Chemotherapy effects on bone mineral density and microstructure in women with breast cancer.

INTRODUCTION: Chemotherapy involves the administration of steroids to prevent nausea and vomiting; however, its effect on bone microstructure remains unknown. This study aimed to evaluate the changes in bone mineral density (BMD) and bone microstructure associated with chemotherapy using high-resolution peripheral quantitative computed tomography (HR-pQCT) in women with early breast cancer. MATERIALS AND METHODS: This prospective single-arm observational study included non-osteoporotic, postmenopausal women with breast cancer. The patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide (P1NP) measurements at baseline, end of chemotherapy, and 6 months after chemotherapy. The primary endpoint was the change in total volumetric BMD at the distal tibia and radius. RESULTS: Eighteen women were included in the study (median age: 57 years; range: 55-62 years). At 6 months after chemotherapy, HR-pQCT indicated a significant decrease in total volumetric BMD (median: distal tibia -4.5%, p < 0.01; distal radius -2.3%, p < 0.01), cortical volumetric BMD (-1.9%, p < 0.01; -0.8%, p = 0.07, respectively), and trabecular volumetric BMD (-1.1%, p = 0.09; -3.0%, p < 0.01, respectively). The DXA BMD also showed a significant decrease in the lumbar spine (median: -4.5%, p < 0.01), total hip (-5.5%, p < 0.01), and femoral neck (-4.2%, p < 0.01). TRACP-5b and P1NP levels were significantly increased at the end of chemotherapy compared to baseline. CONCLUSION: Postmenopausal women undergoing chemotherapy for early breast cancer experienced significant BMD deterioration in weight-bearing bone, which was further reduced 6 months after chemotherapy.

Impact of spinal surgery on locomotive syndrome in patients with lumbar spinal stenosis in clinical decision limit stage 3: a retrospective study.

BACKGROUND: Locomotive syndrome (LS) is characterized by reduced mobility. Clinical decision limit (CDL) stage 3 in LS indicates physical frailty. Lumbar spinal canal stenosis (LSS) is one of the causes of LS, for which lumbar surgery is considered to improve the CDL stage. This study aimed to investigate the efficacy of lumbar surgery and independent factors for improving the CDL stage in patients with LSS. METHODS: This retrospective study was conducted at the Department of Orthopaedic Surgery at our University Hospital. A total of 157 patients aged ≥ 65 years with LSS underwent lumbar surgery. The 25-Question Geriatric Locomotive Function scale (GLFS-25) was used to test for LS, and the Timed Up and Go test (TUG) was used to evaluate functional ability. Lower limb pain was evaluated using a visual analog scale. Patients with at least one improvement in the CDL stage following lumbar surgery were included in the improvement group. Differences in lower limb pain intensity between the groups were evaluated using the Wilcoxon rank-sum test. The Spearman's rank correlation coefficient was used to determine correlations between Δ lower limb pain and Δ GLFS-25. Logistic regression analysis was used to identify factors associated with improvement in LS. RESULTS: The proportion of patients with improved CDL stage was 45.1% (improvement/non-improvement: 32/39). Δ Lower limb pain was significantly reduced in the improvement group compared with that in the non-improvement group (51.0 [36.3-71.0] vs 40.0 [4.0-53.5]; p = 0.0107). Δ GLFS-25 was significantly correlated with Δ lower limb pain (r = 0.3774, p = 0.0031). Multiple logistic regression analysis revealed that TUG and age were significantly associated with improvement in LS (odds ratio, 1.22; 95% confidence interval: 1.07-1.47). CONCLUSIONS: Lumbar surgery effectively improved the CDL stage in patients with LSS. In addition, TUG was an independent factor associated with improvement in the CDL.

Simultaneous bilateral mastectomy and RRSO for BRCA2-positive non-invasive breast cancer in Japan: a case report and analysis of initial experience.

BACKGROUND: In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient's own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. CASE PRESENTATION: The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient's own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. CONCLUSIONS: We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues.

Development and evaluation of an original phantom model of ultrasonography-guided thyroid gland biopsy for the training of surgical residents and students.

