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Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS.A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed.Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS-) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23-0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18-0.72, p 0.01). PD-L1 expression was not significantly different between TLS+ and TLS- patients (p = 0.54). TMB in TLS+ was similar to that in TLS- patients (p = 0.39); however, it tended to be lower than that in TLS- especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+.TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.

Purpose: We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid). Experimental Design: Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing. Results: Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months. Conclusions: Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA. See related commentary by Jacobsen Skanderup et al., p. 1381

Purpose:We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid).Experimental Design:Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing.Results:Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months.Conclusions:Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA.See related commentary by Jacobsen Skanderup et al., p. 1381

Supplementary Figure S1. Consort diagram. Supplementary Figure S2. Frequency of the targetable gene alterations detected by plasma cfDNA sequencing (A) and tissue assay (B) in squamous cell carcinoma Supplementary Figure S3. Positive percent agreement of plasma cfDNA sequencing compared to tissue assay according to patient characteristics. PPA, positive percent agreement. Supplementary Figure S4. Positive percent agreement of plasma cfDNA sequencing compared to tissue assay according to metastatic site. PPA, positive percent agreement.

Supplementary Table S1 Patient characteristics in patients with 8 oncogene drivers and squamous cell carcinoma Supplementary Table S2 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay Supplementary Table S3 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay in patients only with brain metastasis Supplementary Table S4 Clinical outcomes of patients treated with a genotype-matched therapy who had oncogenic alterations detected by only plasma cfDNA sequencing.

Supplementary Figure from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)

Supplementary Data from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)

Supplemental Legends

Supplementary Figure S1 to S6

Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring EGFR mutations. Previous evidence suggested that subsets of preexisting resistant cells are selected by EGFR-TKI treatment, or alternatively, that diverse acquired resistance mechanisms emerge from drug-tolerant persister (DTP) cells. Many studies have used bulk tumor specimens or subcloned resistant cell lines to identify resistance mechanism. However, intratumoral heterogeneity can result in divergent responses to therapies, requiring additional approaches to reveal the complete spectrum of resistance mechanisms. Using EGFR-TKI-resistant cell models and clinical specimens, we performed single-cell RNA-seq and single-cell ATAC-seq analyses to define the transcriptional and epigenetic landscape of parental cells, DTPs, and tumor cells in a fully resistant state. In addition to AURKA, VIM, and AXL, which are all known to induce EGFR-TKI resistance, CD74 was identified as a novel gene that plays a critical role in the drug-tolerant state. In vitro and in vivo experiments demonstrated that CD74 upregulation confers resistance to the EGFR-TKI osimertinib and blocks apoptosis, enabling tumor regrowth. Overall, this study provides new insight into the mechanisms underlying resistance to EGFR-TKIs.Significance:Single-cell analyses identify diverse mechanisms of resistance as well as the state of tolerant cells that give rise to resistance to EGFR tyrosine kinase inhibitors.

Introduction: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC). Methods: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs), and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n=3). Results: Patients with high P-AMs had significantly shorter overall survival (OS) (pEx vivoBALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2, 3.0, and 10.0-fold; CCL-2: 3.0, 3.1, and 3.2-fold). Moreover, addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. Conclusion: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of peritumoral tumor microenvironment in lung SqCC progression.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25–40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1–LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1–LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1–LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1–LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1–LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1–LTK fusion as a target in NSCLC that could be treated with lorlatinib. Whole-transcriptome sequencing of a subset of 75 non-small-cell lung cancer specimens in a multi-institutional genome screening study identified a fusion of the CLIP1 and LTK genes with transformational potential due to constitutive LTK kinase activity.

Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring EGFR mutations. Previous evidence suggested that subsets of preexisting resistant cells are selected by EGFR-TKI treatment, or alternatively, that diverse acquired resistance mechanisms emerge from drug-tolerant persister (DTP) cells. Many studies have used bulk tumor specimens or subcloned resistant cell lines to identify resistance mechanism. However, intratumoral heterogeneity can result in divergent responses to therapies, requiring additional approaches to reveal the complete spectrum of resistance mechanisms. Using EGFR-TKI-resistant cell models and clinical specimens, we performed single-cell RNA-seq and single-cell ATAC-seq analyses to define the transcriptional and epigenetic landscape of parental cells, DTPs, and tumor cells in a fully resistant state. In addition to AURKA, VIM, and AXL, which are all known to induce EGFR-TKI resistance, CD74 was identified as a novel gene that plays a critical role in the drug-tolerant state. In vitro and in vivo experiments demonstrated that CD74 upregulation confers resistance to the EGFR-TKI osimertinib and blocks apoptosis, enabling tumor regrowth. Overall, this study provides new insight into the mechanisms underlying resistance to EGFR-TKIs. Significance: Single-cell analyses identify diverse mechanisms of resistance as well as the state of tolerant cells that give rise to resistance to EGFR tyrosine kinase inhibitors.

The development of immune checkpoint inhibitors (ICIs), such as anti-programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, has been a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Durvalumab, a PD-L1 inhibitor, has shown survival benefit as a maintenance therapy for patients with unresectable stage III NSCLC following definitive chemoradiotherapy, and is approved by the U.S. Food and Drug Administration and the European Medicines Agency.In this article, we review the development of durvalumab, its pharmacology, and its safety profile as a monotherapy and in combination with other agents, including epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), ICIs such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockers, and cytotoxic chemotherapy.ICIs, including durvalumab, cause unique side effects, known as immune-mediated adverse events, which are commonly manageable with standard treatment algorithms. The safety profile of durvalumab monotherapy is similar to those of other PD-1/PD-L1 inhibitors. In the PACIFIC trial, durvalumab after radiotherapy resulted in a slight increase in pulmonary toxicity, but most cases were mild. The enhanced effect of ICIs when used in combination therapies is accompanied by an increased risk of side effects. Therefore, the authors evaluated the safety profile and risk-benefit balance of durvalumab combined with various agents.

Background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)‐A, has shown efficacy in patients with advanced nonsquamous non‐small cell lung cancer (NSCLC). There are no identified or clinically validated biomarkers to determine the efficacy of bevacizumab. In this study, we assessed the adequacy of chemokine (C‐X‐C motif) ligand 16 (CXCL16) as a biomarker for patients treated with bevacizumab‐containing chemotherapy regimen. Methods Patients diagnosed histologically with NSCLC were enrolled. Serial serum CXCL16 levels during treatment were measured by enzyme‐linked immunosorbent assay. The relationship between serum CXCL16 levels before and after treatment, progression‐free survival, and overall survival were analyzed. CXCL16 and VEGF‐A expressions in lung cancer tissue were also evaluated by immunohistochemical tests. Results The median serum level of CXCL16 in these patients was 3.4 ng/mL, which was significantly higher than that in age‐matched healthy adults (2.2 ng/mL). Immunohistochemistry results showed that CXCL16 was predominantly localized in the tumor stroma, whereas VEGF was expressed in tumor cells. Including bevacizumab with chemotherapy led to lower CXCL16 levels post‐chemotherapy, which correlated with better response rates. In addition, evaluation of differences in serum CXCL16 levels before and after the first‐line chemotherapy showed that longer overall survival was achieved in patients who showed a larger decrease in serum CXCL16 levels. Conclusions According to our findings, serum CXCL16 level was identified as a potential biomarker for the efficacy of therapy, including anti‐VEGF. Key points Significant findings of the study Patients with NSCLC whose serum CXCL16 levels decreased below 0.07 ng/mL after chemotherapy, showed longer overall survival than those without this decrease. Moreover, low CXCL16 levels corresponded to better response rates among patients with advanced NSCLC treated with bevacizumab‐containing chemotherapy. What this study adds Previously there were no identifiable predictive biomarkers to determine the efficacy of bevacizumab. Data from our findings identified serum CXCL16 level as a potential biomarker for the efficacy of bevacizumab‐containing chemotherapy.

