Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Application of spatial transcriptomics analysis using the Visium system for the mouse nasal cavity after intranasal vaccination.

Intranasal vaccines that elicit mucosal immunity are deemed effective against respiratory tract infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their ability to induce humoral immunity characterized by immunoglobulin A (IgA) and IgG production is low. It has been reported that vaccination with a mixture of a viscous base carboxyvinyl polymer (CVP) and viral antigens induced robust systemic and mucosal immune responses. In this study, we analyzed the behavior of immunocompetent cells in the nasal cavity over time by spatial transcriptome profiling induced immediately after antigen vaccination using CVP. We established a method for performing spatial transcriptomics using the Visium system in the mouse nasal cavity and analyzed gene expression profiles within the nasal cavity after intranasal vaccination. Glycoprotein 2 (Gp2)-, SRY-box transcription factor 8 (Sox8)-, or Spi-B transcription factor (Spib)-expressing cells were increased in the nasal passage (NP) region at 3-6 hr after SARS-CoV-2 spike protein and CVP (S-CVP) vaccination. The results suggested that microfold (M) cells are activated within a short period of time (3-6 hr). Subsequent cluster analysis of cells in the nasal cavity showed an increase in Cluster 9 at 3-6 hr after intranasal vaccination with the S-CVP. We found that Il6 in Cluster 9 had the highest log2 fold values within the NP at 3-6 hr. A search for gene expression patterns similar to that of Il6 revealed that the log2 fold values of Edn2, Ccl20, and Hk2 also increased in the nasal cavity after 3-6 hr. The results showed that the early response of immune cells occurred immediately after intranasal vaccination. In this study, we identified changes in gene expression that contribute to the activation of M cells and immunocompetent cells after intranasal vaccination of mice with antigen-CVP using a time-series analysis of spatial transcriptomics data. The results facilitated the identification of the cell types that are activated during the initial induction of nasal mucosal immunity.

Analysis for the diagnostic accuracy of PCR detection of Macrorhabdus in companion birds.

Background: Macrorhabdus ornithogaster, a yeast-like fungus, has the potential to infect various bird species, including companion birds. Although birds infected with M. ornithogaster may often remain asymptomatic, the infection can develop into chronic wasting gastritis and even progress to gastric cancer, highlighting the importance of early detection of M. ornithogaster infection. Despite direct fecal examination being a commonly used diagnostic method, the polymerase chain reaction (PCR) is anticipated to offer a higher detection rate. However, the actual diagnostic accuracy of the PCR for M. ornithogaster remains unknown. Case Description: Ninety fecal samples collected from companion birds that visited or were admitted to a hospital, regardless of their stage of Macrorhabdus diagnosis or treatment, were subjected to PCR testing. An accuracy analysis was then performed, considering symptomatology, direct fecal testing (FT), and sequencing. The PCR test had a sensitivity of 83.33%, specificity of 95.00%, false negative rate of 16.67%, false positive rate of 5.00%, positive predictive value of 89.29%, negative predictive value of 91.94%, prevalence of 33.33%, positive likelihood ratio of 16.67, negative likelihood ratio of 0.18, and diagnostic odds ratio of 95.00. Conclusion: The findings suggest that the PCR for Macrorhabdus possesses high diagnostic accuracy, with the ability to accurately identify uninfected individuals as negative. While the direct fecal examination is appropriate for routine primary screening, in cases where M. ornithogaster is not detected by FT, the PCR may provide a more accurate and definitive diagnosis due to its high specificity.

Real-World Data of Trifluridine/Tipiracil for Patients With Advanced Gastric Cancer: A Multi-Institutional Retrospective Study.

