Deep learning based clinico-radiological model for paediatric brain tumor detection and subtype prediction.

Aim: Early diagnosis of paediatric brain tumors significantly improves the outcome. The aim is to study magnetic resonance imaging (MRI) features of paediatric brain tumors and to develop an automated segmentation (AS) tool which could segment and classify tumors using deep learning methods and compare with radiologist assessment. Methods: This study included 94 cases, of which 75 were diagnosed cases of ependymoma, medulloblastoma, brainstem glioma, and pilocytic astrocytoma and 19 were normal MRI brain cases. The data was randomized into training data, 64 cases; test data, 21 cases and validation data, 9 cases to devise a deep learning algorithm to segment the paediatric brain tumor. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the deep learning model were compared with radiologist's findings. Performance evaluation of AS was done based on Dice score and Hausdorff95 distance. Results: Analysis of MRI semantic features was done with necrosis and haemorrhage as predicting features for ependymoma, diffusion restriction and cystic changes were predictors for medulloblastoma. The accuracy of detecting abnormalities was 90%, with a specificity of 100%. Further segmentation of the tumor into enhancing and non-enhancing components was done. The segmentation results for whole tumor (WT), enhancing tumor (ET), and non-enhancing tumor (NET) have been analyzed by Dice score and Hausdorff95 distance. The accuracy of prediction of all MRI features was compared with experienced radiologist's findings. Substantial agreement observed between the classification by model and the radiologist's given classification [K-0.695 (K is Cohen's kappa score for interrater reliability)]. Conclusions: The deep learning model had very high accuracy and specificity for predicting the magnetic resonance (MR) characteristics and close to 80% accuracy in predicting tumor type. This model can serve as a potential tool to make a timely and accurate diagnosis for radiologists not trained in neuroradiology.

Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI): stakeholder views, objectives, and procedures.

Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit-risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

Preferences for first-line treatment of advanced urothelial carcinoma among US practicing oncologists and patients.

Aim: Investigate oncologist and patient preferences for the first-line treatment of advanced urothelial carcinoma. Materials & methods: A discrete-choice experiment was used to elicit treatment attribute preferences, including patient treatment experience (number and duration of treatments and grade 3/4 treatment-related adverse events), overall survival and treatment administration frequency. Results: The study included 151 eligible medical oncologists and 150 patients with urothelial carcinoma. Both physicians and patients appeared to prefer treatment attributes related to overall survival, treatment-related adverse events and the number and duration of the medications in a regimen over frequency of administration. Overall survival had the most influence in driving oncologists' treatment preferences, followed by the patient's treatment experience. Patients found the treatment experience the most important attribute when considering options, followed by overall survival. Conclusion: Patient preferences were based on treatment experience, while oncologists preferred treatments that prolong overall survival. These results help to direct clinical conversations, treatment recommendations and clinical guideline development.

Different treatments are available for people with urothelial cancer that has spread to other parts of the body. Researchers wanted to find out what specialist cancer doctors and people with urothelial cancer think is important when choosing the first treatment. To do this, researchers asked 150 cancer specialists and 150 people with urothelial cancer to complete an internet questionnaire. It included questions about side effects, if treatment could help people live longer, and how often people would need to be treated. Researchers found that cancer specialists think that helping people live longer is the most important. However, people with advanced urothelial cancer think that having fewer severe side effects is the most important.

Teledentistry: Evaluation of Instagram posts related to bruxism.

BACKGROUND: Instagram statistic has attracted roughly one billion, monthly active users. In 2021, Instagram belonged to the most popular social networks worldwide. It has been considered an effective tool that contributes to the contemporary sharing of information for raising public awareness while providing educational information. The growing presence of Instagram and frequent user engagement has made it a potentially effective platform for patient communication, seeking educational information, product information for consumers, and advertisements in the form of images and videos. OBJECTIVE: To assess and compare the contents of Instagram posts by healthcare professionals (HP) and non-professional healthcare workers (NPHW) on bruxism and to assess public engagement with this content. METHODS: Twelve "hashtag" terms linked to bruxism were searched. HP and NPHW analyzed the content of relevant posts for the presence of domains. Discourse analysis assessed the post quality for themes. We conducted the descriptive and univariate statistical analysis, whereas inter-rater reliability was tested using Cohen's kappa. RESULTS: A total of 1184 posts were retrieved, with the majority uploaded by NPHW (622 posts). The posts by HPs were in text and image(s) format (53%) with the range of 25-1100 Instagram post "Likes." "Mouthguard" (90) % was the most frequently included domain posted by HP, followed by "treatment plan/pain management", and complaints of clicking or locking of TMJ" (84%). Greater number of domains (p= 0.03) were seen in the posts by NPHWs, compared to HP's having more bruxism-related content. The inter-rater reliability method (0.89) was used for the presence of domains. CONCLUSION: NPHW uses Instagram more frequently to post bruxism-related information than HP. HPs must ascertain that the content posted by NPHW is relevant and the concerns addressed in posts are to the purpose.

