Search

Background: Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test., Method: Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated., Results: Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR., Conclusions: Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.

The utility of regional nodal irradiation (RNI) is being considered in cases of 1-3 axillary node metastases after breast-conserving surgery (BCS) with axillary lymph-node dissection (ALND). Therefore, we examined the necessity of RNI by examining the sites of recurrences in cases at our institution. We retrospectively analyzed 5,164 cases of primary breast cancer between January 2000 and December 2014 at the Aichi Cancer Centre, identifying local and distant recurrences in 152 patients with primary breast cancer treated with BCS and ALND and who had 1-3 positive axillary nodes. All patients received whole-breast irradiation (WBI) and adjuvant systemic therapy with either chemotherapy or anti-endocrine therapy with or without anti-human epidermal growth factor receptor 2 therapy. The present study excluded patients with ipsilateral breast tumor recurrence, contralateral breast cancer, neoadjuvant chemotherapy, T4 tumors or N2-3 nodes and distant metastasis. From the database of our institution, we identified 152 cases that met the defined criteria. The median follow-up period was 71 months (1-176). Isolated locoregional recurrences were found in three patients (2.0%) and were recurrent only in the breast. Only one patient had local lymph node recurrence with distant recurrence. The 10-year rates of isolated regional disease-free survival (DFS), DFS, and overall survival were 95.41, 89.50 and 96.75%, respectively, which was better compared with previous studies. We conclude that the addition of RNI to WBI is not necessary for Japanese patients who have 1-3 positive axillary nodes and ALND., (Copyright © 2020, Spandidos Publications.)

Background: Immediate breast reconstruction (IBR) has been become a standard treatment for patients with breast cancer undergoing mastectomy. However, whether IBR is appropriate in patients undergoing neoadjuvant chemotherapy (NAC) is still unclear. Therefore, in this study we examined the rates of operative adverse events (AEs), risk factors for operative AEs, and effects on chemotherapy and radiotherapy of IBR with NAC., Methods: Between January 2012 and March 2018, 593 patients underwent IBR at the Aichi Cancer Center Hospital. We retrospectively obtained clinical data of all these patients from their medical records and identified 56 patients (65 breasts) who had received NAC (NAC group) and 537 patients (568 breasts) who had not (non-NAC group). We compared the rates of operative AEs, risk factors for operative AEs, chemotherapy-related AEs, and duration to radiotherapy between the NAC and non-NAC cohorts., Results: The rate of operative AEs was significantly higher in the NAC than the non-NAC group (35% vs. 22%, p < 0.05). However, axillary lymph node dissection was the most influential risk factor, and NAC was not identified as a risk factor for operative AEs in patients who had undergone IBR. Additionally, there were no statistically significant differences in chemotherapy-related AEs or interval between surgery and postoperative radiotherapy between the NAC and non-NAC groups., Conclusions: NAC remains likely to contribute to increased postoperative AEs in patients undergoing IBR; however, it does not affect postoperative treatment and IBR is appropriate for patients undergoing NAC.

The efficacy of potassium iodide (KI) for Graves' disease (GD) has been reported, although few clinical reports have examined the long-term efficacy of treatment. The objective of this study was to investigate the efficacy and limitations of KI treatment for GD. This study enrolled patients newly diagnosed with mild GD, defined as free thyroxine (FT4) <5.0 ng/dL, between July 2014 and June 2016. KI was started at a dose of 50 mg/day, and if FT4 values did not decrease after initiation of treatment, doses were increased to 100 mg/day. Patients for whom thyroid hormone levels could not be controlled with KI at 100 mg/day were regarded as non-responders. Of the 122 patients (13 males, 109 females) included in this study, 71 (58.2%) responded to KI therapy. The remaining 51 patients (41.8%) were non-responders. The median duration required to judge non-responsiveness was 5.9 months. Multiple logistic regression analysis performed on parameters measured at the initial visit indicated FT4 (odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.75; p = 0.0007) and male sex (OR 3.58, 95%CI 1.04-12.3; p = 0.04) were significantly associated with KI responsiveness. Receiver operating characteristic (ROC) curve analysis of the relationship between FT4 and KI responsiveness indicated an FT4 cut-off of 2.76 ng/dL was optimal for differentiating between responders and non-responders. KI therapy was effective and safe for about 60% of patients with mild GD.

The genome is the blueprint for an organism. Interrogating the genome, especially locating critical cis-regulatory elements, requires deletion analysis. This is conventionally performed using synthetic constructs, making it cumbersome and non-physiological. Thus, we created Cas9-mediated Arrayed Mutagenesis of Individual Offspring (CAMIO) to achieve comprehensive analysis of a targeted region of native DNA. CAMIO utilizes CRISPR that is spatially restricted to generate independent deletions in the intact Drosophila genome. Controlled by recombination, a single guide RNA is stochastically chosen from a set targeting a specific DNA region. Combining two sets increases variability, leading to either indels at 1-2 target sites or inter-target deletions. Cas9 restriction to male germ cells elicits autonomous double-strand-break repair, consequently creating offspring with diverse mutations. Thus, from a single population cross, we can obtain a deletion matrix covering a large expanse of DNA at both coarse and fine resolution. We demonstrate the ease and power of CAMIO by mapping 5'UTR sequences crucial for chinmo's post-transcriptional regulation., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Pulmonary sarcoidosis should be considered in the differential diagnosis of miliary opacities in bilateral upper lobes predominance., (© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Wiring a complex brain requires many neurons with intricate cell specificity, generated by a limited number of neural stem cells. Drosophila central brain lineages are a predetermined series of neurons, born in a specific order. To understand how lineage identity translates to neuron morphology, we mapped 18 Drosophila central brain lineages. While we found large aggregate differences between lineages, we also discovered shared patterns of morphological diversification. Lineage identity plus Notch-mediated sister fate govern primary neuron trajectories, whereas temporal fate diversifies terminal elaborations. Further, morphological neuron types may arise repeatedly, interspersed with other types. Despite the complexity, related lineages produce similar neuron types in comparable temporal patterns. Different stem cells even yield two identical series of dopaminergic neuron types, but with unrelated sister neurons. Together, these phenomena suggest that straightforward rules drive incredible neuronal complexity, and that large changes in morphology can result from relatively simple fating mechanisms., Competing Interests: YL, CY, RM, YH, YH, QR, HC, TK, MI, HO, KS, YA, KI, TL No competing interests declared, (© 2020, Lee et al.)

Purpose: Among patients with various cancers receiving anticancer drugs, sarcopenia is associated with poor survival and treatment outcomes. We conducted an observational study using skeletal muscle index (SMI) evaluation to investigate the association between sarcopenia and treatment outcomes of tyrosine kinase inhibitors (TKIs) in metastatic thyroid cancer patients., Methods: We included 54 patients (19 men, 35 women; age, 66.5 ± 10.9 years) with differentiated thyroid carcinoma (DTC) or medullary thyroid carcinoma (MTC). The records of patients with metastatic DTC and MTC treated with TKIs were retrospectively reviewed. Patients were divided into sarcopenia and non-sarcopenia groups based on SMI. The SMI cutoff values for sarcopenia were 42 and 38 (cm 2 /m 2 ) for males and females, respectively. Thirty-three patients had sarcopenia before TKI treatment., Results: The sarcopenia group had more females and a lower body mass index. The median progression-free survival (PFS) durations were 13.6 (95% confidence interval (CI): 6.1-29.9) and 41.9 (95% CI: 25.2-not estimable) months in the sarcopenia and non-sarcopenia groups (p= 0.017), respectively. Univariate analysis showed that sarcopenia was significantly associated with PFS (p= 0.037). Sex, age, and performance status did not affect PFS. Multivariate analysis showed that sarcopenia was the only independent prognostic factor for PFS (hazard ratio: 2.488, 95% CI: 1.058-5.846, p= 0.037)., Conclusions: Sarcopenia could be a predictive factor of TKI treatment outcomes in patients with metastatic thyroid cancer as well as intervention target to improve prognosis. Further prospective investigations are needed to confirm these preliminary data.

