Recurrent distal cholangiocarcinoma and humoral hypercalcemia of malignancy: report of a rare case and literature review.

A 61-year-old Japanese woman presented with epigastric pain and jaundice. Imaging showed the presence of primary distal cholangiocarcinoma (DCC). A subtotal stomach-preserving pancreaticoduodenectomy was performed, followed by chemotherapy using S-1. However, second-line chemotherapy with gemcitabine and cis-diamminedichloroplatinum was required for the treatment of hepatic metastasis of the DCC 3 months following the surgery. Nine months after the surgery, the serum calcium and parathyroid hormone-related peptide concentrations were high, at 16.5 mg/dL and 28.7 pmol/L, respectively, which suggested the presence of humoral hypercalcemia of malignancy (HHM) secondary to the DCC. Moreover, marked leukocytosis, with a white blood cell count of 40,400/µL, was also present. The patient died 11 months after the diagnosis of DCC. Because hypercalcemia of malignancy is associated with a poor prognosis, and HHM and leukocytosis caused by DCC are very rare, we have presented the present case in detail and provide a review of the existing literature.

Comparison of outcomes after plasma therapy or eculizumab in pediatric patients with atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare and life-threatening disease. For decades, plasma therapy was used to manage patients with aHUS. Since eculizumab, a recombinant humanized anti-C5 monoclonal antibody, was approved for treatment of aHUS, it has been used to treat patients with aHUS. Here, we examined the effectiveness of eculizumab and plasma therapy, respectively in the treatment of pediatric patients with aHUS. METHODS: Data were collected from questionnaires sent to 75 institutions known to be treating thrombotic microangiopathy (TMA). RESULTS: A total of 24 patients were evaluable, in which no recurrence of TMA was reported at last observation. There were four therapy groups: two patients receiving supportive therapy, one receiving plasma therapy alone, 17 switching from plasma therapy to eculizumab (therapy switched), and four receiving eculizumab alone. Among 17 patients of therapy-switched group, only one patient achieved complete remission at the end of plasma therapy, 15 patients achieved complete remission after eculizumab initiation, and two patients reached end-stage renal disease. Adverse events were reported in nine cases; among these, meningococcal infection, anaphylaxis, and eculizumab-related infusion reaction were reported among those treated with eculizumab. CONCLUSION: This study provided substantial evidence from a Japanese population that the conversion from plasma therapy to eculizumab therapy should be considered in patients with aHUS who show an incomplete response to plasma therapy. In addition, although no new safety events were detected, careful attention should be paid to meningococcal infection, eculizumab-related infusion reactions and allergic reactions with administration of eculizumab.

Serum sodium level is inversely correlated with body temperature in children.

BACKGROUND: Several studies have demonstrated that non-osmotic antidiuretic hormone activity contributes to the development of hyponatremia in children with common febrile diseases. However, the relationship between hyponatremia and body temperature has remained unclear. We therefore examined this relationship in children with common diseases. METHODS: In this retrospective case study based on a chart review, 1,973 children presenting with acute illnesses at Hirakata City Hospital between November 2008 and October 2009, and for whom blood test data were available, were enrolled. The median age of this cohort was 2.7 years and the mean serum sodium concentration was 136.4 mEq/L; 454 patients showed hyponatremia (<135 mEq/L). The patients were classified into four groups on the basis of body temperature, <37 °C, 37 °C (37.0-37.9 °C), 38 °C (38.0-38.9 °C) and ≥39 °C, and their serum sodium concentration was compared. RESULTS: The mean sodium level was significantly lower in febrile (135.9 mEq/L) than in non-febrile (138.5 mEq/L) patients. The mean serum sodium levels in the four temperature groups were, in ascending order, 138.5 mEq/L (95% CI, 138.3-138.8 mEq/L), 137.3 mEq/L (137.1-137.5 mEq/L), 136.1 mEq/L (135.8-136.3 mEq/L) and 134.6 mEq/L (134.4-134.9 mEq/L), respectively. The serum sodium level in each individual temperature range became significantly lower as body temperature increased (P < 0.001). CONCLUSIONS: There is a clear inverse correlation between serum sodium level and body temperature in children with common febrile diseases, and fever may play an important role in this relationship.

Locally advanced anorectal malignant melanoma in septuagenarian patient treated by laparoscopic abdominoperineal resection: A case report.

