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BACKGROUND: Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear. OBJECTIVES: To analyze the association between bone metastatic sites and the clinical efficacy of the first-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKI), in these patients. DESIGN: Retrospective multicenter cohort study. METHODS: The clinical data of patients with advanced-NSCLC harboring EGFR mutation, who were treated by EGFR-TKIs as first-line treatment at five medical institutions (N = 411), were retrospectively assessed for bone metastatic sites, overall survival (OS), and progression-free survival (PFS). RESULTS: Bone metastases were found in 41.1% of the patients at diagnosis, including 13.1%, 8.0%, and 20.0 for single, double, and multiple lesions (⩾3), respectively. The vertebra (76.3%) and pelvis (60.9%) were the most frequent metastatic sites. Femoral-, sternum-, and scapula-metastases were remarkably increased in the patients with multiple-bone metastases. In the EGFR-mutant NSCLC patient treated with osimertinib, both the OS and the PFS of the patients with femoral bone metastasis were significantly shorter than those of the patients without femoral bone metastasis (OS: not reached vs 12.1 months, p < 0.0001; and PFS: 17.2 vs 9.3 months, p < 0.0018). Furthermore, a multivariable Cox regression analysis, including several poor prognostic factors, such as L858R mutation and liver metastasis, demonstrated that femoral bone metastasis was a statistically independent predictor of OS. CONCLUSION: Femoral bone metastasis is associated with poor survival of EGFR-mutant NSCLC patients who were treated with EGFR-TKIs, including osimertinib, and is an independent prognostic factor of OS.

DOI： 10.1177/17588359241303090

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BACKGROUND: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. METHODS: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. FINDINGS: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. INTERPRETATION: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. FUNDING: Eli Lilly Japan K.K.

DOI： 10.1016/j.eclinm.2023.102303

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BACKGROUND: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. METHODS: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. RESULTS: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. CONCLUSION: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

DOI： 10.1007/s00262-023-03528-x

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Currently, immune checkpoint inhibitors (ICIs) are widely considered the standard initial treatment for advanced non-small cell lung cancer (NSCLC) when there are no targetable driver oncogenic alternations. NSCLC tumors that have two alterations in tumor suppressor genes, such as liver kinase B1 (LKB1) and/or Kelch-like ECH-associated protein 1 (KEAP1), have been found to exhibit reduced responsiveness to these therapeutic strategies, as revealed by multiomics analyses identifying immunosuppressed phenotypes. Recent advancements in various biological approaches have gradually unveiled the molecular mechanisms underlying intrinsic reprogrammed metabolism in tumor cells, which contribute to the evasion of immune responses by the tumor. Notably, metabolic alterations in glycolysis and glutaminolysis have a significant impact on tumor aggressiveness and the remodeling of the tumor microenvironment. Since glucose and glutamine are essential for the proliferation and activation of effector T cells, heightened consumption of these nutrients by tumor cells results in immunosuppression and resistance to ICI therapies. This review provides a comprehensive summary of the clinical efficacies of current therapeutic strategies against NSCLC harboring LKB1 and/or KEAP1 mutations, along with the metabolic alterations in glycolysis and glutaminolysis observed in these cancer cells. Furthermore, ongoing trials targeting these metabolic alterations are discussed as potential approaches to overcome the extremely poor prognosis associated with this type of cancer.

DOI： 10.3389/fonc.2023.1249237

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PURPOSE: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC). METHODS: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high. RESULTS: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test). CONCLUSIONS: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors.

DOI： 10.1007/s00432-022-04300-x

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DOI： 10.1016/j.gie.2023.04.1087

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BACKGROUND: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC. PATIENTS AND METHODS: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR. RESULTS: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity. CONCLUSIONS: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.

