Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis. METHODS: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study. Patients with biopsy-confirmed NASH and stage 3 fibrosis (N = 197) received weekly subcutaneous pegbelfermin (10, 20, or 40 mg) or placebo injections for 48 weeks. The week 24 primary endpoint was a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = 0.05). Secondary/exploratory endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: At week 24, the primary endpoint was met by 14% (placebo) vs 24%-31% (pegbelfermin arms); statistical significance was not reached due to lack of pegbelfermin dose response (P = .134). At weeks 24 and 48, more patients who received pegbelfermin had ≥30% relative reductions in hepatic fat fraction (magnetic resonance imaging-proton density fat fraction) vs placebo, although no differences reached statistical significance. In the pegbelfermin arms, improvements in liver fibrosis (magnetic resonance elastography and N-terminal type III collagen propeptide) and liver injury/inflammation (alanine aminotransferase, aspartate aminotransferase) were observed vs placebo. Adverse events occurred at similar frequencies across arms. No treatment-related serious adverse events were observed. CONCLUSIONS: The FALCON 1 study did not meet its primary endpoint; a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening assessed via biopsy. Pegbelfermin was generally well tolerated during 48 weeks of treatment.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis. METHODS: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P = .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). CONCLUSIONS: FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Automatic surgical phase recognition-based skill assessment in laparoscopic distal gastrectomy using multicenter videos.

BACKGROUND: Gastric surgery involves numerous surgical phases; however, its steps can be clearly defined. Deep learning-based surgical phase recognition can promote stylization of gastric surgery with applications in automatic surgical skill assessment. This study aimed to develop a deep learning-based surgical phase-recognition model using multicenter videos of laparoscopic distal gastrectomy, and examine the feasibility of automatic surgical skill assessment using the developed model. METHODS: Surgical videos from 20 hospitals were used. Laparoscopic distal gastrectomy was defined and annotated into nine phases and a deep learning-based image classification model was developed for phase recognition. We examined whether the developed model's output, including the number of frames in each phase and the adequacy of the surgical field development during the phase of supra-pancreatic lymphadenectomy, correlated with the manually assigned skill assessment score. RESULTS: The overall accuracy of phase recognition was 88.8%. Regarding surgical skill assessment based on the number of frames during the phases of lymphadenectomy of the left greater curvature and reconstruction, the number of frames in the high-score group were significantly less than those in the low-score group (829 vs. 1,152, P < 0.01; 1,208 vs. 1,586, P = 0.01, respectively). The output score of the adequacy of the surgical field development, which is the developed model's output, was significantly higher in the high-score group than that in the low-score group (0.975 vs. 0.970, P = 0.04). CONCLUSION: The developed model had high accuracy in phase-recognition tasks and has the potential for application in automatic surgical skill assessment systems.

Trends in endometrial carcinoma: experience of a single institute for four decades.

OBJECTIVE: To determine the current prognosis of endometrial carcinoma in Japan by analyzing long-term trends in endometrial carcinoma at our hospital. METHODS: We divided 1463 patients with endometrial carcinoma who visited our hospital between 1984 and 2022 into group 1984-1991, group 1992-1999, group 2000-2006, group 2007-2014 and group 2015-2022. Trends were determined using the Jonckheere-Terpstra and Cochran-Armitage tests. Data were analyzed using Cox regression analysis. RESULTS: When group 2015-2022 was used as a reference in the univariate analysis, the hazard ratios for the other groups were <1. In particular, the hazard ratio for group 2007-2014 was 0.65 (95% confidence interval, 0.47-0.90, P = 0.009), suggesting that the prognosis of group 2015-2022 was worse than that of group 2007-2014 and seemed to be the worst among all prognoses. In multivariate analysis, the hazard ratios for each group were 1.38, 1.42, 1.88, 1.16 and 1, respectively; the group with the worst prognosis changed from group 2015-2022 to group 2000-2006 (hazard ratio, 1.88; 95% confidence interval, 1.27-2.78, P = 0.001). Age and the rate of non-endometrioid carcinoma exhibited significantly increasing trends (P < 0.001 and P < 0.001, respectively), as did the rates of serous and mixed carcinomas (P = 0.001 and 0.024, respectively). The rates of non-endometrioid carcinoma, serous carcinoma and mixed carcinoma were 19.0%, 5.5% and 3.1% in group 2007-2014 and 28.2%, 10.8% and 4.6% in group 2015-2022, respectively. CONCLUSIONS: The increasing rates of non-endometrioid carcinoma-especially serous and mixed carcinoma-may be associated with the worsening prognosis of endometrial carcinoma at our institution. Careful monitoring is needed to confirm whether this phenomenon is observed throughout Japan.

