Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

Pathological examination of factors involved in PD-L1 expression in patients with oral tongue squamous cell carcinoma.

BACKGROUND: Tumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining. RESULTS: Seven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS < 20, and six participants had CPS < 1. The overall positivity rate of α-SMA, a marker for cancer-associated fibroblasts (CAFs), was 27% (10/37 participants), and the positivity rates of α-SMA for the three CPS groups were 85.7% (6/7 participants), 16.7% (4/24 participants), and 0% (0/6 participants), respectively. In addition, the overall positivity rate of p53 was 37.8% (14/37 participants), and the positivity rates of p53 for the three CPS groups were 71.4% (5/7 participants), 37.5% (9/24 participants), and 0% (0/6 participants), respectively. CONCLUSIONS: The expression of PD-L1 demonstrated an association with α-SMA and p53 positivity. In addition, compared with the expression of p53, the expression of α-SMA demonstrated a higher association with PD-L1 expression in patients with a high CPS. The abovementioned findings suggest that the interactions between CAFs, cancer cells, and immunocompetent cells may regulate the expression of PD-L1.

Oral Administration of Glucosylceramide Suppresses Tumor Growth by Affecting the Ceramide/Sphingosine-1-Phosphate Balance in Breast Cancer Tissue.

Background: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer. Methods: E0771 cells were inoculated into the breast tissue of female C57BL/6NJcl mice. Glucosylceramide was administered orally to the mice for nine consecutive days. The concentrations of sphingolipid mediators including ceramide, glucosylceramide, and S1P in tumor tissues and serum were determined by mass spectrometry. Results: Oral administration of glucosylceramide significantly suppressed E0771 tumor growth compared with the control group (P = 0.006). There were no significant differences in the serum concentrations of sphingolipid mediators including ceramide and S1P between the mice treated with glucosylceramide and control-treated mice. The ceramide concentration was significantly lower in tumor tissues (P = 0.026), and the S1P concentration was significantly higher than that in paired non-tumor tissues (P = 0.009). The S1P concentration in tumor tissues was significantly lower in mice treated with glucosylceramide than in control-treated mice (P = 0.001). The ceramide-to-S1P concentration ratio in tumor tissues was significantly higher in mice treated with glucosylceramide than in control-treated mice (P = 0.034). Conclusions: Breast tumors could enhance their survival by increasing S1P conversion from ceramide. Oral administration of glucosylceramide suppressed tumor growth by affecting the ceramide/S1P balance. Oral administration of glucosylceramide is a promising basis for a new therapeutic approach.

Post-Migration Changes in Dietary Patterns and Physical Activity among Adult Foreign Residents in Niigata Prefecture, Japan: A Mixed-Methods Study.

The migrant population of Japan is gradually increasing, but it is not well known how and why diet and physical activity (PA) change post-migration. Therefore, this study used a mixed-method approach to investigate the changes in dietary patterns and PA through a web- and paper-based survey (n = 128) and understand the contextual factors for those changes through semi-structured interviews (n = 21). Descriptive and thematic analyses of quantitative and qualitative data were conducted, respectively. The majority of survey (57.8%) and interview (66.7%) participants were female, and the mean duration of stay in Japan was 5 and 3.6 years, respectively. The survey revealed an increased consumption of foods attached to Japanese culture, frozen and microwavable food, and a reduced consumption of fruits. We identified environmental (availability, accessibility, and affordability of foods; food safety and diet-related information; and climate), individual (living status; post-migration lifestyle; and food preferences and limitations), or socio-cultural (relationships with Japanese people; cultural differences; and religious influences) factors that impact diet changes. Language proficiency and the duration of stay shape dietary behaviors. Determinants of PA changes were climate, lifestyle, and the influence of Japanese culture. In conclusion, immigrants in Japan experience post-migration diet and PA changes, and this study adds knowledge about how and why such changes occur.

