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Background: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. Objective: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups. Results: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6–9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7–3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3–Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9–15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis. Conclusions: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. Objective: The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. Patients and Methods: A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. Results: The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50–89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. Conclusions: In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy. [ABSTRACT FROM AUTHOR]

Background: Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant NSCLC and osimertinib resistance has not yet been fully evaluated. Objective: We aimed to conduct a prospective multicenter observational study to evaluate the efficacy and safety of 1G and 2G EGFR-TKIs after the development of osimertinib resistance. Methods: Patients with EGFR-mutant NSCLC who received 1G or 2G EGFR-TKIs after developing resistance to osimertinib monotherapy were prospectively assessed at eight institutions in Japan. The primary endpoint was progression-free survival (PFS). Results: A total of 29 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. The objective response and disease control rates were 6.9% (2/29) and 58.6% (17/29), respectively. The median PFS was 1.9 months [95% confidence interval (CI): 1.3–5.3]. There was no significant difference in PFS between the 1G and 2G EGFR-TKI groups (3.7 versus 1.5 months, log-rank test p = 0.20). However, patients with normal cytokeratin 19 fragment (CYFRA 21-1) and pro-gastrin-releasing peptide (ProGRP) levels experienced longer PFS than those with elevated CYFRA 21-1 and/or ProGRP (5.5 versus 1.3 months, log-rank test p < 0.001). Conclusion: Administration of 1G or 2G EGFR-TKIs after the development of osimertinib resistance has limited efficacy in patients with EGFR-mutant NSCLC. Moreover, normal CYFRA 21-1 and ProGRP levels could be promising indicators for 1G and 2G EGFR-TKI administration after osimertinib resistance development. Trial Registration Number: UMIN000044049. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum–etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age. Objective: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L1 inhibitor plus platinum–etoposide chemotherapy as first-line therapy. Patients and Methods: Between September 2019 and October 2021, we prospectively evaluated patients with ES-SCLC treated with immunochemotherapy at ten institutions in Japan. The G8 score was assessed before treatment initiation. Results: We evaluated 44 patients with ES-SCLC. Patients with G8 score > 11 had longer overall survival (OS) than those with G8 score ≤ 11 (not reached versus 8.3 months; log-rank test, p = 0.005). In univariate and multivariate analyses, G8 score > 11 [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.15–0.75; p = 0.008 and HR 0.34; 95% CI 0.14–0.82; p = 0.02, respectively) and performance status (PS) of 2 (HR 5.42; 95% CI 2.08–14.2; p < 0.001 and HR 6.94; 95% CI 2.25–21.4; p < 0.001, respectively) were independent prognostic factors for OS. Among patients with good PS (0 or 1), the OS in patients with G8 score > 11 was significantly longer than that in patients with G8 score ≤ 11 (not reached versus 12.3 months; log-rank test, p = 0.02). Conclusions: G8 score evaluation before treatment initiation was useful as a prognostic factor for ES-SCLC patients who received PD-L1 inhibitors and platinum–etoposide chemotherapy, even with good PS. [ABSTRACT FROM AUTHOR]

Background: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. Methods: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. Results: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). Conclusion: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. Methods: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. Results: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). Conclusion: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this study was to identify the potential predictors to assess the impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods: We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at 8 hospitals in Japan between January 2019 and December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results: Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents, whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas, among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions: This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy. Methods: We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy. Results: On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38–3.37, p < 0.001 and HR 2.32, 95% confidence interval: 1.40–3.84, p = 0.001, respectively). There was no obvious difference in PFS between the group in which induction chemotherapy ended in two or three courses leading to partial or complete response, and the group that continued at least four courses of induction chemotherapy (log-rank test p = 0.53). Conclusion: Treatment efficacy may be maintained if induction chemotherapy is completed in less than four courses owing to development of AEs, and is administered for more than two courses with partial or complete response; efficacy is maintained even on transitioning to maintenance therapy. [ABSTRACT FROM AUTHOR]

Combined immunotherapy and chemotherapy is a promising standard treatment in patients with advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the relationship between the combined therapy and pretreatment serum antinuclear antibody (ANA) levels as a prognostic indicator in patients with NSCLC. We retrospectively analyzed patients with advanced NSCLC who were treated with combinatorial immunotherapy and chemotherapy between January and December 2019 at six institutions in Japan. Relationship between ANA status and patients' characteristics were reviewed. A total of 77 patients with advanced NSCLC were enrolled in the study. Patients were divided into ANA-positive (ANA ≥ 1:160) and ANA-negative (ANA < 1:160) groups. The ANA-positive group tended to have a shorter progression-free survival and significantly shorter overall survival in univariate (hazard ratio [HR], 2.11, 95% confidence interval [CI] 0.88–5.07, p = 0.093; and HR 3.11, 95% CI 1.14–8.49, p = 0.027, respectively) and multivariate (HR 1.90, 95% CI 0.77–4.68, p = 0.16; and HR 3.37, 95% CI 1.15–9.86, p = 0.027, respectively) analyses than ANA-negative group. The incidence of discontinuation of all treatment components due to severe adverse events was significantly higher in the ANA-positive than in ANA-negative group (50% vs. 15.9%, p = 0.042). The study showed that the presence of antinuclear antibodies may result in a poor prognosis in patients treated with combinatorial immunotherapy and chemotherapy, although further prospective investigations are needed. [ABSTRACT FROM AUTHOR]