INTRODUCTION: Anorectal malignant melanoma (ARMM) is a rare disease with a poor prognosis. In cases involving locally advanced disease, the treatment strategy is difficult, especially in octogenarian patients, because the prognosis is poor, despite the corresponding decrease or loss of the anal function. PRESENTATION OF CASE: A 78-year-old woman was admitted to a local hospital with chief complaints of severe anal discomfort due to an egg-sized tumor that was protruding out of the anus and melena. A diagnosis of ARMM was confirmed based on the examination of biopsy specimens and imaging study showed swollen lymph nodes on the dorsal side of the middle rectum and left internal iliac lymph nodes. Laparoscopic abdominoperineal resection with left lateral lymph node dissection was performed. The examination of the resected specimen revealed two polypoid tumors with a maximum diameter of 38 mm and 14 mm with a metastatic lymph node of 62 mm in the mesorectum. The postoperative course was uneventful. Relapse and local recurrence free survival without any complaints was obtained for more than 12 months. DISCUSSION: With respect to locoregional disease control, it has been reported that abdominoperineal resection can obtain better control of local disease in comparison to local resection. Laparoscopic surgery is advantageous in its facilitation of an early postoperative recovery for elderly patient. CONCLUSION: Laparoscopic abdominoperineal resection may control locoregional disease and improve the patient's QOL with early postoperative recovery. -even in septuagenarian patients-may become a treatment strategy for advanced ARMM.

Correction to: A nationwide survey on clinical practice patterns and bleeding complications of percutaneous native kidney biopsy in Japan.

In the original publication, some errors have been found in the alignment of Table 9. The corrected table is given below.

A nationwide survey on clinical practice patterns and bleeding complications of percutaneous native kidney biopsy in Japan.

BACKGROUND: Practice patterns and bleeding complications of percutaneous native kidney biopsy (PNKB) have not recently been investigated and the Japanese Society of Nephrology performed a nationwide questionnaire survey in 2018. METHODS: The survey consisted of nine sections about PNKB: (1) general indications; (2) indications for high-risk patients; (3) informed consent; (4) pre-biopsy evaluation; (5) procedures; (6) sedation; (7) post-biopsy hemostasis, bed rest, and examinations; (8) bleeding complications; and (9) specimen processing. A supplementary survey examined bleeding requiring transcatheter arterial embolization (TAE). RESULTS: Overall, 220 directors of facilities (nephrology facility [NF], 168; pediatric nephrology facility [PF], 52) completed the survey. Indications, procedures, and monitoring protocols varied across facilities. Median lengths of hospital stay were 5 days in NFs and 6 days in PFs. Gauge 14, 16, 18 needles were used in 5%, 56%, 33% in NFs and 0%, 63%, 64% in PFs. Mean limits of needle passes were 5 in NFs and 4 in PFs. The bed rest period was 16-24 h in 60% of NFs and 65% of PFs. Based on 17,342 PNKBs, incidence rates of macroscopic hematuria, erythrocyte transfusion, and TAE were 3.1% (NF, 2.8%; PF, 6.2%), 0.7% (NF, 0.8%; PF, 0%), and 0.2% (NF, 0.2%; PF, 0.06%), respectively. Forty-six percent of facilities processed specimens all for light microscopy, immunofluorescence, and electron microscopy, and 21% processed for light microscopy only. Timing of bleeding requiring TAE varied among PNKB cases. CONCLUSION: Wide variations in practice patterns of PNKB existed among facilities, while PNKBs were performed as safely as previously reported.

Efficacy of a mitochondrion-targeting agent for reducing the level of urinary protein in rats with puromycin aminonucleoside-induced minimal-change nephrotic syndrome.

BACKGROUND: Oxidative stress is a major factor responsible for minimal-change nephrotic syndrome (MCNS), which occurs most commonly in children. However, the influence of oxidative stress localized to mitochondria remains unclear. We examined the effect of a mitochondrion-targeting antioxidant, MitoTEMPO, in rats with puromycin aminonucleoside (PAN)-induced MCNS to clarify the degree to which mitochondrial oxidative stress affects MCNS. MATERIALS AND METHODS: Thirty Wistar rats were divided into three groups: normal saline group (n = 7), PAN group (n = 12), and PAN + MitoTEMPO group (n = 11). Rats in the PAN and PAN + MitoTEMPO groups received PAN on day 1, and those in the PAN + MitoTEMPO group received MitoTEMPO on days 0 to 9. Whole-day urine samples were collected on days 3 and 9, and samples of glomeruli and blood were taken for measurement of lipid peroxidation products. We also estimated the mitochondrial damage score in podocytes in all 3 groups using electron microscopy. RESULTS: Urinary protein excretion on day 9 and the levels of lipid peroxidation products in urine, glomeruli, and blood were significantly lower in the PAN　+　MitoTEMPO group than in the PAN group (p = 0.0019, p = 0.011, p = 0.039, p = 0.030). The mitochondrial damage score in podocytes was significantly lower in the PAN　+　MitoTEMPO group than in the PAN group (p <0.0001). CONCLUSIONS: This mitochondrion-targeting agent was shown to reduce oxidative stress and mitochondrial damage in a MCNS model. A radical scavenger targeting mitochondria could be a promising drug for treatment of MCNS.

Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study examined the epidemiological characteristics of pediatric patients with TMA classified according to etiology. METHODS: The survey evaluated 258 Japanese pediatric patients diagnosed with TMA between 2012 and 2015. RESULTS: The primary diseases responsible for TMA were categorized as TTP (15 cases), Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) (166 cases), atypical HUS (aHUS) (40 cases), and secondary TMA (27 cases). The remaining 10 cases were unable to be classified to one of the four categories of the primary disease. Renal replacement therapy was required in the acute phase in 103 patients with TMA, including 65 with STEC-HUS, 22 with aHUS, two with TTP, 10 with secondary TMA, and four unclassified cases. The last observational findings were normal renal function in 95 patients and chronic kidney disease (CKD) stage 1 in 62. For 31 patients, chronic renal insufficiency (CKD stage 2-5) persisted, including four patients with end-stage kidney disease (CKD stage 5). Seventeen patients suffered recurrence of TMA, and eight patients died. CONCLUSION: This study clarified differences in the relative proportions of primary diseases between patients from Japan and North America and Europe. The difference may be attributable to the lower estimated incidence of STEC-HUS in Japan.

A case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis in a pediatric patient with nephrotic syndrome
.

INTRODUCTION: Glucocorticoid therapy has a number of adverse effects, among which osteoporosis and bone fracture can be major complications. Immunosuppressive therapy for nephrotic syndrome is effective and can help to reduce the cumulative dose of glucocorticoids. Therefore, for this reason, the number of patients with nephrotic syndrome who develop glucocorticoid-related osteoporotic compression fracture is decreasing. Here we describe a pediatric case of multiple vertebral compression fractures due to glucocorticoid-induced osteoporosis during treatment for nephrotic syndrome. CASE PRESENTATION: A 12-year-old boy with nephrotic syndrome was treated with the standard corticosteroid regimen stipulated by the International Study of Kidney Disease in Children (ISKDC). Although he achieved complete remission, he suffered two episodes of relapse, and after the second such episode, the disease became resistant to the steroid therapy. Therefore, the patient received steroid pulse therapy followed by steroid tapering concomitant with cyclosporine administration. However, ~ 9 months after the start of steroid therapy, the patient developed multiple vertebral compression fractures with severe back pain. CONCLUSION: It is necessary to evaluate the state of bone at an early stage of treatment for nephrotic syndrome in children, even if the cumulative dose of glucocorticoid is not particularly high.
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Clinical characteristics of rotavirus gastroenteritis with urinary crystals.

BACKGROUND: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. In addition, some patients with acute obstructive uropathy due to ammonium acid urate stones, developing approximately 6-7 days after the onset of rotavirus gastroenteritis, have been reported, mainly in Japan. The pathophysiological mechanism responsible for stone formation has not been clarified. In the present study, we investigated the clinical characteristics of these patients, and analyzed the pathophysiology underlying the formation of urinary stones. METHODS: A total of 164 patients were enrolled. All had acute gastroenteritis due to rotavirus infection and were treated at Osaka Medical College Hospital and affiliated hospitals between January 2009 and May 2011. All were younger than 15 years of age, and their laboratory data, including urinalysis, were available. RESULTS: Among the enrolled patients, 30 (20 boys and 10 girls aged 0.2-10 years; median, 1.5 years; interquartile range, 1-3 years) had crystals in their urine. Most of the patients were admitted approximately 2 days after onset of gastroenteritis and had hyperuricemia and aciduria. The crystals consisted mainly of uric acid, and rarely of ammonium acid urate. CONCLUSION: In order for ammonium acid urate stones to form in patients with acute obstructive uropathy associated with rotavirus gastroenteritis, prolonged continuous acidosis with hyperuricemia, might be necessary. Therefore, normalization of metabolic acidosis is important in order to prevent the onset of obstructive uropathy associated with rotavirus gastroenteritis.

Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stage.

