responses were collected, reviewed, and discussed. RESULTS: Surveyed centers from the nine developing countries continue to experience a similar set of common challenges, including a lack of awareness among providers and patients, cultural and religious constraints, lack of insurance coverage and funding to help to support oncofertility programs, and high out-of-pocket costs for patients. Despite these barriers, many opportunities exist and there is great potential for the future. CONCLUSION: The current need is to unify the new technologies and best practices that emerge from rural communities and developing countries with those in large metropolitan cities, both domestically (US based) and abroad, into a functional unit: the Oncofertility Professional Engagement Network. The Oncofertility Professional Engagement Network will bridge the gap between domestic and international programs to establish a strong global network in which members share resources, methodologies and experiences and further build cultural competency.

Halving Time of BCR-ABL1 in Chronic Myeloid Leukemia: Is It Better Than Day-90 Value-A Multicenter Study From South India.

BACKGROUND: The 90-day BCR-ABL1 (breakpoint cluster region-Abelson 1) level has been one of the accepted milestones for predicting the molecular response in patients with chronic myeloid leukemia (CML). The rate of decline in BCR-ABL1 has been considered a better predictor of the response but has not been uniformly accepted. A paucity of evidence is available to predict the accuracy of the rate of decline in the Indian context. Therefore, we tested the accuracy of the rate of decline of BCR-ABL1 in predicting the molecular response compared with the single 90-day values in a retrospective cohort study of selected cancer centers in south India. METHODS AND MATERIALS: Patients with chronic-phase CML diagnosed from January 2013 to December 2018, the serial BCR-ABL1 levels were estimated at 0, 45, and 90 days, 6 months, and 1 year. Data on patient demographics, risk stratification assessed using the Sokal and EUTOS (European Treatment and Outcome Study) scores were extracted using a mobile-based data capture tool from the medical records of the enrolled patients. The halving time, determined by log reduction, was compared with the 90-day BCR-ABL1 values using the receiver operating characteristic curve for the major and complete molecular response at 6 months and 1 year as standards. Accuracy was determined from the area under the curve. The cutoff for the halving time was chosen to balance the sensitivity and specificity. RESULTS: The rate of decline had more predictive accuracy compared with the 90-day BCR-ABL1 values (area under the curve for rate of decline, 0.83; 90-day, 0.80). A halving time of < 20 days identified 95% of the patients who had achieved major molecular response at 12 months compared with 80% using the single 90-day BCR-ABL1 response. CONCLUSIONS: The halving time of BCR-ABL1 appears promising as a predictor of the outcomes for patients with CML.

Quality of Sleep in Patients with Cancer: A Cross-sectional Observational Study.

BACKGROUND: Insomnia and poor sleep quality are common problems in patients with cancer. It interferes with the coping ability, symptoms, and treatment outcomes. The Pittsburgh Sleep Quality Index (PSQI) is a reliable, valid instrument to assess the quality of sleep in patients with cancer. PATIENTS AND METHODS: The study was conducted at the department of medical oncology of a tertiary cancer care center. Consecutive eligible participants were recruited and evaluated for sleep quality using PSQI questionnaire. The questionnaire was administered only once with the questions evaluating to the quality of sleep over the last 1 month. A PSQI total score of ≤5 was suggestive of good quality of sleep and a score of >5 was indicative of poor quality of sleep. RESULTS: Ninety-two consecutive consenting cancer patients admitted for chemotherapy participated in the study. Thirty-one (33.7%) patients had early cancer and 35 (38%) patients had Stage IV metastatic disease. Thirty-six (39.1%) patients reported sleep of <6 h and 30 (32.6%) patients had impaired functioning during day due to sleepiness. Fifty-three (57.6%) patients had poor total PSQI score, of which 39 (73.5%) were female and 14 (26.5%) were male. The study showed no correlation of the PSQI scores with the stage of the disease, and the prior treatment received. CONCLUSIONS: The study showed that Indian cancer patients have short sleep duration and poor quality of sleep. A higher prevalence of sleep disturbances was seen among female cancer patients. PSQI questionnaire can be a cost-effective way of screening cancer patients for poor quality of sleep.