MR Imaging Findings of Carcinoma Ex Pleomorphic Adenoma Related to Extracapsular Invasion and Prognosis.

BACKGROUND AND PURPOSE: MR imaging can reflect the pathologic progression of carcinoma ex pleomorphic adenoma (CXPA). This study aimed to identify the imaging findings related to extracapsular invasion of CXPA. Additionally, the pathologic background of these findings was investigated. MATERIALS AND METHODS: This retrospective study included 37 patients with histologically confirmed CXPA. Three radiologists independently evaluated whether the CXPA showed the following characteristic MR imaging findings: border, capsule, the corona sign on fat-saturated T2WI and contrast-enhanced fat-saturated T1WI, and the black ring sign. The corona sign appeared larger on fat-saturated and/or contrast-enhanced fat-saturated T1WI than on T1WI. The black ring sign was defined as an intratumoral nodule with a thick low-intensity rim on T2WI. Interreader agreement of the visual assessment was performed using κ analysis, and MR imaging and histopathologic findings were also correlated. Kaplan-Meier survival and the log-rank test were used to estimate the 3-year disease-free survival. RESULTS: MR imaging findings, especially peritumoral findings, showed a significant difference between invasive and noninvasive CXPA. The reliability was poor for the border and capsule. In contrast, it was good for the corona sign on fat-saturated and contrast-enhanced fat-saturated T1WI and the black ring sign. Pathologically, the corona sign reflected the invasiveness of the tumor and inflammatory cells, while the black ring sign reflected hyalinization or fibrosis. The corona sign also showed a significant difference in the 3-year disease-free survival. CONCLUSIONS: MR imaging findings, including the corona and black ring signs, reliably differentiated invasive and noninvasive CXPA. The corona sign can be used as a prognostic factor for CXPA.

Anxiety relaxation during MRI with a patient-friendly audiovisual system.

INTRODUCTION: Many patients experience anxiety, not limited to claustrophobia, before magnetic resonance imaging (MRI) examination. We performed a non-randomized controlled trial to evaluate whether a patient-friendly audiovisual (AV) system in the MR scanner room reduces patient anxiety. METHODS: We randomly selected 61 participants from outpatients who required brain MRI examination. Patients were informed that they could choose to undergo an MRI examination with a patient-friendly AV system (Ambient Experience, Philips Healthcare, Best, The Netherlands) or the standard system. To complete the MRI examination without affecting clinical practice, all patients who preferred the patient-friendly AV system were assigned to the preferring AV group. Patients who indicated that either system was acceptable were randomly assigned to the no preference but allocated AV group or control (using the standard system) groups. In both groups, state anxiety using the State-Trait Anxiety Inventory (STAI) was assessed before and after the MRI examination (A-State-before and A-State-after MRI, respectively). The changes in A-State-before and A-State-after MRI were categorized as follows: relieved high-state anxiety, no change in high-state anxiety, stable easiness, and intensified anxiety. RESULTS: Among the 61 included patients, 19 were assigned to the preferring AV group, 20 to the no preference but allocated AV group, and 22 to the control group. There were no significant differences between the group. However, in patients with high-state anxiety before MRI, the preferring AV group and the no preference but allocated AV group, which used the patient-friendly AV system, relieved high-state anxiety by 63.6% (7 of 11 patients) and 81.8% (9 of 11 patients), respectively. In contrast, the control group using the standard system relieved high-level anxiety by only 42.9% (three out of seven patients). CONCLUSION: The patient-friendly AV system may reduce anxiety in patients undergoing MRI examinations. IMPLICATIONS FOR PRACTICE: The patient-friendly AV system may reduce anxiety in patients undergoing MRI examination by providing a more patient-centered MRI examination environment. These findings may help ameliorate negative perceptions associated with MRI examination.

Prognostic Factors of Stroke-Like Migraine Attacks after Radiation Therapy (SMART) Syndrome.