A retrospective study of Pipelle endometrial biopsy for ovarian, fallopian tube, and peritoneal cancers.

OBJECTIVES: Although the Pipelle endometrial biopsy is widely performed as a practical and minimally invasive test for endometrial disease(s), its effectiveness in ovarian cancer has not been explored. The aim of the present study was to evaluate the results of Pipelle endometrial biopsy for ovarian, fallopian tube, and peritoneal cancers. METHODS: A pre-treatment Pipelle-endometrial biopsy was performed in 90 patients with ovarian, fallopian tube, or peritoneal cancers between January 2014 and November 2021. We retrospectively analysed the association between the results of Pipelle endometrial biopsy and clinicopathological data. Moreover, we evaluated their impact on the following treatment in advanced cases initially treated with chemotherapy. RESULTS: The sensitivity and false-negative rates for Pipelle endometrial biopsy were 25/90 (27.8%) and 65/90 (72.2%) in all patients, respectively, and 23/56 (41.0%) and 33/56 (58.9%) in cases with advanced disease (stages III and IV), respectively. Pipelle-positive endometrial biopsy-positive (Pipelle-positive) was not observed in 29 patients with clinical stage I disease, and Pipelle-positive patients exhibited significantly more high-grade serous carcinomas, and positive peritoneal, endometrial, and cervical cytologies than Pipelle-endometrial biopsy-negative cases. Surgical pathology was confirmed in 23 Pipelle-positive patients, and 17/23 (74.0%) had the same diagnosis as that for Pipelle endometrial biopsy. Conversely, 6/23 (26.0%) patients exhibited a minor diagnostic discrepancy between Pipelle endometrial biopsy and surgical pathology. Nineteen of the 38 (50.0%) patients initially treated with chemotherapy were identified as Pipelle-positive, contributing to a prompt histological diagnosis and pre-treatment tumour sampling. Companion diagnostic tests were performed using Pipelle endometrial biopsy samples from 4 inoperable patients. CONCLUSION: Although the positive rate of Pipelle endometrial biopsy in ovarian, fallopian tube, and peritoneal cancers is low, Pipelle endometrial biopsy may enable prompt histological diagnosis and initiation of chemotherapy while collecting tumour tissue for genetic testing in some cases with advanced disease.

The effectiveness of pre-treatment Pipelle endometrial biopsy for ovarian, fallopian tube, and peritoneal cancers remains unclear. This study demonstrated that Pipelle endometrial biopsy may enable prompt histological diagnosis and initiation of chemotherapy while collecting tumour tissue for genetic testing in some cases with advanced disease. This was a single-centre, retrospective study; as such, the effectiveness of Pipelle endometrial biopsy should be evaluated in larger prospective studies, including comparisons with other tumour sampling methods.

