Surfactant protein D prevents mucin overproduction in airway goblet cells via SIRPα.

Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air-liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.

Impact of increased plasma levels of calreticulin on prognosis of patients with advanced lung cancer undergoing combination treatment of chemotherapy and immune checkpoint inhibitors.

BACKGROUND: Damage-associated molecular pattern (DAMP)-related immunogenic cell death triggers secondary adaptive immune responses. The relationship between DAMP levels and prognosis in patients with non-small cell lung cancer (NSCLC) who undergo a combination therapy of immune checkpoint inhibitors (ICI) and chemotherapy remains unclear. METHODS: Serial plasma samples were prospectively collected from 45 patients treated with ICI combination therapy for advanced NSCLC. Plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), annexin A1, and heat shock protein 70 were measured. Associations between increases in plasma DAMP levels and the efficacy of the ICI combination therapy were evaluated. RESULTS: The maximum fold changes in plasma levels differed across individuals but demonstrated a marked increase, especially for CRT (mean ± SEM, 11.61 ± 46.15). Increased plasma DAMP levels were not clearly associated with clinical responses. There was a significant correlation between the maximum fold change in CRT levels and progression-free survival (PFS; r = 0.49, P < 0.001). Median PFS and overall survival (OS) rates were higher in patients with a ≥ 2-fold increase in plasma CRT levels than in those with a < 2-fold increase (PFS, 14.9 versus 6.0 months, hazard ratio (HR), 0.58; P = 0.17; OS, not reached versus 21.6 months, HR, 0.31, P = 0.02). CONCLUSIONS: Plasma CRT level monitoring has the potential to predict the efficacy of ICI combination therapy and shed light on the mechanisms underlying DAMP-related immunogenic cell death.

Mass cytometry identifies characteristic immune cell subsets in bronchoalveolar lavage fluid from interstitial lung diseases.

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2- monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2- subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.

Imaging Changes and Immune-Checkpoint Expression on T Cells in Bronchoalveolar Lavage Fluid from Patients with Pulmonary Sarcoidosis.

Sarcoidosis is a systemic, granulomatous disease caused by unknown immunological abnormalities. The organs most vulnerable to sarcoidosis are the lungs. Patients often resolve spontaneously, but the lungs can also be severely affected. Although details regarding prognostic factors in sarcoidosis patients with lung involvement remain unclear, several reports have suggested that immune checkpoint molecules are involved in the pathogenesis of sarcoidosis. In this study, we divided sarcoidosis patients into two groups based on chest computed tomography (CT) findings and compared immune checkpoint molecules expressed on T cells in bronchoalveolar lavage fluid (BALF) in the two groups, using flow cytometry. We found elevated programmed cell death 1 (PD-1) or T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) expression on T cells in BALF in patients with spontaneous improvement in CT findings, compared with those in patients without improvement in CT findings. In conclusion, our study implies that PD-1 or TIM-3 expression on T cells in BALF may be a prognostic factor for pulmonary lesions in sarcoidosis.

Increased plasma levels of damage-associated molecular patterns during systemic anticancer therapy in patients with advanced lung cancer.

BACKGROUND: Immunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells may contribute to the synergistic antitumor effect of cytotoxic chemotherapy combined with an immune checkpoint inhibitor. The kinetics of circulating DAMP levels in cancer patients have remained largely uncharacterized, however. METHODS: We evaluated the possible effects of various systemic anticancer therapy modalities on the kinetics of plasma DAMP concentrations in a prospective observational study of patients with advanced lung cancer. The plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), annexin A1, and histone H3 were thus determined in 121 such patients at four time points during the first cycle of treatment. RESULTS: The mean of the maximum fold change in HMGB1, HSP70, or annexin A1 concentration observed during treatment was significantly greater than the corresponding baseline value (P<0.005). The maximum fold changes in HMGB1 and CRT concentrations tended to be associated with clinical response as evaluated by RECIST criteria, although the changes in the levels of these two DAMPs were not correlated, suggestive of differential induction mechanisms. Among the various treatment modalities administered, platinum-based combination or single-agent chemotherapy tended to elicit robust increases in the concentrations of HMGB1 and CRT. CONCLUSIONS: Serial monitoring of plasma revealed that systemic anticancer therapy increased the circulating levels of HMGB1 and CRT and that these changes tended to be associated with clinical response, suggesting that agents capable of releasing these DAMPs into plasma might induce ICD in advanced lung cancer patients.

