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Background: Intra-articular platelet-rich plasma (PRP) injections have been proposed for the treatment of knee osteoarthritis (OA); however, their effectiveness in Japanese patients remains unclear. Purpose: To investigate whether 3 intra-articular injections of leukocyte-poor PRP (LP-PRP) improve symptoms and joint function in symptomatic Japanese patients with mild to moderate knee OA. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Of 72 patients screened, 30 were included and randomized to receive LP-PRP (n = 15) or saline (placebo; n = 15) injections between March 2019 and February 2023. Patients attended a screening visit and 3 treatment visits at 1 week apart, followed by 3 follow-up visits (at 4, 12, and 24 weeks) after the initial treatment visit. The primary efficacy outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, whereas the secondary efficacy outcome measures were the proportion of patients showing a visual analog scale (VAS) improvement of ≥50%. Magnetic resonance imaging was performed to evaluate joint effusion and bone marrow lesions using the Whole-Organ Magnetic Resonance Imaging Score. Patients were followed for 24 weeks. Results: Patients in the PRP group (mean age, 65.9 years) had a mean hip-knee-ankle angle of 5.1°, with 7 and 8 patients demonstrating Kellgren-Lawrence grade 2 and 3 knee OA, respectively. Patients in the placebo group (mean age, 67.9 years) had a mean hip-knee-ankle angle of 3.8°, with 6 and 9 patients showing Kellgren-Lawrence grade 2 and 3 knee OA, respectively. No significant differences were identified in any baseline factors. The percentage change in Western Ontario and McMaster Universities Osteoarthritis Index scores from baseline to 24 weeks was significantly different (P=.032) between the PRP (median, 75.9%; quantile 1 [Q1], 49.6; quantile 3 [Q3], 94.1]) and placebo (median, 27.7%; Q1, –9.4; Q3, 80.9]) groups. Overall, 73.3% and 28.6% of the PRP group and placebo group, respectively, exhibited an improvement in visual analog scale scores of ≥50%, with a significant improvement observed in the PRP group (P =.027). Changes in bone marrow lesions from baseline to 24 weeks, as assessed on magnetic resonance imaging, significantly differed between groups (P =.017), with no significant differences in other secondary endpoints. Conclusion: In Japanese patients with knee OA, 3 intra-articular LP-PRP injections led to clinical improvements at 24-week follow-up and significant functional improvements and pain relief after 24 weeks. [ABSTRACT FROM AUTHOR]

Qualitative urinalysis using the Sternheimer stain is a common method in Japan for identifying bacteriuria, but there is a lack of studies examining its test characteristics. In this study, we aimed to investigate the sensitivity and specificity of the Sternheimer stain for urine culture results and compare it with the sensitivity and specificity of the Gram stain. Our goal was to determine the usefulness of the Sternheimer stain in identifying bacteriuria. Among 986 patients aged 16 years or older from whom samples for both urinalysis and urine culture were obtained at the emergency room of Tenri Hospital from January 2019 to December 2019, 342 patients with pyuria, defined as the presence of 10 or more white cells per cubic millimeter in a urine specimen, who had not received prior antimicrobial therapy were included. Urine cultures were used for comparison to determine the sensitivity and specificity of Sternheimer and Gram stain in this patient group. A positive Sternheimer stain result was defined as bacteriuria ≥ (1+), and that of Gram stain was defined as ≥ 1/1 field of high-power (× 1000) oil immersion. Using urine culture results for comparison, the sensitivity of Sternheimer stain was 92.2%, the specificity was 48.5%, the positive likelihood ratio was 1.79, and the negative likelihood ratio was 0.16. Sternheimer stain is a rapid and useful method to exclude bacteriuria in a group of patients with pyuria in the emergency department. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP) increase the risk of preterm births and cesarean delivery. This study aimed to investigate whether maternal blood leukocyte, monocyte, or neutrophil counts in the first trimester are related to the development of HDP. Data were collected from the Japan Environment and Children's Study, a large birth cohort study (n = 38,194) that recruited pregnant women in 15 Regional Centers across Japan (from January 2011 to March 2014). The odds ratios (ORs) for mild/severe HDP according to the cut-off value of leukocyte/neutrophil/monocyte counts by the receiver operating characteristic curve showed high ORs. Furthermore, pregnant women with the highest quartiles of leukocyte and monocyte counts had higher adjusted ORs (aORs) for mild (leukocyte: aOR = 1.27, 95% confidence interval [CI]: 1.02–1.58; monocyte: aOR = 1.30, 95% CI 1.04–1.63) and severe HDP (leukocyte: aOR = 1.51, 95% CI 1.08–2.13; monocyte: aOR = 1.44, 95% CI 1.03–2.01) compared with those with the lowest quartiles of those counts. In addition, pregnant women with the highest neutrophil counts had higher aOR for mild HDP (aOR = 1.26, 95% CI 1.02–1.56) compared with those with the lowest count. In conclusion, high leukocyte and monocyte counts in the first trimester are associated with the development of HDP. Thus, they may be used to predict subsequent HDP. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study is to investigate the relationships between Type 1 interferon (T1-IFN) signatures and clinical characteristics of lupus patients. Methods: We examined 49 new-onset lupus patients who were diagnosed between 1999 and 2017. The patients treated with >10 mg of prednisolone or hydroxychloroquine were excluded from this study. Serum T1-IFN signatures were revealed by a functional reporter assay and standardized by recombinant IFN-α. Patient backgrounds, clinical findings, and treatments were retrospectively extracted from their electrical medical records. Clinical data were also available, including SLE Disease Activity Index of SLE patients on admission. Results: T1-IFN signatures of lupus patients closely correlated with lupus disease activities, such as SLE Disease Activity Index-2K, white blood cell, C3 levels, and the titre of double-strand DNA antibody. We found fever and acute lupus dermatitis closely associated with T1-IFN signature. Conclusions: In lupus patients, fever and acute lupus dermatitis are good indicators of a strong T1-IFN signature. [ABSTRACT FROM AUTHOR]

Background. The Coccomyxa sp. strain KJ (Coccomyxa KJ), a microalga found in Japan, has a potential function in controlling viral infections. Recently, its dry powder has been marketed as a health food product. Objectives. This pilot study investigated the effects of Coccomyxa KJ powder tablet intake on allergic reactions and immune functions in healthy participants. Materials and methods. Nine healthy volunteers (4 males and 5 females) who expressed interest in foods containing Coccomyxa KJ, and were willing to undergo blood tests, were recruited. Each individual was asked to take 2 Coccomyxa KJ powder tablets (0.3 g) before breakfast once a day for 4 weeks. The salivary immunoglobulin A (IgA) level and blood parameters (white blood cell (WBC) count, eosinophil and lymphocyte counts and percentages, natural killer (NK) cell activity, interleukin (IL)-6 level, and T helper (Th)1/Th2 cell ratio) were evaluated at baseline and weeks 2 and 4. Results. The 4-week intake of Coccomyxa KJ did not affect salivary IgA levels, WBC count, eosinophil and lymphocyte counts and percentages, or the Th1/Th2 ratio. There were significant differences in the NK cell activity after 4 weeks, with an average increase of 11.78 (95% confidence interval (95% CI): 6.80-16.76). None of the patients experienced adverse reactions during or after the study. Conclusions. Long-term Coccomyxa KJ intake improved NK cell activity without causing adverse effects on the indicators of local immunity, systemic inflammation and immune response balance. This study suggests that Coccomyxa KJ powder tablets can induce beneficial immune modifications without causing any adverse effects. [ABSTRACT FROM AUTHOR]

The present study investigated the potential role of the composition of dietary fatty acids in the regulation of biological rhythms, such as the sleep architecture, core body temperature and leukocyte clock gene expression, in subjects fed meals rich in palmitic acid (PA) or oleic acid (OA). Eleven males participated in two sessions of indirect calorimetry in a whole-room metabolic chamber. In each session, subjects consumed three meals rich in PA (44·3 % of total fat as PA and 42·3 % as OA) or OA (11·7 % of total fat as PA and 59·3 % as OA) in the metabolic chamber. The ratio of PA to OA in plasma was significantly lower and fat oxidation was significantly higher during 24 h of indirect calorimetry in the session with meals rich in OA than in that with meals rich in PA. The duration of slow wave sleep (SWS) was shorter, the latency of SWS was longer and the nadir of core body temperature after bedtime was later in the session with meals rich in PA than in that with meals rich in OA. The peak in CRY1 gene expression was earlier and its amplitude was higher in the session with meals rich in PA than in that with meals rich in OA. In healthy young males, meals rich in PA decreased fat oxidation and disrupted biological rhythms, particularly the sleep architecture and core body temperature during sleep, more than meals rich in OA. [ABSTRACT FROM AUTHOR]

