An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.

A case of pyogenic spondylitis caused by Paludibacteriumpurpuratum.

Paludibacterium purpuratum was first reported as a Gram stain-negative, curved, rod-shaped bacterium isolated from a wetland soil in 2016. We report the first case in the world, to our knowledge, of pyogenic spondylitis caused by P. purpuratum. The patient, a 78-year-old man, came to our hospital complaining chiefly of fever and pain in the left knee. He did not complain of low back pain at the time of examination, although increased low back pain was observed for the first time after admission. Magnetic resonance imaging of the lumbar spine and percutaneous needle biopsy at the L2/L3 disc level were performed, and pyogenic spondylitis was diagnosed. A curved, Gram stain-negative rod was detected in the blood culture obtained at admission that was identified as P. purpuratum by 16S rDNA gene analysis.

Clinical practice guidelines for the management of children with mother-to-child transmitted hepatitis C virus infection.

BACKGROUND: The first guidelines for care of pregnant women carrying the hepatitis C virus (HCV) and their infants were published in 2005 in Japan. Since then, evidence has gradually accumulated worldwide regarding the natural course and treatment of this condition and, especially in recent years, treatment for chronic hepatitis C in adult patients has made great progress. However, the clinical practice policy for children has not been standardized, and new clinical practice guidelines for children with mother-to-child (MTC) transmitted HCV infection have become necessary. METHODS: In the development of the current guideline, we requested cooperation from The Japanese Society for Pediatric Infectious Diseases, The Japan Society of Hepatology, and the Japan Society of Obstetrics and Gynecology. The committee members were recommended and approved by each society to participate in developing the guidelines. The guideline was also created in accordance with the Minds Guide for Practice Guideline Development. The statements were prepared by consensus-building using the Delphi method, based on the comprehensively searched academic papers and guidelines. These articles were retrieved through searching the PubMed, Cochrane Library, and the Igaku Chuo Zasshi databases. RESULTS: Eight clinical questions (CQs) with clinical statements were developed regarding etiology (CQs 1-3), diagnosis (CQs 4 and 5), and treatment (two CQs 6 and 7). In each statement, the consensus rate, evidence level, and recommendation level were determined. CONCLUSION: The guidelines will be helpful in the management of children with hepatitis C MTC transmission.

A nationwide survey on central nervous system multiple myeloma in Japan: analysis of prognostic and treatment factors that impact survival.

This nationwide multicentre retrospective study was performed to analyze clinical features that predict the prognosis of central nervous system invasion in multiple myeloma (CNS-MM, approximately 1% of MM). Overall, of the 77 adult patients with CNS-MM identified between 2005 and 2016, those diagnosed at MM diagnosis (n = 3) had longer overall survival (OS) than those diagnosed at relapse (n = 74; median: 48·5 vs 2·7 months). Therefore, we compared the relapsed MM with CNS-MM in patients with any treatment (n = 60). Multivariate analyses revealed that lenalidomide treatment [hazard ratio (HR) 0·27, P = 0·003], intrathecal chemotherapy (IT; HR 0·54, P = 0·05), and radiation therapy (RTx; HR 0·33, P < 0·001) for CNS-MM had a positive effect on longer OS. These factors were used to develop a scoring system combining the number of treatments with lenalidomide, IT, and RTx (0, 1, 2, 3). The OS of CNS-MM patients was stratified based on these factors, with a median OS of 1·1, 4·5, and 7·5 months for patients with zero, one, two to three favourable features, respectively (0 vs 1, P = 0·0002; 1 vs 2-3, P = 0·08). Multimodal treatment including lenalidomide in addition to conventional IT and RTx can improve OS.

Tumor-to-tumor metastasis of diffuse large B cell lymphoma to gastric adenocarcinoma via CXCL12 (SDF-1)/CXCR4 axis: a case report.

BACKGROUND: Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma. CASE PRESENTATION: A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission. CONCLUSIONS: This patient's case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma.

[Successful preoperative replacement of prothrombin with prothrombin complex concentrate for Prothrombin Himi].

Dysprothrombinemia is the rarest inherited bleeding disorder that is characterized by a decrease in the prothrombin activity, but normal antigen levels. In this study, we report the case of a compound heterozygote of two mutations in prothrombin; Met337Thr and Arg388His, which has previously been identified as "Prothrombin Himi." A systemic blood coagulation evaluation revealed a prolonged prothrombin time (39%) and activated partial thromboplastin (64.4 sec), with an isolated severe decrease in the prothrombin activity (8.6%). Preoperative replacement of prothrombin with prothrombin complex concentrate, PPSB-HT "Nichiyaku," successfully prevented abnormal postoperative bleeding after laparoscopic hysterectomy for cervical cancer. This is the second reported case of Prothrombin Himi.

[Successful treatment of myelomatous pleural effusion with daratumumab administration before autologous peripheral stem cell transplantation].

