Rechallenge With Switching Immune Checkpoint Inhibitors Following Autoimmune Myocarditis in a Patient With Lynch Syndrome.

Immune checkpoint inhibitors (ICIs) induce profound benefits in cancer patients with mismatch repair gene mutations or high levels of microsatellite instability. Herein, we present a case of a patient with history of Muir-Torre/Lynch syndrome and metastatic gastric adenocarcinoma in the presence of an MSH2 gene mutation. The patient was initially treated with a PD-1 inhibitor, pembrolizumab, but developed grade 4 myocarditis requiring treatment with infliximab and a prolonged steroid taper. Following discontinuation of pembrolizumab, surveillance testing showed no radiographic or endoscopic evidence of progression for 7 months, until biopsy results from a repeat upper endoscopy indicated local disease recurrence. The patient was subsequently rechallenged with another PD-1 inhibitor, nivolumab, at a 50% dose reduction without recurrent adverse events and eventually achieved a complete response after 13 cycles. This case highlights the relative importance of considering careful rechallenge with ICI therapy in patients with microsatellite instability-high malignancies and a high risk of severe adverse events.

Changes in Prescribing Patterns in Stage III Colon Cancer.

BACKGROUND: For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. PATIENTS AND METHODS: To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. RESULTS: A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). CONCLUSIONS: Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome.

PURPOSE: Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes. METHODS: Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions. RESULTS: Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult. CONCLUSIONS: Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.

Molecular Simulation and Statistical Learning Methods toward Predicting Drug-Polymer Amorphous Solid Dispersion Miscibility, Stability, and Formulation Design.

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API-carrier mixture and the principal API-carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API-carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.

Isothiourea-Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution.

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5-S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

A Systematic Review and Network Meta-Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer.

BACKGROUND: Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies. MATERIALS AND METHODS: We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons. RESULTS: Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26-0.63; TAS-102: HR, 0.46 CI, 0.40-0.52) and OS (Rego 160: HR, 0.67; CI, 0.48-0.93; TAS-102: HR, 0.67; CI, 0.57-0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23-0.84) and PFS (HR, 0.37; CI, 0.21-0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160. CONCLUSION: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. IMPLICATIONS FOR PRACTICE: Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.

Evaluating Computational and Structural Approaches to Predict Transformation Products of Polycyclic Aromatic Hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) undergo transformation reactions with atmospheric photochemical oxidants, such as hydroxyl radicals (OH•), nitrogen oxides (NOx), and ozone (O3). The most common PAH-transformation products (PAH-TPs) are nitrated, oxygenated, and hydroxylated PAHs (NPAHs, OPAHs, and OHPAHs, respectively), some of which are known to pose potential human health concerns. We sampled four theoretical approaches for predicting the location of reactive sites on PAHs (i.e., the carbon where atmospheric oxidants attack), and hence the chemoselectivity of the PAHs. All computed results are based on density functional theory (B3LYP/6-31G(d) optimized structures and energies). The four approaches are (1) Clar's prediction of aromatic resonance structures, (2) thermodynamic stability of all OHPAH adduct intermediates, (3) computed atomic charges (Natural Bond order, ChelpG, and Mulliken) at each carbon on the PAH, and (4) average local ionization energy (ALIE) at atom or bond sites. To evaluate the accuracy of these approaches, the predicted PAH-TPs were compared to published laboratory observations of major NPAH, OPAH, and OHPAH products in both gas and particle phases. We found that the Clar's resonance structures were able to predict the least stable rings on the PAHs but did not offer insights in terms of which individual carbon is most reactive. The OHPAH adduct thermodynamics and the ALIE approaches were the most accurate when compared to laboratory data, showing great potential for predicting the formation of previously unstudied PAH-TPs that are likely to form in the atmosphere.

A C=O⋠⋠⋠Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols.

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study.

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-π interactions over C-H···π is responsible for diastereoselectivity.