Background: In the recent American Thyroid Association (ATA) guidelines for adult differentiated thyroid carcinoma (DTC) patients, risk stratification is clearly defined and lobectomy is acceptable for low-risk DTC. However, risk stratification for children with DTC in the ATA pediatric guidelines is rather unclear, and total thyroidectomy is recommended for all patients with any risk. The aim of this study was to attempt risk stratification based on our experience and to consider the appropriate extent of thyroidectomy, especially for low-risk DTC in the pediatric population. Patients and Methods: The subjects were 153 patients with DTC ≤18 years old, including 58 patients ≤15 years old and 136 female patients, who underwent initial curative surgery in our hospital between 1979 and 2014. Underlying pathology was papillary thyroid carcinoma in 130 patients and follicular thyroid carcinoma in 23. Risk factors related to disease-free survival (DFS) were analyzed and risk stratification was performed. Results: No patient died of the disease and 34 patients (22.2%) developed recurrences. At initial surgery, 30 patients (19.6%) had lymph node metastases diagnosed before initial surgery (cN1) and 9 (5.9%) had gross extrathyroidal extension (ETE). Significant factors related to DFS on multivariate analysis were cN1, ETE, and number of metastatic lymph nodes (NMLNs) ≥10, including microscopic MLNs. According to these factors, subjects were divided into three categories: low risk (no risk factors, n  = 89); intermediate risk (1 risk factor, n  = 37); and high risk (≥2 risk factors, n  = 27). Ten-year DFS rates in the low-, intermediate-, and high-risk groups were 96%, 83%, and 48%, respectively. Only 12% of low-risk patients underwent total thyroidectomy. Because NMLNs become obvious only after surgery, another analysis after excluding "NMLNs" as a factor showed that cN and ETE were significant factors related to poor DFS. According to these two factors, risk stratification was attempted in the same manner. Ten-year DFS rates in the low- (no risk factor, n  = 117), intermediate- (one risk factor, n  = 29), and high-risk (two risk factors, n  = 7) groups were 92%, 59%, and 43%, respectively. Only 12% of low-risk patients underwent total thyroidectomy. Conclusions: For low-risk pediatric patients, lobectomy may be sufficient as the initial surgical procedure.

Objective: The relationship between the body mass index (BMI) at the time of breast cancer diagnosis and the prognosis of breast cancer patients has not yet been clarified. We investigated the impact of obesity for clinical outcomes in Japanese breast cancer patients., Methods: Women with primary breast cancer operated between 2002 and 2014 were identified. All patients are categorized into four groups according to BMI. The range of BMI is <18.5 kg/m2, from 18.5 to 24.9 kg/m2, 25 to 29.9 kg/m2, >30 kg/m2 in underweight, normal, overweight and obesity groups, respectively. The correlation between BMI and overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS) were statistically analyzed., Results: From the database of our institution, we identified 3223 patients. The median follow-up period was 57 months (1-149). We categorized 2257 (70.0%), 318 (9.9%), 545 (16.9%) and 103 (3.2%) patients into normal, underweight, overweight obesity groups respectively. There were189 patients (5.9%) deaths due to breast cancer recurrence (137 patients) and other disease (52 patients). Obesity groups was significantly high compared with normal groups for OS (adjusted HR, 2.43; 95% CI, 1.38-4.28; P < 0.001), BCSS (adjusted HR, 2.73; 95% CI, 1.15-6.44; P = 0.02) and DFS (adjusted HR, 1.83; 95% CI, 1.11-3.02; P = 0.017) by multivariate analysis. Especially, OS (adjusted HR, 4.87; 95% CI, 2.15-11.04; P < 0.001), BCSS (adjusted HR, 4.51; 95% CI, 1.52-13.34; P < 0.001) and DFS (adjusted HR, 4.87; 95% CI, 1.02-4.89; P = 0.04) were statistically insignificant in postmenopausal ER-positive breast cancer patients., Conclusion: Obesity might be risk factor for OS, BCSS and DFS, especially postmenopausal ER-positive women., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Some thyroid cancer patients experience a rapid disease progression after the discontinuation of tyrosine kinase inhibitors (TKIs), which is called flare phenomenon. The incidence of the flare phenomenon of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) ranged from 4% to 11.1% and the median time to occurrence of the flare phenomenon ranged from 7 to 12 days in previous reports. In this study, we investigate the timing and incidence of the flare phenomenon in thyroid cancer patients treated with lenvatinib.The records of patients treated with lenvatinib were retrospectively reviewed. The primary outcomes were the incidence rate and timing of the flare phenomenon after the discontinuation of lenvatinib. The flare phenomenon was defined as death, hospitalization attributable to tumor progression, or unexpected event (e.g., pleural drainage) within 1 month of lenvatinib cessation. We excluded patients with progression of underlying diseases other than thyroid cancer or infection, those in whom the disease progressed, or those who died without achieving a clinical response (stable disease, partial response, or complete response).In total, 8 (14.3%) of the 56 patients experienced the flare phenomenon. The median time from lenvatinib cessation to the flare phenomenon was 9 (range, 4-30) days. Three patients in the flare group died within 1 month of lenvatinib cessation without an imaging evaluation. The remaining 5 patients had dyspnea and pleural effusion, and pleural drainage was performed in 3 of the 5 patients. Lenvatinib was resumed in 4 of the 8 patients in the flare group. Median overall survival (OS) was 15.1 months in the flare group and 41.9 months in the non-flare group. The OS tended to be poor in the flare group than in the non-flare group; however, this difference was not statistically significant (P = .051).In lenvatinib treatment for thyroid cancer, the incidence and timing of the flare phenomenon were similar to those observed with other TKIs. OS tended to be poor in the flare group than in the non-flare group. Further studies are needed to determine the mechanism of the flare phenomenon and establish measures and treatment policies.

Background: The clinical course of Graves' disease (GD) in women who switched from methimazole (MMI) to potassium iodide (KI) during the first trimester of pregnancy has never been reported in detail. Objective: To investigate the characteristics of GD patients whose thyroid hormone levels increase after substituting KI for MMI. Patients: Two hundred forty women with GD who had been treated with MMI and switched from MMI to inorganic iodide to control hyperthyroidism during the first trimester between January 1, 2005, and March 31, 2018. Results: In 133 (55.4%) of the GD patients, medication was completely tapered during pregnancy, and the other 107 (44.6%) GD patients were taking medication at delivery: 57 were taking KI alone and 50 were taking an antithyroid drug with or without KI. It was difficult to control the maternal thyrotoxicosis of 22 of the 107 patients with KI alone, and a higher dose of MMI compared with the dose at the time of conception was required (worsened group). Multivariate analysis revealed that the TRAb value at the time of switch from MMI to KI was the only factor that predicted continuation of the thyroid suppression medication, but none of the parameters was a predictor of the worsened group. Conclusions: It must be kept in mind that a certain proportion of GD patients escape from the antithyroid effect of iodide and that careful follow-up is necessary after switching a pregnant patient's medication to KI.

Background: The ultimate clinical goal of advanced cancer treatment is improvement of survival. Tyrosine kinase inhibitors (TKIs) were recently approved for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC) that is resistant to conventional therapies since they have significant potential to improve survival in patients who previously had no more treatment strategies available. However, eligible patients are limited in clinical practice, making it difficult to accurately determine the efficacy of TKIs. Patients and Methods: We retrospectively analyzed the efficacy of lenvatinib at a single institution, enrolling 42 RR-DTC patients. Results: The best overall response was partial remission in 26 (62%) patients, stable disease in 10 (24%) patients, and progressive disease (PD) in 6 (14%) patients. The results indicated three-year overall survival (OS) and progression-free survival rates of 51.0% and 32.4%, respectively. Twenty-three (55%) patients had backgrounds that did not match the inclusion criteria of the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. Furthermore, PD-experienced patients individually decided whether to continue lenvatinib, and 17 (41%) made the decision themselves; these patients had a three-year OS of 43.0% and postprogression survival (PPS) of 13.3 [95% confidence interval 6.1-not reached] months. Conclusions: Our real-world investigation revealed that patients have wide-ranging background characteristics, and the decision regarding continuation of therapy after PD is based on the patient's general condition. Our management protocol resulted in good PPS. Furthermore, our results indicated equivalent efficacy of lenvatinib as in the SELECT trial. In conclusion, lenvatinib proved effective for RR-DTC patients in a real-world setting.

Inner ear cochlear spiral ganglion neurons (SGNs) transmit sound information to the brainstem. Recent single cell RNA-Seq studies have revealed heterogeneities within SGNs. Nonetheless, much remains unknown about the transcriptome of SGNs, especially which genes are specifically expressed in SGNs. To address these questions, we needed a deeper and broader gene coverage than that in previous studies. We performed bulk RNA-Seq on mouse SGNs at five ages, and on two reference cell types (hair cells and glia). Their transcriptome comparison identified genes previously unknown to be specifically expressed in SGNs. To validate our dataset and provide useful genetic tools for this research field, we generated two knockin mouse strains: Scrt2-P2A-tdTomato and Celf4-3xHA-P2A-iCreER-T2A-EGFP . Our comprehensive analysis confirmed the SGN-selective expression of the candidate genes, testifying to the quality of our transcriptome data. These two mouse strains can be used to temporally label SGNs or to sort them., Competing Interests: CL, XL, ZB, KS, GW, TZ, ZL No competing interests declared, (© 2020, Li et al.)

Purpose: Lymphedema (LE) decreases the quality of life of breast cancer patients. Objective quantification of PRO may improve the discordance between patient-reported outcomes (PROs) and objective assessments of LE by establishing a standard follow-up for LE. This study determined the prevalence of subjective and objective LE and evaluated the correlation between objective assessment and PRO of LE in primary breast cancer patients undergoing breast and axilla surgery., Methods: Breast cancer patients who underwent sentinel lymph node biopsy (SN) or axillary lymph node dissection (ALND) more than 1 year after surgery were enrolled. We prospectively evaluated LE using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and two objective assessments (arm circumference and bioimpedance) and analyzed their correlations., Results: Between November 2018 and January 2019, 631 patients (SN; n = 415, ALND; n = 216) were enrolled. The median age, body mass index, and duration from surgery was 56 years, 21.9 kg/m 2 , and 3.8 years, respectively. The prevalences of subjective and objective LE were 4.1% and 1.4% in the SN group and 51.8% and 24.1% in the ALND group, respectively. The objective assessments were weakly positively correlated with PRO-CTCAE. Arm circumference measurement correlated better than bioimpedance overall and was most strongly correlated with "frequency" (r = 0.485, p < 0.01)., Conclusions: LE occurred in few SN patients. The prevalence of subjective LE was higher than that of objective LE. Arm circumference measurements better reflected PRO than did bioimpedance. These results underscore the limitation of LE detection by subjective or objective methods alone.

A 76-year-old man was diagnosed with type 1 early gastric cancer. Attempted ESD on the lesion resulted in perforation, and distal gastrectomy with D1+dissection was performed. After 1 year and 6 months, a mass measuring 2.4 cm appeared in the abdominal wall. Cytological examination revealed adenocarcinoma, and the patient was diagnosed with abdominal wall metastasis of gastric cancer. There were no evidences of recurrence in the other organs, and extraction was performed. After 6 months, 1 year, and 2 years, the same metastases were found in the abdominal wall, and repeated extractions were performed. All 4 masses had resulted from the metastasis of gastric cancer, but the patient has been alive without recurrence for 1 year and 6 months after the surgery.

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

Differentiated thyroid cancer (DTC) is associated with a good long-term prognosis, but bone metastases can adversely affect patients' quality of life and survival. Stereotactic radiotherapy (SRT) can deliver high-dose irradiation to target lesions and it has been reported to be useful for various cancers. However, few studies have examined the efficacy of SRT for thyroid cancer. In the present study, the aim was to investigate the efficacy of SRT using the CyberKnife for bone metastases from DTC. From September 2013 to April 2018, SRT with the CyberKnife system was used to treat 60 bone metastases from DTC in 13 patients. The patients' medical records were retrospectively reviewed to obtain information about the adverse events associated with SRT. Of the 60 lesions, 40 could be evaluated by follow-up CT for therapeutic effectiveness, and the RECIST criteria were used to assess the response. The cancers were papillary cancer in 3 patients, follicular cancer in 9 and poorly differentiated cancer in 1. SRT was delivered in 1-10 fractions, with a median dose of 27 Gy (range, 8-48 Gy). Adverse events were infrequent and mild. The median follow-up of the 40 lesions was 11 (range, 2-56) months. The responses were partial response in 2 lesions, stable disease in 37 lesions and progressive disease in 1 lesion, with a 1-year local control rate of 97.1%. The present study showed that SRT using the CyberKnife system was a feasible and effective treatment for bone metastases of DTC., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The prevalence of antithyroid drug (ATD)-related drug-induced liver injury (DILI) has been reported to vary among patients in several countries. The purpose of this study was to summarize the prevalence of liver injury induced by ATD and to determine the actual prevalence of severe liver injury. Methods: The medical records of 18,558 patients who were newly diagnosed with Graves' disease between January 2005 and December 2016 were retrospectively reviewed. Severe DILI was defined as alanine aminotransferase (ALT) 8 times higher than the upper limit of normal (ULN) or total bilirubin (T-bil) 3 times higher than the ULN. The most severe DILI was defined as ALT higher than 20 times the ULN or T-bil higher than 10 times the ULN. Results: A total of 461 subjects (470 cases) were analyzed, and they consisted of 10 males and 451 females, with a median age of 37 years (range 10-82 years). Nine of 461 patients had severe DILI with both drugs. The total prevalence of severe DILI in this study was 2.5%, and the prevalence of DILI by drug was 1.4% with metimazole (MMI) ( n  = 198) and 6.3% with propylthiouracil (PTU) ( n  = 272) ( p  < 0.001). The prevalence of the most severe ATD-related DILI was 0.22% ( n  = 40), and the prevalence for each drug was 0.08% with MMI ( n  = 11) and 0.68% with PTU ( n  = 29). The median time to DILI development was 30 days (range 7-314 days), and all patients recovered from DILI, with no fatalities. The prevalence of MMI-related DILI was significantly age dependent ( p  < 0.001). Conclusions: Though there were no fatalities in this study, the prevalence of PTU-related severe DILI was significantly higher than that of MMI-related severe DILI.

