Change in quality of life and potentially associated factors in patients receiving home-based primary care: a prospective cohort study.

BACKGROUND: The trajectories for health-related quality of life of patients receiving home-based primary care are not well identified. Our objective was to investigate changes in the quality of life (QOL) and factors that affected the QOL of patients receiving home-based primary care. METHODS: Our prospective cohort study, the Observational study of Nagoya Elderly with HOme MEdical (ONE HOME) study, recruited 184 patients undergoing home-based primary care with a 5-year follow-up period. Patients' demographic data, socioeconomic status, physical diseases, medication use, feeding intake status, nutritional status, and functional status were measured annually. The 4-item quality of life index (QOL-HC [home care]) including self-perceived and family-reported QOL ratings that had been developed and previously validated in home care settings was used. Linear regression models were used for cross-sectional and longitudinal analyses. RESULTS: The participants' mean age was 78.8 ± 10.8 years, and 55.9% of the sample was male. Most patients were frail, disabled, and/or malnourished. Self-perceived and family-reported QOL scores dropped sequentially on annual follow-ups. In the multivariate longitudinal analysis, patients who were divorced (ß = 1.74) had high baseline QOL scores (ß = 0.75) and reported higher QOL ratings. In addition, high functional dependency was associated with a low self-perceived QOL rating, with a ß-value of - 1.24 in the pre-bedridden group and - 1.39 in the bedridden group. Given the family-reported QOL rating, the baseline QOL scores (ß = 0.50) and Mini-Nutritional Assessment-Short-Form scores (ß = 0.37) were found to have positive associations with the QOL rating. CONCLUSIONS: For the disabled receiving home-based primary care, independent functional status and divorce were positively associated with better self-perceived QOL, whereas nutritional status was correlated with better family-reported QOL.

[Agreement in the responses to self-reported and proxy-reported versions of QOL-HC: a new quality-of-life scale for patients receiving home-based medical care].

AIM: We developed quality-of-life (QOL) scales for patients receiving home medical care. The objective of this study was to examine the agreement between the scores of the scales answered by patients and those answered by their proxy, as cognitive decline may interfere with one's ability to understand complex topics, such as the QOL. METHODS: Participants were pairs of patients receiving home medical care and their proxy. The patients were asked to complete self-reported QOL scales (QOL-HC), and their proxies were asked to complete proxy-reported versions of the QOL scales (QOL-HC for caregivers). We then statistically examined the extent of agreement between the self- and proxy-reported QOL-HC scores using contingency tables and Spearman's rank correlation coefficient. The SPSS software program, version 24, was used for all statistical analyses. RESULTS: The concordance rate between patients and caregivers for questions 1 ( "Do you have peace of mind?" ), 2 ( "Do you feel satisfied with your life when you reflect on it?" ), 3 ( "Do you have someone that you spend time talking with?" ), and 4 ( "Are you satisfied with the home care service system?" ) were 52.3%, 52.3%, 79.5%, and 81.8%, respectively. The total scores for the patients and caregivers were significantly correlated (Spearman's ρ=0.364*). CONCLUSIONS: We created the first QOL scale for patients receiving home-based medical care and for caregivers. The findings of this study suggest that the QOL-HC can be used in clinical practice for the assessment of patients receiving professional home care.

Feline sarcoma-related protein expression correlates with malignant aggressiveness and poor prognosis in renal cell carcinoma.

Feline sarcoma-related protein (Fer) is a ubiquitously expressed non-receptor protein tyrosine kinase associated with proliferation in various cancer cells. However, no reports have described the pathological roles and prognostic value of Fer expression in renal cell carcinoma (RCC). We investigated Fer expression in three RCC cell lines (ACHN, Caki-1, and Caki-2) and in normal tubule cells (HK-2) by immunoblotting. Fer expression was highest in ACHN cells, with Caki-1 showing intermediate levels and Caki-2 showing low levels, and was undetectable in HK-2. RNA interference was therefore used to assess the effects of Fer knockdown in ACHN. Knockdown of Fer expression was found to inhibit RCC cell proliferation and colony formation. Immunohistochemical analysis of 131 human RCC tissues (110 conventional, 11 chromophobe, and 10 papillary) investigated relationships between Fer expression and clinicopathological features, including cancer cell proliferation, apoptosis, and prognostic value for survival. In human tissues, Fer expression was significantly higher in cancer cells than in normal tubules. In addition, expression levels correlated with cancer cell proliferation, but not with apoptosis. Multivariate analysis indicated associations of Fer expression with pT stage, tumor grade, and metastasis (P < 0.001). Fer expression was also prognostic for cause-specific survival according to multivariate analysis (hazard ratio, 3.89; 95% confidence interval, 1.02-14.84, P = 0.047). Fer expression correlates with RCC cell proliferation both in vitro and in vivo, and with tumor progression and survival. This represents useful information for discussing the pathological and clinical significance of Fer in RCC.