PURPOSES: Fine-needle aspiration cytology (FNAC) is a specific and important test used for the diagnosis of thyroid gland cancer. We developed a thyroid gland phantom using original manufacturing techniques and direct three-dimensional (3D) printing. The aim of this study was to confirm the effectiveness of this phantom by collecting data to evaluate puncture training. METHODS: Data from 45 ultrasonography-guided thyroid nodule FNAC procedures performed on our thyroid phantom were evaluated in our department. The first group comprised qualified physicians who specialized in thyroid gland treatment (group A; n = 10). The second and third groups comprised senior and junior residents (group B; n = 8 and group C; n = 12; respectively). The fourth group comprised students (group D; n = 15). We measured the times taken by these groups to complete each task. RESULTS: The skills of all participants in groups B, C, and D improved after using this phantom involving the major (parallel)- (0.47 ± 0.07) and short (orthogonal)-axes (0.52 ± 0.07) methods (P < 0.001). The number of erroneous punctures decreased from 53 to 3. CONCLUSIONS: Our original phantom improved the puncture skills of students and junior doctors and was suitable as a tailored training model for practicing thyroid gland transfixion.

A Survey of the Awareness and Educational Needs of Nurses in Nagasaki Prefecture Regarding Hereditary Breast and Ovarian Cancer.

The aim of this study was to evaluate the knowledge and educational needs with regard to hereditary breast and ovarian cancer among nurses working in breast cancer care in the Nagasaki Prefecture. In breast cancer care, the identification of patients at risk for hereditary breast and ovarian cancer is necessary for the implementation of genetic testing and counseling. Nurses should be involved in this process, since they play a crucial role in the care of patients with breast cancer. However, the knowledge regarding hereditary breast and ovarian cancer among nurses working in oncology care in Japan has not been assessed. The design of this study is cross-sectional design. We distributed 597 surveys to nurses working in breast cancer care. The surveys assessed the nurses' demographic data, their current knowledge and practices regarding cancer genetics and hereditary breast and ovarian cancer, and their attitude and preferences regarding learning about the condition. We received 317 valid replies. Nurses had limited knowledge about hereditary breast and ovarian cancer characteristics: 41.6% reported that they do not know about the condition, whereas less than 10% knew its characteristics. However, nurses were aware of hereditary breast and ovarian cancer significance and were willing to learn about it: 91% wished to learn about the condition, and 88.6% wanted to participate in study group meetings. Further, nurses' preferences regarding educational programs were clarified. Overall, our results show that educational programs should be implemented to advance nurses' knowledge of hereditary breast and ovarian cancer characteristics.

EFFICACY AND SAFETY OF A DEXAMETHASONE-BASED MOUTHWASH TO PREVENT CHEMOTHERAPY-INDUCED STOMATITIS IN WOMEN WITH BREAST CANCER: A MULTICENTRE, OPEN-LABEL, RANDOMISED PHASE 2 STUDY.

PURPOSE: No standard approach other than oral care is available for preventing chemotherapy-induced stomatitis in patients with breast cancer. In this randomized, controlled phase 2 trial, we aimed to assess the efficacy and safety of a dexamethasone-based mouthwash in preventing chemotherapy-induced stomatitis in patients with early breast cancer. BASIC PROCEDURES: Patients with breast cancer scheduled for epirubicin and cyclophosphamide (EC) or docetaxel and cyclophosphamide (TC) therapy were selected and allocated in a 1:1 ratio to the intervention and control groups. The intervention group received chemotherapy, oral care, and a dexamethasone-based mouthwash, whereas the control group received chemotherapy and oral care. The primary endpoint was the incidence of stomatitis. This was a phase 2 study, and the significance level for the analysis of the primary endpoint was set a priori at 0.2. MAIN FINDINGS: Data pertaining to 58 patients in the control group and 59 patients in the intervention group were analyzed. Stomatitis incidence was 55% and 38% in the control and intervention groups, respectively (risk ratio, 0.68; 80% confidence interval, 0.52-0.88; P = .052). Stomatitis severity was lower in the intervention group than in the control group (P = .03). The proportion of patients who adhered to the mouthwash regimen was 87% (interquartile range, 67.8%-95.3%). No severe oral infections were observed. PRINCIPAL CONCLUSIONS: The dexamethasone-based mouthwash safely reduced stomatitis incidence and severity in patients receiving chemotherapy for early breast cancer. Phase 3 clinical trials are warranted for validating our results.

An Evaluation of the Efficacy of Compression Therapy Using Sleeves and Stockings to Prevent Docetaxel-induced Peripheral Neuropathy in Breast Cancer Patients.

