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Pulmonary tumor thrombotic microangiopathy (PTTM) is an acute, progressive, and fatal disease. PTTM manifests as subacute respiratory failure with pulmonary hypertension, progressive right-sided heart failure, and sudden death. An antemortem diagnosis of PTTM is very difficult to obtain, and many patients die within several weeks. We herein report a case of PTTM diagnosed based on a transbronchial lung biopsy. In this case, we finally diagnosed PTTM due to gastric cancer because of its histological identity. The patient was administered chemotherapy, including angiogenesis inhibitors, against gastric cancer at an early age and survived for a long time.

Objectives To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Materials and methods Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). Results In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. Conclusion The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab.

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7–14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS., Author summary Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne virus infection caused by Dabie bandavirus (formerly SFTS virus, SFTSV), which belongs to the Bandavirus genus of the Phenuiviridae family. The case fatality rate of patients with SFTS is high ranging from 16.2% to 47%. SFTS is endemic to East and Southeast Asia. Favipiravir, an antiviral agent with an inhibitory activity on the RNA-dependent RNA polymerase, inhibited replication of SFTSV in vitro and in vivo. It was suggested that favipiravir treatment lowered the case fatality rate of patients with SFTS by approximately 10% in comparison with those reported so far through epidemiological survey in Japan. People living in the SFTS-endemic regions can not escape from the risk of being infected with SFTSV. Favipiravir might be an effective drug for treatment of patients with SFTS and reduces the mortality and morbidity of patients with SFTS.

Objectives We conducted a subanalysis of data from the multicentre, retrospective observational Nivolumab Japan Real World (CA209-9CR) study to evaluate nivolumab effectiveness and safety in elderly patients (aged ≥75 years) with advanced/metastatic non-small cell lung cancer.Materials and methods Medical record data of patients initiating nivolumab treatment between April 2016 and December 2016 were collected using electronic data capture from 23 cancer hospitals in Japan between March 2017 and August 2018. Nivolumab treatment data were collected to investigate the treatment patterns by age group (

Pulmonary tuberculosis is a common disease that may result in hemoptysis. Fetal hemoptysis is known to be related to the rupture of a pulmonary aneurysm formed in the cavity wall. We herein report a case of non-cavity pulmonary tuberculosis that developed with massive hemoptysis following bronchial artery aneurysm. Bronchial artery embolization was performed, and autofluorescence imaging bronchoscopy was conducted one month after the anti-tuberculosis treatment. Bright-green color was observed in the ulcerative lesion with a white coat, corresponding to the bronchial artery aneurysm. This is the first report of the autofluorescence imaging observation of an ulcerative lesion caused by bronchial tuberculosis.

Objectives The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. Materials and methods A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. Results The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). Conclusion This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).

Background and Objectives: The assessment of the treatment including the evaluation of quality of life is important in the elderly patients. We performed the phase II study to evaluate the efficacy and safety of S-1 and the quality of life in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients aged ≥75 years with stage IIIB or IV NSCLC and performance status 2 or lower were eligible. A tailored dose of S-1 was administrated orally for 14 days followed by 7 days of no treatment. This treatment course was repeated until disease progression or the emergence of intolerable toxicities. The primary end point was the disease control rate. Secondary end points were progression-free survival, overall survival, toxicity and quality of life. Results: Among 40 patients enrolled, 38 patients were evaluable for the response. The median age was 78 years. The disease control rate was 89.5% (CR/PR/SD/PD; 0/4/32/4). The progression-free survival and overall survival was 4.4 months and 17.0 months, respectively. Neutropenia, anorexia, hyponatremia, hypokalemia, and pneumonia of grade ≥3 occurred in 5.0, 7.5, 5.0, 2.5, and 2.5%, respectively. In the patient-reported outcome, most individual factors in patients’ quality of life including upper intestine-related symptoms were improved with the treatment, although only dyspnea slightly but continuously worsened throughout the study. Conclusions: These results indicate that 2-week treatment of tailored S-1 monotherapy with 1-week rest in elderly patients is well tolerated and demonstrates encouraging activity.

