Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: The L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. METHODS: To search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors' institutions. RESULTS: Median sL-index(30) was 11 712 (range, 4419-18 511) and median ALC(30) was 404 (range, 0-3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00-1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00-1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89-1.00, P = 0.04 for every increase of 100/µL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88-1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3-4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00-1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99-1.01, P = 0.63). ALC(30) was not associated with rates of grade 3-4 acute GVHD (HR, 1.02, 95% CI, 0.88-1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98-1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. CONCLUSIONS: sL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Super-resolution for a dispersive spectrometer using a tilted area sensor and spectrally varying blur kernel interpolation.

The grating, lens, and linear sensor determine a spectrometer's wavelength resolution and measurement range. While conventional methods have tried to improve the optical design to obtain a better resolution, they have a limitation caused by the physical property. To improve the resolution, we introduce a super-resolution method from the computer vision field. We propose tilting an area sensor to realize accurate subpixel shifting and recover a high-resolution spectrum using interpolated spectrally varying kernels. We experimentally validate that the proposed method achieved a high spectral resolution of 0.141nm in 400-800nm by just tilting the sensor in the spectrometer.

Time-of-flight imaging in fog using multiple time-gated exposures.

We propose a time-of-flight measurement algorithm for depth and intensity that is robust to fog. The key idea of the algorithm is to compensate for the scattering effects of fog by using multiple time-gating and assigning one time-gated exposure for scattering property estimation. Once the property is estimated, the depth and intensity can be reconstructed from the rest of the exposures via a physics-based model. Several experiments with artificial fog show that our method can measure depth and intensity irrespective of the traits of the fog. We also confirm the effectiveness of our method in real fog through an outdoor experiment.

Homozygous single nucleotide duplication of SLC38A8 in autosomal recessive foveal hypoplasia: The first Japanese case report.

PURPOSE: To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene. METHODS: We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation. RESULTS: In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting. CONCLUSIONS: This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

Diagnostic Value of Flow Cytometry Standardized Using the European LeukemiaNet for Myelodysplastic Syndrome.

BACKGROUND: Myelodysplastic syndromes (MDS) and idiopathic cytopenia of undetermined significance (ICUS) are heterogeneous hematological disorders characterized by hematopoietic dysplasia and/or chromosomal aberrancy. OBJECTIVES: This study aimed to evaluate the diagnostic value of flow cytometry standardized using the European LeukemiaNet (ELN) for MDS and ICUS by analyzing samples obtained from patients with cytopenia based on morphological examination, cytogenetic analysis, and flow cytometry. METHODS: We retrospectively analyzed bone marrow samples aspirated from 253 consecutive patients (median age: 66 years [range: 1-92]) to identify the cause of cytopenia. RESULTS: Sixty patients presented with MDS, and 16 with ICUS. MDS subtypes were distributed as follows: MDS with single-lineage dysplasia (n = 10); MDS with multi-lineage dysplasia (n = 10); MDS with ringed sideroblasts (n = 4); MDS with excess blasts-1 (n = 9); MDS with excess blasts-2 (n = 13), MDS unclassified (n = 5); 5q-syndrome (n = 6); and MDS/myeloproliferative neoplasms (n = 3). Four representative ELN indexes were used. Two or more ELN MDS indexes were in the abnormal range in 35 MDS cases (58.3%) and 4 ICUS cases (25.0%). CONCLUSIONS: Morphological examination remains the standard for MDS diagnosis. Considering the low incidence of genetically proven ICUS (20.2-27.5%), the low sensitivity of ELN MDS indexes for ICUS is considered a valuable alternative.

c-D-index is a risk factor for prolonged febrile neutropenia during chemotherapy in patients with acute myeloid leukemia.

BACKGROUND: D-index is a recently established clinical tool for assessing neutropenia severity. This study examined whether the D-index can predict the onset of various infections in patients with febrile neutropenia (FN). METHODS: We retrospectively investigated FN events in consecutive patients aged < 65 years who were treated for newly diagnosed acute myeloid leukemia at our institution. We collected data on all FN events during chemotherapy and evaluated the association of FN severity with infectious events. RESULTS: This study included 35 patients (18 women and 17 men; median age, 51 years [range 18-65 years]) with 122 FN events. The response rate to induction chemotherapy was 60% (21/35), and all but one patient survived the treatment. The D-index did not predict FN onset. However, in multivariate analysis, high-dose cytarabine and total D-index were statistically significant explanatory factors for microbiological-proven infections. In addition, multivariate analysis showed that diabetes mellitus is the only risk factor for FN onset. Furthermore, older age, consolidation therapy, and cumulative D-index (c-D-index) were risk factors for prolonged FN. The FN period was the longest in patients with respiratory infections. CONCLUSION: The D-index did not predict the onset of infection. However, FN duration might be prolonged during consolidation therapy in elderly patients with diabetes mellitus, and it is important to manage respiratory infections. These findings indicate the c-D-index is a useful tool to predict prolonged FN.

