[Management of iron overload during pregnancy and childbirth in a patient with ferroportin disease].

An asymptomatic woman in her early 40s with a history of hyperferritinemia (5,412 ng/ml) was referred to our hospital after repeated phlebotomy for hemosiderosis. She had unexplained hyperferritinemia, low-normal transferrin saturation, and high hepcidin levels, in the absence of iron overload-induced organ injury. She was diagnosed with ferroportin disease based on detection of the SLC40A1 variant SLC40A1 c.485_487del (p.Val162del) on genetic analysis. Her ferritin levels remained stable during pregnancy, and postpartum anemia was successfully treated with 2-week oral iron therapy. Ferroportin disease is characterized by impaired iron export and preferential iron trapping in tissue macrophages. To reduce risk of anemia, a non-aggressive phlebotomy regimen is recommended in patients with ferroportin disease, which shows a milder clinical course compared with other classical hemochromatosis subtypes.

Nonbrain metastases seen on magnetic resonance imaging during metastatic brain tumor screening.

Although metastases found during head magnetic resonance imaging (MRI) are not limited to metastatic brain tumors, the MRI is a very common method for "brain metastasis screening," a modality that is being increasingly performed. In this review, we describe MRI findings of nonbrain metastases and discuss ways to avoid missing these lesions. Metastatic cranial bone tumors are among the most common nonbrain metastatic lesions found on head MRI, followed by leptomeningeal carcinomatosis. The other less-frequent metastatic lesions include those in the ventricle/choroid plexus, the pituitary gland and stalk, and the pineal gland. Metastases in the head and neck area, as well as cranial and intracranial lesions, should be carefully evaluated. Furthermore, direct geographical invasion, perineural spread, and double cancers should also be considered. While it is important to recognize these metastatic lesions on MRI, because they may necessitate a change in treatment strategy that could lead to an improvement in prognosis due to early introduction of therapy, nonbrain lesions should also be given greater attention, given the increasing survival of patients with cancer and advances in MRI technology, such as contrast-enhanced-3D T1-weighted imaging.

[Diagnostic efficacy of WT1 expression in asymptomatic acute promyelocytic leukemia].

We report a case of early asymptomatic acute promyelocytic leukemia (APL) with leukopenia as the only hematologic abnormality. A 55-year-old woman was referred to our hospital with leukopenia (white blood cell [WBC] count of 1,500/µl with 36% neutrophils), which was incidentally determined during an annual medical checkup. Two months before the presentation, her WBC was 3,400/µl with 60% neutrophils. A WBC count was 1,200/µl with 40% neutrophils. Immature myeloid cells were not observed. Her hemoglobin level and platelet count were normal. Moreover, no clinical or laboratory evidence was suggestive of disseminated intravascular coagulation or infection. The peripheral blood WT1 mRNA level was increased to 26,000 copies/µg RNA. The bone marrow aspirate smear revealed 40% myeloperoxidase-positive promyelocytes with occasional Auer rods and faggots; however, circulating leukemia cells were not revealed by cell morphology or flow cytometry analysis. Quantitative reverse-transcription polymerase chain reaction analysis revealed WT1 and PML-RARA fusion transcripts in both the peripheral blood and bone marrow samples. Thus, the determination of peripheral blood WT1 expression may be sufficiently sensitive for detecting a small number of circulating APL cells.

Reference intervals of red blood cell parameters and platelet count for healthy adults in Japan.

Although it is known that red blood cell (RBC) parameters and platelet count depend on ethnicity and sex, their reference intervals in healthy Asian populations are limited. The aim of this study was to establish reference intervals for RBC parameters and platelet count for healthy adults in Japan. A total of 750 healthy adults (447 women and 303 men; median age 40 years (18-67 years) at seven Japanese centers who participated in regular medical checkups entered this study. Their RBC parameters and platelet count were measured using automated hematocytometers. The reference intervals of the RBC parameters and platelet count according to sex in healthy adults were determined. There was an age-specific decrease in RBC counts and an age-specific increase in mean corpuscular volume in men. This study emphasizes the need to consider sex and age in the clinical use of reference intervals of RBC parameters.

