The utility of the [-2]pro-prostate-specific antigen level as a prognostic marker in patients with castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: The prostate health index (phi) derived using [-2]pro-prostate-specific antigen (p2PSA), a precursor of PSA, has been shown to predict cancer in the gray zone. However, the utility of p2PSA in predicting outcomes for castration-resistant prostate cancer (CRPC) patients remains unknown. Therefore, in this study, we aimed to evaluate the usefulness of p2PSA in predicting the efficacy and prognosis of enzalutamide treatment in CRPC patients. METHODS: We conducted a prospective study of CRPC patients treated with enzalutamide at our institution, measuring p2PSA levels in 98 pre-treatment serum samples. All patients were divided into two groups based on the median values of each parameter. The PSA progression-free survival (PSA-PFS) and overall survival (OS) were compared using the Kaplan-Meier method. This study was approved by the Institutional Review Board of Gunma University Hospital (IRB No. 2021-092, 1983). RESULTS: The median PSA level before enzalutamide treatment was 25.59 ng/mL, the median p2PSA level was 208.75 pg/mL, and the median phi was 187.95. PSA, p2PSA, and phi were not all predictors of PSA-PFS. However, the OS was significantly better in the low-value groups (log-rank p-values of PSA, p2PSA, and phi were 0.024, 0.034, and 0.018, respectively). In the docetaxel (DOC)-naive group (n = 58), PSA was not a predictor of OS, but p2PSA and phi were significantly associated with better OS in the low group. This relationship was not observed in the DOC-treated group. CONCLUSIONS: Our study elucidates the usefulness of p2PSA in predicting outcomes for CRPC patients treated with enzalutamide. It suggests that p2PSA and phi may be prognostic markers after enzalutamide administration in CRPC patients.

[Malignant Central Nervous System Lymphoma after Radical Total Cystectomy : A Diagnostic Challenge].

We report a case of primary central nervous system lymphoma (PCNSL) in an 81-year-old man who had undergone radical cystectomy with an ileal conduit urostomy due to a diagnosis of muscle-invasive bladder cancer. The postoperative diagnosis was invasive urothelial carcinoma (pT2bN1M0, stage IV). Gemcitabine-cisplatin therapy was provided as adjuvant chemotherapy, and there was no recurrence during follow-up. Four years after surgery, he visited the emergency department because of weakness of the lower extremities and stuttering. He was found to have a parietal lobe mass on magnetic resonance imaging (MRI) and hospitalized with suspicion of brain metastasis. Despite examination by a neurosurgeon, it was not possible to make a clinical diagnosis, and the patient gradually deteriorated and died 21 days later. The pathology results were diagnostic of PCNSL.

Correlation of quantitative pancreatic T1 value and HbA1c value in subjects with normal and impaired glucose tolerance.

BACKGROUND: Signal intensity on T1 -weighted images (T1 WI) is associated with pancreatic fibrosis and HbA1c levels. PURPOSE: To evaluate the feasibility of the pancreatic T1 value for assessment of subjects with normal and impaired glucose tolerance (IGT). STUDY TYPE: A prospective single-institution study. POPULATION: In all, 95 consecutive patients with a known or suspected pancreatic disease. FIELD STRENGTH/SEQUENCES: 3T/fast pancreatic T1 mapping using a modified Look-Locker sequence. ASSESSMENT: Following the American Diabetes Association criteria, patients were classified into three groups, as follows: no-diabetes subject, HbA1c < 5.7%; prediabetes, 5.7% ≤ HbA1c < 6.5%; and type 2 diabetes mellitus (T2DM), HbA1c ≥ 6.5%. Pancreatic T1 value and signal intensity ratio (SIR = SIpancreas /SImuscle ) using T1 WI were compared with the HbA1c values. STATISTICAL TESTS: Quantitative data were assessed with one-way analysis of variance, Fisher's and Mann-Whitney U tests, and receiver-operating characteristic analysis. RESULTS: The pancreatic T1 value was significantly longer in T2DM than in no-diabetes and prediabetes subjects (P < 0.05) and was significantly longer in prediabetes than in no-diabetes subjects (P < 0.05). The mean pancreatic T1 value was significantly lower in the low-value group (HbA1c < 5.7%) (906.3 msec) compared with the high-value group (HbA1c ≥ 6.5%) (993.8 msec) (P < 0.0001). SIR on T1 WI was significantly higher in the low-value group compared with the high-value group (P = 0.029). The sensitivities, specificities, and area under the receiver-operating characteristic curve (AUCs) for differentiating the low- and high-value groups were 74.1%, 83.8%, and 0.82 in the pancreatic T1 values and 77.8%, 54.4%, and 0.63 in SIR on T1 WI, respectively. The specificity (P < 0.0001) and AUC (P = 0.0020) were significantly higher in the pancreatic T1 values than in SIR on T1 WI. DATA CONCLUSION: Pancreatic T1 value has the potential of being an imaging biomarker for the assessment of IGT. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:711-718.