Computational Insights into the Central Role of Nonbonding Interactions in Modern Covalent Organocatalysis.

The flexibility, complexity, and size of contemporary organocatalytic transformations pose interesting and powerful opportunities to computational and experimental chemists alike. In this Account, we disclose our recent computational investigations of three branches of organocatalysis in which nonbonding interactions, such as C-H···O/N interactions, play a crucial role in the organization of transition states, catalysis, and selectivity. We begin with two examples of N-heterocyclic carbene (NHC) catalysis, both collaborations with the Scheidt laboratory at Northwestern. In the first example, we discuss the discovery of an unusual diverging mechanism in a catalytic kinetic resolution of a dynamic racemate that depends on the stereochemistry of the product being formed. Specifically, the major product is formed through a concerted asynchronous [2 + 2] aldol-lactonization, while the minor products come from a stepwise spiro-lactonization pathway. Stereoselectivity and catalysis are the results of electrophilic activation from C-H···O interactions between the catalyst and the substrate and conjugative stabilization of the electrophile. In the second example, we show how knowledge and understanding of the computed transition states led to the development of a more enantioselective NHC catalyst for the butyrolactonization of acyl phosphonates. The identification of mutually exclusive C-H···O interactions in the computed major and minor TSs directly resulted in structural hypotheses that would lead to targeted destabilization of the minor TS, leading to enhanced stereoinduction. Synthesis and evaluation of the newly designed NHC catalyst validated our hypotheses. Next, we discuss two works related to Lewis base catalysis involving 4-dimethylaminopyridine (DMAP) and its derivatives. In the first, we discuss our collaboration with the Smith laboratory at St Andrews, in which we discovered the origins of the regioselectivity in carboxyl transfer reactions. We disclose how different Lewis base catalysts (NHC or DMAP) can lead to different regiomeric products as a result of differing magnitudes of aromatic and C-H···O interactions present in the respective transition states. In the second example, we discuss the mechanism and origins of the stereoselectivity of a reaction catalyzed by a planar-chiral 4-(pyrrolidino)pyridine derivative, namely, the coupling of ketenes with cyanopyrrole. We discovered that the chiral base mechanism is operative, in contrast to the originally proposed Brønsted acid mechanism. The selectivity is determined by the ease with which the major and minor TSs can realize strong stabilizing C-H···N interactions between the pyrrole cyano group and the catalyst. These interactions induce increased catalyst distortion in the minor TS, thereby leading to enantioselectivity. Finally, we discuss our computations related to amine-based organocatalysis in collaboration with the Carter laboratory at Oregon State. We probed the mechanism and stereoselectivity of a bifunctional amine thiourea-catalyzed Michael reaction. Our computations led to the design of an improved catalyst. However, synthesis and tests revealed that this catalyst was prone to degradation to side products that also catalyze the reaction, ultimately reducing the observed enantioselectivity. Lastly, we discuss our study of the mechanism and stereoselectivity of a proline sulfonamide-catalyzed Robinson annulation, in which we discovered that the enantioselectivity is controlled by the first Michael step but the diastereoselectivity is controlled by the following Mannich step.

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α-Ketoesters.

A general and enantioselective N-heterocyclic carbene (NHC)-catalyzed lactonization of simple enals and α-ketoesters has been discovered using a new ternary cooperative catalytic system. The highly selective annulation was achieved by using a combination of a chiral NHC, a hydrogen-bond donor, and a metal salt, facilitating self-assembly of the reactive partners. A proposed model for this new mode of NHC chiral relay catalysis is supported by experimental and computational mechanistic studies.

Formation of Aza-ortho-quinone Methides Under Room Temperature Conditions: Cs2CO3 Effect.

Since the first report of a facile, room temperature process to access aza-ortho-quinone methides (aoQMs) by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014. We report a theoretical and experimental study of the key to success behind these successful examples to enable broader exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (ΔG > 30 kcal/mol), precluding their formation under mild conditions. The use of Cs2CO3 as base is critical. It provides a thermodynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The exothermic formation of salt byproducts provides a driving force (average ΔG = -30.8 kcal/mol) compensating for the majority of the inherent unfavorable thermodynamics of aoQM formation.

