Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：English   Publisher：(一社)日本癌学会  

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INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

DOI： 10.1002/cam4.7393

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OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

DOI： 10.1016/j.lungcan.2024.107540

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IMPORTANCE: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. OBJECTIVE: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. EXPOSURES: Systemic therapy. MAIN OUTCOMES AND MEASURES: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). CONCLUSIONS AND RELEVANCE: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

DOI： 10.1001/jamaoncol.2023.6277

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INTRODUCTION: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. METHODS: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. RESULTS: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. CONCLUSIONS: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

DOI： 10.1016/j.jtocrr.2024.100668

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jtocrr.2024.100655

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. METHODS: We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. RESULTS: In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. CONCLUSION: Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

DOI： 10.1002/cam4.6393

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Language：English   Publisher：(一社)日本癌学会  

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BACKGROUND: Rechallenge with platinum-combination chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) after disease progression on platinum-combination chemotherapy occasionally leads to a favorable response. The efficacy and safety of platinum-combination chemotherapy with or without immune-checkpoint inhibitor (ICI) for patients with recurrent NSCLC after surgery followed by adjuvant platinum-doublet chemotherapy remains uncertain. METHODS: Patients who relapsed after surgery plus adjuvant platinum-doublet chemotherapy and received platinum-combination chemotherapy with or without ICI between April 2011 and March 2021 at four Nippon Medical School hospitals were retrospectively analyzed. RESULTS: Among 177 patients who received adjuvant platinum-doublet chemotherapy after surgery, a total of 30 patients who received platinum-combination rechemotherapy with or without ICI after relapse were included in this study. Seven patients received ICI-combined chemotherapy. The median disease-free survival (DFS) after surgery was 13.6 months. The objective response rate and disease-control rate were 46.7% and 80.0%, respectively. The median progression-free survival and overall survival were 10.2 and 37.5 months, respectively. Patients with longer DFS (≥12 months) had a better prognosis than others. The most common grade ≥3 toxicity associated with this treatment was neutropenia (33%). Grade ≥3 immune-related adverse events were pneumonitis (14%) and colitis (14%). Treatment-related deaths did not occur in this study. CONCLUSION: Platinum-combination chemotherapy with or without ICI for patients with postoperative recurrent NSCLC who previously received adjuvant platinum-doublet chemotherapy was effective and safe. In particular, this therapy may be promising for patients with longer DFS.

DOI： 10.1111/1759-7714.14992

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PURPOSE: For patients with locally advanced non-small-cell lung cancer (LA-NSCLC) that progressed after definitive chemoradiotherapy (CRT) and durvalumab consolidation therapy, no subsequent standard treatment exists. The type of treatment selected for each timing of disease progression and its efficacy have not been investigated. METHODS: We retrospectively enrolled patients with LA-NSCLC or inoperable NSCLC that progressed after definitive CRT and durvalumab consolidation therapy at 15 Japanese institutions. Patients were classified into the following: Early Discontinuation group (disease progression within 6 months after durvalumab initiation), Late Discontinuation group (disease progression from 7 to 12 months after durvalumab initiation), and Accomplishment group (disease progression from 12 months after durvalumab initiation). RESULTS: Altogether, 127 patients were analyzed, including 50 (39.4%), 42 (33.1%) and 35 (27.5%) patients from the Early Discontinuation, Late Discontinuation, and Accomplishment groups, respectively. Subsequent treatments were Platinum plus immune checkpoint inhibitors (ICI) in 18 (14.2%), ICI in 7 (5.5%), Platinum in 59 (46.4%), Non-Platinum in 35 (27.6%), and tyrosine kinase inhibitor in 8 (6.3%) patients. In the Early Discontinuation, Late Discontinuation, and Accomplishment groups, 4 (8.0%), 7 (16.7%), and 7 (20.0%) patients were receiving Platinum plus ICI; 21 (42.0%), 22 (52.4%), and 16 (45.7%) were receiving Platinum, and 20 (40.0%), 8 (19.0%), and 7 (20.0%) were receiving Non-Platinum, respectively. No significant difference in progression-free survival was observed in the timing of disease progression. CONCLUSION: In patients with LA-NSCLC hat progressed after definitive CRT and durvalumab consolidation therapy, subsequent treatment may change depending on the timing of disease progression.

DOI： 10.1007/s00280-023-04547-2

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Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

DOI： 10.1007/s10637-023-01358-3

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Adenoid cystic carcinoma (ACC) is a rare type of malignant tracheal tumor originating from the secretory glands. Complete surgical resection is the current standard of care for tracheal ACC. However, there have been few case reports of chemoradiotherapy for unresectable tracheal ACC. We herein report a 28-year-old man with unresectable tracheal ACC who received concurrent chemoradiotherapy (CCRT) followed by maintenance therapy with durvalumab. CCRT was completed with a good response and safety, and the patient is currently receiving durvalumab as maintenance therapy. Durvalumab after CCRT can be a treatment option for patients with unresectable tracheal ACC.