Prognostic evaluation of pancreatic ductal adenocarcinoma: Associations between molecular biomarkers and CT imaging findings.

OBJECTIVES: To investigate association between molecular biomarkers and computed tomography (CT) imaging findings in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Fifty-three consecutive patients with PDAC (34 men and 19 women; mean age, 70.6 ±â€¯8.1 years; range, 56-86 years) who underwent dynamic contrast-enhanced CT prior to pancreatectomy were included. The Ki-67 index and expressions of E-cadherin, Vimentin, and TWIST were immunohistochemically evaluated. Qualitative image analysis and histogram analysis of CT numbers were conducted. Clinical and molecular biomarkers were tested as possible prognostic factors for overall survival (OS) using Kaplan-Meier method and Cox proportional hazards regression. In addition, associations between CT imaging findings and significant molecular biomarkers were investigated. RESULTS: The TNM stage (P = 0.018) and E-cadherin expression status (P = 0.018) were independently associated with OS. E-cadherin-negative PDACs had a worse prognosis than E-cadherin-positive PDACs (hazard ratio: 2.21). Irregular tumor margin was observed more frequently in E-cadherin-negative PDACs (54.7%) than in E-cadherin-positive PDACs (45.3%) (P = 0.00054). The kurtosis of CT number during the pancreatic parenchymal phase was significantly higher in E-cadherin-negative PDACs than in E-cadherin-positive PDACs (P = 0.035). CONCLUSIONS: E-cadherin suppression was found to be a prognostic factor for OS in patients with PDAC, and irregular tumor margin and kurtosis of CT numbers during the pancreatic parenchymal phase could be indicators for E-cadherin suppression.

Tris-acryl gelatin microspheres versus gelatin sponge particles in uterine artery embolization for leiomyoma.

Background Tris-acryl gelatin microspheres (TAGM) and gelatin sponge particles (GS) have been used in uterine artery embolization (UAE) for leiomyoma. No direct comparisons of both embolic agents have been reported. Purpose To compare the outcomes of UAE with TAGM with those of UAE with GS for uterine leiomyoma. Material and Methods This was a non-randomized, single-institute, non-inferiority study. Between July 2008 and August 2015, 67 consecutive patients with symptomatic leiomyoma underwent UAE. GS was used for the first 49 patients and TAGM was used for the following 18 patients. The primary endpoint was tumor infarction on contrast-enhanced magnetic resonance imaging (MRI) 1 week after UAE. The secondary endpoints were changes in symptoms and quality-of-life scores with UFS-QOL questionnaires at 4 months, and adverse events (AEs) in the 4 months after UAE. Results The baseline characteristics of both groups were similar. Complete or nearly complete tumor infarction (≥90%) was achieved in 94.4% (17/18) of the TAGM group and 93.6% (44/47) of the GS group. This difference (0.8%; 95% CI, -11.9% to 13.5%) indicated the non-inferiority of the TAGM group to the GS group, with a pre-specified non-inferiority margin of 20%. No significant differences were observed in improvements in symptoms or quality-of-life scores at 4 months ( P = 0.56 and P = 0.19) or in 4-month AEs ( P = 0.29). Conclusion The outcomes of UAE with TAGM were comparable to those of UAE with GS, suggesting that both embolic agents are acceptable for the treatment of leiomyoma.

Overexpression in yeast, photocycle, and in vitro structural change of an avian putative magnetoreceptor cryptochrome4.

