Prospective Observational Study of Ramucirumab Plus Docetaxel After Combined Chemoimmunotherapy in Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies.

BACKGROUND: Hypertension or elevated blood pressure (BP) is an important risk factor for aortic dissection (AD); however, few prospective studies on this topic have been published. We investigated the association between hypertension/elevated BP and AD in 2 cohorts and conducted a meta-analysis of published prospective studies, including these 2 studies. METHODS: We analyzed data from the J-SHC study (Japan-Specific Health Checkups) and UK Biobank, which prospectively followed up 534 378 and 502 424 participants, respectively. Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for the association of hypertension/elevated BP with AD incidence in the UK Biobank and AD mortality in the J-SHC Study. In the meta-analysis, summary relative risks were calculated with random-effects models. A potential nonlinear dose-response relationship between BP and AD was tested with fractional polynomial models, and the best-fitting second-order fractional polynomial regression model was determined. RESULTS: In the J-SHC study and UK Biobank, there were 84 and 182 ADs during the 4- and 9-year follow-up, and the adjusted hazard ratios of AD were 3.57 (95% CI, 2.17-6.11) and 2.68 (95% CI, 1.78-4.04) in hypertensive individuals, 1.33 (95% CI, 1.05-1.68) and 1.27 (95% CI, 1.11-1.48) per 20-mm Hg increase in systolic BP (SBP), and 1.67 (95% CI, 1.40-2.00) and 1.66 (95% CI, 1.46-1.89) per 10-mm Hg increase in diastolic BP (DBP), respectively. In the meta-analysis, the summary relative risks were 3.07 (95% CI, 2.15-4.38, I2=76.7%, n=7 studies, 2818 ADs, 4 563 501 participants) for hypertension and 1.39 (95% CI, 1.16-1.66, I2=47.7%, n=3) and 1.79 (95% CI: 1.51-2.12, I2 = 57.0%, n=3) per 20-mm Hg increase in SBP and per 10-mm Hg increase in DBP, respectively. The AD risk showed a strong, positive dose-response relationship with SBP and even more so with DBP. The risk of AD in the nonlinear dose-response analysis was significant at SBP >132 mm Hg and DBP >75 mm Hg. CONCLUSIONS: Hypertension and elevated SBP and DBP are associated with a high risk of AD. The risk of AD was positively dose dependent, even within the normal BP range. These findings provide further evidence for the optimization of BP to prevent AD.

Acute Infarcts on Brain MRI Following Aortic Arch Repair With Circulatory Arrest: Insights From the ACE CardioLink-3 Randomized Trial.

BACKGROUND: to investigate the frequency and distribution of new ischemic brain lesions detected by diffusion-weighted imaging on brain magnetic resonance imaging after aortic arch surgery. METHODS: This preplanned secondary analysis of the randomized, controlled ACE (Aortic Surgery Cerebral Protection Evaluation) CardioLink-3 trial compared the safety and efficacy of innominate versus axillary artery cannulation during elective proximal aortic arch surgery. Participants underwent pre and postoperative magnetic resonance imaging. New ischemic lesions were defined as lesions visible on postoperative, but not preoperative diffusion weighted imaging. RESULTS: Of the 111 trial participants, 102 had complete magnetic resonance imaging data. A total of 391 new ischemic lesions were observed on diffusion-weighted imaging in 71 (70%) patients. The average number of lesions in patients with ischemic lesion were 5.5±4.9 with comparable numbers in the right (2.9±2.0) and left (3.0±2.3) hemispheres (P=0.49). Half the new lesions were in the middle cerebral artery territory; 63% of the cohort had ischemic lesions in the anterior circulation, 49% in the posterior circulation, 42% in both, and 20% in watershed areas. A probability mask of all diffusion-weighted imaging lesions revealed that the cerebellum was commonly involved. More severe white matter hyperintensity on preoperative magnetic resonance imaging (odds ratio, 1.80 [95% CI, 1.10-2.95]; P=0.02) and lower nadir nasopharyngeal temperature during surgery (odds ratio per 1°C decrease, 1.15 [95% CI, 1.00-1.32]; P=0.05) were associated with the presentation of new ischemic lesion; older age (risk ratio per 1-year increase, 1.02 [95% CI, 1.00-1.04]; P=0.03) and lower nadir temperature (risk ratio per 1°C decrease, 1.06 [95% CI, 1.00-1.14]; P=0.06) were associated with greater number of lesions. CONCLUSIONS: In patients who underwent elective proximal aortic arch surgery, new ischemic brain lesions were common, and predominantly involved the middle cerebral artery territory or cerebellum. Underlying small vessel disease, lower temperature nadir during surgery, and advanced age were risk factors for perioperative ischemic lesions. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02554032.

Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin.