DOI： 10.1111/1759-7714.14729

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BACKGROUND: Osimertinib-the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-has been widely used as a first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib demonstrated central nervous system activity in patients with brain metastasis; however, its efficacy against other distant metastatic organs, including bone and liver, remains unclear. Therefore, we retrospectively analyzed the clinical efficacy of osimertinib in these patients in comparison to other EGFR-TKIs. METHODS: Clinical data of patients with advanced NSCLC receiving gefitinib/erlotinib (n = 183), afatinib (n = 55), or osimertinib (n = 150) at five medical institutions were retrospectively assessed for progression-free survival (PFS), overall survival (OS), and best overall response rate (ORR). RESULTS: In univariate and multivariate analyses, most distant metastases, including the brain and bone, were unrelated to the therapeutic efficacy of osimertinib, although liver metastasis and L858R mutation were independently associated with shorter PFS. PFS and OS in patients with liver metastases were significantly shorter than those in patients without liver metastases (PFS: 7.4 vs. 19.7 months, OS: 12.1 months vs. not reached, respectively). Osimertinib provided significantly longer PFS in patients with brain or bone metastasis and exon 19 deletion than the other EGFR-TKIs. The PFS of patients with liver metastases was not significantly different among the three EGFR-TKI groups. Furthermore, the ORR of osimertinib in patients with liver metastases was significantly attenuated, and the effectiveness was similar to 1st- or 2nd -generation EGFR-TKIs. CONCLUSION: Osimertinib provided better clinical benefits than 1st- and 2nd-generation EGFR-TKIs for patients with EGFR-mutant NSCLC, particularly those with brain or bone metastases and exon 19 deletion; however, its efficacy against liver metastasis was remarkably attenuated. New therapeutic developments for patients with EGFR-mutant NSCLC with liver metastases are needed.

DOI： 10.1186/s12885-022-09741-8

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<p>Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a <i>BRAF V600E</i> mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with <i>BRAF V600E</i> mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression. </p>

DOI： 10.2169/internalmedicine.6657-20

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OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

DOI： 10.1016/j.lungcan.2021.10.006

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Carboplatin (CBDCA)-induced emetic risk is currently classified on the basis of CBDCA-area under the curve (CBDCA-AUC). We investigated the utility of three CBDCA dosage parameters for predicting emesis by CBDCA. Patients with thoracic cancer treated with CBDCA were included. The endpoints were complete response (CR) and total control (TC). CR was defined as no vomiting and no use of rescue medication during the overall assessment period, whereas TC was defined as no vomiting, nausea, nor use of rescue medication during the overall assessment period. The parameters of CBDCA were defined as follows: (1) CBDCA-AUC; (2) CBDCA/body surface area (BSA): the administered dose of CBDCA per body surface area (mg/m2); and (3) total CBDCA/body: the total administered dose of CBDCA (mg). Eighty-five patients were evaluated. The median CBDCA/BSA but not CBDCA-AUC was higher in patients with non-CR compared to those with CR. Receiver operating characteristic curve analysis revealed that the AUC of CBDCA/BSA for predicting non-CR was higher than that of CBDCA-AUC. CBDCA/BSA shows greater potential for predicting CBDCA-induced emetic risk compared with CBDCA-AUC, which is the parameter in current antiemetic guidelines.

DOI： 10.18999/nagjms.83.4.773

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

<p><b><i>Objective. </i></b>In clinical practice, durvalumab has been used as a standard maintenance treatment after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). However, it is unknown as to how often practitioners avoid using durvalumab. The present study aimed to analyze the factors that influence decision-making in relation to the administration of durvalumab. <b><i>Methods. </i></b>We retrospectively analyzed the treatment of locally advanced NSCLC in 12 hospitals with lung cancer specialists. We evaluated patients with NSCLC who were treated with CRT from May 2018 to December 2019 and compared the characteristics between patients who received durvalumab and those who did not. We also conducted a questionnaire-based survey to determine the reasons for avoidingdurvalumab.<b><i>Results. </i></b>Among199patientswhoreceivedCRT,durvalumabwas administered to 169 patients (84.9%). The median age of the patients in the non-administration group was significantly higher than that in the administration group (70 vs. 67 years, p=0.0465), and the performance status (PS) ≥1 in the non-administration group was significantly higher than that in the administration group (65.5 vs. 40.4%, p=0.0148). According to the questionnaire responses, durvalumab administration was avoided for the following reasons: adverse events due to CRT (n=7); patient needs (n=5); disease progression (n=4); poor PS (n=3); driver mutation of NSCLC (n=3); and complications of autoimmune disease (n=2). <b><i>Conclusion. </i></b>Durvalumab was administered to 84.9% of patients in this study. Each practitioner considered age, PS, adverse events due to CRT, and driver mutations of NSCLC, before prescribing durvalumab.</p>

DOI： 10.2482/haigan.60.966

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In advanced non-small cell lung cancer (NSCLC), the reported incidence of febrile neutropenia (FN) caused by docetaxel (DTX) is 10-20% in clinical trial data. However, FN incidence caused by DTX in real-world setting remains unclear. We evaluated FN incidence caused by DTX and identify risk factors of FN in real-world setting. One hundred and seventy-one NSCLC patients treated with DTX were retrospectively analyzed and 44 (26%) developed FN. Multivariate analysis identified higher age (≥65 years) and prior history of FN as independent risk factors for FN. Primary prophylaxis for FN might be recommended in elderly patients with/without prior history of FN.