Increased RUNX3 expression mediates tumor-promoting ability of human breast cancer-associated fibroblasts.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a major stromal component of human breast cancers and often promote tumor proliferation, progression and malignancy. We previously established an experimental CAF (exp-CAF) cell line equipped with a potent tumor-promoting ability. It was generated through prolonged incubation of immortalized human mammary fibroblasts with human breast cancer cells in a tumor xenograft mouse model. RESULTS: Herein, we found that the exp-CAFs highly express Runt-related transcription factor 3 (RUNX3), while counterpart fibroblasts do not. In breast cancer patients, the proportion of RUNX3-positive stromal fibroblast-like cells tends to be higher in cancerous regions than in non-cancerous regions. These findings suggest an association of RUNX3 with CAF characteristics in human breast cancers. To investigate the functional role of RUNX3 in CAFs, the exp-CAFs with or without shRNA-directed knockdown of RUNX3 were implanted with breast cancer cells subcutaneously in immunodeficient mice. Comparison of the resulting xenograft tumors revealed that tumor growth was significantly attenuated when RUNX3 expression was suppressed in the fibroblasts. Consistently, Ki-67 and CD31 immunohistochemical staining of the tumor sections indicated reduction of cancer cell proliferation and microvessel formation in the tumors formed with the RUNX3-suppressed exp-CAFs. CONCLUSION: These results suggest that increased RUNX3 expression could contribute to the tumor-promoting ability of CAFs through mediating cancer cell growth and neoangiogenesis in human breast tumors.

Kissing molars class III detected at a young age.

BACKGROUND: Kissing molars (KMs) is defined as a state in which the apex of two impacted molars face opposite directions and the occlusal surfaces touch each other and the crown is in one follicle. Class III KMs have been reported previously; however, reports on class III KMs in young people (< 18 years of age) are limited. CASE PRESENTATION: Here, we present the case of KMs class III confirmed at an early age, supported by a review of the literature. The patient was a 16-year-old female and experienced discomfort in the left molar of the lower jaw and visited in our department. We diagnosed KMs based on an impacted teeth on the buccal side, near the lower jaw wisdom teeth, and a cyst-like low-density area observed around the crown of both teeth, as revealed by computed tomography. We decide to extract the tooth and enucleate the cyst under local anesthesia as the patient experienced discomfort due to occlusion. Furthermore, the cyst-like structure removal and tooth extraction including tooth root were necessary as the patient had KM class III, possibly inducing complicated malocclusion. Although no previous reports recommended timing for KMs tooth extraction, we propose that extraction at an early stage is important regardless of age especially in class III cases. CONCLUSIONS: We report a case of KM class III detected at an early age.

Mixed reality for extraction of maxillary mesiodens.

BACKGROUND: Mesiodentes are the most common supernumerary teeth. The cause is not fully understood, although proliferations of genetic factors and the dental lamina have been implicated. Mesiodentes can cause delayed or ectopic eruption of permanent incisors, which can further alter occlusion and appearance. Careful attention should be paid to the position and direction of the mesiodentes because of possible damage to adjacent roots in the permanent dentition period, errant extraction in the deciduous and mixed dentition periods, and damage to the permanent tooth embryo. To avoid these complications, we applied mixed reality (MR) technology using the HoloLens® (Microsoft, California). In this study, we report on three cases of mesiodentes extraction under general anesthesia using MR technology. RESULTS: The patients ranged in age from 6 to 11 years, all three were boys, and the direction of eruption was inverted in all cases. The extraction approach was palatal in two cases and labial in one case. The average operative time was 32 min, and bleeding was minimal in all cases. No intraoperative or postoperative complications occurred. An image was shared preoperatively with all the surgeons using an actual situation model. Three surgeons used Microsoft HoloLens® during surgery, shared MR, and operated while superimposing the application image in the surgical field. CONCLUSIONS: The procedure was performed safely; further development of MR surgery support systems in the future is suggested.

Development and Psychometric Evaluation of a Japanese Version of Newly Graduated Nurses' Difficulties with End-of-Life Care for Cancer Patients (NDEC Scale).

(1) Background: End-of-life care (EoL care) for cancer patients is stressful for nurses and can easily lead to burnout. Newly graduated nurses (NGNs) have a particularly difficult time, but no scale or inventory has been designed to evaluate their difficulties. This study developed and tested the reliability and validity of a scale to measure NGNs' difficulties with EoL care for cancer patients (NDEC scale). (2) Methods: This study population consisted of 1000 NGNs and 1000 nurses with at least five years of clinical experience (GNs) that were working in hospitals in Japan. The initial scale consisted of six factors and 28 items. The reliability and validity of the scale were tested. (3) Results: A total of 171 NGNs and 194 GNs responded to the survey. The scale consisted of five factors and 25 items with the factors including "Feeling painful", "Can't deal with patients and their families", "Don't know the answer", "Cannot afford", and "Being afraid of death". The criteria validity, known population validity, and internal consistency were confirmed. (4) Conclusions: The scale was validated to have a certain level of reliability and validity. The NDEC scale is expected to be used for self-care for NGNs and as an effectiveness indicator for educational programs.

A clinico-statistical study of factors associated with intraoperative bleeding in orthognathic surgery.