Temporal patterning is a seminal method of expanding neuronal diversity. Here we unravel a mechanism decoding neural stem cell temporal gene expression and transforming it into discrete neuronal fates. This mechanism is characterized by hierarchical gene expression. First, Drosophila neuroblasts express opposing temporal gradients of RNA-binding proteins, Imp and Syp. These proteins promote or inhibit chinmo translation, yielding a descending neuronal gradient. Together, first and second-layer temporal factors define a temporal expression window of BTB-zinc finger nuclear protein, Mamo. The precise temporal induction of Mamo is achieved via both transcriptional and post-transcriptional regulation. Finally, Mamo is essential for the temporally defined, terminal identity of α'/β' mushroom body neurons and identity maintenance. We describe a straightforward paradigm of temporal fate specification where diverse neuronal fates are defined via integrating multiple layers of gene regulation. The neurodevelopmental roles of orthologous/related mammalian genes suggest a fundamental conservation of this mechanism in brain development., Competing Interests: LL, XL, CY, RM, KS, TL No competing interests declared, RS Reviewing editor, eLife, (© 2019, Liu et al.)

Background: The Turin criteria including solid, trabecular, and/or insular architecture, lack of typical nuclear features of papillary carcinoma, and mitoses, necrosis, or convoluted nuclei were adopted in the recent 4th edition of the World Health Organization classification published in 2017., Materials and Methods: Between 2006 and 2017, 11,001 cases underwent initial surgery for primary malignant thyroid tumor derived from follicular cells. A total of 75 (0.7%) cases were diagnosed with PDTC according to the 2004 WHO classification. Based on the Turin criteria, 30 (40%) cases were re-classified as PDTC-Turin (+) and 45 (60%) cases were PDTC-Turin (-). Clinicopathological features and prognosis were compared between PDTC-Turin (+) and PDTC-Turin (-)., Results: Seventy-five patients (48 females and 27 males) had a median age at the time of surgery of 57 years. Preoperative diagnosis was benign in 16 (21%), follicular tumor in 40 (53%), and malignant in 19 (25%). The 5-year cause-specific survival (CSS) and disease-free survival (DFS) rates were 97% and 44% for PDTC-Turin (+) and 100% and 88% for PDTC-Turin (-). On univariate analysis, CSS and DFS rates were significantly worse in the PDTC-Turin (+) than in the PDTC-Turin (-) (p = 0.0096, and p = 0.0016). Multivariate analysis showed that Turin criteria status, Ki-67 labeling index ≥ 10%, and age 55 ≥ years were the independent prognostic factors for recurrence., Conclusions: The prevalence of PDTC diagnosed with the Turin criteria was low, but it showed more aggressive behavior. The 2017 WHO classification reflects the prognosis more accurately than the 2004 WHO classification.

Background: Although lobectomy is considered acceptable as a primary surgical treatment for papillary thyroid carcinoma in properly selected patients, a standard treatment for postlobectomy lymph node recurrence has not been established. Here we compared the effectiveness of therapy with lymphadenectomy alone to that of treatment with completion thyroidectomy and lymphadenectomy followed by radioactive iodine., Methods: This was a retrospective study of patients with papillary thyroid carcinoma who underwent surgery for lymph node recurrence in the period from January 2003 to December 2008, all of whom had previously undergone initial lobectomy with or without lymph node dissection. One-hundred and twenty-five patients were included in the primary analysis., Results: Ninety-eight of these patients underwent lymphadenectomy alone (L group), and 27 received lymphadenectomy and completion thyroidectomy followed by radioactive iodine (LC&R group). The median follow-up time was 10.2 years. The overall survival, distant relapse-free survival, and lymph node relapse-free survival were not significantly different between the LC&R and L groups (P = .89, 0.58, and .22, respectively), whereas the LC&R group patients had significantly longer operation time, higher blood loss, and a higher rate of postoperative hypoparathyroidism compared with the L group (P < .001, respectively)., Conclusion: Compared with completion thyroidectomy and lymphadenectomy followed by radioactive iodine, lymphadenectomy alone was considered an acceptable therapeutic option which decreased the surgical disadvantages but did not decrease survival for at least 10 years after recurrence surgery for PTC patients with only lymph node recurrence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: There are little data regarding the overall survival (OS) of patients without adjuvant systemic therapy, because most patients have been subject to standardized systemic therapies. We evaluated the baseline risk to facilitate making decisions about adjuvant therapy., Patients and Methods: A total of 1835 breast cancer patients who did not receive adjuvant systemic therapy between 1964 and 1992 were retrospectively evaluated. We investigated the 10-year disease-free survival (DFS) and OS according to the number of metastatic lymph nodes, pathological T classification, stage, and estrogen receptor (ER) status., Results: Survival curves showed that as the number of metastatic lymph nodes, pathological T classification, and staging increased, the 10-year OS and DFS decreased. In univariate and multivariable analyses, the number of metastatic lymph nodes was significantly associated with the DFS and OS, while in a univariate analysis, the pathological T classification and stage were significantly associated with the DFS and OS. ER positivity was a good prognostic factor for the 5-year DFS. However, between 6 and 7 years after surgery, ER negativity was a better prognostic factor than ER positivity., Conclusion: We showed survival rates of patients without adjuvant therapy according to TNM classification and ER status. This information can aid in treatment selection for doctors and patients through a shared decision-making approach.

Background: Giant cell tumor (GCT) of the breast is scarce. We report a case of GCT of the breast which was suspected as a malignant breast tumor., Case Presentation: A 74-year-old woman noticed a tender lump in her right breast. We suspected a malignant tumor spreading widely with axillary lymph node metastasis on clinical examination and imaging. Histological evaluation of the biopsy tissue revealed a tumor composed the proliferation of oval to spindle-shaped cells and multinucleated giant cells without malignant epithelial cells. The tumor cells stained positively for CD68 and negatively for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The pathological findings suggested GCT, and fine needle aspiration biopsy for the axillary lymph node was negative. However, there was a gap between the clinical presentation, such as a tender mass suggesting rapid growth and multiple lymphadenopathies, and the pathological presentation of biopsy, which made us hesitate to conclude GCT as the final preoperative diagnosis. We could not rule out the possibility of malignant tumors with OGCs before surgery. We performed mastectomy and sentinel lymph node biopsy according to a surgical procedure for node-negative breast cancer with a wide ductal spread. The resected tissue histologically showed the same findings to the biopsy tissue. The definitive diagnosis of GCT of the breast was given, because the tumor lacked epithelial components, marked cellular atypia, and pleomorphism., Conclusions: GCT of the breast occasionally pretends as breast malignant tumors. Complete tumor resection should be performed for local control and the definitive diagnosis.

Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here, we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases, we provide an extensive resource for further investigation of mouse neuronal cell types., Competing Interests: KS, EC, AS, YS, LW, DH, BH, DT, JC, SP, AL, NS, AH, SN No competing interests declared, (© 2019, Sugino et al.)

