Impact of combined resection of the internal iliac artery on loss of volume of the gluteus muscles after pelvic exenteration.

PURPOSE: To clarify the influence of additional internal iliac artery (IIA) resection on the loss of the gluteus muscle volume after pelvic exenteration (PE). METHODS: The subjects of this retrospective analysis were 78 patients who underwent PE with or without IIA resection (n = 44 and n = 34, respectively) between 2006 and 2018. The areas of gluteal muscles (GMs) and psoas muscles (PSMs) were calculated using CT images before and 6 months after PE, and the difference was compared. RESULTS: The volumes of the GMs and PSMs were significantly reduced after PE (P < 0.001 and P = 0.005, respectively). In the IIA resection group, the GMs were significantly reduced after surgery, but the PSMs were not. The maximum GM (Gmax) was the most atrophied among the GMs. Multivariable analysis revealed that complete IIA resection was an independent promotor of the loss of volume of the Gmax (P = 0.044). In 18 patients with unilateral IIA resection, the downsizing rate of the Gmax was significantly greater on the resected side than on the non-resected side (P = 0.008). CONCLUSIONS: The GMs and PSMs were significantly smaller after PE. Complete IIA resection reduced the Gmax area remarkably. Preservation of the superior gluteus artery is likely to help maintain Gmax size, suggesting a potential preventative measure against secondary sarcopenia.

Stoma creation is associated with a low incidence of midline incisional hernia after colorectal surgery: the "fighting over the fascia" theory concerning the incision and stoma hole.

PURPOSE: Parastomal hernia (PH) develops more frequently than incisional hernia (IH) after colorectal surgery with stoma. This study evaluated our hypothesis that inward traction of the fascia when closing a midline incision widens the stoma hole and increases the incidence of PH. METHODS: A total of 795 patients who underwent colorectal resection between 2006 and 2016 were retrospectively analyzed. The risk classification was constructed from IH risk factors extracted from the non-stoma group. Then, the classification was extrapolated to the stoma group for predicting midline IH and PH. RESULTS: The incidence of IH was 5.3% in the stoma group and 12.5% in the non-stoma group (p = 0.005). PH developed in 19.6% of 97 patients with permanent stoma. The risk classification was able to predict PH without a significant difference but was well balanced in patients with permanent stoma; however, it failed to predict IH in the stoma group. CONCLUSION: The risk classification constructed from the non-stoma group was useful for predicting not midline IH but PH, suggesting that the stoma site was the most vulnerable for herniation. The "fighting over the fascia" theory between the midline incision and stoma hole may explain the causal relationship between the midline IH and PH.

Radiomics in breast MRI: current progress toward clinical application in the era of artificial intelligence.

Breast magnetic resonance imaging (MRI) is the most sensitive imaging modality for breast cancer diagnosis and is widely used clinically. Dynamic contrast-enhanced MRI is the basis for breast MRI, but ultrafast images, T2-weighted images, and diffusion-weighted images are also taken to improve the characteristics of the lesion. Such multiparametric MRI with numerous morphological and functional data poses new challenges to radiologists, and thus, new tools for reliable, reproducible, and high-volume quantitative assessments are warranted. In this context, radiomics, which is an emerging field of research involving the conversion of digital medical images into mineable data for clinical decision-making and outcome prediction, has been gaining ground in oncology. Recent development in artificial intelligence has promoted radiomics studies in various fields including breast cancer treatment and numerous studies have been conducted. However, radiomics has shown a translational gap in clinical practice, and many issues remain to be solved. In this review, we will outline the steps of radiomics workflow and investigate clinical application of radiomics focusing on breast MRI based on published literature, as well as current discussion about limitations and challenges in radiomics.

Phosphorylation-dependent Akt-Inversin interaction at the basal body of primary cilia.