Taxanes are key drugs for patients with breast cancer. A major adverse effect of taxanes is peripheral neuropathy (PN). To investigate the ability of compression therapy using sleeves and stockings to prevent PN due to the taxane docetaxel, we conducted a single-center historical control trial. Patients receiving docetaxel at 75 mg/m2 every 3 weeks for 4 cycles as first-line chemotherapy for breast cancer were eligible. PN was evaluated using the common terminology criteria for adverse events version 4.0. The primary endpoint was the incidence of allgrade PN until 3 weeks after the fourth docetaxel administration. We evaluated 26 patients in the intervention group and compared their data to those collected retrospectively from 52 patients treated with docetaxel without compression. Neither the incidence of all-grade PN until 3 weeks after the fourth docetaxel administration (63.5% in the control group vs. 76.9% in the intervention group, p=0.31) nor that of PN grade ≥ 2 (13.5% vs. 15.4%, p=0.99) differed between the groups. In this study, the efficacy of compression therapy using sleeves and stockings to prevent PN induced by docetaxel was not demonstrated. Further clinical studies including medications or intervention are needed to reduce the incidence and severity of PN induced by chemotherapy.

Adjuvant endocrine therapy effects on bone mineral density and microstructure in women with breast cancer.

INTRODUCTION: Although aromatase inhibitors (AIs) are typical drugs for cancer treatment-induced bone loss, their effects on the bone microstructure remain unclear. In this study, we evaluated changes in the bone mineral density (BMD) and bone microstructure associated with AI treatment using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with early breast cancer. MATERIALS AND METHODS: This prospective, single-arm, observational study included non-osteoporotic, postmenopausal women with hormone receptor-positive breast cancer. Patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide measurements at baseline and 6 and 12 months after AI therapy. The primary endpoint was changes in the total volumetric BMD (Tt.vBMD), trabecular vBMD (Tb.vBMD), and cortical vBMD (Ct.vBMD) longitudinally at the distal radius and tibia. RESULTS: Twenty women were included (median age 57.5 years; range 55-72 years). At 12 months, HR-pQCT indicated a significant decrease in the Tt.vBMD (median distal radius - 5.3%, p < 0.01; distal tibia - 3.2%, p < 0.01), Tb.vBMD (- 3.2%, p < 0.01; - 1.0%, p < 0.05, respectively), and Ct.vBMD (- 3.2%, p < 0.01; - 2.7%, p < 0.01, respectively). Estimated bone strength was also significantly decreased. The DXA BMD value in the total hip (p < 0.01) and femoral neck (p = 0.03), but not in the lumbar spine, was significantly decreased. The TRACP-5b levels was significantly negatively associated with changes in the Tt.vBMD in both the distal radius and tibia (r =  - 0.53, r =  - 0.47, respectively) CONCLUSION: Postmenopausal women who received AIs for early breast cancer experienced significant trabecular and cortical bone deterioration and a decrease in estimated bone strength within only 1 year.

Shigella effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation.

Subversion of antigen-specific immune responses by intracellular pathogens is pivotal for successful colonisation. Bacterial pathogens, including Shigella, deliver effectors into host cells via the type III secretion system (T3SS) in order to manipulate host innate and adaptive immune responses, thereby promoting infection. However, the strategy for subverting antigen-specific immunity is not well understood. Here, we show that Shigella flexneri invasion plasmid antigen H (IpaH) 4.5, a member of the E3 ubiquitin ligase effector family, targets the proteasome regulatory particle non-ATPase 13 (RPN13) and induces its degradation via the ubiquitin-proteasome system (UPS). IpaH4.5-mediated RPN13 degradation causes dysfunction of the 19S regulatory particle (RP) in the 26S proteasome, inhibiting guidance of ubiquitinated proteins to the proteolytically active 20S core particle (CP) of 26S proteasome and thereby suppressing proteasome-catalysed peptide splicing. This, in turn, reduces antigen cross-presentation to CD8+ T cells via major histocompatibility complex (MHC) class I in vitro. In RPN13 knockout mouse embryonic fibroblasts (MEFs), loss of RPN13 suppressed CD8+ T cell priming during Shigella infection. Our results uncover the unique tactics employed by Shigella to dampen the antigen-specific cytotoxic T lymphocyte (CTL) response.

Study Protocol for Assessing the Efficacy of Compression Therapy Using Stockings and Sleeves to Prevent Docetaxel-Induced Peripheral Neuropathy in Breast Cancer Patients.

Taxanes are key drugs for patients with breast cancer. A major adverse effect associated with the administration of the taxane docetaxel is chemotherapy-induced peripheral neuropathy (CIPN). We are conducting a singlecenter, single-arm, open-label historical control trial to evaluate the ability of compression therapy using stockings or sleeves to prevent CIPN due to docetaxel treatment. The primary endpoint is the incidence of all-grade CIPN according to patients' records until 3 weeks after the fourth docetaxel administration. This study's results will clarify whether compression therapy using stockings or sleeves can prevent CIPN in breast cancer patients.