Background: A trial with trifluridine/tipiracil (FTD/TPI) versus placebo in patients with heavily pretreated metastatic gastric cancer showed that FTD/TPI is effective with manageable toxicity in these patients. However, real-world data on the effects of FTD/TPI in patients with advanced gastric cancer (AGC) are limited. Methods: We retrospectively collected and analyzed the clinicopathological data of patients with AGC who received FTD/TPI monotherapy at our institutions (Kobe City Medical Center General Hospital, Osaka Red Cross Hospital, Himeji Red Cross Hospital, and Kansai Medical University Hospital) between September 2019 and July 2021. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 53 patients were included in the study. The median age was 70 (range, 37-85) years; 39 patients (74%) were men; the numbers of patients with Eastern Cooperative Oncology Group performance status scores of 0, 1, and 2 were 10 (19%), 39 (74%), and 4 (8%), respectively; and 27 patients (51%) had diffuse-type histology. A total of 29 patients (56%) had ascites. Prior nivolumab therapy was administered to 49 patients (92%). The response rate and disease control rate (DCR) were 2% and 35%, respectively. The median progression-free survival was 2.4 months, and OS was 5.8 months. Patients with ascites exhibited significantly shorter OS (8.6 vs 4.7 months, P = .0291) than those without ascites, and DCR (54% vs 18%, P = .0055) was significantly worse in patients with ascites. There was no significant difference in the frequency of adverse events of grade 3 or higher between patients with and without ascites. Conclusion: In a real-world setting, FTD/TPI has similar effectiveness as late-line chemotherapy for patients with AGC, including those who previously had received nivolumab.

Improvement of Body Weight and Nutritional Status in Gastric Cancer Patients Enhances the Benefit of Nivolumab Therapy.

Nivolumab improves overall survival (OS) in patients with advanced gastric cancer (AGC) refractory to at least two previous chemotherapy regimens. We investigated whether changes in body weight and nutrition from first-line chemotherapy to nivolumab affected its efficacy. The correlation between weight change and nutritional status up to the start of nivolumab treatment and OS and progression-free survival (PFS) after starting nivolumab treatment was determined. Nutritional status was examined using the C-reactive protein/albumin ratio (CAR). A loss in body weight (LBW) from the onset of the first treatment of <4.5% led to OS prolongation and improved PFS outcomes. The median OS values in the LBW < 4.5% and ≥4.5% groups were 11.4 and 3.6 months, respectively. Similarly, changes in CAR from first-line chemotherapy (ΔCAR) affected OS; the ΔCAR < 0.01 group had a better prognosis than the ΔCAR ≥ 0.01 group. The median OS values in the ΔCAR < 0.01 and ≥0.01 groups were 9.4 and 4.5 months, respectively. The median OS in the group with LBW < 4.5% and ΔCAR < 0.01 was 12.9 months. LBW and deterioration of nutritional status following first-line chemotherapy are poor prognostic factors in AGC patients who received nivolumab as third- or later-line therapy. Early intervention to maintain body weight and nutritional status may improve the efficacy of immune checkpoint inhibitors.

Ingenuity of precordial leads in diagnosing a patient with dextroversion of the heart complicated by Takotsubo syndrome: A case report.

A 71-year-old male with history of a right lung lobectomy for cancer of the right lung complained of resting chest pain. Through the typical echocardiographic findings, takotsubo syndrome was suspected; however, because of dextroversion of the heart, the standard 12­lead electrocardiogram did not show the typical findings of takotsubo syndrome. Based on the finding of the chest-X-ray, in order to adjust for his dextroversion of the heart, the electrodes were then placed on the right side of his chest as modified right-sided precordial leads, in which leads V1-2 were equivalent to basal portion and V5-6 to the apex of the dextroversion of his heart. Negative T waves in the apical leads (V5-6) as a typical finding of takotsubo syndrome were clearly seen. Based on coronary angiogram and left ventriculogram, takotsubo syndrome was definitively diagnosed. Learning objectives: The proper modification of the precordial leads with consideration of the heart position can provide a valuable finding and may be very useful in diagnosing patients with cardiac malposition complicated by cardiac diseases in which identification of impaired site is important.

A Potential Role of Adhesion Molecules on Lung Metastasis Enhanced by Local Inflammation.