Reference intervals of white blood cell parameters for healthy adults in japan.

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.

Successful treatment with lenalidomide for relapsed adult T-cell leukemia/lymphoma after cord blood cell transplantation.

The prognosis for relapsed adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic stem cell transplantation is poor. Here, we report the case of a 67-year-old man who survived for 26 months after treatment with lenalidomide for post-transplant relapsed ATL. He underwent induction therapy with two cycles of modified VCAP-AMP-VECP and achieved complete remission. He received cord blood cell transplantation following a reduced-intensity conditioning regimen. Seven months after transplantation, swelling of the systemic lymph nodes appeared, and relapsed ATL was diagnosed based on a biopsy of the cervical lymph node. Treatment with 10 mg of lenalidomide induced partial remission. At 18 months after transplantation, skin tumors were successfully treated by increasing the dose of lenalidomide to 15 mg with the emergence of skin graft-versus-host disease. Although he died from ATL at 34 months after transplantation, systemic relapsed lesions were controlled by treatment with lenalidomide for 26 months. Our case suggests that lenalidomide is well tolerated and is an effective option for the treatment of post-transplant relapsed ATL.

Influence of hyperuricemia treatment on postoperative acute kidney injury among hyperuricemia patients: a single-center retrospective database analysis.

OBJECTIVE: Hyperuricemia has been reported to be associated with the development of postoperative acute kidney injury (pAKI). However, it remains underdetermined whether hyperuricemia treatment could decrease the potential risk of pAKI. Here, we investigated this hypothesis among hyperuricemia patients with previously normal renal function by performing a retrospective database analysis. RESULTS: The study screened 18,169 patients, and were examined preoperative serum creatinine, uric acid, and postoperative serum creatinine. Eight hundred thirty-six patients were finally analyzed for the study, of whom 232 were in the treatment group and 604 were in the non-treatment control group. After adjustment for multi-covariates including baseline (pre-treatment) serum uric acid (SUA) levels, the incidence of pAKI in the treatment group (9.05%; 95% CI 6.04-12.1%) was significantly lower than that in the control group (14.2%; 95% CI 11.2-17.2%). On the other hand, further adjusting for preoperative SUA levels, there was no significant difference in the expected incidence of pAKI between the groups.

Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

Performance of an atrial fibrillation detection algorithm using continuous pulse wave monitoring.

BACKGROUND: Detecting asymptomatic and undiagnosed atrial fibrillation (AF) is increasingly important. Recently, we developed a wristwatch-based pulse wave monitor (PWM; Seiko Epson, Japan) capable of long-term recording, with an automatic diagnosis algorithm that uses frequency-based pulse wave analysis. The aim of this study was to evaluate the validity of continuous pulse wave monitoring for detection of AF. METHODS: During the electrophysiological study (EPS) in patients with AF, simultaneous pulse wave monitoring and Holter electrocardiograms (ECG) were recorded (n = 136, mean age 62.7 ± 10.9 years). The diagnostic accuracy of the PWM for AF was compared to the Holter ECG diagnosis. Standard performance metrics (sensitivity [Se], specificity [Sp], positive predictive value [PPV], and negative predictive value [NPV]) were calculated. The duration-based measurements were based on the diagnosis concordance ratios for the duration of time between diagnosis detected by the PWM and true diagnosis by the Holter ECG (AF or not AF). The episode-based performance metrics were based on the proportion of episodes appropriately detected with the PWM relative to episodes determined by the Holter ECG. RESULTS: The total recording time was 1,542,770 s (AF: 270,945 s). A high diagnostic Sp (patient average: 96.4%, cumulative: 97.7%) and NPV (patient average: 95.1%, cumulative: 96.8%) were obtained in the duration-based results. In the episode-based metrics, all indices significantly improved with longer AF episode durations. CONCLUSIONS: Continuous pulse wave monitoring can provide accurate and dependable information to aid in AF diagnosis. A high validity in confirming freedom from AF was shown by a high NPV.

Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer.

Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

Genetic and Environmental Influences on Regional Brain Uptake of 18F-FDG: A PET Study on Monozygotic and Dizygotic Twins.

UNLABELLED: Genetic or environmental influences on cerebral glucose metabolism are unknown. We attempted to reveal these influences in elderly twins by means of (18)F-FDG PET. METHODS: (18)F-FDG uptake was studied in 40 monozygotic and 18 dizygotic volunteer twin pairs aged 30 y or over. We also created 18 control pairs by pairing age- and sex-matched genetically unrelated subjects from dizygotic and monozygotic pairs. SUV images of the brain were reconstructed and analyzed by voxel-based statistical analysis with automated region-of-interest setting. The (18)F-FDG uptake in each cerebral lobe was semiquantified by taking a ratio of SUVmean in each region of interest to whole-brain SUVaverage. We calculated an intraclass correlation coefficient of SUV ratio in each region of interest for monozygotic and dizygotic pairs. By comparing differences in coefficients between monozygotic and dizygotic pairs, genetic and environmental contributions were estimated. RESULTS: The intraclass correlation coefficient in monozygotic pairs was significantly higher than that in dizygotic pairs in the parietal lobes bilaterally (P < 0.001) and in the left temporal lobe (P < 0.05) but was not significantly different in other lobes. CONCLUSION: The present study indicated that in the right and left parietal lobes and left temporal lobe, cerebral glucose metabolism is influenced more by genetics than by environment, whereas in other brain regions the influence of environment is dominant.

[Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer].

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells.

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25% of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

[A case of hepatocellular carcinoma complicated by pleural effusion mixed with bile after radiofrequency ablation].

An 84-year-old Japanese man was admitted with hepatocellular carcinoma (HCC). He underwent transcatheter arterial chemoembolization and percutaneous radiofrequency ablation (RFA). Three weeks later, he developed sudden-onset right pleural effusion mixed with bile. Drip infusion cholangiography-computed tomography revealed leakage of the contrast agent, which passed from the HCC to the pleural cavity through a perforation in the diaphragm. The patient's condition improved after thoracic and endoscopic nasobiliary drainage. The occurrence of pleural effusion mixed with bile is a rare complication of RFA. This case provides important information about the morbidity, prevention, and treatment of this complication.

[Evaluation of Payne's formula for the correction of calcium: comparison with improved calcium and albumin measurement methods].

The ionized or free fraction of serum calcium is physiologically important for cellular function, but we most often measure total serum calcium. There are a number of correction formulas that can be used to estimate whether low total serum calcium can be attributed simply to low albumin or serum protein. In Japan, Payne's formula has been widely used to correct calcium concentration. However, there are some problems in the measurement methods of total calcium and serum albumin which were used to establish Payne's formula with respect to specificity, calibration curve and stability. Recently, improved measurement methods of calcium and albumin have been adopted at clinical laboratories. Here we evaluated Payne's formula by comparing it with improved measurement methods of total calcium and serum albumin. For the total calcium measurement, o-CPC (o-cresolphthaleincomplexone), CPZ(chlorophosphonazo) III, and enzymatic methods were used. For the serum albumin measurement, BCG (bromocresol green) and improved BCP(bromocresol purple) methods were used. The results of this comparison study suggest that the calcium correction equation is not affected by changes in total calcium concentration, but the assay used for albumin may affect the calcium correction equation. Using multiple linear regression, the following equations were derived: BCG between CPZ III [corrected Ca(mg/dL) = total Ca-0.76ALB + 3.2], and improved BCP between CPZ III [corrected Ca = total Ca-0.7ALB + 2.6]. These formulas are simplified respectively as [corrected Ca = total Ca + 0.8(4-ALB], and [corrected Ca = total Ca + 0.7 (4-ALB)]. We conclude that Payne's formula is valid with the BCG method, but with the improved BCP method, our formula is more suitable for correcting calcium.