Introduction: The Atellica Hema (Siemens Healthineers, Tarrytown, NY, USA) is a new generation multi‐parameter analyzer for full blood count, 6‐part differential and reticulocyte testing by impedance variation and fluorescence flow cytometry. In this study, we verified the whole blood and limited body fluid modes of the Atellica Hema 580. Methods: We evaluated precision, linearity, carry‐over, throughput and performed a method comparison to assess the performance of the Atellica Hema 580. For comparison of the Atellica Hema 580 with the Sysmex XN‐1000 (Sysmex, Kobe, Japan), 140 samples from adult and pediatric patients including both normal and abnormal hematology profiles were analyzed in parallel. Results: The Atellica Hema 580 demonstrated acceptable imprecision within the manufacturer's specifications for whole blood and body fluid modes, good linearity for high and low ranges and no significant carryover. The full blood count, differential and reticulocyte correlated well with the Sysmex XN‐1000, except for mean cell hemoglobin concentration, basophil and large immature cells. The optical platelet count, reflexed in 34 samples with a platelet count <150 × 109/l, showed a strong correlation with the fluorescent platelet count on the Sysmex XN‐1000. The morphology flagging efficiency was 92% for white blood cells, 95% for red blood cells and 87% for platelets. Conclusion: The Atellica Hema 580 showed good analytical performance and workflow efficiency for a wide range of patient samples. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma. Human leukocyte antigen (HLA) self-recognition through killer immunoglobulin-like receptor (KIR), a process termed "licensing", raises the NK cell capacity. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy. Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma (HCC). We performed adaptive immunotherapy using donor-liver-derived natural killer (NK) cells after living-donor liver transplantation (LDLT) to prevent HCC recurrence. Dominant inhibitory signals tightly regulate NK cell activity via human leukocyte antigen (HLA)-specific inhibitory receptors, such as killer immunoglobulin-like receptors (KIRs). The functional recognition of HLA through KIR raises the NK cell capacity, which is a process termed "licensing." Here, we investigated the effect of polymorphic KIR-HLA genotypes on the efficacy of NK-cell-based immunotherapy after LDLT. Seventy-seven Japanese recipients with HCC who underwent LDLT and their corresponding donors between 1996 and 2016 were enrolled in this study. The median follow-up period was 8.3 years. The HCC recurrence risk was stratified using radiological and pathological assessments according to the Milan criteria. Of the 77 recipients, 38 received immunotherapy. Immunotherapy improves early post-transplantation survival and lowers the recurrence rate in the intermediate-risk recipients. We analyzed the genotypes of five inhibitory KIRs and HLA using sequence-specific polymorphism-based typing. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tickborne zoonotic disease, endemic to Asian regions, including western Japan. Cats appear to suffer a particularly severe form of the disease; however, feline SFTS is not clinically well characterized. Accordingly, in this study, we investigated the associations of, demographic, hematological and biochemical, immunological, and virological parameters with clinical outcome (fatal cases vs. survivors) in SFTSV-positive cats. Viral genomic analysis was also performed. Viral load in blood, total bilirubin, creatine phosphokinase, serum amyloid A, interleukin-6, tumor necrotic factor-α, and virus-specific IgM and IgG differed significantly between survivors and fatal cases, and thus may have utility as prognosticators. Furthermore, survivor profiling revealed high-level of viremia with multiple parameters (white blood cells, platelet, total bilirubin, glucose, and serum amyloid A) beyond the reference range in the 7-day acute phase, and signs of clinical recovery in the postacute phase (parameters returning to, or tending toward, the reference range). However, SFTSV was still detectable from some survived cats even 14 days after onset of disease, indicating the risk of infection posed by close-contact exposure may persist through the post-acute phase. This study provides useful information for prognostic assessments of acute feline SFTS, and may contribute to early treatment plans for cats with SFTS. Our findings also alert pet owners and animal health professionals to the need for prolonged vigilance against animal-to-human transmission when handling cats that have been diagnosed with SFTS. [ABSTRACT FROM AUTHOR]

The article presents a case of relapsing polychondritis (RP) with pulmonary arteritis that was treated successfully with prednisolone (PSL), MTX and infliximab. Topics include medical history of the patient evaluated in the study, treatment given to the patient, and effectiveness of high-dose corticosteroids and biological agents for RP associated with large-vessel vasculitis (LVV).

High fish consumption may be associated with lower inflammation, suppressing atherosclerotic CVD (ASCVD). Long sleep duration, as well as short sleep, may contribute to inflammation, thus facilitating ASCVD. This study investigated the overall association between fish consumption, sleep duration and leucocytes count. We conducted a cross-sectional study between April 2019 and March 2020 with a cohort of 8947 apparently healthy participants with no history of ASCVD (average age, 46·9 ± 12·3 years and 59 % males). The average frequency of fish consumption and sleep duration were 2·13 ± 1·26 d/week and 6·0 ± 0·97 h/d. Multivariate linear regression analysis revealed that increased fish consumption was an independent determinant of sleep duration (β = 0·084, P < 0·0001). Additionally, habitual aerobic exercise (β = 0·059, P < 0·0001) or cigarette smoking (β = −0·051, P < 0·0001) and homoeostasis model assessment-insulin resistance (HOMA-IR) (β = −0·039, P = 0·01) were independent determinants of sleep duration. Furthermore, multivariate linear regression analysis identified fish consumption as an independent determinant of leucocytes count (β = −0·091, P < 0·0001). However, a significant U-shaped curve was found between leucocytes count and sleep duration, with 6–7 h of sleep as the low value (P = 0·015). Higher fish consumption may be associated with a lower leucocytes count in the presence of adequate sleep duration and healthy lifestyle behaviors. However, long sleep duration was also related to increased inflammation, even in populations with high fish consumption. Further studies are needed to clarify the causality between these factors. [ABSTRACT FROM AUTHOR]

To investigate the relationship between white blood cell (WBC) count and incidence of hyper-low-density lipoprotein (LDL) cholesterolemia in a population-based longitudinal study. This is a retrospective study using data of annual health check-ups for residents of Iki City, Japan. A total of 3312 residents (≥ 30 years) without hyper-LDL cholesterolemia at baseline were included in this analysis. Primary outcome was incidence of hyper-LDL cholesterolemia (LDL cholesterol levels ≥ 3.62 mmol/L and/or use of lipid lowering drugs). During follow-up (average 4.6 years), 698 participants development of hyper-LDL cholesterolemia (incidence 46.8 per 1000 person-years). Higher incidence of hyper-LDL cholesterolemia was observed among participants with higher leukocyte count (1st quartile group: 38.5, 2nd quartile group: 47.7, 3rd quartile group: 47.3, and 4th quartile group: 52.4 per 1,000 person-years, P = 0.012 for trend). Statistically significant relation was observed even after adjustment for age, gender, smoking, alcohol intake, leisure-time exercise, obesity, hypertension and diabetes: hazard ratio 1.24 (95% confidence interval 0.99 to 1.54) for 2nd quartile group, 1.29 (1.03–1.62) for 3rd quartile group and 1.39 (1.10–1.75) for 4th quartile group, compared with 1st quartile group (P for trend = 0.006). Increased WBC count was related to incidence of hyper-LDL cholesterolemia in general Japanese population. [ABSTRACT FROM AUTHOR]

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18–9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1–10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1–10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system. [ABSTRACT FROM AUTHOR]

Waterproofing spray-associated lung injury (WALI) is an acute respiratory disorder characterized by bilateral diffuse lung injury on chest computed tomography (CT). In most cases, the symptoms and abnormal radiographic findings of WALI patients improve spontaneously over several days; however, some cases have persistent symptoms and abnormal shadows for >1 week. The distinctive features of each WALI are unknown. Herein, we present two new cases of WALI that we encountered in our hospital, and we previously reported two other cases of WALI. We examined the characteristics of WALI in our cases and 39 other cases of WALI definitively diagnosed and reported in PubMed and the Japan medical board with verifiable data during a 15-year period. We compared the clinical characteristics of the 22 cases in which the patients' symptoms were resolved within 1 week (early improvement) to those of the 21 cases in which the symptoms were resolved after >1 week (delayed improvement). The WALI cases with delayed improvement had significantly more shadowing that extended over the entire lung field and was not biased in intensity toward the upper or lower lung field. In addition, the serum white blood cell (WBC) counts and serum Krebs von den Lungen-6 (KL-6) levels differed significantly between the cases of early and delayed improvement of WALI. [ABSTRACT FROM AUTHOR]

Polymorphisms of canine leukocyte antigen (DLA) class I (DLA-88 and DLA-12/88L) and class II (DLA-DRB1) genes are important for disease susceptibility studies, but information on the genetic diversity among dog breeds is still lacking. To better elucidate the polymorphism and genetic diversity between breeds, we genotyped DLA-88, DLA-12/88L, and DLA-DRB1 loci using 829 dogs of 59 breeds in Japan. Genotyping by Sanger sequencing identified 89, 43, and 61 alleles in DLA-88, DLA-12/88L, and DLA-DRB1 loci, respectively, and a total of 131 DLA-88–DLA-12/88L–DLA-DRB1 haplotypes (88-12/88L-DRB1) were detected more than once. Of the 829 dogs, 198 were homozygotes for one of the 52 different 88-12/88L-DRB1 haplotypes (homozygosity rate: 23.8%). Statistical modeling suggests that 90% of the DLA homozygotes or heterozygotes with one or other of the 52 different 88-12/88L-DRB1 haplotypes within somatic stem cell lines would benefit graft outcome after 88-12/88L-DRB1-matched transplantation. As previously reported for DLA class II haplotypes, the diversity of 88-12/88L-DRB1 haplotypes varied remarkably between breeds but was relatively conserved within most breeds. Therefore, the genetic characteristics of high DLA homozygosity rate and poor DLA diversity within a breed are useful for transplantation therapy, but they may affect biological fitness as homozygosity progresses. [ABSTRACT FROM AUTHOR]