Pathological significance and predictive value for biochemical recurrence of c-Fes expression in prostate cancer.

BACKGROUND: c-Fes is a proto-oncogene encoded non-receptor protein-tyrosine kinase (PTK). However, genetic studies have indicated that it has anti-tumorigenic effects in certain cancers. The pathological and clinical significance of c-Fes in prostate cancer are unknown. METHODS: Expression of c-Fes was evaluated in normal glands, prostatic intraepithelial neoplasia (PIN), cancer cells in tissues of knock-in mouse adenocarcinoma prostate (KIMAP) model, and prostate cancer patients free of metastasis. Expression of c-Fes was analyzed by immunohistochemistry, and quantified by using the immunoreactivity score (IRS) (staining intensity × percentage of positive cells). Relationships between c-Fes expression and pT stage, Gleason's score (GS), and biochemical recurrence in patients who underwent radical surgery were also investigated. RESULTS: In KIMAP, the percentage in normal glands, PIN and cancer cells positive for c-Fes expression were 0 (0/7), 25.0 (2/8), and 100% (7/7), respectively. In human tissues, c-Fes expression was also significantly higher in cancer cells than in normal cells and PIN, and it correlated with pT stage (P < 0.001) and GS (P = 0.047). Multivariate analysis showed that c-Fes expression was an independent predictor of poor outcome poor prognosis (hazard ratio = 3.21, 95% confidence interval = 1.11-9.37, P = 0.032). CONCLUSION: The results suggested that c-Fes expression is a useful predictor of biochemical recurrence after radical surgery. The results also suggested that c-Fes is a potentially useful therapeutic target in prostate cancer and a predictor of biochemical recurrence after radical prostatectomy.

Downregulation of the c-Fes protein-tyrosine kinase inhibits the proliferation of human renal carcinoma cells.

The c-Fes protein-tyrosine kinase is associated with growth and differentiation of hematopoietic, neuronal, vascular endothelial and epithelial cell types. In this study, we investigated whether small interfering RNA (siRNA)-mediated knockdown of c-Fes expression affected proliferation of the human renal carcinoma cell lines, ACHN and VMRC-RCW. Immunofluorescence microscopy showed that c-Fes was expressed in both the cytosol and nuclei of these cells, and siRNA treatment preferentially downregulated c-Fes expression in the cytosol. Knock-down of c-Fes inhibited cellular proliferation in a dose-dependent manner with minimal increase in cell death. c-Fes siRNA treatment also downregulated the phosphorylation of Akt1 on S473 and IKKalpha on T23, and cyclin D1 expression, enhanced the expression of IkappaBalpha, and prevented the nuclear localization of NFkappaB. Treatment with an NFkappaB inhibitory peptide (SN50) also blocked the proliferation and nuclear localization of NFkappaB in these cells. The effect of SN50 treatment was not enhanced by c-Fes siRNA, suggesting that downregulation of c-Fes expression inhibited cell cycle progression through the Akt1/NFkappaB pathway. In contrast to siRNA-mediated knockdown, ectopic expression of either wild-type or kinase-inactive c-Fes in renal carcinoma cells failed to alter their proliferation in vitro and in vivo. Thus, suppression of proliferation resulting from siRNA-mediated knockdown may depend upon an expression of c-Fes protein rather than its kinase activity. Taken together, our results indicate that downregulation of c-Fes expression may be a potential therapeutic strategy for advanced human renal cell carcinoma and inhibition of its kinase activity as an antiangiogenic therapy does not seem to induce the growth of human renal carcinoma cells.

TFE3-renal carcinoma in an adult patient: a case with strong expression of phosphorylated hepatocyte growth factor (HGFR)/Met.