Background S-1 is an oral fluoropyrimidine that is active in the treatment of non-small cell lung cancer (NSCLC); however, an optimal treatment schedule and appropriate dose adjustments of S-1 in elderly patients have not yet been established. Methods We conducted a phase II trial to evaluate the efficacy and safety of a 2-week S-1 monotherapy treatment followed by a 1-week interval as a first-line treatment of elderly NSCLC patients, by adjusting the dose based on the individual creatinine clearance (Ccr) and body surface area (BSA). The primary endpoint was the disease control rate. Results Forty patients were enrolled. The disease control and response rates were 89.5% (95% confidence interval [CI] = 79.8–99.2) and 7.9% (95% CI=0.0–16.4), respectively. The median progression-free survival and overall survival times were 4.4 months (95% CI=4.2–8.5) and 17.0 months (95% CI=11.2–18.7), respectively. Neutropenia, anorexia, hyponatremia, hypokalemia, and pneumonia of grade ≥ 3 occurred in 5.0%, 7.5%, 5.0%, 2.5%, and 2.5% of patients, respectively. Among the patient-reported outcomes, most of the individual factors in the patients' quality of life, including upper intestine-related symptoms improved with the treatment, except for dyspnea, which slightly albeit continuously worsened throughout the study. Conclusions In elderly patients with previously untreated advanced NSCLC, a 2-week S-1 monotherapy treatment, tailored to both the Ccr and BSA, with a 1-week interval was well tolerated and demonstrated promising efficacy. This study was registered at the University Hospital Medical Information Network (UMIN) Center (ID: UMIN000002035), Japan.

Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection.

N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys (L18), romurtide) is a synthetic muramyl dipeptide derivative, and has immunomodulating activities including activation of cells of monocyte-macrophage lineage. We examined the effect of intrapleural instillation of MDP-Lys (L18) against malignant pleurisy associated with lung cancer. Six patients with cytologically-positive malignant pleural effusion (four with adenocarcinoma, one with small cell carcinoma and one with large cell carcinoma) were treated with single intrapleural instillation of MDP-Lys (L18) of 200 microg. Clinically, no reaccumulation of pleural effusion for at least 4 weeks was observed in four patients. No major side effects were observed. Total cell number elevated remarkably 4 h after instillation, and main increased population was that of neutrophils. Levels of chemotactic cytokines, such as interleukin (IL)-8, and monocyte chemotactic protein (MCP)-1 and levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, elevated in pleural effusion, and peak IL-1beta and IL-6 levels tended to be higher in clinical responders than non-responders. These results suggest MDP-Lys (L18) instilled by intrapleural route had a potential local immunomodulatory activity. Further study is warranted to further determine the critical factors which correlate with the clinical response.

In the present study, we examined the ability of interleukin (IL)-12 to generate an antitumor effect in the tumor-growing site. Mononuclear cells (MNC) were obtained from 12 malignant pleural effusions due to lung cancer in the tumor-growing site. Non-major-histocompatibility-complex-restricted killer activity, examined by 4-h 51Cr release assay against Daudi lymphoma cells as well as various lung cancer cell lines (H69 and PC-9), and in vitro production of interferon gamma (IFNgamma), measured by enzyme immunoassay, were investigated as mediators of antitumor effects of host cells activated by IL-12. IL-12 induced killer activity of MNC in pleural effusions (pleural MNC) dose-dependently. Moreover, pleural MNC produced a signficant amount of IFNgamma in response to IL- 12. The killer activities of IL-12-activated blood MNC were higher than those of pleural MNC. The supernatants of pleural effusions of these untreated patients suppressed killer induction by IL-12 of blood MNC of healthy volunteers. These observations suggest that MNC present at the site of growing tumors may act as effector cells against lung cancer in the presence of IL-12.

The effect of intrapleural instillation of recombinant human interferon gamma (IFN gamma) at increasing doses of (1-12) x 10(6) U was examined in six patients with cytologically positive pleural effusion due to lung cancer. Intrapleural instillation was repeated up to three times. Clinically, no reaccumulation of pleural effusion was observed in one patient and disappearance of lung cancer cells from the pleural effusion was seen in two other patients. No severe side-effects were observed. Considerable levels of IFN gamma remained in the pleural effusion as well as in patients' serum up to 7 days after instillation of 2 x 10(6) U and higher doses. The total cell number showed a transient decrease on day 1 of therapy. Levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin(IL)-1 beta and IL-6, in the pleural effusion remained almost stable after IFN gamma instillation. On the other hand, intrapleural IL-1 receptor antagonist levels were remarkably elevated by the instillation of IFN gamma. IL-2- and IL-12-inducible killer activity of pleural mononuclear cells tended to increase slightly. Despite the inability of IFN gamma to control pleural effusion in this treatment schedule, IFN gamma instilled by an intrapleural route had a potential local antitumor activity. Moreover, since IFN gamma persists in pleural effusions for a long time after a single instillation, such a therapy in combination with other fibrogenic biological response modifiers can be promising.

