Classification and regression tree for estimating predictive markers to detect T790M mutations after acquired resistance to first line EGFR-TKI: HOPE-002.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis following concurrent chemoradiotherapy: a multicenter prospective cohort study.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).

Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Prediction of patients with a tumor proportion score > 50% who do not respond to first-line monotherapy with pembrolizumab.

BACKGROUND: Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown. METHODS: We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data. RESULTS: A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50-89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32-31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15-6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03-4.68; p = 0.0402) were significantly associated with non-response to treatment. CONCLUSION: In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39-91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0-1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50-74%, 75-89%, and 90-100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0-1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05-2.72; p = 0.03138), CRP/Alb (<0.3 vs. ≥0.3: HR: 1.92, 95.0% CI: 1.28-2.87; p = 0.00153), steroid usage (not usage vs. usage: HR: 2.94, 95.0% CI: 1.45-5.95; p = 0.00267), and PD-L1 TPS (50-89% vs. 90-100%: HR: 0.65, 95.0% CI: 0.43-1.00; p = 0.04984) were significantly and independently correlated with PFS of pembrolizumab. Conclusion The results confirm the efficacy and safety of pembrolizumab in real-world patients. Poor PS and steroid usage at the time of commencing pembrolizumab treatment indicate poor outcomes. First-line pembrolizumab particularly benefits patients with PD-L1 TPS ≥90% or low inflammatory states (CRP/ALB<0.3).

Rapidly Growing Locally Advanced Non-Small Cell Lung Cancer Treated with Definitive Chemoradiotherapy Using Adaptive Volumetric Modulated Arc Therapy Followed by Durvalumab Maintenance: A Case Report.

BACKGROUND It is difficult to reduce lung toxicity in chemoradiotherapy for locally advanced lung cancer. Volume-modulated arc therapy (VMAT) is a useful lung dose-lowering radiation technique, but it is time-consuming because of its complexity. We present a case of a rapidly growing bulky lung cancer treated with VMAT and intensive adaptation to volume change. CASE REPORT A 43-year-old man with chest pain was diagnosed with non-small cell lung cancer, cT4N3M0 stage IIIC (UICC 8th edition). Concurrent chemoradiotherapy with a VMAT of 60 Gy in 30 fractions and carboplatin/paclitaxel was performed. Despite initiating chemoradiation, monitoring with cone-beam computed tomography (CT) revealed tumor progression. The peak tumor volume was 1.5 times larger than that on CT simulation. The VMAT plan was recreated to cover the increased tumor size. After the irradiation field was enlarged, the tumor, on the contrary, shrank rapidly. Therefore, VMAT planning was performed again to further shrink the irradiation field. CT at the end of the treatment showed a good volume reduction response. Durvalumab therapy was continued for 1 year. After that, the patient was alive and showed no sign of progression. Only asymptomatic radiation pneumonitis was observed as a sub-acute adverse event. CONCLUSIONS We present a case in which proper adaptive VMAT and durvalumab for dramatically progressive non-small cell lung cancer were effective, resulting in 1-year progression-free survival. Even when rapid progression of bulky lung cancer is suggested, the combination of VMAT and adaptive radiotherapy with improved target coverage and reduced lung dose can be a treatment option.

Prospective multicenter cohort study of durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis.

OBJECTIVE: Durvalumab was safe and effective in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in a phase 3 trial (PACIFIC trial). Although a history of radiation pneumonitis (RP) has been reported to increase the risk of exacerbation of pneumonitis associated with programmed death-1 axis inhibitors, the detailed clinical results of durvalumab treatment in patients with baseline grade 1 RP were not reported in the PACIFIC trial. Therefore, we aimed to evaluate the safety and effectiveness of durvalumab therapy in these patients. MATERIALS AND METHODS: This was a multicenter prospective cohort study involving 35 patients. Patients were eligible if they met the following criteria: inoperable stage III NSCLC, administration of durvalumab within 42 days after CCRT using platinum-based chemotherapy, no disease progression after CCRT, Eastern Cooperative Oncology Group performance status of 0-1, and presence of grade 1 RP at baseline. We assessed the effectiveness and safety of durvalumab with a minimum 1-year follow-up period for all patients. RESULTS: Thirty-five patients were enrolled in our study from February 2019 to December 2019. The median progression-free survival was 11.4 months (95 % confidence interval, 7.1 months-not reached), and the median overall survival was not reached. Eleven (31 %) patients had grade ≥2 pneumonitis/RP, 10 (28 %) developed grade 2 pneumonitis/RP, and 1 (3 %) developed grade 5 pneumonitis/RP. Five (14 %) patients experienced treatment-related grade ≥3 adverse events. CONCLUSION: Durvalumab might be safe and effective in patients with stage III NSCLC with baseline grade 1 RP following chemoradiotherapy.

