The association between 11C-methionine uptake, IDH gene mutation, and MGMT promoter methylation in patients with grade II and III gliomas.

AIM: To evaluate the association between 11C-methionine positron-emission tomography (11C-methionine PET) findings, isocitrate dehydrogenase (IDH) gene mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with grade II and III gliomas. MATERIALS AND METHODS: Data were collected from 40 patients with grade II and III gliomas who underwent both magnetic resonance imaging (MRI) and 11C-methionine PET as part of their pre-surgical examination. IDH mutation was examined via DNA sequencing, and MGMT promoter methylation via quantitative methylation-specific polymerase chain reaction (PCR). RESULTS: A threshold of MGMT promoter methylation of 1% was significantly associated with tumour/normal tissue (T/N) ratio. The T/N ratio in samples with MGMT promoter methylation ≥1% was higher than that in samples with MGMT promoter methylation <1%, and the difference was statistically significant (p=0.011). Reliable prediction of MGMT promoter methylation (<1% versus ≥1%) was possible using the T/N ratio under the receiver operator characteristic (ROC) curve with a sensitivity and specificity of 75% each (cut-off value=1.6: p=0.0226, area under the ROC curve [AUC]=0.76172). Conversely, the T/N ratio had no association with IDH mutation (p=0.6). The ROC curve revealed no reliable prediction of IDH mutation using the T/N ratio (p=0.606, AUC=0.60577). CONCLUSION: 11C-methionine PET parameters can predict MGMT promoter methylation but not IDH mutation status. 11C-methionine uptake may have limited potential to reflect DNA methylation processes in grade II and III gliomas.

Risk model for severe postoperative complications after total pancreatectomy based on a nationwide clinical database.

BACKGROUND: Total pancreatectomy is required to completely clear tumours that are locally advanced or located in the centre of the pancreas. However, reports describing clinical outcomes after total pancreatectomy are rare. The aim of this retrospective observational study was to assess clinical outcomes following total pancreatectomy using a nationwide registry and to create a risk model for severe postoperative complications. METHODS: Patients who underwent total pancreatectomy from 2013 to 2017, and who were recorded in the Japan Society of Gastroenterological Surgery and Japanese Society of Hepato-Biliary-Pancreatic Surgery database, were included. Severe complications at 30 days were defined as those with a Clavien-Dindo grade III needing reoperation, or grade IV-V. Occurrence of severe complications was modelled using data from patients treated from 2013 to 2016, and the accuracy of the model tested among patients from 2017 using c-statistics and a calibration plot. RESULTS: A total of 2167 patients undergoing total pancreatectomy were included. Postoperative 30-day and in-hospital mortality rates were 1·0 per cent (22 of 2167 patients) and 2·7 per cent (58 of 167) respectively, and severe complications developed in 6·0 per cent (131 of 2167). Factors showing a strong positive association with outcome in this risk model were the ASA performance status grade and combined arterial resection. In the test cohort, the c-statistic of the model was 0·70 (95 per cent c.i. 0·59 to 0·81). CONCLUSION: The risk model may be used to predict severe complications after total pancreatectomy.

ANTECEDENTES: La pancreatectomía total está indicada cuando se requiere la resección completa de tumores localmente avanzados o ubicados en el centro del páncreas. Sin embargo, existen pocos artículos que describan los resultados clínicos después de una pancreatectomía total. El objetivo de este estudio observacional retrospectivo fue evaluar los resultados clínicos después de una pancreatectomía total utilizando un registro nacional y crear un modelo de riesgo de complicaciones postoperatorias graves. MÉTODOS: Se incluyeron aquellos pacientes que se sometieron a una pancreatectomía total entre 2013 y 2017 y que fueron registrados en la base de datos de la Sociedad Japonesa de Cirugía Gastrointestinal y de la Sociedad Japonesa de Cirugía Hepato-Bilio-Pancreática. Las complicaciones graves a los 30 días se definieron como Clavien-Dindo grado III con reintervención o grado IV/V. Se analizó la aparición de complicaciones graves de los pacientes desde 2013 a 2016 y se evaluó la precisión del modelo entre los pacientes operados desde 2017 usando estadísticos c y un gráfico de calibración. RESULTADOS: Se incluyeron 2.167 pacientes sometidos a una pancreatectomía total. La mortalidad postoperatoria a los 30 días y la mortalidad hospitalaria fueron del 1,0% (22/2167) y del 2,7% (58/2167), respectivamente, y las complicaciones graves ocurrieron en el 6,0% (131/2167) de los pacientes. Los factores que mostraron una fuerte asociación positiva con los resultados en este modelo de riesgo fueron el estado funcional según la Sociedad Americana de Anestesiología y la resección arterial combinada. En la cohorte de prueba, el estadístico c del modelo fue de 0,70 (i.c. del 95% 0,59-0,81). CONCLUSIÓN: El modelo de riesgo puede usarse para predecir las complicaciones graves después de una pancreatectomía total.

