Proteomics associated with coronary high-risk plaques by optical coherence tomography.

Biomarkers are widely used for the diagnosis and monitoring of cardiovascular disease. However, markers for coronary high-risk plaques have not been identified. The aim of this study was to identify proteins specific to coronary high-risk plaques. Fifty-one patients (71.2 ± 11.1 years, male: 66.7%) who underwent intracoronary optical coherence tomography imaging and provided blood specimens for proteomic analysis were prospectively enrolled. A total of 1470 plasma proteins were analyzed per patient using the Olink® Explore 1536 Reagent Kit. In patients with thin-cap fibroatheroma, the protein expression of Calretinin (CALB2), Corticoliberin (CRH) and Alkaline phosphatase, placental type (ALPP) were significantly increased, while the expression of Neuroplastin (NPTN), Folate receptor gamma (FOLR3) and Serpin A12 (SERPINA12) were significantly decreased. In patients with macrophage infiltration, the protein expressions of Fatty acid-binding protein, intestinal (FABP2), and Fibroblast growth factor 21 (FGF21) were significantly decreased. In patients with lipid-rich plaques, the protein expression of Interleukin-17 C (IL17C) was significantly increased, while the expression of Fc receptor-like protein 3 (FCRL3) was significantly decreased. These proteins might be useful markers in identifying patients with coronary high-risk plaques. Clinical Trial Registration: https://www.umin.ac.jp/ctr/ , UMIN000041692.

Layered plaque is associated with high levels of vascular inflammation and vulnerability in patients with stable angina pectoris.

Layered plaque, a signature of previous plaque destabilization and healing, is a known predictor for rapid plaque progression; however, the mechanism of which is unknown. The aim of the current study was to compare the level of vascular inflammation and plaque vulnerability in layered plaques to investigate possible mechanisms of rapid plaque progression. This is a retrospective, observational, single-center cohort study. Patients who underwent both coronary computed tomography angiography (CTA) and optical coherence tomography (OCT) for stable angina pectoris (SAP) were selected. Plaques were defined as any tissue (noncalcified, calcified, or mixed) within or adjacent to the lumen. Perivascular inflammation was measured by pericoronary adipose tissue (PCAT) attenuation at the plaque levels on CTA. Features of plaque vulnerability were assessed by OCT. Layered plaques were defined as plaques presenting one or more layers of different optical densities and a clear demarcation from underlying components on OCT. A total of 475 plaques from 195 patients who presented with SAP were included. Layered plaques (n = 241), compared with non-layered plaques (n = 234), had a higher level of vascular inflammation (-71.47 ± 10.74 HU vs. -73.69 ± 10.91 HU, P = 0.026) as well as a higher prevalence of the OCT features of plaque vulnerability, including lipid-rich plaque (83.8% vs. 66.7%, P < 0.001), thin-cap fibroatheroma (26.1% vs. 17.5%, P = 0.026), microvessels (61.8% vs. 34.6%, P < 0.001), and cholesterol crystals (38.6% vs. 25.6%, P = 0.003). Layered plaque was associated with a higher level of vascular inflammation and a higher prevalence of plaque vulnerability, which might play an important role in rapid plaque progression.Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04523194 .

Effectiveness of remimazolam in preventing postoperative delirium in elderly patients with proximal femoral fractures.