New Cluster Analysis Method for Quantitative Dynamic Contrast-Enhanced MRI Assessing Tumor Heterogeneity Induced by a Tumor-Microenvironmental Ameliorator (E7130) Treatment to a Breast Cancer Mouse Model.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide insight into tumor perfusion. However, a method that can quantitatively measure the intra-tumor distribution of tumor voxel clusters with a distinct range of Ktrans and ve values remains insufficiently explored. HYPOTHESIS: Two-dimensional cluster analysis may quantify the distribution of a tumor voxel subregion with a distinct range of Ktrans and ve values in human breast cancer xenografts. STUDY TYPE: Prospective longitudinal study. ANIMAL MODEL: Twenty-two female athymic nude mice with MCF-7 xenograft, treated with E7130, a tumor-microenvironmental ameliorator, or saline. FIELD STRENGTH/SEQUENCE: 9.4 Tesla, turbo rapid acquisition with relaxation enhancement, and spoiled gradient-echo sequences. ASSESSMENT: We performed two-dimensional k-means clustering to identify tumor voxel clusters with a distinct range of Ktrans and ve values on Days 0, 2, and 5 after treatment, calculated the ratio of the number of tumor voxels in each cluster to the total number of tumor voxels, and measured the normalized distances defined as the ratio of the distance between each tumor voxel and the nearest tumor margin to a tumor radius. STATISTICAL TESTS: Unpaired t-tests, Dunnett's multiple comparison tests, and Chi-squared test were used. RESULTS: The largest and second largest clusters constituted 44.4% and 27.5% of all tumor voxels with cluster centroid values of Ktrans at 0.040 min-1 and 0.116 min-1 , and ve at 0.131 and 0.201, respectively. At baseline (Day 0), the average normalized distances for the largest and second largest clusters were 0.33 and 0.24, respectively. E7130-treated group showed the normalized distance of the initial largest cluster decreasing to 0.25, while that of the second largest cluster increasing to 0.31. Saline-treated group showed no change. DATA CONCLUSION: A two-dimensional cluster analysis might quantify the spatial distribution of a tumor subregion with a distinct range of Ktrans and ve values. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

PET/MR imaging for the evaluation of cervical cancer during pregnancy.

BACKGROUND: Malignancy during pregnancy is increasing, and the most common type of malignancy is uterine cervical cancer. When planning the treatment of cervical cancer, it is important to look for signs of metastasis before surgery, especially metastasis to the lymph nodes. In this report, we assessed the diagnostic value of positron emission tomography/magnetic resonance imaging (PET/MRI) for evaluating cervical cancer propagation before surgery, with a focus on pregnant women. CASE PRESENTATION: 18F Fluorodeoxyglucose (FDG)-PET/MRI was performed in seven pregnant cervical cancer patients (28-34 years old) at 9-18 gestational weeks. In case #5, a second PET/MRI was performed at 24 gestational weeks. Of seven FDG-PET/MRI examination series in six cases (cases #1-6), FDG-PET/MR imaging could detect cervical tumors with abnormal FDG accumulation; these tumors were confirmed with a standardized uptake value max (SUV max) titer of 4.5-16. A second PET/MRI examination in case #5 revealed the same SUV max titer as the first examination. In these six imaging series (cases #1-5), there were no signs of cancer metastasis to the parametrium and lymph nodes. However, in case #6, abnormal FDG accumulation in the left parametrial lymph nodes was also detectable. Pathological examination showed lymph node metastasis in case #6. In case #7, PET/MRI could not detect any abnormal FDG accumulation in the cervix and other sites. Cone biopsy demonstrated only micro-invasive squamous cell carcinoma. After treatment for cervical cancer, all seven patients have had no recurrence of disease within the follow-up period (2.8-5.6 years), and their children have developed appropriately. CONCLUSION: PET/MRI is an effective imaging tool to evaluate cervical cancer progression in pregnancy.

A successfully treated case of an acute presentation of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) with decreased ADAMTS13 during late stage of pregnancy.

We herein report the case of a 28-year-old pregnant woman with an acute presentation of remarkable petechiae on her lower extremities and severe thrombocytopenia (16 000/mm3 ) at the 35th week of gestation. Although idiopathic thrombocytopenic purpura was initially suspected, subsequent examinations revealed that her ADAMTS13 (a Disintegrin And Metalloprotease, with ThromboSpondin type 1 repeats, member 13) titer was extremely decreased, while she was negative for antibodies against ADAMTS13. Infusion of fresh frozen plasma was immediately performed, and the platelet count was observed to increase. However, severe pregnancy-induced hypertension and proteinuria emerged at 36 weeks and 2 days of gestation, and a male infant was delivered by emergency cesarean section on the 37th week of gestation. The postnatal development was uncomplicated. After delivery, although the mother's platelet count and ADAMTS13 activity decreased temporarily, both values increased following fresh frozen plasma transfusion. This case showed interesting aspects of congenital thrombocytopenic purpura (Upshaw-Schulman syndrome) in pregnancy. Moreover, the rapid measurement of the patient's ADAMTS13 activity and the subsequent accurate diagnosis of congenital thrombocytopenic purpura made it possible to treat the patient with fresh frozen plasma infusion and avoid contraindicated platelet infusion. Close cooperation between obstetricians, hematologists and pediatricians is necessary to achieve successful outcomes in cases of thrombocytopenic purpura during pregnancy.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Treatment margins in radiotherapy for liver tumors visualized as T2*-hypointense areas on SPIO-enhanced MRI at 9.4 T.