A primary cilium is a microtubule-based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two-hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co-immunoprecipitation assays show that Akt interacts with INVS via the C-terminus. In vitro kinase assays demonstrate that Akt phosphorylates INVS at amino acids 864-866 that are required not only for Akt interaction, but also for INVS dimerization. Co-localization of INVS and phosphorylated form of Akt at the basal body is augmented by PDGF-AA Akt-null MEF cells as well as siRNA-mediated inhibition of Akt attenuated ciliary growth, which was reversed by Akt reintroduction. Mutant phosphodead- or NPHP2-related truncated INVS, which lack Akt phosphorylation sites, suppress cell growth and exhibit distorted lumen formation and misalignment of spindle axis during cell division. Further studies will be required for elucidating functional interactions of Akt-INVS at the primary cilia for identifying the molecular mechanisms underlying NPHP2.

Identification of RNA aptamer which specifically interacts with PtdIns(3)P.

The phosphinositide PtdIns(3)P plays an important role in autophagy; however, the detailed mechanism of its activity remains unclear. Here, we used a Systematic Evolution of Ligands by EXponential enrichment (SELEX) screening approach to identify an RNA aptamer of 40 nucleotides that specifically recognizes and binds to intracellular lysosomal PtdIns(3)P. Binding occurs in a magnesium concentration- and pH-dependent manner, and consequently inhibits autophagy as determined by LC3II/I conversion, p62 degradation, formation of LC3 puncta, and lysosomal accumulation of Phafin2. These effects in turn inhibited lysosomal acidification, and the subsequent hydrolytic activity of cathepsin D following induction of autophagy. Given the essential role of PtdIns(3)P as a key targeting molecule for autophagy induction, identification of this novel PtdIns(3)P RNA aptamer provides new opportunities for investigating the biological functions and mechanisms of phosphoinositides.

Background parenchymal enhancement in preoperative breast MRI.

We aimed to assess the influence of background parenchymal enhancement (BPE) on surgical planning performed using preoperative MRI for breast cancer evaluation. Between January 2009 and December 2010, 91 newly diagnosed breast cancer patients (mean age, 55.5 years; range, 30-88 years) who underwent preoperative bilateral breast MRI followed by planned breast conservation therapy were retrospectively enrolled. MRI was performed to assess the tumor extent in addition to mammography and breast ultrasonography. BPE in the contralateral normal breast MRI at the early dynamic phase was visually classified as follows: minimal (n=49), mild (n=27), moderate (n=7), and marked (n=8). The correlations between the BPE grade and age, menopausal status, index tumor size, changes in surgical management based on MRI results, positive predictive value (PPV) of MRI, and surgical margins were assessed. Patients in the strong BPE groups were significantly younger (p=0.002) and generally premenopausal (p<0.001). Surgical treatment was not changed in 67 cases (73.6%), while extended excision and mastectomy were performed in 12 cases (13.2%), each based on additional lesions on MRI. Six of 79 (7.6%) patients who underwent breast conservation therapy had tumor-positive resection margins. In cases where surgical management was changed, the PPV for MRI-detected foci was high in the minimal (91.7%) and mild groups (66.7%), and 0% in the moderate and marked groups (p=0.002). Strong BPE causes false-positive MRI findings and may lead to overly extensive surgery, whereas MRI may be beneficial in select patients with weak BPE.

Prediction of background parenchymal enhancement on breast MRI using mammography, ultrasonography, and diffusion-weighted imaging.

This retrospective study assessed the effects of menopausal status and menstrual cycle on background parenchymal enhancement (BPE) of breast magnetic resonance imaging (MRI), and investigated whether the degree of BPE can be predicted by findings of mammography, ultrasonography (US), and diffusion-weighted MR imaging (DWI). There were 160 study patients (80 premenopausal, 80 postmenopausal). Degree of BPE was classified into minimal, mild, moderate, or marked. Mammographic density was classified into fatty, scattered, heterogeneously dense, and extremely dense. BP echotexture on US and BP intensity on DWI were visually classified as homogeneous or heterogeneous. Apparent diffusion coefficient (ADC) values of normal breast tissue were measured. Associations of the degree of BPE with menopausal status, menstrual cycle, or imaging features were evaluated by univariate and multivariate analyses. No significant correlation was found between mammographic density and BPE (p=0.085), whereas menopausal status (p=0.000), BP echotexture (p=0.000), and BP intensity on DWI (p= 0.000), and ADC values (p=0.000) showed significant correlations with BPE. Multivariate analysis showed that postmenopausal status was an independent predictor of minimal BPE (p=0.002, OR=3.743). In premenopausal women, there was no significant correlation between menstrual cycle and BPE, whereas BP echotexture was an independent predictor of whether BPE was less than mild or greater than moderate (p=0.001, OR=26.575). BPE on breast MRI is associated with menopausal status and the findings of US and DWI. Because premenopausal women with heterogeneous BP echotexture may be predicted to show moderate or marked BPE, scheduling of breast MRI should preferentially be adjusted to the menstrual cycle.

