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Abstract Amphibians shape their limbs by differential outgrowth of digits and interdigital regions. In contrast, amniotes employ cell death, an additional developmental system, to determine the final shape of limbs. Previous work has shown that high oxygen availability is correlated with the induction of cell death in developing limbs. Given the diversity of life histories of amphibians, it is conceivable that some amphibians are exposed to a high–oxygen environment during the tadpole phase and exhibit cell death in their limbs. Here, we examined whether air–breathing behavior underlies the cell death in limbs of aquatic tadpoles of the frog species Rana pirica. Our experimental approach revealed that R. pirica tadpoles exhibit cell death in their limbs that is likely to be induced by oxidative stress associated with their frequent air–breathing behavior.

Introduction: Autologous mononuclear cells (MNCs) have been used in vascular regenerative therapy since the identification of endothelial progenitor cells (EPCs). However, the efficacy of autologous EPC therapy for diseases such as diabetes and connective tissue disorders is limited due to deficiencies in the number and function of EPCs. To address this, we developed a novel RE-01 cells that enriches pro-angiogenic cells from peripheral blood MNCs (PBMNCs). Methods: PBMNCs were collected from healthy volunteers following ethical guidelines. RE-01 cells were cultured in the presence of specific growth factors for 5 days without media change. Flow cytometry was used to analyze cell surface markers. Tube formation assays, EPC culture assays, and mRNA analysis were performed to evaluate angiogenic potential. The efficacy of RE-01 cells upon transplantation into ischemic hind limbs of mice was evaluated. Results: RE-01 cells exhibited a significant increase in pro-angiogenic cells such as M2 macrophages and angiogenic T cells, in contrast to PBMNCs, while the number of inflammatory cells reduced. In vitro assays demonstrated the enhanced angiogenic abilities of RE-01 cells, supported by increased mRNA expression of angiogenesis-related cytokines. In vivo studies using mouse ischemic hind limb models have shown that blood flow and angiogenesis improved following RE-01 cell transplantation. Transplantations for 3 consecutive days significantly improved the number of pericyte-recruited vessels in the severely ischemic hind limbs of mice. Conclusions: RE-01 cells showed promising results in enhancing angiogenesis and arteriogenesis, possibly owing to the presence of M2 macrophages and angiogenic T cells. These cells also demonstrated anti-fibrotic effects. The efficacy of RE-01 cells has been confirmed in mouse models, suggesting their potential for treating ischemic vascular diseases. Clinical trials are planned to validate the safety and efficacy of RE-01 cell therapy in patients with connective tissue disease and unhealed ulcers. We hope that this new RE-01 cell therapy will prevent many patients from undergoing amputation.

This study reports on the microstructure and magnetism of pure iron irradiated with high doses of helium ions. Iron alloys are important structural materials used as components in fusion reactors, and a comprehensive database of their various properties has been developed. But little has been investigated on magnetic properties, in particular, the effects of high doses and helium cavities are lacking. Single-crystal iron films, with a thickness of 200 nm, were prepared using the ultra-high vacuum evaporation method. These films were then irradiated with 30 keV He+ ions at room temperature up to a dose of 18 dpa. X-ray diffraction measurements and cross-sectional transmission electron microscope observations revealed significant microstructural changes, including a large lattice expansion perpendicular to the film plane and the formation of high-density cavities after irradiation. However, the saturation magnetization and the shape of the magnetization curve showed almost no change, indicating the robustness of the magnetic properties of iron.

This study examined the differences in English learning goals and specific actions for goal achievement according to the degree of willingness to communicate (WTC) among Japanese English as a Foreign Language (EFL) learners through qualitative analysis. This study aimed to ascertain: 1) the characteristics of English learning goals among learners with higher or lower levels of WTC, and 2) the differences in learner actions for goal achievement among learners with higher or lower levels of WTC. The participants were 84 undergraduate students in Japan, and they were divided into high-WTC and low-WTC groups using the WTC scale (Peng & Woodrow, 2010). Open-ended responses of the goals for learning English and actions for goal achievement were compared between these two groups using KH Coder 3. Coded data were analyzed in a co-occurrence network diagram. Results showed that high-WTC learners tended to have high-level goals, whereas low-WTC learners tended to have the lowest possible goals. High-WTC learners also had more interest in foreign countries and studying abroad. Furthermore, high-WTC learners tended to take a variety of specific actions for goal achievement, while low-WTC learners took rather general and common actions. The results showed clear differences between these two groups.

