Impact of immune-related adverse events on survival outcomes in extensive-stage small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer. METHODS: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events. RESULTS: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013). CONCLUSIONS: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer.

Efficacy and Safety of Amrubicin in Small Cell Carcinoma Previously Treated with Immune Checkpoint Inhibitors and Chemotherapy.

Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors.

[First case of lung abscess due to Yersinia pseudotuberculosis in Japan].

A 63-year-old previously healthy man was admitted to our hospital with diarrhea that had lasted for about 4 weeks, high fever and dyspnea. Chest computed tomography showed consolidation with a low-density area in the right middle lobe and small nodules with feeding vessels in the right upper lobe. On Day 8, a cavity was observed in the consolidation, and the lymph nodes in the mediastinum became necrotic. Yersinia pseudotuberculosis (serotype 4b) was cultured from blood, bronchial washing fluid, and lung tissue specimens. We diagnosed the lung lesions as septic pulmonary embolism caused by enterocolitis. We started treatment with tazobactam/piperacillin. It has been reported that high-dose ceftriaxone (CTRX) is effective, but CTRX at normal doses and other beta-lactams are less effective or even ineffective. Therefore, we changed to CTRX (4g/day) on Day 5, CTRX (2g/day) on Day 8, and oral cefditoren pivoxil (600 mg/day; a third-generation cephalosporin) on Day 18. Antibiotic therapy resulted in a favorable response. The patient was discharged from our hospital on day 25 in good health. To the best of our knowledge, this is the first case of a lung abscess caused by Y. pseudotuberculosis reported in Japan.

A new strategy for healthcare-associated pneumonia: a 2-year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy.

BACKGROUND: Optimal empiric therapy for hospitalized patients with healthcare-associated pneumonia (HCAP) is uncertain. METHODS: We prospectively applied a therapeutic algorithm, based on the presence of risk factors for multidrug-resistant (MDR) pathogens in a multicenter cohort study of 445 pneumonia patients, including both community-acquired pneumonia (CAP; n = 124) and HCAP (n = 321). RESULTS: MDR pathogens were more common (15.3% vs 0.8%, P < .001) in HCAP patients than in CAP patients, including Staphylococcus aureus (11.5% vs 0.8%, P < .001); methicillin-resistant S. aureus (6.9% vs 0%, P = .003); Enterobacteriaceae (7.8% vs 2.4%, P = .037); and Pseudomonas aeruginosa (6.9% vs 0.8%, P = .01). Using the proposed algorithm, HCAP patients with ≥2 MDR risk factors, one of which was severity of illness (n = 170), vs HCAP patients with 0-1 risk factor (n = 151) had a significantly higher frequency of MDR pathogens (27.1% vs 2%, P < .001). In total, 93.1% of HCAP patients were treated according to the therapy algorithm, with only 53% receiving broad-spectrum empiric therapy, yet 92.9% received appropriate therapy for the identified pathogen. Thirty-day mortality was significantly higher for HCAP than for CAP (13.7% vs 5.6%, P = .017), but among HCAP patients with 0-1 MDR risk factor, mortality was lower than with ≥2 MDR risk factors (8.6% vs 18.2%, P = .012). In multivariate analysis, initial treatment failure, but not inappropriate empiric antibiotic therapy, was a mortality risk factor (odds ratio, 72.0). CONCLUSIONS: Basing empiric HCAP therapy on its severity and the presence of risk factors for MDR pathogens is a potentially useful approach that achieves good outcomes without excessive use of broad-spectrum antibiotic therapy. CLINICAL TRIALS REGISTRATION: Japan Medical Association Center for Clinical Trials, JMA-IIA00054.

Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients.

The rapid increase in the elderly population is leading to a corresponding increase in the number of people requiring medical care. To date no comparative study between community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) has been reported in the very elderly non-intubated patients. The present study was undertaken to compare the clinical characteristics and microbial etiology between CAP and NHAP in elderly patients >/=85-years old. There were 54 patients with NHAP and 47 with CAP. Performance status was significantly worse in the NHAP than in the CAP group. Among all patients, the most frequent pathogens were Chlamydophilia pneumoniae followed by Streptococcus pneumoniae, Mycoplasma pneumoniae influenza virus and Staphylococcus aureus. The frequency of S. peumoniae was significantly higher in NHAP patients than in CAP patients after adjusting for age and sex. Physical activity, nutrition status and dehydration were significant prognostic factors of pneumonia among all patients. In-hospital mortality was significantly higher in NHAP than in CAP after adjusting for age and sex. This study demonstrated that the etiology and clinical outcome differ between CAP and NHAP patients in the very elderly non-intubated population.

