Prognostic factors for the successful conservative management of nonocclusive mesenteric ischemia.

BACKGROUND: The criteria for deciding upon non-operative management for nonocclusive mesenteric ischemia (NOMI) are poorly defined. The aim of this study is to determine the prognostic factors for survival in conservative treatment of NOMI. METHODS: Patients with bowel ischemia were identified by searching for "ICD-10 code K550" in the Diagnosis Procedure Combination database between June 2015 and May 2020. A total of 457 patients were extracted and their medical records, including the clinical factors, imaging findings and outcomes, were analyzed retrospectively. Diagnosis of NOMI was confirmed by the presence of specific findings in contrast-enhanced multidetector-row CT. Twenty-six patients with conservative therapy for NOMI, including four cases of explorative laparotomy or laparoscopy, were enrolled. RESULTS: Among the 26 cases without surgical intervention, eight patients (31%) survived to discharge. The level of albumin was significantly higher, and the levels of lactate dehydrogenase, total bilirubin, C-reactive protein, and lactate were significantly lower in the survivors than the non-survivors. Sepsis-related Organ Failure Assessment (SOFA) score was significantly lower in the survivors than the non-survivors. The most reliable predictor of survival for NOMI was SOFA score (cutoff value ≤ 3 points), which had the highest AUC value (0.899) with odds ratio of 0.075 (CI: 0.0096-0.58). CONCLUSIONS: The SOFA score and several biological markers are promising predictors to determine a treatment plan for NOMI and to avoid unnecessary laparotomy.

Dual common bile duct examination with transcystic choledochoscopy and cholangiography in laparoscopic cholecystectomy for suspected choledocholithiasis: a prospective study.

BACKGROUND: Detection of common bile duct (CBD) stones is a major objective of intraoperative cholangiography (IOC) in laparoscopic cholecystectomy (LC). We evaluated the feasibility and safety of the routine use of transcystic choledochoscopy following IOC (dual common bile duct examination: DCBDE), which may improve the diagnostic accuracy of CBD stones and facilitate one-stage clearance, in LC for suspected choledocholithiasis. METHODS: Between May 2017 and November 2018, 38 patients with suspected choledocholithiasis were prospectively enrolled in this study, regardless of whether they underwent endoscopic sphincterotomy. Transcystic choledochoscopy was routinely attempted following IOC in LC. RESULTS: Five cases were excluded due to cholecystitis, bile duct anomaly, or liver cirrhosis. DCBDE was performed in the remaining 33 patients. The biliary tree was delineated by IOC in all patients. Subsequently, choledochosope was performed in 32 patients except for one who was found to have pancreaticobiliary malunion in IOC. The scope was successfully passed into the CBD in 25 (78.1%) patients. Choledochoscopy detected 3 (9.4%) cases of cystic duct stones and 4 (12.5%) cases of CBD stones which were not identified by IOC. All those stones were removed via cystic duct. There were no intra- and postoperative complications, except for two cases of wound infection and one case of a transient increase in serum amylase. CONCLUSIONS: DCBDE in LC is a safe and promising approach for intraoperative diagnosis and one-stage treatment of suspected choledocholithasis.

A novel classification of aberrant right hepatic ducts ensures a critical view of safety in laparoscopic cholecystectomy.

BACKGROUND: Based on the spatial relationship of an aberrant right hepatic duct (ARHD) with the cystic duct and gallbladder neck, we propose a practical classification to evaluate the specific form predisposing to injury in laparoscopic cholecystectomy (LC). METHODS: We retrospectively investigated the preoperative images (mostly magnetic resonance cholangiopancreatography) and clinical outcomes of 721 consecutive patients who underwent LC at our institute from 2015 to 2018. We defined the high-risk ARHD as follows: Type A: communicating with the cystic duct and Type B: running along the gallbladder neck or adjacent to the infundibulum (the minimal distance from the ARHD < 5 mm), regardless of the confluence pattern in the biliary tree. Other ARHDs were considered to be of low risk. RESULTS: A high-risk ARHD was identified in 16 cases (2.2%): four (0.6%) with Type A anatomy and 12 (1.7%) with Type B. The remaining ARHD cases (n = 34, 4.7%) were categorized as low risk. There were no significant differences in the operative outcomes (operative time, blood loss, hospital stay) between the high- and low- risk groups. Subtotal cholecystectomy was applied in four cases (25%) in the high-risk group, a significantly higher percentage than the low-risk group (n = 1, 2.9%). In all patients with high-risk ARHD, LC was completed safely without bile duct injury or conversion to laparotomy. CONCLUSIONS: Our simple classification of high-risk ARHD can highlight the variants located close to the dissecting site to achieve a critical view of safety and may contribute to avoiding inadvertent damage of an ARHD in LC.