Development of a Conceptual Model of the Patient Experience in Small Cell Lung Cancer: A Qualitative Interview Study.

INTRODUCTION: Small cell lung cancer (SCLC) is a subtype of lung cancer, the second most common cancer diagnosis worldwide. Currently, there is little published qualitative research that provides insight into the disease-related symptoms and impacts that are relevant to patients living with SCLC as directly reported by patients themselves. METHODS: This qualitative, cross-sectional, noninterventional, descriptive study included concept elicitation interviews with participants diagnosed with SCLC and the development of a conceptual model of clinical treatment benefit. RESULTS: Concept elicitation interview data from 26 participants with SCLC were used to develop a conceptual model of clinical treatment benefit that organized 28 patient-reported concepts into two domains: disease-related symptoms (organ-specific and systemic) and impacts. Organ-specific symptoms included cough, chest pain, and difficulty breathing. Systemic symptoms included pain, fatigue, appetite loss, and dizziness. Impacts included physical functioning, role functioning, reduced movement, impact on sleep, and weight loss. CONCLUSION: As evidenced by this study, people with SCLC experience considerable and significant symptoms and impacts, including physical and role functioning challenges, that affect their quality of life. This conceptual model will inform the design of a patient-reported outcome (PRO) questionnaire for a future SCLC clinical trial, helping to establish the content validity of the items and questionnaires used in the trial and ensuring that the questionnaires and items selected are appropriately targeted to the population. This conceptual model could also be used to inform future SCLC clinical trials.

Investigating the trends in patient-reported outcomes pre-treatment and implications to efficacy analyses: A post-hoc analysis of a cancer clinical trial.

Background: Uncertainty around key elements of an appropriate patient-reported outcome (PRO) baseline assessment introduces trial-specific variation in oncology clinical trials with a poorly understood consequence on drug evaluation decisions. This research investigated the impact of multiple pre-treatment PRO assessments and timing of assessments in a clinical trial. Methods: A post-hoc analysis of a completed phase 3, open-label, randomized, parallel arm clinical trial in non-small cell lung cancer with two pre-treatment PRO assessments (screening and Week 1 Day 1 [W1D1]). Descriptive analyses, mixed models for repeated measures and time until definitive deterioration analyses were performed to estimate differences between treatment arms. Through model adjustments, different baseline specifications and assessment timing (pre/post-randomization) on W1D1 PROs were evaluated. Results: Patients with both pre-treatment PRO assessments were included in the analysis (N = 535). Numerically small average change scores were observed between screening and W1D1 (mean change, 0-100 scale ranges): Chest pain (-0.94), Cough (-0.94), Dyspnea (1.27), Physical functioning (-1.19). Both pre-treatment assessments were moderately-highly correlated (r: 0.55-0.78) and no trend was found for deterioration or improvement during this period. Varying baseline definitions in the models produced slight differences in model fit but no impact on the between treatment group effect estimate. W1D1 PRO scores were not statistically influenced by assessment timing pre/post-randomization (p-values: 0.142-0.628). Conclusion: Findings from this study question the need for multiple pre-treatment PRO assessments in oncology drug development trials and the degree of bias thought to be introduced through patient knowledge of treatment assignment. Implications for researchers are presented.

Poly-L-lysine Coated Oral Nanoemulsion for Combined Delivery of Insulin and C-Peptide.