The Efficacy of Software to Help Patients Understand Drug for Adjuvant Treatment for Breast Cancer: A Pilot Randomized Controlled Trial.

We assessed the usefulness of ChemoCalc, a software package for calculating drug costs, in helping patients understand these costs. We randomly assigned, in a 1 : 1 ratio, 20 women who had undergone surgery for early breast cancer to a group that discussed adjuvant treatment with their physicians using the ChemoCalc software (ChemoCalc group) or a group that discussed adjuvant treatment without ChemoCalc (Usual Explanation group). The participants completed a five-grade evaluation questionnaire after these discussions. The primary endpoint was the intergroup comparison of the questionnaire scores regarding participants' understanding of their treatment-associated drug costs. Median age was not significantly different between the ChemoCalc group and Usual Explanation group (57 vs. 50, respectively; p=0.27). Patients in the ChemoCalc group had a significantly higher perceived level of understanding of the drug cost than those in the Usual Explanation group (5 [4-5] vs. 2.5 [1-5], respectively; p=0.002). Scores related to the patients' perception that understanding drug costs is an important part of breast cancer treatment were also higher in the ChemoCalc group than the Usual Explanation group (5 [2-5] vs. 3 [1-5], respectively; p=0.049). ChemoCalc was found to be useful for understanding drug costs.

Grinding and chemical mechanical polishing process for micropore x-ray optics fabricated with deep reactive ion etching.

Silicon micropore optics using deep reactive ion etching of silicon wafers has been being developed for future x-ray astronomy missions. Sidewalls of the micropores through a thin wafer with a typical thickness of hundreds of micrometers and a pore width of ∼20 µm are used for x-ray mirrors. However, burr structures observed after etching with a typical height of a few micrometers at the micropore edges are known to significantly reduce x-ray reflectivity. A new grinding and chemical mechanical polishing process is introduced to remove the burr structures. Both sides of the silicon wafer were ground and precisely polished after etching. X-ray reflectivity measurements confirmed an increase of reflectivity by 2-15 times at incident angles of 0.8-0.2 deg. The surface microroughness worsened from 2.0±0.2 nm rms to 7.8-0.8+0.6 nm rms; however, an additional annealing recovered the smooth surface and the estimated surface microroughness was <1.4 nm rms. This new process enables not only removing the burr structures but also choosing a flat part of the sidewalls for better angular resolution.

Discordance of hormone receptor, human epidermal growth factor receptor-2, and Ki-67 between primary breast cancer and synchronous axillary lymph node metastasis.

PURPOSE: We herein report the discordance rate between primary breast cancer and synchronous axillary node metastasis, its characteristics and its prognostic impact. METHODS: One hundred and four patients with invasive breast cancer with synchronous axillary node metastasis who underwent surgery were included. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2), and Ki-67 were stained by immunohistochemistry in both primary and node metastasis. The cut-off values of the ER/PgR and Ki-67 labeling index were set at 10% and 14%, respectively. HER2 was classified according to the ASCO/CAP guidelines. RESULTS: Cases positive for ER, PgR, and HER2 were 65.4%, 51.0%, and 27.9% and those with a high Ki-67 labeling index were 47.1% in primary breast cancer, respectively, while they were 47.1%, 30.8%, 16.3%, and 75.0% in node metastasis, respectively. The discordance rates between primary and node were 28.8% for ER (positive in primary→negative in node/negative→positive 22.1%/6.7%), 31.7% for PgR (26.9%/4.8%), 13.5% for HER2 (12.5%/1.0%), and 43.3% for Ki-67 (high in primary→low in node/low→high 12.5%/30.8%). The proportions of labeled cells in primary/node were as follows: ER 42.7%/25.2%, PgR 32.1%/14.0%, Ki-67 20.3%/37.1% (p<0.01 each). Regarding the cut-off value of Ki-67 in node metastasis as defined by a receiver operating characteristic (ROC) analysis, the patients with values >33.2% tended to have a poor recurrence-free survival (RFS) (p=0.08). CONCLUSIONS: The expression of hormone receptors tended to weaken while the proliferative status remained strong in axillary metastasis. A high Ki-67 labeling index in axillary lymph node metastasis may be a risk factor for recurrence.