DOI： 10.2169/internalmedicine.1142-22

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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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Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor as standard therapy for ALK-rearranged non-small cell lung cancer (NSCLC). Hemolytic anemia is considered as a rare but significant adverse event with alectinib. Here, we report a case of a 73-year-old female with lung adenocarcinoma, harbouring an ALK fusion gene, who received alectinib as second-line therapy and developed gradually progressive grade 4 (6.4 g/dL) drug-induced hemolytic anemia (DIHA) after complete response. We discontinued alectinib and performed a blood transfusion for the severe anemia. The anemia improved with no recurrence of lung adenocarcinoma over 10 months. Regular hematologic monitoring and the possibility of DIHA should be considered in case of progressive hemolytic anemia during alectinib treatment.

DOI： 10.2147/OTT.S398375

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Anaplastic lymphoma kinase-positive (ALK-positive) lung adenocarcinoma with multiple liver metastases accounts for a relatively small number of cases of non-small cell lung cancer. Several ALK-tyrosine kinase inhibitors (ALK-TKIs) are available for the treatment of lung cancer. However, there is limited evidence on the treatment of multiple liver metastases in patients with lung cancer that are refractory to ALK-TKIs. We report the case of a 42-year-old male patient with ALK-positive lung adenocarcinoma who experienced rapid progression to multiple liver metastases while receiving treatment with alectinib. Biopsy of the liver metastases revealed echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion and tumor protein p53 (TP53) mutation; notably, ALK secondary mutations were not detected. Despite the sequential administration of third-generation ALK-TKIs, the liver metastases did not respond, the serum levels of total bilirubin and biliary enzymes continued to increase, and the patient's general appearance worsened. Finally, the patient exhibited a remarkable clinical response to treatment with a combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP). ABCP is one of the optimal options for ALK-positive lung cancer with liver metastasis that is refractory to ALK-TKIs therapy.

DOI： 10.2147/OTT.S404035

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin; in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC.

DOI： 10.3390/cancers14184363

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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A 59-year-old woman complaining of wet cough, hemoptysis, slight fever, anorexia, and malaise was admitted to hospital with suspected lobar pneumonia. She received treatment for myocardial infarction and deep venous thrombosis caused by familial protein C deficiency. Rapid deterioration due to respiratory failure occurred despite intensive care with broad-spectrum antibiotics. At a later date, sputum examination revealed the presence of Aspergillus niger. Based on clinical and autopsy findings, she was diagnosed with acute respiratory failure due to pulmonary aspergillosis with acute fibrinous and organizing pneumonia. This is the first reported case of pulmonary aspergillosis with acute fibrinous and organizing pneumonia complicated by calcium oxalate resulting from Aspergillus niger infection, leading to severe inflammation and tissue injury in the lungs.

DOI： 10.1016/j.rmcr.2022.101641

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Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.

DOI： 10.2147/OTT.S361467

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BACKGROUND: Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies. AIMS: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. METHODS AND RESULTS: We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups. CONCLUSION: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

DOI： 10.1002/cnr2.1414

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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

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BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.

DOI： 10.21873/anticanres.14980

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several companion diagnostic (CDx) tests for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been approved. In our institute, the CDx test for EGFR-TKIs was changed from the Therascreen test (Therascreen) to the Cobas EGFR v2 test (Cobas) because only Cobas was approved for the use of osimertinib in patients with EGFR-mutated non-small cell lung cancer (NSCLC) with T790M mutations. The clinical influence of switching the CDx test has not yet been examined comprehensively. METHODS: All serial patients with lung cancer tested for EGFR mutations with CDx tests between February 2014 and February 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) were enrolled in this analysis. RESULTS: Therascreen was used as a CDx test for EGFR-TKI therapy in 607 patients between February 2014 and January 2015, and Cobas was used in 621 patients between February 2015 and February 2016. EGFR mutations were detected in 218 patients (35.9%) and 244 patients (39.3%) tested with Therascreen and Cobas, respectively. At the initial diagnosis, 400 and 459 patients were tested with Therascreen and Cobas, respectively. EGFR mutation subtypes, including del19, L858R, and others, were detected in 13.0%, 17.0%, and 2.5% of patients using Therascreen and 17.4%, 14.4%, and 1.5% of patients using Cobas, respectively. CONCLUSIONS: No significant impact of switching from Therascreen to Cobas as the CDx test for EGFR mutations in clinical practice was observed. However, the detection pattern of the EGFR mutation subtypes between the two CDx tests was slightly different. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We examined the influence of changing the EGFR test in 1228 patients in total. The detection rate of EGFR mutations was similar. However, the detection pattern for EGFR subtype mutations was slightly different between the two tests. WHAT THIS STUDY ADDS: Switching CDx tests from target polymerase chain reaction (PCR)- to next-generation sequencing (NGS)-based methods may lead to obvious changes in clinical practice. When the CDx test is required to change, the investigation of this influence is warranted in future studies.