Idiopathic non-infectious meningoencephalomyelitis (NIME), which is thought to be an immune-mediated disease, is a common inflammatory disease in dogs. Meningoencephalomyelitis of unknown origin (MUO), a subgroup of NIME, consists of necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis, and granulomatous meningoencephalomyelitis. Recent studies have shown associations between disease development and dog leukocyte antigen (DLA) class II genes in NME in Pugs and in NIME in Greyhounds. This study focused on Chihuahuas, which have a high incidence of MUO and are one of the most common dog breeds in Japan. Because the development of MUO seems to be associated with DLA class II genes, we aimed to evaluate the association between DLA class II genes and MUO development in Chihuahuas. Blood samples were obtained from 22 Chihuahuas with MUO (MUO group) and 46 without neurological diseases (control). The allele sequences of three DLA class II loci were determined, and haplotypes were estimated from these data. In total, 23 haplotypes were detected. The frequency of one haplotype (DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01) was significantly higher in the MUO group than in the control group (odds ratio, 7.11; 95% confidence interval, 1.37-36.81; P=0.0141). The results suggest that the development of MUO in Chihuahuas may be associated with DLA class II genes. Because the identified risk haplotypes differed from those of other breeds, the pathogenesis of NIME-related diseases may differ among dog breeds. [ABSTRACT FROM AUTHOR]

Stroke is a progressive disease with remissions and exacerbations; it significantly reduces the quality of life of patients and their family and caregivers. Primary prevention is necessary to reduce the growing incidence of stroke globally. In this study, we determined the risk factors for cerebral infarction in elderly Japanese residents and proposed a primary care strategy to prevent cerebral infarction. We investigated the relationship between the incidence of cerebral infarction and the results of checkups 10 years ago. Multivariate logistic regression analysis was performed to determine the variables related to the occurrence of cerebral infarction in biochemical tests and questionnaires administered ten years ago. Hypertension and abnormal creatinine levels were related to increased risk of cerebral infarction based on our findings of the health checkups conducted 10 years previously. Furthermore, weight gain or loss of >3 kg over the last year and habit of eating an evening meal within 2 h before going to bed were associated with an increased risk of cerebral infarction based on the questionnaire results from the specific health checkups. Long-term, large-scale prospective studies are required to determine the specific health items related to increased risk of cerebral infarction. [ABSTRACT FROM AUTHOR]

OBJECTIVE The Kobayashi score (KS) is the most widely used tool for predicting intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD). The KS has shown good sensitivity (86%) and specificity (68%) in Japanese children; however, its use is limited outside of Japan. No models accurately predict IVIG resistance of children with KD in the United States. We sought to develop and test a novel scoring system to predict IVIG resistance in hospitalized children with KD. METHODS A retrospective chart review was conducted of all children diagnosed with KD from January 2000 to December 2015. Subjects were divided into 2 groups: IVIG susceptible or resistant. Variables that differed between the groups were identified and used to create a "new score" to predict resistance to IVIG. The new score was then compared with the KS and performance characteristics were determined. RESULTS A total of 208 subjects were reviewed. White blood cell count, neutrophil percentage, age, and serum albumin were used in the new score with equal weighting. Overall, the new score achieved improved sensitivity (54% vs 26%) and similar specificity (69% vs 74%) compared with the KS in predicting IVIG resistance in hospitalized children diagnosed with KD. CONCLUSIONS Predicting IVIG resistance in children diagnosed with KD remains challenging. The KS has low sensitivity in predicting IVIG resistance in children with KD in the United States. The new score resulted in improved sensitivity, but many children with true IVIG resistance may be missed. Further research is needed to improve IVIG resistance prediction. ABBREVIATIONS ALT, alanine aminotransferase; AST, aspartate transaminase; CAA, coronary artery aneurysm; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; KS, Kobayashi score; ROC, receiver operator curve; WBC, white blood cell; WNY, Western New York. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/μL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF. [ABSTRACT FROM AUTHOR]

Objectives: Although the prognosis of Sézary syndrome (SS) is highly unfavorable, the prognostic factors have not been fully understood. In this study, we tried to investigate the prognostic factors in Japanese SS patients for the first time. Methods: We performed a retrospective cohort study of 19 SS patients who visited our hospital between January 1, 1999, and December 31, 2019. The collected clinical findings were age, gender, performance status (PS), and TNMB staging at diagnosis. TNMB staging was determined according to the International Society for Cutaneous Lymphomas and the cutaneous task force of the European Organization of Research and Treatment of Cancer criteria. The collected hematological findings were serum levels of soluble IL‐2 receptor (sIL‐2R), lactate dehydrogenase (LDH), thymus and activation‐regulated chemokine (TARC), and immunoglobulin E (IgE), Sézary cell count, Sézary cell ratio among white blood cells, and eosinophil count in peripheral blood at diagnosis. Results: We analyzed the correlations between overall survival and various clinical and hematological findings. In the log‐rank test, PS1‐3, N2‐3 stage, higher serum levels of LDH (≥355 IU/L), sIL‐2R (≥1729 U/ml) and TARC (≥19,867 pg/ml), and higher Sézary cell count (≥7480/μl) and Sézary cell ratio among white blood cells (≥52%) at diagnosis were associated with decreased overall survival. Conclusions: This is the first report evaluating prognostic factors in Asian SS patients. This study may contribute to selecting the treatment strategy and improving survival and quality of life of Asian SS patients. [ABSTRACT FROM AUTHOR]

Background: Prediction of inpatients with community-acquired pneumonia (CAP) at high risk for severe adverse events (SAEs) requiring higher-intensity treatment is critical. However, evidence regarding prediction rules applicable to all patients with CAP including those with healthcare-associated pneumonia (HCAP) is limited. The objective of this study is to develop and validate a new prediction system for SAEs in inpatients with CAP.Methods: Logistic regression analysis was performed in 1334 inpatients of a prospective multicenter study to develop a multivariate model predicting SAEs (death, requirement of mechanical ventilation, and vasopressor support within 30 days after diagnosis). The developed ALL-COP-SCORE rule based on the multivariate model was validated in 643 inpatients in another prospective multicenter study.Results: The ALL-COP SCORE rule included albumin (< 2 g/dL, 2 points; 2-3 g/dL, 1 point), white blood cell (< 4000 cells/μL, 3 points), chronic lung disease (1 point), confusion (2 points), PaO2/FIO2 ratio (< 200 mmHg, 3 points; 200-300 mmHg, 1 point), potassium (≥ 5.0 mEq/L, 2 points), arterial pH (< 7.35, 2 points), systolic blood pressure (< 90 mmHg, 2 points), PaCO2 (> 45 mmHg, 2 points), HCO3- (< 20 mmol/L, 1 point), respiratory rate (≥ 30 breaths/min, 1 point), pleural effusion (1 point), and extent of chest radiographical infiltration in unilateral lung (> 2/3, 2 points; 1/2-2/3, 1 point). Patients with 4-5, 6-7, and ≥ 8 points had 17%, 35%, and 52% increase in the probability of SAEs, respectively, whereas the probability of SAEs was 3% in patients with ≤ 3 points. The ALL-COP SCORE rule exhibited a higher area under the receiver operating characteristic curve (0.85) compared with the other predictive models, and an ALL-COP SCORE threshold of ≥ 4 points exhibited 92% sensitivity and 60% specificity.Conclusions: ALL-COP SCORE rule can be useful to predict SAEs and aid in decision-making on treatment intensity for all inpatients with CAP including those with HCAP. Higher-intensity treatment should be considered in patients with CAP and an ALL-COP SCORE threshold of ≥ 4 points.Trial Registration: This study was registered with the University Medical Information Network in Japan, registration numbers UMIN000003306 and UMIN000009837. [ABSTRACT FROM AUTHOR]

Introduction: While white blood cell (WBC) parameters have been suggested to depend on ethnicity and gender, reference intervals in healthy Asian populations are limited. The present study established reference intervals of WBC parameters for healthy adults in Japan. Methods: A total of 750 healthy adults (447 women and 303 men; 18‐67 years old, median 40 years old) at 7 Japanese centers who participated in regular medical checkups entered this study. The WBC parameters were measured using automated hematocytometers and blood film reviews by a manual microscopic examination. Results: The reference intervals of the WBC parameters according to gender in healthy adults were determined. Age‐specific decreases in WBC counts of both gender groups and in neutrophil counts of women were noted. Favorable correlations between the hematocytometer and microscopic methods were found in neutrophils, lymphocytes, and eosinophils but not in monocytes or basophils. Conclusion: This study suggests the need to consider gender and age in the clinical use of reference intervals of WBC parameters. [ABSTRACT FROM AUTHOR]