Cryptochromes (CRYs) have been found in a wide variety of living organisms and can function as blue light photoreceptors, circadian clock molecules, or magnetoreceptors. Non-mammalian vertebrates have CRY4 in addition to the CRY1 and CRY2 circadian clock components. Though the function of CRY4 is not well understood, chicken CRY4 (cCRY4) may be a magnetoreceptor because of its high level of expression in the retina and light-dependent structural changes in retinal homogenates. To further characterize the photosensitive nature of cCRY4, we developed an expression system using budding yeast and purified cCRY4 at yields of submilligrams of protein per liter with binding of the flavin adenine dinucleotide (FAD) chromophore. Recombinant cCRY4 dissociated from anti-cCRY4 C1 mAb, which recognizes the C-terminal region of cCRY4, in a light-dependent manner and showed a light-dependent change in its trypsin digestion pattern, suggesting that cCRY4 changes its conformation with light irradiation in the absence of other retinal factors. Combinatorial analyses with UV-visible spectroscopy and immunoprecipitation revealed that there is chromophore reduction in the cCRY4 photocycle and formation of a flavosemiquinone radical intermediate that is likely accompanied by a conformational change in the carboxyl-terminal region. Thus, cCRY4 seems to be an intrinsically photosensitive and photoswitchable molecule and may exemplify a vertebrate model of cryptochrome with possible function as a photosensor and/or magnetoreceptor.

Simvastatin Enhances the Radiosensitivity of Androgen-independent Prostate Cancer Cells via Inhibition of RAD51 Expression.

BACKGROUND/AIM: Statins exert antitumor effects via various mechanisms. Additionally, the recurrence rate of prostate cancer after radiation therapy is lower in patients taking statins. This study investigated the efficacy of combination therapy with statins and irradiation in androgen-independent prostate cancer cells. MATERIALS AND METHODS: PC-3 and LNCaP human prostate cancer cell lines were used in this study. We developed androgen-independent LNCaP cells (LNCaP-LA) by gradually replacing fetal bovine serum (FBS) with charcoal-stripped FBS. Microarray analysis was performed, followed by Ingenuity Pathway Analysis. Cell viability was determined using the MTS assay. RESULTS: Simvastatin alters gene expressions in PC-3 cells. Microarray data showed that the number of differentially expressed genes was the highest in the pathway of "Role of BRCA1 in DNA Damage Response". In the validation, the expression of RAD51, listed in "Role of BRCA1 in DNA Damage Response", decreased significantly by simvastatin in PC-3 cells. Reduction in RAD51 expression following siRNA transfection increased the cytocidal effects of X-ray therapy in PC-3 and LNCaP-LA cells. The combination of simvastatin and irradiation further inhibited cell proliferation compared with monotherapy with either therapy in PC-3 or LNCaP-LA cells. In addition, compared with X-ray monotherapy, the combination of simvastatin and irradiation further enhanced the expression of γH2AX, which is reported to be one of the accurate markers of DNA damage in PC-3 cells. CONCLUSION: Simvastatin decreased the expression of RAD51 in androgen-independent prostate cancer cells. The combination of irradiation and drugs that reduce RAD51 expression can potentially affect androgen-independent prostate cancer growth.

Simvastatin Induces Autophagy and Inhibits Proliferation in Prostate Cancer Cells.

BACKGROUND/AIM: Statin has recently been studied for its effects on inducing cell death and inhibiting metastasis. Nevertheless, the precise mechanism of its anti-tumor effect is not yet fully understood. We conducted research on statin as a novel treatment for castration-resistant prostate cancer (CRPC). This study focused on autophagy in prostate cancer cells and assessed the effects of simvastatin. MATERIALS AND METHODS: After administering simvastatin to PC-3 cells, we conducted a microarray analysis. Simvastatin was administered to prostate cancer cell lines (PC-3, LNCaP-LA; cultured under androgen-depleted conditions, DU145, 22RV1), and the tumor proliferation inhibition was evaluated using the MTS assay and cell count. Autophagy was measured by observing autophagosome staining under a fluorescence microscope and quantifying LC-3 protein using western blot. We also investigated the effects of rapamycin, an autophagy inducer, and chloroquine as an inhibitor. RESULTS: Simvastatin demonstrated a significant concentration-dependent growth inhibition effect on prostate cell lines. Moreover, a significant increase in autophagy was observed in all cell lines following simvastatin administration. When we administered simvastatin with rapamycin at a concentration that did not show a tumor growth inhibitory effect, it significantly enhanced autophagy induction compared to simvastatin alone, and also significantly enhanced the growth inhibition effect on PC-3 cells. CONCLUSION: Simvastatin induced autophagy and inhibited the proliferation of prostate cancer cell lines. The combination of simvastatin and rapamycin significantly induced autophagy and enhanced the inhibitory effect of simvastatin on proliferation. This mechanism may serve as a novel therapeutic target.