Although Kupffer cells (KCs) play an important role in the liver's immune response, their role in colon cancer metastasis to the liver is unclear. We here analyzed the relationship between KCs and tumor cells (TCs) in colon cancer metastasis to the liver. Fischer 344 (F344) rats were divided into control group (KC+ group) and KC elimination group (KC­ group), in which KC elimination was induced by Cl2MDP liposome injection. RCN­H4 colon cancer cells were injected into the rats of both groups, and the relationship between the two types of cells was observed by intravital microscopy (IVM) for 6 h. Moreover, to investigate the effect of KCs on liver metastasis formation, KCs were eliminated at different time points before and after the TC injection. The number of metastatic nodules 2 weeks after the injection was evaluated. In the KC­ group, IVM revealed that the number of adherent TCs had increased 1.5­fold at 6 h after the TC injection as compared with in the KC+ group. Moreover, in the KC+ group, 74% of the TCs adhered to the KCs, and KC activation and KC phagocytosis of the TCs were observed. Two weeks after the injection, the number of metastatic nodules was significantly increased in rats in which the KCs had been eliminated before the injection, but not in rats in which the KCs had been eliminated after the injection. KC activation and KC phagocytosis of TCs decreased colon cancer cell metastasis to the liver.

Interaction of kupffer cells and platelets determines the severity of ischemia-reperfusion injury in steatosis.

Liver steatosis increases the risk of postoperative complications following major liver resection, since the steatotic liver is susceptible to ischemia-reperfusion (IR) injury. However, it is unclear how IR injury changes in relation to the degree of hepatic steatosis. Previously, we reported that interaction between Kupffer cells (KCs) and platelets induced hepatic IR injury. The aim of our present study was to evaluate the relationship between the degree of liver steatosis and IR injury by focusing on the interaction of KCs and platelets. Mild and moderate steatotic liver models were generated in Wistar rats by feeding a choline-deficient diet for 2 and 4 weeks, respectively. The intensity of steatosis was defined based on the proportion of hepatocytes with fatty infiltration: normal (less than 5%), a mild steatosis (5-30%), and moderate steatosis (30-60%). All groups were subjected to 20 min of warm ischemia followed by 120 min of reperfusion. The number of adhesion of KCs to platelets in sinusoids was observed by intravital microscopy. IR injury was evaluated with serum alanine aminotransferase levels, histological findings, and sinusoidal perfusion. Compared to the normal liver, mild steatosis reduced the adhesion of KCs to platelets, inducing the attenuation of IR injury. In contrast, moderate steatosis increased the adhesion of KCs to platelets, aggravating IR injury relative to the normal liver. IR injury in the steatotic liver was not simply proportional to the degree of steatosis. Mild steatosis ameliorates IR injury compared to the normal liver, whereas moderate steatosis increases IR injury.

Clinico-radiological spectrum of reversible splenial lesions in children.

Recently, many cases of children presenting reversible splenial lesions during febrile illness (RESLEF) have been reported; however, their overall clinico-radiological features are unclear. To describe the clinico-radiological features, we retrospectively reviewed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography (EEG) findings, therapy, and prognosis of 23 episodes in 22 children (1 child recurred) who presented neurological symptoms, with RESLEF. The etiologies (pathogens) varied. Seizure occurred in 7 episodes, disturbance of consciousness (DC) in 13, and delirious behavior in 18. Serum sodium levels <136 mEq/L were observed in 18 episodes. Lesions outside the splenium were found in 4 cases. Slow waves were observed on EEG in 10 episodes. Methylprednisolone pulse therapy was given in 7 cases. No case resulted in neurological sequelae. Among 23 episodes, clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) was diagnosed in 6 episodes, whereas non-MERS was observed in 17 episodes. No difference was observed in almost all the clinico-radiological features' data between the 2 groups. The largest differences were observed in the rate of purposeless movement, DC, extension of the abnormal lesions outside the splenium, and marked slowing of background activity on EEG. RESLEF exhibit a spectrum of clinico-radiological features. These results suggest that non-MERS and MERS both are a part of a larger pathological condition, which we have termed as RESLEF spectrum syndrome. Given the view that such a syndrome exists, the clinical characteristics and position of non-MERS and MERS become clear.

Molecular effect of a novel missense mutation, L266V, on function of ClC-5 protein in a Japanese patient with Dent's disease.

UNLABELLED: We report the use of three dimensional computational analysis of chloride channel 5 (ClC-5) based on a novel mutation, L266V, identified in a 15-year-old Japanese boy with Dent's disease. Since both leucine and valine are branched-chain amino acids, it has not been proved conclusively whether L266V mutation is actually responsible for the development of Dent's disease. In the present study using molecular analysis, we investigated the mechanism for loss of function of the ClC-5 protein resulting from the L266V mutation. Structural analysis of the normal ClC-5 transmembrane region using molecular modeling showed that the two respective Leu266 residues were located at the interface of the dimer formed by the aligned ClC-5 monomers. The Leu266 side-chains were positioned close to each other through hydrophobic interaction, resembling two interconnecting hooks. When Leu266 was replaced by a valine residue, the hydrophobic interaction between the CLC-5 monomers was reduced, and dimer formation was impaired. This computer simulation analysis has thus provided strong evidence for the important role of Leu266 in the dimerization of human ClC-5 in membranes. CONCLUSION: The finding of the present study suggest that computational modeling and molecular analysis could be an alternative to labor-intensive in vitro functional studies.

