Mannitol versus furosemide in patients with thoracic malignancies who received cisplatin-based chemotherapy using short hydration: A randomized phase II trial.

BACKGROUND: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.

Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. PATIENTS AND METHODS: Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. RESULTS: Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). CONCLUSION: Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.

Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L).

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

PURPOSE: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses. METHODS: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety. RESULTS: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively. CONCLUSION: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.

A Phase II Study of High-Flow Nasal Cannula for Relieving Dyspnea in Advanced Cancer Patients.

CONTEXT: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. OBJECTIVES: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care. METHODS: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). RESULTS: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. CONCLUSION: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.

The effect of 1-hydroxy-vitamin D treatment in hospitalized patients with COVID-19: A retrospective study.

BACKGROUND & AIMS: The efficacy of vitamin D supplementation in coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to evaluate the effect of 1-hydroxy-vitamin D on the prevention of severe disease and mortality in patients hospitalized for COVID-19. METHODS: This retrospective study included 312 patients with COVID-19 who were admitted to our hospital between April 2021 and October 2021 (primarily the Delta variant) and between July 2022 and September 2022 (primarily Omicron variant). Serum 25-hydroxyvitamin D (25(OH)D) levels were measured at the time of admission and 1-hydroxy-vitamin D was prescribed by the treating physicians. The patients were divided into two groups: those administered 1-hydroxy-vitamin D (Vit D group) and those who were not (control group). The composite primary endpoint was the need for additional respiratory support, including high-flow oxygen therapy or invasive mechanical ventilation, and in-hospital mortality rate. RESULTS: Of 312 patients, 122 (39%) received 1-hydroxy-vitamin D treatment. Although the median age was not significantly higher in the Vit D group than in the control group (66 vs. 58 years old, P = 0.06) and there was no significant difference in the proportion of vitamin D deficiency (defined as serum 25(OH)D level less than 20 ng/mL, 77% vs. 65%, P = 0.07), patients in the control group had a more severe baseline profile compared to the Vit D group according to the Japanese disease severity definition for COVID-19 (P = 0.01). The proportion of those requiring more respiratory support and in-hospital mortality was significantly lower in the Vit D group than in the control group (6% vs. 14%, P = 0.01 log-rank test). After propensity score matching, a statistically significant difference in the primary endpoint was observed (P = 0.03 log-rank test). CONCLUSIONS: 1-hydroxy-vitamin treatment may improve outcomes in hospitalized patients with COVID-19, reducing composite outcomes including the need for additional respiratory support and in-hospital mortality.

Afatinib plus osimertinib in the treatment of osimertinib-resistant non-small cell lung carcinoma: a phase I clinical trial.

BACKGROUND: Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. METHODS: This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. RESULTS: Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n = 12), the response rate was 7.7% and the disease-control rate was 46.2%. CONCLUSION: Combination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. TRIAL REGISTRATION: Japan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.

Creation of an Integrated Clinical Trial Database and Data Sharing for Conducting New Research by the Japan Lung Cancer Society.

Introduction: Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. Methods: The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results: A total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusions: The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

Impact of pre-existing interstitial lung abnormal shadow on lung injury development and severity in patients of non-small cell lung cancer treated with osimertinib.

BACKGROUND: First-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sometimes causes lung injury, thereby affecting survival. Although pre-existing interstitial lung abnormal shadow (pre-ILS) increases the risk of lung injury by EGFR-TKIs, its impact on osimertinib, a third-generation EGFR-TKI, remains unknown. PATIENTS AND METHODS: This retrospective cohort study consecutively enrolled patients of EGFR-mutated non-small cell lung cancer treated with osimertinib. Computed tomography images were obtained and evaluated independently by three pulmonologists in a blinded manner. Factors associated with lung injury were assessed using a logistic regression model. Survival curves were calculated by the Kaplan-Meier method and compared using a log-rank test. RESULTS: Of the 195 patients, 40 had pre-ILS, and 21 (8 with and 13 without pre-ILS) developed lung injury during the observation period. Multivariate analysis revealed that pre-ILS was independently associated with lung injury (odds ratio, 3.1; 95% confidence interval [CI], 1.1-8.2; p = 0.025). Severe (≥Grade 3) lung injury was observed in eight (4.1%) patients, of whom, two (5%) and six (3.9%) had and did not have pre-ILS (p = 0.67), respectively. Grade 5 lung injury was not observed, and survival curves were similar between the patients who developed lung injury and those who did not (median 11 vs. 12 months; hazard ratio, 1.2; 95% CI, 0.56-2.7; p = 0.60). CONCLUSIONS: Pre-ILS increased the risk of lung injury in patients of non-small cell lung cancer treated with osimertinib, while the severity of lung injury was not clearly affected by the presence of pre-ILS.