PURPOSE: Elderly patients with proximal femoral fractures are known to be a high-risk group for postoperative delirium (POD). The aim of this study was to determine the association of the benzodiazepine drug remimazolam with POD in elderly patients with proximal femoral fractures. METHODS: In this single-center retrospective observational study, we included patients aged 65 years or older who underwent general anesthesia for proximal femoral fractures. We collected data for the incidence of POD within 3 days after surgery. We also obtained data for complications, preoperative blood examinations, maintenance anesthetic and intraoperative vital data. The occurrence of POD in patients who received remimazolam for general anesthesia (remimazolam group) was compared to that in patients who received general anesthesia with other anesthetic agents (other group). We finally conducted a multivariate analysis to assess the independent association of remimazolam with the risk of POD. RESULTS: A total of 230 patients, including 54 patients who received remimazolam for maintenance anesthesia, were included in this study. The incidence of POD in the patients was 26.1%. The incidence of delirium within 3 days after surgery was significantly lower in the remimazolam group than in the other group (14.8% vs. 29.5%, p = 0.03). The multivariate analysis showed that the use of remimazolam independently reduced the occurrence of POD (adjusted odds ratio = 0.42, p = 0.04). CONCLUSION: This retrospective observational study showed that the use of remimazolam is independently associated with a reduced incidence of POD. Remimazolam may be considered as an option to reduce POD in elderly patients with proximal femoral fractures.

Rocuronium action can be affected by hyperventilation: a case report and computational simulation.

The neuromuscular blocking potency of rocuronium varies with respiratory pH changes, increasing at lower pH and decreasing at higher pH; thus, hyperventilation-induced respiratory alkalosis is expected to decrease the potency of rocuronium. We report a case of anesthetic management of modified electroconvulsive therapy (m-ECT) for a patient monitored with electromyography-based neuromuscular monitoring during two patterns of ventilation to elucidate their relationship and propose the possible mechanisms underlying the effects by computational simulations. Case presentation: The patient was a 25-year-old man with schizophrenia. In m-ECT, hyperventilation may be used to produce longer seizures. We compared the neuromuscular monitoring data recorded during hyperventilation and during normal ventilation while receiving the same dose of rocuronium. Despite receiving the same dose of rocuronium, the time required for the first twitch to decrease to 80% of the control value was delayed in hyperventilation compared to normal ventilation. Conclusions: This case report and computational simulation suggest that respiratory alkalosis might delay the action of rocuronium. It is necessary to consider the delayed action of rocuronium when hyperventilation is performed.

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.

Real-world clinical outcomes of percutaneous transluminal septal myocardial ablation for patients with drug-refractory hypertrophic obstructive cardiomyopathy: results from a retrospective multicenter registry of non-high-volume centers.

Percutaneous transluminal septal myocardial ablation (PTSMA) is a well-established interventional therapy for drug-refractory hypertrophic obstructive cardiomyopathy (HOCM) as an alternative to surgical myectomy. Although guidelines recommend that PTSMA should be performed in institutions with extensive experience, it is not centralized to such high-volume centers in real-world clinical practice. Thus, this study aimed to assess the feasibility of PTSMA in non-high-volume centers. We retrospectively examined patients with HOCM who underwent PTSMA between August 2012 and May 2020 at four institutions that experienced fewer than 20 cases of PTSMA procedures. The primary clinical endpoint was a composite of safety (all-cause death, electrical defibrillation for ventricular tachycardia or fibrillation, cardiac tamponade, permanent pacemaker implantation, and repeated interventions) and efficacy endpoints (repeated interventions [PTSMA or surgical myectomy]). Fifty-eight consecutive patients were enrolled. During the 30-day follow-up, no major clinical adverse events were noted except three patients (5.2%) requiring permanent pacemaker implantation for complete atrioventricular block. The percentage of patients with New York Heart Association functional class 1 or 2 significantly increased from 8.6 to 100% (p < 0.001). In the Cox proportional hazard model, left ventricular outflow tract pressure gradient at rest ≥ 30 mmHg (hazard ratio [HR] 6.56; 95% confidence interval [CI] 1.44-29.90; p = 0.015) and mitral regurgitation grade ≥ 3 (HR 10.75; 95% CI 1.81-63.79; p = 0.009) at the 30-day follow-up were associated with a composite of major clinical adverse events. The current study demonstrated that 58 patients who underwent PTSMA in non-high-volume centers had favorable 30-day clinical outcomes, with a primary composite endpoint rate of 5.2%. A prospective study with a larger sample size and longer follow-up is warranted to verify the safety and efficacy of PTSMA in non-high-volume centers.