A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products.

The Armillaria and Lactarius genera of fungi produce the antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. We report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The key features of these syntheses are 1) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, 2) the utility of a key 1,2-cyclobutanediol intermediate to serve as a precursor to each natural product class, and 3) a direct chemical conversion of a protoilludane to a marasmane through serendipitous ring contraction, which provides experimental support for their proposed biosynthetic relationships.

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.

PURPOSE: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Identification of an optimal mutant allele frequency to detect activating KRAS, NRAS, and BRAF mutations in a commercial cell-free DNA next-generation sequencing assay in colorectal and pancreatic adenocarcinomas.

Background: Evaluation for activating mutations in KRAS, NRAS, and BRAF in colorectal cancer (CRC) and in KRAS in pancreatic ductal adenocarcinoma (PDAC) is essential for clinical care. Plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) allows convenient assessment of a tumor's molecular profile, however low tumor DNA shedding limits sensitivity. We investigated mutant allele frequency (MAF) of other oncogenic dominant genes to identify a threshold for accurate detection of KRAS, NRAS, and BRAF (RAS/RAF) mutations in cfDNA. Methods: Molecular and clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA study. Patients with CRC or PDAC and a KRAS, NRAS, or BRAF activating single nucleotide variant (SNV) present on tissue NGS and with available cfDNA assays were included. Recursive partitioning and Wilcoxon-rank statistics methods identified potential cut-points for discriminative MAF values. Results: One hundred and thirty-five CRC and 30 PDAC cases with 198 total cfDNA assays met criteria. Greatest non-RAS/RAF dominant gene MAF of 0.34% provided maximum discrimination for predicting RAS/RAF SNV detection. Sensitivity for RAS/RAF SNVs increased with dominant gene MAF, with MAF ≥1% predicting sensitivity >98%, MAF between 0.34 and 1% predicting sensitivity of 84.0%, and MAF £0.34% predicting sensitivity of 50%. For 43 cfDNA assays that did not detect RAS/RAF SNVs, 18 assays detected 34 other oncogenic variants, of which 80.6% were not also detected on tissue. Conclusions: Non-RAS/RAF dominant oncogenic mutation MAF ≥1% on cfDNA NGS predicts high sensitivity to detect RAS/RAF oncogenic SNVs in CRC and PDAC. MAF £0.34% indicates an assay may not reliably detect RAS/RAF SNVs, despite detection on tissue testing. Most variants from assays that did not detect RAS/RAF had MAF <1% and were not detected on tissue, suggesting potential confounding. These data suggest a practical approach to determining cfDNA assay adequacy, with implications for guiding clinical decisions in CRC and PDAC.

Tucatinib: an investigational novel therapeutic agent for the treatment of HER-2 colorectal cancer.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER-2) is an oncogenic driver and target in gastroesophageal and breast cancer; there is also evidence for a role in non-small cell lung cancer (NSCLC). In colorectal cancer (CRC), the incidence of HER-2 overexpression occurs in up to 10% of patients. While its role of HER-2 as a biomarker for prognosis in CRC remains uncertain, it remains of interest as a potential therapeutic target. Tucatinib is an investigational agent which functions as a selective HER-2 inhibitor. AREAS COVERED: In this article, the authors discuss the incidence of HER-2 in CRC and its rationale in the treatment of CRC. An overview of the market is offered, followed by a scientific summary of tucatinib including its clinical development in CRC. EXPERT OPINION: Tucatinib is a selective HER-2 inhibitor that has unique properties which distinguishes it from other HER-2 directed therapies. In the clinical setting, it has demonstrated clinical efficacy of HER-2 inhibition across various solid tumors including CRC. Given the evidence of clinical activity observed with tucatinib in breast cancer and frequency of HER-2 overexpression in CRC, the investigation of tucatinib as a monotherapy and in combination with other therapeutic agents remains of interest.

