Yes-associated protein 1 mediates initial cell survival during lorlatinib treatment through AKT signaling in ROS1-rearranged lung cancer.

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

Relapsing polychondritis after treatment with PD-1 blockade.

Nivolumab, a programmed death 1 blockade drug, is used in various types of cancers and can cause a unique immune-related adverse event (irAE). Relapsing polychondritis (RP) is a rare autoimmune disease that mainly involves inflammation of the auricle, nose and airway cartilage. A 72-year-old man with mandibular cancer received nivolumab after surgery for the primary lesion and radiation therapy for lung metastases. He then developed radiation pneumonitis, and prednisolone (PSL) was started. During the tapering of PSL, he developed exertional dyspnea and cough. The condition of mandibular cancer and radiation pneumonitis had not deteriorated. Fluorodeoxyglucose (FDG)-PET/CT showed a thickening of and abnormal FDG uptake in the tracheobronchial and nasal septum cartilage. These characteristic findings were not observed before nivolumab was initiated; thus, we clinically diagnosed the patient as having RP induced by nivolumab. Since the symptoms were mild, the patient's condition was carefully managed with inhaled corticosteroids, and the RP has not progressed thus far. Physicians should be aware that RP can occur as an irAE because RP may progress to serious respiratory symptoms.

Hydro-dispersion of subincisional cortex.

BACKGROUND: A simple technique to facilitate removal of subincisional cortex in cataract surgery is presented. METHODS: A disposable 27-gauge blunt needle attached to a 5.0-ml syringe containing balanced salt solution (BSS) is introduced through the side port incision into the anterior chamber. The tip of the needle is directed toward the capsule fornix beneath the incision site, and BSS is flushed to disperse the remaining cortex. Thereafter, the coaxial irrigation/aspiration device is used to remove the loosened cortex. RESULTS: This technique was used in 60 eyes of 60 patients with difficulty of removing cortical remnant in the subincisional space. Subincisional cortical material was successfully removed in 93.3% (56/60 eyes). There were no intraoperative and postoperative complications related to this procedure. CONCLUSIONS: The hydro-dispersion technique is a simple and safe approach to remove the subincisional cortical material that is difficult to manage with the standard coaxial irrigation/aspiration device.

Structurally different lysophosphatidylethanolamine species stimulate neurite outgrowth in cultured cortical neurons via distinct G-protein-coupled receptors and signaling cascades.

Neurite outgrowth is important in neuronal circuit formation and functions, and for regeneration of neuronal networks following trauma and disease in the brain. Thus, identification and characterization of the molecules that regulate neurite outgrowth are essential for understanding how brain circuits form and function and for the development of treatment of neurological disorders. In this study, we found that structurally different lysophosphatidylethanolamine (LPE) species, palmitoyl-LPE (16:0 LPE) and stearoyl-LPE (18:0 LPE), stimulate neurite growth in cultured cortical neurons. Interestingly, YM-254890, an inhibitor of Gq/11 protein, inhibited 16:0 LPE-stimulated neurite outgrowth but not 18:0 LPE-stimulated neurite outgrowth. In contrast, pertussis toxin, an inhibitor of Gi/Go proteins, inhibited 18:0 LPE-stimulated neurite outgrowth but not 16:0 LPE-stimulated neurite outgrowth. The effects of protein kinase C inhibitors on neurite outgrowth were also different. In addition, both 16:0 LPE and 18:0 LPE activate mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2, but the effect of the MAPK inhibitor differed between the 16:0 LPE- and 18:0 LPE-treated cultures. Collectively, the results suggest that the structurally different LPE species, 16:0 LPE and 18:0 LPE stimulate neurite outgrowth through distinct signaling cascades in cultured cortical neurons and that distinct G protein-coupled receptors are involved in these processes.

Management and Outcomes of Newly Diagnosed Non-Small Cell Lung Cancer Patients with Brain Metastases: A Real-World Study in Japan.