Lenvatinib is a substrate of cytochrome P450 (CYP) 3A and ATP-binding cassette (ABC) transporters. In this study, we aimed to evaluate how CYP3A4/5 and ABC transporter polymorphisms affected the mean steady-state dose-adjusted plasma trough concentrations (C 0 ) of lenvatinib in a cohort of 40 Japanese patients with thyroid cancer. CYP3A4 20230G > A (*1G), CYP3A5 6986A > G (*3), ABCB1 1236C > T, ABCB1 2677G > T/A, ABCB1 3435C > T, ABCC2 -24C > T, and ABCG2 421C > A genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. In univariate analysis, there were no significant differences in the mean dose-adjusted C 0 values of lenvatinib between the ABCB1, ABCG2, and CYP3A5 genotypes. However, the mean dose-adjusted C 0 values of lenvatinib in patients with the CYP3A4*1/*1 genotype and ABCC2 -24T allele were significantly higher than those in patients with the CYP3A4*1G allele and -24C/C genotype, respectively (P = 0.018 and 0.036, respectively). In multivariate analysis, CYP3A4 genotype and total bilirubin were independent factors influencing the dose-adjusted C 0 of lenvatinib (P = 0.010 and 0.046, respectively). No significant differences were found in the incidence rates of hypertension, proteinuria, and hand-foot syndrome following treatment with lenvatinib between the genotypes of CYP3A4/5 and ABC transporters. Lenvatinib pharmacokinetics were significantly influenced by the CYP3A4*1G polymorphism. If the target plasma concentration of lenvatinib for efficacy or toxicity is determined, elucidation of the details of the CYP3A4*1G genotype may facilitate decision-making related to the appropriate initial lenvatinib dosage to achieve optimal plasma concentrations.

The aim of this study was to examine the association of lenvatinib-induced adverse events with the trough plasma concentration (C 0 ) in Japanese patients with thyroid cancer. Patients received lenvatinib 24 mg as an initial dose, and sequential dose reductions were conducted based on the grade of each side effect. Assessment of adverse events, assay of lenvatinib C 0 , and analysis of clinical laboratory tests were performed at the same time of day and were retrospectively analyzed. There were no significant differences in lenvatinib C 0 among grades of hypertension, proteinuria, hand-foot syndrome, and diarrhea. However, levels of aspartate transaminase, alanine transaminase, and total bilirubin were significantly higher in lenvatinib C 0 quartile (Q) 4 (≥ 88 ng/mL) than in Q1 (< 42 ng/mL) and Q2-3 (42-88 ng/mL). Additionally, platelet counts were highest in the lowest Q1 group. The median dose of lenvatinib in patients with UGT1A1*6/*6 or *6/*28 (poor metabolizers [PMs]) was significantly lower than that in patients with UGT1A1*1/*1 (10 and 14 mg, respectively), whereas the median bilirubin levels were significant higher in UGT1A1 PMs (0.9 and 0.5 mg/dL, respectively). There were no significant differences in median lenvatinib C 0 values between patients with UGT1A1*1/*1 and PMs (58.0 and 50.0 ng/mL, respectively). The threshold between the C 0 and toxicity of lenvatinib may be more than 88 ng/mL. Therefore, the dose of lenvatinib could be controlled to maintain a lower C 0 of less than 88 ng/mL. The target C 0 for lenvatinib as the threshold between the C 0 and optimal response may be in the range from 42 to 88 ng/mL; however, further studies are necessary.

Skin-sparing mastectomy (SSM) with immediate reconstruction is standard surgical treatment for early breast cancer with widespread ductal carcinoma in situ (DCIS). The local recurrence rate after SSM is up to 7.0%. We investigated prediction of the pathological margin using contrast-enhanced MRI, and evaluated the cut-off point to obtain the safety margin. We performed SSM with immediate reconstruction in 216 early breast cancer patients with widespread DCIS and/or invasive cancer from January 2014 to December 2015. Forty cases were retrospectively reviewed after excluding those with >15 mm between skin and tumor, determined by preoperative contrast-enhanced MRI, or involving reconstructive surgery for local recurrence, immeasurable lesion by preoperative contrast-enhanced MRI, or neoadjuvant chemotherapy. We defined a positive pathological margin as <1 mm from the cancer nest. We reviewed the distance between skin and tumor by MRI and pathological examination. To identify the cut-off for predicting a positive pathological margin, we performed sensitivity analysis using an ROC curve. The margin-positive rate by pathological examination was 27.5% (n = 11/40), with a moderate correlation of MRI margin and pathological margin (r = 0.44). The best cut-off point for margin positivity was 5 mm of MRI margin, with sensitivity and specificity of 54% and 86%, respectively (P = 0.009). This is the first prediction of pathological margin by preoperative contrast-enhanced MRI in early breast cancer patients with SSM. Care is required for SSM if the MRI margin is less than 5 mm due to pathological margin positivity., (© 2019 Wiley Periodicals, Inc.)

The extent of thyroidectomy in Graves' disease remains controversial. In our institution, long-term euthyroidism without thyroxin replacement therapy has been the aim, and it has long been the standard surgical procedure used to treat Graves' disease in many institutions, including our hospital. Based our several clinical studies, it was concluded that subtotal thyroidectomy is not suitable as a standard surgical procedure for the treatment of Graves' disease. In 2009, the surgical strategy for Graves' disease was changed from subtotal thyroidectomy to total thyroidectomy in our hospital. In this study, how surgical complications have changed after this modification was examined. The subjects were 1,476 patients with Graves' disease treated by thyroidectomy between 2006 and 2014. There were 1,119 females and 357 males with a median age of 39 years. A total of 660 patients underwent bilateral subtotal thyroidectomy (ST group), and 816 patients underwent total thyroidectomy (TT group). Both transient hypocalcemia and prolonged hypocalcemia were observed significantly more frequently in the TT group than in the ST group (p < 0.001). Total thyroidectomy was identified as risk factors for prolonged hypocalcemia on multivariate analysis. In conclusion, total thyroidectomy is a reliable and effective therapy for controlling hyperthyroidism in terms of controlling of hyperthyroidism. However, it should be noted that total thyroidectomy resulted in increased rate of prolonged hypocalcemia. Surgeons should try to reduce the surgical complication rate as much as possible.

Background: Amyloid tumor of the breast is a rare disease, which was first reported in 1973. To date, only six cases have been reported in Japan., Case Presentation: A 45-year-old woman who had a medical history of Sjogren's syndrome presented with a lump of 3 cm in diameter on the outer side of the right breast. Mammography showed no abnormality. Ultrasonography showed a well-defined and rough hypoechoic mass of 32 mm in diameter at the site of the lump. With suspicion of breast cancer, an ultrasound-guided vacuum-assisted breast biopsy was performed. For pathological diagnosis, hematoxylin and eosin staining showed deposits of nonstructural substances in the interstitium. The specimen stained red with Congo red staining and showed green birefringence under a polarizing microscope. Thus, the mass was diagnosed as an amyloid tumor. Since the patient had Sjogren's syndrome, it was considered a breast finding of autoimmune disease. We considered further therapy to be unnecessary, and annual follow-up was recommended., Conclusions: We diagnosed the mass as an amyloid tumor by an ultrasound-guided vacuum-assisted breast biopsy without resection. The patient had no systemic symptoms suspected systemic amyloidosis, and we diagnosed localized amyloidosis. An amyloid tumor of the breast may show findings suggestive of breast cancer. Pathological diagnosis before surgery is important to avoid excessive invasion. If deposits of nonstructural substances are observed by hematoxylin and eosin staining, Congo red staining should be added.