A Randomized Phase II Study Comparing Nivolumab with Carboplatin-Pemetrexed for EGFR-Mutated NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors (WJOG8515L).

PURPOSE: Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. PATIENTS AND METHODS: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. CONCLUSIONS: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study): primary analysis.

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

Impact of interstitial lung disease associated with immune checkpoint inhibitors on prognosis in patients with non-small-cell lung cancer.

PURPOSE: Immune checkpoint inhibitor-associated interstitial lung disease (ICI-ILD) is a serious immune-related adverse event. We aimed to evaluate the impact of ICI-ILD severity and imaging patterns or post-ILD cancer therapy on prognosis in patients with non-small-cell lung cancer (NSCLC). METHODS: We retrospectively analysed NSCLC patients who developed ICI-ILD in our institution between January 2016 and March 2019. The primary objective was to report prognosis following onset of ICI-ILD, stratified by severity grade or imaging pattern. The secondary objective was the analysis of cancer therapy after ICI-ILD. RESULTS: Among 222 patients treated with ICI, 27 (12.2%) developed ICI-ILD. No trend for different prognosis depending on severity grade was seen unless ICI-ILD was fatal. Most patients (91.3%) with organising pneumonia (OP) or nonspecific interstitial pneumonia pattern on imaging showed grade 1 or 2, while all patients with a diffuse alveolar damage (DAD) pattern showed grade 3 or higher, and one reached grade 5. Among patients who overcame ICI-ILD, eight patients (30.8%) have been followed up without chemotherapy because of long-term disease control and seven had shown an OP pattern on imaging at onset of ICI-ILD. Three patients underwent ICI rechallenge, but two showed ICI-ILD recurrence and no patient achieved response to rechallenge treatment. CONCLUSION: The DAD pattern may predict short-term adverse prognosis for ICI-ILD. Once ICI-ILD is overcome, severity grade is not associated with prognosis. Even if initial immunotherapy proves effective, ICI rechallenge requires careful consideration.

Alectinib re-challenge in small cell lung cancer transformation after chemotherapy failure in a patient with ALK-positive lung cancer: A case report.

Small cell lung cancer (SCLC) transformation is a rare resistance mechanism to anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), for which cytotoxic chemotherapy is often initiated. However, no case has been reported so far in which the SCLC component disappeared after chemotherapy and the tumor responded to ALK-TKI treatment again. A 41-year-old, never-smoker man was diagnosed with multiple metastatic lung adenocarcinoma harboring ALK gene rearrangements. After tumor re-growth was treated with alectinib, histological analysis of re-biopsy of the primary lesion showed combined small cell carcinoma, and cytotoxic chemotherapy was administered. After resistance to chemotherapy developed, the third biopsy of the primary lesion showed the original ALK gene rearrangements without the SCLC component. Alectinib was re-administered, and partial response was obtained. Biopsy for ALK-positive lung cancer that progressed after chemotherapy for SCLC transformation might be useful for decision-making regarding the therapeutic strategy.

Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer.

PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

The in vitro effect of a collagenolytic enzyme inhibitor on lesion development in root dentin.

PURPOSE: To evaluate the effects of a new active collagenase inhibitor, Pirocton Olamine (PO), on acid demineralization in dentin and to investigate possible mechanisms of the inhibitory effects. METHODS: Demineralized bovine dentin sections were cyclically exposed to one of the test solutions containing PO (0-0.33%) and NaF (0.07%) for 3 minutes, then to a Clostridium histolyticum (Ch-collagenase) collagenase solution for 16 hours and finally to an acetate buffer solution for 6 hours for further demineralization within a single day. This cyclic treatment was repeated three times for 3 days. Changes in the mineral loss and lesion depth were quantified by transverse microradiography, and the extent of the degradation by the collagenase in the collagen matrix was measured by microscopic observation after the completion of the 3-day cyclic treatments. Possible mechanisms of PO inhibitory effects on collagen matrix degradation were tested by incubating PO with one of the substances (Ch-collagenase, bovine tendon collagen pieces, zinc2+ (acetate) which is essential ion for collagenolytic activity) at 37 degrees C. Following 1 hour incubation, the incubated solutions were filtrated and PO concentrations (unbound to the substances) in the filtrates were spectroscopically measured. RESULTS: With increasing PO concentrations, the inhibition rates of collagen matrix degradation and the mineral loss were increased. Moreover, there was a positive statistical correlation between mineral loss and collagen matrix degradation, demonstrating that preservation of the collagen matrix would contribute to inhibiting acid demineralization. While the spectroscopic measurements indicated that PO possessed binding to these substances, PO exerted its inhibitory action primarily on the collagenolytic activity.

Heat-not-burn cigarettes induce fulminant acute eosinophilic pneumonia requiring extracorporeal membrane oxygenation.