This study aimed to investigate the protective effect of the metabolites produced by a new

Identification of targetable fusions as oncogenic drivers in non-small cell lung cancer has transformed its diagnostic and therapeutic paradigm. In a recent article in Nature, Izumi et al. report the discovery of CLIP1-LTK fusion as a novel oncogenic driver in lung cancer, targetable using the ALK tyrosine kinase inhibitor lorlatinib.

Small cell lung cancer(SCLC)is one of the histological types of lung cancer showing the worst prognosis, and is often diagnosed as an inoperable advanced stage disease. Recently, several comprehensive genomic analyses for SCLC have shown that inactivating mutations of tumor suppressor genes such as TP53 and RB1 and MYC family gene amplifications are involved in the development and progression of SCLC. However, actionable gene alterations for targeted therapies have not yet been identified, and there has been no significant advance in the development of targeted therapies for SCLC. In a nationwide lung cancer genome screening project in Japan, LC‒SCRUM‒Japan, a large‒scale genomic analysis was prospectively performed for Japanese SCLC patients, and based on this genomic analysis, a clinical study to evaluate the efficacy of a targeted therapy for PI3K/AKT/mTOR pathway gene‒altered SCLC(EAGLE‒PAT trial)was conducted. In this article, we describe the results of the genomic analysis in LC‒SCRUM‒Japan and the EAGLE‒PAT trial, and also provide the overview of genetic alterations reported in SCLC and the current and future development of targeted therapies for SCLC.

Introduction: The development of immune checkpoint inhibitors (ICIs) has been a breakthrough in the treatment of several types of cancer. With the widespread use of ICIs in clinical practice, checkpoint inhibitor pneumonitis (CIP) is expected to increase and its management will pose a challenge for clinicians.Areas covered: In this article, we review the incidence, associated risk factors, radiological patterns, clinical features, and management of CIP.Expert opinion: Several clinical trials assessing the efficacy and safety of combination treatments with various drugs and ICIs have been conducted. From the results of these trials, CIP is thought to be an acceptable side effect because the frequency of its development was slightly higher during combination therapies than during ICI monotherapies. However, the risk of developing CIP associated with combinations of chemotherapy and ICIs may be higher in the real world than in clinical trials. Because combinations of chemotherapy and ICIs are associated with increased toxicity, the proper management of immune-related adverse events is necessary to maximize the efficacy of the treatment.

Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ~5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment in the advanced NSCLC setting. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in, ~10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ~225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Citation Format: Yi-Long Wu, Ji-Youn Han, Terufumi Kato, Fabrice Barlesi, Edward B. Garon, Federico Cappuzzo, Yuji Shibata, Nathalie Smith, Sadhvi Khanna, Riccardo Belli, Alejandro Yovine, Daniel Tan. Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT559.