Predictive Performance of Radiomic Features Extracted from Breast MR Imaging in Postoperative Upgrading of Ductal Carcinoma in Situ to Invasive Carcinoma.

PURPOSE: To investigate the predictive performance of radiomic features extracted from breast MRI for upgrade of ductal carcinoma in situ (DCIS) to invasive carcinoma. METHODS: This retrospective study included 71 women with DCIS lesions diagnosed preoperatively by biopsy. All women underwent breast dynamic contrast-enhanced (DCE) MRI of the breast, which included pre-contrast and five post-contrast phases continuously with a time resolution of 60s. Lesion segmentation was performed manually, and 144 radiomic features of the lesions were extracted from T2-weighted images (T2WI), pre-contrast T1-weighted images (T1WI), and post-contrast 1st, 2nd, and 5th phase subtraction images on DCE-MRI. Qualitative features of mammography, ultrasound, and MRI were also assessed. Clinicopathological features were evaluated using medical records. The least absolute shrinkage and selection operator (LASSO) algorithm was applied for features selection and model building. The predictive performance of postoperative upgrade to invasive carcinoma was assessed using the area under the receiver operating characteristic curve. RESULTS: Surgical specimens revealed 13 lesions (18.3%) that were upgraded to invasive carcinoma. Among clinicopathological and qualitative features, age was the only significant predictive variable. No significant radiomic features were observed on T2WI and post-contrast 2nd phase subtraction images on DCE-MRI. The area under the curves (AUCs) of the LASSO radiomics model integrated with age were 0.915 for pre-contrast T1WI, 0.862 for post-contrast 1st phase subtraction images, and 0.833 for post-contrast 5th phase subtraction images. The AUCs of the 200-times bootstrap internal validations were 0.885, 0.832, and 0.775. CONCLUSION: A radiomics approach using breast MRI may be a promising method for predicting the postoperative upgrade of DCIS. The present study showed that the radiomic features extracted from pre-contrast T1WI and post-contrast subtraction images in the very early phase of DCE-MRI were more predictable.

¹H-magnetic resonance spectroscopy of the breast at 3.0-T: comparison of results obtained before and after administration of gadolinium-based contrast agent.

PURPOSE: To assess the effects of gadolinium-based contrast agent (GBCA) on (1) H-magnetic resonance spectroscopy (MRS) of the breast at 3.0-T. MATERIALS AND METHODS: Patients (n = 98) with breast cancer (98 lesions) underwent MRS (point-resolved spectroscopy sequence [PRESS]; TR/TE, 2000/100 msec; voxel size, 15 × 15 × 15 mm) before the administration of GBCA. In 52 of those patients, MRS was also performed after the administration of GBCA. The voxel-of-interest (VOI) was placed by referring to the noncontrast-enhanced MRI (diffusion-weighted images combined with fat-suppressed T2-weighted images). We reviewed and graded the appropriateness of VOI location compared to the correlating enhancement lesions. Integral values of the choline peak at a frequency of 3.2 ppm on MRS were compared before and after the administration of GBCA. RESULTS: The VOI was placed correctly in 64 lesions (65%), although the VOI was placed outside the targeted lesion in 34 lesions (35%). The integral value of the choline peak on MRS decreased significantly after the administration of GBCA (P < 0.001). CONCLUSION: Accumulation of GBCA in breast cancer could affect the choline peak on MRS. MRS of breast cancer at 3.0-T can be recommended to be acquired before contrast-enhanced study; however, some problems remain in VOI placement with reference to the noncontrast-enhanced study.