Cancer cells harbor many genetic mutations and gene expression profiles different from normal cells. Patient-derived cancer cells (PDCC) are preferred materials in cancer study. We established patient-derived spheroids (PDSs) and patient-derived organoids (PDOs) from PDCCs isolated from the malignant pleural effusion in 8 patients. The morphologies suggested that PDSs may be a model of local cancer extensions, while PDOs may be a model of distant cancer metastases. The gene expression profiles differed between PDSs and PDOs: Gene sets related to inflammatory responses and EMT were antithetically regulated in PDSs or in PDOs. PDSs demonstrated an attenuation of the pathways that contribute to the enhancement of transforming growth factor beta (TGF-β) induced epithelial mesenchymal transition (EMT), while PDOs demonstrated an attenuation of it. Taken together, PDSs and PDOs have differences in both the interaction to the immune systems and to the stroma. PDSs and PDOs will provide a model system that enable intimate investigation of the behavior of cancer cells in the body.

ObjectivesThis study aimed to investigate the relationship between night shifts and snacking behaviors during pregnancy using Japanese maternal-infant longitudinal data from a large-scale study.MethodsThis study used the Japan Environment and Children's Study dataset jecs-ta-20190930, released in October 2019. After simple analysis using analysis of variance and multiple comparisons, crude odds ratios (cOR) and adjusted odds ratios (aORs) were calculated. To evaluate eating habits, we examined habitual fast food and snacks (e.g., potato chips, corn puffs and tortilla chips) consumption, midnight snacks, and regular missing breakfast.ResultsThere was no significant association between inappropriate weight gain during pregnancy and night shift work in early pregnancy. The aOR for consuming snacks more than once a week after noticing pregnancy for shift workers was 1.34 (95% confidence interval 1.27-1.41; p < 0.001) compared with worker without night shiftwork. The aOR for shift workers consuming fast food more than three times a week during pregnancy was 1.40 (95% confidence interval 0.79-2.33; p > 0.05).ConclusionsPregnant night shift workers did not show excessive weight gain but had an increased frequency of consumption of snack foods compared with pregnant dayshift workers.

Objective: To describe the detailed clinical course of patients with coronavirus disease 2019 (COVID-19) who received invasive mechanical ventilation. Methods: We conducted a case series of patients with COVID-19 who received invasive mechanical ventilation in Osaka, Japan, between January 29 and May 28, 2020. We describe the patient characteristics and clinical course from onset. Additionally, we fitted logistic regression models to investigate the associations between patient characteristics and the 30-day mortality rate. Results: A total of 125 patients who received invasive mechanical ventilation (median age [interquartile range], 68 [57–73] years; male, 77.6%) were enrolled. Overall, the 30-day mortality was 24.0%, and the median (interquartile range) length of ICU stay and length of invasive mechanical ventilation use were 16 (12–29) days and 13 (9–26) days, respectively. From clinical onset, 121 patients (96.8%) were intubated within 14 days. In multivariable logistic regression analysis, age of 65 years or older (odds ratio, 3.56; 95% confidence interval, 1.21–10.49; P = 0.02) and male sex (odds ratio, 3.75; 95% confidence interval, 1.00–11.24, P = 0.04) were significantly associated with a higher 30-day mortality rate. Conclusions: In this case series of patients with COVID-19 who received invasive mechanical ventilation in Japan, the 30-day mortality rate was 24.0%, and age 65 years or older and male sex were associated with higher 30-day mortality rate.