Background: The discovery of oncogenic driver has uncovered the pathogenesis of non-small cell lung cancer (NSCLC), and development of corresponding kinase inhibitors has changed treatment strategies and improved survival of patients with druggable oncogenic drivers. However, no targeted therapies have been developed for the large proportion of advanced NSCLC. We established a multi-institutional lung cancer genome screening platform (LC-SCRUM-Asia) to identify lung cancer patients with oncogenic drivers and to clinically develop molecular-targeted therapies. Here, we apply this platform to search for novel druggable oncogenic drivers in NSCLC. Methods: We performed transcriptome sequencing of non-squamous NSCLC samples negative for known oncogenic drivers in the LC-SCRUM-Asia cohort. The presence of gene fusion was validated by RT-PCR, LTK break-apart fluorescence in situ hybridization (FISH). Sanger sequencing of gDNA and cDNA was performed to verify the breakpoint of these genes. The ability of oncogenic transformation was evaluated using NIH3T3 and Ba/F3 cell models in vitro and in vivo. The efficacy of seven compounds developed as ALK tyrosine kinase inhibitors (alectinib, brigatinib, ceritinib, crizotinib, entrectinib, lorlatinib, repotrectinib) were assessed. Results: Of consecutive 75 samples analyzed, we identified a novel in-frame fusion transcript of CLIP1 and LTK in a Japanese woman with lung adenocarcinoma. RT-PCR and LTK break apart FISH analyses confirmed the presence of LTK fusion and rearrangement, respectively, in this individual. Sanger sequencing verified the breakpoint in CLIP1 intron16 and LTK exon10, resulting in fusion sequence of CLIP1 exon16 to LTK exon11 in the expressed transcript. We show that kinase activity of CLIP1-LTK fusion protein is constitutively activated, along with phosphorylation of AKT and ERK, downstream of CLIP1-LTK, and has transformation potential dependent on LTK kinase activity. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited phosphorylation of CLIP1-LTK, AKT, and ERK, suppressed proliferation, and induced apoptosis. Conclusion: We identified the CLIP1-LTK fusion as a novel oncogenic driver in NSCLC, and the fusion protein can be targeted by lorlatinib. Urgent clinical development of molecular targeted agents and companion diagnostics for this new oncogenic driver are now warranted. Citation Format: Hiroki Izumi, Shingo Matsumoto, Jie Liu, Kosuke Tanaka, Shunta Mori, Shogo Kumagai, Takuma Hayashida, Yuji Shibata, Saori Takata, Eriko Tabata, Haruyasu Murakami, Reiko Taki, Satoshi Hara, Tomohiro Sakamoto, Koichi Goto, Susumu S. Kobayashi. CLIP1-LTK: A novel druggable gene fusion in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5238.

Background: CLIP1-LTK was recently discovered as a novel oncogenic gene fusion in non-small cell lung cancer (NSCLC). Lorlatinib, an ALK/ROS1 inhibitor, can inhibit CLIP1-LTK constitutive kinase activity, and showed dramatic and promising efficacy in a patient with NSCLC harboring CLIP1-LTK fusion. However, acquired resistance to lorlatinib will be inevitably developed, especially by mutations in LTK gene, as 50-60% of oncogenic driver-positive NSCLC develop resistance to kinase inhibitors by acquired mutations in the target gene. The aim of this study is to identify the LTK mutations responsible for resistance to lorlatinib in CLIP1-LTK fusion positive NSCLC, and to explore compounds that can overcome resistance. Methods: As LTK and ALK share nearly 80% protein sequence identity in their respective kinase domains, we established Ba/F3 cells expressing CLIP1-LTK (Ba/F3-CLIP1-LTK) with six different LTK mutations (I565N, F568C, L590M, L592F, G596R, and G663A), all of which are analogous to reported ALK mutations responsible for resistance to lorlatinib. Ba/F3 cells expressing CLIP1-LTK with these different LTK mutations, as well as CLIP1-LTK-wild type (WT) were treated with several concentrations of lorlatinib. Then, the efficacy of other compounds including crizotinib, alectinib, ceritinib, brigatinib, entrectinib, giltertinib, repotorectinib was assessed to detect which compounds can overcome lorlatinib resistance. Results: All LTK mutations tested showed resistance to lorlatinib, with IC50s of lorlatinib ranging 2.7 to 31.3 nM, which were higher than that in Ba/F3-CLIP-LTK-WT (1.0 nM) in cell viability assay. An IC50 of giltertinib in Ba/F3-CLIP1-LTK-F568C was lower than that of lorlatinib (0.9 vs 2.7 nM). Moreover, an IC50 of giltertinib in Ba/F3-CLIP1-LTK-G663A was lower than that of lorlatinib (2.7 vs 19.4 nM). Ba/F3-CLIP1-LTK-L592F was rather sensitive to crizotinib compared with Ba/F3-CLIP1-LTK-WT (IC50, Conclusion: We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC. Citation Format: Shunta Mori, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa, Yuji Shibata, Shingo Matumoto, Koichi Goto, Susumu Kobayashi. LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5351.