Diffusion-weighted imaging of breast masses: comparison of diagnostic performance using various apparent diffusion coefficient parameters.

OBJECTIVE: The purpose of our study was to assess the utility of the minimum apparent diffusion coefficient (ADC), average ADC, maximum ADC, and ADC difference value and to find optimum ADC parameters for differentiation between benign and malignant lesions in breast diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Sixty-seven women with 75 masslike lesions (27 benign, 48 malignant) were examined with 3-T MRI. To assess heterogeneity within the lesion, the difference between minimum and maximum ADCs was recorded as the ADC difference value. Diagnostic performances of these parameters were compared by receiver operating characteristic (ROC) curve analysis. RESULTS: Each ADC parameter showed significant differences between malignant and benign lesions. The optimal cutoff levels for differentiating benign versus malignant lesions were determined by identifying the points where the sensitivity and specificity were equal on the ROC curves. According to ROC analyses, the following sensitivities and specificities were obtained: average ADC, 75.6% and 75.6%; minimum ADC, 85.5% and 85.5%; maximum ADC, 63.5% and 63.5%; ADC difference value, 70.1% and 70.1%. Minimum ADC had the largest area under the ROC curve (AUC) of 0.93. Minimum ADC combined with the ADC difference value improved the AUC to 0.95, with sensitivity and specificity of 89.1% and 89.1%. CONCLUSION: Minimum ADC may be an optimal DWI single parameter for differentiation between malignant and benign lesions of breast masses. Furthermore, the combination of the minimum ADC and ADC difference value significantly elevated diagnostic performance of breast DWI in comparison with average ADC.

Features from MRI texture analysis associated with survival outcomes in triple-negative breast cancer patients.

PURPOSE: The purpose of the study is to evaluate the associations between intratumoral or peritumoral textural features derived from pretreatment magnetic resonance imaging (MRI) and recurrence-free survival (RFS) in triple-negative breast cancer (TNBC) patients. METHODS: Forty-three patients with TNBC who underwent preoperative MRI between February 2008 and March 2014 were included. We performed two-dimensional texture analysis on the intratumoral or peritumoral region of interest (ROI) on axial of T2-weighted image (T2WI), dynamic contrast-enhanced (DCE)-MRI and DCE-MRI subtraction images. We also analyzed histopathological data. Cox proportional hazards models were used to investigate associations with survival outcomes. RESULTS: Twelve of the 43 patients (27.9%) had recurrence disease, at a median of 32.5 months follow-up (1.4-61.5 months). In univariate analysis, nine texture features in T2WI and DCE-MRI subtraction images were significantly associated with RFS. In multivariate analysis, intratumoral difference entropy in DCE-MRI subtraction images in the initial phase (hazard ratio 11.71; 95% confidence interval (CI) [1.41, 97.00]; p value 0.023) and, peritumoral difference variance in DCE-MRI subtraction images in the delayed phase (hazard ratio 9.60; 95% CI [1.98, 46.51]; p value 0.005), were both independently associated with RFS. Moreover, multivariate analysis revealed the presence of lymphovascular invasion as independently associated with RFS (hazard ratio 8.13; 95% CI [2.16, 30.30]; p value 0.002). CONCLUSIONS: At pretreatment MRI, an intratumoral and peritumoral quantitative approach using texture analysis has the potential to serve as a prognostic marker in patients with TNBC.

Physiological background parenchymal uptake of 18F-FDG in normal breast tissues using dedicated breast PET: correlation with mammographic breast composition, menopausal status, and menstrual cycle.

