Topological enhancement of non-normality in non-Hermitian skin effects

The non-Hermitian skin effects are representative phenomena intrinsic to non-Hermitian systems: the energy spectra and eigenstates under the open boundary condition (OBC) drastically differ from those under the periodic boundary condition (PBC). Whereas a non-trivial topology under the PBC characterizes the non-Hermitian skin effects, their proper measure under the OBC has not been clarified yet. This paper reveals that topological enhancement of non-normality under the OBC accurately quantifies the non-Hermitian skin effects. Correspondingly to spectrum and state changes of the skin effects, we introduce two scalar measures of non-normality and argue that the non-Hermitian skin effects enhance both macroscopically under the OBC. We also show that the enhanced non-normality correctly describes phase transitions causing the non-Hermitian skin effects and reveals the absence of non-Hermitian skin effects protected by average symmetry. The topological enhancement of non-normality governs the perturbation sensitivity of the OBC spectra and the anomalous time-evolution dynamics through the Bauer-Fike theorem.Comment: 33 pages, 14 figure

第768回千葉医学会例会・第3回磯野外科例会 83.

Chest computed tomography of DMM lesions of Case 4. Figure-path-case-4 (a) Low-power image of case 4. (b) High-power image of case 4. (ZIP 7796 kb

Analysis of DOC and Ram for NSCLC

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients

Treatment Strategies for Non-Small Cell Lung Cancer Harboring Common and Uncommon EGFR Mutations: Drug Sensitivity Based on Exon Classification, and Structure-Function Analysis

The identification of epidermal growth factor receptor (EGFR) mutations and development of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon 21 L858R substitutions, which comprise the majority of common EGFR mutations, are predictors of good sensitivity to EGFR-TKIs. However, not all cancers harboring EGFR mutations are sensitive to EGFR-TKIs. Most patients harboring uncommon EGFR mutations demonstrate a poorer clinical response than those harboring common EGFR mutations. For example, cancers harboring exon 20 insertions, which represent approximately 4–12% of EGFR mutations, are generally insensitive to first- and second-generation EGFR-TKIs. Although understanding the biology of uncommon EGFR mutations is essential for developing treatment strategies, there is little clinical data because of their rarity. Moreover, clarifying the acquired resistance of EGFR-mutated NSCLC may lead to more precise treatments. Sequencing and structure-based analyses of EGFRmutated NSCLC have revealed resistance mechanisms and drug sensitivity. In this review, we discuss the strategies in development for treating NSCLC harboring common and uncommon EGFR mutations. We will also focus on EGFR-TKI sensitivity in patients harboring EGFR mutations based on the structural features

Re-challenging immune checkpoint inhibitor in a patient with advanced non-small cell lung cancer: a case report

Abstract Background Currently, immune checkpoint (ICP) inhibitors are essential drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICP inhibitors, the efficacy and safety of re-challenging the same or another ICP inhibitor remain unclear. Case presentation We present the case of a patient treated with nivolumab for advanced NSCLC who was previously treated with an ICP inhibitor as the first-line chemotherapy along with heavy cytotoxic chemotherapy. After the failure of five lines of chemotherapy, 3 cycles of nivolumab, as the ICP inhibitor re-challenge, the patient achieved a partial response. Conclusions This case might suggest that re-challenging an ICP inhibitor could be clinically active in selected patients with advanced NSCLC who progress after achieving an initial clinical benefit with an ICP inhibitor

Molecular and Morphological Profiling of Lung Cancer: A Foundation for “Next-Generation” Pathologists and Oncologists

The pathological diagnosis of lung cancer has largely been based on the morphological features observed microscopically. Recent innovations in molecular and genetic technology enable us to compare conventional histological classifications, protein expression status, and gene abnormalities. The introduction of The Cancer Genome Atlas (TCGA) project along with the widespread use of the next-generation sequencer (NGS) have facilitated access to enormous data regarding the molecular profiles of lung cancer. The World Health Organization classification of lung cancer, which was revised in 2015, is based on this progress in molecular pathology; moreover, immunohistochemistry has come to play a larger role in diagnosis. In this article, we focused on genetic and epigenetic abnormalities in non-small cell carcinoma (adenocarcinoma and squamous cell carcinoma), neuroendocrine tumor (including carcinoids, small cell carcinoma, and large cell neuroendocrine carcinoma), and carcinoma with rare histological subtypes. In addition, we summarize the therapeutic targeted reagents that are currently available and undergoing clinical trials. A good understanding of the morphological and molecular profiles will be necessary in routine practice when the NGS platform is widely used