Visual and auditory stimuli associated with swallowing activate mirror neurons: a magnetoencephalography study.

In the present study, we evaluated activated areas of the cerebral cortex with regard to the mirror neuron system during swallowing. To identify the activated areas, we used magnetoencephalography. Subjects were ten consenting volunteers. Swallowing-related stimuli comprised an animated image of the left profile of a person swallowing water with laryngeal elevation as a visual swallowing trigger stimulus and a swallowing sound as an auditory swallowing trigger stimulus. As control stimuli, a still frame image of the left profile without an additional trigger was shown, and an artificial sound as a false auditory trigger was provided. Triggers were presented at 3,000 ms after the start of image presentation. The stimuli were combined and presented and the areas activated were identified for each stimulus. With animation and still-frame stimuli, the visual association area (Brodmann area (BA) 18) was activated at the start of image presentation, while with the swallowing sound and artificial sound stimuli, the auditory areas BA 41 and BA 42 were activated at the time of trigger presentation. However, with animation stimuli (animation stimulus, animation + swallowing sound stimuli, and animation + artificial sound stimuli), activation in BA 6 and BA 40, corresponding to mirror neurons, was observed between 620 and 720 ms before the trigger. Besides, there were also significant differences in latency time and peak intensity between animation stimulus and animation + swallowing sound stimuli. Our results suggest that mirror neurons are activated by swallowing-related visual and auditory stimuli.

Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain.

During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories. In this study, we investigated the abnormalities of the commissural fibers that connect the left and right cerebral hemispheres in mice lacking heparan sulfate 6-O endosulfatases, Sulf1 and Sulf2 (Sulf1/2), which are extracellular enzymes that remove 6-O sulfate from heparan sulfate and thereby modulate the function of axon guidance factors. We previously demonstrated that Sulf1/2 double knockout (DKO) mouse embryos harbored defects in their corticospinal tract and that some of these DKO mice experienced corpus callosum agenesis. However, abnormalities of the commissural fibers in the adult DKO brain have not been systematically assessed. In this study, we investigated commissural fiber abnormalities in these mice by the combined use of radiological and histological analyses. First, we acquired diffusion-weighted images and three-dimensional-T2 weighted images of adult brains using a 9.4 T animal magnetic resonance imaging system and found that Sulf1/2 DKO mice had a smaller corpus callosum and dorsal hippocampal commissure. Next, we performed myelin staining and anterograde tracing, revealing that the dorsal hippocampal commissure was elongated in a rostral direction. These results suggest that Sulf1/2 play an important role in the formation of commissural tracts and that diffusion tensor imaging associated with microscopic analysis is a powerful tool to clarify nerve tract abnormalities.

Avelumab plus axitinib therapy for renal cell carcinoma in a patient with pulmonary alveolar proteinosis: A case report.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the abnormal accumulation of surfactant-derived substances in the lungs. To the best of our knowledge, the successful treatment of metastatic renal cell carcinoma in patients with PAP has not been reported. Here, we describe such treatment of a patient via avelumab plus axitinib therapy. After four courses of treatment, computed tomography showed size reduction of the pulmonary metastatic nodule and improvement of PAP. This study highlights that avelumab plus axitinib therapy is a safe and effective treatment option for metastatic renal cell carcinoma, even in patients with PAP.

Pancreatic extracellular volume fraction using T1 mapping in patients with impaired glucose intolerance.