OBJECTIVE: This study aimed to quantitatively evaluate the effects of age, mammographic density, menopausal status, and menstrual cycle on background parenchymal uptake (BPU) using ring-shaped dedicated breast positron emission tomography (dbPET). METHODS: This study included 186 adult women who underwent mammography and dbPET on the same day and had no abnormalities classified as Breast Imaging Reporting and Data System (BI-RADS) category 1 on both examinations. The volume of interest (VOI) was placed in the glandular tissue of both breasts, and the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and metabolic breast volume (MBV) were measured as indicators of BPU. We analyzed the correlation between BPU and age, mammographic density, menopausal status, and menstrual cycle. RESULTS: The SUVmax and SUVmean for normal breast tissue were inversely correlated with age (both p < 0.001). The SUVmax, SUVmean, and MBV of mammographically dense breast tissues were significantly higher than those of non-dense breast tissues (all p < 0.001). The SUVmax, SUVmean, and MBV of normal breast tissue in premenopausal women were significantly higher than those in postmenopausal women (p < 0.001, p < 0.001, p = 0.002, respectively). In the study, 59 premenopausal women, the SUVmax of normal breast tissue in the menstrual-follicular phase was significantly lower than that in the periovulatory-luteal phase (p = 0.02). When we sorted the premenopausal women by mammographic breast composition, the SUVmax and SUVmean of normal breast tissues in the menstrual-follicular phase were significantly lower than those in the periovulatory-luteal phase in the 44 premenopausal women with dense breasts (p = 0.007, and p = 0.038, respectively), whereas no statistically significant difference was found between the menstrual-follicular phase and the periovulatory-luteal phase in the 15 premenopausal women with non-dense breasts. CONCLUSIONS: BPU in normal breast tissues assessed using ring-shaped dbPET was associated with mammographic density, menopausal status, and women's menstrual cycle. The menstrual cycle was significantly associated with BPU in premenopausal women with dense breasts but not in women with non-dense breasts.

Predictive value for malignancy of suspicious breast masses of BI-RADS categories 4 and 5 using ultrasound elastography and MR diffusion-weighted imaging.

OBJECTIVE: The aim of this study is to evaluate the ability of ultrasound elastography and MR diffusion-weighted imaging (DWI) to predict malignancy of breast masses, with subsequent recommendation for biopsy. MATERIALS AND METHODS: For 115 breast masses classified as BI-RADS category 4 or 5, which were assessed according to combined findings of mammography, B-mode sonography, and dynamic contrast-enhanced MRI, two radiologists retrospectively evaluated the elasticity scores using ultrasound elastography and the apparent diffusion coefficient (ADC) values using MR DWI. The diagnostic abilities of these two techniques were analyzed by using univariate and multivariate logistic regression analysis. RESULTS: In the analysis of all 115 breast masses, the elasticity score was predictive of malignancy, whereas the ADC value was not independently predictive. In an analysis of the 52 masses assessed as BI-RADS category 4, the elasticity score was found to be a significant predictor of malignancy, compared with the ADC value, which was a nonsignificant predictor. In an analysis of the 63 masses assessed as BI-RADS category 5, neither the elasticity score nor the ADC value was a significant predictor of malignancy. CONCLUSION: Our results show that elasticity imaging provides relatively reliable predictions for malignancy, especially in BI-RADS category 4 masses, compared with MR DWI.

Early prediction of response to neoadjuvant chemotherapy for locally advanced breast cancer using MRI.

Neoadjuvant chemotherapy (NAC) is the favored treatment of choice among locally advanced breast cancer patients because it significantly increases the possibility of breast-conserving surgery. However, for non-responders, an early prediction of response to NAC is essential. The purpose of this study was to determine whether an early prediction of response to NAC is possible using MRI. Eleven breast cancer patients (12 lesions) scheduled to receive NAC were recruited for this study. The patients were examined by MRI prior to and after the first and fourth courses of anthracycline-containing chemotherapy and after subsequent taxane-containing chemotherapy. Lesions were divided into 2 types (mass type and non-mass type) based on contrast MRI prior to chemotherapy. Among 8 mass types, 6 were responders (R) and 2 were non-responders (NR). R cases showed either an increased apparent diffusion coefficient (ADC) or volume reduction after the first course of NAC, whereas NR cases showed neither (p < 0.005). Of the 4 non-mass types, 2 were R and 2 were NR. Changes in ADC or volume after the first course of NAC may indicate chemo-sensitivity for mass-type breast cancer. However, the same method cannot be used to predict the response to NAC for non-mass types.

Kinetic volume analysis on dynamic contrast-enhanced MRI of triple-negative breast cancer: associations with survival outcomes.