TFE3-renal carcinoma is rare in adults. Patients with this disease often have a poor prognosis, because it has reached an advanced stage at presentation, and there is lack of an effective therapy. The exact mechanism of its malignant behavior is still unclear. In recent years, a significant relationship between TFE3 fusion protein and hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase activity was reported in several malignancies. We previously reported that phosphorylation of HGFR/Met was associated with malignant aggressiveness and survival in patients with conventional RCC. Here, using immunohistochemical techniques, we examined two types of phosphorylated HGFR/Met (pY1234/1235 and pY1349) in a specimen of a 29-year-old man with TFE3-renal carcinoma. Strong expression of both proteins was detected in carcinoma cells, but not in normal kidney tissues. In addition, they were expressed more strongly in TFE3-renal carcinoma than in conventional RCC. Although tumor was diagnosed at T1N0M0 and the patient received radical nephrectomy, the tumor metastasized to multiple organs, and he died 2 years after surgery. We speculate that upregulated phosphorylation of HGFR/Met could be partly associated with the malignant aggressiveness and poor survival of this patient.

[Potent and continuous relief of spinal bone pain due to metastasis of non-small cell lung cancer by treatment with gefitinib--a case report].

A 79-year-old woman with advanced non-small cell lung cancer was admitted to our hospital for palliative terminal care after failure of initial radiotherapy followed by chemotherapy with S-1. She had severe back pain due to metastasis at the sixth thoracic spinal bone. Gefitinib was administered and rapid relief of bone pain was obtained. During the first four months, gradual reduction of all measurable lesions was obtained. However, these lesions except for spinal bone metastasis re-grew and five months later, she died of cachexia. Treatment with gefitinib was continued until she died because of the complete relief of bone pain.

Prevalence and risk factors of constipation and pollakisuria among older home-care patients.

AIM: The prevalence of constipation and prevalence of pollakisuria among older patients receiving home medical care have not been reported, and risk factors for these symptoms are not clear in this setting. The present study sought to determine the prevalence and risk factors of constipation and pollakisuria among older patients receiving home medical care in Japan. METHODS: This study utilized data from patients in the Observational Study of Nagoya Elderly with Home Medical Care (n = 153). We carried out univariate and multivariate logistic regression analyses with the presence of constipation or pollakisuria as the dependent variable to evaluate the relationships between constipation or pollakisuria and several covariates. RESULTS: The prevalence of constipation and pollakisuria were 56.9% and 15.7%, respectively. Multivariate logistic analysis showed that constipation was associated with Charlson Comorbidity Index score, polypharmacy and pollakisuria, and pollakisuria was associated with constipation and insomnia. Cardiovascular disease was inversely associated with constipation. CONCLUSIONS: The prevalence of constipation among home-care patients was as high as that reported for nursing home residents and higher than that among community-dwelling individuals. Clinicians should be aware of increased constipation risk among home-care patients, particularly for those with a high Carlson Comorbidity Index score, polypharmacy and/or pollakisuria. Geriatr Gerontol Int 2019; 19: 277-281.

Potentially inappropriate medications according to STOPP-J criteria and risks of hospitalization and mortality in elderly patients receiving home-based medical services.

BACKGROUND: Although potentially inappropriate medications (PIMs) have been linked to poor health outcomes, country-specific PIM criteria have not been compared. Thus, we compared the identification of PIMs between the Screening Tool for Older Person's Appropriate Prescriptions for Japanese (STOPP-J) and the 2015 American Geriatrics Society Beers Criteria in elderly patients receiving home-based medical services. METHODS: A 5-year prospective cohort study was conducted with 196 patients receiving home-based medical services. Data were collected using questionnaires and chart reviews and included detailed information on prescription medication. STOPP-J and the Beers Criteria were used to categorize PIM and non-PIM recipients. All-cause mortality and first hospitalization were compared using a multivariate Cox regression model. RESULTS: PIMs were detected in 132 patients (67.3%) by STOPP-J and in 141 patients (71.9%) by the Beers Criteria, and the mean numbers of PIMs were 1.3 ± 1.3 and 1.2 ± 1.1, respectively. The three most frequently prescribed STOPP-J PIMs were hypnotics (26.8%), diuretics (25.6%), and NSAIDs (12.6%), compared with proton pump inhibitors (PPIs) (29.8%), hypnotics (26%), and NSAIDs (8.1%) according to the Beers Criteria. STOPP-J PIMs were associated with all-cause mortality (HR 3.01, 95% CI 1.37-6.64) and hospitalization (HR 1.91, 95% CI 1.17-3.09); neither was associated with Beers Criteria PIMs. Using a modified Beers Criteria (excluding PPIs), PIMs were correlated with first hospitalization (HR 1.91, 95% CI 1.17-3.09). CONCLUSIONS: PIMs categorized by STOPP-J are associated with hospitalization and mortality in Japanese patients receiving home-based medical services. PPIs, commonly used for acid-related diseases, do not seem to have deleterious effects on health outcomes. Country-oriented, medication-specific criteria would be of considerable clinical utility.