BACKGROUND: The cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling. METHODS: A total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m2 and those who had a baseline LVMi > 60 g/m2. Subgroup comparisons were conducted using a linear regression model adjusted for baseline values (ANCOVA) that included an interaction term between LVMi subgroup and treatment. RESULTS: Baseline LVMi was 53.3 g/m2 (49.2-57.2) and 69.7 g/m2 (64.2-76.1) for those with baseline ≤ 60 g/m2 (n = 54) and LVMi > 60 g/m2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were - 0.46 g/m2 (95% CI: -3.44, 2.52, p = 0.76) in the baseline LVMi ≤ 60 g/m2 subgroup and - 7.26 g/m2 (95% CI: -11.40, -3.12, p = 0.0011) in the baseline LVMi > 60 g/m2 subgroup (p-for-interaction = 0.007). No significant associations were found between baseline LVMi and 6-month change in LV end systolic volume-indexed (p-for-interaction = 0.086), LV end diastolic volume-indexed (p-for-interaction = 0.34), or LV ejection fraction (p-for-interaction = 0.15). CONCLUSIONS: Patients with higher LVMi at baseline experienced greater LVM regression with empagliflozin.

Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.

BACKGROUND: This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined whether the previously reported benefit of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) mass (LVM) regression differs between individuals of South Asian and non-South Asian ethnicity. METHODS: EMPA-HEART CardioLink-6 was a double-blind, placebo-controlled clinical trial that randomised 97 individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to either empagliflozin 10 mg daily or placebo for 6 months. LV parameters and function were assessed using cardiac magnetic resonance imaging. The 6-month changes in LVM and LV volumes, all indexed to baseline body surface area, for South Asian participants were compared to those for non-South Asian individuals. RESULTS: Compared to the non-South Asian group, the South Asian sub-cohort comprised more males, was younger and had a lower median body mass index. The adjusted difference for LVMi change over 6 months was -4.3 g/m2 (95% confidence interval [CI], -7.5, -1.0; P = 0.042) for the South Asian group and -2.3 g/m2 (95% CI, -6.4, 1.9; P = 0.28) for the non-South Asian group (Pinteraction = 0.45). There was no between-group difference for the adjusted differences in baseline body surface area-indexed LV volumes and LV ejection fraction. CONCLUSIONS: There was no meaningful difference in empagliflozin-associated LVM regression between South Asian and non-South Asian individuals living with T2DM and CAD in the EMPA-HEART CardioLink-6 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02998970 (First posted on 21/12/ 2016).

A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study.

BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).

Valve deterioration: A victim of construct over time?

Surgical aortic valve replacement (sAVR) remains one of the most common cardiac operations performed globally on an annual basis. Biological and mechanical valves comprise the two classes of prosthetic valves available to surgeons. Biological prosthetic valves can be prone to failure and structural valve deterioration (SVD), which may necessitate reintervention. Recent literature suggests that the Trifecta heart valve is susceptible to early failure. In this retrospective study, Yount et al. use institutional data to assess the longevity of the Trifecta heart valve. The investigators included patients who had undergone sAVR and had received either a Trifecta prosthetic heart valve or a Magna/Magna Ease heart valve. While there were some baseline differences between the patient groups, the study found that those who had received a Trifecta valve had higher rates of valve failure. This is an important study that adds valuable evidence pertaining to the incidence of failure and SVD with the Trifecta heart valve. Although further studies may shed light on the precise mechanisms that drive valve failure and deterioration, surgeons should be aware of the mounting clinical data in this area.

Aortic valve neocuspidization and its technical nuance.

Aortic valve neocuspidization or Ozaki procedure represents an advanced surgical strategy for the management of patients with aortic valvulopathy. It has been shown to have clinical and hemodynamic outcomes that compare favorably with aortic valve replacement as it restores physiological aortic valve function and left ventricular remodeling. There are, however, a new set of issues including structural valve deterioration, leaflet tear/perforation, and need for reoperation. A keen understanding of the technical nuances involved with the Ozaki procedure may help in reducing the incidence of such adverse outcomes.

Complete transcatheter versus complete surgical management for combined aortic stenosis and coronary artery disease: A false dichotomy?

Coronary artery disease and aortic stenosis often occur concomitantly owing to their shared risk factor profile. While standard management of these patients has been through surgical methods including surgical aortic valve replacement and coronary artery bypass grafting, recent studies have investigated the potential role of complete transcatheter management (i.e., transcatheter aortic valve implantation and percutaneous coronary intervention) for these patients. In this editorial, we discuss the growing body of evidence suggesting long-term risks of transcatheter interventions despite their short-term benefits and also look to the future of hybrid approaches for multifaceted structural heart pathologies.