Influence of Kupffer cells and platelets on ischemia-reperfusion injury in mild steatotic liver.

AIM: To investigate the effect of mild steatotic liver on ischemia-reperfusion injury by focusing on Kupffer cells (KCs) and platelets. METHODS: Wistar rats were divided into a normal liver group (N group) and a mild steatotic liver group (S group) induced by feeding a choline-deficient diet for 2 wk. Both groups were subjected to 20 min of warm ischemia followed by 120 min of reperfusion. The number of labeled KCs and platelets in sinusoids and the blood perfusion in sinusoids were observed by intravital microscopy (IVM), which was performed at 30, 60 and 120 min after reperfusion. To evaluate serum alanine aminotransferase as a marker of liver deterioration, blood samples were taken at the same time as IVM. RESULTS: In the S group, the number of platelets adhering to KCs decreased significantly compared with the N group (120 after reperfusion; 2.9 ± 1.1 cells/acinus vs 4.8 ± 1.2 cells/acinus, P < 0.01). The number of KCs in sinusoids was significantly less in the S group than in the N group throughout the observation periods (before ischemia, 19.6 ± 3.3 cells/acinus vs 28.2 ± 4.1 cells/acinus, P < 0.01 and 120 min after reperfusion, 29.0 ± 4.3 cells/acinus vs 40.2 ± 3.3 cells/acinus, P < 0.01). The blood perfusion of sinusoids 120 min after reperfusion was maintained in the S group more than in the N group. Furthermore, elevation of serum alanine aminotransferase was lower in the S group than in the N group 120 min after reperfusion (99.7 ± 19.8 IU/L vs 166.3 ± 61.1 IU/L, P = 0.041), and histological impairment of hepatocyte structure was prevented in the S group. CONCLUSION: Ischemia-reperfusion injury in mild steatotic liver was attenuated compared with normal liver due to the decreased number of KCs and the reduction of the KC-platelet interaction.

Polycrystalline silicon films with nanometer-sized dense fine grains formed by flash-lamp-induced crystallization.

Flash lamp annealing (FLA) with millisecond-order pulse duration can crystallize microm-order-thick a-Si films on glass substrates through explosive crystallization (EC), and flash-lamp-crystallized (FLC) poly-Si films consist of densely-packed nanometer-sized fine grains. We investigate the impact of the hydrogen concentration and the defect density of precursor a-Si films on crystallization mechanism and the microstructures of FLC poly-Si films, by comparing chemical-vapor-deposited (CVD) and sputtered precursor a-Si films. Transmission electron microscopy (TEM) observation reveals that FLC poly-Si films with similar periodic microstructures are formed by the FLA of the two kinds of precursor films, meaning no significant influence of hydrogen atoms and defect density on crystallization mechanism. This high flexibility of the properties of precursor a-Si films would contribute to a wide process window to reproducibly form FLC poly-Si films with the particular periodic microstructures.

Clinical characteristics of obstructive uropathy associated with rotavirus gastroenteritis in Japan.

AIMS: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. However, we have encountered four children with acute obstructive uropathy associated with acute rotavirus gastroenteritis, and several similar cases have been reported. Therefore, the aim of the present study was to clarify the epidemiology and clinical features of acute obstructive uropathy associated with acute rotavirus gastroenteritis in Japanese children. PATIENTS AND METHODS: We sent questionnaires to all members of the Japanese Society for Nephrology and all authors who had published case reports of this disease in Japan, inquiring about patient age at diagnosis, sex, the type of stones, laboratory data and other factors. RESULTS: 21 reported patients were evaluable, ranging from 0.4 to 3 years. The sex distribution showed a strong male prevalence. Oliguria had appeared about 7 days after the onset of gastroenteritis. Most of the patients showed hyperuricemia and hyponatremia. The stones consisted mainly of ammonium acid urate. The patients were discharged with normal renal function. CONCLUSION: Although obstructive uropathy associated with rotavirus gastroenteritis is very rare, this disease condition should be explored when anuria is refractory to sufficient fluid replacement therapy or when oliguria persists despite recovery of the gastrointestinal symptoms.