BACKGROUND: Although the cause of acute eosinophilic pneumonia (AEP) has not yet been fully clarified, cigarette smoking is reported to be a risk factor for developing AEP. The heat-not-burn cigarette (HNBC) was developed to reduce the adverse effects of smoke on the user's surroundings. However, the health risks associated with HNBCs have not yet been clarified. We report a successfully treated case of fatal AEP presumably induced by HNBC use. PRESENTATION OF CASE: A 16-year-old man commenced HNBC smoking two weeks before admission and subsequently suffered from shortness of breath that gradually worsened. The patient was transferred to emergency department and immediately intubated because of respiratory failure. Computed tomography showed mosaic ground-glass shadows on the distal side of both lungs with a PaO2/FIO2 ratio of 76. The patient required veno-venous extracorporeal membrane oxygenation (ECMO) for severe respiratory failure. He was diagnosed with AEP by clinical course and detection of eosinophils in sputum; thus, methylprednisolone was administrated. The patient was weaned off ECMO four days after initiation and extubated the day after. He fully recovered without sequelae. CONCLUSION: As far as we know, our patient is the first case of AEP induced by HNBC use successfully treated with ECMO. Emergency physicians must be aware that HNBCs can induce fatal AEP.

Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: A retrospective multicenter cohort study in Japan.

BACKGROUND: Pembrolizumab is currently approved as a first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with a programed death ligand-1 (PD-L1) expression ≥50%. However, the association between the efficacy of pembrolizumab and PD-L1 expression levels in patients with PD-L1 expression ≥50% has not been fully elucidated. METHODS: We retrospectively analyzed patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% who received pembrolizumab as a first-line therapy at 11 institutions in Japan between February 2017 and January 2018. Patients were divided into TPS 50-89% and TPS 90-100% (ultra-high PD-L1 expression) cohorts. RESULTS: In total, 149 patients were included: 99 (66.4%) and 50 (33.6%) patients were in the TPS 50-89% and TPS 90-100% cohorts, respectively. Baseline characteristics were similar between the TPS 90-100% and TPS 50-89% cohorts. The objective response rates (ORR) in the TPS 90-100% and TPS 50-89% cohorts were 58.0% and 46.5%, respectively (p = 0.23). Time to treatment failure (TTF) was longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (hazard ratio [HR]: 0.67, 95% confidence interval (CI): 0.42-1.07; p = 0.09). Although TTF within 120 days after the initiation of pembrolizumab therapy was comparable between both cohorts (p = 0.54), TTF after 120 days was significantly longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (HR: 0.22, 95% CI: 0.06-0.87; p = 0.031). Immune related adverse events of grade 3 or more occurred in 16.0% and 19.2% of patients in the TPS 90-100% and TPS 50-89% cohorts, respectively. CONCLUSIONS: The patients with an ultra-high PD-L1 expression continued pembrolizumab therapy longer, driven by a reduced risk of treatment failure in the late phase. PD-L1 expression levels might be a predictive biomarker of a first-line immunotherapy benefit in the late phase among NSCLC patients with TPS ≥50%.

Pseudoprogression in Previously Treated Patients with Non-Small Cell Lung Cancer Who Received Nivolumab Monotherapy.

INTRODUCTION: Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression. METHODS: We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death. RESULTS: Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p < 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001). CONCLUSIONS: Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.

INTRODUCTION: Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS: We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. RESULTS: Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). CONCLUSIONS: Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Enhancement of the liver on dynamic MDCT: investigation among three groups consisting of noncirrhotic patients and cirrhotic patients with and without a large portosystemic shunt.

PURPOSE: The aim of this study was to determine any difference in hepatic enhancement values on dynamic multidetector row computed tomography (MDCT) among three groups: noncirrhotic patients and cirrhotic patients with and without a large portosystemic shunt. MATERIALS AND METHODS: A group of 20 noncirrhotic patients (group A), 43 cirrhotic patients without a large shunt (group B), and 20 cirrhotic patients with a large shunt (group C) underwent dynamic MDCT of the liver using a standard concentration (300 mg I/ml) and volume (100 ml) of contrast material. The attenuation values of the liver were measured during arterial, portal, and late phases. RESULTS: The hepatic enhancement value during the portal phase was significantly higher in group A (56.2 +/- 13.7 HU) than in the other two groups (group B 39.8 +/- 11.9 HU, group C 41.3 +/- 8.3 HU) (P < 0.01). No significant difference was present between group B and group C. The regression line of the scattergram, which shows the relation between the hepatic enhancement value during the portal phase and the iodine dose per the patients' body weight was more gently sloping in group C than in the other two groups. CONCLUSION: In cirrhotic patients without a large shunt, injection of a larger amount of total iodine is necessary to optimize hypovascular tumor visualization. However, in cirrhotic patients with a large shunt, further investigation is needed concerning the effectiveness of administering a larger amount of total iodine.