Cardiopulmonary bypass and cardiac surgery associated pulmonary hypertension: The need for proactivity and reactivity.

Pulmonary hypertension remains an important postcardiac surgical problem requiring prompt identification and management. In this edition of the Journal of Cardiac Surgery, Fayad and colleagues provide a detailed review of this topic, including epidemiology, mechanistic underpinnings, and available treatment options. In addition to responding to postoperative pulmonary hypertension, however, proactive measures including optimal timing of intervention are paramount to preventing the development of pulmonary hypertension and its associated complications.

Stuck between a rock and a hard place: The clinical conundrum of managing cardiac surgical patients during the SARS-CoV-2 pandemic.

Deferring nonemergent cardiac surgery became the strategy of choice for several international healthcare systems afflicted by high case burdens of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) to both conserve valuable healthcare resources and protect patients from possible exposure. Missing from the available dataset to help guide policy development has been a clear understanding of the extent to which COVID-19 infection modulates cardiac surgery outcomes. In their investigation, Bonalumi et al. uncovered an inpatient COVID-19 positivity rate of almost 10 times higher than that of the general Italian population, as well as a mortality rate over 20 times higher amongst cardiac surgery patients with perioperative COVID-19 infection compared to those COVID-negative. While the summation of available evidence points to the serious consideration cardiac surgeons must give to delaying surgeries during the COVID-19 pandemic, recognition must be given to the risks that postponing cardiac surgery may have on patient outcomes. Emerging data is beginning to demonstrate the efficacy of vaccination in preventing postoperative COVID-19 infection and morbidity.

[CHARACTERISTICS OF BUDEFORU® FOR BUDESONIDE AND FORMOTEROL MIXTURE].

BACKGROUND: Recently, BudeForu® (BF), a generic of Symbicort Turbuhaler® (SMB), is widely used in Japan. Although appearance of BF resembles to SMB, several differences in length, weight, and side-hole sizes are seen with precise inspection. As particle releases from the inhalation device is strongly influenced by its mechanical characteristics, we compared their particle release patterns. METHODS: An inhalation simulator generated either ramp-up or triangular (time to reach peak inhaling flow (PIF) = 0.42 s) inhalation pattern. Time trajectories of inhaled flow and released particles from either device were depicted with a photo-reflection method. Internal resistances of them were also measured. RESULTS: Particle release patterns of both dry powder inhalers resembled each other. Immediately after release from the inhaler, they reached the peak value and then completed in 0.5 s. In either ramp-up or triangular inspiration pattern, a single burst developed at early inhalation. There were linear relationships between PIFs and emitted doses. The regression lines using ramp-up patters were: Y = 0.00241 X - 0.039, r2 = 0.700, p ＜ 0.0001 (BF), Y = 0.00210 X - 0.038, r2 = 0.654, p ＜ 0.0001 (SMB), and those using triangular patterns were: Y = 0.00223X － 0.0015, r2 = 0.445, p ＜ 0.0001 (BF), and Y = 0.00229X － 0.0023, r2 = 0.687, p ＜ 0.0001 (SMB). Internal resistances of the BF and SMB were 0.105±0.004 and 0.119±0.105 cmH2O0.5/L/min respectively. CONCLUSIONS: Present experimental study suggested that aerodynamic characteristics of BF were quite similar to those of SMB.

Midterm outcomes after the rescue THV-in-THV procedure: Insights from the multicenter prospective OCEAN-TAVI registry.

OBJECTIVES: To confirm whether the rescue transcatheter heart valve in the transcatheter heart valve (THV-in-THV) procedure is effective and feasible, we aimed to assess the midterm outcomes following rescue THV-in-THV procedures. The trends in the usage of the rescue THV-in-THV procedure at the time of transcatheter aortic valve implantation (TAVI) have also been explored. BACKGROUND: Midterm outcomes of the rescue THV-in-THV procedure have been poorly defined, though it is popular as an effective method to bail-out some complications in TAVI. METHODS: We reviewed data from the Optimized transCathEter vAlvular iNtervention-Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry and compared the outcomes of TAVI with rescue THV-in-THV and TAVI without rescue THV-in-THV. We also examined the annual rates of rescue THV-in-THV procedures in all the TAVI procedures between 2013 and 2017. RESULTS: Among 2,588 patients who underwent TAVI, 26 patients have required rescue THV-in-THV for valve malposition (n = 23) or severe transvalvular regurgitation because of stuck THV leaflets (n = 3). Three cases needed an open conversion, and two died in the hospital. The rates of new permanent pacemaker implantation, acute kidney injury, and stroke were higher in the THV-in-THV group. A two-year cumulative survival and echocardiographic outcomes succeeding rescue THV-in-THV procedure were comparable to non-THV-in-THV cases. The rate of rescue THV-in-THV procedure lessened from 2.6% in 2013 to 0.6% in 2017. CONCLUSIONS: The rescue THV-in-THV procedure is an effective and feasible option for THV malpositioning and stuck valve. It has given a comparable survival and a stable valve function over midterm observation periods.