Pemigatinib for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements.

Biliary tract cancers are a diverse and aggressive malignancy that carry a poor chance for curative treatment and significant associated mortality. Current first-line treatment only extends median overall survival to roughly 1 year and is associated with a significant adverse event profile. Recently, advancements in genetic sequencing have opened new avenues of targeted treatment. In cholangiocarcinoma, FGFR2 alterations have been shown to be present in roughly 10-15% of intrahepatic cholangiocarcinoma. Pemigatinib, a FGFR1-4 inhibitor, has been shown to significantly extend survival in the second-line setting to over 20 months in patients who harbor FGFR2 fusions. Here, we outline the development and future direction of pemigatinib and other FGFR2 inhibitors in the field of advanced biliary tract cancers.

Rapid Feedback: Assessing Pre-clinical Teaching in the Era of Online Learning.

Introduction: Medical schools vary in their approach to providing feedback to faculty. The purpose of this study was to test the effects of rapid student feedback in a course utilizing novel virtual learning methods. Methods: Second-year medical students were supplied with an optional, short questionnaire at the end of each class session and asked to provide feedback within 48 h. At the close of each survey, results were emailed to faculty. After the course, students and faculty were asked to rate the effectiveness of this method. This study did not affect administration of the usual end-of-course summative evaluations. Results: Ninety-one percent of students who participated noted increased engagement in the feedback process, but only 18% on average chose to participate. Faculty rated rapid feedback as more actionable than summative feedback (67%), 50% rated it as more specific, and 42% rated it as more helpful. Some wrote that comments were too granular, and others noted a negative personal emotional response. Conclusion: Rapid feedback engaged students, provided actionable feedback, and increased communication between students and instructors, suggesting that this approach added value. Care must be taken to reduce the student burden and support relational aspects of the process.

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study.

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ-metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ-metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure-property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug-drug interactions resulting from coadministration at an earlier stage in the drug development pipeline.

Maintenance Therapy in First-Line Gastric and Gastroesophageal Junction Adenocarcinoma: A Retrospective Analysis.

BACKGROUND: Fluoropyrimidine with platinum-based chemotherapy has become the standard of care for advanced gastric and gastroesophageal (GEJ) cancer. Trials in colon cancer show that induction chemotherapy followed by maintenance chemotherapy is an efficacious strategy to maximize clinical response while minimizing toxicity. The current retrospective study aims to evaluate the efficacy and tolerability of maintenance versus continuous treatment in advanced GEJ malignancy. METHODS: A retrospective analysis of patients with metastatic gastric/GEJ adenocarcinoma treated with fluoropyrimidine and platinum chemotherapy between 2007-2017 was performed. Patients who achieved at least stable disease after initial induction treatment were included. After 16 weeks of induction chemotherapy, patients were categorized into the continuous group if induction chemotherapy was continued and the maintenance group if chemotherapy was switched to maintenance fluoropyrimidine monotherapy or observed off treatment. Endpoints were progression-free survival (PFS), overall survival (OS), and toxicities. RESULTS: In total, 90 patients met the criteria, 48 received continuous therapy, and 42 received maintenance. Baseline characteristics were comparable. No difference in PFS (9.9 vs 8.4 months p = .28) or in OS (16.1 vs 21.3 months p = .75) was observed, including after controlling for the best response on induction therapy and other variables. In patients on continuous induction therapy, there was a higher prevalence of grade three neuropathy (42.6% vs 9.8% p = .001) and neutropenic fever (13% vs 0% p =.03). CONCLUSIONS: Maintenance therapy following induction fluoropyrimidine and platinum-based therapy is associated with an improved toxicity profile and appears to have comparable efficacy to continuous treatment in metastatic gastric/GEJ cancer.