DOI： 10.1111/1759-7714.13797

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The usefulness of the Oncomine Dx Target test (Oncomine Dx), a next-generation sequencing (NGS) test, has already been proven in clinical trials. However, NGS requires high-quality tumor samples and takes a long time to generate results. The feasibility of NGS for use in advanced non-small cell lung cancer (NSCLC) patients in clinical practice has not yet been determined. METHODS: Patients serially diagnosed with advanced NSCLC were evaluated in our hospital. The Oncomine Dx, Cobas EGFR mutation test (Cobas EGFR), and ALK-IHC were performed. The patients were divided into four sets: the full analysis set (FAS) that referred to patients diagnosed with NSCLC, the intent to perform companion diagnostics (CDx) set (IPS) that referred to patients in which CDx had been ordered regardless of sample quality, the per-performed CDx set (PPS) that referred to patients who could undergo CDx regardless of the results, and the per-completed CDx set (CCS) that referred to patients in which informative results were received from the CDx. RESULTS: The total number of patients analyzed in the study was 167. The IPS/FAS of Oncomine Dx (80.2%) was lower than that of the ALK-IHC (85.0%) and Cobas EGFR (92.8%). The CCS/FAS of Oncomine Dx (65.9%) was lower than that of the ALK-IHC (82.0%) and Cobas EGFR (92.2%). PPS/IPS and CCS/PPS of the Oncomine Dx with nonsurgical biopsy ranged between 78.6% and 90.9%, which was lower than those patients who underwent surgical resection (95.0% and 100%). CONCLUSIONS: The feasibility of Oncomine Dx in clinical practice was lower than the other CDx. The feasibility of Oncomine Dx will increase by improving the biopsy procedure. KEY POINTS: SIGNIFICANT STUDY FINDINGS: The usefulness of a next-generation sequencing (NGS) test has been proven in clinical trials. The feasibility of NGS is lower than other diagnostics in clinical practice especially with regard to nonsurgical biopsy. WHAT THIS STUDY ADDS: It is necessary to improve the feasibility of NGS in clinical practice. To improve NGS feasibility, turnaround time must be shortened, and larger samples must be obtained during surgical procedures.

DOI： 10.1111/1759-7714.13786

PubMed

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/1759-7714.13557

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1759-7714.13557

Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.lungcan.2020.04.021

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors.

Methods

This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation.

In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as ‘true PD’. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models.

Results

The present study included 62 NSCLC patients aged 27–82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17–0.94).

Conclusions

Patients with DR exhibited a relatively favorable prognosis.

DOI： 10.1186/s12885-020-6704-z

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Other Link： http://link.springer.com/article/10.1186/s12885-020-6704-z/fulltext.html

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

背景.末梢肺病変に対するガイドシース併用気管支腔内超音波断層法(endobronchial ultrasonography with a guide sheath:EBUS-GS)を用いた肺生検(EBUS-GS-TBB)の有用性が示されているが、診断に影響を与える因子は明らかになっていない。目的.EBUS-GS-TBBの診断に影響を与える因子を明らかにすることを目的とした。方法.日本医科大学付属病院において2016年7月から2018年4月までにEBUS-GSを用いて肺生検が施行された118例の中で、最終的に確定診断が得られた101例を後方視的に検討した。EBUSのプローブの位置によって、エコー所見を'within'、'outside'、'broadly adjacent to'、'narrowly adjacent to'の4つに分類した。Adjacent toの中でプローブ周囲の180度以上360度未満の範囲に病変が描出されたものをbroadly adjacent toと新たに定義し、それ以外をnarrowly adjacent toと新たに定義した。結果.EBUS-GSによる確定診断率は78.2%であった。多変量解析にて、エコー所見がwithinまたはbroadly adjacent toの患者は診断率が有意に高かった(オッズ比4.25、P<0.01)。肺気腫を合併する患者では有意に診断率が低かった(オッズ比0.29、P=0.02)。検査前のthin-section CTにおけるbronchus sign陽性は診断に寄与する有意な因子であった(オッズ比6.86、P=0.03)。結論.EBUS-GS-TBBでは、エコー所見がbroadly adjacent toの場合でも診断率は高く、withinが得られない症例でもよりよいエコー描出を目指すべきである。肺気腫合併例は診断率が低い可能性があり、検査前の背景肺の評価も重要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: STK11/LKB1 mutation has been suggested as a poorly responding candidate biomarker of the anti-programmed cell death-1 (PD-1) antibody; however, the association between STK11/LKB1 expression and the effects of anti-PD-1 antibodies is uncertain. The aim of the study was to correlate the efficacy of pembrolizumab monotherapy and STK11/LKB1 expression in untreated patients with non-small-cell lung carcinoma (NSCLC) and high PD-ligand 1 expression. PATIENTS AND METHODS: From February 2017 to January 2020, we retrospectively analyzed 30 previously untreated patients with NSCLC and a tumor proportion score (TPS) ≥50% treated with pembrolizumab monotherapy. STK11/LKB1 expression in tumor tissue was evaluated by immunohistochemistry. RESULTS: Twenty-three (76.7%) of the 30 patients were classified with low-STK11/LKB1 expression. The median progression-free survival and overall survival of patients with low-STK11/LKB1 expression was shorter than those with high-STK11/LKB1 expression, although the results were not statistically significant. The disease progression rate for the low-STK11/LKB1 group was higher than that of the high-STK11/LKB1 group. CONCLUSION: STK11/LKB1 expression, as measured by immunohistochemistry, could be a useful biomarker associated with the efficacy of pembrolizumab monotherapy for patients with NSCLC and a TPS ≥50%.