Aim: This study aimed to appropriately establish a Japanese style healthcare program under the ISO9001:2008 (ISO: International Organization for Standardization) in Minowa, Japan and Rayong, Thailand to improve problem areas and inspect its effectiveness. Furthermore, we want to make this health promotion through ISO widely available in Asian countries and to make an international contribution. Method: We implemented a 6-month health program in the c Rayong city, Thailand, and a 12 month health program in the Minowa town, Japan. This study assessed findings from pedometry, anthropometry and blood pressure measurements, physical fitness, blood chemistry, and brain function tests. Results: The comparisons were made using interaction effects between the participants in Rayong and Minowa. They showed significant differences in the 10-m obstacle walk, the 6-minute walk, HDL, the reverse and reverse differentiation time, the total number of forgets, the total number of mistakes, and the total number of brain function errors. Conclusions: To improve the brain function in participants from Rayong through this health education program, measures such as increasing the number of steps, adding muscular strength/stretching exercises, and home training every day is suggested.

Emergency transport data from Tottori Prefecture, Japan were used to evaluate the indirect impact of coronavirus disease 2019 (COVID-19) restrictions on heat stroke. There were 426 cases of emergency transport owing to heat stroke in summer 2020 compared with 1465 cases combined for the summers of 2017–2019. The mean age of cases in 2020 was 66.2 years—significantly higher than the 60.0 years in 2017 (p = 0.004), 57.4 years in 2018 (p < 0.001), and 57.6 years in 2019 (p < 0.001). In 2020, 47.7% of cases were older than 75 (previously, 35.6–44.2%), and 36.9% were transported from their residence, (previously, 26.6–29.3%). Thus, COVID-19 measures, such as “stay at home” requests, may have increased the risk of heat stroke in older adults.

Ficifolidione, a natural insecticidal compound isolated from the essential oils of Myetaceae species, is a spiro phloroglucinol with an isobutyl group at the C-4 position. We found that ficifolidione showed cytotoxicity against cancer cells via apoptosis. Replacement of the isobutyl group by n-propyl group did not influence the potency, but the effect of the replacement of this group by a shorter or longer alkyl group on the biological activity remains unknown. In this study, ficifolidione derivatives with alkyl groups such as methyl, n-pentyl, and n-heptyl group—instead of the isobutyl group at the C-4 position—were synthesized to evaluate their cytotoxicity against the human promyelocytic leukaemia cell line HL60 and their insecticidal activity against mosquito larvae. The biological activities of their corresponding 4-epimers were also evaluated. As a result, the conversion of the isobutyl group to another alkyl group did not significantly influence the cytotoxicity or insecticidal activity. In HL60 cells treated with the n-heptyl-ficifolidione derivative, the activation of caspase 3/7 and the early stages of apoptosis were detected by using immunofluorescence and flow cytometric techniques, respectively, suggesting that the cytotoxicity should be induced by apoptosis even though the alkyl group was changed.

Pulmonary involvement is one of the extra-articular manifestations of rheumatoid arthritis and can be due to the disease itself or secondary to the medications used in order to treat it. We report the case of a 60-year-old woman who had been diagnosed with rheumatoid arthritis and developed multiple pulmonary nodules during treatment with leflunomide.

The aim of this study was to compare computed tomography (CT) scans of chest and lung function among patients with Human T-Lymphotropic Virus Type 1 (HTLV) with and without HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this cross-sectional study performed between January 2013 and June 2016, we included 48 patients with HAM/TSP (19 women and 11 men) and without HAM/TSP (12 women and 6 men). We compared CT findings and lung functions of these groups. Patients who had HAM/TSP had abnormal CT findings (P = 0.000), including more frequent bronchiectasis (P = 0.049), parenchymal bands (P = 0.007), interlobular septal thickening (P = 0.035), and pleural thickening (P = 0.009). In addition, neither patients with HAM/TSP (9/30; 30%) nor the controls (0/18; 0%) had obstructive or restrictive lung disease (P = 0.009). HTLV diagnosis should be considered in all patients with abnormal CT findings in whom no other cause is apparent. It is important to remember that lung disease increases the rates of morbidity and mortality in developing countries.

[This corrects the article DOI: 10.1371/journal.pone.0186055.].