An attempt of co-delivery of insulin and C-peptide enclosed in linseed oil globules has been made employing a protective coating of positively charged poly-L-lysine to manage diabetes-associated complications. Oral water in oil in water (w/o/w) nanoemulsion manufactured by double emulsification method showed good entrapment efficiency of 87.6 ± 7.48% for insulin and 73.4 ± 6.44% for C-peptide. The optimized uncoated nanoemulsion showed a mean globule size of 210.6 ± 9.87 nm with a good PDI of 0.145 ± 0.033 and -21.7 ± 4.5 mV ZP. The poly-L-lysine coating of the nanoemulsion resulted in the reversal of surface charge to positive i.e. 18.3 ± 2.7 mV due to the cationic nature of poly-L-lysine. In vitro drug release showed an initial burst of 15-20% release within 4 h followed by controlled release up to 24 h. The poly-L-lysine coated nanoemulsion showed an 8.28-fold higher uptake than fluorescein isothiocyanate (FITC) solution in HCT116 intestinal cell lines. In vivo studies confirmed that orally administered insulin and C-peptide bearing coated nanoemulsion has the potential to improve glycemic control confirmed by blood glucose level under 200 mg/dL for 12 h compared to that of subcutaneous administration of insulin. The formulation was found stable at 25 °C as well as 4°C for up to 3 months. These findings show a promising approach for delivering oral insulin along with C-peptide for effective glycemic control and management of complications associated with diabetes.

Modeling Challenges in Cost-Effectiveness Analysis of First-Line Immuno-Oncology Therapies in Non-small Cell Lung Cancer: A Systematic Literature Review.

INTRODUCTION: The introduction of immuno-oncology (IO) therapies has changed the treatment landscape of non-small cell lung cancer (NSCLC). Numerous cost-effectiveness analyses (CEAs) and technology appraisals (TAs) evaluating IO therapies have been recently published. OBJECTIVE: We reviewed economic models of first-line (1L) IO therapies for previously untreated advanced or metastatic NSCLC to identify methodological challenges associated with modeling cost effectiveness from published literature and TAs and to make recommendations for future CEAs in this disease area. METHODS: A systematic literature review was conducted following Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched MEDLINE, Embase, EconLit (January 2009-January 2020), and select conferences (since 2016) for CEAs of 1L IO treatments in patients with recurrent or metastatic, epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC, published in English. TAs from England, Scotland, Canada, Australia, Germany, and France were also examined. Two reviewers screened the results and extracted the data. The quality of the CEAs was described using the Drummond checklist. RESULTS: In total, 46 records reporting on 38 unique models met protocol-defined criteria and were included. Five models adjusted for treatment switching or crossover in base-case analyses, and the remainder considered treatment switching or crossover to represent clinical practice and made no adjustment. Seven models used external real-world data for survival modeling or extrapolation validation. Six models that assumed long-term treatment benefit stopped at 3 or 5 years after initiation. Seven models used the observed time-on-treatment distribution from the trial, and eight used progression-free survival for treatment duration. All models compared one or more IO monotherapies or combination therapies with chemotherapy. Only one study directly compared different IO agents but did not consider the concordance issue across programmed death-ligand 1 (PD-L1) testing methods. Utilities were modeled by health state in 12 models, four applied a time-to-death approach, and ten explored both. None applied cure models. CONCLUSION: Variations in methodological challenges were seen across studies. Previous models took approaches that were followed in subsequent models, such as a 2-year stopping rule of IO duration or treatment-effect waning. Challenges such as heterogeneity in PD-L1 testing and survival extrapolation and validation using real-world data should be further considered for future models in advanced or metastatic NSCLC.

Management of Patients With Advanced Urothelial Carcinoma in an Evolving Treatment Landscape: A Qualitative Study of Provider Perspectives of First-Line Therapies.