OBJECTIVE: To investigate whether a SPIO-labeling technique could enable MR visualization of the treatment margin after X-irradiation at a single dose of 30 Gy. MATERIALS AND METHODS: Fifteen rats bearing N1-S1 hepatoma in either the left (group 1) or right (group 2) liver lobe were examined. Four hours after systemic SPIO administration, the left lobe was selectively irradiated at 30 Gy. Liver T2* maps were acquired 7 days later using a 9.4 T scanner. The livers were excised and examined histologically. RESULTS: The irradiated area showed T2*-weighted hypointensity with significantly shorter T2* values than those in the non-irradiated area (p < 0.001). Tumors in group 1 completely disappeared, whereas tumors in group 2 had grown outside the T2*-weighted hypointensity by up to ~ 2.3 times that at baseline. Group 1 showed significantly higher probability of tumor regression than group 2 (p = 0.048). Histologically, iron deposition was heavier in irradiated areas than in non-irradiated areas. DISCUSSION: Even at a single dose of 30 Gy, which is a slightly higher dose than can be used clinically in stereotactic body radiotherapy, MR visualization of the treatment margin was achieved, because tumors showed significant growth outside the T2*-hypointense areas. In contrast, tumors disappeared inside the T2*-hypointense areas.

MR signal changes in superparamagnetic iron oxide nanoparticle-labeled macrophages in response to X irradiation.

To investigate whether MR signals associated with macrophages labeled with superparamagnetic iron oxide nanoparticles (SPIONs) change in response to X irradiation, we performed in vitro MRI of SPION-labeled macrophage-like J774A.1 cells that were subsequently X irradiated. We labeled the cells with ferucarbotran at a concentration of 10 µg iron/mL in culture medium for 16 h and subsequently performed X irradiation at doses of 0, 2, 10, or 20 Gy using a low-energy X-ray unit. On Days 3 and 6, we suspended the cells in agar at a concentration of 2 × 106 cells/mL and acquired multi-gradient echo and multi-spin echo images of the cell samples using a 3 T scanner to estimate R2 * and R2 . In addition, we microscopically investigated the relationship among the MR signal changes, intracellular SPIONs, and acidic organelles. Our data showed that X irradiation of labeled cells caused increased SPION deposition in lysosomes compared with the non-irradiated control. On Day 3, R2 * and R2 values in the 0 to 10 Gy irradiated samples were dose-dependently increased 5.4- and 1.5-fold compared with 17 ± 2 and 13 ± 1/s, respectively, in the non-irradiated control; these values plateaued at more than 10 Gy. Although the increases in R2 *, R2 , and SPION deposition were still observed in the 10 and 20 Gy samples on Days 6 and 7, the 2 Gy samples showed recovery in these parameters as cell growth was restored. Acidic organelles were temporarily increased in the irradiated cells, which suggests that the reduction in lysosomal acidity was not attributable to SPION deposition. In conclusion, X irradiation of macrophages can cause SPION deposition and R2 * and R2 elevation in a specific dose range. MRI of SPION-labeled and subsequently X-irradiated macrophages may be utilized as a novel technique for investigating macrophage responses to X irradiation.

Treatment for patients with recurrent fetal losses positive for anti-cardiolipin beta2 glycoprotein I antibody using Sairei-to (Chai-ling-tang) and low-dose aspirin.