Dietary consumption has recently been identified as a major environmental source of pro-inflammatory advanced glycation end-products (AGEs) in humans. It is disputed whether dietary AGEs represent a risk to human health. Nε-(carboxymethyl)lysine (CML), a representative AGE compound found in food, has been suggested to make a significant contribution to circulating CML levels. However, recent studies have found that the dietary intake of AGEs is not associated with plasma CML concentrations. We have shown that the serum levels of glyceraldehyde-derived AGEs (Glycer-AGEs), but not hemoglobin A1c, glucose-derived AGEs (Glu-AGEs), or CML, could be used as biomarkers for predicting the progression of atherosclerosis and future cardiovascular events. We also detected the production/accumulation of Glycer-AGEs in normal rats administered Glu-AGE-rich beverages. Therefore, we assessed the concentrations of various AGEs in a total of 1,650 beverages and foods that are commonly consumed in Japan. The concentrations of four kinds of AGEs (Glu-AGEs, fructose-derived AGEs (Fru-AGEs), CML, and Glycer-AGEs) were measured with competitive enzyme-linked immunosorbent assays involving immunoaffinity-purified specific antibodies. The results of the latter assays indicated that Glu-AGEs and Fru-AGEs (especially Glu-AGEs), but not CML or Glycer-AGEs, are present at appreciable levels in beverages and foods that are commonly consumed by Japanese. Glu-AGEs, Fru-AGEs, CML, and Glycer-AGEs exhibited concentrations of ≥85%, 2-12%,

There are very few reports about prevalence of presenile dementia in Brazil. We reviewed files of patients evaluated with early onset of cognitive impairment in our institution. Among 141 patients (61% males) there was no difference between gender by age at onset or at first evaluation. We have observed an increasing number of patients after 50 years. The most frequent causes were: vascular dementia (36.9%), Alzheimer's disease (20.3%) and traumatic brain injury (9.2%). There was difference among dementia type by age of onset and first evaluation, educational level and length of dementia. These results may be compared with those from other neurologic services in order to replicate or confirm these results.

We report a case of a 26-year-old man who presented a lower motor neuron syndrome due to hyperparathyroidism. Electromyography showed neurogenic features with normal nerve conduction studies. Hypercalcemia led to the discovery of a primary hyperparathyroidism with gland hyperplasia. Following parathyroid surgery there was recovery of the neurological symptoms.Descrevemos o caso de homem de 26 anos que apresentou síndrome do neurônio motor inferior devido a hiperparatiroidismo. A eletromiografia mostrou aspecto neurogênico com estudos da condução normal. Hipercalcemia levou à descoberta de hiperparatiroidismo primário com hiperplasia da glândula. Após a cirurgia de ressecção da paratiróide, houve regressão dos sintomas neurológicos.

Human T-lymphotropic virus type-1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATL). Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM) is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Sjögren’s Syndrome (SS). The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4+ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4+ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity.

ABSTRACT The X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy’s disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient’s creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy’s disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy’s disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects.

The present study aimed to evaluate the rate of positive surgical margins for magnetic resonance imaging (MRI) performed in the supine position prior to breast-conserving surgery (BCS). The rate of positive surgical margins and the clinicopathological factors were examined in consecutive patients with BCS who underwent preoperative MRI performed in the supine position at Sapporo Medical University Hospital (Sapporo, Japan) and related hospitals and clinics between January 2012 and December 2013. Of 1,175 eligible patients, 1,150 were included after excluding 25 patients with either bilateral breast cancer or stage IV disease. Positive margin was defined as no cancer seen on the resected margin. The primary endpoint was the rate of positive surgical margins when preoperative MRI was performed in the supine position and the secondary endpoint was identification of the factors that predict positive margins. Of the 1,150 female patients (median age, 55 years; range, 29-97 years) who underwent BCS for breast cancer following MRI performed in the supine position, 215 (18.8%) had positive margins, which is similar to the rate with MRI in the prone position, and 930 (81.2%) had negative margins. The rate of positive surgical margins in patients of the human epidermal growth factor receptor 2 (HER2) type was significantly higher than that in the non-HER2 type group (6.5 and 2.9%; χ 2 P=0.0103). There was no increase in the rate of positive margins in breast cancers with a diameter of >T2. The rate of positive surgical margins following MRI performed in the supine position was 18.8%. Supine MRI appears to be suitable for informing on the extent of resection of breast cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Shima et al.)