BACKGROUND: Excessive bleeding is a major intraoperative risk associated with orthognathic surgery. This study aimed to investigate the factors involved in massive bleeding during orthognathic surgeries so that safe surgeries can be performed. Patients (n=213) diagnosed with jaw deformities and treated with bimaxillary orthognathic surgery (Le Fort I osteotomy and bilateral sagittal split ramus osteotomy) in the Department of Oral and Maxillofacial Surgery at the Suidobashi Hospital, Tokyo Dental College between January 2014 and December 2016 were included. Using the patients' medical and operative records, the number of cases according to sex, age at the time of surgery, body mass index (BMI), circulating blood volume, diagnosis of maxillary deformity, direction of maxillary movement, operative duration, incidence of bad split, injury of nasal mucosa, and blood type were analyzed. RESULTS: The results revealed that BMI, circulating blood volume, nasal mucosal injury, and operative time were associated with the risk of intraoperative massive bleeding in orthognathic surgeries. Chi-square tests and binomial logistic regression analyses showed significant differences in BMI, circulating blood volume, direction of maxillary movement, operative duration, and injury to the nasal mucosa. Operative duration emerged as the most important risk factor. Furthermore, a >4-mm upward migration of the posterior nasal spine predicted the risk of massive bleeding in orthognathic surgery. CONCLUSIONS: The upward movement of the maxilla should be recognized during the preoperative planning stage as a risk factor for intraoperative bleeding, and avoiding damage to the nasal mucosa should be considered a requirement for surgeons to prevent massive bleeding during surgery.

Advanced Stage Is a Risk for Severe Neutropenia in Breast Cancer Patients Undergoing Neoadjuvant Adriamycin/Cyclophosphamide/Docetaxel Chemotherapy.

Background: Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe neutropenia may occur during neoadjuvant chemotherapy even when the patients are free from known risk factors. Pegfilgrastim, a covalent conjugant of filgrastim that stimulate the production of neutrophils, is used for prevention. The current study aimed to reveal the characteristics of patients who need pegfilgrastim for primary prophylaxis to prevent severe neutropenia, including febrile neutropenia and grade 3 neutropenia, during neoadjuvant chemotherapy. Methods: A retrospective analysis of 83 patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy was performed. The factors which associated with severe neutropenia were examined by univariate and multivariate analyses. Results: Severe neutropenia developed in one of 22 patients (5%) with pegfilgrastim for primary prophylaxis and in 17 of 61 patients (28%) without it. In 83 patients, the incidence of severe neutropenia was significantly decreased in the patients with pegfilgrastim for primary prophylaxis shown by the univariate analysis (P = 0.023) and multivariate analysis (P = 0.030). In 61 patients without pegfilgrastim for primary prophylaxis, the univariate analysis showed that severe neutropenia was associated with tumor size (P = 0.004), clinical stage (P = 0.009), and cancer antigen 15-3 (CA15-3) (P = 0.026). The multivariate analysis showed that clinical stage was associated with severe neutropenia (P = 0.021). Conclusions: The current study demonstrated that advanced stage is a risk for severe neutropenia in patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy. Given that prophylaxis with pegfilgrastim was associated with significantly lower incidence of severe neutropenia, patient with advance stage breast cancer may benefit from pegfilgrastim during neoadjuvant chemotherapy.

Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer.

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

Mixed reality and three dimensional printed models for resection of maxillary tumor: a case report.

In the field of oral and maxillofacial surgery, many institutions have recently begun using three-dimensional printers to create three-dimensional models and mixed reality in a variety of diseases. Here, we report the actual situation model which we made using three-dimensional printer from virtual operation data and the resection that was performed while grasping a maxillary benign tumor and neighboring three-dimensional structure by designing an application for Microsoft® HoloLens, and using Mixed Reality surgery support during the procedure.

Cancer-associated fibroblast migration in non-small cell lung cancers is modulated by increased integrin α11 expression.

Cancer-associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer-stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non-small-cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC-associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5ß1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer-stroma interactions may serve as a novel, promising anti-tumor strategy.

How to perform appropriate flushing after lipid emulsion administration using totally implantable venous access devices in long-term total parenteral nutrition and home parenteral nutrition.