Association between dysphagia risk and unplanned hospitalization in older patients receiving home medical care.

AIM: Home medical care for older adults with chronic conditions is becoming an increasing important issue in Japan. We need to support long-term medical care at home and avoid unplanned hospitalizations, which can adversely affect activities of daily living and quality of life. In this study, we investigated whether swallowing function is a risk for unplanned hospitalization in older patients with functional decline who are receiving home medical care. METHODS: In the current study, we examined data obtained in the Observational study of Nagoya Elderly with HOme MEdical study (ONEHOME) that investigated the medical health of older adults receiving home medical care services in Nagoya City, Japan. The data analyzed were patients' age, sex, number of medications, Dysphagia Severity Scale, Charlson Comorbidity Index, Barthel Index, Mini Nutritional Assessment - Short Form, Frailty Index and dementia independent scale. The Dysphagia Severity Scale was categorized into the presence or absence of dysphagia risk. The association between dysphagia risk and days until first hospitalization was investigated by Cox regression analysis. RESULTS: In total, 86 out of 178 patients had a hospitalization during the study period of 4 years. Cox regression analysis with adjustment for age, sex, Charlson Comorbidity Index, Barthel Index and Mini Nutritional Assessment - Short Form scores showed that a lower Dysphagia Severity Scale score was significantly associated with unexpected hospitalization. CONCLUSIONS: Dysphagia risk predicts the first unexpected hospitalization in older individuals receiving home medical care. Patients' swallowing function is an important factor for estimating prognosis. Geriatr Gerontol Int 2019; 19: 977-981.

Role of Src in angiopoietin 1-induced capillary morphogenesis of endothelial cells: Effect of chronic hypoxia on Src inhibition by PP2.

Signal transduction pathways leading to angiopoietin 1 (Ang1)-induced capillary morphogenesis by endothelial cells remain poorly defined. Angiogenic cellular responses by endothelial cells may be modulated in vivo by chronic hypoxia, such as that induced by tumors. Here, we studied Ang1-induced capillary morphogenesis in human umbilical-vein endothelial cells (HUVECs) cultured chronically under normoxic (21% oxygen) or hypoxic (1.5% oxygen) conditions. Downregulation of Src using a small interfering RNA (siRNA) inhibited Ang1-induced capillary morphogenesis of HUVECs cultured under both conditions by blocking cell spreading and protrusion. Ang1 upregulated the Src-dependent secretion of vascular endothelial growth factor-A (VEGF-A). Blockade of endogenous VEGF-A also inhibited Ang1-induced capillary morphogenesis. Addition of exogenous VEGF-A restored cell spreading and protrusion, leading to Ang1-induced capillary morphogenesis of Src siRNA-treated HUVECs, suggesting that Ang1-induced VEGF-A secretion through Src was required for capillary morphogenesis. PP2 inhibited both Ang1-induced capillary morphogenesis and Src activation in HUVECs cultured under normoxic conditions, but the PP2 activity was significantly impaired in HUVECs cultured under hypoxic conditions. Expression of multidrug resistance-associated protein 1 (MRP 1) was upregulated in hypoxic HUVECs, and treatment with MRP 1 siRNA restored the inhibitory action of PP2. Taken together, our results suggest that Ang1 induces capillary morphogenesis in HUVECs through Src-dependent upregulation of endogenous VEGF-A. Conditions of chronic hypoxia impaired the effect of PP2, possibly via MRP 1.