Timing, Threshold, and Duration of Intraoperative Hypotension in Cardiac Surgery: Their Associations With Postoperative Delirium.

OBJECTIVES: To study the timing, threshold, and duration of intraoperative hypotension (IOH) associated with the risk of postoperative delirium (POD). DESIGN: A single-center retrospective observational study. SETTING: University teaching hospital. PARTICIPANTS: A total of 503 adult patients who underwent cardiac valvular surgery that required cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: The authors predefined the following 4 periods: (1) during surgery, (2) pre-CPB, (3) during CPB, and (4) post-CPB, and 8 thresholds of mean arterial pressure for IOH according to every 5 mmHg between 50 mmHg and 85 mmHg. The authors calculated the cumulative duration below the 8 thresholds in each period. The primary outcome was delirium defined as a score of ≥4 for at least one Intensive Care Delirium Screening Checklist assessment during 48 h after the surgery. Among 503 patients, POD occurred in 95 patients (18.9%). There was no significant association of POD with all of the thresholds of IOH in the periods of pre-CPB, during CPB, and during surgery. However, in the post-CPB period, the patients with POD had a significantly longer cumulative duration of IOH according to all of the thresholds of mean arterial pressure. In multivariate analyses, 4 IOH thresholds in the post-CPB period were associated independently with POD: <60 mmHg (odds ratio [OR] =1.84 [95% CI 1.10-3.10]), <65 mmHg (OR = 1.72 [1.01-2.92]), <70 mmHg (OR = 1.83 [1.03-3.26]), and <75 mmHg (OR = 1.94 [1.02-3.69]). CONCLUSIONS: A longer cumulative duration of IOH with the threshold between <60 and <75 mmHg that occurred after CPB was independently associated with the risk of POD.

Sputum characteristics of patients with severe COVID-19: report of two cases with immunocytochemical detection of SARS-CoV-2 spike protein.

Patients with SARS-CoV-2 infection and with severe COVID-19 often have multiple coinfections, and their treatment is challenging. Here, we performed cytology analysis on sputum samples from two patients with severe COVID-19. The specimens were prepared using the rubbing method and stained with Papanicolaou stain. In both cases, several cells with frosted nuclei were observed, and the cytological findings per 100 cells were evaluated. The infected cells were mononuclear to multinuclear, showing chromatin aggregation at the nuclear margins, intranuclear inclusion bodies, eosinophilic cytoplasmic inclusion bodies, and mutual pressure exclusion of the nuclei. Immunocytochemical staining revealed that the cells were positive for AE1/AE3 and negative for CD68 expression, indicating their epithelial origin. Furthermore, infected cells with frosted nuclei were positive for surfactant protein A (SP-A) in Case 2, suggesting infection of type II alveolar pneumocytes or Clara cells. Moreover, in Case 2, the infected cells were positive for herpes simplex virus (HSV) I + II and SARS-CoV-2 spike protein, confirming double infection in these cells. In conclusion, sputum cytology is an important tool for determining the diversity of viral infection, and additional immunocytochemistry can be used for definitive diagnosis.

[Current Status and Future of the Research Using Real World Data].

The use of patient data in the real world settings, so-called real world data(RWD), for clinical research is attracting attention worldwide. Therefore, it is essential to know the important points in conducting or interpreting clinical research utilizing RWD. This review describes international trends in RWD utilization research and collection methods. First, representative examples of RWD utilization studies are presented, followed by a discussion of the increasing use of RWD in the future. In particular, the trend of utilizing RWD as an external control group for clinical trials has been increasing in recent years, and I discuss examples of overseas RWD utilization studies. Next, there is a growing trend to utilize RWD for regulatory aspects such as approval applications, and examples of such applications is presented. Finally, methods have been developed to efficiently collect the patient information necessary for clinical cancer research with minimal burden on medical professionals in order to create larger-scale, high-quality RWDs that can be used for a variety of research purposes. This effective methods for collecting RWDs on a larger-scale and of high-quality, as well as global developments, are described.