AIM: Recently, it is widely recognized that positivity for anti-phospholipid antibodies is a causative factor for a range of reproductive failures. Anti-cardiolipin beta2 glycoprotein I antibody (anti-CL-beta2-GPI) is a representative anti-phospholipid antibody, which strongly correlates with the development of thrombotic events and diversity of adverse pregnancies. In this series, we aimed to elucidate effective treatment for patients with recurrent fetal losses positive for anti-CL-beta2-GPI using Japanese-modified Chinese herbal medicine. METHODS: Twenty-one patients with recurrent fetal losses who were positive for anti-CL-beta2-GPI were treated with the Japanese-modified Chinese herbal medicine, Sairei-to (Chai-ling-tang), and low-dose aspirin with or without adrenal corticosteroid hormone. Of the 21 patients, the value of anti-CL-beta2-GPI ranged from 1.9 to 3.4 in 10 patients, and it was over 3.5 in 11 patients. RESULTS: Of the 21 patients treated with the current protocol, the pregnancy successfully continued in 17 patients (success rate: 81.0%). Of the four patients who showed repeated abortion, chromosome abnormality of chorionic villi was observed in two; thus, the success rate would be 89.5% (17 of 19 cases) on excluding these cases from the evaluation. CONCLUSION: The efficacy of the current treatment adopting the modified Japanese version of the Chinese herbal medicine Sairei-to for patients with recurrent fetal losses positive for anti-CL-beta2-GPI was indicated.

The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy.

OBJECTIVES: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. METHODS/MATERIALS: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. RESULTS: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. CONCLUSIONS: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby.

Effectiveness of fetal cardiac screening for congenital heart disease using a combination of the four-chamber view and three-vessel view during the second trimester scan.

AIM: We aimed to assess the accuracy and effectiveness of fetal cardiac screening for congenital heart disease (CHD) during the second trimester by general obstetricians in a non-selected population. METHODS: In this multicenter, prospective cohort study of fetal cardiac screening, four-chamber and three-vessel views were recorded by obstetricians at 18-21 gestational weeks (GW). A total of 3005 fetuses that were scheduled for delivery at our institution were included. RESULTS: Thirty-seven newborns were born with CHD (1.2%). On excluding 23 cases of ventricular septal defects, the prenatal detection rate of CHD was 42.8%. Although six cases (75.0%) of severe structural abnormality were diagnosed prenatally, the prenatal detection rate of valvular abnormalities was 0%. CONCLUSION: One-point ultrasound screening of the fetal heart using a combination of four-chamber and three-vessel views at 18-21 GW by general obstetricians in a non-selected population may be useful for detecting severe structural abnormalities but not valvular abnormalities. However, this limitation may be improved by conducting another fetal cardiac screening at approximately 30 GW along with the routine use of color Doppler.

Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer.

Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

Persistent T2*-hypointensity of the liver parenchyma after irradiation to the SPIO-accumulated liver: An imaging marker for responses to radiotherapy in hepatic malignancies.

PURPOSE: To determine whether T2*-weighted MRI has the ability to visualize the irradiated liver parenchyma and liver tumor after irradiation to the previously superparamagnetic iron oxide (SPIO)-accumulated liver. MATERIALS AND METHODS: We examined 24 liver tumor-bearing rats. Nine rats (Group 1) received 20 µmol Fe/kg SPIO and subsequent 70-Gy irradiation to the tumor-bearing liver lobe. Four rats (Group 2) received SPIO and sham irradiation. Six rats (Group 3) received saline and irradiation. Finally, five rats (Group 4) received saline and sham irradiation. We acquired sequential 3 Tesla T2*-weighted images of the liver on day 7, and assessed MR image findings including signal intensity of the tumors and tumor-bearing liver lobes. RESULTS: In six rats in Group 1, tumors shrunk by 39-100% (303-0 mm3 ), and severely, well-defined hypointense irradiated areas were observed. In the other two rats, tumors enlarged by 25 and 172% (595 and 1148 mm3 ), and hypointense rings surrounded the tumors. The normalized relative signal intensity of the irradiated areas was significantly lower than that of the tumor (0.53 ± 0.06 versus 0.94 ± 0.06; P < 0.05). The severely, well-defined hypointense areas were not observed in the other groups. Histologically, necrotic regions dominated and minimal nonnecrotic tumor cells remained in irradiated areas. The number of CD68-positive cells was higher in irradiated areas than in nonirradiated areas. CONCLUSION: T2*-weighted MR imaging visualized the irradiated liver parenchyma as markedly, well-defined hypointense areas and liver cancer lesions as hyperintense areas only when SPIO was administered before irradiation. The visualization of the hypointense area was associated with tumor regression after irradiation. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:303-312.