New ultrasonography-based method for predicting total skeletal muscle mass in male athletes.

[Purpose] This study aimed 1) to assess whether a prediction model for whole body skeletal muscle mass that is based on a sedentary population is applicable to young male athletes, and 2) to develop a new skeletal muscle mass prediction model for young male athletes. [Subjects and Methods] The skeletal muscle mass of 61 male athletes was measured using magnetic resonance imaging (MRI) and estimated using a previous prediction model (Sanada et al., 2006) with B-mode ultrasonography. The prediction model was not suitable for young male athletes, as a significant difference was observed between the means of the estimated and MRI-measured skeletal muscle mass. Next, the same subjects were randomly assigned to a development or validation group, and a new model specifically relevant to young male athletes was developed based on MRI and ultrasound data obtained from the development group. [Results] A strong correlation was observed between the skeletal muscle mass estimated by the new model and the MRI-measured skeletal muscle mass (r=0.96) in the validation group, without significant difference between their means. No bias was found in the new model using Bland-Altman analysis (r=-0.25). [Conclusion] These results validate the new model and suggest that ultrasonography is a reliable method for measuring skeletal muscle mass in young male athletes.

[Multidisciplinary treatment of leptomeningeal metastasis in patients with lung adenocarcinoma: the triple modality combination of EGFR-TKI, VP shunt and irradiation].

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of systemic cancers. New therapies that have beneficial effects on primary cancers outside the central nervous system (CNS) have underscored the significance of LM. Intrathecal chemotherapy plus radiation therapy are less effective for LM from lung adenocarcinoma. We retrospectively studied outcomes of patients with LM from lung adenocarcinoma who underwent multidisciplinary treatments in our institute. METHODS: Four patients with LM from lung adenocarcinoma treated with EGFR-TKI, VP shunt and irradiation. Of those four, two presented with increased intracranial pressure, one with epilepsy, and the other with truncal ataxia. Treatment was indicated when LM was confirmed by MR images or cytology, and Karnofsky Performance Status scale was more than 40%, and life expectancy was more than three months if LM was controlled. EGFR mutation was not examined, because of the unsettled approval of Japanese public health insurance at the time of this study. The patients selected for treatment by EGFR-TKI were all Asian women who had never smoked. Treatment sequence was based on clinical symptoms depending on the individual situation. RESULT: The mean time from diagnosis of lung adenocarcinoma to LM onset was 28 (24 to 36) months. Mean survival time from LM diagnosis was 9 months. All patients died of LM. No patients suffered from peritoneal carcinomatosis or infection after VP shunt. CONCLUSION: The triple modality combination of EGFR-TKI, VP shunt and radiation therapy may improve outcomes and symptoms of patients with LM from lung adenocarcinoma.

[The role of oral fluoropyrimidines in colorectal cancer treatment--a review].

Oral fluoropyrimidines, such as uracil plus tegafur (UFT), S-1 and capecitabine, have been developed and evaluated in the treatment of colorectal cancer. Their efficacy and safety are not inferior to infusional FU regimens. They provide more convenient therapy and better QOL. Careful observation and management of adverse events to preserve treatment compliance is important.

T-cell antigen receptor-induced signaling complexes: internalization via a cholesterol-dependent endocytic pathway.