YTH domain-containing 2 (YTHDC2) is known to be an important regulator for RNA metabolism. Here, we show that YTHDC2 is essential for breast cancer tumorigenesis and metastasis. We examined YTHDC2 expression levels by immunohistochemistry in human breast tumor tissues from 99 patients and found a significantly positive correlation between the YTHDC2 expression level and the tumor stage. We established YTHDC2-knocked-down cell lines using four breast cancer cell lines with different subtypes. Knockdown of YTHDC2 attenuated the sphere-forming and the metastatic ability of breast cancer cells. Although stemness and EMT markers, such as SOX2, c-MYC, and NANOG, were downregulated in several YTHDC2-knocked-down breast cancer cells, a common target gene of YTHDC2 in breast cancer cells was not identified. These findings suggest that while YTHDC2 is involved in malignant progression of breast cancers, the mechanism by which YTHDC2 regulates those phenotypes is different between subtypes of breast cancers., Competing Interests: The authors declare no conflicts of interest for this article., (Copyright © 2022 Atsushi Tanabe et al.)

Background: In clinical practice, drains had been routinely used for reducing seroma formation after breast surgery. However, an optimal timing to remove drains does not identify yet., Methods: This study aimed to compare the clinical outcome, such as seroma formation, surgical site infection (SSI), and a length of hospital stay between early removal and late removal. A systematic review was performed using PubMed, MEDLINE, and the Cochrane Library. Breast cancer patients who received surgery using drains were eligible. Those parameters were compared between early vs late removal., Results: Eleven studies included in this meta-analysis. Seroma formation in the early removal group was significantly higher than the one in the late removal group (RR = 1.58: 95%CI [1.25-2.01], P = 0.0001), meanwhile no significant difference was found among the groups for SSI (RR = 0.82: 95%CI [0.51-1.31], P= 0.40). A length of hospital stay in the early removal group was also significantly shorter than late removal (RR -3.31: 95%CI [-5.13-1.49], P = 0.0004)., Conclusions: Seroma formation was significantly higher in patients who had early drain removal. Conversely, SSI incidence was low, and early removal did not increase SSI incidence. In conclusion, early drain removal has no proved clinical benefit in these settings besides reduction of hospital stays., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A 62-year-old woman who underwent surgery to treat pancreatic cancer provided written, informed consent to undergo adjuvant therapy with gemcitabine, tegafur, and uracil. However, this was stopped after only 14 days due to Grade 4 neutropenia. She was then started on vaccine therapy with Survivin 2B peptide (SVN-2B) including IFA and INF-α. Although metastatic lung tumors were identified and resected at 82 months after surgery, the patient has remained free of new or relapsed disease for 12 years thereafter. Tetramer and ELISPOT assays revealed the continuous circulation of SVN-2B-restricted cytotoxic T-lymphocytes (CTLs) in her peripheral blood, and CTL clones had specific activity for SVN-2B at 12 years after surgery. The adverse effects of the peptide vaccination were tolerable and comprised low-grade headache, nausea, and fatigue. A prognosis beyond 10 years in the face of pancreatic cancer with distant metastasis is extremely rare. This experience might indicate the value of cancer vaccination therapy.

Purpose: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen., Experimental Design: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study., Results: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs., Conclusion: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer., Competing Interests: The authors have declared that no competing interests exist.