Blood pressure, hypertension and the risk of sudden cardiac death: a systematic review and meta-analysis of cohort studies.

Cardiovascular disease is the leading cause of death worldwide, while sudden cardiac death (SCD) accounts for over 60% of all cardiovascular deaths. Elevated blood pressure and hypertension have been associated with increased risk of SCD, but the findings have not been consistent. To clarify whether blood pressure or hypertension is associated with increased risk of SCD and to quantify the size and the shape of any association observed. PubMed and Embase databases were searched for published prospective studies on blood pressure or hypertension and SCD up to 30 April 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. The meta-analysis included 2939 SCDs among 418,235 participants from 18 studies. The summary RRs were 2.10 (95% CI 1.71-2.58, I2 = 56.7%, pheterogeneity = 0.018, n = 10) for prevalent hypertension, 1.28 (95% CI 1.19-1.38, I2 = 45.5%, pheterogeneity = 0.07, n = 10) per 20 mmHg increment in systolic blood pressure (SBP) and 1.09 (95% CI 0.83-1.44, I2 = 83.4%, pheterogeneity = 0.002, n = 3) per 10 mmHg increment in diastolic blood pressure (DBP). A nonlinear relationship was suggested between SBP and SCD. The results persisted in most subgroup and sensitivity analyses. There was no evidence of publication bias. This meta-analysis found an increased risk of SCD with hypertension diagnosis and increasing SBP. Future studies should clarify the association for DBP and the shape of the dose-response relationship between blood pressure and SCD.

Inflammatory myopathy associated with PD-1 inhibitors.

OBJECTIVE: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). METHODS: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. RESULTS: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. CONCLUSIONS: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Blood pressure, hypertension and the risk of abdominal aortic aneurysms: a systematic review and meta-analysis of cohort studies.

Abdominal aortic aneurysms (AAA) are fatal in 80% of the cases when ruptured. Hypertension has been considered a potential risk factor for AAA; but the findings from prospective cohort studies have not been entirely consistent, nor have they been summarised in a comprehensive meta-analysis. Our aim was to conduct a systematic review and meta-analysis of cohort studies of the association between blood pressure, hypertension and AAA to clarify the strength and shape of these associations. We searched PubMed and Embase databases for relevant cohort studies up to April 30th, 2018. Random-effects models were used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs). The meta-analysis included 21 cohort studies (20 publications) with data on 28,162 cases and 5,440,588 participants. The findings indicate that the RR of AAA in hypertensive patients is 1.66 times (95% CI: 1.49-1.85, I2 = 79.3%, n = 13) that of non-hypertensive patients. In addition, there was a 14% (95% CI: 6-23%, I2 = 30.5%, n = 6) and a 28% (95% CI: 12-46%, I2 = 80.1%, n = 6) increase in the RR of AAA for every 20 mmHg and 10 mmHg increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. The analysis of DBP showed evidence of a strong and highly significant nonlinear dose-response relationship (p < 0.001) with a steeper association from 80 mmHg and above. This meta-analysis suggests that hypertension increases the risk of developing AAA by 66%. Further studies are needed to clarify the underlying mechanism explaining the much stronger association between DBP and AAA than for SBP.

[IS IT NECESSARY TO PROHIBIT SIDE-HOLE CLOSURE IN USE OF THE DRY POWDER INHALERS?]

BACKGROUND: In use of Ellipta (EPT), Diskus (DKS) or Turbuhaler (TBH), an instruction not to close side holes is sometimes given, but validity of such instruction has not been proved. METHOD: Using an inhalation simulator we measured peak inhaled flow (PIF), peak inhaled pressure (PIP) and amount of the drug release from these DPIs before and after closure of side holes (SHC). In the case of EPT, incomplete obstruction was also assessed. RESULTS: SHC increased internal resistance by 2.8 times in TBH, 1.0 in DKS, and 1.28 (incomplete obstruction) and 1.86 (complete) in EPT. Inhaled flows at pressure of -15cmH2O were 14L/min in TBH, 47 in DKS and 34 in EPT (incomplete obstruction). SHC suppressed drug release from TBH but statistical significance was not obtained. Drug release was not suppressed by SHC in DKS, while it was almost half during SHC in EPT. The level of PIF decreased by SHC was serious since fine particles generation is not expected. Such severe decreases were not found in DKS and EPT. CONCLUSION: SHC severely inhibited drug release from TBH, but almost no effects on DKS. Such negative effect was limited in usual use of EPT.