Midori-ishi Cyan/monomeric Kusabira-Orange-based fluorescence resonance energy transfer assay for characterization of various E3 ligases.

Many bacterial pathogens hijack the host ubiquitin system for their own benefit by delivering effectors with ubiquitin ligase (E3) into host cells via the type III secretion system. Therefore, screening for small compounds that selectively inhibit bacterial but not mammalian E3 ligases is a promising strategy for identifying molecules that could substitute for antibiotics. To facilitate high-throughput screening for bacterial E3 ligase inhibitors, we developed a MiCy/mKO (Midori-ishi Cyan/monomeric Kusabira-Orange)-based FRET (fluorescence resonance energy transfer) assay and validated it on Shigella IpaH E3 ligase effectors. We showed the feasibility of using the MiCy/mKO-based FRET assay to identify the most appropriate ubiquitin-conjugating enzymes (E2s) and determine the lysine specificity of a given E3, both hallmarks of E3 activity. Furthermore, we showed the usefulness of the FRET assay in characterizing mammalian E3 ligases, such as TNF receptor-associated factor 6 (TRAF6) and mouse double minute 2 homologue (MDM2). In addition, we confirmed the feasibility of determining the efficiency of inhibition of E3 ligase activity using inhibitors of E1 ubiquitin-activating enzymes, such as UBE1-41, by measuring the IC50 . Based on these results, we concluded that the MiCy/mKO-based FRET assay is useful for characterizing E3 enzyme activity, as well as for high-throughput E3 inhibitor screening.

Evaluation of totally implantable central venous access devices with the cephalic vein cut-down approach: Usefulness of preoperative ultrasonography.

BACKGROUND: The aims of this retrospective study, were to evaluate totally implantable central venous access device (TICVAD) implantation and to validate the efficacy of preoperative ultrasonography. METHODS: A total of 380 cases implanted with TICVADs were divided into four groups: cut-downs with ultrasonography (group A, n = 112); cut-downs without ultrasonography (group B, n = 37); venous puncture (group C, n = 122); and replacements using the existing catheter (group D, n = 109). Operation time, completion rate, and complications were compared. RESULTS: The average operating time was 41.7, 52.4, and 40.6 min in groups A, B (P < 0.01), and C, respectively. Group A and B experienced no postoperative pneumothorax, arterial puncture, or pinch-off syndrome. Completion rates were 93.7% in group A and 86.5% in group B. Preoperative ultrasonography identified the cephalic vein in 94.1% of subjects with an average diameter of 3.1 mm and depth of 10.2 mm. Identifying convergence of the cephalic vein and the axillary vein improved the completion rate. CONCLUSIONS: This study showed that the cephalic vein cut-down approach for TICVAD implantation reduced complications. Preoperative ultrasonography resulted in a shorter operating time and higher completion rate.

Association between p53-binding protein 1 expression and genomic instability in oncocytic follicular adenoma of the thyroid.

Oncocytic follicular adenomas (FAs) of the thyroid are neoplasms of follicular cell origin that are predominantly composed of large polygonal cells with eosinophilic and granular cytoplasm. However, the pathological characteristics of these tumors are largely unexplored. Both the initiation and progression of cancer can be caused by an accumulation of genetic mutations that can induce genomic instability. Thus, the aim of this study was to evaluate the extent of genomic instability in oncocytic FA. As the presence of p53-binding protein 1 (53BP1) in nuclear foci has been found to reflect DNA double-strand breaks that are triggered by various stresses, the immunofluorescence expression pattern of 53BP-1 was assessed in oncocytic and conventional FA. The association with the degree of DNA copy number aberration (CNA) was also evaluated using array-based comparative genomic hybridization. Data from this study demonstrated increased 53BP1 expression (i.e., "unstable" expression) in nuclear foci of oncocytic FA and a higher incidence of CNAs compared with conventional FA. There was also a particular focus on the amplification of chromosome 1p36 in oncocytic FA, which includes the locus for Tumor protein 73, a member of the p53 family implicated as a factor in the development of malignancies. Further evaluations revealed that unstable 53BP1 expression had a significant positive correlation with the levels of expression of Tumor protein 73. These data suggest a higher level of genomic instability in oncocytic FA compared with conventional FA, and a possible relationship between oncocytic FA and abnormal amplification of Tumor protein 73.

Novel diagnostic procedure for determining metastasis to sentinel lymph nodes in breast cancer using a semi-dry dot-blot method.