The aim of the present study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in thyroid surgery. Patients with resectable thyroid cancer and Basedow's disease were assigned to ultrasonic scalpel or conventional technique (knot-tying and electrocoagulation). The present study used the Harmonic FOCUS ® (HF) as an ultrasonic scalpel. Between February 2013 and May 2016, 45 patients were enrolled into the study. Duration of the surgery was significantly decreased in the HF group compared with the conventional surgery (CS) group (median 142 vs. 151 min; P=0.0406). Intraoperative blood loss and total volume of drainage fluid were significantly decreased in the HF group compared with the CS group (median 40 vs. 125 ml; P=0.0054, and median 120 vs. 175.5 ml; P=0.0490). Duration of drain placement and length of hospitalization stay were similar in the two groups. Furthermore, the overall incidence of postoperative complications did not differ between the two groups. Overall, the present study suggests that open thyroidectomy using the HF is safe and effective and not associated with any increase in complications.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy. Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy ( P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response ( P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy ( P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Biomarkers that facilitate the prediction of breast cancer prognosis can improve the quality of life in patients during the long period of illness and treatment. Particularly in recent years, with the advent of a more exhaustive analysis of genetic information and gene products, the molecular mechanisms at play during breast cancer have gradually become clearer. In the present study, a systematic review of the literature between 2009 and 2014 was conducted by searching for the keywords 'breast cancer', 'biomarkers', 'diagnosis', 'prognosis' and 'drug response' to clarify the present state of knowledge regarding biomarkers. In the final analysis, 16 studies on biomarkers for the breast cancer prognosis were retrieved. From these, 7 biomarkers in 9 studies were found to be strongly reliable predictors of prognosis and a further 7 biomarkers in 7 studies were poorly reliable. The use of these prognostic biomarkers should increase the options available for treatment algorithms.

It has been reported that use of the free dermal fat graft (FDFG) technique produces a good cosmetic outcome for breast cancer. An FDFG is harvested from the lower abdomen as a columnar-shaped specimen and implanted into the defect of the breast after a partial mastectomy as a volume replacement technique. In this report, two patients who underwent breast-conserving surgery with immediate reconstruction using an autologous FDFG are described in order to show the difference in status between one case with and one without blood flow in the graft. To assess the benefit of this technique using FDFGs, their cosmetic satisfaction was evaluated using a questionnaire, graft shrinkage was measured by CT, and blood flow was assessed using contrast-enhanced ultrasound (CEUS). Both patients scored 10 of 12 points on the questionnaire. After 2 years, shrinkage of the grafts was 21.6 and 25.2 %, respectively. Although one patient had no blood flow in the center of the graft, the other had blood flow from the pectoralis major muscle to the center of the graft. While satisfaction and graft shrinkage were similar in the two patients, one case showed blood flow and had a somewhat softer graft than the other. The graft status was maintained with a good cosmetic outcome for 3 years after breast-conserving surgery with immediate reconstruction using an autologous FDFG, despite mild shrinkage and hardness of the graft. It is notable that blood flow was observed into the graft on CEUS, and more distinct perfusion was seen in the softer graft case after more than 3 years.

Fine-needle aspiration (FNA) is commonly used as a preoperative assessment to diagnose thyroid cancer. However, misdiagnosis of malignancy by FNA is not rare, even if image examination suggests the possibility of thyroid cancer. In the present study, the clinicopathological factors of patients whose preoperative FNA examination had not led to a diagnosis of thyroid cancer were examined. In total, 125 patients with thyroid cancer who underwent FNA and surgery (total thyroidectomy, subtotal thyroidectomy or hemithyroidectomy) at the Department of Surgery, Surgical Oncology and Science of the Sapporo Medical University Hospital between 2006 and 2013 were retrospectively analyzed. The patients were divided into two groups: Group A, malignancy determined by FNA, and group B, no malignancy. The groups were then compared by gender, age, tumor size, stage, tumor stage, lymph node metastasis, histology, surgical procedure methods, presence or absence of calcification and thyroglobulin levels. The mean age of the patients in group A (5 males and 59 females) was 53.0 years. The mean age in group B (11 males and 49 females) was 54.2 years. The mean tumor size in both groups was 1.6 cm. The mean thyroglobulin levels were 82.7 ng/ml in Group A and 525.5 ng/ml in group B. There were also significant differences between the groups for tumor stage (P=0.046), histological type (P=0.024) and thyroglobulin levels (P=0.035). The results of the present study suggested that it may be difficult to diagnose thyroid cancer by FNA in cases with non-papillary carcinoma and higher thyroglobulin levels.