Pleuropulmonary Paragonimiasis with Multiple Nodules in the Pleura.

An asymptomatic 47-year-old woman was admitted with pleural effusion and pulmonary infiltrates 1 month after ingesting raw wild boar and deer meat. Both her blood and pleural fluid were eosinophilic. Thoracoscopy revealed multiple nodules of the pleura, and biopsy samples of the nodules showed necrosis with epithelioid cell granulomas. An enzyme-linked immunosorbent assay was positive for antibodies against Paragonimus westermani, and the patient was successfully treated with praziquantel. This is the first reported case of pulmonary or pleuropulmonary paragonimiasis where several pleural nodules were observed. The detection of pleural nodules on thoracoscopy can contribute to the prompt and accurate diagnosis of paragonimiasis.

Relationship between functional end-to-end anastomosis for colon cancer and surgical site infections.

PURPOSE: Surgical site infections (SSI) are a common complication of gastrointestinal tract surgery. In this study, we explored the correlation between the anastomosis method and the incidence of SSI. METHODS: A total of 110 patients underwent ileocecal resection or right hemicolectomy for the excision of colon cancer. Two methods (open and closed, 28 and 82 patients, respectively) of functional end-to-end anastomosis were adopted. RESULTS: Increased perioperative blood loss (p = 0.029214), a longer hospital stay (p = 0.026668) and the development of SSI (p = 0.000181) were significantly correlated with the open method. There was no correlation between SSI and the body mass index, or between SSI and the length of the surgery or diabetes mellitus. However, patients that developed SSI tended to be obese. CONCLUSION: The open method was associated with a higher incidence of SSI. Therefore, it is necessary to consider potential contamination of the surgical field at the time of anastomosis to reduce the incidence of SSI.

The usefulness and safety of the introducer technique using a bumper-button-type device as compared with the pull method for percutaneous endoscopic gastrostomy.

PURPOSE: To describe our initial experiences with the standardized introducer technique for percutaneous endoscopic gastrostomy and to compare clinical outcomes and complications with the pull technique. METHODS: The introducer technique was used on 91 patients. The clinical outcomes of procedures were retrospectively collected and compared with those of 22 patients who had procedures using the pull technique. RESULTS: Mean operation time was significantly longer in the introducer technique group as compared with the pull technique group. Increased inflammation markers (body temperature, white blood cell count, and C-reactive protein) were observed in the pull technique group as compared with the introducer technique group. Incidences of peristomal infection and pneumonia were lower in the introducer method group than in the pull method group. CONCLUSIONS: The introducer technique is a useful and safe method for percutaneous endoscopic gastrostomy in terms of reduced incidences of peristomal infection, pneumonia, pain, and discomfort.

Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs.

AIM: To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. METHODS: After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. RESULTS: Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. CONCLUSION: After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity.

A multicenter long-term study of imatinib treatment for Japanese patients with unresectable or recurrent gastrointestinal stromal tumors.

BACKGROUND AND OBJECTIVES: This multicenter study, which was conducted in northern Kanto, Japan, aimed to assess the efficacy of imatinib mesylate against advanced or recurrent gastrointestinal stromal tumors (GIST). METHODS: The clinicopathological data of 234 GIST patients who were treated at one of the 11 participating hospitals from 2001-2011 were retrospectively reviewed. Imatinib was administered as a first-line therapy in cases involving unresectable disease or postoperative recurrence (41 cases). The median follow-up period was 4.0 years. RESULTS: After a median follow-up period of 4.0 years, the patients treated with imatinib (n = 41) exhibited 1-, 3-, and 5-year overall survival (OS) rates of 92.3%, 74.9%, and 53.8%, respectively. In univariate and multivariate analyses, imatinib dose reduction and achieving a complete or partial response were found to be associated with increased OS. CONCLUSIONS: Long-term imatinib treatment is recommended for patients with non-progressive disease. If patients experience significant toxicities, temporary dose reduction might be useful.

Successful surgical treatment of a spontaneous rupture of the esophagus diagnosed two days after onset.