DOI： 10.1080/07357907.2020.1793350

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DOI： 10.1016/j.cllc.2019.11.013

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INTRODUCTION: Pneumonitis is one of the immune-related adverse events of programmed death 1 (PD-1) inhibitors that sometimes cause lethal outcomes. Although some recent reports have described PD-1 inhibitors as more effective in non-small-cell lung cancer (NSCLC) patients with immune-related adverse events than in those without, few data are available on the prognosis of those treated with PD-1 inhibitors who developed immune-related pneumonitis (IRP). Additionally, the robust risk factors of IRP have not been well elucidated. PATIENTS AND METHODS: A retrospective review of patients with recurrent or advanced NSCLC who took a PD-1 inhibitor (nivolumab or pembrolizumab monotherapy) between January 2016 and March 2018 was undertaken. Radiologic findings such as unilateral infiltration were also defined as IRP as long as they were deemed relevant to PD-1 inhibitors. RESULTS: Twenty-seven (16%) of 170 patients developed IRP. Although 22 (81%) of 27 patients with IRP recovered with drug cessation with or without corticosteroid therapy, 8-week landmark analysis showed the overall survival after administration of the PD-1 inhibitor was significantly shorter in patients with IRP than in those without (8.7 vs. 23.0 months, P = .015). Patients with IRP tended to not receive next-line treatment and choose best supportive care after cessation of PD-1 inhibitor therapy. In the multivariate analysis, pembrolizumab (vs. nivolumab) and low serum albumin were independent risk factors for IRP. CONCLUSION: Development of IRP was correlated with poor prognosis in patients with NSCLC. Further study is necessary for establishing the best prediction and management strategies for IRP.

DOI： 10.1016/j.cllc.2019.07.006

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Most patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI). The mechanisms of resistance to EGFR-TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR-TKI therapy. We evaluated the feasibility of a molecular barcode method using next-generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation-positive NSCLC patients after the development of EGFR-TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next-generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR-sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR-sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell-free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.

DOI： 10.1111/cas.14153

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OBJECTIVE: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy. MATERIALS AND METHODS: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated. RESULTS: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p =  0.002]; progressive disease [PD]: -12% [-42 to +6; p =  0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p =  0.034], day 0 of second cycle: 8% [-5 to +37; p =  0.002], day 0 of third cycle: 9% [-3 to +55; p =  0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p =  0.006). CONCLUSION: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.

DOI： 10.1016/j.lungcan.2019.04.022

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<p><b><i>Background.</i></b> Aortic dissection during bronchoscopy is a rare, albeit potentially fatal, complication. <b><i>Case.</i></b> A 68-year-old man with low-grade B-cell lymphoma who achieved complete remission with treatment in 2013 was found to have lymphadenopathy with ¹⁸F-fluorodeoxyglucose accumulation in the mediastinal lymph node by positron emission computed tomography in November 2016, with suspicious recurrence. His medical history included myocardial infarction and abdominal aortic aneurysm, and bronchoscopy was performed in January 2017 for definitive diagnosis. During bronchoscopy, he complained of chest discomfort after the lidocaine spray on the trachea, and the right main bronchus. His chest discomfort continued although the procedure was stopped, and the bronchoscope was removed, and the pain spread from the chest to the back. An enhanced computed tomography acquired immediately revealed Stanford type B acute aortic dissection. The patient was transferred to a specialized facility and rescued. <b><i>Conclusion.</i></b> Special attention should be paid to patients with multiple vascular complications as illustrated in the current case of aortic dissection during bronchoscopy.</p>

DOI： 10.18907/jjsre.41.3_315

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OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice. MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation. RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E. CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.