Pre-treatment serum protein levels predict survival of non-small cell lung cancer patients without durable clinical benefit by PD-1/L1 inhibitors.

While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39-56), 211 days (95% CI: 158-425), and 193 days (95% CI: 118-349), respectively. By multivariate analysis for OS, CRP (> 1.44 mg/dl) [HR 2.59 (95% CI:1.33-5.04), P = 0.005] and follistatin (> 685 pg/ml) [HR 2.29 (95% CI:1.12-4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.

High-purity Isolation for Genotyping Rare Cancer Cells from Blood Using a Microfluidic Chip Cell Sorter.

BACKGROUND/AIM: A multistep sorting method for enrichment of rare cells, such as circulating tumor cells, in the blood without cumbersome pretreatments required by most flow cytometry-based methods, which lead to high cost and decreased detection efficiency, was developed. MATERIALS AND METHODS: After only hemolysis and cell staining, cancer cells are enriched by repetitive sorting (3×) based on nuclear-positive, cytokeratin-positive, and CD45-negative expression. RESULTS: Experiments using spikes of PC-9 cells showed a mean recovery of 65% and mean purity of 83%, which was retained up to 72 hours after blood draw using preservative tubes. Significant differences in expression level of programmed death-ligand 1 or vimentin were observed between high- and low-expressing cell lines, concurrently with enrichment. Next-generation sequencing analysis of recovered PC-9, A549, and MDA-MB231 cells successfully detected all known mutations. CONCLUSION: This novel isolation method applicable for preserved samples with sufficient recovery and purity may be substantially beneficial for recovering cells for subsequent molecular analysis.

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.

Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study.

INTRODUCTION: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. METHODS: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1-3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). RESULTS: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%-72.2%). Median PFS was 4.0 months (95% CI: 2.8-7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3-21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

Longitudinal Evaluation of PD-L1 Expression on Circulating Tumor Cells in Non-Small Cell Lung Cancer Patients Treated with Nivolumab.

Although programmed death-ligand 1 (PD-L1) expression on tumor tissue is a validated predictive biomarker for a PD-1 pathway blockade in non-small cell lung cancer (NSCLC), longitudinal changes in its expression during treatment remains elusive. Circulating tumor cells (CTCs) are assumed to reflect the transition of characteristics of the primary tumor undergoing anticancer treatment. Here, we sequentially evaluated the PD-L1 expression on CTCs in NSCLC patients treated with nivolumab. Forty-five patients were enrolled, and CTCs were enriched from 3 mL of peripheral blood using a microcavity array system at baseline and weeks 4, 8, 12, and 24 or until progressive disease. The effective responses to therapy were compared between patients without progressive disease (PD) at week 8 (i.e., non-PD patients) and in those with PD between weeks 4 and 8 (PD patients) in terms of increased vs. decreased or equal CTC status at week 8 (for non-PD patients) or at the point of PD (for PD patients) compared to the baseline. Significantly more non-PD patients were classified as decreased or equal in number and proportion to PD-L1-positive CTCs among the detected CTCs (PD-L1 positivity rates) (p < 0.05). Moreover, progression-free survival was significantly longer in patients with ≥7.7% PD-L1 positivity rates (n = 8) than in those with <7.7% rates (n = 8; p < 0.01) at week 8. These results suggest the predictive significance of the early evaluation of PD-L1 expression on CTCs for maintaining the benefits from nivolumab treatment.

Bloodborne Cytokines for Predicting Clinical Benefits and Immune-Related Adverse Events in Advanced Non-Small Cell Lung Cancer Treated With Anti-Programmed Cell Death 1 Inhibitors.

BACKGROUND: Programmed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non-small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs). PATIENTS AND METHODS: Patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated. RESULTS: Sixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset. CONCLUSIONS: Serum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment.

Comparison of Systemic Inflammatory Response Syndrome and quick Sequential Organ Failure Assessment scores in predicting bacteremia in the emergency department.

AIM: The emergency department requires simple and useful clinical indicators to identify bacteremia. This retrospective study explored the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores for predicting bacteremia. METHODS: Between April and September 2017, we assessed blood cultures of 307 patients in our emergency department. We calculated the SIRS and qSOFA scores for these patients and evaluated their correlation with bacteremia. RESULTS: Of 307 patients, 66 (21.5%) had bacteremia, 237 (77.2%) were SIRS-positive, and 123 (40.0%) were qSOFA-positive. The sensitivity and specificity of the SIRS score for predicting bacteremia were 87.9% and 25.7%, respectively. The sensitivity and specificity of the qSOFA score were 47.0% and 61.8%, respectively. Multivariate analysis revealed that body temperature (odds ratio, 2.16; 95% confidence interval, 1.22-3.84; P = 0.009) and blood pressure (odds ratio, 2.72; 95% confidence interval, 1.39-5.35; P = 0.004) significantly associated with bacteremia. CONCLUSIONS: The SIRS score was a more sensitive indicator than the qSOFA score for predicting bacteremia.

