CD244+ polymorphonuclear myeloid­derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model.

Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid­derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M­MDSCs) and polymorphonuclear MDSCs (PMN­MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD­relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD­relevant TIME. As a result, intraperitoneal PMN­MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN­MDSCs. In addition, the concentrations of interleukin (IL)­6 and granulocyte­colony stimulating factor (G­CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN­MDSCs. In vivo depletion of the PMN­MDSCs by anti­Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4+ and CD8+ T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN­MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T­cell­based immunotherapy for CRC­derived PD.

Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.

Application of iNKT Cell-targeted Active Immunotherapy in Cancer Treatment.

In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy.

Immunosuppression Induced by Perioperative Peritonitis Promotes Lung Metastasis.

BACKGROUND/AIM: Perioperative intra-abdominal infection has been reported as a risk factor for metastasis. The aim of this study was to investigate the mechanism by which peritonitis induces immunosuppression in the lung, which in turn promotes lung metastasis. MATERIALS AND METHODS: C57BL/6 mice were intravenously administered B16F10 melanoma cells to induce lung metastasis and subsequently subjected to cecal ligation and puncture (CLP) to induce peritonitis or sham surgery. The number of lung metastatic nodules was evaluated. Cell fractions in lungs and serum cytokines after CLP were investigated. RESULTS: CLP mice showed an increased number of lung metastases compared to sham-treated mice. The fraction and number of natural killer (NK) cells in lungs of CLP mice were significantly reduced in early post-CLP phase. Myeloid-derived suppressor cells (MDSCs) in lungs were significantly decreased in CLP mice. Serum IL-6 and TNF levels were significantly elevated in CLP mice. CONCLUSION: Peritonitis promoted lung metastasis in a murine model, which may be attributable to the impact of NK cells and MDSCs in the lungs.

Synthesis of Aryl Triflones through the Trifluoromethanesulfonylation of Benzynes.

The direct synthesis of aryl triflones, that is, trifluoromethanesulfonyl arenes, was achieved through the trifluoromethanesulfonylation of benzynes. The trifluoromethanesulfonyl group, one of the fluorinated functional groups, is a highly electron-negative and mild lipophilic substituent. Aryl triflones have high potential in the synthesis of bioactive compounds and specialty materials. The treatment of 2-(trimethylsilyl)aryl trifluoromethanesulfonates with cesium fluoride in the presence of 15-crown-5 generated benzynes, which reacted with sodium trifluoromethanesulfinate followed by protonation with tBuOH under heating conditions, provided aryl triflones in moderated to good yields. Both symmetrical and unsymmetrical triflones were nicely accessed under the same reaction conditions. Interestingly, the trifluoromethanesulfonylation of unsymmetrical benzyne precursors proceeded smoothly to furnish corresponding aryl triflones in good yields with good to high regioselectivities. The balance of polarization of electric charge as well as steric hindrance of the benzyne intermediates are central factors to control the outcome of regioselectivity.

Incidence and predictive factors of lung cancer in patients with idiopathic pulmonary fibrosis.

The incidence and risk factors of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated. We conducted a retrospective study of 632 patients with IPF to assess the incidence and risk factors of lung cancer development. Seventy patients developed lung cancer over a median follow-up period of 3.8 years. The incidence density of lung cancer development was 25.2 cases per 1000 person-years. The most frequent type was squamous cell carcinoma (30%), the majority developed lung cancer in the peripheral lung (82.9%) and adjacent to usual interstitial pneumonia (75.7%). In a multivariate Cox regression hazard model, pack-years of smoking ≥35 and coexisting emphysema were associated with lung cancer development. The 1-, 3- and 5-year all-cause mortality rates after lung cancer diagnosis were 53.5%, 78.6% and 92.9%, respectively. The incidence density of lung cancer is high in IPF patients and occurs more frequently in patients with smoking history of pack-years of smoking ≥35 and with coexisting emphysema. The majority of lung cancers develop adjacent to usual interstitial pneumonia. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

Frequency of Myeloid-derived Suppressor Cells in the Peripheral Blood Reflects the Status of Tumor Recurrence.