Several adsorptive type devices for ulcerative colitis are used for the induction of remission in patients with active severe disease worldwide. In 2020, the novel apheresis device Immunopure for ulcerative colitis was launched in Japan. Immunopure, like the polyethylene terephthalate column, uses polyarylate, a type of polyester resin, as the adsorbent. Similar to the cellulose acetate column, Immunopure is filled with adsorbent beads and expected to provide ease of use, with minimal risk of column clogging. Immunopure adsorbs leukocytes and platelets, especially activated platelets and platelet‐leukocyte aggregates. In this article, the capability of Immunopure is evaluated from clinical perspective based on a clinical trial in Japan/Europe. As a result, Immunopure is comparable to other products in clinical effectiveness and indicated for the treatment of patients with refractory moderate ulcerative colitis, making it highly useful in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Tracheostomy is an important surgical procedure for coronavirus disease-2019 (COVID-19) patients who underwent prolonged tracheal intubation. Surgical indication of tracheostomy is greatly affected by the general condition of the patient, comorbidity, prognosis, hospital resources, and staff experience. Thus, the optimal timing of tracheostomy remains controversial.Methods: We reviewed our early experience with COVID-19 patients who underwent tracheostomy at one tertiary hospital in Japan from February to September 2020 and analyzed the timing of tracheostomy, operative results, and occupational infection in healthcare workers (HCWs).Results: Of 16 patients received tracheal intubation with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, five patients (31%) received surgical tracheostomy in our hospital. The average consultation time for surgical tracheostomy was 7.4 days (range, 6 - 9 days) from the COVID-19 team to the otolaryngologist. The duration from tracheal intubation to tracheostomy ranged from 14 to 27 days (average, 20 days). The average time of tracheostomy was 27 min (range, 17 - 39 min), and post-wound bleeding occurred in only one patient. No significant differences in hemoglobin (Hb) levels were found between the pre- and postoperative periods (mean: 10.2 vs. 10.2 g/dl, p = 0.93). Similarly, no difference was found in white blood cell (WBC) count (mean: 12,200 vs. 9,900 cells /µl, p = 0.25). After the tracheostomy, there was no occupational infection among the HCWs who assisted the tracheostomy patients during the perioperative period.Conclusion: We proposed a modified weaning protocol and surgical indications of tracheostomy for COVID-19 patients and recommend that an optimal timing for tracheostomy in COVID-19 patients of 2 - 3 weeks after tracheal intubation, from our early experiences in Japan. An experienced multi-disciplinary tracheostomy team is essential to perform a safe tracheostomy in patients with COVID-19 and to minimize the risk of occupational infection in HCWs. [ABSTRACT FROM AUTHOR]

Background: Currently, supplementary serological testing for β-D glucan (BDG) is often selected to diagnose deep mycosis in care covered by the health insurance in Japan. The Wako method used by our center has low sensitivity, and different studies have used different cut-off values due to factors that cause false positives and false negatives. One possible cause of false negatives is the use of platelet-rich plasma (PRP) as the sample material. Because phagocytic white blood cells (WBC) are precipitated by centrifugation and only plasma is measured, it seems unlikely that the actual amount of BDG is being measured when using PRP. Further, a frequent cause of false positives is contamination from blood products and gauze containing BDG. To resolve these issues, the blood cell separator, hydroxyethyl starch, is used to precipitate only the red blood cells to obtain leukocyte-rich plasma (LRP). We hypothesized that it might be possible to improve the diagnostic rate of deep mycosis by measuring the BDG content of plasma containing WBC and fungal components and by comparing the BDG content of PRP and LRP measured simultaneously. Materials and Methods: Healthy human blood, albumin-added blood, wrung-out gauze fluid-added blood, and fungal solution-added blood were prepared, and PRP and LRP were prepared using hydroxyethyl starch. The BDG content of each sample was measured using the Wako method and compared. In addition, PRP and LRP of fungal-added blood were Gramstained and examined under a microscope, and the number of WBCs and phagocytosed fungi was counted visually and compared. Results: Measuring the BDG content of LRP confirmed that there were no false positives with LRP, and in vitro experiments comparing albumin-added false-positive blood to fungal-added blood showed significant differences between PRP and LRP only in the fungal-added blood. Conclusion: Calculating the BDG-ratio (LRP/PRP) by measuring both LRP and PRP may eliminate false positives and false negatives of true deep mycosis and improve the diagnostic rate. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to clarify the relationship between the white blood cell (WBC) count and hypertension in the general Japanese population. Methods: We conducted a population-based retrospective cohort study using annual health check-up data of residents of Iki City, Nagasaki Prefecture, Japan. A total of 2935 participants without hypertension at baseline were included in the present analysis. WBC counts were classified as tertile 1 (<4700/μL), tertile 2 (4700–5999/μL), and tertile 3 (≥6000/μL). The outcome was incident hypertension (blood pressure ≥140 mmHg). Multivariable-adjusted hazard ratios and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazards model. Result: During an average follow-up of 4.5 years, 908 participants developed hypertension. The incidence (per 100 person-years) of hypertension increased with an elevation in the WBC count (6.3 in tertile 1, 7.0 in tertile 2, and 7.4 in tertile 3). This association was significant, even after adjustment for other risk factors, including age, sex, current smoking habits, current alcohol intake, exercise habits, obesity, elevated blood pressure, diabetes mellitus, and dyslipidemia. The hazard ratios were 1.07 for tertile 2 (95% CI 0.90–1.26) and 1.27 for tertile 3 (95% CI 1.06–1.51) compared with the reference group of tertile 1 (p = 0.009). Conclusion: The WBC count was associated with future development of hypertension in the general Japanese population. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the effect of daily folic acid supplementation on methotrexate (MTX) toxicity and efficacy in Japanese patients with rheumatoid arthritis (RA). Methods: We followed 19 patients treated with MTX who switched from taking weekly 5mg folic acid supplementation (weekly regimen) to 1.25mg daily (daily regimen). White blood cell (WBC) and platelet (PLT) counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were collected for 24 weeks following the change. Results: We observed no significant changes in WBC or PLT counts. AST and ALT levels, which had exceeded the upper limits of their normal ranges at the beginning of the study, were improved significantly at weeks 4 and 8, no subsequent deterioration in liver function was found. Further, no significant changes in ESR and CRP levels were observed. Conclusion: Our data indicate that supplementing 1.25mg of folic acid daily rather than 5mg weekly reduces toxicity caused by MTX without affecting its efficacy. [ABSTRACT FROM AUTHOR]

Aim: To clarify the prevalence and degree of maternal microchimerism in Japanese children with type 1 diabetes, as well as its effect on phenotypic variation. Methods: We studied 153 Japanese children with type 1 diabetes, including 124 children positive for β‐cell autoantibodies, and their 71 unaffected siblings. The number of circulating microchimeric cells per 105 host cells was estimated by the use of quantitative‐polymerase chain reaction targeting non‐transmitted maternal human leukocyte antigen alleles. The results were compared to previous data from white European people. Phenotypic comparison was performed between maternal microchimerism carriers and non‐carriers with diabetes. Results: Maternal microchimerism was detected in 15% of children with autoantibody‐positive type 1 diabetes, 28% of children with autoantibody‐negative type 1 diabetes, and 16% of unaffected siblings. There were no differences in the prevalence or levels of maternal microchimerism among the three groups or between the children with type 1 diabetes and their unaffected siblings. Furthermore, maternal microchimerism carriers and non‐carriers exhibited similar phenotypes. Conclusions: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people. Our data indicate that maternal microchimerism is unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children and that the biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups. What's new?: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people with this condition.Circulating microchimeric cells are unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children.The biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups. [ABSTRACT FROM AUTHOR]

Leukocyte apheresis (LCAP) is a safe and effective treatment for active ulcerative colitis (UC) in Japan. Nevertheless, a limitation of LCAP is its requirement for two puncture sites (double‐needle [DN] apheresis), sometimes leading to problems with needle puncture. Single‐needle (SN) apheresis is useful in hemodialysis and reduces needle puncture pain. If SN apheresis were found to be useful in LCAP for UC, it may reduce patient burden. The aim of this study was to compare the safety and efficacy of SN apheresis with that of DN apheresis. Twenty‐four patients with active UC were retrospectively enrolled. They underwent either SN apheresis (n = 12) or conventional double‐needle (DN) apheresis (n = 12) at the Kurume University Hospital from February 2014 to March 2018. At each session, we recorded access problems defined by the time required to initiate apheresis and the frequency of puncture‐related problems, as well as blood circuit clotting, defined as clotting necessitating interruption of apheresis and changing of the circuit. Efficacy was assessed using partial Mayo scores. The number of apheresis sessions was comparable between SN and DN apheresis (9.0 ± 2.0 times vs 9.6 ± 1.4 times, mean ± SEM). SN significantly reduced the time required to start apheresis (10.0 ± 5.4 minutes vs 19.4 ± 11.9 minutes, P <.05) as well as needle puncture troubles (0.9% vs 11.5%, P <.05). SN had comparable frequency of blood clotting episodes (5.6% vs 8.7%). SN apheresis had similar clinical efficacy (P <.001 in SN and P <.01 in DN). The improvement and remission rates were comparable between groups. SN apheresis may be safe and effective and may reduce patient burden during UC treatment. Nevertheless, further comparative studies are needed. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence, background factors, and progression of and recovery from clozapine‐induced agranulocytosis in Japan. Methods: Data on treatment‐resistant schizophrenia patients registered with the Clozaril Patient Monitoring Service (CPMS) between July 29, 2009 and January 20, 2016 were extracted. Patients with a neutrophil count <500/mm3 were defined as having agranulocytosis, and those with a leukocyte count <3,000/mm3 or a neutrophil count <1,500/mm3 but not meeting the criteria for agranulocytosis were defined as having leukopenia/neutropenia. Results: Of 3,746 patients, agranulocytosis and leukopenia/neutropenia were observed in 38 (1.0%) and 182 (4.9%) patients, respectively. Age was significantly higher in the agranulocytosis group (p <.001). Decreased leukocyte counts 1 week prior to discontinuation were observed only in the agranulocytosis group. The median number of days to recovery from agranulocytosis and leukopenia/neutropenia was 10 and 4, respectively, with more variation in the latter. Conclusions: Although some patients with leukopenia/neutropenia might carry less pathologic significance, the results of this study reconfirmed the importance of regular blood monitoring for preventing agranulocytosis. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infection (UTI) in children is a common illness. The gold standard for UTI diagnosis is urine culture, but it takes a long time and often gives negative results. Currently developed a method of flow cytometry for checking urine sediments. This tool is able to detect leukocytes urine and urine bacteria in quick time. The purpose of this study is to analyze the relationship of urine leukocyte count and the number of urine bacteria using flow cytometry with urine culture in patients with UTI Method: Eighty-four patients were enrolled in this study that consisting of 43 patients with suspected UTI and 43 patients with non-ISK treated at Inpatient Installation, Emergency Installation Department of Health Sciences at Dr.Soetomo General Hospital, Surabaya for 4 months. The examination of urine leukocytes and urine bacteria was using current cytometry method (UF-500i, Sysmex, Japan). While, examination of urine culture using blood agar plate and Mac. Conkey. Results: There was a significant relationship between the number of leukocytes and the number of colonies. The relationship between leukocytes and the number of colonies was weak, this was indicated by Spearman correlation coefficient (rho) value of 0.376. There was a significant relationship between bacteria and the number of colonies. p <0.05. The relationship between the number of urine bacteria and the number of colonies was quite strong indicated by rho = 0.729. Conclusion: There was a relationship between urine leukocyte count and the number of urine bacteria using flow cytometry with a urine culture. [ABSTRACT FROM AUTHOR]