OBJECTIVE: To evaluate the associations between computer-aided diagnosis (CAD)-generated kinetic volume parameters and survival in triple-negative breast cancer (TNBC) patients. METHODS: 40 patients with TNBC who underwent pre-operative MRI between March 2008 and March 2014 were included. We analyzed CAD-generated parameters on dynamic contrast-enhanced MRI, visual MRI assessment, and histopathological data. Cox proportional hazards models were used to determine associations with survival outcomes. RESULTS: 12 of the 40 (30.0%) patients experienced recurrence and 7 died of breast cancer after a median follow-up of 73.6 months. In multivariate analysis, higher percentage volume (%V) with more than 200% initial enhancement rate correlated with worse disease-specific survival (hazard ratio, 1.12; 95% confidence interval, 1.02-1.22; p-value, 0.014) and higher %V with more than 100% initial enhancement rate followed by persistent curve type at 30% threshold correlated with worse disease-specific survival (hazard ratio, 1.33; 95% confidence interval, 1.10-1.61; p-value, 0.004) and disease-free survival (hazard ratio, 1.27; 95% confidence interval, 1.12-1.43; p-value, 0.000). CONCLUSION: CAD-generated kinetic volume parameters may correlate with survival in TNBC patients. Further study would be necessary to validate our results on larger cohorts. ADVANCES IN KNOWLEDGE: CAD generated kinetic volume parameters on breast MRI can predict recurrence and survival outcome of patients in TNBC. Varying the enhancement threshold improved the predictive performance of CAD generated kinetic volume parameter.

LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren's syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren's syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease.ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.

Histogram analysis of quantitative pharmacokinetic parameters on DCE-MRI: correlations with prognostic factors and molecular subtypes in breast cancer.

BACKGROUND: Breast cancer heterogeneity influences poor prognoses thorough therapy resistance. This study quantitatively evaluated intratumoral heterogeneity through a histogram analysis of dynamic contrast-enhanced MRI (DCE-MRI) pharmacokinetic parameters, and determined correlations with prognostic factors and molecular subtypes. METHODS: We retrospectively investigated 101 invasive ductal breast cancers from 99 women who underwent preoperative DCE-MRI between July 2012 and November 2014. Pharmacokinetic parameters (Ktrans, kep, and ve) were obtained by the Tofts model. For each parameter, the mean, standard deviation, coefficient of variation, skewness, and kurtosis values of tumor were calculated, and prognostic factors and subtypes associations were assessed. RESULTS: The mean of ve was lower in cancers with high Ki-67 than in cancers with low Ki-67 (P = 0.002). The coefficient of variation of ve was higher in cancers with estrogen receptor negativity than in cancers with estrogen receptor positivity (P < 0.001). The coefficient of variation of ve was also higher in cancers with high Ki-67 than in cancers with low Ki-67 (P < 0.001). The skewness of ve was higher in cancers with high nuclear grade than in cancers with low nuclear grade (P = 0.006). Triple-negative cancers showed higher ve coefficient of variation than did those with luminal A (P < 0.001) and B (P = 0.006). CONCLUSIONS: Various ve parameters correlated with breast cancer prognostic factors and molecular subtypes.

Functional characterization of lysosomal interaction of Akt with VRK2.