T-cell antigen receptor engagement causes the rapid assembly of signaling complexes. The adapter protein SLP-76, detected as SLP-yellow fluorescent protein, initially clustered with the TCR and other proteins, then translocated medially on microtubules. As shown by total internal reflection fluorescence microscopy and the inhibition of SLP-76 movement at 16 degrees C, this movement required endocytosis. Immunoelectron microscopy showed SLP-76 staining of smooth pits and tubules. Cholesterol depletion decreased the movement of SLP-76 clusters, as did coexpression of the ubiquitin-interacting motif domain from eps15. These data are consistent with the internalization of SLP-76 via a lipid raft-dependent pathway that requires interaction of the endocytic machinery with ubiquitinylated proteins. The endocytosed SLP-76 clusters contained phosphorylated SLP-76 and phosphorylated LAT. The raft-associated, transmembrane protein LAT likely targets SLP-76 to endocytic vesicles. The endocytosis of active SLP-76 and LAT complexes suggests a possible mechanism for downregulation of signaling complexes induced by TCR activation.

Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy.

Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets.

Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways.

Activation of T cells via the stimulation of the TCR plays a central role in the adaptive immunological response. Although much is known about TCR-stimulated signaling pathways, there are still gaps in our knowledge about the kinetics and sequence of events during early activation and about the in vivo specificity of kinases involved in these proximal signaling pathways. This information is important not only for understanding the activation of signaling pathways important for T cell function but also for the development of drug targets and computer-based molecular models. In this study, phospho-specific Abs directed toward individual sites on signaling proteins were used to investigate the early phosphorylation kinetics of proteins involved in proximal TCR-induced pathways. These studies indicate that linker for activation of T cells' tyrosines have substantially different phosphorylation kinetics and that Src homology 2 domain-containing leukocyte protein of 76 kDa has rapid, transient phosphorylation kinetics compared to other proteins. In additions, we provide evidence that ZAP-70 is the primary in vivo kinase for LAT tyrosine 191 and that Itk plays a role in the phosphorylation of tyrosine 783 on phospholipase C-gamma1. In total, these studies give new insight into the sequence, kinetics and specificity of early TCR-mediated signaling events that are vital for T cell activation.

[Angioimmunoblastic T-cell lymphoma accompanied by pure red cell aplasia].

A 71-year-old woman was admitted in December 2002 because of lymphadenopathy, hepatosplenomegaly and pleural effusion. She had severe anemia with hemoglobin 5.9 g/dl and a reticulocyte count of 1% per hundred. Direct/indirect Coombs tests and anti-double stranded DNA antibody were positive, her serum CH50 level was reduced and an increase in serum LDH isoenzyme 3 was observed. Bone marrow aspiration showed an almost total absence of erythroblasts and no pathological cell proliferation. The diagnosis of angioimmunoblastic T-cell lymphoma (AILT) was made based on the lymph node histological findings. Proliferation of arborizing small vessels with hyperplastic endothelium and infiltration of atypical T-lymphocytes were observed. After combination chemotherapy (THP-COP), remission was achieved in both the pure red cell aplasia (PRCA) and AILT. Remission was also accompanied by normalization of the Coombs tests, suggesting that autoimmune mechanisms in AILT may contribute to the development of PRCA.

Co-stimulated/Tc2 cells abrogate murine marrow graft rejection.