Medial meniscus posterior root tear induces pathological posterior extrusion of the meniscus in the knee-flexed position: An open magnetic resonance imaging analysis.

BACKGROUND: A medial meniscus posterior root tear (MMPRT) is defined as an injury to the posterior meniscal insertion on the tibia. In MMPRT, the medial meniscus (MM) hoop function is damaged, and the MM undergoes a medial extrusion into the interior from the superior articular surface of the tibia. However, the details of MM position and movement during knee joint movement are unclear in MMPRT cases. The present study aims to evaluate MM position and movement via magnetic resonance imaging (MRI) examination of the MM posterior extrusion (MMPE) at knee flexion angles of 10° and 90°. We hypothesized that, during knee flexion, the MM will shift to the posterior and the posterior extrusion will increase compared to that when the knee is extended. MATERIALS AND METHODS: Twenty-four patients were diagnosed with symptomatic MMPRT on open MRI examination. Preoperative MMPE, anteroposterior interval (API) of the MM, and MM medial extrusion (MMME) at knee flexion angles of 10° and 90° were measured. RESULTS: For patients with MMPRT, the MMPE increased from -4.77±1.43mm to 3.79±1.17mm (p<0.001) when the knee flexion angle increased from 10° to 90°. Further, flexing the knee from 10° to 90° decreased the API of the MM from 20.19±4.22mm to 16.41±5.14mm (p<0.001). MMME showed no significant change between knee flexion angles of 10° and 90°. DISCUSSION: This study demonstrated that, in cases of MMPRT, the MMPE clearly increases when the knee is flexed to 90°, while MMME does not change. Our results suggest that open MRI examination can be used to evaluate the dynamic position of the posterior MM by scanning the knee as it flexes to 90°. LEVEL OF EVIDENCE: IV: retrospective cohort study.

Medial meniscus extrusion correlates with disease duration of the sudden symptomatic medial meniscus posterior root tear.

INTRODUCTION: Medial meniscus posterior root tear (MMPRT) leads to abnormal biomechanics of the knee by inducing the medial meniscus extrusion (MME). However, a time-dependent increase of the MME is not fully elucidated in patients suffering from the acute MMPRT. The aim of this study was to investigate the relationships among disease duration of the MMPRT and severity of the MME. We hypothesized that MME measurement correlates with disease duration after a sudden onset of the minor traumatic MMPRT during the short-term follow-up period. MATERIALS AND METHODS: Forty-six patients who had an accurate episode of the posteromedial painful popping were investigated. All the patients were diagnosed having a symptomatic MMPRT with magnetic resonance imaging (MRI) examinations. Absolute MME was measured using MRI scans within 12 months after painful popping events. A correlation coefficient between duration from injury to MRI examination and absolute MME was evaluated. RESULTS: Mean absolute MME was 4.5±1.6mm (range, 1.1-8.8mm) on MRI measurements. A good correlation was observed between MME measurement and duration from injury to MRI examination (R2=0.612). The best-fit equation for predicting each value was: MME=0.014×disease duration+3.288mm. DISCUSSION: This study demonstrated that absolute MME increases progressively within the short duration after the onset of symptomatic MMPRT. Our results suggest that preoperative MME assessment may be important in determining disease duration and treatment strategy of the MMPRT. LEVEL OF EVIDENCE: Retrospective cohort study level IV.

A new aiming guide can create the tibial tunnel at favorable position in transtibial pullout repair for the medial meniscus posterior root tear.