BACKGROUND/AIM: Local and systemic inflammations are associated with negative long-term outcomes; however, their precise mechanism of action remains unclear. We previously demonstrated that hepatocyte growth factor (HGF)/c-Met signaling contributed to the enhancement of liver metastasis associated with peritonitis model. The aim of this study is to investigate the effect of local inflammation on the development of lung metastasis. MATERIALS AND METHODS: NL-17 cells were injected into BALB/c mice via the tail vein to produce a high potential model for lung metastasis. After injection of NL-17 cells, lipopolysaccharide (LPS) and live Pseudomonas aeruginosa, and phosphate-buffered saline were administered intratracheally to induce acute lung injury (ALI) and pneumonia, respectively. RESULTS: In both ALI and pneumonia mice, lung metastasis was significantly promoted compared to control mice. Concentrations of Interleukin-6, tumor necrosis factor-α, and HGF in the bronchoalveolar lavage fluid were significantly higher in ALI and pneumonia mice than in control mice. Neither administration of recombinant mouse HGF nor c-Met knockdown in NL-17 cells influenced the magnitude of lung metastasis. Yet stimulation with LPS increased the expression of α2 integrin, vascular cell-adhesion protein-1, and intercellular adhesion molecule-1 (ICAM-1) in the lung. Invasive activity of NL-17 cells was significantly up-regulated by LPS, but was suppressed by anti-ICAM-1 antibody. While LPS-stimulated NL-17 cells showed significantly promoted lung metastasis, E-selectin expression in the lungs of mice with ALI or pneumonia was significantly enhanced compared with control mice. CONCLUSION: Up-regulation of adhesion molecules, but not HGF/c-Met signaling, may contribute to the lung metastasis enhanced by local infection/inflammation.

A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway.

BACKGROUND: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.

Claudin-1 inhibits human parainfluenza virus type 2 dissemination.

Tight junctions enable epithelial cells to form physical barriers that act as an innate immune defense against respiratory infection. However, the involvement of tight junction molecules in paramyxovirus infections, which include various respiratory pathogens, has not been examined in detail. Human parainfluenza virus type 2 (hPIV2) infects airway epithelial cells and causes respiratory illness. In the present study, we found that hPIV2 infection of cultured cells induces expression of claudin-1 (CLDN1), an essential component of tight junctions. This induction seemed to be intrinsically restricted by V, an accessory protein that modulates various host responses, to enable efficient virus propagation. By generating CLDN1 over-expressing and knockout cell lines, we showed that CLDN1 is involved in the restriction of hPIV2 spread via cell-to-cell contact. Taken together, we identified CLDN1 an inhibitory factor for hPIV2 dissemination, and that its V protein acts to counter this.

The role of video-assisted thoracoscopic surgery in the diagnosis of interstitial lung disease.

BACKGROUND: When a clinical context is indeterminate for idiopathic pulmonary fibrosis (IPF), or a chest high-resolution computed tomography (HRCT) pattern is not indicative of typical or probable usual interstitial pneumonia (UIP) in patients with interstitial lung disease (ILD), surgical lung biopsy should be considered to make a confident diagnosis on the basis of multidisciplinary diagnosis (MDD). AIM: The aim of this study was to evaluate the role and safety of video-assisted thoracoscopic surgery (VATS) in patients with ILD. METHODS: A total of 143 patients with ILD underwent VATS at Toho University Medical Center Omori Hospital between March 2004 and April 2017. We conducted a retrospective study on the usefulness and safety of VATS in the diagnosis of ILD under MDD. RESULTS: The 30-day mortality was 0%. The postoperative complication rate was 12.6%, which included 5 cases of pneumothorax after discharge (3.5%), 4 cases of prolonged air leakage (2.8%), and 2 cases of acute exacerbation (1.4%). Three of 9 cases (33.3%) complicated by pneumothorax after discharge or prolonged air leakage were resected specimens of pleuroparenchymal fibroelastosis (PPFE). Two patients had acute exacerbation, who were ultimately diagnosed as having idiopathic unclassifiable IP and had histologically significant irregular dense fibrosis and numerous fibroblastic foci. The comparison between chest HRCT and histopathological findings revealed 55 cases of possible UIP [UIP (45%), NSIP (25%), and unclassifiable IP (29%)] and 21 cases of inconsistent with UIP [UIP (10%), NSIP (33%), organizing pneumonia (10%), unclassifiable IP (24%), and PPFE (24%)]. CONCLUSION: VATS can be safely performed to obtain a confident diagnosis for appropriate treatment strategies in patients with ILD.