DOI： 10.1016/j.lungcan.2019.03.008

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BACKGROUND: Recent studies have suggested a correlation between immune-related thyroid dysfunction (irTD) and the superior efficacy of anti-programmed cell death protein-1 (anti-PD-1) treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. We explored our hypothesis that TTF-1 expression in NSCLC might correlate with irTD incidence and anti-PD-1 treatment efficacy. METHODS: We identified 132 patients with NSCLC treated with anti-PD-1 antibody at our hospital between December 2015 and June 2017. We evaluated TTF-1 expression in tumor by immunohistochemistry using a mouse monoclonal antibody (clone 8G7G3/1, 1:100, Dako). IrTD was defined as two or more successive abnormal levels of thyroid-stimulating hormone (TSH) during anti-PD-1 treatment. We retrospectively assessed correlations between TTF-1 expression in tumor, irTD incidence, and anti-PD-1 treatment efficacy. RESULTS: Of 132 patients, 67 (51%) and 65 (49%) were positive and negative for TTF-1, respectively. We observed irTD in 19 patients (6 positives and 13 negatives for TTF-1). The incidence of irTD was 9% and 20% in TTF-1-positive and TTF-1-negative NSCLCs, respectively (P=0.086). Particularly, in non-squamous (NSQ) cell carcinomas, the irTD incidence was significantly higher in patients negative for TTF-1 (30%) than in those positive for TTF-1 (9%; P=0.010), and TTF-1 expression was identified as a significant risk factor for irTD on multivariate logistic regression analysis [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.05-0.59; P=0.005]. Furthermore, longer median progression-free survival (10.3 months) was observed in patients with TTF-1-negative NSCLC with irTD compared to those with TTF-1-positive NSCLC with irTD, TTF-1-positive NSCLC without irTD, and TTF-1-negative NSCLC without irTD (4.2, 1.4, and 2.4 months, respectively). CONCLUSIONS: TTF-1 expression in NSCLC might correlate with irTD and anti-PD-1 treatment efficacy.

DOI： 10.21037/jtd.2019.04.102

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BACKGROUND: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented. PATIENTS AND METHODS: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics. RESULTS: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%). CONCLUSION: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed.

DOI： 10.1016/j.cllc.2018.04.006

PubMed

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OBJECTIVES: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. MATERIALS AND METHODS: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We performed EGFR mutation analysis of cytological samples from 33 patients using droplet digital PCR. We calculated the ratio of T790M to EGFR activating mutations and correlated it with the systemic response to osimertinib. RESULTS: In tumors from the 33 patients, the average ratio of T790M to EGFR activating mutations was 0.420. Twenty-one of the 33 patients had tumors with a T790M ratio of ≥0.4. The osimertinib response rate was significantly higher (92.3%) in patients with a T790M ratio of ≥0.4 than in those with a T790M ratio of <0.4 (52.6%; p = 0.0237). We examined the correlation between the T790M ratio and the tumor reduction rate and obtained a coefficient of r = 0.417 (p = 0.0175). In patients with a T790M ratio of ≥0.4, the median progression-free survival was 355 days, which was longer, but not significant, than that in patients with a T790M ratio of <0.4 (median: 264 days). In patients with a T790M ratio of ≥0.4, the median treatment duration from first-line therapy onward was 931 days, which was significantly longer than that in patients with a T790M ratio of <0.4 (median, 567.5 days) (p = 0.044). CONCLUSION: The T790M ratio to EGFR activating mutation in tumor may correlate with the response to osimertinib, and patients with a higher T790M ratio have a longer treatment history.

DOI： 10.1016/j.lungcan.2017.12.018

PubMed

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In non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, 50%-65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) because of an EGFR T790M point mutation and 3%-14% of these cases transformed to small cell lung cancer (SCLC). Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation.

DOI： 10.1016/j.rmcr.2018.03.009

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Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.

DOI： 10.1093/jjco/hyx133

PubMed

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BACKGROUND/AIM: Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. PATIENTS AND METHODS: Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. RESULTS: Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. CONCLUSION: Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms.

PubMed

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In patients with non-small-cell lung cancer harboring an epithelial growth factor receptor (EGFR) active mutation, central nervous system progression after a response to EGFR tyrosine kinase inhibitors is frequent. Central nervous system metastasis, especially leptomeningeal carcinomatosis (LMC), is a serious complication and no standard treatment has been established for LMC. Here, we report two cases in which the addition of bevacizumab to erlotinib enhanced the efficacy against LMC; as a result, radiographic abnormalities decreased markedly and symptoms were well controlled. This combination treatment may be useful to treat LMC in patients with EGFR-positive non-small-cell lung cancer.