Interleukin (IL)-1 is a key cytokine in inflammatory reactions. To clarify the mechanism of inflammation in the pleural cavity, we investigated the contribution of IL-1 and its antagonism to inflammatory processes in the pleural cavity. Interleukin-1 receptor antagonist (IL-1Ra) levels as well as IL-1 beta and interferon-gamma (IFN-gamma) levels were measured by enzyme immunoassay in pleural effusions from 70 patients. Pleural macrophages were also examined as possible sources of these cytokines in 10 patients. IL-1Ra was detectable in 28 patients (40%) out of 70 patients with pleural effusions. Patients with tuberculosis had significantly higher IL-1Ra as well as IFN-gamma levels in pleural effusion than patients with lung cancer. Transudative pleural effusions had low or undetectable IL-IRa levels. On the other hand, IL-1 beta levels were low, except in cases of parapneumonic pleural effusion. Spontaneous production of IL-1Ra pleural macrophages was observed in six patients, and IL-4 significantly augmented its production. Although spontaneous production of IL-1 beta was observed in only two patients, pleural macrophages produced significant amounts of IL-1 beta in response to lipopolysaccharide in all 10 patients examined. These results suggest that interleukin-1 receptor antagonist regulates various reactions by interleukin-1 in pleural effusion, and that pleural macrophages may act in situ as a source of interleukin-1 receptor antagonist.

Interleukin (IL)-10 is known to be an autoregulatory factor of functions of monocyte macrophages. The purpose of this study was to determine whether IL-10 production by alveolar macrophages (AMs) is altered in patients with lung cancer. AMs were obtained by bronchoalveolar lavage from 25 patients with lung cancer and 14 control patients. The production of IL-10 by AMs was quantitated by enzyme immunoassay with or without stimulation with lipopolysaccharide (LPS). No significant difference in spontaneous and LPS-stimulated IL-10 production by AMs was observed between lung cancer patients and control patients (mean ± sem; 288·0 ± 56·7 vs. 249·6 ± 58·4 pg ml −1 ). IL-10 production of LPS-stimulated AMs was not impaired even in lung cancer patients with systemic metastasis. IL-4 failed to suppress LPS-induced production of IL-10 by AMs both in control patients and in lung cancer patients. In eight patients with lung cancer, IL-10 production by AMs was estimated before and after systemic chemotherapy and IL-10 production by LPS-stimulated AMs tended to increase after systemic chemotherapy from 152·3 ± 51·9 to 278·0 ± 112·8 pg ml −1 . As IL-10 is a potent inhibitor of tumour angiogenesis, an important process of tumour progression, these results suggest that, even in advanced cancer patients, macrophages can produce potent angiogenesis inhibitor and systemic chemotherapy may augment this inhibitory activity in the lung.

A 24-year-old man who had uveitis and showed intrathoracic lymph node swelling on a chest X-ray, was admitted to our hospital for further examination. Transbronchial lung biopsy specimens revealed non-caseating granulomas compatible to sarcoidosis. As the renal function became progressively worse, a specimen was obtained by renal biopsy. It showed a granuloma formation, and was diagnosed as renal sarcoidosis. A high level of interleukin(IL)-6 was detected in his urine. After oral administration of prednisolone, the renal function improved, and the urinary IL-6 level was reduced. These findings suggest that in sarcoidosis associated with renal failure, steroid therapy is effective and that IL-6 plays an important role in the pathogenesis of renal involvement of sarcoidosis.(Internal Medicine 37: 757-761, 1998)

The authors investigated the interleukin (IL)-12-inducible killer activity of blood mononuclear cells (MNC) from 30 untreated primary lung cancer patients and 24 control subjects. Cytotoxicity was assayed as 4-h 51 Cr release from Daudi lymphoma cells or lung cancer cells (H-69, N-291 and PC-9). MNC from lung cancer patients exhibited similar killer activity to those from control subjects after in vitro incubation with IL-12 for 4 days. Effective killer induction by IL-12 was observed even in MNC from advanced lung cancer patients and patients with small cell lung cancer. IL-12 and a suboptimal dose of IL-2 had additive effects in inducing killer activity in MNC from both lung cancer patients and control subjects. On the other hand, with an optimal dose of IL-2, IL-12 suppressed killer induction. Addition of IL-12 alone or in combination with IL-2 resulted in interferon (IFN)-γ production by MNC from lung cancer patients as well as control subjects. These observations suggest that IL-12 could be useful for immunotherapy of lung cancer in humans.