BACKGROUND AND PURPOSE: Prognostic factors of stroke-like migraine attacks after radiation therapy (SMART) syndrome have not been fully explored. This study aimed to assess clinical and imaging features to predict the clinical outcome of SMART syndrome. MATERIALS AND METHODS: We retrospectively reviewed the clinical manifestations and imaging findings of 20 patients with SMART syndrome (median age, 48 years; 5 women) from January 2016 to January 2020 at 4 medical centers. Patient demographics and MR imaging features at the time of diagnosis were reviewed. This cohort was divided into 2 groups based on the degree of clinical improvement (completely versus incompletely recovered). The numeric and categoric variables were compared as appropriate. RESULTS: There were statistically significant differences between the completely recovered group (n = 11; median age, 44 years; 2 women) and the incompletely recovered group (n = 9; median age, 55 years; 3 women) in age, months of follow-up, and the presence of steroid treatment at diagnosis (P = .028, .002, and .01, respectively). Regarding MR imaging features, there were statistically significant differences in the presence of linear subcortical WM susceptibility abnormality, restricted diffusion, and subcortical WM edematous changes in the acute SMART region (3/11 versus 8/9, P = .01; 0/11 versus 4/9, P = .026; and 2/11 versus 7/9, P = .022, respectively). Follow-up MRIs showed persistent susceptibility abnormality (11/11) and subcortical WM edematous changes (9/9), with resolution of restricted diffusion (4/4). CONCLUSIONS: Age, use of steroid treatment at the diagnosis of SMART syndrome, and MR imaging findings of abnormal susceptibility signal, restricted diffusion, and subcortical WM change in the acute SMART region can be prognostic factors in SMART syndrome.

An Investigation of Water Diffusivity Changes along the Perivascular Space in Elderly Subjects with Hypertension.

BACKGROUND AND PURPOSE: Hypertension may be related to alterations of the glymphatic system, a waste metabolite drainage system in the brain. We aimed to investigate analysis along the perivascular space index changes in elderly subjects with hypertension. MATERIALS AND METHODS: Diffusion-weighted images were acquired from 126 subjects, including 63 subjects with hypertension (25 men and 38 women; mean age, 72.45 years) and 63 age- and sex-matched controls (25 men and 38 women; mean age, 72.16 years). We calculated the analysis along the perivascular space index as a ratio of the mean of x-axis diffusivities in the projection and association areas to the mean of y-axis diffusivity in the projection area and z-axis diffusivity in the association area. The left, right, and mean analysis along the perivascular space indices of both hemispheres were compared between the hypertension and control groups using a Mann-Whitney U test. The Spearman correlation coefficient was used to assess the correlation between the left, right, and mean ALPS indices and blood pressure and pulse pressure. RESULTS: The left (P = .011) and mean (P = .024) analysis along the perivascular space indices of the hypertension group were significantly lower than that of the control group. The left, right, and mean analysis along the perivascular space indices of all subjects were significantly negatively correlated with blood pressure values (r = -0.200 to -0.278, P = .002-0.046) and pulse pressure values (r = -0.221 to -0.245, P = .006-0.013). CONCLUSIONS: Our results are consistent with a model in which hypertension causes glymphatic dysfunction.

Selective Motor Control is a Clinical Correlate of Brain Motor Tract Impairment in Children with Spastic Bilateral Cerebral Palsy.

