Clinical Phenotyping of Out-of-Hospital Cardiac Arrest Patients With Shockable Rhythm　- Machine Learning-Based Unsupervised Cluster Analysis.

BACKGROUND: The hypothesis of this study is that latent class analysis could identify the subphenotypes of out-of-hospital cardiac arrest (OHCA) patients associated with the outcomes and allow us to explore heterogeneity in the effects of extracorporeal cardiopulmonary resuscitation (ECPR).Methods and Results:This study was a retrospective analysis of a multicenter prospective observational study (CRITICAL study) of OHCA patients. It included adult OHCA patients with initial shockable rhythm. Patients from 2012 to 2016 (development dataset) were included in the latent class analysis, and those from 2017 (validation dataset) were included for evaluation. The association between subphenotypes and outcomes was investigated. Further, the heterogeneity of the association between ECPR implementation and outcomes was explored. In the study results, a total of 920 patients were included for latent class analysis. Three subphenotypes (Groups 1, 2, and 3) were identified, mainly characterized by the distribution of partial pressure of O2(PO2), partial pressure of CO2(PCO2) value of blood gas assessment, cardiac rhythm on hospital arrival, and estimated glomerular filtration rate. The 30-day survival outcomes were varied across the groups: 15.7% in Group 1; 30.7% in Group 2; and 85.9% in Group 3. Further, the association between ECPR and 30-day survival outcomes by subphenotype groups in the development dataset was as varied. These results were validated using the validation dataset. CONCLUSIONS: The latent class analysis identified 3 subphenotypes with different survival outcomes and potential heterogeneity in the effects of ECPR.

Trends in In-Hospital Advanced Management and Survival of Out-of-Hospital Cardiac Arrest Among Adults From 2013 to 2017　- A Multicenter, Prospective Registry in Osaka, Japan.

BACKGROUND: The aim of our study was to investigate in detail the temporal trends in in-hospital characteristics, actual management, and survival, including neurological status, among adult out-of-hospital cardiac arrest (OHCA) patients in recent years.Methods and Results:From the prospective database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study in Osaka, Japan, we enrolled all OHCA patients aged ≥18 years for whom resuscitation was attempted, and who were transported to participating hospitals between the years 2013 and 2017. The primary outcome measure was 1-month survival with favorable neurological outcome after OHCA. Temporal trends in in-hospital management and favorable neurological outcome among adult OHCA patients were assessed. Of the 11,924 patients in the database, we included a total of 10,228 adult patients from 16 hospitals. As for in-hospital advanced treatments, extracorporeal cardiopulmonary resuscitation (ECPR) use increased from 2.4% in 2013 to 4.3% in 2017 (P for trend <0.001). However, the proportion of adult OHCA patients with favorable neurological outcome did not change during the study period (from 5.7% in 2013 to 4.4% in 2017, adjusted odds ratio (OR) for 1-year increment: 0.98 (95% confidence interval: 0.94-1.23)). CONCLUSIONS: In this target population, in-hospital management such as ECPR increased slightly between 2013 and 2017, but 1-month survival with favorable neurological outcome after adult OHCA did not improve significantly.

Vaccination Status and Antibody Titers against Rubella and Measles among Japanese Female College Students Majoring in Childcare between 2015 and 2018.

In 2014, for the protection of medical workers against measles and rubella infection, the Japanese Society for Infection Prevention and Control (JSIPC) recommended either maintaining antibody titers of seroprotective range or two-dose vaccination. JSIPC defined antibody titers into 3 ranges: seroprotective as expected prevention of infection, seronegative as under detection levels, and seropositive as antibody titers ranged between seronegative and seroprotective. This study aimed to explore the association between the number of vaccine doses received and the antibody titers against measles and rubella among Japanese college students majoring in childcare. A total of 841 female students with no history of measles or rubella were serologically screened at the time of college admission between 2015 and 2018. All 841 students had been vaccinated against measles; 738 (87.8%) received two doses of the measles vaccine and 103 (12.2%) received one dose. Likewise, 839 students, except for two, had been vaccinated against rubella; 719 (85.7%) received two doses of the rubella vaccine and 120 (14.3%) received one dose. We thus found that 107 students (12.7%) were seropositive for measles-specific IgG and 731 (86.9%) attained seroprotective titers. By contrast, in case of rubella-specific IgG, only 462 students (55.1%) attained seroprotective titers, and 371 students (44.1%) were seropositive. The two students without receiving rubella vaccination were classified as seronegative. In conclusion, despite that > 85% of students surveyed had received two doses of measles and rubella vaccines, a substantial number of students remain susceptible to measles and especially rubella at the time of college admission.

[Examination of Patients with Malignant Obstruction Treated with Chemotherapy after Ileo/Coleostomy].

Management for obstructive cancer of the colon diverges into many ways. The aim of this study was to evaluate the treatment course of patients with malignant obstruction after ileo/coleostomy. Thirty-six patients with malignant obstruction who underwent ileo/coleostomy in our hospital from May 2012 to January 2016were enrolled in the study. Clinical outcomes were the period before treatment initiation, chemotherapy, radiotherapy, primary lesion resection, and death, and these were retrospectively analyzed. Although 9 stomal complications occurred, no case experienced a delayed treatment start. However, patients with perioperative complications, sepsis due to the tumor, pneumonia, cerebral infractions, and ileus needed a long recovery period before treatment initiation. Patients who need ileo/coleostomy must be considered for performance status and ways to decrease perioperative complications to prevent stomal complications from chemo/radiotherapy.

[A Case of an Elderly Patient with Unresectable Gastric Cancer Treated by Paclitaxel and Ramucirumab].

An 80-year-old man was admitted to our hospital with appetite loss in December 2014. Gastroduodenal scope, abdominal computed tomography(CT), and laparoscopy revealed type 4 advanced gastric cancer(poorly differentiated adenocarcinoma) with multiple lymph node(LN)involvement and multiple peritoneal metastasis. S-1(80mg/body)was administrated between January 2015 and September 2015 in the outpatient clinic. A partial response was obtained, but a gastric tumor, ascites, and LN re-growth were observed. Since October 2015, paclitaxel(PTX)(70mg/m2; day 1, 8, and 15)and ramucir- umab(RAM)(8mg/kg; day 1 and 15)have been administered. After 2 courses, bi-weekly PTX plus RAM were continued for grade 3 neutropenia and grade 2 anorexia. The tumor and LNs partially responded, and the ascites disappeared. With this dosage and administration schedule, the partial response(PR)was maintained for approximately 8 months without any severe adverse reactions. This successful case might indicate that it is important for elderly patients with gastric cancer that progressed with prior chemotherapy regimens to consider appropriate reduction of the PTX dosage, schedule, and continuation of RAM.

[A Case of Invasive Ductal Carcinoma in the Fat Replacement of the Pancreatic Body and Tail].

A 56 year-old woman with obesity (BMI3 2) and diabetes mellitus was diagnosed with right renal cell carcinoma. She underwent right nephrectomy 1 year ago. Seven months after surgery, CT revealed a rapidly growing mass near the spleen. The mass showed slight accumulation of FDG (SUVmax=2.4) on PET-CT. Since the lesion grew rapidly and was not enhanced in the early phase of enhanced CT, we diagnosed pancreatic cancer. Distal pancreatectomy and splenectomy were performed. The final pathological diagnosis was invasive ductal carcinoma in the fat replacement of the pancreatic body and tail. Postoperatively, the patient had no complications such as pancreatic fistula or aggravation of glucose intolerance. She received postoperative chemotherapy with gemcitabine. Since she developed pulmonary artery thrombosis, postoperative chemotherapy was interrupted after 8 courses. Thirty-two months after the surgery, she was still living without any recurrence. Acinar cells were absent in the fat replacement of the pancreas, but the pancreatic duct cells were still present. There was carcinoma in situ in the main pancreatic duct surrounding chronic inflammation. Fat replacement itself could be potentially precursor of the pancreatic cancer.

Clustering out-of-hospital cardiac arrest patients with non-shockable rhythm by machine learning latent class analysis.

Aim: We aimed to identify subphenotypes among patients with out-of-hospital cardiac arrest (OHCA) with initial non-shockable rhythm by applying machine learning latent class analysis and examining the associations between subphenotypes and neurological outcomes. Methods: This study was a retrospective analysis within a multi-institutional prospective observational cohort study of OHCA patients in Osaka, Japan (the CRITICAL study). The data of adult OHCA patients with medical causes and initial non-shockable rhythm presenting with OHCA between 2012 and 2016 were included in machine learning latent class analysis models, which identified subphenotypes, and patients who presented in 2017 were included in a dataset validating the subphenotypes. We investigated associations between subphenotypes and 30-day neurological outcomes. Results: Among the 12,594 patients in the CRITICAL study database, 4,849 were included in the dataset used to classify subphenotypes (median age: 75 years, 60.2% male), and 1,465 were included in the validation dataset (median age: 76 years, 59.0% male). Latent class analysis identified four subphenotypes. Odds ratios and 95% confidence intervals for a favorable 30-day neurological outcome among patients with these subphenotypes, using group 4 for comparison, were as follows; group 1, 0.01 (0.001-0.046); group 2, 0.097 (0.051-0.171); and group 3, 0.175 (0.073-0.358). Associations between subphenotypes and 30-day neurological outcomes were validated using the validation dataset. Conclusion: We identified four subphenotypes of OHCA patients with initial non-shockable rhythm. These patient subgroups presented with different characteristics associated with 30-day survival and neurological outcomes.

Association between serum lactate level during cardiopulmonary resuscitation and survival in adult out-of-hospital cardiac arrest: a multicenter cohort study.

We aimed to investigate the association between serum lactate levels during cardiopulmonary resuscitation (CPR) and survival in patients with out-of-hospital cardiac arrest (OHCA). From the database of a multicenter registry on OHCA patients, we included adult nontraumatic OHCA patients transported to the hospital with ongoing CPR. Based on the serum lactate levels during CPR, the patients were divided into four quartiles: Q1 (≤ 10.6 mEq/L), Q2 (10.6-14.1 mEq/L), Q3 (14.1-18.0 mEq/L), and Q4 (> 18.0 mEq/L). The primary outcome was 1-month survival. Among 5226 eligible patients, the Q1 group had the highest 1-month survival (5.6% [74/1311]), followed by Q2 (3.6% [47/1316]), Q3 (1.7% [22/1292]), and Q4 (1.0% [13/1307]) groups. In the multivariable logistic regression analysis, the adjusted odds ratio of Q4 compared with Q1 for 1-month survival was 0.24 (95% CI 0.13-0.46). 1-month survival decreased in a stepwise manner as the quartiles increased (p for trend < 0.001). In subgroup analysis, there was an interaction between initial rhythm and survival (p for interaction < 0.001); 1-month survival of patients with a non-shockable rhythm decreased when the lactate levels increased (p for trend < 0.001), but not in patients with a shockable rhythm (p for trend = 0.72). In conclusion, high serum lactate level during CPR was associated with poor 1-month survival in OHCA patients, especially in patients with non-shockable rhythm.

The production of IL-10 by human regulatory T cells is enhanced by IL-2 through a STAT5-responsive intronic enhancer in the IL-10 locus.

STAT5 molecules are key components of the IL-2 signaling pathway, the deficiency of which often results in autoimmune pathology due to a reduced number of CD4(+)CD25(+) naturally occurring regulatory T (Treg) cells. One of the consequences of the IL-2-STAT5 signaling axis is up-regulation of FOXP3, a master control gene for naturally occurring Treg cells. However, the roles of STAT5 in other Treg subsets have not yet been elucidated. We recently demonstrated that IL-2 enhanced IL-10 production through STAT5 activation. This occurred in two types of human Treg cells: a novel type of umbilical cord blood-derived Treg cell, termed HOZOT, and Tr1-like Treg cells, IL-10-Treg. In this study, we examined the regulatory mechanisms of IL-10 production in these Treg cells, focusing specifically on the roles of STAT5. By performing bioinformatic analysis on the IL-10 locus, we identified one STAT-responsive element within intron 4, designated I-SRE-4, as an interspecies-conserved sequence. We found that I-SRE-4 acted as an enhancer element, and clustered CpGs around the I-SRE-4 were hypomethylated in IL-10-producing Treg cells, but not in other T cells. A gel-shift analysis using a nuclear extract from IL-2-stimulated HOZOT confirmed that CpG DNA methylation around I-SRE-4 reduced STAT5 binding to the element. Chromatin immunoprecipitation analysis revealed the in situ binding of IL-2-activated STAT5 to I-SRE-4. Thus, we provide molecular evidence for the involvement of an IL-2-STAT5 signaling axis in the expression of IL-10 by human Treg cells, an axis that is regulated by the intronic enhancer, I-SRE-4, and epigenetic modification of this element.

[A case report: multiple air embolism after the laryngopharyngoesophagectomy occurred by the cervical infection from postoperative fistula].

Systemic air embolism, a very rare clinical condition, has many causes. We report a case of multiple air embolisms following laryngopharyngoesophagectomy salvage surgery for hypopharyngeal residual cancer after concurrent chemoradiotherapy. Cervical infection arose from a fistula caused by postoperative suture failure in which the 56-year-old man suddenly lost consciousness and went into shock. A few days post operation, an air embolism happened and caused in the brain, pulmonary, myocardiac and cerebral infarction. The man died two months after initial occurrence. We suspect that air entered through the ruptured left internal jugular vein via infection due to aspiration at the injury site. Air embolisms are associated with different medical maneuvers, and it is necessary to recognize that they may become a serious perioperative complication.

Development and Validation of a Clinical Score to Predict Neurological Outcomes in Patients With Out-of-Hospital Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation.

Importance: Extracorporeal cardiopulmonary resuscitation (ECPR) is expected to improve the neurological outcomes of patients with refractory cardiac arrest; however, it is invasive, expensive, and requires substantial human resources. The ability to predict neurological outcomes would assist in patient selection for ECPR. Objective: To develop and validate a prediction model for neurological outcomes of patients with out-of-hospital cardiac arrest with shockable rhythm treated with ECPR. Design, Setting, and Participants: This prognostic study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest registry, a multi-institutional nationwide cohort study that included 87 emergency departments in Japan. All adult patients with out-of-hospital cardiac arrest and shockable rhythm who were treated with ECPR between June 2014 and December 2017 were included. Patients were randomly assigned to the development and validation cohorts based on the institutions. The analysis was conducted between November 2019 and August 2020. Exposures: Age (<65 years), time from call to hospital arrival (≤25 minutes), initial cardiac rhythm on hospital arrival (shockable), and initial pH value (≥7.0). Main Outcomes and Measures: The primary outcome was 1-month survival with favorable neurological outcome, defined by Cerebral Performance Category 1 or 2. In the development cohort, a simple scoring system was developed to predict this outcome using a logistic regression model. The diagnostic ability and calibration of the scoring system were assessed in the validation cohort. Results: A total of 916 patients were included, 458 in the development cohort (median [interquartile range {IQR}] age, 61 [47-69] years, 377 [82.3%] men) and 458 in the validation cohort (median [IQR] age, 60 [49-68] years; 393 [85.8%] men). The cohorts had the same proportion of favorable neurological outcome (57 patients [12.4%]). The prediction scoring system was developed, attributing a score of 1 for each clinical predictor. Patients were divided into 4 groups, corresponding to their scores on the prediction model, as follows: very low probability (score 0), low probability (score 1), middle probability (score 2), and high probability (score 3-4) of good neurological outcome. The mean predicted probabilities in the groups stratified by score were as follows: very low, 1.6% (95% CI, 1.6%-1.6%); low, 4.4% (95% CI, 4.2%-4.6%); middle, 12.5% (95% CI, 12.1%-12.8%); and high, 30.8% (95% CI, 29.1%-32.5%). In the validation cohort, the C statistic of the scoring system was 0.724 (95% CI, 0.652-0.786). The predicted probability was evaluated as well calibrated to the observed favorable outcome in both cohorts by visual assessment of the calibration plot. Conclusions and Relevance: In this study, the scoring system had good discrimination and calibration performance to predict favorable neurological outcomes of patients with out-of-hospital cardiac arrest and shockable rhythm who were treated with ECPR.

IL-2 activation of STAT5 enhances production of IL-10 from human cytotoxic regulatory T cells, HOZOT.

OBJECTIVE: Interleukin (IL)-10 is an immunosuppressive cytokine produced by many cell types, including T cells. We previously reported that a novel type of regulatory T (Treg) cells, termed HOZOT, which possesses a FOXP3+CD4+CD8+CD25+ phenotype and dual suppressor/cytotoxic activities, produced high levels of IL-10. In this study, we examined the mechanisms of high IL-10 production by HOZOT, focusing on Janus activating kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway. MATERIALS AND METHODS: We prepared five different types of T cells, including HOZOT from human umbilical cord blood. Cytokine productions of IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were compared among these T cells after anti-CD3/CD28 antibody stimulation in the presence or absence of IL-2. Specific inhibitors for JAK/STAT, nuclear factor-kappaB (NF-kappaB), and nuclear factor for activated T cell (NFAT) were used to analyze signal transduction mechanisms. RESULTS: IL-10 production by HOZOTs was greatly enhanced by the addition of IL-2. Little or no enhancement of IFN-gamma and TNF-alpha production was observed under the same conditions. The enhancing effect of IL-2 was specific for both HOZOT and IL-10-secreting Treg cells. T helper type 2 cells, whose IL-10 production mechanisms involve GATA-3, failed to show IL-2-mediated enhancement of IL-10. Similar enhancing effects of IL-15 and IFN-alpha suggested a major role of JAK/STAT activation pathway for high IL-10 production. Further inhibitor experiments demonstrated that STAT5 rather than STAT3 was critically involved in this mechanism. CONCLUSION: Our results demonstrated that IL-2 selectively enhanced production of IL-10 in HOZOT primarily through activation of STAT5, which synergistically acts with NF-kappaB/NFAT activation, implying a novel regulatory mechanism of IL-10 production in Treg cells.

Preoperative concurrent chemoradiotherapy versus pre- and postoperative radiotherapy for advanced hypopharyngeal carcinoma: a single-center study.

OBJECTIVE: The purpose of this study was to improve the survival and phonatory rates in patients with advanced hypopharyngeal carcinoma. METHODS: Seventy-two consecutive patients with advanced hypopharyngeal carcinoma were treated with pre- and postoperative radiotherapy (RTS), or preoperative concomitant chemoradiotherapy (CCRTS). Surgical procedures, including total laryngectomy plus partial pharyngectomy (TLPP) to preserve the posterior pharyngeal wall offering a functional neoglottis for esophageal or tracheoesophageal shunt phonation postoperatively, were conducted for patients who did not achieve CR. RESULTS: A significantly higher survival rate at 5 years (93.3%) was observed for N0-2b stage patients in the CCRTS group (n=16) than the RTS group (n=34; 41.5%) (p<.005). The distant metastasis-free rate was 92.9% (CCRTS group) versus 55.4% (RTS group) (p<.05) in these patients. In the CCRTS group, the 5-year survival rate with laryngeal or esophageal and/or tracheoesophageal shunt phonation was 22.2%. CONCLUSION: It is suggested that the CCRTS protocol and TLPP procedure may improve the survival rates without deterioration of phonatory rates in patients with N0-2b advanced hypopharyngeal carcinoma.

IL-2-independent generation of FOXP3(+)CD4(+)CD8(+)CD25(+) cytotoxic regulatory T cell lines from human umbilical cord blood.

OBJECTIVE: Since the existence of mouse naturally occurring CD4(+)CD25(+) T regulatory (Treg) cells was demonstrated, a variety of human Treg subsets have been identified as distinct T cell populations. Here we show the establishment of novel Treg cell lines possessing unique characteristics. METHODS: Novel Treg cell lines, designated HOZOT, were generated by coculturing human umbilical cord blood cells with mouse stromal cell lines in the absence of exogenous IL-2 or other cytokines. HOZOT were characterized and compared with CD4(+)CD25(+) Treg cells in terms of the CD phenotype, FOXP3 expression, suppressor activity against allogeneic MLR, anergy property, and IL-10 production. RESULTS: HOZOT were generated and expanded as normal lymphoblastoid cells with cytotoxic activity against the cocultured stromal cells. HOZOT consisted of three subpopulations as defined by phenotype: CD4(+)CD8(+), CD4(+)CD8(dim), and CD4(-)CD8(+). All three subpopulations showed both suppressor and cytotoxic activities. While HOZOT's expression of FOXP3, CD25, GITR, and cytoplasmic CTLA-4 implied a similarity to naturally occurring CD4(+)CD25(+) Treg cells, these two Treg cells differed in IL-2 responsiveness and IL-10 production. CONCLUSIONS: Our studies introduce a new method of generating Treg cells in an IL-2-independent manner and highlight a unique Treg cell type with cytotoxic activity and a phenotype of FOXP3(+)CD4(+)CD8(+)CD25(+).

Erythropoietin induces sustained phosphorylation of STAT5 in primitive but not definitive erythrocytes generated from mouse embryonic stem cells.

OBJECTIVE: During embryonic development murine erythropoiesis occurs in two waves by producing first primitive erythroid cells (EryPs) and then definitive erythroid cells (EryDs). Erythropoietin (EPO) signaling is compared between EryPs and EryDs. METHODS: We studied the EPO signaling in EryPs and EryDs using an embryonic stem-derived culture system, which can recapitulate this in vivo development process and has thus been used as a convenient in vitro model system of erythropoiesis. RESULTS: We found that EPO induced sustained phosphorylation and nuclear translocation of signal transducer and activator of transcription 5 (STAT5) in EryPs but not EryDs. EryPs expressed dramatically higher amounts of EPO receptor compared with EryDs, indicating there was excessive signaling from the receptor upon EPO stimulation. In addition, reduced expression of tyrosine phosphatase, Src homology region 2 domain-containing phosphatase-1, and decreased total phosphatase activity in EryPs partly explain the persistent activation of STAT5. Nevertheless, Janus kinase 2 (JAK2) phosphorylation, which is essential for transduction of EPO signaling from the EPO receptor to STAT5, was observed in a transient but not a persistent manner. Inhibition of JAK activity resulted in partial suppression of transient phosphorylation of STAT5 and no suppression of sustained phosphorylation of STAT5. CONCLUSION: This study presents a unique feature of EryPs, as this is the first known example of sustained activation of STAT5 in normal cells. Our results also imply the existence of a JAK2-independent pathway of EPO signaling to induce STAT5 activation.

Delta-4 Notch ligand promotes erythroid differentiation of human umbilical cord blood CD34+ cells.

OBJECTIVE: Important roles of Notch signaling have been demonstrated in hematopoiesis. In many cases, activation of the Notch pathway leads to the inhibition of differentiation of immature precursors, suggesting a potential role in self-renewal promotion. However, the function of Notch and Notch ligands is not so straightforward because it is considerably dependent on cytokine context. In this study, we analyzed effects of one Notch ligand, Delta-4, whose function is less clear than others, such as Delta-1 and Jagged-1 and -2. METHODS: CD34(+) cells isolated from human umbilical cord blood were cocultured with a Delta-4-expressing murine stromal cell line, SC9-19, and induced to erythroid differentiation by adding stem cell factor and erythropoietin. To examine the involvement of Delta-4, we utilized stromal cell subclones expressing Delta-4 protein at higher or lower level than parental SC9-19 by plasmid transfection. Erythroid maturation was examined by surface phenotype (CD34 and glycophorin A) and cytospin morphology. Recombinant human Delta-4 protein was prepared to analyze direct effects of Delta-4. RESULTS: Under erythroid lineage-inducing conditions, we found that the increase in Delta-4 expression of SC9-19 promoted erythroid differentiation whereas the decrease in Delta-4 expression inhibited it. Morphologic examination as well as colony formation analysis supported this observation. Moreover, the experiment using recombinant Delta-4 provided direct evidence of the Delta-4 activity found in coculture system. CONCLUSIONS: By modifying Delta-4 expression of the stromal cells and using the recombinant protein, we demonstrated that Delta-4 had a differentiation promoting activity for human primitive hematopoietic cells into erythroid lineage.

A phase I study of concurrent chemoradiotherapy with S-1 for T2N0 glottic carcinoma.

OBJECTIVE: Chemoradiation based on S-1, a novel oral antitumor agent of fluorinated pyrimidines, is the treatment for T2N0 glottic carcinoma; however, the optimal scheduling and dosing have still not been established. A phase I study was conducted to determine the maximum tolerated dose of S-1 with radiotherapy of 2 Gy/day for 5 days a week to a total dose of 60 Gy. Endpoints of this study were to examine the toxicity profile of this regimen and to determine the recommended dose of S-1. METHODS: Concomitant administration with the above-mentioned radiotherapy of S-1 once a day for 2 weeks, beginning on the day therapy was started, followed by 2 weeks off the drug and 2 weeks on the drug with the dose escalating from S-1 60 mg/body (level 1) to 80 mg/body/day (level 2), and then to 100 mg/body/day (level 3). RESULTS: Twenty-one patients were valid for safety. Eighteen patients were enrolled in the dose-escalation phase. In all patients, S-1 was administered. The maximum tolerated dose was determined to be 100 mg/body/day and the dose-limiting toxicity was indicated by the onset of grade 3 chemoradiation dermatitis. Therefore, the determined recommended dose of S-1 was 80 mg/body/day. Objective response according to Response Evaluation Criteria in Solid Tumors were observed in 20 of 21 patients who had measurable disease (95.2%). CONCLUSION: Concurrent S-1 and radiotherapy was feasible and well tolerated, and was suggested to produce a worthwhile response in T2N0 glottic carcinoma. These results warrant further investigation, and a phase II has already been started.

[Clinical phase I trial of concurrent chemo-radiotherapy with S-1 for T2NO glottic carcinoma].

We conducted a phase I study to determine a recommended dose (RD) of S-1 for chemo-radiotherapy consisting of S-1+ radiotherapy for T 2 N 0 larynx cancer. The method of administration used to assess the RD was irradiation with 2 Gy/day for 5 days a week until a total dose of 60 Gy, and concomitant administration of S-1 once a day for 2 weeks beginning on the day therapy was started followed by 2 weeks off the drug and 2 weeks on the drug with the dose escalating from S-1 60 mg/body/day (level 1) to 80 mg/body/day (level 2), and then to 100 mg/body/day (level 3). 18 patients were enrolled. 4 patients developed an adverse event of grade 3 radiation dermatitis which became a dose-limiting toxicity (DLT) at level 3. We then concluded that 100 mg/body/day was the maximum tolerated dose (MTD) of S-1 and decided that the RD of S-1 was 80 mg/body/day.

Progenitor analysis of primitive erythropoiesis generated from in vitro culture of embryonic stem cells.

OBJECTIVE: A variety of hematopoietic lineage cells have been produced from embryonic stem (ES) cells, but their differentiation processes have not been elucidated well, especially from the point of view of progenitor analysis. In this study, we utilized our coculture system, in which ES-derived Flk-1+ cells differentiated into TER-119+ primitive erythroid (EryP) cells on OP9 cells, and looked for progenitors in primitive erythropoiesis. MATERIALS AND METHODS: We studied the kinetics of TER-119+ erythroblast generation from Flk-1+ cells by monitoring the expression of TER-119, CD41, VE-cadherin, CD34, and c-kit antigens. Multicolor analysis was performed to detect CD41+TER-119+ cells and the stained cells were sorted to examine their morphology and EryP-producing potential in colony formation. RESULTS: Kinetic studies showed that the CD41+ population appeared early in the coculture and its expression pattern implied a role as an immediate progenitor of TER-119+ EryP cells. Multicolor analysis and colony-formation study supported this notion. Other progenitor markers such as VE-cadherin, CD34, and c-kit did not seem to define an immediate progenitor of EryP cells. One interesting observation is the detection of unique populations, CD41dim and CD41bright, detectable after 48 hours of the coculture. Majority of the CD41dim population progressed to the EryP lineage, whereas the CD41bright population seemingly advanced on a pathway distinct from the CD41dim population. CONCLUSIONS: CD41 expression was a useful marker to trace hematopoietic progenitors in ES-derived differentiation system. In particular, the CD41dim but not CD41bright population could serve as immediate precursors of EryP cells.

Meningococcemia in Adults: A Review of the Literature.

We mainly refer to the acute setting of meningococcemia. Meningococcemia is an infection caused by Neisseria meningitidis, which has 13 clinically significant serogroups that are distinguishable by the structure of their capsular polysaccharides. N. meningitidis, also called meningococcus, is a Gram-negative, aerobic, diplococcus bacterium. The various consequences of severe meningococcal sepsis include hypotension, disseminated intravascular coagulation (DIC), multiple organ failure, and osteonecrosis due to DIC. The gold standard for the identification of meningococcal infection is the bacteriologic isolation of N. meningitidis from body fluids such as blood, cerebrospinal fluid (CSF), synovial fluid, and pleural fluid. Blood, CSF, and skin biopsy cultures are used for diagnosis. Meningococcal infection is a medical emergency that requires antibiotic therapy and intensive supportive care. Management of the systemic circulation, respiration, and intracranial pressure is vital for improving the prognosis, which has dramatically improved since the wide availability of antibiotics. This review of the literature provides an overview of current concepts on meningococcemia due to N. meningitidis infection.