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation.

BACKGROUND/AIM: To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma. PATIENTS AND METHODS: Six advanced lung adenocarcinoma patients with EGFR mutation were treated with osimertinib 80 mg/day plus ramucirumab 10 mg/kg, every two weeks. Defined dose-limiting toxicity (DLT) was assessed within the first two treatment cycles. RESULTS: Of those enrolled, five patients had both EGFR exon 20 T790M mutation and sensitizing mutation. DLT was observed in one patient (grade 3 appetite loss). During the entire period, no other severe adverse event was observed. Five patients showed partial response and one disease progression. Median progression-free survival for patients with EGFR T790M was 9.2 months. In an exploratory analysis, changes of cell-free DNA at 2 weeks predicted radiological tumor responses. CONCLUSION: The safety results of osimertinib plus ramucirumab in Japanese lung adenocarcinoma patients with EGFR mutation will lead to further efficacy investigation.

CD24, not CD47, negatively impacts upon response to PD-1/L1 inhibitors in non-small-cell lung cancer with PD-L1 tumor proportion score < 50.

CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti-phagocytic factors and the immune response with immune-checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non-small-cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression-free survival (PFS) of ICI when PD-L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD-L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4-6 wk later, and such increase was notably observed only when PD-L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)-A, D and PDGF-AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non-small-cell lung cancer with PD-L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).

Importance of doctor-initiated management of the balance between work and treatment for lung cancer patients: Results of a nationwide survey by the Japan Lung Cancer Society.

BACKGROUNDS: Since the recent development of molecular targeted drugs and immune checkpoint inhibitors has improved lung cancer treatment options and outcomes, supporting patients in balancing work and pharmacotherapy have become even more important in the field of lung cancer treatment. This study sought to identify the current status and roles of doctors in balancing work and treatment for lung cancer patients. METHODS: Patients and doctors were recruited to complete a web-based questionnaire survey by the Japan Lung Cancer Society. RESULTS: About 287 lung cancer patients and 381 doctors were included in the analysis. About 42.9% of patients responded that "there was no discussion" about their working conditions or work before the initiation of pharmacotherapy, while 22.6% responded that "there was an inquiry from a doctor/health care provider and a discussion that included the doctor was held." About 45.3% of patients took leave or resigned from work at the time of diagnosis. The most common reasons for patients to resign before or during pharmacotherapy were "poor physical condition due to side effects of treatment or illness" and "concern about causing problems in the workplace." To assist in balancing work and pharmacotherapy, patients desired "increased opportunities to consult about work" (36.9%) and "provision of treatment options with few adverse events" (28.9%). CONCLUSION: This study highlights the importance of doctor-initiated management of the balance between work and treatment for lung cancer patients. An important first step is for doctors themselves to take an interest in their patients' professions and initiate discussions of work-related topics with their patients.

Prospective, multicentre, single-arm phase II trial of pembrolizumab combined with carboplatin and pemetrexed in elderly patients with advanced, non-squamous non-small cell lung cancer.

INTRODUCTION: Triplet regimen of carboplatin or cisplatin with pemetrexed and pembrolizumab is a standard treatment for patients with advanced, chemo-naïve, non-squamous non-small cell lung cancer. However, subgroup analysis for patients aged ≥75 years indicated that elderly patients who received the triplet regimen may have had shorter survival times than if they had chemotherapy alone (HR of 2.09). Treatments in the elderly are not always as effective or safe as for non-elderly patients, so there remains concern over whether the triplet regimen can be widely used in the elderly. METHODS AND ANALYSIS: This is a single-arm, prospective, multicentre phase II study. The primary endpoint is set as the overall response rate according to Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints are progression-free survival, disease control rate and safety. This trial will enrol 22 patients. ETHICS AND DISSEMINATION: This study was approved by the Wakayama Medical University Central Review Board on 2 December 2019 (approval number: W-32). Patients have been enrolled since February 2020. As the study will complete accrual in January 2022, results will be submitted for publication in peer-reviewed medical journals within 2023 and international scientific meetings. This study will provide significant information on whether the triplet regimens are clinically beneficial to elderly patients. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCTs051190095).