INTRODUCTION: The treatment landscape in locally advanced/unresectable or metastatic urothelial carcinoma (aUC) has evolved with the use of immune checkpoint inhibitors (ICIs) in the first line (1L) and platinum-refractory settings and with the recent approval of avelumab as 1L maintenance therapy for patients achieving disease control with platinum-containing regimens. Oncology provider perspectives and decision-making processes regarding aUC management, especially with the integration of recently approved strategies, such as maintenance therapy, have not been well-described. PATIENTS AND METHODS: Qualitative interview study with US oncologists and oncology nurses in academic and community settings in August 2020. Interviews explored decision-making around aUC 1L treatment eligibility determinants and selection, programmed cell death 1 ligand 1 (PD-L1) testing practices, and use of maintenance therapy. Thematic analysis was used to identify drivers of 1L treatment decisions. RESULTS: Eighteen oncologists (women, 11%; >15 years in practice, 55%; academic, 39%) and 18 oncology nurses (women, 94%; >15 years in practice, 34%; academic, 50%) participated. Providers preferred platinum-based regimens in 1L setting and reserved 1L ICI monotherapy for frail patients. Providers preferred chemotherapy followed by switch maintenance ICI, as opposed to concurrent combination chemotherapy and ICI, followed by ICI as continuation maintenance. Decision-making was driven by need to adhere to treatment decision-making guidelines, characteristics of the patient, treatment efficacy and patient preference. CONCLUSION: Providers adhered to guidelines and level I evidence in decision-making in the aUC 1L setting. Future studies should further evaluate barriers to the adoption of standard-of-care strategies and factors impacting decision-making in the real-world setting.

Oncology drugs and added benefit: insights from 3 European health technology assessment agencies on the role of efficacy endpoints.

OBJECTIVE: This study aimed to understand the impact of different efficacy endpoints on reimbursement decisions made by health technology assessment (HTA) bodies. MATERIALS AND METHODS: European Medicines Agency (EMA) oncology product marketing authorizations were screened to identify products that completed review by 3 HTA bodies during 2016-2019: United Kingdom's National Institute for Health and Care Excellence, Germany's Gemeinsamer Bundesausschuss, and France's Haute Autorité de Santé. Each decision's endpoint information, including overall survival (OS) and progression-free survival (PFS), was extracted. Each endpoint's influence on added benefits rating (the degree of added benefit as judged by the HTA agency) and full reimbursement (i.e. reimbursed population to label) decisions was tested using bivariate analyses. RESULTS: An increasing trend was observed toward HTA submissions with immature OS data (36.8% and 71.4% in 2016 and 2019, respectively), which was a predictor of limited added benefit (p < .001). Regarding data availability, 63% of submissions provided OS, 2% provided PFS without OS; and 35% provided neither. OS availability significantly influenced added benefit (p < .001) but not full reimbursement (p > .05) decisions, whereas PFS without OS had no significant impact compared with either OS or PFS data for either outcome (p = .99). CONCLUSIONS: The trend toward fewer products filing mature OS data over time suggests sponsors may be increasingly confident achieving reimbursement with surrogate endpoint data, although mature OS data provided the strongest correlation to positive reimbursement decisions. Notably, in some locally advanced settings, OS data maturity will take a long time to obtain. To expedite patient access to new medicines, payers should consider the acceptance of surrogate endpoints predictive of clinical benefit.

Enhancement of Odontoblastic Differentiation of Stem Cells from Exfoliated Deciduous Tooth Using N-acetylcysteine-An In Vitro Study.

AIM AND OBJECTIVE: The study was conducted to evaluate the effects of N-acetylcysteine (NAC) on the propagation and differentiation of stem cells from human exfoliated deciduous teeth(SHED). MATERIALS AND METHODS: SHEDs were isolated by explant culture method and characterized for stem cell properties using flow cytometry method. MTT assay and Cell Counting Kit-8 (CCK-8) assay were used to examine the viability and proliferation of the SHEDs. The effects of NAC-induced osteo/odontoblastic differentiation of SHEDs were determined by functional staining for mineralization, and the gene expression of osteo/odontoblastic transcription factors and proteins was evaluated by real-time quantitative reverse transcription-polymerase chain reaction(qRT-PCR) analyses. Protein levels of collagen type 1 (COL1), dentin sialophosphoprotein (DSPP), and dentin matrix acidic phosphoprotein 1(DMP-1) were calculated by the Western blot method to assess the osteo/odontogenic differentiation. RESULTS: SHEDs presented mesenchymal stem cell (MSC)-like characteristics on flow cytometric analysis. The cell viability and metabolic activity of SHEDs were increased with an increase in the concentrations of NAC from 0.5 to 10 nM. However, the concentrations of NAC from 0.5 to 2.5 mM did not affect cell proliferation. NAC incorporated at a concentration of 2.5 mM showed higher mineralization and considerably increased gene expression levels of runt-related transcription factor 2 (RUNX2), COL1A1, DSPP, and DMP-1. It significantly increased the protein expression of odontoblast-related matrix proteins like COL1, DSPP, and DMP-1. CONCLUSION: NAC regulates the healthy propagation of dental stem cells in vitro. Its effects on the differentiation of dental pulp SHEDs remain unidentified. This study explores that NAC can encourage the mineralization of SHEDs and differentiate them into the odontoblastic lineage. CLINICAL SIGNIFICANCE: The results propose that NAC could have a significant pharmacological role in activating and enhancing odontogenic differentiation of dental stem cells and possibly a prospect in regenerative dentistry.