BACKGROUND: Malignant tumors inhibit antitumor immune responses, which are driven by T-regulatory cells or myeloid-derived suppressor cells (MDSCs). Since MDSCs are involved in invasion, migration, and metastasis of tumor cells, we hypothesized that MDSCs are also involved in tumor recurrence after surgical resection. MATERIALS AND METHODS: C57BL/6 mice were subcutaneously inoculated with B16F10 melanoma cells in the right flank. In some experiments, established tumors were surgically resected. Peripheral blood was drawn over time, and immune cells and cytokines were evaluated using flow cytometry. RESULTS: MDSCs and relevant pro-inflammatory cytokines increased in the peripheral blood of tumor-bearing mice. Moreover, the frequency of MDSCs rapidly increased in mice with tumor recurrence. CONCLUSION: The frequency of MDSCs in the peripheral blood of tumor-bearing mice reflects the status of tumor progression as well as tumor recurrence. Continuous monitoring of MDSCs in the peripheral blood might be a useful indicator of tumor recurrence.

Simple and reliable method for tumor localization during totally laparoscopic gastrectomy: intraoperative laparoscopic ultrasonography combined with tattooing.

We have developed a new method to localize a tumor during totally laparoscopic gastrectomy that uses intraoperative laparoscopic ultrasonography combined with preoperative clipping and tattooing. One or 2 days before the surgery, endoscopic clipping was performed just proximal to the tumor, followed by tattooing with India ink at the clipping site. Examination by intraoperative laparoscopic ultrasonography was performed at the tattooed site to detect the clips. The resection line of the stomach was determined with use of the detected clips as a marker of the proximal margin of the tumor. This method was attempted in 14 patients who underwent totally laparoscopic gastrectomy, and the clips were successfully identified in all patients. The clips were visualized as several layers of a hyperechoic bar, which was termed a "ladder sign." The mean time from insertion of the laparoscopic probe to identification of the clips was 2 min. The ladder sign is an important finding in this method.

Case Series of Pulmonary Tumor Embolism and Intravascular Lymphoma: Evaluation of the Usefulness of Pulmonary Microvascular Cytology.

Pulmonary tumor embolism (PTE) and intravascular lymphoma cause rapidly progressive deterioration and an antemortem diagnosis is difficult. The usefulness of pulmonary microvascular cytology (PMC) in the diagnosis of these disorders has been reported in sporadic case reports. We retrospectively evaluated the records of 7 patients with tumor cells in the pulmonary microvasculature (4 with PTE and 3 with malignant lymphoma) who underwent pulmonary microvascular cytology. Two of the 4 patients with PTE and 2 of the 3 patients with malignant lymphoma (all 3 had intravascular metastasis) had positive PMC results. These findings suggested that PMC may be useful in the diagnosis of these disorders.

The Long-term Clinical Course of Chronic Eosinophilic Pneumonia.

Objective The long-term clinical course and prognosis of patients with chronic eosinophilic pneumonia (CEP) including factors predictive of the relapse of CEP have not been fully investigated. The aim of the present study was to investigate these issues. Methods We retrospectively investigated the rate of relapse and prognosis in 73 patients diagnosed as having CEP. Results Systemic corticosteroid therapy was administered at a prednisolone dose of 29.4±7.6 mg/day. During a median follow-up period of 1,939 days, 27 patients suffered from relapse of CEP. Two patients developed steroid-induced diabetes mellitus, and 1 patient developed pulmonary nontuberculous mycobacteriosis. Five patients died; however, none died of CEP. A history of smoking was the only independent negative risk factor for relapse of CEP [hazard ratio, 0.37 (0.14-0.98)]. Conclusion Patients with CEP frequently relapse. During the follow-up, metabolic and infectious complications under prolonged corticosteroid therapy are problematic. A history of smoking was a negative factor for predicting the risk of CEP relapse.

Diagnostic criteria that can most accurately differentiate allergic bronchopulmonary mycosis from other eosinophilic lung diseases: A retrospective, single-center study.