Surgery for gastroesophageal reflux disease with Gaucher disease type 2.

Gaucher disease, the most common lysosomal storage disease, is sometimes complicated with gastroesophageal reflux disease (GERD). The present patient was a 136-day-old Japanese boy with Gaucher disease type 2. Enzyme replacement therapy and chemical chaperone therapy were successful for the skin disorders, joint contractures, hepatosplenomegaly and thrombocytopenia, but he also had GERD. Accordingly, a Nissen fundoplication with gastrostomy was performed. There was no vulnerability of organs, easy bleeding or difficulty of maintaining the visual field because of hepatosplenomegaly during operation. In the perioperative period, there was no prolonged wound healing or infection. GERD was improved. In the near future, the number of long-term survivors of Gaucher disease will increase due to improvements in medical therapy. Therefore, it is expected that the number of patients requiring fundoplication will also increase. In patients with successful medical therapy, surgical fundoplication can be safely and effectively performed.

Is yolk sac tumor related to the pathophysiology of low birthweight?

An 8-year-old Japanese girl was admitted with an ovarian yolk sac tumor. Regarding birth history, the patient had been delivered by cesarean section at 25 weeks of gestation with a birthweight of 711g. She had required neonatal intensive care including oxygenation, various medications, and tests. After surgery and chemotherapy, there was no recurrence for 2 years, at the time of writing. Yolk sac tumor, which is a malignant germ cell tumor, is rare in children. Although the cause and risk factors are unclear, it has been reported that malignant germ cell tumors in childhood have been associated with pathophysiology at birth. Given that premature infants are more likely to survive due to advances in perinatal care, it is expected that such cases will increase in the near future. We suggest that children born prematurely require careful follow up.

Immunohistochemical analysis of transporters related to clearance of amyloid-ß peptides through blood-cerebrospinal fluid barrier in human brain.

A large number of previous reports have focused on the transport of amyloid-ß peptides through cerebral endothelial cells via the blood-brain barrier, while fewer reports have mentioned the transport through the choroid plexus epithelium via the blood-cerebrospinal fluid barrier. Concrete roles of these two pathways remain to be clarified. In this study, we immunohistochemically examined the expression of transporters/receptors that are supposed to be related to the clearance of amyloid-ß peptides in the choroid plexus epithelium, the ventricular ependymal cells and the brain microvessels, using seven autopsied human brains. In the choroid plexus epithelium, immunoreactivity for low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), LRP2, formylpeptide receptor-like 1 (FPRL1), ATP-binding cassette (ABC) transporter-A1 (ABCA1), ABCC1 and ABCG4 was seen in 7 of 7 brains, while that for ABCB1, ABCG2, RAGE and CD36 was seen in 0-2 brains. In the ventricular ependymal cells, immunoreactivity for CD36, LDLR, LRP1, LRP2, FPRL1, ABCA1, ABCC1 and ABCG4 was seen in 6-7 brains, while that for ABCB1, ABCG2 and RAGE was seen in 0-1 brain. Immunoreactivity for insulin-degrading enzyme (IDE) was seen in three and four brains in the choroid plexus epithelium and the ventricular ependymal cells, respectively. In addition, immunoreactivity for LDLR, ABCB1 and ABCG2 was seen in over 40 % of the microvessels (all seven brains), and that for FPRL1, ABCA1, ABCC1 and RAGE was seen in over 5 % of the microvessels (4-6 brains), while that for CD36, IDE, LRP1, LRP2 and ABCG4 was seen in less than 5 % of the microvessels (0-2 brains). These findings may suggest that these multiple transporters/receptors and IDE expressed on the choroid plexus epithelium, ventricular ependymal cells and brain microvessels complementarily or cooperatively contribute to the clearance of amyloid-ß peptides from the brain.