BACKGROUND AND PURPOSE: Selective voluntary motor control is an important factor influencing gross motor function, interjoint coordination, and the outcome of hamstring-lengthening surgery in spastic cerebral palsy. Using DTI, we investigated whether selective voluntary motor control would show strong correlations with WM motor tract microstructure and whether selective voluntary motor control is more sensitive to global WM impairment than gross motor function. MATERIALS AND METHODS: Children with spastic bilateral cerebral palsy born preterm and typically developing children were recruited. The Selective Control Assessment of the Lower Extremity (SCALE) and Gross Motor Function Measure (GMFM) were assessed in participants with cerebral palsy. Participants underwent brain MR imaging to collect DWI data. Tract-Based Spatial Statistics was used to analyze the WM for between-group differences and correlations with SCALE and GMFM. ROI analyses compared motor regions. RESULTS: Twelve children with cerebral palsy (mean age, 11.5 years) and 12 typically developing children (mean age, 10.3 years) participated. Altered DTI outcomes were found throughout the whole brain for the cerebral palsy group. SCALE, developed to evaluate selective voluntary motor control in cerebral palsy, showed significant positive correlations with fractional anisotropy in more WM voxels throughout the whole brain and for motor regions, including the corticospinal tract and corpus callosum, compared with GMFM. A significant negative correlation between radial diffusivity and SCALE, but not GMFM, was found within the corpus callosum. CONCLUSIONS: SCALE was a more sensitive clinical correlate of motor and whole-brain WM tract impairment in children with spastic bilateral cerebral palsy, suggesting greater anisotropy and myelination in these regions for those with higher selective voluntary motor control.

Lumbosacral subdural hematoma associated with cranial subdural hematoma and craniocerebral surgery: Three cases and a systemic literature review.

OBJECTIVE: The authors aim to focus on lumbosacral subdural hematoma (SDH) associated with cranial subdural hematoma and craniocerebral surgery, which has been rarely reported. MATERIAL AND METHODS: They present 3 cases of lumbosacral SDH, including 2 associated with cranial chronic SDH and 1 following craniotomy for neck clipping of cerebral aneurysm. Using a PubMed search, they also provide a systemic literature review to summarize pathogenesis, treatment and outcome. RESULTS: All cases presented with bilateral radiating leg pain, and recovered completely by conservative managements. Predisposing factors were trauma, anticoagulant therapy and brain atrophy. Literature review revealed 54 such cases, in which 28 cases associated with cranial SDH and 26 cases associated with craniocerebral surgery. In both group, main symptoms were low back and radiating leg pain, and sensorimotor deficits. Regardless of treatments, conservatively or surgically, outcome was favorable. Migration of cranial hematoma is most supported pathogenesis, while intracranial hypotension due to cerebrospinal fluid overdrainage procedures may also be a contributing factor for cases associated with craniocerebral surgery. CONCLUSIONS: Lumbosacral SDH should be considered in patients present with unexpected low back and radiating leg pains associated with cranial SDH and craniocerebral surgery. Conservative treatment would be reasonable for cases with mild symptoms as the first treatment of choice.

Automatic three-dimensional segmentation of mouse embryonic stem cell nuclei by utilising multiple channels of confocal fluorescence images.