BACKGROUND: Several diagnostic criteria have been proposed to differentiate allergic bronchopulmonary mycosis (ABPM) from asthma, but there have been no studies to establish diagnostic criteria to classify ABPM differently from other eosinophilic lung diseases. METHODS: We retrospectively investigated both patients with ABPM (n=42) diagnosed by clinical (Rosenberg-Patterson criteria modified to apply to fungi other than Aspergillus spp., with consideration of computed tomography and bronchoscopy findings) or pathological criteria and those with other eosinophilic lung diseases (n=118) to establish elaborate diagnostic criteria for ABPM. RESULTS: Etiologies of ABPM included fungi other than Aspergillus spp. or unidentified pathogens in 16 patients. Fourteen patients (33.3%) did not have asthma. When the diagnostic cutoff line was set to satisfy six or more primary plus secondary modified Rosenberg-Patterson criteria, ABPM could be diagnosed with good sensitivity, specificity, and positive/negative predictive values (97.6%, 98.3%, 95.3%, and 99.1%, respectively). When the diagnostic criteria were combined with pathological criteria, the values further improved to 100%, 98.3%, 95.5%, and 100%, respectively. CONCLUSIONS: Our results suggest that these novel criteria offer good sensitivity, specificity, and positive/negative predictive values for the diagnosis and classification of ABPM.

Pulmonary Nontuberculous Mycobacteriosis and Chronic Lower Respiratory Tract Infections in Patients with Allergic Bronchopulmonary Mycosis without Cystic Fibrosis.

Objective The frequency of pulmonary nontuberculous mycobacteriosis (pNTM), chronic lower respiratory tract infections (cLRTIs), and pneumonia in patients with allergic bronchopulmonary mycosis (ABPM) without cystic fibrosis has not yet been fully investigated. Methods We retrospectively analyzed 42 patients with ABPM focusing on the frequency of pNTM and cLRTIs, acute exacerbation of cLRTIs, and pneumonia. Results During a median follow-up period of 2,299 days (range, 118-6,138 days), 7 patients developed pNTM (mainly Mycobacterium avium complex), and 21 patients developed cLRTI (mostly from Staphylococcus aureus followed by Pseudomonas aeruginosa). Twelve patients developed 21 episodes of acute exacerbation of cLRTIs, and 4 patients developed pneumonia. Conclusion Patients with ABPM can have concomitant NTM infection and, not uncommonly, cLRTI, and they can also sometimes develop pneumonia or an acute exacerbation of cLRTI.

Clinical and Radiographic Comparison of Influenza Virus-associated Pneumonia among Three Viral Subtypes.

OBJECTIVE: Presently, the predominant subtypes of influenza viruses in the world, except for those in local epidemics, include influenza pandemic H1N1 2009 (pH1N1), H3N2, and B viruses. There are few reports on the differences in the clinical features, radiographic findings, treatment, and outcomes of influenza virus-associated pneumonia among these three viral subtypes. The purpose of this study was to investigate whether the clinical features, radiographic findings, treatment, and outcomes differ among the viral subtypes. METHODS: We retrospectively analyzed 96 patients with influenza virus-associated pneumonia whose viral subtypes were clarified. RESULTS: Patients with pH1N1 virus-associated pneumonia tended to be young. The frequency of primary viral pneumonia differed among the virus-associated pneumonia subtypes (pH1N1, 80%; H3N2, 26.5%; and B, 31%). Patients with pH1N1 virus-associated pneumonia more frequently showed bilateral ground-glass opacities (GGOs), which affected more lobes than in patients with H3N2 and B virus-associated pneumonia. However, patients with H3N2 virus-associated pneumonia showed a higher frequency of consolidation and diffuse bronchial wall thickening than did the patients with pH1N1 virus-associated pneumonia. The severity and mortality did not differ among the three pneumonia subtypes. CONCLUSION: In the patients who developed influenza virus-associated pneumonia, those with pH1N1 virus-associated pneumonia frequently developed primary viral pneumonia resulting in bilateral and broad areas of GGOs on imaging, whereas patients with H3N2 virus-associated pneumonia frequently showed consolidation and diffuse bronchial wall thickening on pulmonary imaging.

Combined Allergic Bronchopulmonary Aspergillosis and Eosinophilic Granulomatosis with Polyangiitis: Three Cases and a Review of the Literature.

