Daichi Fujimoto

Enteral Nutrition Is a Risk Factor for Airway Complications in Subjects Undergoing Noninvasive Ventilation for Acute Respiratory Failure

BACKGROUND: Early enteral nutrition is recommended for mechanically ventilated patients in several studies and guidelines. In contrast, the effects of early enteral nutrition on noninvasive ventilation (NIV) have not been investigated extensively. The lack of an established method of airway protection suggests that enteral nutrition administration to these patients could increase airway complications and worsen outcomes. METHODS: Between January 2007 and January 2015, 150 patients were admitted to our respiratory department for acute respiratory failure and received NIV for >48 h. Of these, 107 subjects incapable of oral intake were retrospectively analyzed. Clinical background and complications were compared in subjects who did and did not receive enteral nutrition. RESULTS: Sixty of the 107 subjects (56%) incapable of oral intake who received NIV also received enteral nutrition. Serum albumin concentration was significantly lower in subjects who received enteral nutrition than in those who did not (mean 2.7 ± 0.68 mg/dL vs 3.0 ± 0.75 mg/dL, P = .048). The rate of airway complications was significantly higher (53% [32/60] vs 32% [15/47], P = .03), and median NIV duration was significantly longer (16 [interquartile range 7–43] d vs 8 [5–20] d, P = .02) in subjects who received enteral nutrition than in those who did not. Multivariate analysis showed that enteral nutrition was unrelated to in-hospital mortality. CONCLUSIONS: Among subjects receiving NIV, enteral nutrition was associated with increased risk of airway complications but did not affect mortality. Enteral nutrition should be carefully considered in these patients.

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

Introduction Retrospective studies have shown immune‐related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy. Methods We conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals. Results A total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1‐positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression‐free survival than those without (6.4 months [95% confidence interval: 2.5‐not reached] versus 1.5 months [95% confidence interval: 1.2–2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment. Conclusions Early irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.

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.

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).

Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.

Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non–Small Cell Lung Cancer

Introduction: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD‐L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. Methods: We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD‐L1 IHC assays (28‐8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%–49%), or negative (TPS <1%). Results: A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD‐L1–stained tumor cells among the 28‐8, 22C3, and SP263 assays (weighted &kgr; coefficient 0.64–0.71), whereas the SP142 assay showed lower concordance with other assays (weighted &kgr; coefficient 0.39–0.55). Progression‐free survival in patients showing strongly positive PD‐L1 staining classified by 28‐8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD‐L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28‐8, 22C3, and SP263 assays (area under the curve 0.75–0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). Conclusions: The 28‐8, 22C3, and SP263 PD‐L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity

Ground glass nodules (GGNs) are frequently encountered in the lungs. We report the natural history and characteristics of multiple GGNs, and propose a management plan for patients with multiple GGNs.

Bevacizumab for ramucirumab refractory malignant pleural effusion in non-small cell lung cancer: a case report and review of the literature

Malignant pleural effusion (MPE) is a major problem associated with advanced non-small cell lung cancer for which an optimum treatment strategy has yet to be determined. Notably, vascular endothelial growth factor (VEGF) signaling has been found to influence MPE, and bevacizumab, a VEGF ligand inhibitor, can effectively control MPE. Ramucirumab, a human monoclonal antibody specific for VEGF receptor-2, has recently been approved for advanced non-small cell lung cancer. However, it remains unclear which of these agents more effectively control MPE. We describe a case of a 68-year-old man with advanced non-small cell lung cancer in whom ramucirumab plus docetaxel-refractory MPE was responsive to bevacizumab plus docetaxel combination therapy. The patient’s MPE progressed after two cycles of ramucirumab plus docetaxel second-line chemotherapy. After switching to bevacizumab plus docetaxel, a computed tomography scan revealed a decreased MPE after two cycles of treatment. Bevacizumab may be more effective for treating MPE. However, further investigations are still warranted to determine the optimal VEGF-targeted agent for this condition.

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study

INTRODUCTION Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. RESULTS Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). CONCLUSIONS Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumabs efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Prior radiotherapy does not predict nivolumab response in non-small-cell lung cancer: a retrospective cohort study

Nivolumab is one of the standard therapy for previously treated advanced non-small-cell lung cancer (NSCLC) [1]. Durable responses are observed in NSCLC patients treated with nivolumab, but there are fewer than half of patients who will benefit [1]. Immunotherapy administration after radiotherapy may provide synergistic effects (i.e. abscopal effect) [2, 3]. However, it is unclear whether past radiotherapy especially to lung is predictive or not in NSCLC who receive immune checkpoint inhibitor. We conducted a multicenter retrospective cohort study. We included consecutive patients treated with nivolumab between January 2016 and October 2016 after the second line systemic chemotherapy outside of a clinical trial. Variables were retrieved from the medical records before the administration of nivolumab. All variables were dichotomized based on previous study or median [4, 5]. Primary endpoint was progression-free survival (PFS) defined by response evaluation criteria in solid tumors (RECIST) 1.1. Two researchers evaluated the endpoint independently. Any disagreements were resolved by discussion. Cox proportional hazards models were used to assess the impact of pretreatment markers on PFS. One hundred forty-six patients were included. Median observation period were 153 days. Patients characteristics were as follows: median age 69 years, female 36 (25%), never smoker 28 (19%), performance status<2 110 (75%), non-squamous histology 107 (73%). The main results are shown in Table 1. No difference of progression free survival between those without past radiotherapy and received in past 6 months was noted [adjusted hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.37–1.14]. Ten patients (7%) suffered pneumonitis. Two patients received radiotherapy to the lung before one year. Eight patients did not received radiotherapy to the lung (risk ratio 1.34; 95% CI 0.30– 5.90). Past radiotherapy was not a predictive factor. Our study had limited sample size (146 patients with 112 events). Assuming a two-sided a of 0.05, the power to detect the HR of 0.65 was 0.63. So, the conclusion might change with the larger sample size. The results do not deny the additional effect of concurrent radiotherapy with immune checkpoint inhibitor in NSCLC. Further investigation of concurrent radiotherapy is warranted.