Time-lapse confocal fluorescence microscopy images from mouse embryonic stem cells (ESCs) carrying reporter genes, histone H2B-mCherry and Mvh-Venus, have been used to monitor dynamic changes in cellular/differentiation characteristics of live ESCs. Accurate cell nucleus segmentation is required to analyse the ESC dynamics and differentiation at a single cell resolution. Several methods used concavities on nucleus contours to segment overlapping cell nuclei. Our proposed method evaluates not only the concavities but also the size and shape of every 2D nucleus region to determine if any of the strait, extrusion, convexity and large diameter criteria is satisfied to segment overlapping nuclei inside the region. We then use a 3D segmentation method to reconstruct simple, convex, and reasonably sized 3D nuclei along the image stacking direction using the radius and centre of every segmented region in respective microscopy images. To avoid false concavities on nucleus boundaries, fluorescence images of the H2B-mCherry reporter are used for localisation of cell nuclei and Venus fluorescence images are used for determining the cell colony ranges. We use a series of image preprocessing procedures to remove noise outside and inside cell colonies, and in respective nuclei, and to smooth nucleus boundaries based on the colony ranges.  We propose dynamic data structures to record every segmented nucleus region and solid in sets (volumes) of 3D confocal images. The experimental results show that the proposed image preprocessing method preserves the areas of mouse ESC nuclei on microscopy images and that the segmentation method effectively segment out every nucleus with a reasonable size and shape. All 3D nuclei in a set (volume) of confocal microscopy images can be accessed by the dynamic data structures for 3D reconstruction. The 3D nuclei in time-lapse confocal microscopy images can be tracked to calculate cell movement and proliferation in consecutive volumes for understanding the dynamics of the differentiation characteristics about ESCs. LAY DESCRIPTION: Embryonic stem cells (ESCs) are considered as an ideal source for basic cell biology study and producing medically useful cells in vitro. This study uses time-lapse confocal fluorescence microscopy images from mouse ESCs carrying reporter gene to monitor dynamic changes in cellular/differentiation characteristics of live ESCs. To automate analyses of ESC differentiation behaviours, accurate cell nucleus segmentation to distinguish respective cells are required. A series of image preprocessing procedures are implemented to remove noise in live-cell fluorescence images but yield overlapping cell nuclei. A segmentation method that evaluates boundary concavities and the size and shape of every nucleus is then used to determine if any of the strait, extrusion, convexity, large and local minimum diameter criteria satisfied to segment overlapping nuclei. We propose a dynamic data structure to record every newly segmented nucleus. The experimental results show that the proposed image preprocessing method preserves the areas of mouse ESC nuclei and that the segmentation method effectively detects overlapping nuclei. All segmented nuclei in confocal images can be accessed using the dynamic data structures to be visualised and manipulated for quantitative analyses of the ESC differentiation behaviours. The manipulation can be tracking of segmented 3D cell nuclei in time-lapse images to calculate their dynamics of differentiation characteristics.

Automatic detection of early gastric cancer in endoscopic images using a transferring convolutional neural network.

Endoscopic image diagnosis assisted by machine learning is useful for reducing misdetection and interobserver variability. Although many results have been reported, few effective methods are available to automatically detect early gastric cancer. Early gastric cancer have poor morphological features, which implies that automatic detection methods can be extremely difficult to construct. In this study, we proposed a convolutional neural network-based automatic detection scheme to assist the diagnosis of early gastric cancer in endoscopic images. We performed transfer learning using two classes (cancer and normal) of image datasets that have detailed texture information on lesions derived from a small number of annotated images. The accuracy of our trained network was 87.6%, and the sensitivity and specificity were well balanced, which is important for future practical use. We also succeeded in presenting a candidate region of early gastric cancer as a heat map of unknown images. The detection accuracy was 82.8%. This means that our proposed scheme may offer substantial assistance to endoscopists in decision making.

Nonsphericity Index and Size Ratio Identify Morphologic Differences between Growing and Stable Aneurysms in a Longitudinal Study of 93 Cases.

BACKGROUND AND PURPOSE: Recent studies have strongly associated intracranial aneurysm growth with increased risk of rupture. Identifying aneurysms that are likely to grow would be beneficial to plan more effective monitoring and intervention strategies. Our hypothesis is that for unruptured intracranial aneurysms of similar size, morphologic characteristics differ between aneurysms that continue to grow and those that do not. MATERIALS AND METHODS: From aneurysms in our medical center with follow-up imaging dates in 2015, ninety-three intracranial aneurysms (23 growing, 70 stable) were selected. All CTA images for the aneurysm diagnosis and follow-up were collected, a total of 348 3D imaging studies. Aneurysm 3D geometry for each imaging study was reconstructed, and morphologic characteristics, including volume, surface area, nonsphericity index, aspect ratio, and size ratio were calculated. RESULTS: Morphologic characteristics were found to differ between growing and stable groups. For aneurysms of <3 mm, nonsphericity index (P < .001); 3-5 mm, nonsphericity index (P < .001); 5-7 mm, size ratio (P = .003); >7 mm, volume (P < .001); surface area (P < .001); and nonsphericity index (P = .002) were significant. Within the anterior communicating artery, the nonsphericity index (P = .008) and, within the posterior communicating artery, size ratio (P = .004) were significant. The nonsphericity index receiver operating characteristic area under the curve was 0.721 for discriminating growing and stable cases on the basis of initial images. CONCLUSIONS: Among aneurysms with similar sizes, morphologic characteristics appear to differ between those that are growing and those that are stable. The nonsphericity index, in particular, was found to be higher among growing aneurysms. The size ratio was found to be the second most significant parameter associated with growth.