INTRODUCTION: Injuries to the medial meniscus (MM) posterior root lead to accelerated cartilage degeneration of the knee. An anatomic placement of the MM posterior root attachment is considered to be critical in transtibial pullout repair of the medial meniscus posterior root tear (MMPRT). However, tibial tunnel creation at the anatomic attachment of the MM posterior root is technically difficult using a conventional aiming device. The aim of this study was to compare two aiming guides. We hypothesized that a newly-developed guide, specifically designed, creates the tibial tunnel at an adequate position rather than a conventional device. MATERIALS AND METHODS: Twenty-six patients underwent transtibial pullout repairs. Tibial tunnel creation was performed using the Multi-use guide (8 cases) or the PRT guide that had a narrow twisting/curving shape (18 cases). Three-dimensional computed tomography images of the tibial surface were evaluated using the Tsukada's measurement method postoperatively. Expected anatomic center of the MM posterior root attachment and tibial tunnel center were evaluated using the percentage-based posterolateral location on the tibial surface. Percentage distance between anatomic center and tunnel center was calculated. RESULTS: Anatomic center of the MM posterior root footprint located at a position of 78.5% posterior and 39.4% lateral. Both tunnels were anteromedial but tibial tunnel center located at a more favorable position in the PRT group: percentage distance was significantly smaller in the PRT guide group (8.7%) than in the Multi-use guide group (13.1%). DISCUSSION: The PRT guide may have great advantage to achieve a more anatomic location of the tibial tunnel in MMPRT pullout repair. LEVEL OF EVIDENCE: III.

Cephalometric evaluation after two-stage palatoplasty combined with a Hotz plate: a comparative study between the modified Furlow and Widmaier-Perko methods.

The effects on craniofacial growth of two different soft palate repair techniques in two-stage palatoplasty were investigated. This was a retrospective, cross-sectional cohort study of 68 children with non-syndromic, complete unilateral cleft lip and palate. Thirty-four patients were treated with the modified Furlow method (F-group) and the remaining 34 with the Widmaier-Perko method (P-group). Craniofacial growth was assessed by analyzing 12 angular and 12 linear measurements on lateral cephalograms. Composite facial diagrams from the two groups were compared with those of a control non-cleft group. Angular and linear measurements did not differ significantly between the two groups, implying that the craniofacial morphology was not affected by the difference in soft palate repair technique. However, small differences in anterior nasal spine and posterior nasal spine were found in cleft patients compared with controls. These findings suggest that the modified Furlow and Widmaier-Perko methods have a similar impact on craniofacial growth. Considering speech function, the modified Furlow method provides better craniofacial growth and speech function. However, the long-term effects of both methods on craniofacial growth after growth cessation remain to be determined.

DS02R1: Improvements to Atomic Bomb Survivors' Input Data and Implementation of Dosimetry System 2002 (DS02) and Resulting Changes in Estimated Doses.

Individual dose estimates calculated by Dosimetry System 2002 (DS02) for the Life Span Study (LSS) of atomic bomb survivors are based on input data that specify location and shielding at the time of the bombing (ATB). A multi-year effort to improve information on survivors' locations ATB has recently been completed, along with comprehensive improvements in their terrain shielding input data and several improvements to computational algorithms used in combination with DS02 at RERF. Improvements began with a thorough review and prioritization of original questionnaire data on location and shielding that were taken from survivors or their proxies in the period 1949-1963. Related source documents varied in level of detail, from relatively simple lists to carefully-constructed technical drawings of structural and other shielding and surrounding neighborhoods. Systematic errors were reduced in this work by restoring the original precision of map coordinates that had been truncated due to limitations in early data processing equipment and by correcting distortions in the old (WWII-era) maps originally used to specify survivors' positions, among other improvements. Distortion errors were corrected by aligning the old maps and neighborhood drawings to orthophotographic mosaics of the cities that were newly constructed from pre-bombing aerial photographs. Random errors that were reduced included simple transcription errors and mistakes in identifying survivors' locations on the old maps. Terrain shielding input data that had been originally estimated for limited groups of survivors using older methods and data sources were completely re-estimated for all survivors using new digital terrain elevation data. Improvements to algorithms included a fix to an error in the DS02 code for coupling house and terrain shielding, a correction for elevation at the survivor's location in calculating angles to the horizon used for terrain shielding input, an improved method for truncating high dose estimates to 4 Gy to reduce the effect of dose error, and improved methods for calculating averaged shielding transmission factors that are used to calculate doses for survivors without detailed shielding input data. Input data changes are summarized and described here in some detail, along with the resulting changes in dose estimates and a simple description of changes in risk estimates for solid cancer mortality. This and future RERF publications will refer to the new dose estimates described herein as "DS02R1 doses."