Rab27a facilitates human parainfluenza virus type 2 growth by promoting cell surface transport of envelope proteins.

Human parainfluenza virus type 2 (hPIV-2) proteins and genomes newly synthesized in the cytoplasm need to be transported to the plasma membrane where budding occurs. This mechanism, where Rab proteins regulate intracellular traffic by switching between GTP-bound active form and GDP-bound inactive form, is not fully understood. mRNA and protein expression levels of Rab8a, Rab11a, and Rab27a are not altered by hPIV-2 infection. hPIV-2 growth is affected by depletion of Rab27a but not Rab8a and Rab11a. Overexpression of a constitutively active mutant of Rab27a Q78L promotes the cell surface levels of fusion (F) and hemagglutinin-neuraminidase (HN) proteins in hPIV-2-infected cells without affecting viral mRNA levels. Increase in the cell surface level of F and HN proteins by Rab27a Q78L is noticeable when these proteins are coexpressed independent of hPIV-2 infection. Our results collectively suggest that the active form of Rab27a enhances hPIV-2 growth by promoting transport of F and HN proteins to the plasma membrane.

Clinical characteristics and outcomes of patients with community-acquired, health-care-associated and hospital-acquired empyema.

BACKGROUND AND AIMS: Patients with pneumonia, a common cause of empyema, are stratified based on their risk factors, and the treatment of empyema might benefit from this risk stratification. METHODS: The etiology, bacteriologic profile and outcome of patients diagnosed with empyema in Shinko Hospital between May 2005 and October 2013 were retrospectively studied. The patients were stratified according to whether they had community-acquired empyema (CAE), health-care-associated empyema (HCAE) or hospital-acquired empyema (HAE). RESULTS: The study included 81 patients, 25 CAE, 40 HCAE and 16 HAE. The comorbidity rate was highest among HAE patients (100%), followed by 95% of HCAE and 72% of CAE patients (P = 0.005). The rates of cancer and central nervous system (CNS) disease were higher in patients with HCAE and HAE than in patients with CAE (P = 0.030, P = 0.018, respectively). Pleural fluid cultures were positive in 58/81 patients. Streptococcus species were the most common organisms cultured from CAE (12/15) and HCAE patients (17/30), but not from HAE patients (3/13). Anaerobic organisms were cultured from 3 CAE, 5 HCAE and 3 HAE patients. Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa were only cultured from HCAE and HAE patients. The mortality rates were higher in HCAE (18%) and HAE (50%) than in CAE (4%) patients (log-rank test: P = 0.0012). CONCLUSIONS: Half of patients with empyema were HCAE patients, who had comorbidities, bacteriological profile and outcome different from CAE patients. The patient with HCAE should be differentiated from CAE patient, and the stratification of patients based on risk factors may be useful for treatment strategy.

Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA Signaling.

UNLABELLED: Rho GTPases are involved in a variety of cellular activities and are regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We found that the activation of Rho GTPases by lysophosphatidic acid promotes the growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, hPIV-2 infection causes activation of RhoA, a Rho GTPase. We hypothesized that Graf1 (also known as ARHGAP26), a GAP, regulates hPIV-2 growth by controlling RhoA signaling. Immunofluorescence analysis showed that hPIV-2 infection altered Graf1 localization from a homogenous distribution within the cytoplasm to granules. Graf1 colocalized with hPIV-2 P, NP, and L proteins. Graf1 interacts with P and V proteins via their N-terminal common region, and the C-terminal Src homology 3 domain-containing region of Graf1 is important for these interactions. In HEK293 cells constitutively expressing Graf1, hPIV-2 growth was inhibited, and RhoA activation was not observed during hPIV-2 infection. In contrast, Graf1 knockdown restored hPIV-2 growth and RhoA activation. Overexpression of hPIV-2 P and V proteins enhanced hPIV-2-induced RhoA activation. These results collectively suggested that hPIV-2 P and V proteins enhanced hPIV-2 growth by binding to Graf1 and that Graf1 inhibits hPIV-2 growth through RhoA inactivation. IMPORTANCE: Robust growth of hPIV-2 requires Rho activation. hPIV-2 infection causes RhoA activation, which is suppressed by Graf1. Graf1 colocalizes with viral RNP (vRNP) in hPIV-2-infected cells. We found that Graf1 interacts with hPIV-2 P and V proteins. We also identified regions in these proteins which are important for this interaction. hPIV-2 P and V proteins enhanced the hPIV-2 growth via binding to Graf1, while Graf1 inhibited hPIV-2 growth through RhoA inactivation.