L-Ribose isomerase from Cellulomonas parahominis MB426 (CpL-RI) can catalyze the isomerization between L-ribose and L-ribulose, which are non-abundant in nature and called rare sugars. CpL-RI has a broad substrate specificity and can catalyze the isomerization between D-lyxose and D-xylulose, D-talose and D-tagatose, L-allose and L-psicose, L-gulose and L-sorbose, and D-mannose and D-fructose. To elucidate the molecular basis underlying the substrate recognition mechanism of CpL-RI, the crystal structures of CpL-RI alone and in complexes with L-ribose, L-allose, and L-psicose were determined. The structure of CpL-RI was very similar to that of L-ribose isomerase from Acinetobacter sp. strain DL-28, previously determined by us. CpL-RI had a cupin-type β-barrel structure, and the catalytic site was detected between two large β-sheets with a bound metal ion. The bound substrates coordinated to the metal ion, and Glu113 and Glu204 were shown to act as acid/base catalysts in the catalytic reaction via a cis-enediol intermediate. Glu211 and Arg243 were found to be responsible for the recognition of substrates with various configurations at 4- and 5-positions of sugar. CpL-RI formed a homo-tetramer in crystals, and the catalytic site independently consisted of residues within a subunit, suggesting that the catalytic site acted independently. Crystal structure and site-direct mutagenesis analyses showed that the tetramer structure is essential for the enzyme activity and that each subunit of CpL-RI could be structurally stabilized by intermolecular contacts with other subunits. The results of growth complementation assays suggest that CpL-RI is involved in a novel metabolic pathway using L-ribose as a carbon source. [ABSTRACT FROM AUTHOR]

The l-rhamnose isomerase gene ( L -rhi) encoding for l-rhamnose isomerase ( l-RhI) from Bacillus pallidus Y25, a facultative thermophilic bacterium, was cloned and overexpressed in Escherichia coli with a cooperation of the 6×His sequence at a C-terminal of the protein. The open reading frame of L -rhi consisted of 1,236 nucleotides encoding 412 amino acid residues with a calculated molecular mass of 47,636 Da, showing a good agreement with the native enzyme. Mass-produced l-RhI was achieved in a large quantity (470 mg/l broth) as a soluble protein. The recombinant enzyme was purified to homogeneity by a single step purification using a Ni-NTA affinity column chromatography. The purified recombinant l-RhI exhibited maximum activity at 65°C (pH 7.0) under assay conditions, while 90% of the initial enzyme activity could be retained after incubation at 60°C for 60 min. The apparent affinity ( K m) and catalytic efficiency ( k cat/ K m) for l-rhamnose (at 65°C) were 4.89 mM and 8.36 × 105 M−1 min−1, respectively. The enzyme demonstrated relatively low levels of amino acid sequence similarity (42 and 12%), higher thermostability, and different substrate specificity to those of E. coli and Pseudomonas stutzeri, respectively. The enzyme has a good catalyzing activity at 50°C, for d-allose, l-mannose, d-ribulose, and l-talose from d-psicose, l-fructose, d-ribose and l-tagatose with a conversion yield of 35, 25, 16 and 10%, respectively, without a contamination of by-products. These findings indicated that the recombinant l-RhI from B. pallidus is appropriate for use as a new source of rare sugar producing enzyme on a mass scale production. [ABSTRACT FROM AUTHOR]

A novel chitinase gene chiC of Clostridium paraputrificum M-21, a chitinolytic and hydrogen-gas-producing bacterium, was characterized along with its translated product. The chi18C gene encodes 683 amino acids (signal peptide included) with a deduced molecular weight of 74,651. Chi18C is a modular enzyme composed of a family-18 catalytic module of glycoside hydrolases, two reiterated modules of unknown function, and a family-12 carbohydrate-binding module. Recombinant Chi18C was active toward soluble and insoluble chitin preparations, and synthetic substrates such as 4-methylumbelliferyl-β- d- N-N′ -N″-triacetylchitotriose, but not active toward 4-MU- N-acetylglucosamine or 4-MU-β- d- N-N′-diacetylchitobioside. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunological analyses suggested that the expression of chi18C was inducible with chitinous substrates and that Chi18C was secreted into the culture medium. A possible role of Chi18C in the chitinolytic system of C. paraputrificum M-21 is discussed. [ABSTRACT FROM AUTHOR]

We analyzed the sugar components of the glycoprotein fractions in human middle ear fluid samples by using gas chromatography. All ear effusions included serous, seromucinous and mucoid samples, and contained appreciable amounts of fucose, mannose, galactose, glucose, N-acetyl glucosamine and sialic acid. Total sugar content to protein was significantly higher in mucoid effusions than in serous effusions. Among the sugar components, the contents of sialic acid, N-acetyl glucosamine, fucose and galactose were much higher in the mucoid effusions. The data show new evidence that some glycoproteins having high proportions of sialic acid, N-acetyl glucosamine, fucose and galactose appear in the middle ear fluid of the glue ear. [ABSTRACT FROM AUTHOR]

Amino acid transport in human tonsillar lymphocytes was investigated in 32 patients of various ages and with different tonsillar diseases. Tonsillar lymphocytes appeared to possess at least four different transport systems for neutral amino acids including the activated Na-dependent A system transport. The transport activity of neutral amino acid was significantly higher in child cases than in adult cases. In adult cases with focal tonsillitis, tonsillar lymphocytes were taken from patients with rheumatoid arthritis (RA) and skin diseases as secondary lesions who showed good improvement of the skin lesions after tonsillectomy. These lymphocytes were revealed to have more activated Na-dependent transport than those from patients with skin diseases who showed poor improvement of the skin lesions after the tonsillectomy, and those from patients with recurrent tonsillitis. The characteristics of amino acid transport in human tonsillar lymphocytes and changes influenced by age and tonsillar diseases are discussed. [ABSTRACT FROM AUTHOR]