Aim: Sex-determining region Y-box binding protein-2 (SOX2) and aldehyde dehydrogenase-1 (ALDH1) are known cancer stem-cell markers, and represent candidate predictors for breast cancer prognosis. In this study we investigated the relationships between SOX2/ALDH1 expression and prognosis., Materials and Methods: One hunred and two breast cancer surgical specimens were immunohistochemically analyzed for SOX2 and ALDH1 expression., Results: Disease-free survival (DFS) and overall survival (OS) were significantly poorer for SOX2-positive patients than SOX2-negative (p=0.0024 and p=0.0021, respectively), and for ALDH1-positive patients than ALDH1-negative (p=0.0049 and p=0.0083). DFS and OS were worse for SOX2- or ALDH1-positive patients than double-negative (p=0.0053 and p=0.0166). While an obvious tendency toward worse DFS was seen for estrogen receptor (ER)-negative patients, and attenuated for ER-positive, only SOX2/ALDH1 any-positive patients showed significantly poorer DFS (p=0.0258)., Conclusion: SOX2 and ALDH1 can be considered markers of poor prognosis, particularly in ER-negative patients. SOX2/ALDH1 any-positivity might also offer a reliable predictor of poor prognosis., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.

Background: The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel (nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer., Methods: nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m(2), while the dose of nab-PTX was increased from 180 mg/m(2) (Level 1) to 220 mg/m(2) (Level 2) and then to 260 mg/m(2) (Level 3)., Results: A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled. Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2., Conclusion: The RD of combination therapy with nab-PTX and CPA was 220 mg/m(2) and 600 mg/m(2), respectively, in patients with metastatic or recurrent breast cancer.

In breast cancer, single-photon emission computed tomography/computed tomography (SPECT/CT) shows the exact anatomical location of sentinel nodes (SN). SPECT/CT mainly exposes axilla and partly exposes atypical sites of extra-axillary lymphatic drainage. The mechanism of how the atypical hot nodes are involved in lymphatic metastasis was retrospectively investigated in the present study, particularly at the level II/III region. SPECT/CT was performed in 92 clinical stage 0-IIA breast cancer patients. Sentinel lymph nodes are depicted as hot nodes in SPECT/CT. Patients were divided into two groups: With or without hot node in level II/III on SPECT/CT. The existence of metastasis in level II/III was investigated and the risk factors were identified. A total of 12 patients were sentinel lymph node biopsy metastasis positive and axillary lymph node dissection (ALND) was performed. These patients were divided into two groups: With and without SN in level II/III, and nodes in level II/III were pathologically proven. In 11 of the 92 patients, hot nodes were detected in level II/III. There was a significant difference in node metastasis depending on whether there were hot nodes in level II/III (P=0.0319). Multivariate analysis indicated that the hot nodes in level II/III and lymphatic invasion were independent factors associated with node metastasis. There were 12 SN-positive patients followed by ALND. In four of the 12 patients, hot nodes were observed in level II/III. Two of the four patients with hot nodes depicted by SPECT/CT and metastatic nodes were pathologically evident in the same lesion. Therefore, the present study indicated that the hot node in level II/III as depicted by SPECT/CT may be a risk of SN metastasis, including deeper nodes.

The aim of the present study was to evaluate whether preoperative computed tomography (CT) is a useful modality for the diagnosis of axillary lymph node metastasis. The axillary lymph node status was examined in patients with primary breast cancer who had undergone surgery. In total, 75 patients were analyzed with preoperative contrast CT images, following which the patients underwent an intraoperative sentinel lymph node biopsy to determine possible predictors of axillary lymph node metastasis. The lymph node shape was classified into three groups, which included fat-, clear-and obscure-types. Multivariate analysis revealed that clear-type lymph nodes in preoperative contrast CT imaging may be an independent predictor of lymph node metastasis (odds ratio, 15; P=0.003). Therefore, the results indicated that preoperative CT examination is useful to predict axillary lymph node metastasis.