Esophageal perforation is a relatively uncommon disease with a high rate of mortality and morbidity. Delay in the diagnosis and treatment occurs in more than 50% of cases, leading to a mortality rate of 40-60%. Primary repair is generally considered the gold standard for patients who present within the first 24 h following perforation of the esophagus. In this paper, we present a case of successful surgical treatment of spontaneous rupture of the esophagus that was diagnosed 2 days after onset. The patient was a 42-year-old man admitted to internal medicine with a diagnosis of pleuritis and complaining of chest and back pain. The next day, computed tomography revealed left-sided pleural effusion and mediastinal emphysema. An esophagogram revealed extravasation of the contrast medium from the lower left esophagus to the mediastinal cavity. These results confirmed a rupture of the esophagus, and an emergency left thoracotomy was performed. The perforation was repaired with a single-layered closure and was covered with elevated great omentum obtained by laparotomy. The patient was discharged 23 days after the first surgery. In conclusion, primary repair surgery must be selected as the best treatment beyond 24 h if the patient's general state was stable and there was no evidence of clinical sepsis.

The utility of a noninvasive 13C-acetate breath test to predict quality of life after gastrectomy.

BACKGROUND: The radioscintigraphic technique has been accepted as the standard by which to measure gastric emptying but it is invasive and expensive. A 13C-acetate breath test was reported to be a noninvasive and reliable method. The aim of this study was to investigate the accuracy of a 13C-acetate breath test in reflecting gastric function and the relationship between food intake and change in body weight after distal gastrectomy. METHODS: Twenty-five patients who had undergone curative distal gastrectomy with Billroth-I reconstruction for gastric cancer and ten healthy volunteers were included in the study. The gastrectomy group was divided into two groups: the stasis group and the nonstasis group. The breath test was performed on the patients with gastrectomy and the healthy volunteers, and the time lag between ingestion and the peak of (13)CO(2) expiration (T lag) was calculated. The manometry study was performed on the patients who underwent gastrectomy and the motility index (MI) was calculated. The relationships between T lag and food intake and body weight were examined. RESULTS: The T lag was significantly shorter in the nonstasis group than in the stasis group. The MI in the duodenum in the nonstasis group was significantly larger than that in the stasis group. There was significant correlation between T lag and food intake, but no significant correlation between T lag and body weight. CONCLUSION: The 13C-acetate breath test might be useful not only for the evaluation of the function of the remnant stomach, but also for the prediction of postoperative status.

Gastric schwannomas show an obviously increased fluorodeoxyglucose uptake in positron emission tomography: report of two cases.

Schwannomas are tumors originating from any nerve that has a Schwann cell sheath. Gastrointestinal (GI) schwannomas represent only 3% of all GI mesenchymal tumors. The stomach is the most common site of GI schwannomas, and schwannomas account for 0.2% of all gastric neoplasms. This report presents two cases of gastric schwannomas showing increased [18F]fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET; maximum standardized uptake value 7.10 and 6.05). Additional immunohistochemical staining of glucose transporter type 1 (GLUT1) and the autocrine motility factor (AMF) was conducted after the tumors were resected, to identify the mechanism that increased FDG uptake on PET. Immunohistochemical expression of AMF was positive in both cases, whereas GLUT1 was negative. Autocrine motility factor is also known as phosphoglucose isomerase. However, the mechanism by which FDG is accumulated in schwannoma cells is uncertain, and may be related to intracellular glycolytic activity.

Clinical significance of melanoma antigen-encoding gene-1 (MAGE-1) expression and its correlation with poor prognosis in differentiated advanced gastric cancer.