A novel synergistic effect of iron depletion on antiangiogenic cancer therapy.

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

F18-FDG PET-CT analyses of small peripheral adenocarcinoma of the lung.

BACKGROUND: Radiological discrimination of histologic subtypes of small peripheral adenocarcinoma of the lung is clinically important. Although there are many articles in which CT findings were used for this purpose, there are only a few reports on the capability of FDG PET-CT findings for histologic classification of this tumor. PURPOSE: To investigate the correlation between visual assessment or maximum standard uptake values (SUVmax) on F18-FDG PET-CT and histology grading of small peripheral adenocarcinoma of the lung. MATERIAL AND METHODS: Proportions of positive PET-CT diagnoses and SUVmax were retrospectively reviewed on 96 solitary pulmonary nodules of ≤2 cm in 90 consecutive patients. Tumors were classified into four groups according to Noguchi's classification (group 1 [n = 10], atypical adenomatous hyperplasia and type A tumors; group 2 [n = 12], type B tumors; group 3 [n = 42], type C tumors; group 4 [n = 32], types D, E, and F tumors). Proportions of positive PET-CT diagnoses and mean SUVmax of lesions among four groups were compared using trend tests to examine if there is a significant linear correlation with the progression of the histology grading of tumors. Then, an optimal threshold of SUVmax was proposed to best discriminate tumors of poor (groups 3 and 4) from good (groups 1 and 2) prognosis. RESULTS: There was a significant linear trend for both visual assessment (P < 0.01) and SUVmax (P < 0.01). A SUVmax of 0.42 showed the highest accuracy of 84% with 95% sensitivity and 50% specificity for predicting tumors of poor prognosis. A SUVmax of 2.05 showed 100% specificity with 49% sensitivity, and 60% accuracy. Positive visual diagnoses showed accuracy of 83% with 90% sensitivity and 59% specificity. CONCLUSION: Visual assessment and SUVmax on PET-CT correlated well with the histology grading of small peripheral adenocarcinoma of the lung.

Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia.

AIM: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial. METHODS: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers. RESULTS: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment. CONCLUSION: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.

Plasma accumulation of fondaparinux 2.5 mg in patients after total hip arthroplasty.

Fondaparinux (FPX), a selective inhibitor of factor Xa, is widely used for the prophylaxis of venous thromboembolism (VTE) after total joint arthroplasty. However, the association between plasma FPX concentration and adverse events and the occurrence of VTE has not been clarified thus far. We aimed to prospectively evaluate these associations by measuring anti-Xa activity of FPX in patients undergoing total hip arthroplasty (THA) and investigate whether factors such as age, body weight, and renal function influence the anti-Xa levels. We enrolled 85 patients who underwent primary THA. All patients received subcutaneous FPX (2.5 mg/day for 14 days) after surgery. Anti-Xa activity was measured on postoperative days 1, 3, 7, and 14. To assess VTE, multidetector row computed tomography was performed in all patients at 1 week after surgery. The median levels of anti-Xa activity increased as follows (medians with 95 % confidence interval): 0.00 (0.00-0.01) mg/L, 0.13 (0.11-0.14) mg/L, 0.19 (0.17-0.20) mg/L, and 0.24 (0.22-0.25) mg/L on postoperative days 1, 3, 7, and 14, respectively. The plasma accumulation of FPX was more likely in patients with renal impairment than in those with normal renal function. In contrast, a poor correlation was observed between the plasma levels of anti-Xa activity and age or body weight. No differences were observed in the anti-Xa activity in patients with and without postoperative VTE or bleeding. Substantial increase in the levels of anti-Xa activity was observed, especially in patients with renal impairment, after subcutaneous administration of FPX 2.5 mg after THA.