We report a patient with metastatic adenocarcinoma of the lung who had a detectable serum interleukin-6 (IL-6) level. Despite systemic chemotherapy, the tumor progressed, with elevation of serum IL-6 level. Palliative steriod therapy with 20 mg/day of prednisolone resulted in the decline of serum IL-6 level and, simultaneously, improved anorexia and oral intake. Although there was no weight gain or improvement in hypoalbuminemia, these results suggest that steriids may suppress the abnormal production of IL-6 in cancer patients and that this action affects symptoms. Further study is warranted to clarify the role of IL-6 in tumor-related symptoms and the effect of steroid therapy in relation to IL-6 production in cancer patients.

Immunoglobulin binding factor (IgBF), which is abundant in human seminal plasma, is known to bind immunoglobulin, interact with anti-Fc gamma RIII antibodies, and block pokeweed mitogen (PWM)-stimulated lymphocyte blastogenesis. In this study, we investigated whether IgBF is present in the lower respiratory tract, whose secretions come into contact with the external environment. For this, IgBF was measured in brochoalveolar lavage fluid (BALF) from 42 healthy normal subjects (23 nonsmokers and 19 smokers) by enzyme-linked immunosorbent assay (ELISA). IgBF was detected in BALF from these normal subjects, and its level was significantly higher in BALF from smokers (127.2 +/- 98.7 ng/ml versus 23.3 +/- 20.7 ng/ml). On gel filtration chromatography of BALF, IgBF was eluted in a region corresponding to a molecular weight of 27 kD. Western blot testing with a monoclonal antibody to IgBF indicated that IgBF in BALF had a molecular weight of 27 kD under nonreducing conditions and of 16 kD under reducing conditions. Thus, the migration pattern of IgBF in BALF corresponded to that of IgBF in seminal plasma. IgBF immunoreactivity was detected histochemically in mucus glands and goblet cells in the lower respiratory tract. These results demonstrate that IgBF is present in the lower respiratory tract, and that smoking may cause its increased production in this region.

Anti-P-glycoprotein antibody (MRK-16)-dependent cell-mediated cytotoxicity (ADCC) by blood mononuclear cells (MNC) was examined in patients with small cell lung cancer (SCLC) before and after systemic chemotherapy. The effect of in vitro treatment of MNC with interleukin (IL)-2 and macrophage-colony-stimulating factor (M-CSF) was also examined. The ADCC reaction was assessed by a 6 h 51Cr-release assay using a multidrug-resistant (MDR) SCLC cell line (H69/VP cells). The MRK-16 monoclonal antibody was able to augment spontaneous cytotoxicity by MNC, even in SCLC patients. Pretreatment of MNC with IL-2 significantly augmented their ADCC ability in SCLC patients, while M-CSF had no effect on ADCC activity. After the first cycle of systemic chemotherapy, the ADCC activity tended to decline, but ADCC of MNC pretreated with IL-2 was not affected. The results suggest that anti-P-glycoprotein antibody, in combination with a cytokine such as IL-2, may be therapeutically useful against human SCLC resistant to chemotherapeutic drugs.

Serum interleukin 6 (IL-6) levels were measured in 75 patients with lung cancer and in 20 patients with benign lung diseases. IL-6 was detectable in 29 patients with lung cancer (39%), but was not detectable in any of the patients with benign lung diseases. Serum C-reactive protein levels and plasma fibrinogen levels were significantly higher and serum albumin concentration was significantly lower in lung cancer patients with detectable serum IL-6 levels than in those without detectable serum IL-6 levels and in patients with benign lung diseases. On the other hand, no significant difference was observed in blood platelet counts in these three groups. Moreover, serum IL-6 levels were not significantly different in lung cancer patients with or without clinically demonstrated distant metastasis. These results suggest that IL-6 may be a mediator of various reactions including an inflammatory response in lung cancer patients.

A 69-year-old woman had plasma cell granuloma of the left middle lobe of the lung. Her symptoms and roentgenologic findings improved with antibiotic treatment. Before treatment, the number of neutrophils and NCA were markedly increased in BAL fluid obtained from the affected region of the left lung and moderately increased in BAL fluid obtained from the nonaffected region of the right lung. The number of neutrophils, the NCA as well as the contents of C5 and C5a des Arg (neutrophil chemotactic factors) in the BAL fluids from both these regions decreased during treatment. These findings suggest that plasma cell granuloma was due to chronic immune and inflammatory reactions in the lung, that neutrophils are involved in development of the symptoms and signs of this disease, and that neutrophil chemotactic factors, including complement-derived factors, are important in neutrophil recruitment at the lesion and in nonaffected parts of the lung.