Real-world treatment patterns and outcomes in PD-L1-positive non-small cell lung cancer.

Aim: We report real-world treatment patterns and outcomes in patients with PD-L1+ non-small-cell lung cancer (NSCLC). Methods: This retrospective, observational study using the ConcertAI Oncology Dataset (Symphony AI, CA, USA), included patients with PD-L1+ (≥1% expression) metastatic NSCLC who began first-line (1L) treatment between 2016 and 2019. Treatment outcomes were assessed by treatment class (immune checkpoint inhibitor [ICI] monotherapy, ICI combinations or chemotherapy). Results: In total, 128 (25.5%), 237 (47.3%) and 136 patients (27.1%) received 1L chemotherapy, 1L ICI monotherapy and 1L ICI combinations, respectively. ICI combinations and monotherapy had improved clinical outcomes versus chemotherapy. Adjusted analyses showed no significant difference in outcome between ICI monotherapy and ICI combinations. Conclusion: ICI-based treatments are being increasingly adopted into clinical practice and were associated with better outcomes versus chemotherapy.

Retrospective analysis of real-world treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer starting first-line systemic therapy in the United Kingdom.

BACKGROUND: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. METHODS: Electronic prescribing records of treatment-naive patients starting first-line (1 L) treatment for aNSCLC between June 2016 and March 2018 (follow-up until December 2018) in the United Kingdom were assessed retrospectively. Patient characteristics and treatment patterns were analyzed descriptively. Outcomes assessed included overall survival (OS), time to treatment discontinuation, time to next treatment, and real-world tumor response. RESULTS: In all, 1003 patients were evaluated (median age, 68 years [range, 28-93 years]; 53.9% male). Use of 1 L IO monotherapy (0-25.9%) and targeted therapy (11.8-15.9%) increased during the study period, but chemotherapy remained the most common 1 L treatment at all time points (88.2-58.2%). Median OS was 9.5 months (95% CI, 8.8-10.7 months) for all patients, 8.1 months (95% CI, 7.4-8.9 months) with chemotherapy, 14.0 months (95% CI, 10.7-20.6 months) with IO monotherapy, and 20.2 months (95% CI, 16.0-30.5 months) with targeted therapy. In the 28.6% of patients who received second-line treatment, IO monotherapy was the most common drug class (used in 51.6%). CONCLUSIONS: Although use of 1 L IO monotherapy for aNSCLC increased in the United Kingdom during the study period, most patients received 1 L chemotherapy. An OS benefit for first-line IO monotherapy vs chemotherapy was observed but was numerically smaller than that reported in clinical trials. Targeted therapy was associated with the longest OS, highlighting the need for improved treatment options for tumors lacking targetable mutations.

DentalVibe reduces pain during the administration of local anesthetic injection in comparison to 2% lignocaine gel: results from a clinical study.

BACKGROUND: This study was designed to compare the efficacy of DentalVibe against 2% lidocaine gel in reducing pain during the administration of local anesthetic injection in the adult population. METHODS: This was a split-mouth open-label, randomized, controlled clinical study conducted in the Department of Oral and Maxillofacial Surgery of a dental institute. Fifty patients who were scheduled for bilateral dental extractions requiring an inferior alveolar nerve block were enrolled in the study. Site A (n = 50) was coated with 2% lidocaine gel followed by a local anesthetic injection, and DentalVibe with local anesthetic injection was used for Site B (n = 50). The primary outcome was pain, which was recorded immediately after the administration of anesthetic injection using the Visual Analogue Scale [VAS 0 - 10]. RESULTS: The VAS pain scores ranged from 4 to 10 for site A and 0 to 6 for site B. Comparison between the two sites showed a statistically significant difference [Mann-Whitney U test value = 51.50, P < 0.001] favoring site B. CONCLUSION: This study showed that DentalVibe reduces pain during injection of local anesthesia compared to topical anesthetic gel.

