The lung microbiome maintains the homeostasis of the immune system within the lungs. In acute respiratory distress syndrome (ARDS), the lung microbiome is enriched with gut-derived bacteria; however, ...the specific microbiome associated with morbidity and mortality in patients with ARDS remains unclear. This study investigated the specific patterns of the lung microbiome that are correlated with mortality in ARDS patients.
We analyzed the lung microbiome from the bronchoalveolar lavage fluid (BALF) of patients with ARDS and control subjects. We measured the copy numbers of 16S rRNA and the serum and BALF cytokines (interleukin IL-6, IL-8, receptor for advanced glycation end products, and angiopoietin-2).
We analyzed 47 mechanically ventilated patients diagnosed with (n = 40) or without (n = 7; control) ARDS. The alpha diversity was significantly decreased in ARDS patients compared with that of the controls (6.24 vs. 8.07, P = 0.03). The 16S rRNA gene copy numbers tended to be increased in the ARDS group compared with the controls (3.83 × 10
vs. 1.01 × 10
copies/mL, P = 0.06). ARDS patients were subdivided into the hospital survivor (n = 24) and non-survivor groups (n = 16). Serum IL-6 levels were significantly higher in the non-survivors than in the survivors (567 vs. 214 pg/mL, P = 0.027). The 16S rRNA copy number was significantly correlated with serum IL-6 levels in non-survivors (r = 0.615, P < 0.05). The copy numbers and relative abundance of betaproteobacteria were significantly lower in the non-survivors than in the survivors (713 vs. 7812, P = 0.012; 1.22% vs. 0.08%, P = 0.02, respectively). Conversely, the copy numbers of Staphylococcus, Streptococcus and Enterobacteriaceae were significantly correlated with serum IL-6 levels in the non-survivors (r = 0.579, P < 0.05; r = 0.604, P < 0.05; r = 0.588, P < 0.05, respectively).
The lung bacterial burden tended to be increased, and the alpha diversity was significantly decreased in ARDS patients. The decreased Betaproteobacteria and increased Staphylococcus, Streptococcus and Enterobacteriaceae might represent a unique microbial community structure correlated with increased serum IL-6 and hospital mortality.
The institutional review boards of Hiroshima University (Trial registration: E-447-4, registered 16 October 2019) and Kyoto Prefectural University of Medicine (Trial registration: ERB-C-973, registered 19 October 2017) approved an opt-out method of informed consent.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin‐dependent kinase 4/6 inhibitor, ...as monotherapy for solid tumors (part 1) and combined with letrozole as first‐line treatment of postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment‐related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100‐mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration–time curve over dosing interval τ: 1322 vs 547.5 ng·h/mL single dose, 2838 vs 1276 ng·h/mL multiple dose; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL single dose, 185.5 vs 77.4 ng/mL multiple dose). Half‐life was 23–26 h. No drug–drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer 100 mg and one with esophageal cancer 125 mg) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125‐mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.
This phase 1 study in Japanese patients evaluates the safety, pharmacokinetics, and preliminary efficacy of palbociclib as monotherapy for solid tumors (part 1) and combined with letrozole as first‐line treatment of postmenopausal patients with ER+/HER2− advanced breast cancer (part 2). Overall, the results of this study suggest that palbociclib 125 mg was tolerated and is a recommended dose for monotherapy and letrozole combination therapy in Japanese patients.
Background
The long-term outcomes and risk factors of paclitaxel-induced peripheral neuropathy (PIPN) have not yet been fully elucidated.
Methods
We identified 219 breast cancer patients who received ...paclitaxel as adjuvant chemotherapy between 2002 and 2009. We retrospectively analyzed the incidence, time to onset, duration, and risk factors for PIPN by chart review.
Results
Of the 219 patients, 212 developed PIPN (97%) during a median follow-up time of 57 months (range 5.3–95.5). Median time to PIPN onset was 21 days (range 11–101) for the entire patient population: 35 days (range 14–77) for weekly administration and 21 days (range 11–101) for tri-weekly administration. PIPN caused termination of paclitaxel treatment in 7 patients (4%). Median duration of PIPN was 727 days (range 14–2621 days). PIPN persisted in 64 and 41% of patients at 1 and 3 years after initiating paclitaxel, respectively. Age ≥60 years and severity of PIPN were significantly associated with PIPN duration.
Conclusions
PIPN persists longer in older patients and in those who experience severe neuropathy. Further studies to identify the risk factors for PIPN are warranted.
BACKGROUND
Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and ...promising antiemetic efficacy in patients receiving cisplatin‐based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double‐blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide (AC/EC) chemotherapy.
METHODS
Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (<55 vs ≥55 years) and study site. The primary end point was the incidence of treatment‐related adverse events (TRAEs) with FosNTP.
RESULTS
Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval CI, 11.1%‐34.7%) and FosAPR (22.0%; 95% CI, 11.5%‐36.0%), with any‐cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment‐related ISRs observed in 0% and 10.0%, respectively. The overall (0‐120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR.
CONCLUSIONS
FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.
Fosnetupitant shows a favorable safety profile in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide chemotherapy. As an intravenous neurokinin 1 receptor antagonist with a low risk of causing injection site reactions, fosnetupitant may be used for protecting patients with cancer from experiencing chemotherapy‐induced nausea and vomiting.
Preclinical models revealed potential synergistic effects of programmed cell death-1 inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies. Therefore, we investigated the use of ...nivolumab, bevacizumab, and paclitaxel triple therapy for metastatic breast cancer.
This phase 2, multicentre, single-arm study (NEWBEAT) investigated the safety and efficacy of first-line nivolumab, paclitaxel, and bevacizumab in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of programmed cell death-ligand 1 expression. The primary end-point was objective response rate. Key secondary end-points included progression-free survival, overall survival, and toxicities. A biomarker study evaluated tumour programmed cell death-ligand 1 expression and serum VEGF-A levels.
Between February 2018 and October 2018, 57 patients were enrolled. An objective response rate was seen in 39/56 patients (70%, 95% confidence interval CI: 55.9–81.2%), meeting the primary end-point. The objective response rate was 74% in patients with hormone receptor-positive breast cancer versus 59% in patients with triple-negative breast cancer. The median progression-free survival and overall survival were 14.0 (95% CI 11.0–16.3) and 32.5 (95% CI 26.0–not evaluable) months, respectively (median follow-up: 29.5 months). Grade 3/4 adverse drug reactions occurred in 33 of 57 patients (58%). There were no grade 5 adverse events. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3/4 events in eight patients (14%). Biomarker analysis showed that tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. Efficacy outcomes were similar between the serum VEGF-high and VEGF-low groups.
First-line nivolumab, bevacizumab, and paclitaxel therapy showed promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.
•First clinical trial to report efficacy of nivolumab, bevacizumab, and paclitaxel.•Objective response rates were promising (74% in HR+HER2− and 59% in patients with triple-negative breast cancer).•The median progression-free survival and overall survival were 14.0 months and 32.5 months, respectively.•Tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy.•Efficacy and prognosis were similar between serum vascular endothelial growth factor-high and vascular endothelial growth factor-low groups.
While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported ...in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.
To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.
The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.
We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coordinated development of excitatory and inhibitory synapses is essential for higher brain function, and impairment in this development is associated with neuropsychiatric disorders. In contrast to ...the large body of accumulated evidence regarding excitatory synapse development, little is known about synaptic adhesion and organization mechanisms underlying inhibitory synapse development. Through unbiased expression screens and proteomics, we identified immunoglobulin superfamily member 21 (IgSF21) as a neurexin2α-interacting membrane protein that selectively induces inhibitory presynaptic differentiation. IgSF21 localizes postsynaptically and recruits axonal neurexin2α in a trans-interaction manner. Deleting IgSF21 in mice impairs inhibitory presynaptic organization, especially in the hippocampal CA1 stratum radiatum, and also diminishes GABA-mediated synaptic transmission in hippocampal CA1 neurons without affecting their excitatory synapses. Finally, mice lacking IgSF21 show a sensorimotor gating deficit. These findings suggest that IgSF21 selectively regulates inhibitory presynaptic differentiation through interacting with presynaptic neurexin2α and plays a crucial role in synaptic inhibition in the brain.Molecular mechanisms regulating the development of inhibitory synapses are poorly understood. Here the authors show that IgSF21 interacts with neurexin2α to induce presynaptic differentiation of inhibitory synapses, and that mice lacking IgSF21 exhibit deficits in inhibitory synaptic transmission.
The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor ...cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio HR 2.36; 95% confidence interval CI, 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.
High PD‐L1 expression on tumor cells was significantly associated with a poor prognosis, whereas high PD‐L1 expression on tumor‐infiltrating mononuclear cells positively affected the prognosis of patients with stage III colorectal cancer.
Asymmetric dimethylarginine (ADMA) is a nonselective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. NO regulates placental blood flow, which plays an ...important role in fetal growth. Many epidemiological studies have disclosed that restricted fetal growth is associated with an increased risk of insulin resistance in adult life. We studied the relationship between ADMA in cord blood and birth size. Nine small for gestational age (SGA) and 32 appropriate for gestational age (AGA) infants were studied. Their cord plasma ADMA, insulin, insulin-like growth factor-1 (IGF-1), and adipocytokine levels were determined using enzyme-linked immunosorbent assays. The relationship between birth weight and ADMA levels followed a U-shaped curve rather than inverse linear associations expected over a full range of birth weight distribution. ADMA positively correlated with birth weight in the AGA group (p<0.001, R=0.590), and inversely correlated with birth weight in the SGA group (p<0.05, R=-0.741). ADMA inversely correlated with adiponectin (p<0.05, R=-0.289) and quantitative insulin sensitivity check index (QUICKI) (p<0.05, R=-0.294) in all subjects, and did not correlate with nitrogen oxides (NOX). Insulin, IGF-1, leptin, adiponectin and QUICKI were lower in the SGA than the AGA group. Plasma ADMA levels in cord blood may be a marker of fetal growth and insulin resistance.
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