9103 Background: Osimertinib is a standard drug for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR mutations (mt). While tumor mutational burden (TMB)-high and co-occurring genetic alterations (alt) have been reported to be negatively associated with the efficacy of other EGFR-TKIs, the impact of co-occurring genetic alt with EGFR major mt on the efficacy of osimertinib remains unclear. Methods: In a multi-institutional genomic screening project (LC-SCRUM-Asia), we have analyzed lung cancer patients for genomic alt by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay and Genexus/OPA. We retrospectively evaluated the association between the genomic profile and efficacy of first-line osimertinib for EGFR-mutated NSCLC based on the LC-SCRUM-Asia database. Results: Between March 2015 and January 2022, 12,705 NSCLC patients were enrolled in the LC-SCRUM-Asia database, and EGFR mt was detected in 2,232 patients. Of these, 324 patients, including 171 with ex19del (53%) and 153 with L858R (47%), received first-line treatment with osimertinib. The patient characteristics were as follows: median age, 69 years (range 31-97); females, 64%; never-smokers, 57%; adenocarcinoma, 97%; and performance status 0-1, 99%. The frequency of compound EGFR mt and TMB were higher in the L858R (LR) group than in the ex19del (Ex19) group (compound mt (%), 12 vs. 4; mean TMB (mt/Mb), 3.4 vs. 2.5). There were no differences in the frequencies of other co-occurring genetic alt between the two groups. Higher TMB, alt of genes encoding receptor tyrosine kinase (RTK), including FGFR1, RET, MET etc., and amp of cell-cycle related genes were significantly associated with shorter progression-free survival (PFS) in the entire group (median PFS: TMB > 3 vs. ≤3 mt/Mb = 11.4 vs. 17.1 months; p = 0.023; RTK gene alt+ vs. alt- = 9.7 vs. 15.2 months; p = 0.014; cell-cycle gene amp+ vs. amp- = 10.6 vs. 15.6 months, p = 0.001). EGFR subgroup analysis showed that a higher TMB was significantly associated with a shorter PFS in the LR group (> 3 vs. ≤3 mt/Mb = 10.0 vs. 17.1 months, p < 0.001), but not in the Ex19 group. On the other hand, alt of genes encoding RTK and amp of cell-cycle related genes were significantly associated with a shorter PFS in the Ex19 group (RTK gene alt+ vs. alt- = 8.4 vs. 17.8 months, p = 0.008; cell-cycle gene amp+ vs. amp- = 10.6 vs. 17.5 months, p = 0.003), but not in the LR group. Multivariate analysis identified RTK gene alt in the Ex19 group and higher TMB in the LR group as being independently associated with a shorter PFS. Conclusions: First-line osimertinib treatment was less effective in NSCLC patients harboring Ex19 with other RTK gene alt or LR with a higher TMB, indicating that co-occurring genetic alt affecting the efficacy of osimertinib differ between NSCLC patients harboring Ex19 and LR.

TPS9153 Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ̃5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in about ten countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment for advanced NSCLC. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in,̃10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ̃225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Clinical trial information: NCT04816214.

