The recent approval of two PD-1 inhibitors for the treatment of non-small cell lung cancer (NSCLC) has rapidly led to the widespread use of these agents in oncology practices. Pneumonitis has been ...recognized as a potentially life-threatening adverse event among NSCLC patients treated with PD-1 inhibitors; however, the detailed clinical and radiographic manifestations of this entity remain to be described. We report on two cases of anti-PD-1 pneumonitis in advanced NSCLC patients treated with nivolumab after its FDA approval. Both patients presented with ground-glass and reticular opacities and consolidations in a peripheral distribution on CT, demonstrating a radiographic pattern of cryptogenic organizing pneumonia. Consolidations were extensive and rapidly developed within 8 weeks of therapy in both cases. Both patients were treated with corticosteroids with subsequent improvement of respiratory symptoms and radiographic findings. One patient experienced recurrent pneumonitis after completing corticosteroid taper, or a "pneumonitis flare," in the absence of nivolumab retreatment, with subsequent improvement upon corticosteroid readministration. With the increasing use of immune checkpoint inhibitors in a growing number of tumor types, awareness of the radiographic and clinical manifestations of PD-1 inhibitor-related pneumonitis will be critical for the prompt diagnosis and management of this potentially serious adverse event.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for
-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired ...drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in
-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.
.
MET inhibitors can be effective therapies in patients with
exon 14 (
ex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In ...this study, we characterize acquired amplification of wild-type (WT)
as a molecular mechanism behind crizotinib resistance in three cases of
ex14-mutant NSCLC and propose a combination therapy to target it.
The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant
ex14-mutant patient tumor with massive focal amplification of WT
. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy
and
using viability and apoptotic assays.
amplification is a recurrent genetic event in crizotinib-resistant
ex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition.
Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by
amplification in
ex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
Evaluating drug responses using primary patient-derived cells
represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib ...combinations in
mutant non-small cell lung cancer (NSCLC) patient
enograft-
erived
rganotypic
pheroids (XDOTS) using a short-term
system.
We generated two
mutant NSCLC PDX models DFCI359 (
exon19 755_757LREdelinsRP) and DFCI315 (
exon20 V777_G778insGSP) and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated
with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious
combination was subsequently validated
using the DFCI359 and DFCI315 PDXs and a
genetically engineered mouse model.
Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab
was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling.
The XDOTS platform can be used to evaluate therapies and therapeutic combinations
using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
A survey of antibiotic stewardship programs was performed to determine essential resources. Increasing physician and pharmacist staffing support predicted effectiveness, and effectiveness was ...mediated by ability to perform antibiotic review with prospective audit and feedback. Recommended staffing ratios are provided.
Abstract
Background
Antibiotic stewardship programs improve clinical outcomes and patient safety and help combat antibiotic resistance. Specific guidance on resources needed to structure stewardship programs is lacking. This manuscript describes results of a survey of US stewardship programs and resultant recommendations regarding potential staffing structures in the acute care setting.
Methods
A cross-sectional survey of members of 3 infectious diseases subspecialty societies actively involved in antibiotic stewardship was conducted. Survey responses were analyzed with descriptive statistics. Logistic regression models were used to investigate the relationship between stewardship program staffing levels and self-reported effectiveness and to determine which strategies mediate effectiveness.
Results
Two-hundred forty-four respondents from a variety of acute care settings completed the survey. Prior authorization for select antibiotics, antibiotic reviews with prospective audit and feedback, and guideline development were common strategies. Eighty-five percent of surveyed programs demonstrated effectiveness in at least 1 outcome in the prior 2 years. Each 0.50 increase in pharmacist and physician full-time equivalent (FTE) support predicted a 1.48-fold increase in the odds of demonstrating effectiveness. The effect was mediated by the ability to perform prospective audit and feedback. Most programs noted significant barriers to success.
Conclusions
Based on our survey's results, we propose an FTE-to-bed ratio that can be used as a starting point to guide discussions regarding necessary resources for antibiotic stewardship programs with executive leadership. Prospective audit and feedback should be the cornerstone of stewardship programs, and both physician leadership and pharmacists with expertise in stewardship are crucial for success.
In many model organisms, diffuse patterning of cell wall peptidoglycan synthesis by the actin homolog MreB enables the bacteria to maintain their characteristic rod shape. In Caulobacter crescentus ...and Escherichia coli, MreB is also required to sculpt this morphology de novo. Mycobacteria are rod‐shaped but expand their cell wall from discrete polar or subpolar zones. In this genus, the tropomyosin‐like protein DivIVA is required for the maintenance of cell morphology. DivIVA has also been proposed to direct peptidoglycan synthesis to the tips of the mycobacterial cell. The precise nature of this regulation is unclear, as is its role in creating rod shape from scratch. We find that DivIVA localizes nascent cell wall and covalently associated mycomembrane but is dispensable for the assembly process itself. Mycobacterium smegmatis rendered spherical by peptidoglycan digestion or by DivIVA depletion are able to regain rod shape at the population level in the presence of DivIVA. At the single cell level, there is a close spatiotemporal correlation between DivIVA foci, rod extrusion and concentrated cell wall synthesis. Thus, although the precise mechanistic details differ from other organisms, M. smegmatis also establish and propagate rod shape by cytoskeleton‐controlled patterning of peptidoglycan. Our data further support the emerging notion that morphology is a hardwired trait of bacterial cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein ...HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.