Collection of Post-treatment PRO Data in Oncology Clinical Trials.

As patient-reported outcome (PRO) measures are being included more frequently in oncology clinical trials, regulatory and health technology assessment agencies have begun to request long-term, post-treatment PRO data to supplement traditional survival/progression endpoints. These data may be collected as part of cohort extension or registry studies to describe long-term outcomes of study participants after concluding their cancer treatment. While post-treatment PRO data may be expected to satisfy regulatory and payer expectations, significant practical barriers exist for the efficient incorporation of these data into oncology clinical trials, such as subject attrition, protocol deviations, and treatment crossover. The incorporation of post-treatment PRO assessments is a resource-intensive task requiring clear objectives for how the data will be analyzed and interpreted by both sponsors and regulators. Incorporating PRO data collection via electronic modalities (e.g., smartphone, web) may be a less expensive and more feasible option for incorporating long-term follow-up, reducing the frequency of manual study staff follow-up and expensive clinic visits. It is essential to include well-defined estimands for the statistical analysis, as well as to document limitations associated with the long-term follow-up data-collection approach. Analytical techniques will likely rely on descriptive and model-based statistics, and conclusions about treatment differences will likely be limited to preliminary findings of effectiveness (instead of efficacy). Finally, communications with health authorities and regulatory agencies regarding the LTFU study design and analysis should occur as early as possible to ensure that the PRO data to be collected offer an opportunity to properly evaluate the research question(s) of interest.

Glucose and Serum Deprivation Led to Altered Proliferation, Differentiation Potential and AMPK Activation in Stem Cells from Human Deciduous Tooth.

Stem cell therapy is an evolving treatment strategy in regenerative medicine. Recent studies report stem cells from human exfoliated deciduous teeth could complement the traditional mesenchymal stem cell sources. Stem cells from human exfoliated deciduous teeth exhibit mesenchymal characteristics with multilineage differentiation potential. Mesenchymal stem cells are widely investigated for cell therapy and disease modeling. Although many research are being conducted to address the challenges of mesenchymal stem cell therapy in clinics, most of the studies are still in infancy. Host cell microenvironment is one of the major factors affecting the homing of transplanted stem cell and understanding the factors affecting the fate of stem cells of prime important. In this study we aimed to understand the effects of serum deprivation in stem cells derived from human deciduous tooth. Our study aimed to understand the morphological, transcriptional, cell cycle and stemness based changes of stem cells in nutrient deprived medium. Our results suggest that stem cells in nutrient deprived media undergo low proliferation, high apoptosis and changed the differentiation potential of the stem cells. Serum deprived mesenchymal stem cells exhibited enhanced chondrogenic differentiation potential and reduced osteogenic differentiation potential. Moreover, the activation of key metabolic sensor AMP-activated kinase (AMPK) leads to activation of transcription factors such as FOXO3, which leads to an S phase quiescence. Serum deprivation also enhanced the expression of stemness related genes Sox2 and c-Myc.

Treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer initiating first-line treatment in the US community oncology setting: a real-world retrospective observational study.

PURPOSE: Treatments for advanced non-small cell lung cancer (NSCLC) have evolved to include targeted and immuno-oncology therapies, which have demonstrated clinical benefits in clinical trials. However, few real-world studies have evaluated these treatments in the first-line setting. METHODS: Adult patients with advanced NSCLC who initiated first-line treatment with chemotherapy, targeted therapies (TT), or immuno-oncology-based regimens in the US Oncology Network (USON) between March 1, 2015, and August 1, 2018, were included and followed up through February 1, 2019. Data were sourced from structured fields of USON electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan-Meier methods used to evaluate time-to-event outcomes, including time to treatment discontinuation (TTD) and overall survival (OS). Adjusted Cox regression analyses and inverse probability of treatment weighting (IPTW) were performed to control for covariates that may have affected treatment selection and outcomes. RESULTS: Of 7746 patients, 75.6% received first-line systemic chemotherapy, 11.7% received immuno-oncology monotherapies, 8.5% received TT, and 4.2% received immuno-oncology combination regimens. Patients who received immuno-oncology monotherapies had the longest median TTD (3.5 months; 95% confidence interval [CI], 2.8-4.2) and OS (19.9 months; 95% CI, 16.6-24.1). On the basis of multivariable Cox regression and IPTW, immuno-oncology monotherapy was associated with reduced risk of death and treatment discontinuation relative to other treatments. CONCLUSION: These results suggest that real-world outcomes in this community oncology setting improved with the introduction of immuno-oncology therapies. However, clinical benefits are limited in certain subgroups and tend to be reduced compared with clinical trial observations.