This study aimed to investigate whether intravoxel incoherent motion (IVIM) parameters can identify ischemic changes in the rat cerebral cortex using a preclinical ultra-high-field 11.7 Tesla magnetic resonance imaging (11.7TMRI) scanner. In nine female Wistar rats (eight weeks old), diffusion-weighted imaging (DWI) for IVIM analysis was successfully performed before (Pre) and after unilateral (UCCAO) and bilateral (BCCAO) common carotid artery occlusion. From the acquired DWI signals averaged in six regions of interest (ROI) placed on the cortex, volume fraction of perfusion compartment (F), pseudo diffusion coefficient (D*), F × D* and apparent diffusion coefficient (ADC) were determined as IVIM parameters in the following three DWI signal models: the bi-exponential, kurtosis, and tri-exponential model. For a subgroup analysis, four rats that survived two weeks after BCCAO were assigned to the long survival (LS) group, whereas the non-LS group consisted of the remaining five animals. Each IVIM parameter change among three phases (Pre, UCCAO and BCCAO) was statistically examined in each ROI. Then, the change in each rat group was also examined for subgroup analysis. All three models were able to identify cerebral ischemic change and damage as IVIM parameter change among three phases. Furthermore, the kurtosis model could identify the parameter changes in more regions than the other two models. In the subgroup analysis with the kurtosis model, ADC in non-LS group significantly decreased between UCCAO and BCCAO but not in LS group. IVIM parameters at 11.7TMRI may help us to detect the subtle ischemic change; in particular, with the kurtosis model.

Many studies about anticoagulant therapy for disseminated intravascular coagulation (DIC) confused gastrointestinal surgery-related DIC with DIC unrelated to a prior operation. Furthermore, the potentially increased risk of bleeding by anticoagulants complicates their use. We carried out a systematic review to describe the efficacy and safety of anticoagulant agents for DIC after gastrointestinal surgery. Several studies have indicated that gabexate mesylate improves DIC score without increasing bleeding events, and that antithrombin is associated with lower mortality of DIC after gastrointestinal surgery. Recombinant thrombomodulin has been the most frequently analyzed anticoagulant agent in this field. DIC score and survival rate were better in patients treated with recombinant thrombomodulin, without increasing bleeding events. In conclusion, anticoagulant therapy may be effective and safe in DIC after gastrointestinal surgery.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.

Objective This retrospective cohort study investigated whether the three components of the blood cell count have prognostic implications in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis. Methods We reviewed patients who were treated by the isoniazid, rifampicin, pyrazinamide, and ethambutol regimen or by the isoniazid, rifampicin, and ethambutol regimen. The association between the patient data on admission and the survival outcome was evaluated. Results We reviewed 367 consecutive patients (male, 60.5%) with a median age of 72 [interquartile range (IQR), 54-82] years. While the white blood cell count did not differ between the two groups, (discharged alive: 7,000/μL; IQR, 5,500-9,300; died in hospital: 7,200/μL; IQR, 5,600-9,400; p=0.797), hemoglobin level (discharged alive: 11.5 g/dL; IQR, 10.0-13.1; died in hospital: 9.9 g/dL; IQR, 8.6-11.3; p

Objectives To compare the effectiveness and safety of antipseudomonal β-lactam empiric monotherapy for febrile neutropenia by network meta-analysis. Methods Searches using Pubmed, Cochrane CENTRAL, EMBASE and Web of Science Core Collection were carried out in June 2016. English articles, non-English articles, full-length articles, short articles and conference abstracts were allowed. Eligible trial design was a parallel-group individual randomization. We included febrile neutropenia adult and paediatric patients undergoing chemotherapy for either solid tumours or haematological malignancies and treated with intravenous antipseudomonal β-lactams for initial empiric therapy. Protocol was registered with PROSPERO ID 42016043377. Results Of 1275 articles detected by the search, 50 studies with 10 872 patients were finally included. Among the guideline-recommended cefepime, meropenem, imipenem/cilastatin, piperacillin/tazobactam and ceftazidime; imipenem/cilastatin showed the highest odds of treatment success without modification, which was the primary endpoint, based on the random-effect model network analysis. Ceftazidime was related to lower treatment success rate without modification compared with imipenem/cilastatin with OR of 0.71 (95% CI 0.57–0.89, p 0.006). Imipenem/cilastatin showed the lowest odds of all-cause death. Patients treated with cefepime had higher risk for all-cause death compared with those treated with imipenem/cilastatin (OR 2.05, 95% CI 1.11–3.78, p 0.029). Any adverse event was significantly more prevalent in the imipenem/cilastatin arm; however, there was no difference concerning adverse events leading to discontinuation. Conclusions Imipenem/cilastatin, piperacillin/tazobactam and meropenem may be reasonable first-choice medications for empiric therapy of febrile neutropenia.