Pathological significance and prognostic significance of FES expression in bladder cancer vary according to tumor grade.

PURPOSE: The feline sarcoma oncogene protein (FES) is a non-receptor tyrosine kinase implicated in both oncogenesis and tumor suppression. Here, cancer cell lines and human tissues were employed to clarify the pathological and prognostic significance of FES in bladder cancer. METHODS: The relationship between FES expression and cancer aggressiveness was investigated using 3 cell lines (T24: corresponding to grade 3, 5637: corresponding to grade 2, and RT4: corresponding to grade 1) and 203 tissues derived from human bladder malignancies. Proliferation, invasion, and migration of cancer cells were assessed following the knockdown (KD) of FES expression by the siRNA method. Relationships between FES expression and pathological features, aggressiveness, and outcome were investigated. RESULTS: FES-KD inhibited the proliferation, migration, and invasion of T24 cells but not of RT4 cells and 5637 cells. Considering all patients, FES expression demonstrated a negative relationship with grade but no association with muscle invasion or cancer cell proliferation. However, it was positively correlated with pT stage and cell proliferation in high-grade tumors (p = 0.002); no such association was found for low-grade tumors. In addition, elevated FES expression was a negative prognostic indicator of metastasis after radical surgery for patients with high-grade tumors (p = 0.021) but not for those with low-grade malignancies. CONCLUSIONS: FES appeared to act as a suppressor of carcinogenesis, being associated with low tumor grade in the overall patient group. However, its expression correlated with cancer aggressiveness and poor outcome in high-grade bladder cancer. FES, therefore, represents a potential therapeutic target and useful prognostic factor for such patients.

Factors associated with polypharmacy in elderly home-care patients.

AIM: Polypharmacy, which is often observed in elderly patients, has been associated with several unfavorable outcomes, including an increased risk of potentially inappropriate medications, medication non-adherence, drug duplication, drug-drug interactions, higher healthcare costs and adverse drug reactions. A significant association between polypharmacy and adverse outcomes among older people living in the community has also been confirmed. A reduction in the number of medications should thus be pursued for many older individuals. Nevertheless, the factors associated with polypharmacy in elderly home-care patients have not been reported. Here, we investigated those factors in elderly home-care patients in Japan. METHODS: We used the data of the participants in the Observational Study of Nagoya Elderly with Home Medical investigation. Polypharmacy was defined as the current use of six or more different medications. We carried out univariate and multivariate logistic regression analyses to assess the associations between polypharmacy and each of several factors. RESULTS: A total of 153 home-care patients were registered. The mean number of medications used per patient was 5.9, and 51.5% of the patients belonged to the polypharmacy group. The multivariate model showed that the patients' scores on the Charlson Comorbidity Index and the Mini-Nutrition Assessment Short Form were inversely associated with polypharmacy, and potentially inappropriate medication was most strongly associated with polypharmacy (odds ratio 4.992). CONCLUSIONS: The present findings showed that polypharmacy was quite common among the elderly home-care patients, and they suggest that home-care physicians should prescribe fewer medications in accord with the deterioration of home-care patients' general condition. Geriatr Gerontol Int 2018; 18: 33-41.

Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy (Review).

Antiangiogenic therapy, including blockade of vascular endothelial growth factor (VEGF) signaling, was highly anticipated to improve the prognosis for patients with advanced cancers following the success of preclinical animal models. However, antiangiogenic monotherapy with VEGF antagonists has produced disappointing results in clinical trials to date. One of the reasons for this poor outcome is that angiogenesis is not solely regulated by VEGF. Inhibition of VEGF signaling, therefore, may select for tumor cell populations that stimulate angiogenesis through VEGF-independent pathways. Successful antiangiogenic therapy, therefore, may require simultaneous blockade of signaling downstream from multiple proangiogenic factor receptors. Recently, we found that non-receptor protein-tyrosine kinases, including members of the Src and Fes families, play vital roles in the responses of cultured endothelial cells to several proangiogenic factors. In this review, we summarize the contributions of these kinase families to angiogenic pathways in endothelial cells, and discuss the potential of these kinases as new targets for antiangiogenic drug discovery.

Presence of phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor progression and survival in patients with conventional renal cell carcinoma.