BACKGROUND: Brain metastases (BM) are one of the strongest negative prognostic factors in patients with non-small cell lung cancer (NSCLC). Molecularly targeted agents are standard of care for NSCLC patients with a driver mutation; however, their efficacy in patients with BM is not fully understood because patients with BM are usually excluded from clinical studies. This study investigated the current management and outcomes of newly diagnosed NSCLC patients with BM in Japanese clinical practice, focusing on their driver mutation status. PATIENTS AND METHODS: We enrolled newly diagnosed, treatment-naïve NSCLC patients with BM between January 2012 and December 2015 from 4 institutions in Japan. The medical records of each patient were retrospectively reviewed, and the treatment details and outcomes were evaluated. RESULTS: In total, 203 patients with BM were enrolled in this study and 73 (36%) were neurologically symptomatic. Regarding initial treatment, 110 patients (54%) received local therapy, including radiotherapy and surgery, whereas 77 (38%) received systemic therapy. The median overall survival (OS) was 14.3 months for all patients, and it was significantly longer among patients with a driver mutation (28.9 months; 95% confidence interval [CI], 20.9-41.0) than among patients without a driver mutation (9.9 months; 95% CI, 7.0-13.4) (hazard ratio [HR] 0.39; 95% CI, 0.27-0.57; p < 0.001). Multivariate analysis identified performance status (HR 1.78; 95% CI, 1.16-2.72; p = 0.009) and driver mutation status (HR 0.27; 95% CI, 0.17-0.44; p < 0.001) as significant prognostic factors. No significant difference in OS was noted according to the type of initial treatment, i.e., local versus systemic. CONCLUSION: The median OS of patients with a driver mutation was longer than 2 years, even of patients with BM, and it was significantly longer than that of patients without a driver mutation. Driver mutation status, in addition to performance status, was a significant prognostic factor in NSCLC patients with BM.

Connective tissue growth factor enhances TGF-ß1-induced osteogenic differentiation via activation of p38 MAPK in mesenchymal stem cells.

OBJECTIVES: Cellular differentiation is based on the effects of various growth factors. Transforming growth factor (TGF)-ß1 plays a pivotal role in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the influence of connective tissue growth factor (CTGF), known to function synergistically with TGF-ß1, on osteogenic differentiation in MSCs. METHODS: UE7T-13 cells were treated with TGF-ß1 and/or CTGF. Subsequently, protein levels of intracellular signaling pathway molecules were determined through western blot analysis. The mRNA expression levels of osteogenic differentiation markers were investigated using reverse transcription-quantitative polymerase chain reaction. Bone matrix mineralization was evaluated through alizarin red staining. RESULTS: Co-treatment with TGF-ß1 and CTGF resulted in the suppression of TGF-ß1-induced phosphorylation of extracellular signal-regulated kinase 1/2, an intracellular signaling pathway molecule in MSCs, while significantly enhancing the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In MSCs, co-treatment with CTGF and TGF-ß1 led to increased expression levels of alkaline phosphatase and type I collagen, markers of osteogenic differentiation induced by TGF-ß1. Osteopontin expression was observed only after TGF-ß1 and CTGF co-treatment. Notably, bone sialoprotein and osteocalcin were significantly upregulated by treatment with CTGF alone. Furthermore, CTGF enhanced the TGF-ß1-induced mineralization in MSCs, with complete suppression observed after treatment with a p38 MAPK inhibitor. CONCLUSIONS: CTGF enhances TGF-ß1-induced osteogenic differentiation and subsequent mineralization in MSCs by predominantly activating the p38 MAPK-dependent pathway.

Successful treatment of lung cancer coexisting with B­cell lymphoma with pembrolizumab following rituximab­included chemotherapy: A case report.

The combined occurrence of lung cancer and B-cell lymphoma, such as mucosa-associated lymphoid tissue (MALT) lymphoma, is rare. The efficacy and safety of immune checkpoint inhibitors (ICIs) remain unknown in this population of patients, and the occurrence of ICI-induced exacerbation of lymphoma is concerning. The present study describes a case of successful treatment with pembrolizumab following rituximab-containing chemotherapy for lung cancer complicated by MALT lymphoma. The patient was a 69-year-old woman diagnosed with MALT lymphoma based on a biopsy of stomach ulcerative lesions, and advanced lung cancer based on a biopsy of a lymph node in the left pulmonary hilum. Complete remission was achieved after one cycle of rituximab and bendamustine therapy for MALT lymphoma. Pembrolizumab monotherapy was subsequently initiated, resulting in a good response for lung cancer without recurrence or exacerbation of the lymphoma. In conclusion, the present study suggested that pembrolizumab, following rituximab-containing therapy, could be a treatment option for patients with lung cancer coexisting with MALT lymphoma.

Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation-positive Lung Cancer.

EGFR-tyrosine kinase inhibitors (TKI) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with subsequent recurrence. Therefore, we aimed to overcome the initial survival against EGFR-TKIs. We hypothesized that yes-associated protein 1 (YAP1) is involved in the initial survival against EGFR-TKIs, and we confirmed the combined effect of EGFR-TKIs and a YAP1-TEAD pathway inhibitor. The KTOR27 (EGFR kinase domain duplication) lung cancer cell lines established from a patient with EGFR mutation-positive lung cancer and commercially available PC-9 and HCC827 (EGFR exon 19 deletions) lung cancer cell lines were used. These cells were used to evaluate the in vitro and in vivo effects of VT104, a TEAD inhibitor. In addition, YAP1 involvement was investigated in pathologic specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using siRNA increased the sensitivity to EGFR-TKIs. Combination therapy with VT104 and EGFR-TKIs showed better tumor-suppressive effects than EGFR-TKIs alone, in vitro and in vivo. Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer.

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Outcomes of immune checkpoint inhibitors for postoperative recurrence of non-small cell lung cancer.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective treatment options for patients with advanced non-small cell lung cancer (NSCLC); however, there is a dearth of data on outcomes of patients receiving ICIs for postoperative recurrence. The objective of this study was to investigate the short- and long-term outcomes of patients who received ICIs for postoperative recurrence. METHODS: A retrospective chart review was performed to identify consecutive patients who received ICIs for postoperative recurrence of NSCLC. We investigated therapeutic responses, adverse events, progression-free survival (PFS), and overall survival (OS). Survival outcomes were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed using the Cox proportional hazards model. RESULTS: Eighty-seven patients, with a median age of 72 years were identified between 2015 and 2022. The median follow-up period after ICI initiation was 13.1 months. Adverse events of grade ≥ 3 were observed in 29 (33.3%) patients, including 17 (19.5%) patients with immune-related adverse events. The median PFS and OS of the whole cohort were 3.2 and 17.5 months, respectively. Limited to those receiving ICIs as first-line therapy, the median PFS and OS were 6.3 and 25.0 months, respectively. On multivariable analysis, smoking history (HR: 0.29, 95% CI 0.10-0.83) and non-squamous cell histology (HR: 0.25, 95% CI 0.11-0.57) were associated with more favorable PFS in patients receiving ICIs as first-line treatment. CONCLUSIONS: Outcomes in patients receiving ICIs as first-line treatment appear acceptable. A multi-institutional study is required to confirm our findings.

CD47 polymorphism for predicting nivolumab benefit in patients with advanced non­small­cell lung cancer.

Immune checkpoint inhibitors (ICIs), such as nivolumab, play an essential role in non-small-cell lung cancer (NSCLC) treatment. Programmed death ligand-1 has been used as a predictive biomarker for the efficacy of ICI treatment in patients with NSCLC; however, its predictive value is considered insufficient. Therefore, there is an urgent need for better predictive biomarkers. The present study focused on the CD47 molecule, which is associated with macrophages and tumor immunity. The study aimed to investigate the association between CD47 single nucleotide polymorphism (SNP) and the therapeutic effect of nivolumab in patients with NSCLC. The CD47 SNP genotypes and clinical outcomes were retrospectively analyzed in 164 patients with NSCLC treated with nivolumab at Kyoto University Hospital (Kyoto, Japan). Patients with the G/G genotype of the CD47 SNP rs3804639 had significantly longer progression-free survival than those with the G/T or T/T genotypes [2.6 months vs. 2.1 months, hazard ratio (HR), 0.70; P=0.026]. Moreover, the G/G genotype of the CD47 SNP rs3804639 was associated with a significantly longer median overall survival than the G/T or T/T genotypes of the CD47 SNP rs3804639 (24.8 months vs. 12.0 months, HR, 0.64; P=0.021). In conclusion, CD47 polymorphism may be a novel predictive biomarker of nivolumab efficacy in patients with advanced NSCLC.

How to Manage the Cortex After CTR Insertion.

Capsular tension ring (CTR) realizes safe cataract surgery. However, residual cortex removal becomes difficult with CTR. Originally, the flushing technique was developed for intracameral antibiotic administration. Using this technique with larger amounts of solution enables surgeons to 1) deliver antibiotics to the anterior chamber and area behind the intraocular lens, resulting in stable, scheduled antibiotic concentration and 2) entirely irrigate and displace the area, leading to the effective cleansing of residual substances and bacterial pollution. When performing the flushing technique, the residual cortex and debris that were not eliminated by ordinary irrigation and aspiration can be pushed out to the anterior chamber. Applying flushing technique to CTR cases, the residual cortex and debris trapped between the CTR loop and capsular equator is lifted into the anterior chamber and easily removed. If the capsular bag is polluted by bacteria, it may also be lifted to the anterior chamber.

Usefulness of pro-gastrin-releasing peptide as a predictor of the incidence of brain metastasis and effect of prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer.

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan-Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI.

Sarcomatoid malignant pleural mesothelioma treated with nivolumab: A case series.

Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

Combination bezafibrate and nivolumab treatment of patients with advanced non-small cell lung cancer.

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

Abundant oleoyl-lysophosphatidylethanolamine in brain stimulates neurite outgrowth and protects against glutamate toxicity in cultured cortical neurons.