BACKGROUND & AIMS: There has been no clear evidence regarding the appropriate method of flushing catheters and totally implantable venous access devices (TIVADs) after lipid emulsion (LE) administration. Therefore, the aim of the study was to identify appropriate methods of flushing to minimize residual LE when using TIVADs to ensure the safety of long-term total parenteral nutrition (TPN) and home parenteral nutrition (HPN). METHODS: A soybean oil LE containing indocyanine green (ICG) was administered from the injection site of the primary infusion set for flowing TPN, and LE dynamics were evaluated by a fluorescence imaging system. TIVADs were connected to the end of the infusion sets. After LE administration, the tubes and chambers were flushed from the injection site using saline at various speeds (20, 40, 60 mL/min), with and without pulsation. The washout effect of TPN solution after LE administration followed by flushing was examined, as was the washout effect of size differences in the infusion sets. RESULTS: When the LE was flushed with 20 mL of saline immediately after administering the LE using a standard infusion set (inner diameter 2.5 mm), the LE still remained in the tubes and chambers under any flushing condition. Flushing the LE from the injection site with 10 mL of saline and then flowing >240 mL of TPN solution were effective for minimizing residual LE inside the tubes and chambers. When using an infusion set with a small inner diameter (1.0 mm), the LE inside the tubes and chambers was almost discharged with ≥20 mL of saline immediately after administering the LE. In all settings, flushing with/without pulsation did not affect LE washout efficacy. CONCLUSIONS: Flushing immediately with saline ≥10 mL and then flowing >240 mL of primary PN solution after soybean oil LE administration using the standard infusion set or flushing with 20 mL saline immediately after administering the soybean oil LE using the infusion set with a small inner diameter are effective for minimizing the residual LE in the catheter and TIVAD, ensuring the safety of long-term TPN and HPN.

Beneficial Effects of Epigallocatechin-3-O-Gallate, Chlorogenic Acid, Resveratrol, and Curcumin on Neurodegenerative Diseases.

Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer's and Parkinson's diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.

[A Case of HER2-Positive Recurrent Breast Cancer and Liver Metastases of GIST Treated with Combined Anti-HER2 Therapy and Imatinib].

A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery. Four months after the surgery, left subclavian lymph node recurrence of breast cancer was found. Since the liver metastases of GIST had been stable, imatinib was discontinued, and paclitaxel and anti-HER2 therapy were administered. After confirming tolerability, imatinib was carefully added in combination. Because the lymph nodes shrank and liver metastases of GIST were stable, both anti-HER2 therapy and imatinib were continued. There are few reports of combined chemotherapy for synchronous double cancer, and we report our experience in which careful treatment was required.

Relationship between the immunohistological examination and fluorescence visualization of oral squamous cell carcinoma.

Disorders of the oral mucosa are considered easy to diagnose since they can be visualized and examined directly. A change in the color of the oral mucosa reflects histopathological changes and is an important diagnostic parameter. However, the subjective perception of color varies. To determine the extent of resection for oral mucosa conditions, it is necessary to digitize the color and perform objective assessments. In recent years, fluorescence visualization devices and analysis software that measure tissue luminance G have been employed for the identification of oral mucosa diseases. Fluorescence visualization is presumably based on the decrease in epithelial flavin adenine dinucleotide content and luminance G values due to the destruction of collagen cross-links [fluorescence visualization loss (FVL)]. However, cases with differences between luminance values and histopathological presentation exist. Therefore, additional factors may affect fluorescence visualization. The present study used a portable, non-contact oral mucosa fluorescence visualization device for luminance measurements in seven patients with oral squamous cell carcinoma. Furthermore, Picro-Sirius Red and immunohistochemical staining were performed for CK13, CK17, Ki67, p53 and E-cadherin in the FVL(+) (lesion) and FVL(-) (resection stump) areas to elucidate the principle of fluorescence visualization. Fluorescence was significantly lower in the FVL(+) than in the FVL(-) areas, and the mean luminance G value was 56. The Picro-Sirius Red stain revealed collagen destruction in the FVL(+) areas but no collagen disruption in the FVL(-) areas. CK13 was negative in the FVL(+) and positive in the FVL(-) areas, whereas the opposite pattern was observed for CK17. In the FVL(+) area, p53 staining was positive. E-cadherin expression was enhanced in the FVL(-) areas and reduced in the FVL(+) areas. Furthermore, the luminance G value tended to be lower in cases with weaker E-cadherin staining. The aforementioned results suggest that decreased E-cadherin expression may be a factor that regulates fluorescence visualization.

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state.

Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial-to-mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E-cadherin- and nuclear ZEB1-positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient-derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient-matched liver metastases presumably developing through mesenchymal-to-epithelial transition. Inhibition of E-cadherin or ZEB1 expression by shRNA notably prevented the PDX-derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E-cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

Efficacy of Physical Activity in Prevention of Muscle Weakness in Patients With Chronic Liver Disease.