MR Imaging of the Superior Cervical Ganglion and Inferior Ganglion of the Vagus Nerve: Structures That Can Mimic Pathologic Retropharyngeal Lymph Nodes.

BACKGROUND AND PURPOSE: The superior cervical ganglion and inferior ganglion of the vagus nerve can mimic pathologic retropharyngeal lymph nodes. We studied the cross-sectional anatomy of the superior cervical ganglion and inferior ganglion of the vagus nerve to evaluate how they can be differentiated from the retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study consists of 2 parts. Cohort 1 concerned the signal intensity of routine neck MR imaging with 2D sequences, apparent diffusion coefficient, and contrast enhancement of the superior cervical ganglion compared with lymph nodes with or without metastasis in 30 patients. Cohort 2 used 3D neurography to assess the morphology and spatial relationships of the superior cervical ganglion, inferior ganglion of the vagus nerve, and the retropharyngeal lymph nodes in 50 other patients. RESULTS: All superior cervical ganglions had homogeneously greater enhancement and lower signal on diffusion-weighted imaging than lymph nodes. Apparent diffusion coefficient values of the superior cervical ganglion (1.80 ± 0.28 × 10-3mm2/s) were significantly higher than normal and metastatic lymph nodes (0.86 ± 0.10 × 10-3mm2/s, P < .001, and 0.73 ± 0.10 × 10-3mm2/s, P < .001). Ten and 13 of 60 superior cervical ganglions were hypointense on T2-weighted images and had hyperintense spots on both T1- and T2-weighted images, respectively. The latter was considered fat tissue. The largest was the superior cervical ganglion, followed in order by the retropharyngeal lymph node and the inferior ganglion of the vagus nerve (P < .001 to P = .004). The highest at vertebral level was the retropharyngeal lymph nodes, followed, in order, by the inferior ganglion of the vagus nerve and the superior cervical ganglion (P < .001 to P = .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral. CONCLUSIONS: The superior cervical ganglion and the inferior ganglion of the vagus nerve can be almost always differentiated from retropharyngeal lymph nodes on MR imaging by evaluating the signal, size, and position.

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. METHODS: Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. RESULTS AND DISCUSSION: The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. WHAT IS NEW AND CONCLUSION: Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients.

Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma.

Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, has a critical role in a mouse model of acute glaucoma. The mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased after IOP-induced retinal ischemia. Blockade of the CXCR3 pathway by deleting CXCR3 gene significantly attenuated ischemic injury-induced upregulation of inflammatory molecules (interleukin-1ß and E-selectin), inhibited the recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented the loss of neurons within the ganglion cell layer. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with chemical chaperones partially blocked ischemic injury-induced CXCL10 upregulation, whereas induction of ER stress with tunicamycin enhanced CXCL10 expression in retina and primary retinal ganglion cells. Interestingly, deleting CXCR3 attenuated ER stress-induced retinal cell death. In conclusion, these results indicate that ER stress-medicated activation of CXCL10/CXCR3 pathway has an important role in retinal inflammation and neuronal injury after high IOP-induced ischemia.

Significance of caveolin-1 and matrix metalloproteinase 14 gene expression in canine mammary tumours.

