International Forum of Allergy & Rhinology

Computational fluid dynamics after endoscopic endonasal skull base surgery—possible empty nose syndrome in the context of middle turbinate resection

Guillermo Maza MD, Chengyu Li PhD, Jillian P. Krebs High school Diploma, Bradley A. Otto MD, Alexander A. Farag MD, Ricardo L. Carrau MD, FACS, Kai Zhao PhD

Version of Record online: 29 November 2018

Changes in the clinical and histological characteristics of Chinese chronic rhinosinusitis with nasal polyps over 11 years

Weiqing Wang MD, Yali Gao MBBS, Zhenzhen Zhu MBBS, Yang Zha MD, Xiaowei Wang MD, Fang Qi MD, Liangrui Zhou MBBS, Junyi Pang MBBS, Zhiqiang Gao MS, Wei Lv MD

Version of Record online: 29 November 2018

Impaired eating‐related quality of life in chronic rhinosinusitis

Nicholas R. Rowan MD, Zachary M. Soler MD, MSc, Kristina A. Storck MSPH, Florence Othieno MD, Kimia G. Ganjaei BA, Timothy L. Smith MD, MPH, Rodney J. Schlosser MD

Version of Record online: 28 November 2018

Patterns of olfactory dysfunction in chronic rhinosinusitis identified by hierarchical cluster analysis and machine learning algorithms

Justin C. Morse MD, Meghan H. Shilts MS, Kim A. Ely MD, Ping Li MD, Quanhu Sheng PhD, Li‐Ching Huang PhD, Todd J. Wannemuehler MD, Naweed I. Chowdhury MD, Rakesh K. Chandra MD, Suman R. Das PhD, Justin H. Turner MD, PhD

Version of Record online: 28 November 2018

Endoscopic Evaluation of the Eustachian Tube: assessment of a novel tool for grading Eustachian tube inflammation

Edward D. McCoul MD, MPH, Scott I. Mayer BS, Abtin Tabaee MD, Jeffrey C. Bedrosian MD, Michael J. Marino MD

Version of Record online: 28 November 2018

Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin‐5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps

Sarina K. Mueller MD, Angela L. Nocera MS, Simon T. Dillon PhD, Xuesong Gu PhD, Olaf Wendler PhD, Hasan H. Otu PhD, Towia A. Libermann PhD, Benjamin S. Bleier MD, FACS

Version of Record online: 28 November 2018

Induction of smell through transethmoid electrical stimulation of the olfactory bulb

Eric H. Holbrook MD, Sidharth V. Puram MD, PhD, Reiner B. See MD, Aaron G. Tripp BS, CNIM, Dinesh G. Nair M.D, M. Tech, Ph.D

Version of Record online: 27 November 2018

Autoimmune Neutropenia of Infancy,Prevalence of Pseudomonas Skin Infections

Autoimmune Neutropenia of Infancy- Unexpected Prevalence of Pseudomonas Skin Infections
http://www.bloodjournal.org/content/132/Suppl_1/4940

Nov 21st, 2018 - Background: Autoimmune neutropenia of infancy (AIN), the most frequent type of severe neutropenia in young children, occurs due to recognition of membrane antigens by anti-neutrophil antibodies, resulting in peripheral neutrophil destruction. Despite the often severe and prolonged neutropenia, serious infectious complications are less frequent in AIN compared with other etiologies of severe neu...

Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC

Purpose:

Osimertinib was initially approved for T790M-positive non–small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.

Experimental Design:

Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.

Results:

In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02).

Conclusions:

Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.

See related commentary by Devarakonda and Govindan, p. 6112.

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Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition

Purpose:

Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775.

Experimental Design:

Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E–mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines.

Results:

Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E–low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.

Conclusions: Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E–high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E–low TNBC tumors.

https://ift.tt/2PAz8Ex

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

Purpose:

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

Patients and Methods:

We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

Results:

Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had 2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 x 10⁶/kg; patients >50 kg: 0.1 to 2.5 x 10⁸ CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response.

Conclusions:

Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.

https://ift.tt/2PBBJ0Y

Kub5-HeraRPRD1B Deficiency Promotes "BRCAness" and Vulnerability to PARP Inhibition in BRCA-proficient Breast Cancers

Purpose:

Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-Hera^RPRD1B (K-H) in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy.

Experimental Design:

Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence, and Western blots. Cell survival with PARP inhibitors was evaluated through colony-forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 nonmutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action.

Results:

K-H expression loss correlates with rucaparib LD₅₀ values in a panel of BRCA1/2 nonmutated breast cancers. Mechanistically, K-H depletion promotes BRCAness, where extensive upregulation of PARP1 activity was required for the survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H reexpression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates HR by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 (CDK1).

Conclusions:

Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expand the use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis, and personalized medicine.

https://ift.tt/2PA5MpS

SLC46A3 as a Potential Predictive Biomarker for Antibody-Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads

Purpose:

Antibody–drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance.

Experimental Design:

The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in vitro models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR.

Results:

Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs.

Conclusions:

Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.

https://ift.tt/2PCYfXc