Previous reports of combined allergic bronchopulmonary mycosis (ABPM) and eosinophilic granulomatosis with polyangiitis (EGPA) are limited; however, among 41 cases of ABPM and 18 cases of EGPA treated at our hospital, we experienced three cases of combined ABPM and EGPA. In two of these cases, the diagnosis of EGPA preceded that of ABPM, however, one of the two cases had already shown findings suggestive of ABPM, such as mucous plugs and central bronchiectasis, at the time of the diagnosis of EGPA. In six previously reported cases of combined ABPM and EGPA, ABPM preceded EGPA in four cases. In the other two cases in which EGPA was diagnosed before or simultaneously with ABPM, findings suggestive of ABPM had been detected when EGPA was diagnosed, which suggests that sensitization to fungi resulting in ABPM may play an important role in the development of EGPA. Careful attention should therefore be paid to the possibility that these diseases may coexist during the course of either disease.

COPD assessment test and severity of airflow limitation in patients with asthma, COPD, and asthma-COPD overlap syndrome.

OBJECTIVE: The COPD assessment test (CAT) consists of eight nonspecific scores of quality of life. The aim of this study was to compare the health-related quality of life and severity of airflow limitation in patients with asthma, COPD, and asthma-COPD overlap syndrome (ACOS) using the CAT. METHODS: We examined CAT and lung functions in 138 patients with asthma, 99 patients with COPD, 51 patients with ACOS, and 44 patients with chronic cough as a control. The CAT score was recorded in all subjects, and the asthma control test was also administered to patients with asthma and ACOS. The CAT scores were compared, and the relationships between the scores and lung function parameters were analyzed. RESULTS: The total CAT scores and scores for cough, phlegm, and dyspnea were higher in patients with ACOS than in patients with asthma and COPD. The total CAT scores were correlated with the percent predicted forced expiratory volume in 1 second only in patients with COPD. The total CAT scores and dyspnea scores adjusted by the percent predicted forced expiratory volume in 1 second were higher in patients with ACOS than in patients with COPD and asthma. The CAT scores and asthma control test scores were more closely correlated in patients with ACOS than in patients with asthma. CONCLUSION: Patients with ACOS have higher disease impacts and dyspnea sensation unproportional to the severity of airflow limitation.

Asbestos exposure increases the incidence of histologically confirmed usual interstitial pneumonia.

AIMS: We hypothesized that asbestos exposure increases the incidence of macroscopically visible and histologically confirmed usual interstitial pneumonia (histological UIP). METHODS AND RESULTS: We retrospectively examined 1718 cases (1202 males; mean age 66.7 years) who underwent lobectomy for resection of pleuropulmonary tumours. Objective markers for asbestos exposure included: the presence of malignant pleural mesothelioma, the presence of pleural plaques (PPs) and asbestos bodies in the histological specimen. Risk factors for histological UIP were examined. Two separate groups were studied: 183 with asbestos exposure, and 239 with histological UIP. The 183 cases with asbestos exposure had higher rates of positive occupational history and histological UIP (31%) than the remaining 1535. Among the asbestos-exposed group, small numbers of asbestos bodies were found in histological specimens of 21 cases of histological UIP. PPs and asbestos bodies were more frequent in the 239 patients with histological UIP than in the remaining 1479 UIP-negative patients. Multivariate analysis showed that asbestos exposure, especially positivity for asbestos bodies, that does not meet the current criteria for asbestosis increases the risk of histological UIP (P < 0.0001). CONCLUSIONS: Asbestos exposure causes asbestosis and increases the incidence of histological UIP.

Risk Factors for Pneumonia and the Effect of the Pneumococcal Vaccine in Patients With Chronic Airflow Obstruction.

Background: To evaluate the risk factors for pneumonia and the efficacy of the pneumococcal polysaccharide vaccine (PPV) in patients with chronic airflow obstruction. Methods: We retrospectively studied the risk factors for pneumonia in 820 consecutive patients with chronic obstructive pulmonary disease (COPD) (n=509) and patients with asthma-COPD overlap syndrome (ACOS) (n=311). The effects of asthma, age, smoking history, chronic sputum, use of inhaled corticosteroids, percent predicted forced vital capacity (%FVC), percent predicted forced expiratory volume in 1 second (%FEV1), body mass index (BMI), computed tomography (CT)-diagnosed emphysema, and the pneumococcal vaccination on the frequency of pneumonia were assessed. Results: There was no difference in the frequency of pneumonia in patients with COPD and those with ACOS. In a univariate analysis, age (p= 0.031), %FVC (p< 0.001), %FEV1 (p < 0.001), BMI (p = 0.003), the presence of emphysema (p < 0.001) and a history of vaccination with the PPV (p = 0.034) were associated with the frequency of pneumonia. A multivariate analysis identified low BMI, the presence of emphysema and the absence of a pneumococcal vaccination as independent risk factors. The combination index of these factors, the BOVE index, which is calculated from low BMI (<22 kg/m2), low %FEV1 (<60%), vaccination history and emphysema was associated with the overall frequency of pneumonia. Conclusions:The index of multidimensional risk factors is useful to predict the frequency of pneumonia in patients with chronic airflow obstruction. The pneumococcal vaccination was associated with significantly lower incidence of pneumonia.