Background: Surgical resection is the preferred treatment for locoregional recurrence of differentiated thyroid cancer (DTC). However, some recurrences are unresectable because of their aggressive invasion or severe adhesions. On the other hand, stereotactic radiotherapy (SRT) enables high-dose irradiation to target lesions, and its usefulness for various cancers has been reported. The objective of the present study was to investigate the feasibility and efficacy of SRT as salvage treatment for locoregional recurrence of DTC., Methods: Between August 2011 and December 2017, 52 locoregional recurrent lesions in 31 patients with recurrent DTC were treated by SRT using the CyberKnife system. Information on the adverse events associated with SRT was retrospectively collected from the patients' medical records. Of the 52 lesions, 33 could be evaluated for therapeutic effectiveness by follow-up CT, and response was assessed using the RECIST criteria., Results: Twenty-five patients had papillary carcinoma, 5 had follicular carcinoma, and 1 had poorly differentiated cancer. SRT was delivered in one to 20 fractions, and the median dose was 30 Gy (range 15-60 Gy). Adverse events were not frequent, but 1 patient developed bilateral vocal cord palsy that required emergent tracheostomy. The median follow-up period of 33 lesions was 14 months (range 1-54 months). Complete response, partial response, stable disease, and progressive disease were seen in 10, 11, 9, and 3 patients, respectively. The 3-year local control rate was 84.6%., Conclusion: SRT using the CyberKnife system was found to be a feasible and effective treatment to suppress the growth of locoregional recurrence of DTC.

The antiviral activities of a nucleoside analog antiviral drug (ribavirin) and a non-nucleoside drug (mycophenolate mofetil) against human parainfluenza virus type 2 (hPIV-2) were investigated, and the restoration of the inhibition by guanosine and S-(4-nitrobenzyl)-6-thioinosine (NBTI: equilibrative nucleoside transporter 1 inhibitor) were also investigated. Ribavirin (RBV) and mycophenolate mofetil (MMF) inhibited cell fusion induced by hPIV-2. Both RBV and MMF considerably reduced the number of viruses released from the cells. Virus genome synthesis was inhibited by RBV and MMF as determined by polymerase chain reaction (PCR) and real time PCR. mRNA syntheses were also reduced. An indirect immunofluorescence study showed that RBV and MMF largely inhibited viral protein syntheses. Using a recombinant green fluorescence protein (GFP)-expressing hPIV-2 without matrix protein (rhPIV-2ΔMGFP), it was found that virus entry into the cells and multinucleated giant cell formation were almost completely blocked by RBV and MMF. RBV and MMF did not disrupt actin microfilaments or microtubules. Both guanosine and NBTI completely or partially reversed the inhibition by RBV and MMF in the viral replication, syntheses of genome RNA, mRNA and protein, and multinucleated giant cell formation. NBTI caused a little damage in actin microfilaments, but had no effect on microtubules. Both RBV and MMF inhibited the replication of hPIV-2, mainly by inhibiting viral genome RNA, mRNA and protein syntheses. The inhibition was almost completely recovered by guanosine. These results indicate that the major mechanism of the inhibition is the depletion of intracellular GTP pools.

Background: When a clinical context is indeterminate for idiopathic pulmonary fibrosis (IPF), or a chest high-resolution computed tomography (HRCT) pattern is not indicative of typical or probable usual interstitial pneumonia (UIP) in patients with interstitial lung disease (ILD), surgical lung biopsy should be considered to make a confident diagnosis on the basis of multidisciplinary diagnosis (MDD)., Aim: The aim of this study was to evaluate the role and safety of video-assisted thoracoscopic surgery (VATS) in patients with ILD., Methods: A total of 143 patients with ILD underwent VATS at Toho University Medical Center Omori Hospital between March 2004 and April 2017. We conducted a retrospective study on the usefulness and safety of VATS in the diagnosis of ILD under MDD., Results: The 30-day mortality was 0%. The postoperative complication rate was 12.6%, which included 5 cases of pneumothorax after discharge (3.5%), 4 cases of prolonged air leakage (2.8%), and 2 cases of acute exacerbation (1.4%). Three of 9 cases (33.3%) complicated by pneumothorax after discharge or prolonged air leakage were resected specimens of pleuroparenchymal fibroelastosis (PPFE). Two patients had acute exacerbation, who were ultimately diagnosed as having idiopathic unclassifiable IP and had histologically significant irregular dense fibrosis and numerous fibroblastic foci. The comparison between chest HRCT and histopathological findings revealed 55 cases of possible UIP [UIP (45%), NSIP (25%), and unclassifiable IP (29%)] and 21 cases of inconsistent with UIP [UIP (10%), NSIP (33%), organizing pneumonia (10%), unclassifiable IP (24%), and PPFE (24%)]., Conclusion: VATS can be safely performed to obtain a confident diagnosis for appropriate treatment strategies in patients with ILD., (Copyright: © 2019.)

Background: Recent clinical trials demonstrated the benefits of several guided-bronchoscopy technologies for the diagnosis of peripheral pulmonary lesions (PPLs). However, introduction of these technologies is expensive. Therefore, in clinical practice, these are unavailable in many hospitals. In contrast, virtual bronchoscopy (VB) using the computed tomography (CT) workstation can be made available immediately without additional cost as many hospitals already have the CT scan facility. However, the effectiveness of VB alone remains to be shown., Objectives: The aim of this study was to investigate the effect of VB using the CT workstation in hospitals performing conventional bronchoscopy., Methods: Results from consecutive patients who underwent bronchoscopy for small PPLs (major diameter ≤30 mm) were retrospectively reviewed. Sixty-nine patients who underwent bronchoscopy without VB from April 2014 to March 2015 and 56 patients who underwent bronchoscopy with VB from April 2015 to December 2015 were assigned to non-VB and VB groups, respectively. We compared the two groups and analyzed the factors affecting the diagnostic yield., Results: The VB group had a significantly higher diagnostic yield than the non-VB group (57.1 vs. 33.3%; p = 0.008). In the multivariate analysis, VB was identified as a significant factor affecting the diagnostic yield (odds ratio: 3.30, p = 0.011)., Conclusions: In the conventional bronchoscopy settings, VB using the CT workstation is efficient for the diagnosis of PPLs when other guided-bronchoscopy techniques are unavailable., (© 2018 S. Karger AG, Basel.)

Background: The serum thyrotropin receptor antibody (TRAb) titers of Graves' disease (GD) patients are known to increase after radioiodine (RAI) therapy, and they can remain high for years. The incidence of neonatal hyperthyroidism (NH) among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. The aims of this study were to investigate the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and to identify predictors of NH., Methods: GD patients (n = 145) who conceived within two years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected., Results: Of the 145 pregnant women, 54 (37%) were treated with antithyroid drugs or potassium iodide for maternal hyperthyroidism during the first trimester. There were eight newborns with NH, resulting in an incidence of 5.5%. Seven of the eight mothers whose newborns had NH were treated with antithyroid drugs or potassium iodide during their pregnancy. The incidence of NH among the newborns of mothers who conceived within 6-12 months after RAI therapy was 8.8%, within 12-18 months was 5.5%, and within 18-24 months was 3.6%. Multivariate analysis revealed that the TRAb values in the third trimester were the only risk factor for NH. The cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference value <2.0 IU/L)., Conclusions: The incidence of NH among newborns of mothers who conceived within two years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose TRAb value is high in the third trimester should be carefully followed by an obstetrician during pregnancy, and the newborns should be carefully followed by a pediatrician after birth.