BACKGROUND: Melanoma antigen-encoding gene-1 (MAGE-1), a cancer/testis antigen, has been reported to be expressed in various types of cancer. We investigated the clinicopathological features and prognostic significance of MAGE-1 expression in advanced gastric cancer (AGC). METHODS: Immunohistochemical staining for MAGE-1 was performed on surgical specimens obtained from 135 patients with AGC. RESULTS: Positive expression of MAGE-1 detected in cytoplasm was observed in 44 of 135 cases (32.6%) in primary tumors and 26 of 96 (27.1%) in lymph node metastases. In noncancerous gastric tissues, apparent MAGE-1 expression was not detected. MAGE-1 in primary tumor was correlated with advanced age (P < 0.001), macroscopic infiltrated type (P = 0.035), and presence of vascular invasion (P = 0.027). The 5-year cancer-specific survival rates of AGC patients with positive MAGE-1 expression were significantly lower than those of patients with negative MAGE-1 (positive: 31.6%, negative: 57.6%, P = 0.038). On multivariate analysis, MAGE-1 expression was not an independent prognostic predictor of AGC (P = 0.064). In differentiated AGC patients, MAGE-1 expression was correlated with advanced age (P = 0.003), macroscopic infiltrated type (P = 0.009), and presence of lymph node metastasis (P = 0.033). The cancer-specific survival rates of differentiated AGC patients with positive MAGE-1 were significantly lower than those of patients with negative MAGE-1 (P = 0.003). Positive MAGE-1 expression was an independent prognostic factor of differentiated AGC patients on multivariate analysis (P = 0.031). CONCLUSIONS: These findings suggest that MAGE-1 protein expression can serve as a predictive marker of poor prognosis in differentiated AGC patients.

Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans.

BACKGROUND: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans. METHODS: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5) was started on Rikkunshito (2.5 g three times daily, orally) from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5). All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin. RESULTS: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period. CONCLUSION: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.

Relationship between clinicopathological features and mucin phenotypes of advanced gastric adenocarcinoma.

AIM: To investigate a relationship between the clinicopathological features and mucin phenotypes in advanced gastric adenocarcinoma (AGA). METHODS: Immunohistochemical staining was performed to determine the mucin phenotypes in 38 patients with differentiated adenocarcinomas (DACs), 9 with signet-ring cell carcinomas (SIGs), and 48 with other diffuse-type adenocarcinomas (non-SIGs) of AGA. The mucin phenotypes were classified into 4 types: gastric (G), gastrointestinal (GI), intestinal, and unclassified. RESULTS: The G-related mucin phenotypes were highly expressed in all the histological subtypes of AGA. The expression of the GI phenotype in SIG patients was lower than that in DAC patients (P = 0.02), and this phenotype was observed in 56% of the non-SIG patients in the intramucosal layer. Among non-SIG cases, the expression of the GI phenotype was significantly higher in patients with extended adenocarcinomas and those with positive rates of lymph node metastasis. There was no difference between the expressions of the G and other GI phenotypes factors. Among DAC and non-SIG patients, there were no differences between the survival rates of the corresponding patient groups. CONCLUSION: The GI phenotype might possess more invasive characteristics than the G phenotype in non-SIG. Neither of the phenotypes indicated a poor prognosis of DAC and non-SIG.

The benefits of laparoscopically assisted distal gastrectomy for obese patients.

BACKGROUND: In Japan, the number of obese patients with gastric cancer is increasing. This study aimed to evaluate the advantages of laparoscopically assisted distal gastrectomy (LADG) for obese patients relative to those of conventional distal gastrectomy (DG). METHODS: Between January 2004 and June 2009, a total of 197 consecutive patients with gastric carcinoma underwent curative distal gastrectomy with Billroth 1 reconstruction in the Gunma University Hospital. The patients were assigned to undergo LADG (n = 120) or DG (n = 77) according to the depth of tumor invasion and lymph node status. A body mass (BMI) of 25 kg/m(2) or higher was defined as obesity, and the amounts of blood loss, the operating time, the number of lymph nodes dissected, and the postoperative complications experienced by obese and nonobese patients were compared. RESULTS: None of the patients in the LADG group required conversion to laparotomy. In the DG group, significantly fewer lymph nodes were retrieved from the obese patients (22.5 ± 3.4) than from the nonobese patients (31.9 ± 2.0; P < 0.05). However, among the obese patients, the number of lymph nodes retrieved did not differ significantly between the LADG and DG groups. In the LADG group, the obese patients had a longer operating time (206.6 ± 6.3 vs. 192.0 ± 3.1 min; P < 0.05) and a greater estimated blood loss (158.2 ± 24.7 vs. 101.9 ± 10.4 ml; P < 0.05) than the nonobese patients. The estimated blood loss correlated the surgical procedures and BMI. No significant difference in postoperative complications was noted between the obese and nonobese groups after each procedure. CONCLUSIONS: Relative to DG, LADG did not affect the radicality of the procedure for the obese patients, and there is no significant difference in the operating time. The estimated blood loss was significantly less for LADG than for DG. Surgeons should elect to perform LADG for obese patients with gastric cancer.