Parainfluenza virus chimeric mini-replicons indicate a novel regulatory element in the leader promoter.

Gene expression of paramyxoviruses is regulated by genome-encoded cis-acting elements; however, whether all the required elements for viral growth have been identified is not clear. Using a mini-replicon system, it has been shown that human parainfluenza virus type 2 (hPIV2) polymerase can recognize the promoter elements of parainfluenza virus type 5 (PIV5), but reporter activity is lower in this case. We constructed a series of luciferase-encoding chimeric PIV2/5 mini-genomes that are basically hPIV2, but whose leader (le), mRNA start signal and trailer sequence are partially replaced with those of PIV5. Studies of the chimeric PIV2/5 mini-replicons demonstrated that replacement of hPIV2 le with PIV5 le results in remarkably weak luciferase expression. Further mutagenesis identified the responsible region as positions 25-30 of the PIV5 le. Using recombinant hPIV2, the impact of this region on viral life cycles was assessed. Insertion of the mutation at this region facilitated viral growth, genomic replication and mRNA transcription at the early stage of infection, which elicited severe cell damage. In contrast, at the late infection stage it caused a reduction in viral transcription. Here, we identify a novel cis-acting element in the internal region of an le sequence that is involved in the regulation of polymerase, and which contributes to maintaining a balance between viral growth and cytotoxicity.

Abdominal Infection Suppresses the Number and Activity of Intrahepatic Natural Killer Cells and Promotes Tumor Growth in a Murine Liver Metastasis Model.

BACKGROUND: Increasing evidence suggests that postoperative infection is associated with poorer long-term outcome in various malignancies. However, the mechanism of poor prognosis induced by postoperative infection has not been clearly explained. We sought to determine whether abdominal infection promotes cancer metastases in a murine liver metastasis model, and to investigate the role of liver natural killer (NK) cells on antitumor immunity during abdominal infection. METHODS: Female BALB/c (8-10 weeks old) mice were inoculated with NL-17 colon cancer cells into the spleen and then subjected to abdominal infection induced by cecal ligation and puncture (CLP) or sham treatment. The extent of liver metastases and cytokine production in the serum and liver were investigated. Cell fraction and cytotoxic activities of liver mononuclear cells (MNCs) were elucidated. RESULTS: CLP mice had poorer survival and their serum levels of IL-6, -10, and -12p70 were significantly elevated on day 1 compared with sham-treated and control mice. No obvious differences in cytokine levels of the liver homogenates were identified among the three groups, except IL-12p70 levels in CLP mice on day 7 significantly decreased. The cytotoxic activities of liver MNCs were significantly suppressed in CLP mice soon after tumor inoculation. Flow cytometry revealed a decrease in NK cells in the liver and perforin and granzyme B expression levels. CONCLUSIONS: Abdominal infection promoted liver metastases in a murine liver metastasis model, which may be partially caused by a decrease in the number and activity of NK cells during abdominal infection.

CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer.

CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47(hi) gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47(lo) , and CD44(hi) CD47(hi) cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer.

Marked improvement in autoimmune pulmonary alveolar proteinosis with severe hypoxemia in a patient treated with ambroxol: a case report.