Wavelength dispersion of birefringence of oriented polyethylene films.

Oriented polyethylene films, in which stacked lamellae grow perpendicular to the flow direction, can show extraordinary wavelength dispersion of birefringence; i.e., birefringence increases with wavelength. Owing to the periodical change of the refractive indices between the crystalline and amorphous layers along the flow direction, with oriented long lamellae having a high refractive index, the form birefringence has negative values. Furthermore, the refractive indices of the crystalline region show a stronger wavelength dependence than those of the amorphous region, which is responsible for the marked wavelength dispersion in the form birefringence. The combination of negative form birefringence with strong wavelength dispersion and positive orientation birefringence can give extraordinary wavelength dispersion.

Quantitative trait loci analysis of grain appearance in Oryza sativa L. 'Emi-no-kizuna'.

A quantitative trait locus (QTL) analysis was conducted on grain appearance in Emi-no-kizuna, a rice cultivar that has superior and stable appearance of the brown rice grain and high tolerance to high temperature stress, by using F3 lines derived from Emi-no-kizuna and Tomohonami. The investigation was performed 2013 and 2015. In summer 2013 the air temperature was higher and the larger differences in grain appearance were observed. In the QTL analysis, a highly contributing locus, qGA8, was detected at the end of the short arm of chromosome 8. Because trends of reduced the occurrence of white immature kernel and increased the percentage of perfect grain were observed in Emi-no-kizuna genotype in both years, qGA8 is likely to be an important QTL that is dominant in the superior grain appearance of Emi-no-kizuna. Also, qGA8 was linked to a QTL associated with days to heading. Another QTL, qGA7, associated with grain appearance was detected on chromosome 7 in 2013. Because no negative correlation was found between the genotype of qGA8 and thousand grain weight, it should be possible to breed cultivars that possess Emi-no-kizuna genotype qGA8 without a decrease in thousand grain weight.

Case with pyoderma gangrenosum abruptly emerging around the wound of cesarean section for placenta previa with placenta accrete.

A 39-year-old woman underwent emergency cesarean section (CS) due to placenta previa totalis with massive bleeding. Two major problems emerged in this patient after CS was carried out. One was partial retention of the placenta due to placenta accreta. Another major and more serious problem was pyoderma gangrenosum (PG) widely appearing at the skin of the abdomen around the CS wound. Conservative treatment was performed for the retained placenta, and it had completely disappeared by 76 days after the CS. The diagnosis of PG was promptly made in consultation with a plastic surgeon and a dermatologist when a wide ulcer emerged around the CS wound, and high-dose prednisolone was administered as treatment. At 90 days following the CS, near-complete epithelialization was achieved. This extremely rare case reflects the importance of rapid diagnosis and treatment of PG.

Chain Packing and Its Anomalous Effect on Mechanical Toughness for Poly(lactic acid).

The effect of chain packing on tensile properties was studied employing amorphous poly(lactic acid) PLA. It was found that the samples cooled in the temperature range from 60 to 80 °C, that is, slightly higher than the glass transition temperature Tg, showed ductile behavior with a low brittle-ductile transition temperature. Furthermore, the samples obtained by prolonged cooling at 56 °C also showed ductile behavior, whereas a shorter cooling time at the same temperature provided a brittle product. Even for the samples quenched at 40 °C, they showed ductile behavior after the exposure to postprocessing annealing operation at 60 °C; that is, the strain at break is larger than 3. This is an anomalous phenomenon for a glassy polymer. The dynamic mechanical analysis and thermal characterization revealed that the ductile samples show slightly higher Tg than the brittle ones, presumably due to high packing density of polymer chains. Moreover, it was found from infrared spectroscopy that the ductile samples show strong absorbance at 1267 cm(-1), ascribed to high energy gauche-gauche gg conformers. Following the classic Robertson's descriptions of plastic flow, it is concluded that the increase in the gauche-gauche gg conformers, which shows the conformation change under a low stress level, reduces the critical onset stress for shear yielding. The results demonstrated that the mechanical toughness of PLA can be controlled by the cooling conditions during processing and the postprocessing annealing operation.