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.).

Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study.

BACKGROUND: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. METHODS: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. RESULTS: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. CONCLUSIONS: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Predictor analysis of 1-year restenosis after percutaneous transluminal angioplasty for femoropopliteal stenotic lesions using intravascular ultrasound.

This retrospective, single-center study evaluated the patency rate and predictors of restenosis after percutaneous transluminal angioplasty (PTA) for femoropopliteal stenotic lesions using intravascular ultrasound. We assessed 78 de novo femoropopliteal stenotic lesions (64 patients; mean age, 73.6 ± 9.4 years; average lesion length, 59.8 mm) that underwent PTA under intravascular ultrasound guidance. The primary endpoint was 1-year primary patency. The 1-year primary patency rate was 63%. The frequency of insulin use was significantly greater (44% vs. 12%, p = 0.005), and lesions were significantly longer (77.8 mm vs. 49.2 mm, p = 0.047) in the restenosis group than in the non-restenosis group. The pre-intervention reference lumen area and minimum lumen area (MLA) were significantly smaller in the restenosis group (reference lumen area: 19.7 ± 6.7 mm2 vs. 23.7 ± 7.4 mm2, p = 0.017; MLA 3.9 ± 2.8 mm2 vs. 5.7 ± 3.9 mm2, p = 0.026; respectively). The MLA was significantly smaller and the maximum angle of dissection was significantly larger in the restenosis group (MLA 9.3 mm2 vs. 12.3 mm2, p = 0.013; maximum angle of dissection: 104.1° vs. 69.6°, p = 0.003; respectively) among post-intervention parameters. Multivariate analysis revealed that the independent predictors of 1-year restenosis were the large post-intervention maximum angle of dissection and insulin use. Per receiver operating curve analysis, the best cut-off value of the post-intervention maximum angle of dissection that predicted 1-year restenosis was 70.2° (sensitivity 72.4%, specificity 63.3%, area under the curve 0.70, p = 0.004). In conclusion, the 1-year primary patency rate after PTA for relatively short stenotic femoropopliteal lesions was 63%. The large post-intervention maximum angle of dissection, measured using intravascular ultrasound, and insulin use were independent predictors of restenosis after PTA.

"Interchangeability" of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy.

Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

Osimertinib in a patient with non-small cell lung cancer and renal failure undergoing hemodialysis: a case report.

Osimertinib is a key drug for cancer patients with EGFR mutations. However, there is little information about its safety in cancer patients who require hemodialysis (HD) for chronic renal failure, despite notable increases in their numbers. Herein, we examined osimertinib safety in such a patient via pharmacokinetics analysis. A 66-year-old man was diagnosed with relapsed stage IV non-small cell lung cancer with an EGFR mutation in exon 21 (L858R) 2 years after stereotactic body radiotherapy. He was undergoing HD three times a week owing to worsening diabetic nephropathy. We administered osimertinib (80 mg/day) as the first-line therapy. We measured osimertinib concentrations on multiple days, either before, after, or in the absence of HD. Maximum concentrations and areas under the curve were determined. We found that HD did not affect the pharmacokinetics of osimertinib. We conclude that osimertinib can be safely administered to cancer patients undergoing HD.

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.

Tumour content ratio matters for detecting epidermal growth factor receptor mutation by cobas test in small biopsies; a retrospective study.

BACKGROUND: Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing. METHODS: We examined 132 patients with EGFR-mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR-positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. RESULTS: The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. CONCLUSIONS: Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

Differential significance of molecular subtypes which were classified into EGFR exon 19 deletion on the first line afatinib monotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive. METHODS: West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay. RESULTS: Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746_A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244). CONCLUSIONS: The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies. TRIAL REGISTRATION: This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).

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.

Long-term preoperative glycemic control restored the perioperative neutrophilic phagocytosis activity in diabetic mice.