PURPOSE: To evaluate pancreatic T1 mapping and extracellular volume (ECV) fraction's feasibility to assess impaired glucose tolerance (IGT) patients. METHODS: A total of 45 consecutive patients with known or suspected pancreatic disease underwent contrast-enhanced magnetic resonance (MR) imaging, including T1 mapping, using saturation recovery sequence. Patients were classified into three groups based on the American Diabetes Association criteria: no-diabetes subjects, HbA1c < 5.7%; pre-diabetes, 5.7% ≤ HbA1c < 6.5%; and type 2 diabetes mellitus (T2DM), HbA1c ≥ 6.5%. Pre-contrast pancreatic T1 value and ECV of the pancreas were computed, and then pre-contrast pancreatic T1 value, ECV and HbA1c values were compared. The present prospective study was approved by our institutional review board. Written informed consent was obtained from all patients. RESULTS: A positive correlation between HbA1c values and both pre-contrast pancreatic T1 value and ECV (r = 0.79, P < 0.001 and r = 0.60, P < 0.001, respectively) were observed. The pre-contrast pancreatic T1 value and ECV were significantly higher in T2DM vs. no-diabetes subjects and pre-diabetes (P < 0.001). No significant difference between two qualitative values (P = 0.14) was found, however, the sensitivity, specificity, and area under the receiver-operating-characteristic curve differentiating no-diabetes subjects and pre-diabetes from T2DM were superior in ECV (100%, 93.5%, and 0.990) vs. pre-contrast pancreatic T1 values (84.6%, 96.8%, and 0.906). CONCLUSIONS: The ECV of the pancreas could serve as a potential imaging biomarker for the assessment of pancreatic fibrosis leading to IGT.

THETA system allows one-step isolation of tagged proteins through temperature-dependent protein-peptide interaction.

Tools to control protein-protein interactions by external stimuli have been extensively developed. For this purpose, thermal stimulation can be utilized in addition to light. In this study, we identify a monoclonal antibody termed C13 mAb, which shows an approximately 480-fold decrease in the affinity constant at 37 °C compared to that at 4 °C. Next, we apply this temperature-dependent protein-peptide interaction for one-step protein purifications. We term this THermal-Elution-based TAg system as the THETA system, in which gel-immobilized C13 mAb-derived single-chain variable fragment (scFv) (termed THETAL) is able to bind with proteins tagged by C13 mAb-epitope(s) (THETAS) at 4 °C and thermally release at 37-42 °C. Moreover, to reveal the temperature-dependent interaction mechanism, molecular dynamics simulations are performed along with epitope mapping experiments. Overall, the high specificity and reversibility of the temperature-dependent features of the THETA system will support a wide variety of future applications such as thermogenetics.

Optimal window settings in single-source dual-energy computed tomography of the abdomen.

PURPOSE: To determine the optimal window settings for monochromatic images with various energy levels in single-source dual-energy computed tomography (DECT) of the abdomen. MATERIALS AND METHODS: Two hundred consecutive patients underwent contrast-enhanced DECT to screen tumor metastases and/or recurrences after surgery for malignant tumors. Two independent radiologists reviewed eight energy levels (40, 45, 50, 55, 60, 65, 70, and 75 kilo-electron volts [keV]) of the portal venous phase monochromatic images. For each keV image, the radiologists adjusted the window level (WL) and width (WW) using settings of 40 HU of WL and 350 HU of WW on 65 keV images as a reference and recorded these values. After removing the top and bottom 5% of the data, the optimal WL and WW in each energy levels were obtained by rounding the median values. In 7 of 200 patients with a total of 23 liver metastases, the tumor-to-liver contrast-to-noise ratio (CNR) was calculated and compared among the energy levels. RESULTS: The optimal WLs and WWs at each energy level were as follows: 40 keV, 140 and 680 HU; 45 keV, 110 and 570 HU; 50 keV, 90 and 490 HU; 55 keV, 70 and 440 HU; 60 keV, 60 and 390 HU; 65 keV, 40 and 350 HU; 70 keV, 30 and 320 HU; and 75 keV, and 20 and 300 HU. The best CNR was obtained using 65 keV images (P < 0.001). CONCLUSION: We clarified the optimal WL and WW available for the preset window settings in abdominal DECT.