Background: Colonic diverticular disease has been increasing in prevalence due to the rapidly aging global population, but standard treatment has not changed dramatically in recent years. Daiobotanpito (DBT; Da Huang Mu Dan Tang in Chinese) has been used in medical treatment of acute abdominal abscesses, such as appendicitis or diverticulitis in traditional Japanese (Kampo) medicine for many years, based on more than 3000 years of experience. Prior to this study, a retrospective open-label trial was conducted to compare patients with acute diverticulitis who received oral DBT combined with intravenous antibiotics with those who received intravenous antibiotic alone; it showed a positive effect of DBT on acute diverticulitis. We aim to investigate whether moderate to severe acute diverticulitis shows greater improvement with intravenous antibiotics plus orally administered DBT compared with intravenous antibiotics plus placebo.Methods: This is a two-group, randomized, double-blind, placebo-controlled, multi-center trial, which is designed to evaluate the efficacy and safety of DBT in patients with moderate to severe diverticulitis treated with intravenous antibiotics. Eligible participants will be randomized to either a treatment group receiving a 10-day oral DBT regimen plus conventional therapy or a control group receiving a 10-day placebo regimen plus conventional therapy. The primary outcome will be success in treating diverticulitis: the success rate will be defined as elimination of abdominal pain within 4 days in all patients, and in patients with fever (body temperature ≧ 37.5 °C) on inclusion into this study, fever relief with reduction in body temperature to < 37.5 °C within 3 days. Secondary endpoints will include the number of hospitalization days, changes in inflammatory response (C-reactive protein (CRP), white blood cell (WBC) and neutrophil counts), fever type, number of days before beginning food intake, recurrence rate (observation for 1 year after registration), and adverse event expression rate. Assessments will be performed at baseline and on the day of discharge. The recurrence rate will be recorded at 1 year after registration.Discussion: This study is expected to provide evidence to support the clinical benefits of DBT in the treatment of acute diverticulitis. It may also provide evidence on the efficacy and safety of DBT in the recurrence of acute diverticulitis.Trial Registration: UMIN-CTR: UMIN000027381. Registered on 27 April 2017. https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000031377, and changed to jRCTs041180063, registered on 30 July 2019; as a result of the revision of the domestic law in 2018 in Japan. [ABSTRACT FROM AUTHOR]

Background: As Japan has an aging population, elderly patients with multiple complicating comorbidities have increased in number. The purpose of the present study was to examine the 90-day mortality and reoperation rate after emergency amputation of the lower limbs and to clarify patient characteristics and preoperative comorbidities that are risk factors for reoperations.Methods: This retrospective case study was conducted between January 2005 and December 2017. Ninety-one patients with 108 limbs who had undergone emergency amputation of the lower limbs were included in this study. Baseline data, medical comorbidities, surgical procedures and laboratory data including C-reactive protein (CRP), white blood cells (WBC) and hemoglobin A1c (HbA1c) were evaluated. Outcome measurements were mortality, reoperation rate, and factors associated with reoperation in 90 days and any complication after amputation of the lower limbs.Results: The patients (male/female ratio = 64/27) had a mean age of 64.9 years, a mean WBC count of 16,747/μL, a mean CRP value of 15.6 mg/dL, and a mean HbA1c value of 7.5%. The 90-day mortality rate in the study population was 12.1%. The 90-day reoperation rate was 35.2% (32/91) patients with 32.4% (35/108) limbs. The factor significantly associated with reoperation in 90 days was peripheral arterial disease (PAD) (p = 0.022, HR = 2.75), identified with Cox proportional hazards regression analysis. A total of 41.8% (38/91) patients with 40.7% (44/108) limbs experienced postoperative wound complications. The overall rate of medical complications was 18.7% (17/91) patients with 16.7% (18/108) limbs.Conclusions: This study indicates that the 90-day mortality and reoperation rates after emergency amputation of the lower limbs were high. Furthermore, PAD influences the rate of reoperation in 90 days. However, there was no association between laboratory results or diabetes mellitus and reoperation. These findings will have important implications for the treatment of lower leg amputation and prevention of reoperation. [ABSTRACT FROM AUTHOR]

Background: Severely burned patients often suffer white blood cell and platelet drop following the injury. Though coagulopathy after burn injury have been reported, the association between leukopenia or thrombopenia and mortality is still unrevealed. To determine whether early drastic drops in white blood cells (WBCs) and platelets following injury can be prognostic markers in patients with major burns.Methods: This is a retrospective cohort study setting in a single Burn Center in Japan. Data comprising patients' characteristics and blood cell counts (red blood cells [RBCs], WBCs including neutrophils, monocytes, and lymphocytes, and platelets) over the first 30 days after burn injury were serially collected from patients suffering major burn injury (≥20% TBSA) from January 1, 2006 to December 31, 2015. To determine blood cell counts affecting 60-day mortality, we used multivariable Cox proportional hazard analysis to assess associations between each blood cell count and mortality, adjusting for age and %TBSA as covariates, and evaluated predicted value of the hazard ratio (HR) of death.Results: We enrolled 280 patients. Following burn injury, all blood cell counts were high at admission, then decreased. RBCs diminished progressively and plateaued 2 weeks after injury. WBCs decreased suddenly 2 days after injury, then increased and stabilized. Platelets decreased more rapidly than WBCs to their nadir at 3 days, then continually increased. After covariate adjustment, low RBCs from day 1 (HR: 0.566, 95% C.I. 0.423, 0.759) to day 5 (HR: 0.524, 95% C.I. 0.175, 0.576) were predictors of mortality. Neutrophil count was not a risk factor, but day 3 lymphocyte count (HR: 0.131, 95% C.I. 0.026, 0.646) and day 10 monocyte count (HR: 0.044, 95% C.I. 0.005, 0.396) were risk factors. Low platelet counts from day 3 (HR: 0.545, 95% C.I. 0.300, 0.981) to day 30 following injury were always a predictor of mortality.Conclusions: Early thrombopenia and lymphopenia were independent risk factors for 60-day mortality, and prolonged thrombopenia and monocytopenia were independent risk factors for mortality. These findings might shed light on mechanisms of immune response following severe burns. [ABSTRACT FROM AUTHOR]

Background SF3B1 (splicing factor 3B subunit-1) somatic mutation is specifically detected in myelodysplastic syndrome (MDS) with ring sideroblasts (MDS-RS). We investigated the sensitivity and utility of SF3B1 mutation analysis as a clinical laboratory test. Method Detection limit for SF3B1 mutations by high-resolution melting (HRM) analysis was investigated by plasmid mixture. In 67 MDS patients, we examined the association between SF3B1 mutation and prognostic evaluation using the Revised International Prognostic Scoring System and revalidated MDS classifications based on the revised 4th edition of the WHO classification. Results HRM analysis enabled mutation detection in the 12.5% SF3B1 mutant alleles. SF3B1 mutation was detected in 9 cases, mostly in the low-risk group. Cases of MDS with ring sideroblasts unrelated to SF3B1 mutation were detected in the high-risk group. Two cases were reclassified as MDS-RS after detecting SF3B1 mutation. Conclusions SF3B1 mutation analysis as an initial screening at diagnosis increases the accuracy of prognostic prediction and disease classification. [ABSTRACT FROM AUTHOR]