Serine-threonine kinase Akt (also known as PKB, protein kinase B), a core intracellular mediator of cell survival, is involved in various human cancers and has been suggested to play an important role in the regulation of autophagy in mammalian cells. Nonetheless, the physiological function of Akt in the lysosomes is currently unknown. We have reported previously that PtdIns(3)P-dependent lysosomal accumulation of the Akt-Phafin2 complex is a critical step for autophagy induction. Here, to characterize the molecular function of activated Akt in the lysosomes in the process of autophagy, we searched for the molecules that interact with the Akt complex at the lysosomes after induction of autophagy. By time-of-flight-mass spectrometry (TOF/MS) analysis, kinases of the VRK family, a unique serine-threonine family of kinases in the human kinome, were identified. VRK2 interacts with Akt1 and Akt2, but not with Akt3; the C terminus of Akt and the N terminus of VRK2 facilitate the interaction of Akt and VRK2 in mammalian cells. The kinase-dead form of VRK2A (KD VRK2A) failed to interact with Akt in coimmunoprecipitation assays. Bimolecular fluorescence complementation (BiFC) experiments showed that, in the lysosomes, Akt interacted with VRK2A but not with VRK2B or KD VRK2A. Immunofluorescent assays revealed that VRK2 and phosphorylated Akt accumulated in the lysosomes after autophagy induction. WT VRK2A, but not KD VRK2A or VRK2B, facilitated accumulation of phosphorylated Akt in the lysosomes. Downregulation of VRK2 abrogated the lysosomal accumulation of phosphorylated Akt and impaired nuclear localization of TFEB; these events coincided to inhibition of autophagy induction. The VRK2-Akt complex is required for control of lysosomal size, acidification, bacterial degradation, and for viral replication. Moreover, lysosomal VRK2-Akt controls cellular proliferation and mitochondrial outer-membrane stabilization. Given the roles of autophagy in the pathogenesis of human cancer, the current study provides a novel insight into the oncogenic activity of VRK2-Akt complexes in the lysosomes via modulation of autophagy.

Prediction of prone-to-supine tumor displacement in the breast using patient position change: investigation with prone MRI and supine CT.

BACKGROUND: One of the challenges for clinical use of preoperative breast magnetic resonance imaging (MRI) is how to transfer prone MRI information to the operating theater with a supine surgical position. The aim of this study was to retrospectively evaluate tumor displacement in the breast by changing the patient position from prone to supine (prone-to-supine tumor displacement), using preoperative prone MRI and supine computed tomography (CT). METHODS: Preoperatively, 55 Japanese women with 57 breast cancer lesions underwent breast MRI in the prone position and breast CT in the supine position. Tumor positions in both the prone and supine positions were measured on X-, Y-, and Z-coordinates by fixing the nipple to the origin (0, 0, 0). As an indicator of the mobility of the breast, the ratio of the breast projection between the prone MRI and supine CT (prone-to-supine projection ratio) was calculated. The direction and distance of prone-to-supine tumor displacement was analyzed by dividing the breast into four quadrants according to the tumor position. RESULTS: When changing the patient position from prone to supine, tumors located in the inner-upper and inner-lower quadrants tended to move radially toward the center of the nipple. The movement distance of the tumors in the inner-lower and outer-lower quadrants was very strongly correlated with the prone-to-supine breast projection ratio (r ≥ 0.8, p < 0.05). Conversely, in the outer-upper quadrant, the direction of tumor displacement was variable, and the distance of tumor displacement did not correlate with the prone-to-supine projection ratio. CONCLUSIONS: The present study showed that prone-to-supine tumor displacement in the breast differs depending on tumor location. The inner-lower quadrant of the breast may be the most predictable area for prone-to-supine tumor displacement.

Multi-slice CT of thyroid nodules: comparison with ultrasonography.

PURPOSE: To evaluate the usefulness of multi-slice computed tomography (MSCT) in comparison with ultrasonography (US) for the differentiation of benign from malignant thyroid nodules and the evaluation of tumor extension. MATERIALS AND METHODS: Thirty patients with thyroid nodules (14 malignant, 16 benign) who underwent both MSCT and US participated in the present study. MSCT with contrast enhancement was performed, and 3D shaded volume rendering (SVR) and multiplanar reconstruction (MPR) were employed to differentiate benign from malignant nodules and to evaluate tumor extension. US images were obtained using a 7.5 MHz annular array probe. A three-point rating scale was used for image interpretation, and the kappa statistic was employed to evaluate agreement between MSCT and US. RESULTS: Sensitivity in differentiating benign from malignant nodules was found to be 85.7% for US and 78.6% for MSCT. Disagreement between MSCT and US occurred in assessing the homogeneity of the solid component and the presence of fibrous capsule. In two of seven T4 cases, MPR provided a more accurate diagnosis than US examination in detecting extracapsular invasion. CONCLUSION: For differential diagnosis of thyroid nodules, US was found to be better than MSCT. However, MSCT could be useful for the evaluation of advanced cases with suspicion of extracapsular extension.