PURPOSE: Hepatocyte growth factor receptor (HGFR/c-Met) signaling is associated with tumor progression in various cancers. The clinical significance and pathologic roles of phosphorylated HGFR/c-Met in renal cell carcinoma (RCC) are not fully understood; therefore, this study sought to clarify the possible role of two tyrosine residues (pY1234/pY1235 and pY1349) in HGFR/c-Met. EXPERIMENTAL DESIGN: The kinetics of tyrosine phosphorylation at these two residues was examined in a human renal carcinoma cell line, ACHN cells. In addition, phosphorylated HGFR/c-Met expression (using phosphorylation site-specific antibodies for pY1234/pY1235 and pY1349) was examined in 114 tumor sections of conventional RCC patients by immunohistochemistry. The relationships between these expressions and clinicopathologic features and survival were also investigated. RESULTS: Although phosphorylation of Y1349 HGFR/c-Met was observed for 120 minutes after HGF treatment of ACHN cells, maximal phosphorylation of Y1234/Y1235 was observed at 30 minutes followed by a rapid inactivation. Median rates (range) of cancer cells immunopositive for pY1234/pY1235 HGFR/c-Met and pY1349 HGFR/c-Met in the tumor sections were 0% (0-5.2%) and 14.3% (0-64.3%), respectively. Positive expression of pY1349 HGFR/c-Met was significantly associated with high pT stage, presence of metastasis, and high-grade carcinoma. Multivariate Cox analysis revealed that the positive expression of pY1349 HGFR/c-Met was a significant and an independent predictor of cause-specific survival (odds ratio, 2.94; 95% confidence interval, 1.12-7.72; P = 0.028). CONCLUSIONS: Phosphorylated HGFR/c-Met may be important in the tumor progression of RCC. Expression of pY1349 HGFR/c-Met is a useful predictor for metastasis and survival of conventional RCC patients.

Expression of matrix metalloproteinase-7 on cancer cells and tissue endothelial cells in renal cell carcinoma: prognostic implications and clinical significance for invasion and metastasis.

PURPOSE: The expression of matrix metalloproteinase-7 (MMP-7) correlates with the malignant potential of various tumors and patient survival. We investigated the clinical and prognostic significance of MMP-7 expression in cancer cells and endothelial cells in human renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: We reviewed tissue samples of 156 patients with RCC who had undergone radical operation. MMP-7 expression was examined by immunohistochemistry. Sections containing MMP-7-positive vessels were also stained for CD34. The density of MMP-7-positive vessels was determined by a computer-aided image analysis system. Multivariate analysis was done to assess relevant variables for invasion, metastasis, and cause-specific survival. RESULTS: The proportion of MMP-7-expressing tumor cells were significantly higher (P < 0.001) than that of normal cells. MMP-7-positive vessels were considered blood vessels based on staining for CD34, and their density was increased in tumor areas. The proportion of MMP-7-expressing cancer cells and density of MMP-7-positive vessels correlated with grade, pathologic tumor stage, and metastasis. Multivariate analysis showed that MMP-7 expression on cancer cells correlated with pathologic tumor stage only, whereas MMP-7-positive vessel density correlated with metastasis only. The elevated status of MMP-7 in cancer tissues was an independent predictor for cause-specific survival (odds ratio, 8.61; P = 0.040) by multivariate analysis. CONCLUSIONS: Our results showed that MMP-7 influences tumor progression by regulating invasion and angiogenesis. Multivariate analysis showed that MMP-7 status of cancer tissues was strong predictor of poor prognosis. Our results suggest that MMP-7 targeting treatment may be a potential target against RCC.

Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D.