• There was an outbreak of aseptic meningitis caused by E30 in Kushiro, Japan. • A neutrophil predominance was shown in CSF samples in many patients. • Phylogenetic analysis showed the same cluster. • Genotype of E30 was more closely related to strains in Europe than those in Japan. • Standard precautions are considered essential to prevent the spread of E30 infection. Background: Echovirus 30 (E30) is one of the most common causative agents for aseptic meningitis. Objectives: In the autumn of 2017, there was an outbreak caused by E30 in Kushiro, Hokkaido, Japan. The aim of this study was to characterize this outbreak. Study design: Fifty-nine patients were admitted to the Department of Pediatrics, Kushiro Red Cross Hospital (KRCH) with clinical diagnosis of aseptic meningitis. Among those, 36 patients were finally diagnosed as E30-associated aseptic meningitis by the detection of viral RNA using reverse transcription-polymerase chain reaction (RT-PCR) and/or the evidence of more than four-fold rise in neutralizing antibody (NA) titers in the convalescent phase relative to those in the acute phase. We investigated these 36 confirmed cases. Results: The median age was 6 years (range: 6 months–14 years). The positive signs and symptoms were as follows: fever (100%), headache (94%), vomiting (92%), jolt accentuation (77%), neck stiffness (74%), Kernig sign (29%), and abdominal pain (28%). The median cerebrospinal fluid (CSF) white cell count, neutrophil count, and lymphocyte count were 222/μL (range: 3–1434/μL), 144/μL (range: 1–1269/μL), and 85/μL (range: 2–354/μL), respectively. Although the detected viral genes demonstrated same cluster, they were different from E30 strains observed in Japan between 2010 and 2014. Conclusion: We mainly showed clinical and virological features of the E30-associated aseptic meningitis outbreak that occurred in Kushiro. To prevent further spread of E30 infection, continuous surveillance of enterovirus (EV) circulation and standard precautions are considered essential. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion.Methods: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.Findings: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response.Interpretation: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab.Funding: Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion.Methods: We did an open-label, dose-escalation and dose-expansion phase 1 trial at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years of age in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with HER2-positive breast cancer has been completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.Findings: Between Aug 28, 2015, and Aug 10, 2018, 115 of 118 patients with HER2-positive breast cancer were treated with at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (16 [14%]), white blood cell (ten [9%]), and platelet (nine [8%]) counts. At least one serious treatment-emergent adverse event occurred for 22 (19%) patients. Investigators reported 20 cases of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. One death unrelated to study treatment was due to progressive disease. 66 (59·5%; 95% CI 49·7-68·7) of 111 patients had a confirmed objective response.Interpretation: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted.Funding: Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: The early identification of patients at risk of severe dengue infection (DI) is critical to guide clinical management. There is currently no validated laboratory test which can predict severe complications of DI. The Atypical lymphocyte count (ALC) is a research parameter generated at no extra cost when an automated Full Blood Count (FBC) is performed. The purpose of this study was to assess the association of ALC with the severity of DI. Methods: We prospectively collected data on patients admitted to Nawaloka Hospital Sri Lanka (NH) with DI between December 2016 and November 2017. DI was diagnosed based on a positive Non-structural antigen 1 (NS1) or dengue IgM antibody. ALC (absolute ALC and percentage) data were extracted from the Sysmex XS500i automated full blood count (FBC) analyzer (Sysmex Corporation Kobe, Japan). Clinical data was recorded from medical records and the computerized data base maintained by NH. Results: 530 patients were enrolled. Patients with clinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. Patients who presented with respiratory compromise had statistically significantly higher AL% compared to those without. (AL%; 8.65±12.09 vs 2.17±4.25 [p = 0.01]). Similarly, patients who developed hypotension had higher AL% compared to those who did not suffered from shock (AL%; 8.40±1.26 vs 2.18±4.25 [p = 0.001]). The AL% of dengue patients presenting with bleeding, at 4.07%, is also higher than those without bleeding complications, at 2.15%. There was a significant negative association between platelet count and AL% (p = 0.04). Conclusions: Clinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. AL % at presentation may be predictive of severe DI and future larger prospective longitudinal studies should be done to determine if AL % on admission is predictive of the complications of DI. [ABSTRACT FROM AUTHOR]