DOI： 10.1097/CAD.0000000000000489

PubMed

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

<p><b><i>Background. </i></b>As the incidence of lung cancer and pulmonary non-tuberculous mycobacterial (NTM) infection is increasing, the incidence of coexistent lung cancer and pulmonary NTM infection is also increasing. Evidence shows that drug interactions can be problematic in the treatment of coexisting lung cancer and pulmonary NTM infection. Gefitinib is normally used to treat lung cancer. However, CYP3A4 inducers, such as rifampicin and rifabutin, reduce the concentration of gefitinib in the blood, whereas CYP3A4 inhibitors, such as clarithromycin, increase its concentration. Consequently, drug interaction is a major problem when gefitinib is used to treat lung cancer in patients with progressive pulmonary NTM infection. <b><i>Case. </i></b>A 72-year-old man was diagnosed with stage IV lung cancer. The cancer was pathologically identified as an adenocarcinoma, and a driver mutation of the epidermal growth factor receptor (L858R) was identified. The patient was treated with gefitinib, but he subsequently developed a progressive pulmonary <i>Mycobacterium avium</i> infection. We also identified drug interactions between gefitinib and rifampicin, rifabutin and clarithromycin. The patient's blood gefitinib concentration was measured because combination therapy with these drugs can lead to instability in the concentration of gefitinib and tumor progression. The gefitinib concentration was reduced to 60% of the original concentration following the administration of rifabutin but increased to 130% of the original concentration after the administration of rifabutin, clarithromycin, and ethambutol. However, the patient developed hyperbilirubinemia after the combined administration of rifabutin, clarithromycin, and ethambutol, and as a consequence, the combination therapy was discontinued. Afatinib is a drug that is largely considered to be unaffected by the CYP3A4 metabolism. Thus, afatinib was administered with clarithromycin, ethambutol, and rifampicin; however, the patient experienced side effects and the therapy was discontinued. <b><i>Conclusion. </i></b>We herein presented a case of a patient with coexisting lung cancer and pulmonary <i>Mycobacterium avium</i> complex disease, who was treated with gefitinib, rifabutin, clarithromycin, and ethambutol. However, this combination therapy resulted in both drug interactions and side effects. It is therefore very important to consider drug interactions and side effects in the treatment of coexisting lung cancer and pulmonary NTM infection.</p>

DOI： 10.2482/haigan.56.355

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Language：Japanese   Publisher：The Japan Lung Cancer Society  

<p><b><i>Background. </i></b>Malignant pleural mesothelioma often spreads locally into the adjacent tissues. However, it rarely invades the spinal canal. <b><i>Case. </i></b>In May 2007, a 69-year-old man presented with an abnormal shadow on a chest X-ray, and was diagnosed with malignant pleural mesothelioma of the right lung (epithelioid-type). He underwent various treatments, including chemotherapy and thermotherapy. However, he developed chest and back pain on the right-hand side and weakness of both lower extremities. He was therefore admitted to our hospital in September 2014. After admission, he developed paraplegia of the lower extremities and bladder and rectal disturbance. Spinal magnetic resonance imaging (MRI) showed that the tumor had invaded the cervical, thoracic, and lumbar epidural space through the Th8/9 intervertebral foramen. His neurological symptoms were temporarily improved by the administration of a corticosteroid. However, he died of respiratory failure due to tumor progression approximately 2 months after admission. On pathological autopsy the malignant pleural mesothelioma was observed to have extensively invaded the epidural space and the spinal dura mater. <b><i>Conclusion. </i></b>Malignant pleural mesothelioma can invade the spinal canal through the intervertebral foramen. When a patient with malignant pleural mesothelioma develops radicular symptoms, such as radiating pain, paralysis, and numbness, physicians should consider the possibility that the tumor has invaded the spinal canal.</p>

DOI： 10.2482/haigan.56.1022

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01244&link_issn=&doc_id=20170317350004&doc_link_id=%2Fec7jaluc%2F2016%2F005607%2F004%2F1022-1027%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2016%2F005607%2F004%2F1022-1027%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.special_s232_4