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•Combined MEK/BET inhibitors are effective in KRAS-mutant NSCLCs•Sensitivity is dependent on HOXC10, which is overexpressed in 51% of tumors•Aberrant HOXC10 expression is largely caused by defects in PRC2 genes•MEK/BET inhibitors co-suppress Ras output and HOXC10 to cause replication defects
Guerra et al. show that combined MEK and BET inhibitors are effective in ∼50% of KRAS-mutant NSCLC. HOXC10 is a biomarker of response and regulates expression of pre-replication complex proteins in conjunction with MEK. MEK/BET inhibitors suppress HOXC10 to trigger replication defects and induce cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abemaciclib was originally FDA approved for patients with ER-positive/HER2-negative breast cancer with Ki-67 expression ≥20%. However, there were no guidelines provided on which specimen to test or ...which scoring method to use. We performed a comprehensive study evaluating the variation in Ki-67 expression in breast specimens from 50 consecutive patients who could have been eligible for abemaciclib therapy. Three pathologists with breast expertise each performed a blinded review with 3 different manual scoring methods estimated (EST), unweighted (UNW), and weighted (WT) (WT recommended by the International Ki-67 in Breast Cancer Working Group). Quantitative image analysis (QIA) using the HALO platform was also performed. Three different specimen types core needle biopsy (CNB) (n=63), resection (RES) (n=52), and axillary lymph node metastasis (ALN) (n=50) were evaluated for each patient. The average Ki-67 for all specimens was 14.68% for EST, 14.46% for UNW, 14.15% for WT, and 11.15% for QIA. For the manual methods, the range between the lowest and highest Ki-67 for each specimen between the 3 pathologists was 8.44 for EST, 5.94 for WT, and 5.93 for UNW. The WT method limited interobserver variability with ICC1=0.959 (EST ICC1=0.922 and UNW=0.949). Using the aforementioned cutoff of Ki-67 ≥20% versus <20% to determine treatment eligibility, the averaged EST method yields 20 of 50 patients (40%) who would have been treatment-eligible, versus 15 (30%) for the UNW, 17 (34%) for the WT, and 12 (24%) for the QIA. There was no statistically significant difference in Ki-67 among the 3 specimen types. The average Ki-67 difference was 4.36 for CNB vs RES, 6.95 for CNB versus ALN, and RES versus ALN (P=0.93, 0.99, and 0.94, respectively). Our study concludes that further refinement in Ki-67 scoring is advisable to reduce clinically significant variation.
Small‐cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next‐generation sequencing (NGS) and by characterizing a ...representative patient‐derived model. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. We established a patient‐derived model from one such patient (DFCI168) harboring an NRASQ61K mutation and characterized the sensitivity of this model to MEK and TORC1/2 inhibitors. Despite the clinical diagnosis of SCLC, the majority (8/11) of cases were either of nonpulmonary origin or of mixed histology and included atypical carcinoid (n = 1), mixed non‐small‐cell lung carcinoma and SCLC (n = 4), unspecified poorly differentiated carcinoma (n = 1), or small‐cell carcinoma from different origins (n = 2). RB1 and TP53 mutations were found in four and five cases, respectively. Predicted driver mutations were detected in EGFR (n = 2), NRAS (n = 1), KRAS (n = 1), BRCA1 (n = 1), and ATM (n = 1), and one case harbored a TMPRSS2‐ERG fusion. DFCI168 (NRASQ61K) exhibited marked sensitivity to MEK inhibitors in vitro and in vivo. The combination of MEK and mTORC1/2 inhibitors synergized to prevent compensatory mTOR activation, resulting in prolonged growth inhibition in this model and in three other NRAS mutant lung cancer cell lines. SCLC in never/former light smokers is rare and is potentially a distinct disease entity comprised of oncogenic driver mutation‐harboring carcinomas morphologically and/or clinically mimicking SCLC. Comprehensive pathologic review integrated with genomic profiling is critical in refining the diagnosis and in identifying potential therapeutic options.
Small‐cell lung cancer occurs infrequently in never/former light smokers. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. The majority of cases were either of nonpulmonary origin or of mixed histology. Predicted driver mutations were detected in EGFR, NRAS, KRAS, BRCA1, and ATM, and one case harbored a TMPRSS2‐ERG fusion.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets.
In this open-label, single-arm ...phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using
models edited by CRISPR-Cas9.
Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion,
, with high overexpression of the fusion partners.
encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib.
Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.
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