Novel Stimuli-Responsive Pectin-PVP-Functionalized Clay Based Smart Hydrogels for Drug Delivery and Controlled Release Application

Stimuli-responsive drug delivery systems are urgently required for injectable site-specific delivery and release of drugs in a controlled manner. For this purpose, we developed novel pH-sensitive, biodegradable, and antimicrobial hydrogels from bio-macromolecule pectin, polyvinylpyrrolidone (PVP), 3-aminopropyl (diethoxy)methyl silane (3-APDEMS), and sepiolite clay via blending and solution casting technique. The purified sepiolite (40 um) was functionalized with 3-APDEMS crosslinker (ex-situ modification) followed by hydrogels fabrication. FTIR and SEM confirmed crosslinked structural integrity and rod-like morphology of hydrogels respectively. The swelling properties of hydrogels could be controlled by varying the concentration of modified clay in pectin/PVP blends. Moreover, the decrease in pH increased the swelling of hydrogels indicating the pH-responsiveness of hydrogels. All hydrogels were degraded after 21 days in phosphate buffer saline pH 7.4 (human blood pH). In-vitro cytotoxicity against 3T3 mouse fibroblast cell line analysis confirmed cytocompatibility of all hydrogels. Ceftriaxone sodium (CTX-S) was selected as a model drug. The release profile of the hydrogel showed 91.82% release in PBS for 2 h in a consistent and controlled manner. The chemical structure of the drug remained intact during and after release confirmed through UV-Visible spectroscopy. Overall, these hydrogels could be used as potential scaffolds for future biomedical applications

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended

Next-generation sequencing based detection of germline and somatic alterations in a patient with four metachronous primary tumors

Introduction: Multiple primary tumors (MPTs) are defined as two or more separate synchronous or metachronous neoplasms occurring in different sites in the same individual. These tumors differ in histology, as well as primary sites from which they arise. Risk factors associated with the occurrence of MPTs include germline alterations, exposure to prior cancer therapies, occupational hazards, and lifestyle and behavioral influences. Case report: We present a case of a patient who was diagnosed with four metachronous primary tumors. In 2013, she was diagnosed with serous proliferations associated with psammomatous bodies of primary peritoneal origin (pT3NxM0). This was followed by invasive ductal carcinoma of the breast (stage pT2N0Mx, histological grade III/III) in 2014, melanoma (stage pT2bNxMx) in 2016 that further advanced to the lung and brain in 2017, and a low-grade lung carcinoid in 2017. To better understand the biology of this patient's MPTs, we performed next-generation sequencing (NGS) to assess for both somatic and germline alterations. The treatment course for this patient aims to target the tumor with the strongest prognostic value, namely her malignant melanoma, and has contributed favorably to the overall survival of this patient. Conclusion: We report the clinical and genomic landscape of a patient with MPTs who had no identifiable unique somatic or germline mutations to explain her predilection to cancer. The treatment course and overall prognosis for this patient is important for understanding future cases with unrelated, metachronous MPTs, the occurrence of which cannot always be explained by underlying genetic mechanisms. Keywords: Multiple primary tumors, Next-generation sequencing, Tumor mutational burden, Immunotherap

Synthesis, characterization, computational studies and in vitro antiparasitic activity of novel flavanoidal-1,2,4,5-tetrazinane-6′-thione

Keeping in view the growing resistance of conventional antiparasitic drugs, this study aimed to synthesize a series of six noble flavanoidal tetrazinane-6′-thione derivatives by employing a facile one pot reaction pathway. Structural characterizations of synthesized compounds were performed by using IR, 1HNMR, 13CNMR and LC-MS spectra. Molecular docking study showed that one of the newly synthesized compounds strongly bind with the amino residues of BSA with two hydrogen bonding interactions. Physiological properties, pharmacokinetic properties (ADME) and toxicity of all synthesized compounds was carried out using Molinspiration and pkCSM softwares. DFT calculations were performed for all synthesized compounds using B3LYP method to obtain various molecular properties. Using a previously established model for parasitic infections, Clinostomum complanatum we showed that the newly synthesized compounds have a very potent parasitic activity. To elucidate the possible mechanisms, we tested the exposed parasites and observed a perturbation in lipid peroxidation and the antioxidant enzyme superoxide dismutase. Implications of this are discussed in the light of development of these molecules as antiparasitic drugs. HIGHLIGHTSSix noble flavanoidal-1,2,4,5-tetrazinane-6′-thiones (7–12) were synthesized using flavanone derivatives and thiocarbohydrazide in acetic acid as a reagent in ethanol employing one-pot synthesis.Structural characterization of synthesized compounds was done using IR, 1HNMR, 13CNMR and LC-MS spectra.Physicochemical analysis determined that all synthesized compounds are efficiently absorbed and have good permeability.In silico ADME and Toxic properties were determined for all synthesized compounds.In vitro antiparasitic activity was performed for all synthesized compounds against Clinostomum complanatum.Molecular Docking studies demonstrated the binding interaction with BSA enzyme through hydrogen bonding.Density functional theory (DFT) have been performed to estimate the various molecular properties of the synthesized compounds. Six noble flavanoidal-1,2,4,5-tetrazinane-6′-thiones (7–12) were synthesized using flavanone derivatives and thiocarbohydrazide in acetic acid as a reagent in ethanol employing one-pot synthesis. Structural characterization of synthesized compounds was done using IR, 1HNMR, 13CNMR and LC-MS spectra. Physicochemical analysis determined that all synthesized compounds are efficiently absorbed and have good permeability. In silico ADME and Toxic properties were determined for all synthesized compounds. In vitro antiparasitic activity was performed for all synthesized compounds against Clinostomum complanatum. Molecular Docking studies demonstrated the binding interaction with BSA enzyme through hydrogen bonding. Density functional theory (DFT) have been performed to estimate the various molecular properties of the synthesized compounds. Communicated by Ramaswamy H. Sarma</p

Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade

Background Pneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.Methods We performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.Results From 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3–4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.Conclusions Steroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future

Impact on Antimicrobial Utilization in the Emergency Department of a Point of Care Polymerase Chain Reaction Compared to Antigen Testing for Influenza

Background: Due to poor sensitivity, the FDA mandated that rapid influenza antigen (IAT) must be phased out by 2018. At our institution, an on-site rapid influenza PCR (PCR) was implemented in emergency departments (ED) at the start of the 2016-2017 influenza season. The purpose of this study was to examine the impact of influenza PCR testing on antimicrobial utilization in the ED. Methods: This multicenter quasiexperimental study included adults over the age of 50 who were tested for influenza, and discharged from the ED. Subjects were matched 2:1 by age, sex, month of testing, and ED site. The pre-implementation group had IAT (Jan-Apr 2016) and the post-implementation had PCR testing (Jan-Apr 2017). The primary outcome was antiviral utilization. Other outcomes included diagnostic yield, test turnaround time (TAT), receipt of antibiotics, and 30-day revisit.Results: The PCR group of 116 patients (pts) were matched to 232 pts in IAT group (Table 1). Positive results for influenza were reported in 37.9% of PCR versus 18.1% of IAT groups (p\u3c0.001); TAT 0.95 (0.75-1.4) hours in PCR vs. 0.60 (0.40-0.85) hours in IAT group (P\u3c0.001). Oseltamivir was initiated in the ED in 21% of PCR vs. 11% of IAT group (p\u3c0.001). An additional 28% in PCR group received oseltamivir at ED discharge vs. 15% in IAT group (p=0.004). Antibiotics were administered in the ED to 8% in PCR group vs. 15% in the IAT group. A positive influenza test was associated with less antibiotic use OR 0.454 (95% CI 0.213-0.967), while abnormal chest radiograph (CXR) and WBC was associated with increased antibiotic use OR 3.667 (1.743-7.715). The 30-day revisit was 3.8% and 10.8% in the PCR vs. IAT groups respectively (p=0.034).Conclusion: Replacing IAT with PCR testing increased diagnostic yield for influenza and receipt of oseltamivir and decreased antibiotic utilization in the ED. Independent predictors for antibiotic use were abnormal CXR and WBC, while positive influenza testing was protective.https://scholarlycommons.henryford.com/merf2019clinres/1014/thumbnail.jp

Outcomes to first-line pembrolizumab in patients with PD-L1-high (≥50%) non–small cell lung cancer and a poor performance status

Background Patients with non–small cell lung cancer (NSCLC) and a poor Eastern Cooperative Oncology Group Performance Status (ECOG PS) have been excluded from phase III immunotherapy clinical trials. We sought to evaluate clinical outcomes to first-line pembrolizumab in patients with advanced NSCLC, a PD-L1 Tumor Proportion Score (TPS) of ≥50%, and an ECOG PS of 2.Methods We performed a multicenter retrospective analysis of patients with metastatic NSCLC and a PD-L1 TPS of ≥50% (negative for genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Clinical outcomes were compared in patients based on ECOG PS.Results Among the 234 patients, 83.3% (n=195) had an ECOG PS of 0 or 1, and 16.7% (n=39) had an ECOG PS of 2. The baseline clinicopathological characteristics were balanced between the ECOG PS 0–1 vs 2 groups in terms of age, sex, tobacco use, histology, KRAS mutation status, presence of other potentially targetable driver mutations (BRAF, MET, HER2, RET), presence of brain metastases, and PD-L1 TPS distribution. Compared with patients with an ECOG PS of 0 or 1, patients with an ECOG PS of 2 had a significantly lower objective response rate (43.1% vs 25.6%; p=0.04), a numerically shorter median progression-free survival (6.6 months vs 4.0 months; HR 0.70 (95% CI 0.47 to 1.06); p=0.09), and a significantly shorter median overall survival (20.3 months vs 7.4 months; HR 0.42 (95% CI 0.26 to 0.68); p&lt;0.001). On disease progression, patients with an ECOG PS of 2 were significantly less likely to receive second-line systemic therapy compared with patients with an ECOG PS of 0–1 (65% vs 22.2%, p=0.001).Conclusions A subset of patients with NSCLC and an ECOG PS of 2 can respond to first-line pembrolizumab. However, clinical outcomes in this population are often poor and use of second-line systemic therapy is infrequent

Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma.

The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1-mutant lung tumors to platinum therapy, was validated using a large patient response data set. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies. SIGNIFICANCE: An experimental and analytical framework to generate in vivo pharmacogenomic maps that relate tumor genotypes to therapeutic responses reveals a surprisingly complex map of genotype-specific resistance and sensitivity