For sentinel lymph node biopsy (SLNB), a combination of dye-guided and γ-probe-guided methods is the most commonly used technique. However, the number of institutes in which the γ-probe-guided method is able to be performed is limited, since special equipment is required for the method. In this study, SLNB with the dye-guided method alone was evaluated, and the clinicopathological characteristics were analyzed to identify any factors that were predictive of whether the follow-up axillary lymph node dissection (ALND) was able to be omitted. A total of 374 patients who underwent SLNB between 1999 and 2009 were studied. The SLN identification rate was analyzed, in addition to the false-positive and false-negative rates and the correlation between the clinicopathological characteristics and axillary lymph node metastases. The SLN was identified in 96.8% of cases, and, out of the patients who had SLN metastasis, 63.0% did not exhibit metastasis elsewhere. The sensitivity was 96.4% and the specificity was 100%. The false-negative rate was 3.6%. Univariate analyses revealed significant differences in the lymph vessel invasion (ly) status, nuclear grade (NG), maximum tumor size and the percentage of the area occupied by the tumor cells in the SLN (SLN occupation ratio) between the patients with and without non-SLN metastasis, indicating that these factors may be predictive of axillary lymph node metastasis. Multivariate analysis revealed that ly status was an independent risk factor for non-SLN metastasis. In conclusion, SLN with the dye-guided method alone provided a high detection rate. The study identified a predictive factor for axillary lymph node metastasis that may improve the patients' quality of life.

Human endoplasmic reticulum oxidoreductin 1-α (hERO1-α) is an oxidizing enzyme that exists in the endoplasmic reticulum and its expression is augmented under hypoxia. It regulates a redox state of various kinds of protein through reoxidation of "client" protein disulfide isomerase. Interestingly, although the expression of hERO1-α in normal tissues was comparatively limited, various types of cancer cells expressed it in large amounts. Therefore, we examined the role of ERO1-α in tumor growth using murine breast cancer line 4T1 and found that knockdown of murine ERO1-α inhibited in vivo tumor growth and decreased lung metastasis compared with wild-type 4T1. Moreover, we investigated the relationship between expression of hERO1-α and prognosis in breast cancer patients. Seventy-one patients with breast cancer who underwent surgery between 2005 and 2006 in Sapporo Medical University Hospital (Sapporo, Japan) were analyzed in this study. Significant differences were found between the hERO1-α-positive group (n = 33) and hERO1-α-negative group (n = 38) in nuclear grade (P < 0.001) and intrinsic subtype (P = 0.021) in univariate analysis. More importantly, in multivariate analysis of disease-free survival by Cox regression, expression of hERO1-α was the only independent prognosis factor (P = 0.035). Finally, in univariate survival analysis, patients positive for hERO1-α had significantly shorter disease-free survival and overall survival than those patients negative for hERO1-α. These findings indicate that the expression of hERO1-α in cancer cells is associated with poorer prognosis and thus can be a prognostic factor for patients with breast cancer., (© 2013 Japanese Cancer Association.)

A case of bilateral congenital conductive deafness with mild auricular deformity is presented, and the anomalous structure deformity of the ossicles was multi-focal in this case, and a previous report indicates that ossicular malformation in the ear with congenital conductive deafness is multi-focal when the external ear is only slightly deformed. Bilateral ossicular reconstruction with replacement of the stapes yielded satisfactory results.

A case of subglottic and tracheal plasma cell granuloma masquerading as tumor invasion by thyroid malignancy was successfully treated using CO2 laser. A 55-year-old woman with a history of inspiratory stridor of almost 10 months duration was admitted to our clinic, and examinations revealed a mass in the subglottic space and trachea obstructing the airway. CT scan findings was suggestive of tumor invasion from a thyroid gland malignancy, however, histopathological examination of a biopsy specimen showed it to be plasma cell granuloma. Cases of plasma cell granuloma of the larynx and trachea are reviewed and discussed.