Association between ICU admission during off-hours and in-hospital mortality: a multicenter registry in Japan.

BACKGROUND: The effect of ICU admission time on patient outcomes has been shown to be controversial in several studies from a number of countries. The imbalance between ICU staffing and medical resources during off-hours possibly influences the outcome for critically ill or injured patients. Here, we aimed to evaluate the association between ICU admission during off-hours and in-hospital mortality in Japan. METHODS: This study was an observational study using a multicenter registry (Japanese Intensive care PAtient Database). From the registry, we enrolled adult patients admitted to ICUs from April 2015 to March 2019. Patients with elective surgery, readmission to ICUs, or ICU admissions only for medical procedures were excluded. We compared in-hospital mortalities between ICU patients admitted during off-hours and office-hours, using a multilevel logistic regression model which allows for the random effect of each hospital. RESULTS: A total of 28,200 patients were enrolled with a median age of 71 years (interquartile range [IQR], 59 to 80). The median APACHE II score was 18 (IQR, 13 to 24) with no significant difference between patients admitted during off-hours and those admitted during office-hours. The in-hospital mortality was 3399/20,403 (16.7%) when admitted during off-hours and 1604/7797 (20.6%) when admitted during office-hours. Thus, off-hours ICU admission was associated with lower in-hospital mortality (adjusted odds ratio 0.91, [95% confidence interval, 0.84-0.99]). CONCLUSIONS: ICU admissions during off-hours were associated with lower in-hospital mortality in Japan. These results were against our expectations and raised some concerns for a possible imbalance between ICU staffing and workload during office-hours. Further studies with a sufficient dataset required for comparing with other countries are warranted in the future.

Longer term hemodialysis-dependent chronic renal failure increases the risk of post-cardiac surgery vasoplegic syndrome.

PURPOSE: We evaluated whether longer term hemodialysis (HD) is associated with a higher incidence of vasoplegic syndrome (VS) after cardiac surgery. METHODS: This retrospective, single-center cohort study included 562 consecutive patients who underwent cardiac surgery in a tertiary hospital from January 2015 to December 2016. We assessed VS occurrence and its relationship with HD duration and other risk factors. To assess the effect of the HD duration on VS occurrence, we constructed ordinal variables: HD = 0 (non-HD), 0 < HD ≤ 5 (HD ≤ 5 years), 5 < HD ≤ 10, and 10 < HD. RESULTS: The overall mean (± standard deviation) age of patients was (73 ± 11) years, and there were 60.9% men. Forty-one patients (7.3%) were HD dependent. Cardiac surgeries included all coronary artery bypass graft procedures, all valvular procedures, and aortic surgery involving cardiopulmonary bypass (CPB). Sixty-six patients (10%) developed VS. Most preoperative patient characteristics were comparable between the VS and no-VS groups; a chronic HD status and a total CPB time of > 180 min were significantly more common in the VS group (P < 0.0001 and P = 0.02, respectively). Longer term HD significantly correlated with VS incidence (P < 0.0001). Ordinal variables for the HD duration and age and known risk factors for VS (preoperative use of angiotensin-converting enzyme inhibitors and beta-blockers, low left-ventricular ejection fraction, and CPB time > 180 min) were subjected to multivariate regression analysis. Long-term HD was identified as an independent predictor of VS (odds ratio, 2.29, 95% confidence interval, 1.66-3.18). CONCLUSIONS: Longer term HD may be associated with a higher VS incidence after cardiac surgery. VS should be given attention after cardiac surgery in chronic HD-dependent patients.

Elevated Adenosine Deaminase Levels in the Cerebrospinal Fluid in Immune Checkpoint Inhibitor-induced Autoimmune Encephalitis.

Immune checkpoint inhibitors (ICIs) are promising drugs for various cancers. However, immune activation by ICIs can lead to immune-related adverse events (irAEs). Autoimmune encephalitis is a rare irAE, and its clinical features remain unknown. We herein report two patients with ICI-associated autoimmune encephalitis who, saliently, showed elevated adenosine deaminase (ADA) levels in the cerebrospinal fluid (CSF). This is the first report of increased ADA levels in the CSF of patients with ICI-induced autoimmune encephalitis. Although the mechanism of the ADA increase is poorly understood, elevated ADA in the CSF may be informative in the diagnosis of this rare disorder.

Exacerbation of autoimmune hemolytic anemia induced by the first dose of programmed death-1 inhibitor pembrolizumab: a case report.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy against various types of cancers. In addition to immune-related adverse events (irAEs) induced by ICIs, exacerbation of baseline autoimmune disease has been occasionally reported. This is the first report of autoimmune hemolytic anemia (AIHA) exacerbated by pembrolizumab. An 82-year-old Japanese male was diagnosed with lung adenocarcinoma 2 years ago. The patient had chronic anemia with positive direct and indirect Coombs test prior to initiating pembrolizumab therapy at a nearby hospital. However, a definitive diagnosis of AIHA was not made at that time. Seventeen days after the first dose of pembrolizumab, the patient was admitted to the Kobe City Medical Center General Hospital with severe hemolytic anemia (Hb 3.6 g/dL). After thorough examinations including bone marrow biopsy, the patient was diagnosed with pre-existing AIHA exacerbated by pembrolizumab therapy. Two weeks after treatment with prednisone, the levels of hemoglobin became stable with the reduced frequency of blood transfusion and improvements of hemolytic findings on blood tests and the patient was discharged from the hospital. This case report highlighted the importance of determining the patient's pre-existing autoimmune status associated with chronic anemia prior to initiating treatment with ICIs.