Lysophosphatidylethanolamines (LPEs) are bioactive lysophospholipids that have been suggested to play important roles in several biological processes. We performed a quantitative analysis of LPE species and showed their composition in mouse brain. We examined the roles of oleoyl-LPE (18:1 LPE), which is one of the abundant LPE species in brain. In cultured cortical neurons, application of 18:1 LPE-stimulated neurite outgrowth. The effect of 18:1 LPE on neurite outgrowth was inhibited by Gq/11 inhibitor YM-254890, phospholipase C (PLC) inhibitor U73122, protein kinase C (PKC) inhibitor Go6983 or mitogen-activated protein kinase (MAPK) inhibitor U0126. Additionally, 18:1 LPE increased the phosphorylation of MAPK/extracellular signal-regulated kinase 1/2. These results suggest that the action of 18:1 LPE on neurite outgrowth is mediated by the Gq/11/PLC/PKC/MAPK pathway. Moreover, we found that application of 18:1 LPE protects neurons from glutamate-induced excitotoxicity. This effect of 18:1 LPE was suppressed by PKC inhibitor Go6983. These results suggest that 18:1 LPE protects neurons from glutamate toxicity via PKC inhibitor Go6983-sensitive PKC subtype. Collectively, our results demonstrated that 18:1 LPE stimulates neurite outgrowth and protects against glutamate toxicity in cultured cortical neurons. Our findings provide insights into the physiological or pathological roles of 18:1 LPE in the brain.

PD-L1 polymorphisms predict survival outcomes in advanced non-small-cell lung cancer patients treated with PD-1 blockade.

BACKGROUND: We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. RESULTS: Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18-0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31-1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. CONCLUSIONS: PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.

Survival impact of treatment for chronic obstructive pulmonary disease in patients with advanced non-small-cell lung cancer.

Chronic obstructive pulmonary disease (COPD) may coexist with lung cancer, but the impact on prognosis is uncertain. Moreover, it is unclear whether pharmacological treatment for COPD improves the patient's prognosis. We retrospectively investigated patients with advanced non-small-cell lung cancer (NSCLC) who had received chemotherapy at Kyoto University Hospital. Coexisting COPD was diagnosed by spirometry, and the association between pharmacological treatment for COPD and overall survival (OS) was assessed. Of the 550 patients who underwent chemotherapy for advanced NSCLC between 2007 and 2014, 347 patients who underwent spirometry were analyzed. Coexisting COPD was revealed in 103 patients (COPD group). The median OS was shorter in the COPD group than the non-COPD group (10.6 vs. 16.8 months). Thirty-seven patients had received COPD treatment, and they had a significantly longer median OS than those without treatment (16.7 vs. 8.2 months). Multivariate Cox regression analysis confirmed the positive prognostic impact of COPD treatment. Additional validation analysis revealed similar results in patients treated with immune checkpoint inhibitors (ICIs). Coexisting COPD had a significant association with poor prognosis in advanced NSCLC patients if they did not have pharmacological treatment for COPD. Treatment for coexisting COPD has the potential to salvage the prognosis.

The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment.

BACKGROUND: EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified. METHODS: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas® ), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360® . Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed. RESULTS: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation. CONCLUSIONS: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M.

Effects of capsular tension ring on surgical outcomes of premium intraocular lens in patients with suspected zonular weakness.

PURPOSE: To assess the influence of capsular tension ring (CTR) on surgical outcomes of toric and multifocal intraocular lenses (IOLs) in eyes at high risk of zonular instability. METHODS: Fifty-five eyes of 43 patients who had undergone phacoemulsification and IOL implantation were included in the analysis. They had some risk of zonular weakness, such as pseudoexfoliation, shallow anterior chamber, high myopia, and phacodonesis, or were judged to have unstable zonules during surgery. Toric IOL was implanted in 9 eyes with CTR and 22 eyes without CTR, while multifocal IOL was used in 9 eyes with CTR and 15 eyes without CTR. Manifest refraction, refractive astigmatism, visual acuity, and degree of IOL decentration and tilt measured using swept-source anterior segment optical coherence tomography were analyzed. Axis misalignment of toric IOLs were also evaluated. RESULTS: In toric IOLs, co-implantation of CTR significantly reduced decentration and axis misalignment of IOL, resulting in better uncorrected and corrected visual acuity after surgery. In multifocal IOLs, combined use of CTR significantly prevented IOL tilt, leading to better intermediate visual acuity. Spherical equivalent and residual astigmatism were not significantly affected by the use of CTR. CONCLUSIONS: CTR reduces decentration and axis misalignment of toric IOL and tilt of multifocal IOL, achieving improvement of postoperative visual function in eyes with suspected zonular instability.