Objective Onodera's Prognostic Nutritional Index (PNI), determined as "10× albumin (g/dL) + 0.005× lymphocyte count (/μL)," was originally designed to determine the risk of complications following gastrointestinal surgery. This single-center, retrospective observational study was designed to investigate whether or not the PNI can predict the treatment outcome. Methods We consecutively reviewed HIV-negative pulmonary tuberculosis adults in an isolation ward. Most patients were being treated with standard three- or four-drug regimens. Patients were discharged after consecutive negative smears/cultures were confirmed. The risk of all-cause death was assessed using a multivariable Cox proportional hazard model and a log-rank trend test. Results During the observation period, we observed 371 consecutive patients with a median age of 72 (interquartile range [IQR]: 54-82) years. In our cohort, 295 (79.5%) patients were discharged alive, and 76 (20.5%) died in-hospital. Patients who died in-hospital had a lower PNI [median 21.2 (IQR: 18.5-25.9)] than those who were discharged alive [median 35.1 (IQR: 28.0-43.3); p

BackgroundSuccessful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. We investigated the ameliorative effects of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR-3) signalling in macrophages in lipopolysaccharide (LPS)-induced lung injury.MethodsLPS was intranasally injected into wild-type and transgenic mice. Gain and loss of VEGF-C/VEGFR-3 signalling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3 (sVEGFR-3) or anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells.ResultsThe early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage (BAL) fluid interleukin-10 (IL-10), but worsened in the later phase by VEGFR-3 inhibition upon administration of Ad-sVEGFR-3 vector. Injection of anti-VEGFR-3 antibodies to mice in the resolution phase inhibited recovery from lung injury. The VEGFR-3-deleted mice had a shorter survival time than littermates and more severe lung injury in the resolution phase. Alveolar macrophages in the resolution phase digested most of the extrinsic apoptotic neutrophils and VEGF-C/VEGFR-3 signalling increased efferocytosisviaupregulation of integrin αvin the macrophages. We also found that incubation with BAL fluid from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreased VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages.ConclusionsVEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution.

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.

Acute aortic syndrome (AAS), a potentially fatal pathologic process within the aortic wall, should be suspected in patients presenting with severe thoracic pain and hypertension. AAS, including aortic dissection (approximately 90% of cases) and intramural hematoma, may be complicated by poor perfusion, aneurysm, or uncontrollable pain and hypertension. AAS is uncommon (approximately 3.5-6.0 per 100,000 patient-years) but rapid diagnosis is imperative as an emergency surgical procedure is frequently necessary.To systematically review the current evidence on diagnosis and treatment of AAS.Searches of MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials for articles on diagnosis and treatment of AAS from June 1994 to January 29, 2016, were performed. Only clinical trials and prospective observational studies of 10 or more patients were included. Eighty-two studies (2 randomized clinical trials and 80 observational) describing 57,311 patients were reviewed.Chest or back pain was the most commonly reported presenting symptom of AAS (61.6%-84.8%). Patients were typically aged 60 to 70 years, male (50%-81%), and had hypertension (45%-100%). Sensitivities of computerized tomography and magnetic resonance imaging for diagnosis of AAS were 100% and 95% to 100%, respectively. Transesophageal echocardiography was 86% to 100% sensitive, whereas D-dimer was 51.7% to 100% sensitive and 32.8% to 89.2% specific among 6 studies (n = 876). An immediate open surgical procedure is needed for dissection of the ascending aorta, given the high mortality (26%-58%) and proximity to the aortic valve and great vessels (with potential for dissection complications such as tamponade). An RCT comparing endovascular surgical procedure to medical management for uncomplicated AAS in the descending aorta (n = 61) revealed no dissection-related deaths in either group. Endovascular surgical procedure was better than medical treatment (97% vs 43%, P .001) for the primary end point of "favorable aortic remodeling" (false lumen thrombosis and no aortic dilation or rupture). The remaining evidence on therapies was observational, introducing significant selection bias.Because of the high mortality rate, AAS should be considered and diagnosed promptly in patients presenting with acute chest or back pain and high blood pressure. Computerized tomography, magnetic resonance imaging, and transesophageal echocardiography are reliable tools for diagnosing AAS. Available data suggest that open surgical repair is optimal for treating type A (ascending aorta) AAS, whereas thoracic endovascular aortic repair may be optimal for treating type B (descending aorta) AAS. However, evidence is limited by the paucity of randomized trials.