[Combination therapy of micafungin and itraconazole for a case of pulmonary aspergillosis].

The patient was a 73-year-old female who visited a physician with a chief complaint of fever, and was diagnosed with pneumonia. Ampicillin/sulbactam was administered, but ineffective, and the patient was referred to our hospital. In addition to severe inflammatory findings, cavity lesions were observed in the right upper lobe on plain chest X-ray and thoracic CT. Since Aspergillus fumigatus was cultured in bronchoalveolar lavage, a definite diagnosis of pulmonary aspergillosis was made. Intravenous administration of micafungin was initiated, but severe inflammatory findings persisted, and infiltrative shadows rapidly expanded. Oral itraconazole was concomitantly administered, and clinical symptoms and findings slowly improved. The plasma trough levels of micafungin, itraconazole, and hydroxyitraconazole were higher than the minimal inhibitory concentrations for the etiologic fungus, A. fumigatus, throughout the treatment period. No adverse events of the concomitant treatment were observed. Combination of the two antifungal agents may be effective for intractable pulmonary aspergillosis.

Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients.

Impairment of fibrinolytic function plays an important role in the mechanism of thrombotic disorders in cancer patients. This study assessed the circulating level of thrombin-activatable fibrinolysis inhibitor in patients with lung cancer and its expression by several lung cancer cell lines. The plasma concentrations of thrombin-activatable fibrinolysis inhibitor were significantly increased in lung cancer patients compared to healthy subjects. The concentration of thrombin-activatable fibrinolysis inhibitor was particularly higher in patients with small cell carcinoma compared to those with adenocarcinoma or squamous cell carcinoma, and in cancer patients that responded to chemotherapy compared to non-responders. In vitro studies showed more expression of thrombin-activatable fibrinolysis inhibitor in small cell carcinoma than in adenocarcinoma cell lines and more expression in lung cancer cell lines sensitive to anti-cancer agents than in resistant cell lines. This study suggests that thrombin-activatable fibrinolysis inhibitor, in part secreted from lung cancer cells, may play a role in the pathogenesis of thrombotic disorders in lung cancer patients.

Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice.

Asthma is one of the most common diseases and is characterized by airway obstruction, airway inflammation, and increased airway responsiveness. Glucocorticoids are very effective in treatment, but their long-term use is associated with several side effects, so that new anti-inflammatory drugs are in development. Activated protein C (APC) is a serine protease with potent anti-inflammatory effects. This study evaluated the effect of inhaled APC on airway inflammation and hyperresponsiveness in a murine asthma model. Asthma was induced in BALB/c mice by exposure to chicken egg ovalbumin (OVA), and the effect of inhaled APC was assessed by administering prior to OVA exposure. Inhalation of APC significantly inhibited the expression of T helper 2 (Th2) cytokines, immunoglobulin E (IgE), eosinophilic inflammation, and hyperresponsiveness. APC also significantly suppressed the expression of Th2 cytokines and IgE from lymphocytes isolated from OVA-sensitized/challenged animals. In addition, binding of signal transducer and activator of transcription 6 (STAT6) and nuclear factor kappa B (NF-kappa B) oligonucleotides to lung nuclear proteins was significantly reduced in mice treated with inhaled APC. In brief, the exogenous supplementation of APC inhibits the immunologic and inflammatory responses induced by Th2 cytokines in a mouse model of asthma and may represent a novel anti-inflammatory treatment.

Thrombin-activatable fibrinolysis inhibitor and protein C inhibitor in interstitial lung disease.

Intraalveolar activation of the coagulation system due to reduced fibrinolytic function plays a critical role in the pathogenesis of interstitial lung disease. Recently, a new potent inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor, has been isolated and characterized from human plasma. This study evaluated the levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, another suppressor of fibrinolysis, in the bronchoalveolar lavage fluid from patients with interstitial lung disease. There were 82 patients with interstitial lung disease and 8 normal subjects. The bronchoalveolar lavage fluid levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were significantly higher in all patients with interstitial lung disease than in normal subjects. Both inhibitors of fibrinolysis were significantly and inversely correlated with fibrinolytic activity in all patients. The levels of thrombin-activatable fibrinolysis inhibitor were significantly correlated with those of protein C inhibitor, thrombin-antithrombin complex, and monocyte chemoattractant protein-1. Reverse transcriptase-polymerase chain reaction showed that alveolar macrophages isolated from patients with interstitial lung disease as well as immortalized lung epithelial cell lines express thrombin-activatable fibrinolysis inhibitor antigen. Overall, these findings suggest that thrombin-activatable fibrinolysis inhibitor and protein C inhibitor may play important roles in the mechanism of intraalveolar hypofibrinolysis associated with interstitial lung diseases.