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia.

INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP. METHODS: Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly. RESULTS: Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response. CONCLUSIONS: Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037).

Aprepitant for refractory nivolumab-induced pruritus.

Although substantial progress has been made in the treatment of non-small-cell lung cancer (NSCLC) patients with immune checkpoint inhibitors (ICIs), severe immune-related adverse events (irAEs) sometimes occur. Here, we report a case of severe refractory pruritus after Stevens-Johnson syndrome (SJS) in a patient with NSCLC treated with nivolumab. The patient was a 76-year-old Japanese woman with advanced NSCLC treated with nivolumab. After the second dose, she experienced severe rash with mucous involvement. We diagnosed SJS and started 50mg of oral prednisolone (1mg/kg). The rash completely resolved after prednisolone was started, but we could not manage the severe pruritus with emollients, antihistamines, and steroids. Finally, we administered aprepitant, an oral neurokinin-1 receptor antagonist, for her refractory pruritus. Her symptoms improved within 5days. Severe refractory pruritus can arise from ICIs, and aprepitant may be a useful treatment.

Characteristics and Prognostic Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patients with Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Data on characteristics, outcomes, and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently lacking. METHODS: We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital. RESULTS: A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09-2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3-7.2 months). CONCLUSIONS: Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC.

The prognostic value of serum CA 19-9 for patients with advanced lung adenocarcinoma.

BACKGROUND: This study aimed to assess the prognostic accuracy of serum CA 19-9 in patients with advanced lung adenocarcinoma. METHODS: We retrospectively reviewed data of 246 patients who were diagnosed at our institute with advanced (stage IIIB or IV) lung adenocarcinoma between March 2006 and December 2012. We excluded patients who received no chemotherapy, or for whom we had no data on pre-treatment tumor markers. We also evaluated 116 consecutive resected specimens from patients with clinical stage I lung adenocarcinoma pathologically. RESULTS: The 76 (31 %) patients who were CA 19-9+ had shorter overall survival (OS) than CA 19-9- group (12.5 vs 26.2 months, P = 0.005). Cox's multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P < 0.001), mutated epidermal growth factor receptor (EGFR) status (P < 0.001), stage IIIB (P < 0.001), CYFRA 21-1- (P < 0.001), CA 19-9- (P = 0.005) and use of platinum doublet therapy (P = 0.034) as independent predictors of longer OS. We stratified patients by CA 19-9 and CYFRA 21-1 as double positive (CA 19-9+/CYFRA 21-1+, n = 59), single positive (either CA19-9+ or CYFRA 21-1+, n = 113), or double negative (CA 19-9-/CYFRA 21-1-, n = 74). Their respective OS were 10.0, 23.3 and 31.8 months (P < 0.001). Pathological analysis also correlated CA 19-9 expression with malignant features such as vessel invasion, pleural invasion, cancer invasive factors and mucin production. CONCLUSIONS: CA 19-9 and CYFRA 21-1 are independent prognostic markers in patients with advanced lung adenocarcinoma. Combined use of CA 19-9 and CYFRA 21-1 provides further prognostic information in patients with advanced lung adenocarcinoma.

Second-line Chemotherapy for Patients with Small Cell Lung Cancer and Interstitial Lung Disease.

BACKGROUND: The safety and efficacy of second-line chemotherapy for treating patients with small cell lung cancer (SCLC) and interstitial lung disease (ILD) have not been elucidated to date. PATIENTS AND METHODS: Between January 2005 and September 2013, we analyzed 23 patients with SCLC and ILD who received second-line chemotherapy. Pre-existing ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography results. RESULTS: The overall objective response rates and disease control rates were 22% and 52%, respectively. The median respective durations of progression-free survival and overall survival were 2.1 months (95% confidence interval (CI)=2.0-3.0 months) and 7.1 months (95% CI=3.6-11.3 months), respectively. Three patients with unusual interstitial pneumonia pattern (13%) developed chemotherapy-related pneumonitis. CONCLUSION: Second-line treatment may be an effective and safe option for SCLC patients with ILD after sufficient evaluation of risks and benefits.

Analysis of advanced lung cancer patients diagnosed following emergency admission.

Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking. We retrospectively analysed data from 771 patients with advanced nonsmall cell lung cancer between April 2004 and April 2012. Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29-0.44), p<0.001; 0.49 (0.38-0.63), p<0.001; 0.64 (0.51-0.80), p<0.001; 0.81 (0.67-0.99), p=0.044; and 0.40 (0.31-0.52), p<0.001, respectively). Good PS just prior to opting for chemotherapy, but not at emergency admission, was a good independent predictor of overall survival in DFEA patients (hazard ratio (95% CI) 0.26 (0.12-0.55); p<0.001). DFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances.