Japanese Red Cross Medical Center Research Articles

Serum KL-6 level is a useful biomarker for evaluating the severity of coronavirus disease 2019.

BackgroundCoronavirus disease 2019 (COVID-19) is currently spreading worldwide. This study examined whether serum Krebs von den Lungen-6 (KL-6) level is a useful biomarker for evaluating the severity of COVID-19.MethodsWe retrospectively examined patients diagnosed with COVID-19 at the Japanese Red Cross Medical Center between February 1, 2020, and May 15, 2020. Patients were divided into four categories based on clinical and radiological findings: mild, moderate, severe, and critical. Patients who presented with a mild or moderate illness and patients who started with or worsened to a severe or critical illness were classified as the non-severe and severe groups, respectively. The two groups were compared for patient characteristics, including serum KL-6 levels. Receiver operating characteristic curves were used to define the optimum cut-off value of serum KL-6 level to evaluate COVID-19 severity.ResultsA total of 54 patients were enrolled, including 33 in the non-severe group and 21 in the severe group, of which four died. Compared with those in the non-severe group, more patients in the severe group were significantly older and had comorbidities. Serum KL-6 levels were significantly higher in the severe group than in the non-severe group both at diagnosis (median, 338 U/mL) and at peak levels within one week after diagnosis (median, 781 U/mL) (both p < 0.001). Serum KL-6 value at peak level (371 U/mL) was used as the optimal cut-off to evaluate disease severity (sensitivity, 85.7%; specificity, 96.6%).ConclusionsSerum KL-6 levels were significantly elevated in severe COVID-19 and is useful for evaluating its severity.

Usefulness of Measurement of End-tidal CO2 Using a Portable Capnometer in Patients with Chronic Respiratory Failure Receiving Long-term Oxygen Therapy.

Objective Patients with chronic respiratory failure requiring long-term oxygen therapy (LTOT) are at a risk of CO2 retention because of excessive oxygen administration. The CapnoEye™ is a novel portable capnometer that can measure end-tidal CO2 (EtCO2) noninvasively. This retrospective study evaluated the usefulness of this device. Methods EtCO2 was measured using the CapnoEye™. The EtCO2 and partial pressure of venous carbon dioxide (PvCO2) were analyzed, and other clinical data were assessed. Patients Sixty-one consecutive patients with chronic respiratory failure receiving LTOT in the outpatient department at the Japanese Red Cross Medical Center between July 2017 and March 2018 were retrospectively reviewed. Results There was a significant correlation between EtCO2 and PvCO2 (r=0.63) in the total study population as well as in the COPD group (r=0.65) and ILD group (r=0.67). The PvCO2 and EtCO2 gradient was correlated with only the body mass index in a multivariate analysis (p=0.0235). The EtCO2 levels on the day of admission were significantly higher than those in the same patients when they were in a stable condition (p=0.0049). There was a significant correlation between ΔEtCO2 and ΔPvCO2 (r=0.4). A receiver-operating characteristic curve analysis revealed the optimal cut-off EtCO2 value for identifying hypercapnia to be 34 mmHg (p=0.0005). Conclusion The evaluation of EtCO2 by the CapnoEye™ was useful for predicting PvCO2. The body mass index was identified as a possible predictor of the PvCO2 and EtCO2 gradient. An increase in EtCO2 may indicate deterioration of the respiratory status in patients with chronic respiratory failure receiving LTOT.

Identification of Clonal Immunoglobulin λ Light-Chain Gene Rearrangements in AL Amyloidosis Using Next Generation Sequencing

[Introduction] AL amyloidosis is caused by the deposition of abnormally folded clonal immunoglobulin (IG) light chains (LCs, λ:κ = 3:1) made by malignant plasma cells in the bone marrow (BM), which leads to multi-organ dysfunction, often involving the heart, kidney, liver, skin, and nerves. However, little is known about what regulates organ tropism of amyloid deposition in this disease. In addition, no study has analyzed the repertoire of IG germlines of plasma cells in the BM in AL amyloidosis using next generation sequencing (NGS). In this study, we aimed to identify the clonal composition of IG λ light-chain variable region (IGLV) genes in BM cells in patients with AL amyloidosis using NGS. [Material and method] BM cells were obtained at diagnosis from 38 patients with AL amyloidosis and those with other plasma cell disorders: multiple myeloma (MM, n = 7), and monoclonal gammopathy of undetermined significance (MGUS, n = 11) with λ-type monoclonal paraprotein. Seven normal control (NC) patients had either immune thrombocytopenia or malignant lymphoma without BM invasion. Genomic DNA was extracted from the BM mononuclear cells preserved in LABO Banker1 or BM clots in O.C.T compound using QIAamp DNA Blood Mini kit. The IGLV1 and IGLV2 genes were amplified by polymerase chain reaction using a 5′ primer for the IGLV1/2 framework 3 (FR3) region and 3′ consensus primers for the IGLJ1/2/3 joining regions. Multiple samples were pooled, and paired-end 2 × 250 base pair sequencing reactions were performed using an Illumina MiSeq sequencer and then analyzed by an open-source program called Vidjil. All subjects provided written informed consent to participate in the study, in accordance with the Declaration of Helsinki. This study was approved by the ethics committee of the Chiba University Graduate School of Medicine and Japanese Red Cross Medical Center. [Results] Clinical and laboratory features of 38 patients with AL amyloidosis were as follows: primary AL amyloidosis (n = 31); 15 and 20 patients had cardiac and renal dysfunctions, respectively, and secondary AL amyloidosis with MM (n = 7); 4 and 1 patient had cardiac and renal dysfunctions, respectively. In patients with AL amyloidosis, the median plasma cell count in BM aspirate smears was 3.3% (0.1%-50.4%), and the median difference in involved and uninvolved light chains (dFLC) was 104.5 mg/L (28.5mg/L -2673.3mg/L). Representative results of the Vidjil analysis in NC, MGUS, AL amyloidosis, and MM are shown in Figure 1. The most abundant IGLV gene accounted for not &gt;1% of the reads, and there was no dominant germline in NC samples. Therefore, we defined the dominant clone as &gt;1% of IG germlines in plasma cells. According to this definition, clonal IG germlines were found in 27 of 31 patients with primary AL amyloidosis (87%), 5 of 7 with secondary AL amyloidosis (71%), 7 of 7 with MM (100%), and 8 of 11 with MGUS (73%). However, the size of clones in AL amyloidosis (median 3.1%, 0.38%-14.3%) was significantly smaller than that in MM (median 17.8%, 2.2%-17.9%) (P&lt;0.001), and similar to that in MGUS (median 3.8%, 0.4%-32.0%). Importantly, in patients with AL amyloidosis, the dFLC and involved/uninvolved FLC ratio was not correlated with the clonal size of plasma cells in our repertoire analysis using NGS, suggesting that small malignant clones of plasma cells may secret FLC and cause LC depositions in AL amyloidosis. Regarding IGLV germline usage, IGLV1-51 was the most frequent repertoire in AL amyloidosis with heart dysfunction (7 of 16 cases) and renal dysfunction (7 of 21 cases). No relationship between the IGLV germlines and organ tropisms was observed. [Conclusion] We successfully identified the clonal composition of IGLV genes in the BM of most patients with AL amyloidosis using NGS, according to the differences in the V and J region recombination and CDR3 sequences using the Vidjil program. In AL amyloidosis, the clonal size of plasma cells in the BM is small and small malignant clones of plasma cells may secret FLC and cause LC depositions in AL amyloidosis. Figure 1 Disclosures Suzuki: Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Red blood cell distribution width is a simple and novel biomarker for survival in light-chain amyloidosis.

Red blood cell distribution width (RDW) has been used for the differential diagnosis of anemia, but high RDW may also be associated with several human disorders. We evaluated the prognostic relevance of RDW in patients with light-chain (AL) amyloidosis. We retrospectively analyzed all patients with AL amyloidosis who were newly diagnosed at the Japanese Red Cross Medical Center between December 2011 and June 2018. RDW was evaluated in 94 patients; 48% (n = 45) of patients had a high RDW (≥ 13.8%) and 52% (n = 49) had a low RDW (< 13.8%). Overall survival (OS) was significantly lower in patients with a high RDW (P < 0.001). On multivariate analysis, increased RDW was an independent predictor for OS. Even in patients without cardiac amyloidosis, the OS was significantly lower in the high-RDW group (P = 0.0064). The survival rate of high-RDW patients without cardiac involvement was as poor as that of patients with cardiac involvement. In addition, in patients with revised Mayo stage I or a normal level of N-terminal pro-B-type natriuretic peptide, high RDW was negatively correlated with OS (P = 0.0086, 0.025). RDW is a simple and strong predictor of early death, and is a prognostic biomarker in patients with AL amyloidosis without cardiac involvement.

Management and utility of transbronchial lung cryobiopsy in Japan.

Transbronchial lung cryobiopsy (TBLC), which is transbronchial lung biopsy performed using a cryoprobe, has emerged as a new method for obtaining lung tissue specimens for diagnosing pulmonary diseases. TBLC has been widely performed, and many reports have documented its safety and feasibility in diagnosing pulmonary diseases such as lung cancer and diffuse parenchymal lung disease. However, to date, no reports have yet been published from Japan. Therefore, the purpose of this study was to describe our experience with TBLC in daily practice in Japan and compare it with those reported in previous studies from other countries. We also evaluated the efficacy and feasibility of TBLC. We retrospectively evaluated the clinical records of 50 consecutive patients who had undergone TBLC between November 2017 and May 2018 at the Japanese Red Cross Medical Center. Demographic data, procedure details, and the diagnostic yield were analyzed. We analyzed the records of 50 patients who underwent diagnostic TBLC. Their median age was 71 years, and they included 34 men (68%). The median maximal diameter of the cryobiopsy specimens was 5.3 mm (range, 2.0-23.0 mm), and the median area of the cryobiopsy specimens was 15.5 mm2 (range, 3.0-136.5 mm2). The rate of obtaining adequate specimens was 91%, and the pathological diagnostic yield was 76%. No complications were observed, except for one case of pneumonia. This is the first report from Japan analyzing the efficacy and feasibility of TBLC in daily clinical practice. TBLC was considered efficacious, safe, and feasible for Japanese patients with various lung diseases.

Baseline and Time-Averaged Values Predicting Residual Renal Function Decline Rate in Japanese Peritoneal Dialysis Patients.

Residual renal function (RRF) is a strong prognostic factor of morbidity and mortality in patients undergoing peritoneal dialysis (PD). We determined predictors of the RRF rate of decline using both baseline values and time-averaged ones. We retrospectively analyzed 94 patients being treated with PD at the Japanese Red Cross Medical Center. The decline rate of RRF was calculated by a diminution in the weekly renal Kt/V between the first and last follow up divided by follow-up years. The mean follow-up period was 2.28 years, and the mean decline rate of weekly renal Kt/V was 0.25 per year. A multivariate analysis using baseline parameters identified dialysis-to-plasma ratios of creatinine at 4 h (P = 0.02), urinary protein (P = 0.02), and mean blood pressure (MBP) (P < 0.01) as being positively associated with the RRF rate of decline, while the use of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) had a negative correlation (P = 0.03). When using time-averaged values as independent variables, a lower weekly total renal Kt/V (P < 0.0001), higher urinary protein (P < 0.0001), and higher MBP (P = 0.04) independently predicted a faster RRF rate of decline. We demonstrated that PD patients with a lower MBP and lower urinary protein both at baseline and throughout their PD duration had a slower RRF rate of decline. We recommend strict control of blood pressure and anti-proteinuric therapy for PD patients.

Distribution of cardiac troponin I in the Japanese general population and factors influencing its concentrations.

BackgroundThe 99th percentile of cardiac troponin I level in the general population is accepted as the cut‐off for the diagnosis of acute myocardial infarction (AMI). However, it is not clear whether the cut‐offs derived in racially and geographically different populations are applicable in Japan.MethodsTroponin I was determined using the Abbott ARCHITECT STAT high‐sensitive troponin I immunoassay in 698 apparently healthy individuals who visited the Japanese Red Cross Medical Center for a health checkup.ResultsThe 99th percentile of the hsTnI in the overall population was 22.5 (95% confidence interval (CI), 16.8‐36.6) pg/mL, 17.7 (95% CI 12.0‐22.8) pg/mL for females and 30.6 (95% CI 17.1‐53.4) pg/mL for males. The median of the hsTnI in the overall population was 3.2 (95% CI, 3.0‐3.3) pg/mL, 2.6 (95% CI 2.4‐2.8) pg/mL for females and 4.0 (95% CI 3.8‐4.3) pg/mL for males. The age and gender had a significant influence on these values. The troponin I level also showed significant associations with the body mass index (BMI), the gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), estimated glomerular filtration rate (eGFR), and cardiac abnormalities by electrocardiography (ECG) but not with the high‐sensitive C‐reactive protein (hsCRP) level.ConclusionsThe 99th percentiles of the troponin I measured in the general population in Japan were comparable as the ones derived in the US, Germany, and Singapore. The troponin I level was dependent on the gender, age, BMI, and cardiac abnormalities found by ECG but not by the hsCRP level.

Efficacy and safety of stereotactic body radiotherapy using CyberKnife in Stage I primary lung tumor.

CyberKnife® (CK) is a new, advanced radiotherapy technique. This study aimed to evaluate its efficacy and toxicity in Japanese patients with early-stage primary lung tumor who were medically unfit and inoperable. This retrospective study investigated patients who received CK treatment for medically inoperable Stage І primary lung tumor at the Japanese Red Cross Medical Center between June 2011 and September 2016. Each patient received a total of 36-48 Gy (median, 43 Gy) administered by CK in 4-5 fractions. Totally, 40 patients (T1a, n = 19; T1b, n = 15; T2a, n = 6) were included. Their median age was 86 (range, 56-95) years. Tracking required the use of fiducial markers in 28 patients and the Xsight Spine Tracking System in 12. The median follow-up was 14.5 (range, 1-51) months. Local recurrence occurred in seven (17.5%) patients. The local progression-free survival rates at 1 and 2 years were 83.9% and 74.0%, respectively. Distant recurrence occurred in regional lymph nodes (n = 5), the lung outside the radiation field (n = 3), and the bone (n = 1). Seven patients died. Overall survival rates at 1 and 2 years were 93.6% and 73.1%, respectively. Radiation pneumonitis was identified in 28 (70%) patients (Grade 1, n = 25; Grade 2, n = 2; Grade 5, n = 1). CK showed good local control with limited toxicity and could be an alternative treatment modality in medically inoperable patients with Stage І primary lung tumor.

10 Years History of Cost-Effectiveness for 209 Newly Diagnosed Multiple Myeloma Patients at a Single-Institute in Japan

Background & ObjectiveThe therapy of multiple myeloma (MM) has improved greatly over the last decade. However, the rise in health care costs has become a big problem. Therefore, it is necessary to consider the cost-effectiveness including Quality of Life (QoL). In this study, we assessed the real-world cost-effectiveness of MM treatment.Methods & PatientsA total of 209 MM patients who were newly diagnosed and treated only at Japanese Red Cross Medical Center (JRC-MC) from January 2006 to December 2015 were registered for this retrospective research. Those patients who were treated at other institute than JRC-MC were excluded. All of the costs for MM treatment in hematology department were analyzed. The costs were calculated based on the health care costs spent in hematology department. Overall survival was evaluated by the Kaplan-Meier method. All of the costs were calculated in US dollars based on average value from 2006 to 2015 (1USD = 100.294 Japanese yen).ResultFirst, the cost paid for treatment of 84 patients who died from symptom onset to death was about 0.14 million USD. We also calculated the total annual health care cost for their patients from 2006 to 2015. Annual cost of all MM patients at 2006 was 0.454 million USD, and the cost at 2015 was 7.505 million USD. The cost/patient-year of 2006, when novel agents were not obtainable was 21,656 USD, and that cost of 2015, when three new agents were available was 55,608 USD. These results showed that the costs of MM treatment became 2.56 times higher in the past 10 years. Individual costs for bortezomib, thalidomide, and lenalidomide is shown in Fig.1. Since 2011 to 2014, the ratio of cost of novel agents exceeded 50%.Secondly, overall survival was evaluated by statistical analysis. The median survival from diagnosis was 56 (range, 0-117) months 95% CI (45.12-66.88). We divided patients into 5 subgroups, according to the time of diagnosis. (1)2006: 21 patients, (2)2007-2008: 26 patients, (3)2009-2010: 38 patients, (4)2011-2012: 42 patients, (5)2013-2015: 82 patients. In Japan, the novel agents such as bortezomib, thalidomide, lenalidomide were approved the year 2006, 2008, 2010 respectively. Median survival of subgroup (1), (2), and (3) were 56 months 95% CI (42.66-69.33), 55 months 95% CI (19.12-90.87) and 54 months 95% CI (36.42-71.57) respectively. Median survival of subgroup (4) and (5) have not been reached. Then we investigated the treatment costs in these groups. In each subgroup the average annual cost was 332, 518, 507, 588 and 631 USD respectively. Compared to subgroup (1), the cost of other groups were significantly high. These results showed that the impact of three novel agents on medical cost were significant. We also investigated the relationship between health care costs and the length of hospital stay or autologous stem cell transplantation. There were no statistically significant differences among them, however, there was tendency that the length of hospital stay shortened by time; Average length of total hospital stay the subgroup (1), (2), and (3) were 205, 125 and 56 days respectively. Subgroup (4) and (5) showed also shortened length of hospital stays, although observation years subgroup (4) and (5) were short (date was not shown). Among 5 subgroups the cases of received autologous stem cell transplantation were not stastically differences (total 56 patients).ConclusionWe revealed the real-world costs of MM treatment in a single-institute, by following up individual patients sequentially. Health care costs for treatment of MM increased drastically, by introduction of three novel agents. We also showed that the introduction of three novel agents shorten hospital stay, which leads to improve QoL. Therefore, bortezomib, thalidomide and lenalidomide had the significant impact of QoL. After the further approval of novel agents in Japan, health care costs will be even higher but on the other hand, they might bring positive impacts on OS and QoL. Our study clearly indicated the importance of considering the balance of cost and effectiveness for the MM treatment is important.Character count: 3477(excluding spaces) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Difference of Treatment Outcomes in AL Amyloidosis and Multiple Myeloma with / without Translocation (11;14)

IntroductionAL amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils accumulated in different organs. Translocation (11;14) (t(11;14)) is seen in about half of AL patients, but the clinical significance is still unknown. So our study has focused on the chromosome aberration of t(11;14). We report the relationship between the chromosome aberration and the organ response, the organ involvement which greatly influence prognosis of AL patients. Furthermore, we examined the prognosis and treatment response to compare t(11;14) influences of AL with t(11;14) influences of multiple myeloma (MM).Patients and MethodsWe analyzed in AL and symptomatic MM patients have t(11;14) using fluorescence in situ hybridization from January 2010 to December 2014 in Japanese Red Cross Medical Center. We examined the overall survival and the therapy response rate. In addition, we compared t(11;14)-positive and negative in AL and MM respectively. Besides, we investigated the involved organ parts and the organ response with melphalan and dexamethasone (MD) therapy in AL. Outcome was assessed based on remission after three months and one year. Remissions were determined according to consensus criteria in 2011 for AL and IMWG uniform criteria for MM. Survival distribution of OS was estimated using the Kaplan-Meier method and compared using the log-rank test. Data between t(11;14)-positive and negative were compared with the Mann-Whitney U test or X2 test. The statistical analysis was performed using IBM SPSS statistics ver.23.ResultsAmong 27 patients with AL, 9 cases were t(11;14)-positive patients (age median, 64yr; range, 37-80), and 13 out of 46 were positive in MM (age median, 64yr; range, 34-86). (excluded complication of both AL and MM cases) In AL cases, the t(11;14)-positive group tended to shorter overall survival (OS) than negative cases. On the other hand, in the patients with MM, positive group tended to superior OS to negative (AL: P=0.442(Fig.1A), MM: P=0.327(Fig.1B)).Compared with t(11;14)-negative AL group, t(11;14) positive group was tended to have much organ involved numbers of amyloid protein (67% v 34%; P=0.109) and much cardiac involvement patients (67% v 39%; P=0.171). On the other hand, there were little cardiac and renal response in both t(11;14)-positive and negative with MD therapy after 3 months (heartF17% v 0% P=0.462/renalF0% v 0%).In MM patients, ORR after 3 months were 67% and 79% in t(11;14)-positive and negative cases respectively (P=0.386). That after 1 year were 78% and 74% respectively (P=0.889).Conclusiont(11;14) is important prognostic factor and showed conflict prognosis between AL and MM. From this investigation, the importance of connecting the chromosome abnormality every disease was shown. In addition, our investigation recognized tendencies that the amyloid involvement rate to the heart was high, and the cardiac response with MD therapy were low in AL t(11;14)-positive group. As these results, we thought that t(11;14)-positive AL patients' OS were shortened. The significant difference did not appear in this examination while these tendencies were clearly accepted in little number of patient cases. Further investigation using rather number of patient samples is needed.In conclusion, the cardiac amyloid involvement is high in the AL t(11;14)-positive group, and the cardiac response by MD therapy is low. We should have doubt eyes of the amyloid involvement to the heart in AL t(11;14)-positive patients, and have the posture that can support cardiac amyloidosis immediately. In addition, breakthrough new treatments are expected urgently for AL patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

NT-25 * EARLY JAPANESE EXPERIENCE WITH NovoTTF-100A SYSTEM FOR RECURRENT GBM

BACKGROUND: NovoTTF-100A System is an FDA-approved treatment for recurrent glioblastoma (GBM) and is defined as a device of high unmet medical need in Japan. Subsequently, the device has been made available on a restricted case basis for compassionate use in Japan. Here we report initial experience with 10 patients treated at Tokyo Women's Medical University, Kashiwaba Neurosurgical Hospital and Japanese Red Cross Medical Center. METHODS: Using retrospective chart review, we analyzed patient demographics, tumor size, location, and treatment compliance with NovoTTF-100A System from the device log files. Duration of therapy was estimated using the Kaplan-Meier estimate. Adverse event frequency and severity was also evaluated. RESULTS: Ten (10) patients with supra-tentorial recurrent GBM were treated between July 8, 2013 and June 3, 2014 at 3 Japanese hospitals. 80% were male and 20% female. The median age was 41 years (range 32-66). The average baseline tumor burden was 13.3 cm2. 40% of patients had bi-hemispheric tumors and 30% left hemispheric tumors. The K-M median duration of therapy was 7.8 months. Average daily device compliance was 17.4 hours. This is consistent with prior global studies which have demonstrated average daily device compliance of 70-80%. The device was well-tolerated with no reported serious adverse events. The only device-related adverse events were mild skin irritation. CONCLUSIONS: NovoTTF-100A System was safe and well-tolerated in an initial cohort of Japanese patients with GBM. Device usage and compliance was consistent with that observed in non-Japanese patients.

Hepatic Tumors: A Continuous Challenge to Achieve Further Improvements

Bucharest (Romania) hosted this year's annual meeting of the International Association of Surgeons, Gastroenterologists and Oncologists. The president of the Congress was Irinel Popescu of the University of Bucharest (Romania) and the meeting was held under the auspices of the International Association of Surgeons, Gastroenterologists and Oncologists president Masatoshi Makuuchi (Japanese Red Cross Medical Center, Tokyo, Japan) and its general secretary, Nicolas J Lygidakis (Athens Medical Center, Greece). The organizing committee of the Congress has made considerable efforts to promote the globalization of medical knowledge and to maintain the values of Médecins Sans Frontières. The Congress was a model of scientific professionalism, and was attended by more than 850 delegates. Approximately 250 specialists from 43 countries on five continents described their most recent advances, providing the delegates with an intense and very rich program. The program included symposia, video presentations, free papers and poster presentations. This article highlights the newest and most original results concerning the treatment of liver tumors, particularly in cirrhotic patients.

Comparison between sitagliptin and nateglinide on postprandial lipid levels: The STANDARD study

To assess the effects of sitagliptin and nateglinide on lipid metabolism. In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medical Center were randomly assigned to receive either sitagliptin (50 mg once daily) or nateglinide (90 mg three times daily before meals). Eligible patients met the following criteria: age ≥ 20 years; hemoglobin A1c (HbA1c) > 6.5% despite diet and exercise; HbA1c between 6.5% and 8.0%; fasting glucose < 7.77 mmol/L; diet and exercise therapy for more than 3 mo; and ability to read and understand the information for written informed consent. Exclusion criteria were contraindications to sitagliptin, contraindications to nateglinide, pregnancy or possible pregnancy, and severe liver/renal failure. Patients who were considered to be unsuitable by the attending physician for other reasons were also excluded. Blood samples were collected at one and three hours after intake of a test meal. The primary outcome measure was the area under the curve (AUC) of apolipoprotein (Apo) B48 at three hours postprandially. Twenty patients were randomly assigned to the sitagliptin group and sixteen patients were randomized to the nateglinide group. All 36 patients took the medication as directed by the physician in both groups, and they all were analyzed. Apart from antidiabetic drugs, there was no difference between the two groups with respect to the frequency of combined use of lipid-lowering, antihypertensive, and/or antiplatelet drugs. The doses of these medications were maintained during 12 wk of treatment. Detailed dietary advice, together with adequate exercise therapy, was given to the patients so that other factors apart from the two test drugs were similar in the two groups. There were no significant differences of the baseline characteristics between the two groups, except for body mass index (the sitagliptin group: 25.14 ± 3.05 kg/m(2); the nateglinide group: 21.39 ± 2.24 kg/m(2)). Fasting levels of HbA1c, glycated albumin, 1.5-anhydroglucitol, and blood glucose, as well as the blood glucose levels at one and three hours postprandially, improved in both groups after 12 wk of treatment, and there were no significant differences between the two groups. However, the glucagon level at one hour postprandially (P = 0.040) and the diastolic blood pressure (P < 0.01) only showed a significant decrease in the sitagliptin group. In the nateglinide group, there was no significant change in the AUC of Apo B48, the glucagon level at one hour postprandially, the fasting triglyceride level, or the diastolic blood pressure. Body weight was unchanged in both groups. However, the AUC of Apo B48 at three hours postprandially showed a significant decrease in the sitagliptin group from 2.48 ± 0.11 at baseline to 1.94 ± 0.78 g/L per hour after 12 wk (P = 0.019). The fasting triglyceride level also decreased significantly in the sitagliptin group (P = 0.035). With regard to lipid-related markers other than Apo B48 and fasting triglycerides, no significant changes were observed with respect to Apo A1, Apo B, or Apo C3 in either group. No adverse events occurred in either group. Sitagliptin significantly improves some lipid parameters while having a comparable effect on blood glucose to nateglinide. A large-scale prospective study of sitagliptin therapy is warranted.

Neurophysiological analysis of the cauda equina in POEMS syndrome

In POEMS syndrome (Crow-Fukase syndrome), the proximal conduction of peripheral nerves innervating leg muscles is difficult to assess using conventional nerve conduction studies (NCSs) when F-waves or H-reflexes are not detectable. Recently, we developed a novel magnetic stimulation method to measure cauda equina conduction time (CECT) using a powerful coil known as a magnetic augmented translumbosacral stimulation coil (MATS coil) [1–3]. This method allows us to investigate CECT even in patients with peripheral neuropathy [3]. In this study, we applied our method to a patient with POEMS syndrome. The patient was a 72-year-old man who was unable to walk 5 months after onset. Neurological findings at 6 months after onset revealed weakness with muscular atrophy (Medical Research Council scale for muscle strength grades: proximal arm 4, distal arm 3, proximal leg 3 and distal leg 1), distal dominant sensory disturbance and areflexia of the extremities. Whole-body computed tomography revealed hepatomegaly and multiple enlarge lymph nodes. We made the diagnosis of POEMS syndrome on the basis of skin hemangioma, skin pigmentation, hirsutism, leg edema, hepatomegaly, lymphadenopathy, monoclonal protein of immunoglobulin G (k type), and subacute motor and sensory polyneuropathy. Conventional NCSs were performed on the right side. In the median nerve, the amplitude of compound muscle action potentials (CMAPs) was severely reduced to 0.4 mV. Neither a pathological temporal dispersion nor a conduction block was detected. Motor conduction velocity (MCV) between wrist and elbow was slowed to 24 m/s with prolonged distal latency (5.6 ms). Sensory nerve action potentials (SNAPs) were not evoked. For the lower extremities, neither CMAPs in the tibial nerve nor SNAPs in the sural nerve were evoked. Additionally, neither F-waves in the median and tibial nerves nor H-reflexes in the tibial nerve were evoked. Needle electromyography (nEMG) was performed in the biceps brachii, first dorsal interossei, rectus femoris, and tibialis anterior muscles on the right side. Abundant spontaneous activities were recorded during relaxation in only the first dorsal interossei and tibialis anterior muscles. In all the contracted muscles, recruitment of motor unit potentials was reduced during voluntary contraction (contraction of the tibialis anterior muscle was impossible). MATS coil stimulation was performed to measure CECT. CMAPs were recorded from the biceps femoris muscle. This particular proximal muscle was selected since it had experienced much less atrophy than the distal muscles. The most distal part of the cauda equina was activated by MATS coil stimulation over the first sacral spinous processes (S1) [1–3]. The most proximal part of the cauda equina was activated by MATS coil stimulation over the first lumbar spinous processes (L1) [2, 3]. As shown in Fig. 1b, this method demonstrated severely prolonged CECT (right 8.1 ms, left 8.0 ms; normal values H. Matsumoto (&) H. Hashida Department of Neurology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo150-8935, Japan e-mail: hideyukimatsumoto.jp@gmail.com

Eleven Cases of Angioedema with Eosinophilia Treated in a Single Hospital in Japan

Angioedema with eosinophilia (AE) is mostly reported in Japanese patients, and only as case reports. In this study, we aimed to determine how prevalent AE cases appear, the characteristic features and the course of AE, and to evaluate whether corticosteroid therapy for AE is necessary or not. The patients whose blood samples showed an eosinophil count of ≥2,000/μL, among the samples tested for blood cell counts and differential counts between January 2006 and December 2010, in Japanese Red Cross Medical Center, were firstly included. Among these, patients with AE were extracted. All of the 11 patients were Japanese young females. One patient with arthralgia showed radioisotope accumulation in the joints by bone scintigraphy. The peak peripheral blood eosinophil count was 7,839 ± 6,008 (2,130-23,170)/μL after visiting our hospital. An increase in white blood cell count was only due to an increase in eosinophil count. Serum C-reactive protein and IgE levels remained almost normal. Peripheral blood eosinophil count decreased steadily for 8 weeks, regardless of corticosteroid use. Edema in all of the patients and arthralgia in 6 patients improved within 12 weeks. As far as followed, none of the patients had a recurrence of AE. AE developed in Japanese young females and likely showed a single course. In AE, the count of eosinophil of 104/μL was observed. Only eosinophil count increased among leukocyte series. Serum C-reactive protein and IgE levels remained almost normal. The eosinophil count in AE patients will return to the normal level within 8 weeks even without corticosteroid therapy.

Study on the usefulness of high-molecular-weight (HMW)-Adiponectin level check of Japanese general population upon health check: Comparison of carotid ultrasonography measurement

ObjectiveHigh-molecular-weight (HMW)-adiponectin is an active and powerful predictor of atherosclerosis. Unfortunately, there is currently no reliable epidemiological reference level data available in Japan. The current ELISA method for HMW-adiponectin measurement is tedious as it requires several sample pre-treatment steps. We studied the reference level of HMW-adiponectin measured by a simple, fully-automated CLEIA. DesignThe study subjects were 858 men and 793 women who underwent health check-ups at a Japanese Red Cross Medical Center. We investigated the relation between HMW-adiponectin and metabolic parameters, including carotid ultrasonography. ResultsThe mean values of HMW-adiponectin were 3.11±1.99μg/ml in men, and 5.52±3.07μg/ml in women. There were significant differences (p<0.001) in relation to gender and age, where levels gradually increased with age. HMW-adiponectin was 3.18±1.45μg/ml in male subjects without carotid lesions, and 2.28±0.90μg/ml in male subjects with lesions. ConclusionsHMW-adiponectin measured by simple CLEIA could be useful for routine risk assessment.

Contrast-enhanced ultrasonographic image of gangrenous gallbladder.

A 6-year-old Japanese boy was admitted to our hospital because of right hypochondrial discomfort, which had started 6 h earlier. His medical history was unremarkable. A physical examination revealed rebound tenderness in the right upper quadrant associated with a low-grade fever (37.4 C). Laboratory tests at presentation showed an increased white cell count of 11,700/lL (normal range 3700–8000) and C-reactive protein 2.56 mg/dL (normal range 0.00–0.29). Liver and renal function tests were normal. Conventional gray-scale transabdominal ultrasonography (US) using the ProSound a10 (Hitachi-Aloca Medical Co., Tokyo, Japan) with a 3.5-MHz transducer demonstrated an enlarged gallbladder with a grossly thickened wall, and a small amount of pericholecystic fluid (Fig. 1). The sonographic Murphy’s sign was positive. There was no evidence of gallbladder stones. Based on the conventional US, our initial diagnosis was acute cholecystitis. However, the gallbladder wall was unusually thickened for typical acute cholecystitis, so we evaluated the blood flow of the gallbladder wall. Doppler imaging confirmed the flow in the cholecystic artery at the neck of the gallbladder, but no blood flow within the gallbladder wall was observed, which was inconsistent with acute cholecystitis [2]. Therefore, CEUS using Sonazoid (Daiichi-Sankyo, Tokyo, Japan) was performed to further assess the gallbladder vascularity, since CEUS is more sensitive in detecting the blood flow than nonenhanced color Doppler US [3]. Sonazoid diluted in 10 mL of saline solution was administered intravenously at 0.015 mL/kg over 3–5 s. Five seconds after administering the Sonazoid , the gallbladder wall was enhanced from the serosal side, and then the mucosal line was enhanced linearly a second later (Figs. 2, 3). Based on a preoperative diagnosis of acute cholecystitis due to incomplete gallbladder torsion, the boy underwent an emergency laparotomy. At surgery, the gallbladder was markedly swollen and the cystic duct had twisted 180 in a counter-clockwise manner around the mesentery (Fig. 4). Y. Yashima (&) T. Tsujino R. Nakata Department of Gastroenterology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan e-mail: y-yashima@umin.ac.jp

Left Liver With Right Paramedian Sector—Can It Be An Option in Living Donor Liver Transplantation?

We read with interest the article titled “The changes of the medial right lobe, transplanted with left lobe liver graft from living donors” by Ikegami et al. (1). This type of graft was reported previously by the same group (2), and the clinical results of living donor liver transplantation using the grafts were described in detail in Ref. 1. The authors suggest that procurement of a left lobe living donor graft with the medial part of the right lobe (mRL), a full left liver with the medial part of the anterior ventral segment according to Couinaud’s portal segmentation, is an innovative technique in living donor liver transplantation. In all cases, the mRL volume had increased after transplantation. However, we have some difficulties accepting the authors’ conclusion that the volume of the mRL increased in the recipients as we responded to their previous work (3). The blood supply to the mRL still remains as a matter for speculation. They suggested lobar communication through sinusoidal perfusion as one of the potential reasons for regeneration of the mRL. However, clinical experience has taught us that a lack of portal inflow as a result of tumor growth or surgical maneuvers results in atrophy of the region and that the role of sinusoidal perfusion is limited (4). They described the area whose surface was not discolored by right or left Glissonean pedicle (Fig. 4C and D). This phenomenon was suggested to be caused by lobar communication through sinusoidal perfusion. However, the possibility could not be excluded that the no discoloration area was provided just by communicating arcades between the right and left small-hepatic arteries close to the hilar bile duct (5). The method of volumetry in the postoperative computed tomography (CT) scans must be carefully evaluated. It is difficult to understand how they determined the dotted line in Figure 3(B), which was drawn to discriminate the mRL from the left liver. The right side of the dotted line (their mRL) seems to include the portal branch of the left portal vein. The territory of the portal branch coming from the left portal vein should be defined as the left liver. A volume evaluation with a region-growing software (Hitachi Image Processing System, Hitachi Medical Corporation, Japan) in the postoperative CT (6) will provide a more accurate volume evaluation similar to that in the preoperative CT (2). Ikegami et al. (1) claimed that the mRL area should have regenerated because the area was enhanced in the venous phase CT taken 1 month after transplantation. However, we must note that the hypervascular area on CT will not always secure the regenerative potential. Hwang et al. (7) reported 18 donors who donated a left lateral segment liver as a graft. CT scans of all donors were obtained at 1 week and 3 months after surgery. The parenchyma of segment 4 was enhanced in 16 donors (89%) after 1 week. This segment became atrophic in all donors at 3 months. Finally, as they commented in the discussion, the most concerned point in their technique is the increased risk of bile leakage both in the donors and recipients because the transaction line is set near the right anterior Glissonean bundle. Careful discussion may be necessary to analyze whether this new left liver graft is truly adequate option in the living donor liver transplantation. Junichi Kaneko Yasuhiko Sugawara Sumihito Tamura Norihiro Kokudo Artificial Organ and Transplantation Division Department of Surgery, Graduate School of Medicine University of Tokyo Tokyo, Japan Masatoshi Makuuchi Japanese Red Cross Medical Center Tokyo, Japan

Factors associated with acute otitis media in children due to penicillin intermediately resistant Streptococcus pneumoniae

Objectives This study was conducted to analyze the association between recent antimicrobial use and acute otitis media (AOM) due to Streptococcus pneumoniae intermediately resistant to penicillin (PISP). The influence of drug resistance on the clinical course of AOM was also assessed. Methods A retrospective cohort study was conducted in infants at Japanese Red Cross Medical Center, Tokyo. Children included in the study were under 24 months of age and diagnosed with AOM due to infection with S. pneumoniae between April 2002 and March 2007. Crude risk ratios (cRR) of PISP infection in cases with recent antibiotic use and other factors were obtained. The Mantel–Haenszel estimate was applied for the adjustment of cRR. Results Of 35 children, 13 had AOM due to penicillin-susceptible S. pneumoniae (PSSP) and 22 had AOM due to PISP. The adjusted risk ratio (aRR) of penicillin antibiotic use within 1 month was 1.99 (95% confidence interval (CI): 1.36–2.92), and the aRR of penicillin antibiotic use within 1 week was 1.93 (95% CI: 1.33–2.67). Recent use of penicillin antibiotics was an associated factor for AOM due to PISP. The clinical course was not clearly different between cases infected with PSSP and those with PISP. Conclusion Recent use of penicillin antibiotics might be a selective pressure for PISP.

Evaluation of the risk factors for febrile neutropenia associated with hematological malignancy

Febrile neutropenia (FN) can frequently become a very serious problem. In 2002, Klastersky and colleagues established the Multinational Association for Supportive Care in Cancer (MASCC) score, which consisted of risk factors for conditions that included solid tumors. However, hematopoietic tumors, in comparison to solid tumors, are plagued by such problems as the quantity and quality of abnormalities associated with leukocytes and neutrophils and the requirement for higher dosages of both radio- and chemotherapy. FN is a complication associated with hematological malignancies that can lead to a fatal outcome, but it is avoidable if the appropriate preventive treatment is performed at an early stage. The subjects of the present study consisted of 354 patients with hematopoietic malignancies who were treated at the Japanese Red Cross Medical Center Hospital, Tokyo, between August 2000 and September 2004. They were retrospectively evaluated for the risk factors of FN by applying Wilcoxon's rank sum test. A scoring index was defined and the patients were classified into high- and low-risk groups before evaluation. The following nine risk factors, which may significantly influence the relationship between the time required for defervescence and the duration of neutropenia - age; hematological diseases; the leukocyte count during the febrile period; the reduction in leukocyte count per day before the onset of FN; the prophylactic administration of antimycotic agents; sterilization of the intestinal tract; and urine albumin content, creatine level, and C-reactive protein (CRP) level - were expressed in points and their sum was termed risk points. The range of risk points was classified as 0-3 and 4-9. The time required for defervescence was 5.1 days when the risk points were in the range of 0-3 and 8.1 days when the points were in the range of 4-9. These figures were distributed normally and there was a significant difference between the two groups (P = 0.0016). FN associated with hematological malignancies is somewhat different from that related to other malignancies; it is therefore associated with unique risk factors. Most of the risk factors used in the present study can be evaluated objectively. At the onset of FN, they were expressed in points for evaluation. Further prospective studies are needed to determine whether these risk factors are suitable for use in actual cases.