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DOI： 10.1016/j.annonc.2023.10.612

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Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(NPO)日本肺癌学会  

目的.局所進行非小細胞肺癌患者に対しデュルバルマブが用いられるようになったが、どの程度非投与患者がいるのか明確でなく、投与割合を調査し、投与回避理由を調査した。研究計画。肺癌治療専門医がいる12施設のデータを後方視的に評価した。2018年5月から2019年12月に治療された局所進行非小細胞肺癌患者を対象とした。デュルバルマブの投与群と非投与群で患者背景を比較し、非投与理由を質問票で確認した。結果.199人が化学放射線療法を施行され、169人(84.9%)にデュルバルマブが投与された。年齢中央値が非投与群で有意に高く(70歳 vs 67歳、p=0.0465)、PS≧1の患者が非投与群で有意に多かった(65.5% vs 40.4%、p=0.0148)。質問票により確認された非投与理由は、「化学放射線療法の副作用」7例、「患者希望」5例、「腫瘍進行」4例、「PS低下」「遺伝子変異陽性」3例、「自己免疫疾患の合併」2例であった。結論.デュルバルマブは84.9%の患者に投与され、投与回避要因として、年齢、PS、化学放射線療法の有害事象、遺伝子変異などがあった。(著者抄録)

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DOI： 10.1016/j.jtho.2019.08.1526

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DOI： 10.1093/annonc/mdz343.108

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

背景.大動脈解離は気管支鏡検査中の合併症として非常に稀であるが、時に致死的となる可能性がある。症例.68歳男性、既往歴に陳旧性心筋梗塞、腹部大動脈瘤がある患者。2013年にlow-grade B-cell lymphomaの診断となり化学療法が施行された。完全寛解が得られていたが、2016年11月のpositron emission computed tomographyで縦隔リンパ節に18F-fluorodeoxyglucoseの集積を伴うリンパ節腫大を認めた。確定診断のため2017年1月に気管支鏡検査を施行した。気管、右主気管支にリドカインを散布していたところ、2度の胸部不快感の訴えがあったため、直ちに検査を中断し症状確認を行った。気管支鏡抜去後も胸部不快感が持続し、経過で背部にかけて疼痛が出現した。CT検査でStanford B型の急性大動脈解離と診断し、専門施設に搬送し救命できた。結論.気管支鏡検査中に急性大動脈解離をきたした1例を経験した。本症例のように血管系の合併症が多い症例では、特に注意が必要と考えられた。(著者抄録)

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Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1430200280

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J06669&link_issn=&doc_id=20180720240002&doc_link_id=10.11477%2Fmf.1430200280&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1430200280&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2018.36.15_suppl.e21051

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＜Point＞ALK融合遺伝子は強力ながん遺伝子であり,ALK融合遺伝子陽性非小細胞肺癌(ALK肺癌)において,その増殖や生存はALKに大きく依存している.ALK肺癌に対しては,ALKチロシンキナーゼ阻害薬(ALK-TKI)が著効する.ALK-TKIは,プラチナ併用化学療法と比べ有意に無増悪生存期間(progression free survival;PFS)を延長することが示されており,1次治療から推奨される.複数のALK-TKI(クリゾチニブ,アレクチニブ,セリチニブ)が承認されており,それぞれの薬剤の特徴を知ることが重要である.(著者抄録)

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2012年に,進行固形がんに対するニボルマブの忍容性と効果,特に,長期に奏功を維持する症例もあることが報告され,以後,さまざまな免疫チェックポイント阻害薬が開発されている.免疫チェックポイント阻害薬は,非小細胞肺がん患者の生存期間を延長することが示され,肺がん診療に大きな変革をもたらした.一方で従来の化学療法とは異なる毒性対策の必要性や,医療費負担の問題もあり,実地診療では薬剤の適正使用を心がける必要がある.(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.e20540

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DOI： 10.1200/JCO.2017.35.15_suppl.e23104

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DOI： 10.1200/JCO.2017.35.15_suppl.e23105

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DOI： 10.1200/JCO.2017.35.15_suppl.e23101

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DOI： 10.1200/JCO.2017.35.15_suppl.e20583

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DOI： 10.1200/JCO.2017.35.15_suppl.e20063

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DOI： 10.1200/JCO.2017.35.15_suppl.e20575

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.special_s232_4

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.special_s254_2

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