BACKGROUND: Sarcopenia is a prognostic factor for patients with liver cirrhosis and hepatocellular carcinoma, and it affects the onset of hepatic encephalopathy. Therefore, the prevention of sarcopenia contributes to the improvement of the prognosis of patients with chronic liver disease (CLD). We focused on changes of hand grip strength (HGS), one of the indicators of sarcopenia. However, there are little data investigating the impact of physical activity (PA) on HGS in patients with CLD. This study aimed to clarify whether PA contributes to the prevention of muscle weakness in patients with CLD. METHODS: This was a prospective observational study. We examined the effect of PA on changes in HGS from the baseline to the endpoint in each group. Metabolic equivalents-hour/week (METs-h/w) was used to evaluate PA. In total, 183 outpatients with CLD were analyzed. We divided participants into four groups (low PA in younger patients (n = 20), high PA in younger patients (n = 33), low PA in elderly patients (n = 47), and high PA in elderly patients (n = 83)). RESULTS: Fifty-eight percent of patients were men, and the median (interquartile range) age was 69.0 (63.0, 75.0) years. The most common etiology of liver disease was hepatitis C (38%). The frequency of living alone and low exercise habit was significantly high, and sarcopenia was more obvious in elderly patients with low PA than in those with high PA. Additionally, the elderly with low PA showed significantly reduced HGS compared to that of the elderly with high PA (-1.00 (-2.27, 0.55) kg vs. 0.10 (-1.40, 1.10) kg, P < 0.05). However, changes in HGS in younger patients were not significant (-0.02 (1.83, 1.47) kg vs. 0.25 (-2.45, 2.05) kg, P = 0.96). Logistic regression analyses identified PA as the independent factor for prevention of decrease in HGS (odds ratio: 1.91, 95% confidence interval: 1.00 - 3.62, P = 0.049). CONCLUSIONS: Young patients with low PA were characterized by a long sedentary time; however, there was no loss of HGS. In contrast, elderly patients with CLD and low PA had significantly reduced HGS compared to that in elderly patients with CLD and high PA.

Relationship Between Sarcopenia and Both Physical Activity and Lifestyle in Patients With Chronic Liver Disease.

BACKGROUND: Sarcopenia can affect the prognosis of patients with cirrhosis or hepatocellular carcinoma. Exercise therapy and nutritional therapy are carried out to prevent processing sarcopenia. In addition, changing lifestyle is also important. However, there are only few reports on the physical activities (PAs) and lifestyle of chronic liver disease patients and their association with sarcopenia. The aim of this study is to examine the relationship between sarcopenia in patients with chronic liver disease and both PA and lifestyle. METHODS: A total of 214 out-patients with chronic liver disease were enrolled into the present study. All patients were evaluated for with or without sarcopenia based on the sarcopenia diagnostic criteria of the Japan Society of Hepatology. Then, patient's characteristics and laboratory parameters were divided into two groups with or without sarcopenia and compared. In continuous variable with significant difference in univariate analysis, cut-off value was calculated by receiver operating characteristic curve. We determined which factors were associated with sarcopenia in univariate analyses, and variables significant in the univariate analyses were entered in a multivariable logistic regression model. RESULTS: Patients with chronic liver disease had a prevalence of sarcopenia of 12.6% in this study. Sarcopenia patients were older (76.48 ± 6.69 versus 66.97 ± 11.19 years old; P < 0.01), had lower body mass index (BMI) (20.84 ± 2.44 versus 23.76 ± 3.72 kg/m2; P < 0.01), lower PA (6.6 (2.34 - 19.90) versus 16.5 (6.60 - 41.23) metabolic equivalents (METs)-h/week; P < 0.01) and longer total time sitting and lying on the day (7.43 ± 4.09 versus 5.68 ± 3.17 h/day; P = 0.01); retirement status (81.5% versus 48.1%; P < 0.01) and low frequency of driving (40% versus 20%; P = 0.01) were higher in sarcopenia patients than in non-sarcopenia patients. The independent predictive factors of sarcopenia, analyzed with logistic regression, were age (odds ratio (OR): 5.89, 95% confidence interval (CI): 2.15 - 16.20; P < 0.01), BMI (OR: 4.77, 95% CI: 1.87 - 12.10; P < 0.01) and PA (OR: 3.65, 95% CI: 2.15 - 16.20; P < 0.01). CONCLUSION: Sarcopenia patients' lifestyle characteristics were longer sedentary time and low frequency of driving, high retirement. Independent predictive factors of sarcopenia were elderly, low BMI and low PA. For these patients, intervention in the lifestyle for prevention of sarcopenia may be effective for patients with chronic liver disease.