DOI： 10.21873/invivo.12131

PubMed

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Vascular endothelial growth factor-A (VEGF-A) plays important roles in tumor immune suppression and thus correlates with the efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-1/PD-L1) antibodies. We aimed to determine the association between change in plasma VEGF-A levels and the efficacy of chemotherapy combined with anti-PD-1/PD-L1 antibodies (chemo-PD1) in non-small cell lung cancer (NSCLC) patients. METHODS: We included NSCLC patients treated with chemo-PD1. Plasma VEGF-A levels were measured at baseline (Pre) and days 7 (D7) and 14 (D14) after the initiation of chemo-PD1. Continuous VEGF-A decrease was determined by comparing Pre with the median value of maximum change rate of posttreatment VEGF-A as cutoff. Patients whose change rates of VEGF-A at both D7 and D14 were consistently lower than the cutoff value were classified into the VEGF-A decrease group, whereas those whose VEGF-A at D7 or D14 were higher than the cutoff level were classified into the VEGF-A no-decrease group. The primary outcome was progression-free survival (PFS). RESULTS: A total of 32 patients were evaluated. The median Pre VEGF-A levels was 49 (range, 13-257). The median change rate of VEGF-A at D7 and D14 was -25.6% (range, -77.5-376.9) and -42.3% (range, -100-138.5) respectively. The cutoff value of posttreatment VEGF-A change rate was -9.3%. The PFS was significantly longer in the VEGF-A decrease group than that in the VEGF-A no-decrease group (median, not reached vs 2.4 months; p = 0.017). CONCLUSIONS: Continuous decrease of plasma VEGF-A levels during treatment may be associated with the efficacy of chemo-PD1.

DOI： 10.1016/j.ctarc.2020.100249

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/anticanres.13902

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/omcr/omy094

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/ott.s169321

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/ott.s168598

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

背景.末梢肺病変に対するガイドシース併用気管支腔内超音波断層法(endobronchial ultrasonography with a guide sheath:EBUS-GS)を用いた肺生検(EBUS-GS-TBB)の有用性が示されているが、診断に影響を与える因子は明らかになっていない。目的.EBUS-GS-TBBの診断に影響を与える因子を明らかにすることを目的とした。方法.日本医科大学付属病院において2016年7月から2018年4月までにEBUS-GSを用いて肺生検が施行された118例の中で、最終的に確定診断が得られた101例を後方視的に検討した。EBUSのプローブの位置によって、エコー所見を'within'、'outside'、'broadly adjacent to'、'narrowly adjacent to'の4つに分類した。Adjacent toの中でプローブ周囲の180度以上360度未満の範囲に病変が描出されたものをbroadly adjacent toと新たに定義し、それ以外をnarrowly adjacent toと新たに定義した。結果.EBUS-GSによる確定診断率は78.2%であった。多変量解析にて、エコー所見がwithinまたはbroadly adjacent toの患者は診断率が有意に高かった(オッズ比4.25、P<0.01)。肺気腫を合併する患者では有意に診断率が低かった(オッズ比0.29、P=0.02)。検査前のthin-section CTにおけるbronchus sign陽性は診断に寄与する有意な因子であった(オッズ比6.86、P=0.03)。結論.EBUS-GS-TBBでは、エコー所見がbroadly adjacent toの場合でも診断率は高く、withinが得られない症例でもよりよいエコー描出を目指すべきである。肺気腫合併例は診断率が低い可能性があり、検査前の背景肺の評価も重要である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J00298&link_issn=&doc_id=20200219190004&doc_link_id=%2Fcf0brond%2F2020%2F004201%2F005%2F0014-0020%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2020%2F004201%2F005%2F0014-0020%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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

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

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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J-GLOBAL

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

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