Lenvatinib is a molecular-targeting agent that was recently approved in Japan for treatment of curatively unresectable, radioactive iodine-refractory, progressive differentiated thyroid cancer (DTC). Because only a few Japanese patients have received lenvatinib in clinical trials, there are limited domestic data on its safety and efficacy or prognostic factors. Therefore, a prospective observational study has been designed to collect safety and efficacy data in at least 300 patients with curatively unresectable DTC receiving lenvatinib therapy (24 mg/day), in order to find predictors of antitumor activity and survival. Patients with progressive curatively unresectable DTC refractory to radioiodine therapy will be enrolled and the primary endpoint will be overall survival. This study is designed to estimate the 95% confidence intervals of the 1-year and 2-year survival rates with a two-sided width of less than 10%. Secondary endpoints will be the time to treatment failure, time to strategy failure, progression-free survival time with clinical progressive disease, response rate, quality of life, safety, and patient reports. The ultimate goal is to obtain information for developing evidence-based guidelines for treatment of DTC, including recommendations on patient selection, dosages, and duration of treatment. This study has been registered with the UMIN Clinical Trials Registry (UMIN000022243).

Background: Radiation-associated angiosarcoma (RAAS) is a rare subtype of secondary angiosarcoma that is characterized by rapid proliferation and extensive tissue infiltration. Although various treatments for RAAS (such as surgery, chemotherapy, and radiation therapy) have been reported, there is no consensus as to which approach is the best., Case Presentation: A 76-year-old woman presented with right breast cancer (T1N0M0, stage I) 9 years ago. She had undergone breast-conserving surgery and sentinel lymph node biopsy and was receiving adjuvant chemotherapy and radiation therapy for the malignancy. Six years after presenting with the tumor, she developed pigmented skin and was diagnosed with a RAAS; this angiosarcoma recurred three times within 2 years. The angiosarcoma was resected each of the three times, after which adjuvant radiation therapy was performed. At 76 years old, the patient developed a new mass on her chest skin in the vicinity of the scar. Angiosarcoma was diagnosed following a pathology report, which resulted in a second diagnosis of recurrent RAAS again since the diagnostic criteria were met. After extensive resection of the irradiated area, the patient has remained free of angiosarcoma for the last 3 years., Conclusion: Resection of the entire irradiated field is critical for successful treatment of RAAS.

Background: Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is rare; it may occur in cases of familial adenomatous polyposis (FAP) or be sporadic. To clarify the clinicopathological features of CMV-PTC, the medical records of these patients were investigated retrospectively., Materials and Methods: Between 1979 and 2016, a total of 17,062 cases with PTC underwent initial surgery at Ito Hospital. Of these, 30 (0.2%) cases histologically diagnosed with CMV-PTC were reviewed., Result: The patients were all women, with a mean age at the time of surgery of 24 years. Seven (23%) cases were thought to have FAP because they had colonic polyposis or a family history of FAP or APC gene mutation. The remaining 23 (77%) were thought to be sporadic. Multiple tumors were detected in 6 cases, with a solitary tumor in 24. One patient had lung metastasis at diagnosis. Eleven patients underwent total thyroidectomy or subtotal thyroidectomy, and 19 underwent lobectomy. Twenty-six (87%) patients underwent neck lymph node dissection. Three patients had tumor metastasis in central lymph nodes, but these were incidentally detected metastatic classical PTC (cPTC) based on histological examination. In this series, there were no cases of LN metastases of CMV-PTC. During a mean follow-up of 15 years, one patient had new cPTC in the remnant thyroid after initial surgery, and the other patients showed no signs of recurrence., Conclusion: CMV-PTC occurred in young women, their long-term prognosis was excellent. Total thyroidectomy is recommended for FAP-associated CMV-PTC, but modified neck lymph node dissection is not necessary.

Purpose: Occult breast cancer (OBC) is classified as a carcinoma of unknown primary, and involves axillary lymphadenopathy and is histologically consistent with metastatic breast cancer. OBC has been conventionally considered as a metastatic lymph node lesion, the origin of which is an undetectable breast tumor. Therefore, OBC patients would usually have undergone axillary lymph node dissection, and mastectomy or whole breast radiotherapy (WBRT). However, majority of OBC reports have been based on cases that were diagnosed during a period when diagnostics was still relatively primitive, and when magnetic resonance imaging was not yet a standard preoperative assessment. Therefore, there have been many false negatives in the breast based on preoperative assessment., Methods: We herein hypothesize that the origin of OBC is ectopic breast tissue present in axillary lymph nodes (ALNs). If our hypothesis is true, mastectomy and WBRT may be unnecessary for OBC patients., Results: Our hypothesis is supported by several findings. First, advances in radiological imaging have suggested that a primary breast tumor is absent in OBC patients. Second, proliferative breast lesions arising from ectopic breast present in ALNs have been reported. Lastly, cellular subtypes in OBC based on immunohistochemistry are of various types including ordinary breast cancer and the prognosis is not worse than stage II breast cancer., Conclusion: It is important to distinguish between "primary" OBC in ALNs and "metastatic" OBC from micro-primary breast tumor. Further studies are required to determine if omission of mastectomy and WBRT is acceptable.

Background: Treatment of patients with liver metastasis of differentiated thyroid carcinoma (DTC) has not been sufficiently defined, because liver metastasis of DTC has been described mostly as case reports. Additionally, such patients are considered end-of-treatment responders. A relatively new approach using tyrosine kinase inhibitors (TKIs) may provide opportunities to manage systemic metastasis. This study aims to define the clinical features of DTC patients with liver metastasis and evaluate the benefits of TKIs., Methods: We retrospectively analyzed clinical features of 29 patients (mean age 67.8 years) diagnosed with liver metastasis of DTC at our institution between January 1981 and May 2017., Results: All patients had distant metastasis at other organ sites upon diagnosis of liver metastasis; 41% of them developed new metastasis afterward. Management after diagnosis of liver metastasis comprised palliative care (48%), radioactive iodine therapy (28%), and TKI therapy (24%). The median survival after diagnosis of liver metastasis was only 4.8 months. Survival rates were significantly better in patients with performance statuses between 0 and 2 on the Eastern Cooperative Oncology Group scale at diagnosis of liver metastasis (n = 22, 76%) treated with TKI compared to those who were not (P = 0.017; log-rank test; hazard ratio 0.19). One-year survival rates were 71.4 and 26.7% for patients treated with or without TKI, respectively., Conclusions: Patients with liver metastasis had poor clinical prognosis. When other distant metastases existed at diagnosis of liver metastasis, TKI therapy was considered an effective therapeutic option for patients with liver metastasis of DTC.

Purpose: The aim of this study was to investigate the effect of outpatient pulmonary rehabilitation (PR) program and the use of 6-min walk distance (6MWD), expressed as a percentage of the predicted value (%6MWD), to quantify response to PR in elderly patients with interstitial lung disease (ILD)., Methods: This was a prospective, nonrandomized controlled study. Forty eligible patients with stable ILD (≥65 y old) were advised to attend an outpatient PR program for 3 mo. Thirteen patients completed the PR program and formed the PR group. Ten patients who did not attend the PR program were evaluated after 3 mo and formed the control group. Patients in the PR group underwent a comprehensive 3-mo hospital-based outpatient PR program, consisting of educational support and supervised exercise training, and attended the rehabilitation unit weekly., Results: Change in the absolute 6MWD (Δ6MWD) in the PR group was not significantly different compared with the control group (P = .062). Change in %6MWD (Δ%6MWD) was greater in the PR group than in the control group. Baseline 6MWD was not correlated with Δ6MWD, but baseline %6MWD was significantly correlated with Δ6MWD and Δ%6MWD., Conclusion: PR had a beneficial effect on elderly patients with ILD in terms of exercise endurance. %6MWD might be more useful than the absolute 6MWD as an outcome measure of PR and as a predictor of response to PR in elderly patients with ILD.