Evaluation of antireflux surgery using multichannel intraluminal impedance-pH measurement in neurologically impaired patients.

PURPOSE: This study aimed to evaluate esophageal function before and after antireflux surgery (ARS) in neurologically impaired (NI) patients using 24 h multichannel intraluminal impedance (MII)-pH measurement. METHODS: Seven NI patients (age, 0-33 years; median, 13 years) were assessed before and after ARS using 24 h MII-pH. We described reflux parameters such as pH reflux index, bolus exposure index, number of acidic and nonacidic reflux episodes, mean acid clearance time and median bolus clearance time, and esophageal motility parameters in dry swallows such as bolus presence time (BPT), total bolus transit time (TBTT), and total propagation velocity (TPV). RESULTS: The postoperative reflux parameters such as pH reflux index, acid clearance time, bolus exposure index, and the number of acidic reflux episodes significantly decreased (P < 0.05) compared with the preoperative ones. The esophageal motility parameters including all sites of BPTs, TBTT, and TPV did not change in the MII-pH measurement after ARS (P = non-significant). CONCLUSION: ARS effectively reduced gastro-esophageal reflux (GER) in NI patients without the impairment of esophageal motility by MII-pH measurement. MII-pH was useful to detect the subtype of GER before and after ARS and appeared to be appropriate for evaluating esophageal motility.

Expression profiling using a tumor-specific cDNA microarray predicts the prognosis of intermediate risk neuroblastomas.

To predict the prognosis of neuroblastoma patients and choose a better therapeutic protocol, we developed a cDNA microarray carrying 5340 genes obtained from primary neuroblastomas and examined 136 tumor samples. We made a probabilistic output statistical classifier that provided a high accuracy in prognosis prediction (89% at 5 years) and a highly reliable method to validate it. Kaplan-Meier analysis indicated that the patients in an intermediate group defined by existing markers are divided by microarray into two further groups with 5 year survivals for 36% and 89% of patients (p < 10(-4)), i.e., with unfavorably and favorably predicted neuroblastomas, respectively. According to these results, we developed a gene subset chip for a clinical tool, for which our classifier exhibited 88% prediction accuracy.

Antenatal three-dimensional sonographic features of fetal biliary atresia.

We present antenatal three-dimensional (3D) sonographic features of fetal biliary atresia. A 38-year-old pregnant Japanese woman was referred to our ultrasound clinic because of a fetal intra-abdominal cyst at 19 weeks of gestation. Conventional two-dimensional (2D) sonography and 3D sonography with an inversion mode showed a round cyst with a tiny dip in the subhepatic area. At 34 weeks, conventional 2D sonography and 3D sonography with inversion and transparent X-ray modes clearly revealed a round to oval cyst connected with the gallbladder via the cystic duct. A diagnosis of choledochal cyst (type I) was suggested antenatally. However, the final diagnosis made by employing operative cholangiography during surgery was biliary atresia (type I cyst) at 25 days of life. To the best of our knowledge, this is the first report of biliary atresia employing antenatal 3D sonography with inversion and transparent X-ray modes.

Metabolic Steal of the Myocardium by Primary Cardiac Lymphoma.

Less than 1.0% of malignant lymphomas are primary cardiac lymphoma (PCL), a rare malignant lymphoma. Due to its infrequency, the metabolic dynamics of the treatment have not been completely analyzed. A 62-year-old man who had been complaining of exertional dyspnea for a month arrived at our emergency room. He developed right cardiac failure as a result of a mass in the right atrium, according to a computed tomography (CT) scan. According to an echocardiogram, the mass was obstructing his blood flow and affecting how his heart worked. The lump was pathologically determined to be diffuse large B-cell lymphoma after he underwent urgent heart surgery. The lesion was only localized in the heart, according to a postoperative 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT scan, indicating that the disease was in clinical stage IE. An 18F-FDG-PET/CT scan showed a thickness of the right atrial wall as residual disease despite the majority of the cardiac lymphomatous mass being removed during surgery; it also showed that the usual uptake of 18F-FDG in healthy myocardium had diminished. Following chemotherapy, 18F-FDG uptake recovered in the patient's normal myocardium of the heart in remission. In conclusion, a sort of "metabolic steal phenomenon" that may be connected to PCL is the difference in uptake between tumor-involved and healthy myocardium.