Irradiation at Different Fetal Stages Results in Different Translocation Frequencies in Adult Mouse Thyroid Cells.

While it is generally believed that fetuses are at high risk of developing cancers, including leukemia, after low doses of radiation, it has been reported that atomic bomb survivors exposed in utero did not show a dose response for translocations in blood T lymphocytes when they were examined at approximately 40 years of age. Subsequent mouse studies confirmed that animals irradiated during the fetal stage did not show evidence of radiation effects in lymphocytes and bone marrow cells when they were examined after reaching adulthood. However, in a study of rat mammary epithelial cells, radiation effects were clearly observed after fetal irradiation. These results indicate that the fate of chromosome aberrations induced in a fetus could vary among different tissues. Here we report on translocation frequencies in mouse thyroid cells, which were irradiated at different stages of fetal development. Cytogenetic examination was conducted using fluorescence n situ hybridization (FISH) painting of chromosomes 1 and 3. Adult mice, 2 Gy X-ray irradiated at 15.5-day-old fetuses (E15.5), showed a higher translocation frequency (30/1,155 or 25.3 × 10-3) than nonirradiated adult controls (0/1,007 or 0.1 × 10-3), and was near that experienced by irradiated mothers and non-pregnant adult females (43/1,244 or 33.7 × 10-3). These results are consistent with those seen in rat mammary cells. However, when fetuses were irradiated at an earlier stage of development (E6.5) before thyroid organogenesis, the resulting observed translocation frequency was much lower (3/502 or 5.8 × 10-3) than that in E15.5 mice. These results suggest that after fetal irradiation, tissue stem cells record radiation effects primarily when the exposure occurs in cells that have been integrated into tissue. Embryonic stem cells that have been damaged prior to integration into the niche may undergo negative selection due to apoptosis, mitotic death or stem cell-niche cell interactions. The implications of these results in interpreting cancer risks after fetal irradiation are also discussed.

Pullout repair of a medial meniscus posterior root tear using a FasT-Fix® all-inside suture technique.

A medial meniscus posterior root tear (MMPRT) may increase the tibiofemoral contact pressure by decreasing the tibiofemoral contact area. Meniscal dysfunction induced by posterior root injury may lead to the development of osteoarthritic knees. Repair of a MMPRT can restore medial meniscus (MM) function and prevent knee osteoarthritis progression. Several surgical procedures have been reported for treating a MMPRT. However, these procedures are associated with several technical difficulties. Here, we describe a technique to stabilize a torn MM posterior root using the FasT-Fix® all-inside meniscal suture device and a new aiming device. The uncut free-end of the FasT-Fix® suture can be used as a thread for transtibial pullout repair. Our procedure might help overcome the technical difficulties in arthroscopic treatment of a MMPRT.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Effects of duodenal switch alone or in combination with sleeve gastrectomy on body weight and lipid metabolism in rats.

BACKGROUND: A combined procedure of sleeve gastrectomy and duodenal switch (SG+DS) has been applied to the treatment of super obesity. The aim of the present study was to test whether duodenal switch alone (DS) leads to similar weight loss and changes in lipid metabolism as SG+DS. METHODS: Male Sprague-Dawley rats underwent sham surgery (Sham, N=7), duodenal switch alone (DS, N=5) or sleeve gastrectomy followed by duodenal switch (SG+DS, N=5). Body weight, feed and water intakes, and ambulatory activity were recorded 2 months post surgery. Tissue and faecal lipids, faecal bile acids, plasma cytokines and lipid metabolism-related gene expression in adipose tissue and liver were analysed. RESULTS: Daily energy intake, relative feed uptake, ambulatory activity and body weight reduction were similar between DS and SG+DS rats. The hepatic triacylglycerol content was higher and faecal secretion of triacylglycerol was lower after SG+DS compared to DS (P<0.05). Faecal bile acid secretion was higher in SG+DS than in DS rats (P<0.05) despite similar hepatic CYP7A1mRNA level. Plasma levels of proinflammatory cytokines interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-12, granulocyte-macrophage colony stimulating factor and tumour necrosis factor alpha were higher in SG+DS than in DS rats (P<0.05). CONCLUSIONS: Although DS and SG+DS had similar efficacy in terms of body weight loss, SG+DS resulted in a poorer regulation of lipid metabolism than DS.

Flumequine enhances the in vivo mutagenicity of MeIQx in the mouse liver.

The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods.

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01).