Introduction Lung cancer is a malignant tumor with the highest incidence worldwide, and non–small cell lung cancer (NSCLC) accounts for ~85% of all new lung cancer cases. 1 Although surgical techniques and medical treatment have been advanced by leaps and bounds, the prognosis for lung cancer remains poor, with a 5-year survival rate <15%. 2 For inoperable locally advanced patients, radiotherapy and chemotherapy are now the main treatment methods, but there is a lack of precise biomarkers for efficacy and prognosis. Therefore, sensitive and prognostic factors are needed to guide clinical practice. An increasing number of studies have been devoted to explore the relationship between the occurrence and development of cancer and inflammation. The malignant transformation of inflammation as a very complex biological process often requires pathogens, cells, genes, and other factors involved jointly. In March 2011, two professors published an updated review which briefly describes the hot spots and progresses in oncology in the last 10 years and adds four new features on the basis of the original six features. "Tumor Promotion Inflammation" as one of the tumor cell features was known to us. 3 – 7 Peripheral blood total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are signs of systemic inflammatory response, and they are closely related to prognosis of multiple malignant tumors. 8 As TLC, NLR, and PLR can be calculated by using only blood routine results, they have the advantages of being cheaper, more stable, and repeatable. At present, some studies have confirmed their correlation with the prognosis of various tumors, such as gastric cancer, 9 , 10 colorectal cancer, 11 , 12 liver cancer, cholangio carcinoma, 13 breast cancer, 14 and so on. But there are relatively few studies on the correlation of prognosis of patients with advanced NSCLC alone, especially for unresectable patients. So the aims of this study were to identify the prognostic value of TLC, NLR, and PLR in advanced NSCLC patients treated with chemoradiotherapy and whether they could be better prognostic indicators. Patients and methods Patient selection This study was conducted in accordance with the Declaration of Helsinki and was approved by the Committee Board of Shandong Cancer Hospital (Jinan, China). Written informed consent was obtained from all patients. We retrospectively collected patients with advanced NSCLC from 2011 to 2016. The inclusion criteria were: 1) patients were diagnosed as NSCLC by pathologic examination (histology and/or cytology examination); 2) according to the TNM criteria of NSCLC (Union for International Cancer Control, eighth edition), patients were diagnosed with stage IIIA or IIIB; 3) the whole course of radiotherapy was conducted in our hospital; and 4) availability of laboratory data obtained at the same institution before initiation of any curative treatment (radiotherapy, chemotherapy, or both). The exclusion criteria were: 1) had upfront surgery in the past three years; 2) did not complete radiation therapy. All the enrolled patients received standard treatment in our institution, including chemotherapy followed by concurrent chemoradiotherapy, upfront concurrent chemoradiotherapy followed by adjuvant chemotherapy, induction chemotherapy followed by sequential radiotherapy, or concurrent chemoradiotherapy alone. The standard chemotherapies were platinum-based regimens. Finally, 389 advanced NSCLC patients were included in this study. Patients were generally followed up every 3 months for the first 2 years, every 6 months from 3 to 5 years, and every year thereafter. Thoracic computed tomography (CT) and positron emission tomography-CT scans were performed at each follow-up visit, magnetic resonance imaging (MRI) studies or CT scans of the brain were also obtained at every follow-up visit or on the appearance of any neurologic symptoms. The compliance of making CT was satisfactory, but other examinations were not performed in time unless patients have symptoms. Data collection Patient characteristics and hematologic data were obtained from electronic medical records from Shandong Cancer Hospital. Targeted variables included age, gender, Karnofsky Performance Status (KPS) score, smoking status, and laboratory values from pretreatment data of complete blood count (CBC). The most recent CBC data before the initial point of definitive treatment (radiotherapy, chemotherapy, or both) were used. Treatment variables included chemotherapy regimen and dose, radiation technique and dose, receipt of prophylactic cranial irradiation, and receipt of induction or concurrent chemotherapy. Tumor-specific variables included T status, N status, and TNM stage. Variables from CBC included TLC, NLR, and PLR. All the CBC variables were obtained within 3 months before the initial time they received definitive treatment. Statistical analysis Overall survival (OS) was measured from the date of definitive therapy to the date of death from any cause or the date on which the patients were last known to be alive. In order to determine the independent prognostic factors, a multivariate analysis was performed using Cox proportional hazard model. The optimal cutoff value of TLC, NLR, and PLR were determined by a running log-rank test. The two category comparisons were performed by χ2 test or Fisher's exact test. The comparison of continuous variables was performed by t test. P-values reported were bidirectional, and the significant level was at <0.05. All analyses were performed using SPSS statistics 19.0. Ethics approval and consent to participate Due to the retrospective nature of the study, informed consent was waived. The study was approved by the committee of our hospital. Results A total of 389 patients were treated with definitive therapy for unresectable advanced NSCLC in this study; 345 of these patients had neutrophil, lymphocyte, and platelet counts within 1 month before the initiation of definitive therapy, but only 310 had biopsy-proven stage IIIA or IIIB NSCLC. Of these patients, 43 were excluded from this study, 29 for having been initially treated at other hospital or institution, eight for not receiving integrated course of treatment, and six for having had upfront surgery in the last three years. Finally, 267 patients were enrolled in this study; 170 patients had adenocarcinoma, 89 had squamous cell carcinoma, and eight were not specified further than NSCLC. Patient characteristics and hematologic data are shown in Table 1. The median follow-up for all patients was 28 months. Table 1 Patient characteristics Abbreviation s: 3D-CRT, 3-dimensional conformal radiation therapy; Hb, hemoglobin; IMRT, intensity-modulated radiation therapy; IQR, interquartile range; KPS, Karnofsky Performance Status; TLC, total lymphocyte count; WBC, white blood cells. The median time to obtain the indicators of hematology before treatment was 8 days (interquartile range [IQR], 1–12 days). Median baseline value of TLC was 2.47×103/μL (±0.78), NLR was 3.15 (±3.96), and PLR was 143.82 (±91.77). According to receiver operating characteristic (ROC) analysis, the cutoff values of TLC was 2.4 (sensitivity 43%, specificity 56%), NLR was 3.4 (sensitivity 54%, specificity 73%), and PLR was 136.1 (sensitivity 54%, specificity 73%). According to these different cutoff values, patients were divided into two groups for OS analysis. The median OS time for all patients was 18.37 months (IQR 10.3–48.2). In univariate analysis, KPS score ≥70, TNM stage IIIB, higher TLC (≥2.4× 103/μL), lower NLR (<3.4), and lower PLR (<136.1) were all associated with better survival (P<0.05) (Table 2). Table 2 Univariate analysis of factors potentially associated with overall survival Abbreviations: HR, hazard ratio; KPS, Karnofsky Performance Status; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; TLC, total lymphocyte count. From the Kaplan–Meier plots of OS, we can see that patients with higher pretreatment TLC (≥2.4×103/μL) had better OS than patients with lower TLC (<2.4×10 /μL) (21.78 vs 15.66 months, P<0.001) (Figure 1). Inversely, patients with higher pretreatment NLR (≥3.4) and PLR (≥136.1) had worse median OS times than patients with lower NLR (<3.4) and PLR (<136.1) (NLR: 14.13 vs 23.8 months, P<0.001; PLR: 15.49 vs 22.04 months, P<0.001) (Figures 2 and 3). Because TLC, NLR, and PLR have strong collinearity, these factors cannot be tested simultaneously, so they will be tested separately in multivariate analysis. Figure 1 Kaplan–Meier plots of overall survival among patients who received chemoradiotherapy for advanced NSCLC stratified by baseline TLC. Abbreviations: NSCLC, non–small cell lung cancer; TLC, total lymphocyte count. Figure 2 Kaplan–Meier plots of overall survival among patients who received chemoradiotherapy for advanced NSCLC stratified by baseline NLR. Abbreviations: NSCLC, non–small cell lung cancer; NLR, neutrophil-to-lymphocyte ratio. Figure 3 Kaplan–Meier plots of overall survival among patients who received chemoradiotherapy for advanced NSCLC stratified by baseline PLR. Abbreviations: NSCLC, non–small cell lung cancer; PLR, platelet-to-lymphocyte ratio. The final multivariate Cox regression analysis was adjusted for age, KPS score, disease stage, and the CBC values (Table 3). Results indicate that along with the positive effect of KPS score on OS, higher TLC (≥2.4×103/μL) was associated with superior OS (HR 0.49, 95% CI 0.33–0.95, P=0.041). Conversely, higher baseline NLR (≥3.4) and higher PLR (≥136.1) were associated with inferior OS (NLR: HR 1.66, 95% CI 1.05–2.79, P=0.041; PLR: HR 1.67, 95% CI 1.09–2.78, P=0.038). Table 3 Multivariate analysis of factors potentially associated with overall survival Abbreviations: HR, hazard ratio; KPS, Karnofsky Performance Status; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; TLC, total lymphocyte count. Discussion In recent years, studies have shown that systemic inflammatory response and the body's immune system are correlated with tumor progression and prognosis. Inflammatory response may promote tumor metastasis by upregulating cytokines, producing inflammatory mediators, inhibiting cell apoptosis, promoting angiogenesis, and inducing DNA mutations. The invasiveness of cells is not only related to the essential characteristics of tumor cells, but also depends on the microenvironment. Inflammatory cells secrete inflammatory mediators, cytokines, and so on to stimulate the body to produce a series of stress reaction, then excessive inflammatory cells gathered themselves together and ultimately lead to cell oxidative damage and other negative biological effects, which influence the microenvironment of the body. In the end, normal cells are transformed into tumor cells, and the changed microenvironment could accelerate tumor growth, invasion and metastasis process. 15 As for the immune system, under normal circumstances, the body relies on a complete immune mechanism to effectively monitor and reject cancerous cells, so the vast majority of individuals do not develop tumors. If cancer cells proliferate to a certain extent because they evade immune surveillance and rejection for some reason, the occurrence of tumors is inevitable. Lymphocytes are an important part of the immune system and play a key role in immune response to cancer. TLC is closely related to the immune ability of the body and a low lymphocyte count indicates that the body is immunosuppressed. 16 Hasenclever and Diehl first detected that lymphocyte reduction was an adverse prognostic factor for advanced Hodgkin's lymphoma treated with combination chemotherapy, with or without adjuvant radiotherapy. And patients with peripheral blood lymphocyte count of <0.6×109/L had a worse prognosis. 17 Ray-Coquard et al reported a prospective multicenter study, peripheral blood lymphocyte count was an independent prognostic factor of OS and progression-free survival (PFS) in patients with metastatic breast adenocarcinoma treated with chemotherapy, and in patients with diffuse large B-cell lymphoma. 18 NLR represents the state of balance between neutrophils and lymphocytes. The higher NLR is, the more obvious the imbalance state is, that is, the more severe the inflammatory response and the stronger the immune suppression. The mechanism may be that neutrophils and lymphocytes participate in the escape of the tumor's own immune system, thus promoting the occurrence and diffusion of the tumor. 19 Elevated NLR indicates a decrease in T-lymphocyte-mediated anti-tumor response, and the release of inflammatory cytokines by neutrophils can help stimulate the tumor microenvironment and promote tumor metastasis. 20 Ietomi first proposed in 1990 that the progression of malignant tumors was accompanied by increased neutrophils and decreased lymphocytes, and for the first time suggested that NLR may be associated with the prognosis of tumors. 21 And recent studies confirmed that PFS and OS of patients with high NLR were significantly inferior to those with low NLR in patients with advanced NSCLC receiving first-line targeted therapy or chemotherapy. 22 , 23 Most studies suggest that PLR has the similar effect with NLR in predicting the prognosis of cancer patients. The mechanism of poor prognosis caused by elevated PLR may be related to tumor metastasis or lymphocyte reduction associated with increased platelet count in cancer patients. During the immune process, platelets are activated and release a certain amount of growth factors, which are involved in the proliferation and adhesion of tumor cells and thereby promote the occurrence and invasion of tumors. 24 Qiang et al conducted a meta-analysis on the relationship between PLR and lung cancer prognosis. The research showed that high PLR predicted shorter OS and PFS, which were independent risk factors influencing the prognosis of NSCLC patients. 25 In our study we found that in advanced NSCLC patients treated with chemoradiotherapy, higher pretreatment TLC (≥2.4×103/μL) had better OS than patients with lower pretreatment TLC (<2.4×103/μL). Inversely, patients with higher pretreatment NLR (≥3.4) and PLR (≥136.1) had worse median OS times than patients with lower pretreatment NLR (<3.4) and PLR (<136.1). It can be seen that in advanced NSCLC, patients with high TLC and low NLR and PLR can obtain relatively good treatment effect and prognosis, which was consistent with previous research on other tumors by others. Therefore, the detection of TLC, NLR, and PLR before treatment is of certain value in the evaluation of prognosis of patients with advanced NSCLC. However, there are still some limitations in this study. First, this study is a single-center clinical study with only 267 advanced NSCLC patients included. Therefore, a large sample multicenter clinical study is needed to verify the conclusions of this study. Second, this study did not take into account the mutation of EGFR and ALK in patients with advanced NSCLC, because the prognosis of patients receiving targeted therapy was significantly better than that of patients receiving radiotherapy and chemotherapy, which to some extent affected our evaluation of the value of TLC, NLR, and PLR in the prognosis of advanced NSCLC. In subsequent studies, the genetic status of patients should be further examined to exclude the effect of gene or targeted therapy on this result. Finally, the survival time of patients with advanced NSCLC is affected by a variety of factors, the influence of those factors on the survival time should be excluded as far as possible in subsequent studies. Conclusion Advanced NSCLC patients with high TLC and low NLR and PLR can obtain relatively good treatment effect and prognosis. The lymphopenia indicators (TLC, NLR, and PLR) were significant prognostic indicators of survival in advanced NSCLC patients treated with chemoradiotherapy. Acknowledgment The authors would like to express their gratitude to the enrolled patients and to the members of the Shandong Cancer Hospital Affiliated to Shandong University. Disclosure The authors report no conflicts of interest in this work. References 1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. 2. Li N, Xu M, Cai MY, et al. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer Epidemiol. 2015;39(5):763–768. 3. de Martel C, Franceschi S. Infections and cancer: established associations and new hypotheses. Crit Rev Oncol Hematol. 2009;70(3):183–194. 4. Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M. Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell. 2010;17(1):89–97. 5. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. 6. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 7. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70. 8. Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, Mcmillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218–230. 9. Miyamoto R, Inagawa S, Sano N, Tadano S, Adachi S, Yamamoto M. The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long-term outcomes in gastric cancer patients. Eur J Surg Oncol. 2018;44(5):607–612. 10. Kadam PD, Chuan HH. Erratum to: Rectocutaneous fistula with transmigration of the suture: a rare delayed complication of vault fixation with the sacrospinous ligament. Int Urogynecol J. 2016;27(3):505. 11. Zhang J, Zhang HY, Li J, Shao XY, Zhang CX. The elevated NLR, PLR and PLT may predict the prognosis of patients with colorectal cancer: a systematic review and meta-analysis. Oncotarget. 2017;8(40):68837–68846. 12. Chua W, Charles KA, Baracos VE, Clarke SJ. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer. 2011;104(8):1288–1295. 13. Beal EW, Wei L, Ethun CG, et al. Elevated NLR in gallbladder cancer and cholangiocarcinoma–making bad cancers even worse: results from the US Extrahepatic Biliary Malignancy Consortium. HPB. 2016;18(11):950–957. 14. Iimori N, Kashiwagi S, Asano Y, et al. Clinical significance of the neutrophil-to-lymphocyte ratio in endocrine therapy for stage IV breast cancer. In Vivo. 2018;32(3):669–675. 15. Tazzyman S, Barry ST, Ashton S, et al. Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. Int J Cancer. 2011;129(4):847–858. 16. von Bernstorff W, Voss M, Freichel S, et al. Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res. 2001;7(3 Suppl):925s–932s. 17. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med. 1998;339(21):1506–1514. 18. Ray-Coquard I, Cropet C, van Glabbeke M, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009;69(13):5383–5391. 19. Motomura T, Shirabe K, Mano Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58(1):58–64. 20. Teramukai S, Kitano T, Kishida Y, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer. 2009;45(11):1950–1958. 21. Ietomi K. A study on the role of granulocytes in carcinoma-bearing hosts--G/L ratio as a new host indicator. Nihon Gan Chiryo Gakkai Shi. 1990;25(3):662–671. 22. Lin GN, Peng JW, Liu PP, Liu DY, Xiao JJ, Chen XQ. Elevated neutrophil-to-lymphocyte ratio predicts poor outcome in patients with advanced non-small-cell lung cancer receiving first-line gefitinib or erlotinib treatment. Asia Pac J Clin Oncol. 2017;13(5):e189–e194. 23. Berardi R, Rinaldi S, Santoni M. Prognostic models to predict survival in patients with advanced non-small cell lung cancer treated with first-line chemo- or targeted therapy. Oncotarget. 201;7(18):26916–2624. 24. Majeti BK, Lee JH, Simmons BH, Shojaei F. VEGF is an important mediator of tumor angiogenesis in malignant lesions in a genetically engineered mouse model of lung adenocarcinoma. BMC Cancer. 2013;13:213–216. 25. Qiang G, Liang C, Xiao F, et al. Prognostic significance of platelet-to-lymphocyte ratio in non-small-cell lung cancer: a meta-analysis. Onco Targets Ther. 2016;9:869–876. [ABSTRACT FROM AUTHOR]