CD3/CD28 co-stimulation activates T-cell cytokine and cytolytic effector function and therefore represents an approach to modulate donor T cells before allogeneic bone marrow transplantation (BMT). We hypothesized that co-stimulation of donor T cells under T2 conditions would generate CD4+ T-helper type 2 (Th2) and CD8+ Tc2 cells capable of abrogating marrow graft rejection with reduced graft-versus-host disease (GVHD). Relative to control co-stimulated Th1/Tc1 (T1) cells, co-stimulated T2 cells secreted reduced interleukin (IL)-2 and interferon-gamma and increased IL-4 and IL-10, expressed reduced fas ligand, and had similar total cytolytic capacity. In an F1-into-parent sublethal irradiation model, T2 cells potently abrogated rejection; this veto effect was partially attenuated if T2 cell infusion was delayed for 24 hours after BMT. Cell-tracking studies determined that T2 cells were quantitatively reduced after BMT when administered to hosts capable of mounting a host-versus-graft rejection response; both donor and host cytotoxic T lymphocytes may therefore have been deleted during Th2/Tc2 cell facilitation of engraftment. Donor T2 cells also abrogated rejection in an F1-into-parent model that used lethal host irradiation and subsequent host T-cell addback. Further experiments in a P1-into-P2 transplantation model demonstrated that donor T2 cells abrogated rejection with reduced GVHD in a transplant setting involving full major histocompatibility complex disparity in both the host-versus-graft and graft-versus-host directions. The capacity of T2 cells to abrogate rejection with reduced GVHD was a function of both the number of T2 cells infused and the number of T cells present after host preparation. Co-stimulation under T2 polarizing conditions therefore rapidly generates donor Th2/Tc2 cells that potently abrogate murine marrow rejection with reduced GVHD.

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases.

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.

[Remission induction of refractory diffuse large B-cell lymphoma with allogeneic peripheral blood stem cell transplantation followed by interferon-alpha and donor lymphocyte infusion].

Graft-versus-lymphoma (GVL) effect has been described in patients with malignant lymphoma after allogeneic stem cell transplantation (alloSCT). The effect of interferon-alpha (IFN-alpha) on the GVL effect still remains unclear. Here we report on a 29-year-old woman with refractory diffuse large B-cell lymphoma (DLBL). Her clinical findings included multiple masses in the liver, stomach, bilateral kidneys, thyroid, vertebral bones and a bulky mediastinal mass. Since the patient did not respond to various combination chemotherapies and further developed superior vena cava syndrome, allogeneic peripheral blood stem cell transplantation (PBSCT) from a HLA-identical brother was carried out after a myeloablative TBI/CY-based conditioning regimen. DLIs have been also performed every 4 weeks since day +14. As a result, the lymphoma masses showed a partial response. In order to enhance the GVL effect, IFN-alpha was further given at a maximum of 3 MU four times per week. Although the patient only experienced graft-versus-host disease of the skin (grade II) even after both DLIs and IFN, complete clinical remission was observed. 200 days after transplantation, the patient is still disease-free and in good condition. This report suggests the curative potential of IFN-alpha combined with DLI after allogeneic SCT in refractory DLBL.

Autocrine induction of the human pro-IL-1beta gene promoter by IL-1beta in monocytes.

IL-1beta is produced primarily by activated monocytes/macrophages. We report in this study that IL-1beta induces the human pro-IL-1beta (IL1B) gene promoter in human THP-1 monocytic cells. The -131 to +12 minimal IL1B promoter was induced by IL-1beta in a dose-dependent manner. The promoter possesses two important transcription factor binding motifs, one for an ETS family transcription factor Spi-1 (PU.1), and the other a binding site for NF-IL6 (CCAAT/enhancer binding protein beta). Autocrine promoter activity was completely inhibited by mutation of the Spi-1 site. Mutation of the NF-IL6 binding motif caused partial loss of activity. EMSAs using THP-1 cell nuclear extracts indicated that IL-1beta significantly induced Spi-1 binding to its target site within the IL1B promoter that was maximal at 1 h after stimulation, correlating with the kinetics of IL-1beta induction. The importance of Spi-1 was supported by our observation that Spi-1-deficient EL4 thymocytes exhibited IL-1beta-induced activity only after transfection with a Spi-1 expression vector. Moreover, TNFR-associated factor 6 also required Spi-1 to activate the promoter. Transfection studies using Spi-1 mutant constructs showed that the TATA-binding protein binding and glutamine-rich domains of Spi-1 were important for IL-1beta induction, whereas LPS induction required the proline, glutamic acid, serine, and threonine-rich domain containing serine 148 as well as the TATA-binding protein and glutamine-rich domains. We conclude that the IL1B promoter is an IL-1beta-responsive sequence as a result of its ability to bind Spi-1 in response to IL-1beta.