Canine mammary tumours (CMTs) are the most common neoplasms affecting female dogs. There is an urgent need for molecular biomarkers that can detect early stages of the disease in order to improve accuracy of CMT diagnosis. The aim of this study was to examine whether caveolin-1 (Cav-1) and matrix metalloproteinase 14 (MMP14) are associated with CMT histological malignancy and invasion. Sixty-five benign and malignant CMT samples and six normal canine mammary glands were analysed using quantitative reverse transcription-polymerase chain reaction. Cav-1 and MMP14 genes were highly expressed in CMT tissues compared to normal tissues. Cav-1 especially was overexpressed in malignant and invasive CMT tissues. When a CMT cell line was cultured on fluorescent gelatin-coated coverslips, localisation of Cav-1 was observed at invadopodia-mediated degradation sites of the gelatin matrix. These findings suggest that Cav-1 may be involved in CMT invasion and that the markers may be useful for estimating CMT malignancy.

Chondroprotective effects of Salubrinal in a mouse model of osteoarthritis.

OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92.

The missing boundary in the phase diagram of PbZr(1-x)TixO3.

PbZr(1-x)Ti(x)O3 (PZT) is one of the most important and widely used piezoelectric materials. The study of its local and average structures is of fundamental importance in understanding the origin of its high-performance piezoelectricity. Pair distribution function analysis and Rietveld refinement have been carried out to study both the short- and long-range order in the Zr-rich rhombohedral region of the PZT phase diagram. The nature of the monoclinic phase across the Zr-rich and morphotropic phase boundary area of PZT is clarified. Evidence is found that long-range average rhombohedral and both long- and short-range monoclinic regions coexist at all compositions. In addition, a boundary between a monoclinic (M(A)) structure and another monoclinic (M(B)) structure has been found. The general advantage of a particular monoclinic distortion (M(A)) for high piezoactivity is discussed from a spatial structural model of susceptibility to stress and electric field, which is applicable across the wide field of perovskite materials science.

Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: a JGOG study.

BACKGROUND: Based on the result of our previous study showing better overall survival (OS) at the lower dose (0.2 µg) of immunomodulator Z-100 than higher dose (40 µg) in patients with locally advanced cervical cancer who received radiotherapy, we conducted a placebo-controlled double-blind randomized trial. PATIENTS AND METHODS: Patients of stages IIB-IVA squamous cell carcinoma of the uterine cervix were randomly assigned to receive Z-100 at 0.2 µg (Z) or placebo (P). The study agent was given subcutaneously twice a week during the radiotherapy, followed by maintenance therapy by administering once every 2 weeks until disease progression. Primary end point was OS, and secondary end points were recurrence-free survival, and toxicity. RESULTS: A total of 249 patients were randomized. Death events occurred extremely slower than expected, and Independent Data Monitoring Committee recommended to analyze the survival result prematurely. The 5-year OS rate was 75.7% [95% confidence interval (CI) 66.4% to 82.8%] for Arm Z and 65.8% (95% CI 56.2% to 73.8%) for Arm P (P = 0.07); hazard ratio was 0.65 (95% CI 0.40-1.04). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There was no trend in recurrence-free survival between the two arms. Side-effects were not different between two arms. CONCLUSION: Z-100 showed a trend of improvement on OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Validation of potential survival benefit of immune modulation should be made. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000221.

Surgery for endometrial cancers with suspected cervical involvement: is radical hysterectomy needed (a GOTIC study)?