INTRODUCTION: Pulmonary alveolar proteinosis is characterized by accumulation of surfactant and phospholipids in the pulmonary alveoli. Whole lung lavage is considered the first-line therapy, which requires special techniques. To the best of our knowledge, there have only been limited reports that have demonstrated the effectiveness of ambroxol on a mild case of pulmonary alveolar proteinosis. CASE PRESENTATION: A 72-year-old Japanese woman presented to our hospital with a one-year history of productive cough and progressive dyspnea. Her chest computed tomography scan showed a bilateral crazy-paving pattern in both of her lungs. She was diagnosed with autoimmune pulmonary alveolar proteinosis based on bronchoalveolar lavage findings and the presence of serum anti-granulocyte macrophage colony-stimulating factor antibodies. She was severely hypoxemic, so we recommended whole lung lavage or inhaled granulocyte macrophage colony-stimulating factor treatment, which she refused. We initiated treatment with ambroxol and her symptoms markedly improved. CONCLUSIONS: Although whole lung lavage is the first-line therapy for pulmonary alveolar proteinosis, oral ambroxol could be an alternative treatment option, even in patients with severe respiratory compromise.

[Two cases of recurrent invasive mucinous adenocarcinoma of the lung showing marked responses to platinum-based chemotherapyregimens with pemetrexed and bevacizumab].

Here, we report 2 cases of recurrent invasive mucinous adenocarcinoma of the lung after surgery, which showed marked responses to platinum-based regimens with pemetrexed(PEM)and bevacizumab(BEV). The first patient was diagnosed with stage I B(p-T2N0M0)invasive mucinous adenocarcinoma, and new nodules were detected on computed tomography (CT)after 24 months of adjuvant chemotherapy with uracil/tegafur(UFT). Therefore, the patient was administered carboplatin(CBDCA; AUC 5.0), PEM(500mg/m2), and BEV(15mg/kg)for 6 courses followed by BEV(15mg/kg)for 3 courses, resulting in a complete response. The second patient was diagnosed with stage IV(p-T3N0M1)invasive mucinous adenocarcinoma, and metastases appeared after the surgery. The patient was treated with S-1 for 18 weeks, but the tumor recurred 18weeks after surgery. Therefore, the patient was administered 4 courses of cisplatin(CDDP 60mg/m2), PEM(500mg/m2), and BEV(15mg/kg)followed by 5 courses of PEM(15mg/kg)as maintenance therapy. This resulted in a good response. The first patient had grade 3 toxicities at the sixth course of combined CBDCA-PEM-BEV therapy, while the second patient did not have any adverse events throughout chemotherapy. These 2 cases showed that platinum-based regimens with PEM and BEV may be a good choice for patients with invasive mucinous adenocarcinoma of the lung.

Increased red blood cell distribution width associates with cancer stage and prognosis in patients with lung cancer.

BACKGROUND: Red cell distribution width (RDW), one of many routinely examined parameters, shows the heterogeneity in erythrocyte size. We investigated the association of RDW levels with clinical parameters and prognosis of lung cancer patients. METHODS: Clinical and laboratory data from 332 patients with lung cancer in a single institution were retrospectively studied by univariate analysis. Kaplan-Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival. RESULTS: THE RDW LEVELS WERE DIVIDED INTO TWO GROUPS: high RDW (>=15%), n=73 vs. low RDW, n=259 (<15%). Univariate analysis showed that there were significant associations of high RDW values with cancer stage, performance status, presence of other disease, white blood cell count, hemoglobin, mean corpuscular volume, platelet count, albumin level, C-reactive protein level, and cytokeratin 19 fragment level. Kruskal-Wallis tests revealed an association of RDW values with cancer stage in patients irrespective of comorbidity (patient with/without comorbidity: p<0.0001, patient without comorbidity: p<0.0001). Stages I-IV lung cancer patients with higher RDW values had poorer prognoses than those with lower RDW values (Wilcoxon test: p=0.002). In particular, the survival rates of stage I and II patients (n=141) were lower in the high RDW group (n=19) than in the low RDW group (n=122) (Wilcoxon test: p<0.001). Moreover, multivariate analysis showed higher RDW is a significant prognostic factor (p=0.040). CONCLUSION: RDW is associated with several factors that reflect inflammation and malnutrition in lung cancer patients. Moreover, high levels of RDW are associated with poor survival. RDW might be used as a new and convenient marker to determine a patient's general condition and to predict the mortality risk of lung cancer patients.