A 50-year-old woman diagnosed with surgically resected plasmacytoma of the ovaries and uterus presented with another plasmacytoma in the pancreas with positive uptake on positron emission tomography (PET) and massive right pleural effusion with plasma cell infiltration (myelomatous pleural effusion). After four courses of the bortezomib, lenalidomide, and dexamethasone regimen as induction therapy, partial response was achieved with reduced myelomatous pleural effusion and negative uptake on PET in the pancreatic plasmacytoma. However, soon after she received bortezomib and high-dose cyclophosphamide for peripheral blood stem cell harvesting, right myelomatous pleural effusion increased without signs of heart failure or infection. Because of the progressive nature of the disease, daratumumab was introduced as 2 courses of daratumumab, lenalidomide, and dexamethasone (DLd) regimen, after which she achieved complete response with disappearance of the pleural effusion. After autologous peripheral blood stem cell transplantation, she received an additional four courses of the DLd regimen as consolidation therapy. She maintained relapse-free survival for two years with maintenance therapy containing daratumumab and dose-reduced lenalidomide. Our case may suggest the usefulness of daratumumab before autologous peripheral stem cell transplantation for relapsed/refractory myelomatous pleural effusion.

Growth impairment in individuals with citrin deficiency.

Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.

In vitro Evaluation of Solute Removal Characteristics in Intermittent Infusion Hemodiafiltration.

BACKGROUND: In a typical hemodialysis (HD) session, excessive water removal sometimes induces peripheral circulatory failure and a rapid drop in blood pressure. Intermittent infusion hemodiafiltration (I-HDF), a new modality of dialysis therapy, has been developed to improve peripheral circulation by repeated intermittent infusion of dialysate during an HD session. In a typical I-HDF session, we infuse a volume of 200 mL of ultrapure dialysate by backfiltration at 150 mL/min every 30 min. The same volume is alternately removed from the patient's blood by filtration at a constant rate after each infusion. However, solute removal characteristics in I-HDF have not been clarified previously. We therefore conducted an in vitro study to investigate the characteristics of solute removal and the factors affecting such removal. SUMMARY: We used human plasma to evaluate the effects of filtration (QF)/infusion (QI) flow rates on solute clearance (CL) and to estimate the time-averaged solute CL (TACL) values. The CL values for all solutes decreased with increasing QI. For small molecules such as urea, the CL values predominantly decreased with increasing QI because of decreasing diffusive transport. For medium and large solutes such as ß2 microglobulin or larger, CL values predominantly increased with increasing QF because of increasing convective transport. However, the effects of these changes on TACL values were small compared with the CL value in a typical HD session because of the alternate filtration and infusion in I-HDF. Key Messages: Solute removal characteristics in I-HDF do not differ significantly from those in conventional HD treatment.

The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma.

Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.

Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition.

Genetic amplification, overexpression, and increased signaling from the epidermal growth factor receptor (EGFR) are often found in oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed effects of cetuximab in control of EGF-driven malignant traits of OSCC cells. EGF stimulation promoted progression level of mesenchymal traits in OSCC cells, which were attenuated by cetuximab but incompletely. We pursued a potential mechanism underlying such incomplete attenuation of OSCC malignant traits. Cetuximab promoted secretion of EGFR-EVs by OSCC cells and failed to inhibit EGF-driven secretion of EGFR-EVs. Cetuximab was also found to be robustly secreted with the EGFR-EVs by the OSCC cells. Thus, EGF promotes the level of mesenchymal traits of OSCC cells and secretion of EGFR-EVs, which involve cetuximab resistance.

Suppression of hepatitis B surface antigen production by combination therapy with nucleotide analogues and interferon in children with genotype C hepatitis B virus infection.

AIM: Sustained suppression of hepatitis B surface antigen (HBsAg) production after interferon (IFN) treatment has not been reported for children with genotype C chronic hepatitis B virus (HBV) infection, which is prevalent in Asia. Among children with hepatitis B envelope antigen-positive genotype C chronic HBV infection, we compared the efficacy of combination therapy with nucleotide analogues and IFN-α in 11 children with 12 historical cases treated with IFN monotherapy. METHODS: The combination of lamivudine and conventional IFN-α was introduced for the first three patients; the other eight patients were treated with entecavir and pegylated IFN. RESULTS: Demographic factors as well as baseline HBsAg titers and HBV-DNA levels were similar between the two groups. In the combination therapy group, viral loads were suppressed in 9/11 to below 4.0 log copies/mL both at the end of the therapy (EOT) and at 6 months after EOT. In contrast, in the IFN monotherapy group, suppression of viral loads was observed in 2/12 and 3/12 at EOT and at 6 months after EOT, respectively. In the combination therapy group, HBsAg titers dropped from 4.03 at pretreatment to 2.91 log IU/mL at 6 months after EOT with 4/11 showing a drop to below 1000 IU/mL (one patient achieved HBsAg clearance). In contrast, the amount of HBsAg did not change during the corresponding periods in the IFN monotherapy group. CONCLUSIONS: Our preliminary results suggest that combination therapy might be effective in the suppression of HBsAg production as well as HBV-DNA production for children with genotype C chronic HBV infection.

Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan.

BACKGROUND AND AIM: Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. METHODS: We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. RESULTS: Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 µg/day and between 1 and 3 µg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6 months. CONCLUSIONS: To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3 µg/kg/day and under 75 µg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

Cholesterol ester storage disease with a novel LIPA mutation (L264P) that presented massive hepatomegaly: A case report.

Cholesterol ester storage disease (CESD) is an autosomal recessive disorder caused by deficient lysosomal acid lipase (LAL) activity, resulting in cholesteryl ester (CE) accumulation. CESD patients have liver disease associated with mixed dyslipidemia leading to liver failure. We here report the case of an 11-year-old male CESD patient with a novel mutation who had the chief complaint of massive hepatomegaly. The patient's liver reached to his pelvis, and his spleen was 2 cm below the costal margin. The patient had elevated serum liver enzymes and mixed dyslipidemia. The liver biopsy tissue showed characteristic CESD pathology, which included microvesicular steatosis, mild fibrosis and foamy macrophages. Electron microscopy showed a remnant cleft of CE crystals, and dried blood spot testing showed reduced LAL activity. We identified compound heterozygous mutations in the LIPA gene in this patient, namely, c.607G>C and c.791T>C. The former mutation was previously reported only in a Japanese patient, whereas the latter mutation is novel. The findings of this study suggest that LIPA gene mutations in Japanese CESD patients are different from those in Western patients. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed, and thus the possibility of CESD should be considered in patients with hepatosplenomegaly and dyslipidemia.

Peginterferon Therapy in Children With Chronic Hepatitis C: A Nationwide, Multicenter Study in Japan, 2004-2013.

OBJECTIVES: The aim of the present study was to review the medical treatment of Japanese children and adolescents with chronic hepatitis C in the past 10 years. METHODS: This nationwide, multicenter study evaluated patients who were younger than 18 years of age when diagnosed with chronic hepatitis C virus (HCV) infection and were treated with pegylated interferon (PEG-IFN) monotherapy or PEG-IFN/ribavirin (RBV) combination therapy between 2004 and 2013. The subjects' median age was 10 (3-18) years, with a male to female ratio of 52:50 and a genotype-1 to genotype-2 ratio of 45:57. Among the 102 patients, 18 received PEG-IFN monotherapy and 84 received PEG-IFN/RBV combination therapy. The IL28B genotype polymorphism was analyzed in patients infected with genotype-1. RESULTS: In patients with HCV genotype-1 infections, sustained virological response (SVR) rates obtained by PEG-IFN monotherapy and by PEG-IFN/RBV combination therapy were 100% (2/2) and 72% (31/43), respectively. In patients with HCV genotype-2 infections, SVRs were 75% (12/16) and 100% (41/41), respectively. In 32 genotype-1 patients available for the IL28B genotype (rs8099917), SVR was achieved in more patients in the IL28B major allele group than in the minor allele group (15/17 vs 7/15, P = 0.021) after PEG-IFN/RBV combination therapy. The frequencies of adverse events were similar between the treatment regimens. CONCLUSIONS: Overall, both therapies showed encouraging results, and were reasonably safe in children and adolescents with chronic hepatitis C. The IL28B genotype was useful for predicting the treatment response to PEG-IFN/RBV combination therapy in this cohort.

Effects of protein leakage on online monitoring of ultraviolet absorbance in spent dialysate.

Recently, dialysis dose during hemodialysis treatment has been monitored by measuring the concentration of urea-like solutes such as uric acid in spent dialysate using near-ultraviolet (UV) light. The measured absorbance has been shown to have a good correlation with the time course of urea level even if the absorbance does not result from urea. However, the spent dialysate includes various solutes such as uric acid and albumin as well as unknown solutes that also absorb UV light. The effects of these solutes on monitored absorbance values are not clear. In this study, we evaluated the effect of protein leakage on data from the UV monitoring of spent dialysate. Albumin leakage in the earlier stage of the treatment may result in an increase in absorbance greater than the expected value. As a result, there is a possibility that the dialysis dose is overestimated. On the other hand, the quantity of albumin leakage could be estimated by a spent dialysate monitoring technique combined with a protein removal process.

Mitochondrial respiratory chain complex I deficiency causes intractable gastrointestinal symptoms.

We report the case of a 13-month-old girl with frequent vomiting, intractable diarrhea, hyperlactatemia, and liver dysfunction. Although the symptoms were treatment resistant, enteral nutrition formula containing medium-chain triglycerides reduced the weight loss, vomiting, and diarrhea. Immunostaining of mitochondrial respiratory chain (MRC) complexes of the colonic mucosa confirmed the diagnosis of MRC complex I deficiency. This case shows that this disease should be included in the differential diagnosis of hyperlactatemia and intractable, cryptogenic gastrointestinal symptoms. In addition, the mucosa of the affected gastrointestinal organ should be analyzed on immunostaining or electron microscopy for MRC complexes.