Platinum regimens still play a key role in chemotherapy for incurable non-small cell lung cancer (NSCLC). Although guidelines list many platina regimens, the best regimens have not yet clarified. Electronic searches were carried out during November 26th-28th, 2016. We included individually randomized trials comparing two or more platinum regimes for incurable chemo-naive NSCLC published in English full papers. The platinum doublets should be either Cisplatin (CDDP), Carboplatin (CBDCA), or Nedaplatin (CDGP) plus one of the third-generation agents. The platinum triplet should be the doublet plus bevacizumab (BEV). The data were independently extracted and cross-checked by two investigators. We did not observed heterogeneity (whole network level Q = 28.9, df = 34, P = 0.717) among 59 pairwise comparisons from 45 studies with 16141 cases for the primary outcome, hazard ratio for overall survival (HRos). Using CBDCA + Paclitaxel (PTX) + BEV as a common comparator, CDGP + Docetaxel (DTX) (HRos = 0.98, 95%CI: 0.75–1.29, P = 0.884), CDDP + Tegafur gimeracil oteracil (S1) (HRos = 1.23, 95%CI: 0.96–1.57, P = 0.099), CBDCA + S1 (HRos = 1.23, 95%CI: 0.99–1.53, P = 0.062), and CDGP + Gemcitabine (GEM) (HRos = 1.24, 95%CI: 0.71–2.17, P = 0.45) did not have significantly poorer HRos. We suggest that these regimens as acceptable first-choice regimens.

We conducted a single-center retrospective cohort study to evaluate whether the HbA1c level on admission could predict the in-hospital treatment outcome of smear-positive non-multi-drug-resistant HIV-negative culture-proven pulmonary tuberculosis inpatients. Our standard regimens under the direct observation were HRZE or HRE for the first two months followed by combination therapy with isoniazid and rifampicin. Our cohort consisted of consecutive 239 patients consisted of 147 men and 92 women with a median age of 73 years. The HbA1c level of patients whose HbA1c was above 7.0% on admission showed clear declining trends after admission. HbA1c on admission had no Spearman’s rank correlation with time to discharge alive (r = 0.17) and time to becoming non-infective (r = 0.17). By Kaplan-Meier curves and a log-rank trend test, HbA1c quartile subgroups showed no association with times to discharge alive (p = 0.431), becoming non-infective (p = 0.113), and in-hospital death (p = 0.427). Based on multi-variate Cox analysis, HbA1c on admission had no significant impact on time to discharge alive (hazard ratio = 1.03, 95% CI 0.89–1.20, p = 0.659), becoming non-infective (hazard ratio = 0.93, 95% CI 0.80–1.06, p = 0.277), and in-hospital death (hazard ratio = 0.68, 0.43–1.07, p = 0.097). In conclusion, the HbA1c level on admission did not seem to affect in-hospital tuberculosis treatment outcomes in Japanese cohort.