Paclitaxel-Loaded Colloidal Silica and TPGS-Based Solid Self-Emulsifying System Interferes Akt/mTOR Pathway in MDA-MB-231 and Demonstrates Anti-tumor Effect in Syngeneic Mammary Tumors.

A solid self-emulsifying drug delivery system (SEDDS) of paclitaxel (PTX) was developed that could enhance its oral bioavailability and neutralize other niggles associated with conventional delivery systems of PTX. TPGS-centered SEDDS containing PTX was optimized by Box-Behnken experimental design and then formulated as fumed colloidal silica-based solid SEDDS microparticles (Si-PTX-S-SEDDS). AFM analysis exhibited round-shaped microparticles of approximately 2-3 µM diameter, whereas after reconstitution, particle size measurement showed nanoemulsion droplets of 30.00 ± 2.00 nm with a zeta potential of 17.38 ± 2.88 mV. Si-PTX-S-SEDDS displayed improved efficacy proven by reduced IC50 of 0.19 ± 0.03 µM against MDA-MB-231 cells and a 45.83-fold higher cellular uptake in comparison to free PTX. Molecular mechanistic studies showed mitochondria-mediated intrinsic pathway of apoptosis following Akt/mTOR pathway, which is accompanied by survivin downregulation. Rhodamine 123 assay and chylomicron flow blocking studies revealed P-gp inhibition potential and lymphatic uptake of Si-PTX-S-SEDDS, responsible for over 4-fold increment in oral bioavailability compared to PTX administered as Taxol. In vivo anti-tumor studies in syngeneic mammary tumor model in SD rats revealed higher efficacy of Si-PTX-S-SEDDS as evident from significant reduction in tumor burden. In total, the developed Si-PTX-S-SEDDS formulation was found as an appropriate option for oral delivery of PTX.

Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate.

We have devised a nanocarrier using "tocopheryl polyethylene glycol succinate (TPGS) conjugated to triphenylphosphonium cation" (TPP-TPGS) for improving the efficacy of doxorubicin hydrochloride (DOX). Triphenylphosphonium cation (TPP) has affinity for an elevated transmembrane potential gradient (mitochondrial), which is usually high in cancer cells. Consequently, when tested in molecular docking and cytotoxicity assays, TPP-TPGS, owing to its structural similarity to mitochondrially directed anticancer compounds of the "tocopheryl succinate" family, interferes specifically in mitochondrial CII enzyme activity, increases intracellular oxidative stress, and induces apoptosis in breast cancer cells. DOX loaded nanocarrier (DTPP-TPGS) constructed using TPP-TPGS was positively charged, spherical in shape, sized below 100 nm, and had its drug content distributed evenly. DTPP-TPGS offers greater intracellular drug delivery due to its rapid endocytosis and subsequent endosomal escape. DTPP-TPGS also efficiently inhibits efflux transporter P glycoprotein (PgP), which, along with greater cell uptake and inherent cytotoxic activity of the construction material (TPP-TPGS), cumulatively results in 3-fold increment in anticancer activity of DOX in resistant breast cancer cells as well as greater induction of necroapoptosis and arrest in all phases of the cell cycle. DTPP-TPGS after intravenous administration in Balb/C mice with breast cancer accumulates preferentially in tumor tissue, which produces significantly greater antitumor activity when compared to DOX solution. Toxicity evaluation was also performed to confirm the safety of this formulation. Overall TPP-TPGS is a promising candidate for delivery of DOX.