BACKGROUND: The risk of surgical site infection has been reported to be higher in patients with poorly controlled diabetes. Since chronic hyperglycemia impairs neutrophil functions, preoperative glycemic control may restore neutrophil function. However, long-term insulin therapy may lead to a delay in surgery, which may be a problem, especially in cancer surgery. It is therefore unfortunate that there have been few studies in which the optimal duration of perioperative glycemic control for diabetes with chronic hyperglycemia was investigated. Therefore, we investigated the effects of preoperative long-term insulin therapy and short-term insulin therapy on perioperative neutrophil functions in diabetic mice with chronic hyperglycemia. METHODS: Five-week-old male C57BL/6 J mice were divided into four groups (No insulin (Diabetes Mellitus: DM), Short-term insulin (DM), Long-term insulin (DM), and Non-diabetic groups). Diabetes was established by administrating repeated low-dose streptozotocin. The Short-term insulin (DM) group received insulin therapy for 6 h before the operation and the Long-term insulin (DM) group received insulin therapy for 5 days before the operation. The No insulin (DM) group and the Non-diabetic group did not receive insulin therapy. At 14 weeks of age, abdominal surgery with intestinal manipulation was performed in all four groups. We carried out a phagocytosis assay with fluorescent microspheres and a reactive oxygen species (ROS) production assay with DCFH-DA (2',7'-dichlorodihydrofluorescein diacetate) before and 24 h after the operation using FACSVerse™ with BD FACSuite™ software. RESULTS: Blood glucose was lowered by insulin therapy in the Short-term insulin (DM) and Long-term insulin (DM) groups before the operation. Neutrophilic phagocytosis activities before and after the operation were significantly restored in the Long-term insulin (DM) group compared with those in the No insulin (DM) group (before: p = 0.0008, after: p = 0.0005). However, they were not significantly restored in the Short-term insulin (DM) group. Neutrophilic ROS production activities before and after the operation were not restored in either the Short-term insulin (DM) group or Long-term insulin (DM) group. CONCLUSIONS: Preoperative and postoperative phagocytosis activities are restored by insulin therapy for 5 days before the operation but not by insulin therapy for 6 h before the operation.

Evaluation of the usefulness of protocol-based pharmacist-facilitated laboratory monitoring to ensure the safety of immune checkpoint inhibitors in patients with lung cancer.

WHAT IS KNOWN AND OBJECTIVE: Immune checkpoint inhibitors can cause immune-related adverse events (irAEs). Improved monitoring systems for irAEs, which include laboratory tests by a qualified multidisciplinary team, might prevent patients from irAE-associated events. Kobe City Medical Center General Hospital developed protocol-based pharmacist-facilitated laboratory tests named protocol-based pharmacotherapy management (PBPM) to aid the administration of immunotherapy to patients with lung cancer. The protocol defines the laboratory test items and times at which they should be performed. It requires pharmacists to check laboratory orders initiated by physicians and enter additional test items if the orders are incomplete. We evaluated the efficacy of PBPM in irAE monitoring and compared it with those of conventional care systems. METHODS: From January 2016 to March 2018, 114 patients with lung cancer received immunotherapy, which was managed by conventional care (conventional group). From April to September 2018, 62 patients were managed by PBPM (PBPM group), among those 28 patients were transited from conventional group to PBPM group. Data on whether the laboratory tests were conducted or omitted were collected retrospectively for the conventional group and prospectively for the PBPM group. RESULTS: Within the conventional group, 4604 (87.6%) out of the 5253 laboratory test items were ordered by physicians. Of the remaining 649 test items, 224 (4.3%) items were added by physicians based on recommendations by pharmacists. However, of the 1581 (86.6%, from among 1826) test items that were previously ordered by physicians, only 231 (12.7%) test items were added by pharmacists. The execution rate was found to be significantly higher in the PBPM group (99.2% vs 91.9%, P < .001). WHAT IS NEW AND CONCLUSION: PBPM-based pharmacist-facilitated laboratory monitoring systems provided higher executing rate of laboratory order to monitor irAEs during immunotherapy.