Introduction To provide target values for the manufacturers' survey of the Japanese Society for Laboratory Hematology ( JSLH), accurate standard data from healthy volunteers were needed for the five-part differential leukocyte count. To obtain such data, JSLH required an antibody panel that achieved high specificity (particularly for mononuclear cells) using simple gating procedures. We developed a flow cytometric method for determining the differential leukocyte count ( JSLH-Diff) and validated it by comparison with the flow cytometric differential leukocyte count of the International Council for Standardization in Haematology ( ICSH-Diff) and the manual differential count obtained by microscopy (Manual-Diff). Methods First, the reference laboratory performed an imprecision study of JSLH-Diff and ICSH-Diff, as well as performing comparison among JSLH-Diff, Manual-Diff, and ICSH-Diff. Then two reference laboratories and seven participating laboratories performed imprecision and accuracy studies of JSLH-Diff, Manual-Diff, and ICSH-Diff. Simultaneously, six manufacturers' laboratories provided their own representative values by using automated hematology analyzers. Results The precision of both JSLH-Diff and ICSH-Diff methods was adequate. Comparison by the reference laboratory showed that all correlation coefficients, slopes and intercepts obtained by the JSLH-Diff, ICSH-Diff, and Manual-Diff methods conformed to the criteria. When the imprecision and accuracy of JSLH-Diff were assessed at seven laboratories, the CV% for lymphocytes, neutrophils, monocytes, eosinophils, and basophils was 0.5~0.9%, 0.3~0.7%, 1.7~2.6%, 3.0~7.9%, and 3.8~10.4%, respectively. More than 99% of CD45 positive leukocytes were identified as normal leukocytes by JSLH-Diff. Conclusions When JSLH-Diff method were validated by comparison with Manual-Diff and ICSH-Diff, JSLH-Diff showed good performance as a reference method. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL), which is difficult to cure. In Japan, a nationwide HTLV-1 screening test in pregnant women has been recommended since 2011. A 30-year-old woman was diagnosed as being an HTLV-1 carrier in her previous pregnancy. During the current pregnancy, she had persistent fever and cough. Although she had treatment with antibiotics, peripheral white blood cell count remained high, with an abnormal lymphocyte count. Given that she was an HTLV-1 carrier, she was diagnosed with unfavorable chronic ATL (aggressive ATL) at 12 weeks gestation. After pregnancy termination, her ATL status became favorable chronic ATL (indolent ATL). Therefore, watchful waiting was performed until disease progression. This is the first case report of chronic ATL in early pregnancy, in a woman already diagnosed as an HTLV-1 carrier on screening test. [ABSTRACT FROM AUTHOR]

In previous studies, we have demonstrated that Tokishakuyakusan (TJ-23) can prolong the survival of allogeneic cardiac grafts and induce regulatory T cells. In this study we investigated the effects of Paeoniae radix and Cnidii rhizoma, two components of TJ-23, on alloimmune responses in a murine cardiac transplantation model and whether the two agents have synergistic effect. CBA mice underwent transplantation of a C57BL/6 heart and received oral administration of 2 g/kg/day of Paeoniae radix, Cnidii rhizoma, or the mixture of two agents from the day of transplantation until 7 days afterward. Naïve CBA mice rejected C57BL/6 cardiac graft acutely (median survival time (MST): 7 days). Paeoniae radix and Cnidii rhizoma prolonged C57BL/6 allograft survival (MSTs: 13.5 and 15.5 days, resp.). However, the mixture of two agents prolonged C57BL/6 allograft survival indefinitely (MST > 100 days). Secondary CBA recipients given whole splenocytes fromprimary combination-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MST: 33 days). Flow cytometry studies showed that the CD4+CD25+Foxp3+ regulatory cell population was increased in combination-treated recipients. Combination of Paeoniae radix and Cnidii rhizoma induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4+CD25+Foxp3+ regulatory cells in our model. [ABSTRACT FROM AUTHOR]

Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation This study aimed to investigate the safety and feasibility of physical therapy in cytopenic patients undergoing allogeneic haematopoietic stem cell transplantation (allo- HSCT), and to investigate the effect of physical therapy on physiological functions and quality of life ( QOL) in allo- HSCT patients. The study cohort included 321 patients who underwent allo- HSCT. To investigate the safety and feasibility of physical therapy during cytopenia, patients were assigned to the physical therapy group ( n = 227) or the control group ( n = 94). To determine the effects of physical therapy, patients were divided according to the frequency with which they underwent physical therapy ( n = 51 per group). Handgrip strength, knee extensor strength and a 6-min walk test were used as measures of physiological function. Short-Form 36 was used to assess QOL. The physical therapy group had higher rate of achieving engraftment and lower death rate than the control group ( P < 0.05). After HSCT, the high-frequency physical therapy group showed significantly less decline than the low-frequency physical therapy group with respect to physical functioning of QOL ( P < 0.01). Physical therapy is quite beneficial and can be performed safely and feasibly in cytopenic patients during allo- HSCT. [ABSTRACT FROM AUTHOR]

Background Granulocyte colony-stimulating factor administration is an important component of supportive therapy in chemotherapy-induced leukopenia. Although patient response to granulocyte colony-stimulating factor administration is known to vary, the factors responsible for poor response have not been identified. Objective To identify the predictors of the responses of patients with solid tumors to granulocyte colony-stimulating factor. Setting A 600-bed university hospital offering secondary and tertiary care in Japan. Methods This retrospective cohort study examined the response of 181 patients with solid tumors who were administered prophylactic granulocyte colony-stimulating factor for the first time after they developed severe grade 3/4 leukopenia (white blood cell count <2,000 × 10/L) because of adjuvant or neoadjuvant chemotherapy. The granulocyte colony-stimulating factor response was defined as the length of the leukocyte recovery period, which was assessed as the period within which the normal white blood cell count (white blood cell count >3,000 × 10/L) is reached after the first dosage of granulocyte colony-stimulating factor. After classification of the patients as either poor or normal granulocyte colony-stimulating factor responders according to the confidence interval of the recovery period, their characteristics were compared. Main outcome measure The time for recovery to normal white blood cell count was 2-7 days (90 % confidence interval), and the cutoff value for differentiating poor responders ( n = 14) from normal responders ( n = 167) was 8 days. Univariate analysis identified previous radiotherapy, number of chemotherapy courses, high granulocyte colony-stimulating factor dosage, and hypoalbuminemia to be significantly associated with granulocyte colony-stimulating factor response. Multivariate analysis identified undergoing four or more chemotherapy courses (odds ratio = 5.09; 95 % confidence interval, 1.14-22.71) and heart failure (odds ratio = 5.96; 95 % confidence interval, 1.09-32.57) to be significantly associated with poor granulocyte colony-stimulating factor response. Conclusions Undergoing four or more chemotherapy courses and heart failure are independent risk factors for poor response to granulocyte colony-stimulating factor. These findings may help prevent the complications of leukopenia during chemotherapy and highlight the need to develop better strategies for preventing and treating infectious disease in patients undergoing granulocyte colony-stimulating factor administration. [ABSTRACT FROM AUTHOR]

Infection with a high-risk human papillomavirus (HPV) is established as a major risk factor for cervical cancer. In Japan, eight HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58) confer a much higher risk of cervical cancer and its immediate premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN 3]) than do other high-risk and the low-risk HPV types. However, only a small fraction of infected women develop CIN 3 or invasive cervical cancer, suggesting the involvement of additional cofactors in cervical carcinogenesis. A multicenter prospective cohort study of Japanese women with low-grade cervical abnormalities has demonstrated that tobacco smoking is significantly associated with an increased risk of persistent low-grade cervical lesions, while the presence of human leukocyte antigen Class II DRB1*1302 protects against progression to CIN 3. Understanding the epidemiology of HPV infections and cervical cancer may improve prevention and lead to novel clinical management strategies for cervical precursor lesions. Viral and host factors that affect the risk of cervical cancer are discussed in this review. [ABSTRACT FROM AUTHOR]

The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988–2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5–5.2, 5.3–6.3, or ≥6.4 × 103 cells/μL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection. [ABSTRACT FROM PUBLISHER]