BACKGROUND: Radical hysterectomy is recommended for endometrial adenocarcinoma patients with suspected gross cervical involvement. However, the efficacy of operative procedure has not been confirmed. METHODS: The patients with endometrial adenocarcinoma who had suspected gross cervical involvement and underwent hysterectomy between 1995 and 2009 at seven institutions were retrospectively analysed (Gynecologic Oncology Trial and Investigation Consortium of North Kanto: GOTIC-005). Primary endpoint was overall survival, and secondary endpoints were progression-free survival and adverse effects. RESULTS: A total of 300 patients who underwent primary surgery were identified: 74 cases with radical hysterectomy (RH), 112 patients with modified radical hysterectomy (mRH), and 114 cases with simple hysterectomy (SH). Median age was 47 years, and median duration of follow-up was 47 months. There were no significant differences of age, performance status, body mass index, stage distribution, and adjuvant therapy among three groups. Multi-regression analysis revealed that age, grade, peritoneal cytology status, and lymph node involvement were identified as prognostic factors for OS; however, type of hysterectomy was not selected as independent prognostic factor for local recurrence-free survival, PFS, and OS. Additionally, patients treated with RH had longer operative time, higher rates of blood transfusion and severe urinary tract dysfunction. CONCLUSION: Type of hysterectomy was not identified as a prognostic factor in endometrial cancer patients with suspected gross cervical involvement. Perioperative and late adverse events were more frequent in patients treated with RH. The present study could not find any survival benefit from RH for endometrial cancer patients with suspected gross cervical involvement. Surgical treatment in these patients should be further evaluated in prospective clinical studies.

Rac1 mediates load-driven attenuation of mRNA expression of nerve growth factor beta in cartilage and chondrocytes.

OBJECTIVES: To determine effect of gentle loads applied to the knee on mRNA expression of nerve growth factor, particularly, the active beta subunit (NGFß) in cartilage and chondrocyte. METHODS: Cyclic compressive loads in vivo and fluid flow in vitro were used to determine the mRNA levels. Alteration of Rac1 GTPase as well as effect of salubrinal, a specific inhibitor of eIF2α phosphatase was assessed using fluorescence resonance energy transfer (FRET)-based Rac1 biosensor. RESULTS: Knee loading at 1 N reduced mRNA levels of NGFß and its low affinity receptor, p75 in cartilage and subchondral bone. In cartilage, knee loading at 1 N reduced the phosphorylation level of p38 MAPK (p38-p) and activity of Rac1 GTPase. Consistent with in vivo results, fluid flow at 5 and 10 dyn/cm(2) reduced mRNA levels of NGFß and p75 in C28/I2 human chondrocytes. SB203580, which decreases p38-p, reduced the mRNA levels of NGFß and p75. Silencing Rac1 by siRNA decreased the levels of p38-p and NGFß mRNA but not p75. Furthermore, administration of salubrinal reduced FRET-based activity of Rac1 as well as the mRNA levels of NGFß and p75. CONCLUSIONS: These results provide evidence that mechanical stimulation and salubrinal may attenuate pain perception-linked NGFß signaling through Rac1-mediated p38 MAPK.

UGT1A1 genotype-specific phase I and pharmacokinetic study for combination chemotherapy with irinotecan and cisplatin: a Saitama Tumor Board study.

INTRODUCTION: Genotyping of UGTI1Al could be useful for prediction of severe toxicities for patients treated with irinotecan; however, genotype-based recommended dose (RD) has not been established. The aim of the present study was to determine the RD of irinotecan in combination with cisplatin (CPT-P) for individuals with or without UGT1A1 polymorphisms. MATERIALS AND METHODS: According to polymorphisms of UGTIAl*28, *6, and *27, RDs were determined by three-case cohort methods for patients with wild-type and heterotype, and by inter-patient dose escalation for homotype patients. Pharmacokinetic studies were also evaluated. During May 2009 and July 2011, 18 Japanese patients were enrolled; 16 patients with ovarian carcinoma, and two cases with cervical cancer. The RD of irinotecan was determined as 50 mg/m2 for the patients with wild-type, 40 mg/m2 for those with heterotype, and 30 mg/m2 for homotype UGT IAl genotype. RESULTS: Patients with homotype UGTIAl1 alleles had a significantly lower glucuronidation ratio in comparison with UGTIAI wild-type and heterotype cases. CONCLUSION: UGT1A1 genotype-based RDs of irinotecan in CPT-P therapy were determined. Further studies to investigate efficacy of the RD including response evaluation are needed to confirm the present results.