We developed an easy, quick and cost-effective detection method for lymph node metastasis called the semi-dry dot-blot (SDB) method, which visualizes the presence of cancer cells with washing of sectioned lymph nodes by anti-pancytokeratin antibody, modifying dot-blot technology. We evaluated the validity and efficacy of the SDB method for the diagnosis of lymph node metastasis in a clinical setting (Trial 1). To evaluate the validity of the SDB method in clinical specimens, 180 dissected lymph nodes from 29 cases, including breast, gastric and colorectal cancer, were examined. Each lymph node was sliced at the maximum diameter and the sensitivity, specificity and accuracy of the SDB method were determined and compared with the final pathology report. Metastasis was detected in 32 lymph nodes (17.8%), and the sensitivity, specificity and accuracy of the SDB method were 100, 98.0 and 98.3%, respectively (Trial 2). To evaluate the efficacy of the SDB method in sentinel lymph node (SLN) biopsy, 174 SLNs from 100 cases of clinically node-negative breast cancer were analyzed. Each SLN was longitudinally sliced at 2-mm intervals and the sensitivity, specificity, accuracy and time required for the SDB method were determined and compared with the intraoperative pathology report. Metastasis was detected in 15 SLNs (8.6%), and the sensitivity, specificity, accuracy and mean required time of the SDB method were 93.3, 96.9, 96.6 and 43.3 min, respectively. The SDB method is a novel and reliable modality for the intraoperative diagnosis of SLN metastasis.

TERT Promoter Mutations Increase Tumor Aggressiveness by Altering TERT mRNA Splicing in Papillary Thyroid Carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis than TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of 2 major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated on between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into 3 groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A+B/dB ratio in mut+/exp+ was significantly higher than that in mut-/exp+ PTCs. Analysis with clinicopathological data revealed that +A+B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor-suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Resting phase-administration of lemborexant ameliorates sleep and glucose tolerance in type 2 diabetic mice.

Sleep disorders are associated with increased risk of obesity and type 2 diabetes. Lemborexant, a dual orexin receptor antagonist (DORA), is clinically used to treat insomnia. However, the influence of lemborexant on sleep and glucose metabolism in type 2 diabetic state has remained unknown. In the present study, we investigated the effect of lemborexant in type 2 diabetic db/db mice exhibiting both sleep disruption and glucose intolerance. Single administration of lemborexant at the beginning of the light phase (i.e., resting phase) acutely increased total time spent in non-rapid eye movement (NREM) and REM sleep in db/db mice. Durations of NREM sleep-, REM sleep-, and wake-episodes were also increased by this administration. Daily resting-phase administration of lemborexant for 3-6 weeks improved glucose tolerance without changing body weight and glucose-stimulated insulin secretion in db/db mice. Similar improvement of glucose tolerance was caused by daily resting-phase administration of lemborexant in obese C57BL/6J mice fed high fat diet, whereas no such effect was observed in non-diabetic db/m+ mice. Diabetic db/db mice treated daily with lemborexant exhibited increased locomotor activity in the dark phase (i.e., awake phase), although they did not show any behavioral abnormality in the Y-maze, elevated plus maze, and forced swim tests. These results suggest that timely promotion of sleep by lemborexant improved the quality of wakefulness in association with increased physical activity during the awake phase, and these changes may underlie the amelioration of glucose metabolism under type 2 diabetic conditions.

Association of quantitative analysis of intratumoral reduced E-cadherin expression with lymph node metastasis and prognosis in patients with breast cancer.

Loss of E-cadherin expression is a poor prognostic factor in patients with breast cancer. Breast cancer cells co-cultured with adipocytes reportedly promote E-cadherin attenuation and tumor progression. The current study aimed to investigate the association of reduced E-cadherin expression with adipose tissue invasion (ATI) and prognosis in breast cancer. Surgical specimens were collected from 188 women with invasive ductal carcinoma of the breast who had undergone surgery without neoadjuvant treatment. We compared E-cadherin expression in ATI and invasive front (IF) using immunohistochemistry with ImageJ. Reduced E-cadherin expression was detected not only in the ATI area but also in the IF, and the degree of reduced E-cadherin expression was positively correlated with both areas. In patients with lymph node metastasis compared to those without, E-cadherin expression was reduced and this reduction was associated with poor recurrence-free survival. We concluded that E-cadherin expression is reduced not only at the ATI area but also at the IF of the tumor. Reduced E-cadherin expression is a clear prognostic factor for breast cancer. Hence, future research is warranted for establishing an objective and quantitative E-cadherin staining assay that will allow clinical use of E-cadherin as a prognostic factor.