Randomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after Laparoscopic Gastrectomy

Although epidural analgesia (EDA) is considered standard postoperative analgesia for open gastrectomy, it has been unclear whether EDA has benefits in laparoscopic gastrectomy (LG) because postoperative pain after a laparoscopic procedure is significantly reduced. We are conducting a two-arm, single-center, prospective randomized non-inferiority trial to evaluate the postoperative pain relief of patient-controlled intravenous analgesia (PCIA) compared to EDA. A total of 132 patients undergoing LG will be randomized to EDA and PCIA groups (n=64 each) for postoperative pain control. The primary endpoint is postoperative pain at 24 h after surgery. This study will clarify the optimal pain management after LG

Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker

Immune checkpoint inhibitor (ICI) programmed death (PD)-1/PD-ligand 1 (PD-L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 Ab in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 Ab inhibited tumor angiogenesis and induces net-like hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, interferon-γ (IFN-γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity

抗PD-1抗体への化学療法の併用はmyeloid-derived suppressor cellsを減少させることにより中皮腫の増殖を抑制する

Background: The combination of anti-PD-1/PD-L1 antibody with chemotherapy has been approved for the first-line therapy of lung cancer. However, the effects against malignant mesothelioma (MPM) and the immunological mechanisms by which chemotherapy enhances the effect of targeting PD-1/PD-L1 in MPM are poorly understood. Materials and Methods: We utilized syngeneic mouse models of MPM and lung cancer and assessed the therapeutic effects of anti-PD-1 antibody and its combination with cisplatin (CDDP) and pemetrexed (PEM). An immunological analysis of tumor-infiltrating cells was performed with immunohistochemistry. Results: We observed significant therapeutic effects of anti-PD-1 antibody against MPM. Although the effect was associated with CD8+ and CD4+ T cells in tumors, the number of Foxp3+ cells was not reduced but rather increased. Consequently, combination with CDDP/PEM significantly enhanced the antitumor effects of anti-PD-1 antibody by decreasing numbers of intratumoral myeloid-derived suppressor cells (MDSCs) and vessels probably through suppression of VEGF expression by CDDP+PEM. Conclusions: The combination of anti-PD-1 antibody with CDDP+PEM may be a promising therapy for MPM via inhibiting the accumulation of MDSCs and vessels in tumors

BLOCKADE OF PD-1/PD-L1 ENHANCES APC FUNCTION OF FIBROCYTES

Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8+ T cells by fibrocytes was examined in MLRs with a 3H-thymidine incorporation assay. Fibrocytes expressed CD80low and CD86high as a costimulatory molecule, and expressed PD-L1high, but not PD-L2, as a coinhibitory molecule.Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8+ T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8+ T cells induced by fibrocytes. Anti–PD-L1 Ab further enhanced the proliferation of CD8+ T cells, even in the OVA-specific MLR with OT-1Rag-/- mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8+ T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8+ T cells when the activity is further enhanced by PD-L1/PD-1 blockade

骨髄由来線維細胞は肺がん細胞のがん幹細胞様特性を増強する

Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14þ monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches

Analysis of a pair of END+ and END- viruses derived from the same bovine viral diarrhea virus stock reveals the amino acid determinants in N-pro responsible for inhibition of type I interferon production

The Exaltation of Newcastle disease virus (END) phenomenon is induced by the inhibition of type I interferon in pestivirus-infected cells in vitro, via proteasomal degradation of cellular interferon regulatory factor (IRF)-3 with the property of the viral autoprotease protein N-pro. Reportedly, the amino acid residues in the zinc-binding TRASH motif of N-pro determine the difference in characteristics between END-phenomenon-positive (END) and END-phenomenon-negative (END-) classical swine fever viruses (CSFVs). However, the basic mechanism underlying this function in bovine viral diarrhea virus (BVDV) has not been elucidated from the genomic differences between END+ and END- viruses using reverse genetics till date. In the present study, comparison of complete genome sequences of a pair of END+ and END- viruses isolated from the same virus stock revealed that there were only four amino acid substitutions (D136G, I2623V, D3148G and D3502Y) between two viruses. Based on these differences, viruses with and without mutations at these positions were generated using reverse genetics. The END assay, measurements of induced type I interferon and IRF-3 detection in cells infected with these viruses revealed that the aspartic acid at position 136 in the zinc-binding TRASH motif of N-pro was required to inhibit the production of type I interferon via the degradation of cellular IRF-3, consistently with CSFV

The N-terminal domain of N-pro of classical swine fever virus determines its stability and regulates type I IFN production

The viral protein N-pro is unique to the genus Pestivirus within the family Flaviviridae. After autocatalytic cleavage from the nascent polyprotein, N-pro suppresses type I IFN (IFN-alpha/beta) induction by mediating proteasomal degradation of IFN regulatory factor 3 (IRF-3). Previous studies found that the N-pro-mediated IRF-3 degradation was dependent of a TRASH domain in the C-terminal half of N-pro coordinating zinc by means of the amino acid residues 0112, 0134, D136 and C138. Interestingly, four classical swine fever virus (CSFV) isolates obtained from diseased pigs in Thailand in 1993 and 1998 did not suppress IFN-alpha/beta induction despite the presence of an intact TRASH domain. Through systematic analyses, it was found that an amino acid mutation at position 40 or mutations at positions 17 and 61 in the N-terminal half of N-pro of these four isolates were related to the lack of IRF-3-degrading activity. restoring a histidine at position 40 or both a proline at position 17 and a lysine at position 61 based on the sequence of a functional N-pro contributed to higher stability of the reconstructed N-pro compared with the N-pro from the Thai isolate. This led to enhanced interaction of N-pro with IRF-3 along with its degradation by the proteasome. The results of the present study revealed that amino acid residues in the N-terminal domain of N-pro are involved in the stability of N-pro, in interaction of N-pro with IRF-3 and subsequent degradation of IRF-3, leading to downregulation of IFN-alpha/beta production

Factors and impact of physicians' diagnostic errors in malpractice claims in Japan.

BackgroundDiagnostic errors are prevalent and associated with increased economic burden; however, little is known about their characteristics at the national level in Japan. This study aimed to investigate clinical outcomes and indemnity payment in cases of diagnostic errors using Japan's largest database of national claims.MethodsWe analyzed characteristics of diagnostic error cases closed between 1961 and 2017, accessed through the national Japanese malpractice claims database. We compared diagnostic error-related claims (DERC) with non-diagnostic error-related claims (non-DERC) in terms of indemnity, clinical outcomes, and factors underlying physicians' diagnostic errors.ResultsAll 1,802 malpractice claims were included in the analysis. The median patient age was 33 years (interquartile range = 10-54), and 54.2% were men. Deaths were the most common outcome of claims (939/1747; 53.8%). In total, 709 (39.3%, 95% CI: 37.0%-41.6%) DERC cases were observed. The adjusted total billing amount, acceptance rate, adjusted median claims payments, and proportion of deaths were significantly higher in DERC than non-DERC cases. Departments of internal medicine and surgery were 1.42 and 1.55 times more likely, respectively, to have DERC cases than others. Claims involving the emergency room (adjusted odds ratio [OR] = 5.88) and outpatient office (adjusted OR = 2.87) were more likely to be DERC than other cases. The initial diagnoses most likely to lead to diagnostic error were upper respiratory tract infection, non-bleeding digestive tract disease, and "no abnormality."ConclusionsCases of diagnostic errors produced severe patient outcomes and were associated with high indemnity. These cases were frequently noted in general exam and emergency rooms as well as internal medicine and surgery departments and were initially considered to be common, mild diseases