Etiology and Outcome of Diffuse Acute Infectious Bronchiolitis in Adults.

RATIONALE: The etiology and outcome of diffuse acute infectious bronchiolitis (DAIB) in adults is not well known. OBJECTIVES: To retrospectively review adult patients with DAIB without pneumonia, document the etiologies and outcomes, and assess the relation between DAIB and postinfectious bronchiolitis obliterans. METHODS: We retrospectively analyzed medical records of 1,664 patients with lower respiratory tract infections admitted to our institution in Saitama, Japan. DAIB was diagnosed when patients developed acute feverish lower respiratory tract infection and chest computed tomography demonstrated mainly multiple centrilobular nodules in four or more lobes. Pneumonia was diagnosed when patients developed acute feverish lower respiratory tract infection and chest computed tomography demonstrated consolidation and/or ground-glass opacities with or without centrilobular nodules. MEASUREMENTS AND MAIN RESULTS: Of the 1,664 patients, 20 (1.2%) and 1,644 (98.8%) patients were diagnosed as having DAIB and pneumonia, respectively. Of the 20 patients with DAIB, the etiology was determined in 16 (80%): 13 (65.0%) had a single pathogen and 3 (15.0%) had two pathogens. Detected organisms included Mycoplasma pneumoniae in eight (40.0%) patients, influenza virus in two (10.0%), influenza virus and Streptococcus pneumoniae in two (10.0%), Haemophilus influenzae in three (15.0%), and respiratory syncytial virus and rhinovirus in one (5.0%) patient. All patients improved and none developed postinfectious bronchiolitis obliterans. CONCLUSIONS: The three most common etiologies of DAIB in the studied adults were M. pneumoniae, influenza virus, and H. influenzae. None of the patients with DAIB developed postinfectious bronchiolitis obliterans.

Retrospective study of the predictors of mortality and radiographic deterioration in 782 patients with nodular/bronchiectatic Mycobacterium avium complex lung disease.

OBJECTIVES: Some patients with nodular/bronchiectatic Mycobacterium avium complex lung disease (NB MAC-LD) deteriorate and die. The main aim of the study is to evaluate the prognostic factors and radiographic outcomes in patients with NB MAC-LD. SETTING: Retrospective single-centre review. PARTICIPANTS: 782 HIV-negative patients with NB MAC-LD treated at our institution in Japan. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause and MAC-LD progression mortality rates and the prognostic factors, and radiographic deterioration rates and the prognostic factors. RESULTS: Mean age was 68.1 years, and median follow-up period was 4.3 years. Death from any cause and progression of MAC lung disease (MAC-LD) occurred in 130 (16.6%), and 19 (2.4%) patients, respectively. All-cause and MAC-LD progression 10-year mortality rates were 27.4% and 4.8%, respectively. In 536 patients with MAC-LD who were followed-up for more than 1 year, radiographic deterioration occurred in 221 (41.2%) patients and median time-to-radiographic deterioration was 9 years. A multivariate Cox proportional hazard model showed male sex, older age, body mass index <18.5 kg/m(2), absence of bloody sputum, hypoalbuminaemia and erythrocyte sedimentation rate >40 mm/h to be negative prognostic factors for all-cause mortality, and the presence of idiopathic pulmonary fibrosis, haemoglobin <11.3 mg/dL, C reactive protein >1.0 mg/dL and the presence of cavity to be negative prognostic factors for radiographic deterioration. CONCLUSIONS: Only 2.4% of patients with NB MAC-LD died from MAC-LD progression. As clinical trials testing the effectiveness of drug therapy in patients with NB MAC-LD are being designed and implemented, the primary end point could be time-to-radiographic deterioration, and trial patients need to be stratified according to these prognostic factors before randomisation.