Background: Enhanced magnetic resonance imaging (MRI) and ultrasonography (US) are used to assess residual lesions after preoperative chemotherapy before surgery. However, residual lesion assessments based on preoperative imaging often differ from postoperative pathologic diagnoses. We retrospectively reviewed the accuracy of preoperative residual lesion assessments, including ductal carcinoma in situ (DCIS) cases to find criteria for cases in which surgery can be omitted., Methods: We reviewed 201 patients who received preoperative chemotherapy and surgery in our hospital from January 2013 to November 2016. Presurgical evaluations regarding the possible existence of residual lesions, and clinical Complete Response (cCR) or non-cCR, were compared with postoperative pathological diagnoses., Results: Of the 201 patients, 52 were diagnosed with cCR, and 39 with pathological complete response (pCR). Predictions for residual lesions were 86.4% sensitive, 76.9% specific, and 84.6% accurate. When patients were divided into 4 groups by estrogen receptor (ER) and HER2 status, sensitivity in each group was ER + /HER2 - : 91.4%; ER - /HER2 - : 94.1%; ER + /HER2 + : 78.6%; and ER - /HER2 + : 78.5%. Of the 22 patients preoperatively assessed with cCR, but diagnosed with non-pCR, the median invasive residual tumor size was 2 mm (range 0-46 mm); 5 patients (22.7%) had only DCIS., Conclusions: Predicting residual lesions after preoperative chemotherapy by using MRI and US is a reasonable strategy. However, current methods are inadequate for identifying patients who can omit surgery; therefore, a new strategy for detecting small tumors in these patients is needed.

Background: Recent studies suggested that ALND (axillary lymph node dissection) can be avoided in breast cancer patients with limited SLN (sentinel lymph node) metastasis. However, these trials included only several invasive lobular carcinoma (ILC) cases, and the validity of omitting ALND for ILC remains controversial. Here, we examined whether omitting ALND is feasible in ILC treatment., Methods: A total of 3771 breast cancer patients underwent surgery for breast cancer at the Aichi Cancer Center Hospital between January 2006 and December 2015. We excluded patients with neoadjuvant therapy or without axillary management, and identified 184 ILC patients and 2402 invasive ductal carcinoma (IDC) patients. We compared SLN and non-SLN metastasis rates and the number of total ALN metastases between the ILC and IDC cohorts, and we examined the factors that influenced non-SLN metastasis in the SLN micrometastasis group., Results: SLN biopsies were performed in 171 (93%) ILC and 2168 (90%) IDC cases, and 31 (18%) ILC and 457 (21%) IDC cases were SLN micrometastasis and macrometastasis (p = 0.36). Among SLN macrometastasis patients, 17 (68%) ILC cases and 163 (46%) IDC cases showed non-SLN metastasis (p = 0.03). The number of non-SLN metastases was greater in ILC cases compared with IDC cases. Multivariate analysis showed that ILC was the influential factor predicting non-SLN metastasis in patients with SLN macrometastasis., Conclusion: ILC cases had more non-SLN metastasis than IDC cases among SLN-positive cases, and ILC was an important factor for the prediction of non-SLN positivity in SLN macrometastasis cases. Omitting ALND for ILC with positive SLNs requires more consideration.

Background: Contralateral risk-reducing mastectomy (CRRM) for breast cancer patients with BRCA mutations has been reported to not only reduce breast cancer incidence but also to improve survival. The National Comprehensive Cancer Network guidelines recommend providing CRRM to women with BRCA mutations who desire CRRM after risk-reduction counseling. However, in Japan, CRRM cannot be performed generally because it is not covered by health insurance. Thus, we conducted a feasibility study to confirm the safety of CRRM., Methods: CRRM with bilateral breast reconstructions were performed for breast cancer patients with BRCA mutations. The primary endpoint was early adverse events within 3 months, and secondary endpoints were late adverse events., Results: Between August 2014 and November 2016, ten patients were enrolled. The median age was 37.5 years, and five of the patients had the BRCA1 mutation while five had the BRCA2 mutation. Six patients received neoadjuvant chemotherapy. Eight patients selected silicone breast implants, and two patients selected transverse rectus abdominis myocutaneous flap reconstruction. Pathological findings showed no evidence of occult breast cancers in any of the patients. At a median of 25.5 months follow-up time, CRRM-related early adverse events were hematoma (subsequently removed by re-operation; grade 2, n = 1), wound infection (grade 2, n = 1), skin ulceration (grade 1, n = 2) and wound pain (grade 1, n = 1). Overall, there were no grade 3 or more severe adverse events., Conclusion: Our results confirm that CRRM with reconstruction could be performed safely.

Background: Breast cancer is the most common cancer among women, and its survival rate has improved. As the number of cancer survivors increases, it is important to support their social comeback during and after treatment., Methods: Questionnaires were distributed to breast cancer patients treated in Aichi Cancer Center Hospital between June and November 2014. Responders were categorized according to adjuvant therapy (Group A: none, Group B: endocrine therapy, Group C: chemotherapy), or if they had advanced or recurrent breast cancer (Group D)., Results: A total of 279 patients returned questionnaires (62, 79, 92 and 46 patients in Groups A, B, C and D, respectively). In adjuvant treatment groups, 43 patients (18.5%) quit their job during or after treatment. Most patients had quit their jobs at the time of diagnosis (7.5%), followed by those undergoing chemotherapy (5.6%) and those at the time of operation (4.9%). Quit rate from the workplace in which patients worked at the time of diagnosis was highest in Group C (30%), followed by Group B (20%) and Group A (13%). At the time of operation, 127 patients (57%) were absent from work. In Group D, 16 patients (35%) quit their job during treatment. Rates for patients currently working who had anxiety were 62, 30, 26 and 9% in Groups D, C, B and A, respectively., Conclusions: In adjuvant treatment groups, in which quit rate was highest at the time of diagnosis, consultation about working is necessary immediately after diagnosis. Patients treated most heavily had higher quit rates and experienced more anxiety about working.

In vivo direct conversion of differentiated cells holds promise for regenerative medicine; however, improving the conversion efficiency and producing functional target cells remain challenging. Ectopic Atoh1 expression in non-sensory supporting cells (SCs) in mouse cochleae induces their partial conversion to hair cells (HCs) at low efficiency. Here, we performed single-cell RNA sequencing of whole mouse sensory epithelia harvested at multiple time points after conditional overexpression of Atoh1. Pseudotemporal ordering revealed that converted HCs (cHCs) are present along a conversion continuum that correlates with both endogenous and exogenous Atoh1 expression. Bulk sequencing of isolated cell populations and single-cell qPCR confirmed 51 transcription factors, including Isl1, are differentially expressed among cHCs, SCs and HCs. In transgenic mice, co-overexpression of Atoh1 and Isl1 enhanced the HC conversion efficiency. Together, our study shows how high-resolution transcriptional profiling of direct cell conversion can identify co-reprogramming factors required for efficient conversion., Competing Interests: The authors have declared that no competing interests exist.