Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
Summary
What is known and objective
Higher rate of statin‐related hepatotoxicity has been reported for Koreans than for Westerners. Moreover, statin‐related aminotransferase elevation for those who ...show borderline levels of aspartate transaminase (AST) and alanine transaminase (ALT) (≤×3 of UNL) at baseline has not been fully investigated.
Methods
Post‐statin changes AST/ALT levels during the first year for 21 233 Korean outpatients at two large academic teaching hospitals from January 2009 to December 2013 were analysed using electronic health record data. The date of the first statin prescription was set as baseline. We also performed a comparative analysis of statin‐related AST/ALT elevations according to the type of statin, followed by an analysis of clinical risk factors.
Results and discussion
The progression rate to abnormal AST/ALT values >×3 the upper normal limit (UNL) was significantly higher (2·4–16% vs. 0·3–1·7%, P < 0·001) in subjects with borderline (>×1, but ≤×3 of UNL) compared with normal AST/ALT values at baseline. Those with normal baseline AST/ALT did not show significantly different progression rate between different statin medications (P = 0·801). However, patients taking pitavastatin (HR = 0·76, P = 0·657) were least likely to develop abnormal AST/ALT, whereas those taking fluvastatin (HR = 2·96, P = 0·029) were the most likely to develop abnormal AST/ALT compared with atorvastatin for patients who were with baseline borderline AST/ALT. However, given the small sample sizes and the observational nature of our study, these need further study.
What is new and conclusion
It is advisable to regularly monitor AST/ALT levels even in patients with AST/ALT increases >×1. Future studies should aim to determine the possible risk factors for each specific statin type by analysing various confounding variables.
The progression rate to abnormal AST/ALT values (>×3 the UNL) was significantly higher in subjects with borderline (>×1, but ≤ ×3 of UNL) compared to normal AST/ALT values at baseline. It is advisable to regularly monitor AST/ALT levels in patients with AST/ALT increases >×1, but ≤×3 of UNL.
In the supine position, forced-air warming is more effective on the lower body than on the upper body to prevent intraoperative hypothermia. However, it is unknown in the lateral decubitus position. ...We thus compared forced-air warming on the upper and lower bodies in the lateral position.
Patients (n=123) were randomised to receive forced-air warming on the upper body or lower body during thoracoscopic surgery in the lateral position. We measured the nasopharyngeal temperature at 0, 30, 60, 90, and 120 min after lateral positioning during surgery and the infrared tympanic membrane temperature at 0, 30, 60, 90, and 120 min after surgery. Patients received both upper and lower body warming at a temperature of <35.5°C. The primary outcome was the incidence of intraoperative hypothermia with a temperature of <36.0°C.
Intraoperative hypothermia was less frequent with the upper body warming than with the lower body warming {21/62 vs 35/61, risk ratio 95% confidence interval (CI) 0.6 (0.4–0.9), P=0.011}. The intraoperative temperature was higher with the upper body warming than with the lower body warming at 30 (P=0.002), 60 (P<0.001), and 90 (P<0.001) min after lateral positioning, and the postoperative temperature was higher at 0 (P<0.001) and 30 (P=0.001) min after surgery. Fewer patients received both upper and lower body warming in the upper body warming group than in the lower body warming group during surgery (1 vs 7, P=0.032).
Forced-air warming was more effective on the upper body than on the lower body to prevent hypothermia during thoracoscopic surgery in the lateral decubitus position.
NCT02993666.
Summary
We aimed to investigate the effect of the analgesia nociception index on postoperative pain. We randomly allocated 170 women scheduled for gynaecological laparotomy and analysed results from ...159: in 80 women, remifentanil was infused to maintain analgesia nociception indices 50–70; and in 79 women, remifentanil was infused to maintain systolic blood pressure < 120% of baseline values. The primary outcome was the proportion of women with pain scores ≥ 5 (scale 0–10) within 40 min of admission to recovery. The proportion of women with pain scores ≥ 5 was 62/80 (78%) vs. 64/79 (81%), p = 0.73. Mean (SD) doses of fentanyl in recovery were 53.6 (26.9) μg vs. 54.8 (20.8) μg, p = 0.74. Intra‐operative remifentanil doses were 0.124 (0.050) μg.kg−1.min−1 vs. 0.129 (0.044) μg.kg−1.min−1, p = 0.55.
Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. ...We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population. A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2'-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests. We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV₁), FEV₁/forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters. This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.
We investigated domain kinetics by measuring the polarization switching behaviors of (111)-preferred polycrystalline Pb(Zr,Ti)O3 films, which are widely used in ferroelectric memories. Their ...switching behaviors at various electric fields and temperatures could be explained by assuming the Lorentzian distribution of logarithmic domain-switching times. We suggested that the local field variation due to dipole defects at domain pinning sites could explain the Lorentzian distribution.
Treatment of cirrhotic patients with spontaneous peritonitis using antibiotics occasionally fails. Fungal infections may be one of the causes of antibiotic treatment failure in such patients. In this ...study we evaluated the clinical significance and characteristics of spontaneous fungal peritonitis (SFP). Consecutive cirrhotic patients with spontaneous peritonitis treated between 2000 and 2005 at a tertiary care center in Seoul, Korea, were included. We analyzed the clinical characteristics and the prognosis of SFP patients compared with patients with spontaneous bacterial peritonitis (SBP). During the study period 416 patients developed spontaneous peritonitis and 15 (3.6 %) had SFP. Compared with patients with SBP, nosocomial peritonitis (peritonitis that developed after hospitalization for >72 h) was more common and the Child–Pugh score was higher in SFP patients (both,
P
< 0.01). Ten patients were infected with
Candida
spp. (
C. albicans
, 8;
C. tropicalis
, 1;
C. glabrata
, 1), and 5 with
Cryptococcus neoformans
. Eleven patients were co-infected with bacteria that were susceptible to the antibiotics administered. Only 5 patients were treated using appropriate anti-fungal agents. The 1-month mortality rate for SFP patients was 73.3 % (11 out of 15; median time to death, 2 days range, 0–22), which was significantly higher than patients with SBP alone (28.7 %,
P
= 0.0007). SFP is severe complication related to high mortality in cirrhotic patients. A longer admission and a higher Child–Pugh score may be risk factors. Immediate anti-fungal treatment is warranted in patients with spontaneous peritonitis, once fungus is found in the ascitic fluid.
Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different ...mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
PDF