PURPOSE: Lymph vessel density (LVD) and microvessel density (MVD) correlate with the malignant potential of tumors and patient survival. Vascular endothelial growth factors (VEGF)-A, VEGF-C, and VEGF-D could modulate LVD and MVD. We investigated the clinical and prognostic significance of LVD and MVD on lymphangiogenic and angiogenic function of VEGF-A, VEGF-C, and VEGF-D in human bladder cancer. EXPERIMENTAL DESIGN: We reviewed tissue samples from patients with nonmetastatic bladder cancer who had undergone transurethral resections (n = 126). The densities of D2-40-positive vessels (LVD) and CD34-positive vessels (MVD) were measured by a computer-aided image analysis system. Expression of VEGF-A, VEGF-C, and VEGF-D was examined by immunohistochemistry; survival analyses and their independent roles were investigated using multivariate analysis models. RESULTS: LVD was associated with tumor grade but not with pT stage. LVD was associated with metastasis-free survival (log rank P = 0.039), but was not an independent prognostic factor. Although MVD affected survival, the combination of high LVD and high MVD in tumors was an independent predictor of metastasis-free survival. Although VEGF-C expression was positively associated with both LVD and MVD, VEGF-D was associated only with LVD. VEGF-A expression was associated with MVD in univariate analysis, however, it was not an independent factor. CONCLUSIONS: Lymphangiogenesis and angiogenesis influence metastasis-free survival, and are regulated by VEGF-C and/or VEGF-D. Our results suggest that LVD and MVD are useful tools for the selection of postoperative management and treatment strategies in patients with bladder cancer.

Angiopoietin 1 is mitogenic for cultured endothelial cells.

The angiopoietin (Ang)/Tie2 system is implicated in blood vessel formation and maturation. However, the mitogenic effects of angiopoietins remain to be elucidated. Here, we show that Ang1 is mitogenic for cultured endothelial cells. Ang1 dose-dependently induced the proliferation and increased the labeling index of a murine brain capillary endothelial cell line, IBE cells. Ang1 also increased the labeling index of human umbilical vein endothelial cells (HUVEC). Ang1 up-regulated the expression of cyclin D1 in both of these cells. Ang1 activated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) in IBE cells and HUVECs. Activated PI3K was associated with c-Fes protein tyrosine kinase in these cells, but not with Tie2. p70 S6 kinase (p70 S6K) was activated by Ang1-treatment, although this activation was blocked by a PI3K inhibitor, LY294002. Simultaneous treatment of cells with PD98059 (MAPK/extracellular regulated kinase kinase inhibitor) and rapamycin (mTOR inhibitor) completely blocked Ang1-induced mitogenic activity for IBE cells and HUVECs. Although Ang2 at high concentration weakly activated Tie2 and p70 S6K, it failed to activate Ras and MAPK, or to induce cell proliferation. Taken together, these findings indicate that Ang1 exerts mitogenic activity on endothelial cells, which requires activation of both MAPK and p70 S6K.

Factors associated with unexpected admissions and mortality among low-functioning older patients receiving home medical care.

AIM: The need for and availability of home medical care for elderly patients with limitations in terms of access to medical facilities has been increasing. We investigated the association between low function, malnutrition, dementia and multicomorbidity with patient prognosis, focusing on unexpected hospital admissions and mortality in elderly non-cancer patients receiving home care. METHODS: The study included 124 Japanese patients receiving home medical care in the form of regular visits from doctors and nurses for physical and/or mental disability. RESULTS: Of the patients studied, 36.2% experienced hospital admission. Student's t-test showed that admitted patients had significantly higher Charlson Comorbidity Index scores. Meanwhile, 19.6% of patients died during the course of the study. Student's t-test showed that older patients had a higher risk of mortality, and significantly lower activities of daily living and Mini-Nutritional Assessment Short-Form scores. Cox hazard analysis showed that multicomorbidity was a risk for unexpected hospital admission, and malnutrition was a risk for mortality in frail older adults receiving home medical care. CONCLUSIONS: We found that multicomorbidity was a risk for unexpected hospital admission, and malnutrition was a risk for mortality in frail older adults receiving home medical care. Geriatr Gerontol Int 2017; 17: 1623-1627.

Stromal expression of Fer suppresses tumor progression in renal cell carcinoma and is a predictor of survival.

Fps/Fes related (Fer) is a non-receptor tyrosine kinase that is expressed in fibroblasts, immune cells and endothelial cells. Fer serves an important pathological role in cell survival, angiogenesis and the immune system. However, the pathological role of Fer expression in the stromal cells surrounding renal cell carcinoma (RCC) has not been previously investigated. In the present study, immunohistochemical analysis of Fer was performed using the formalin-fixed tissue samples of 152 patients with RCC. The proliferative and apoptotic indices were used to represent the percentage of proliferation marker protein Ki-67- and cleaved caspase-3-positive cells, respectively. The microvessel density was defined as the number of cluster of differentiation (CD) 31-positively stained vessels/mm2. In addition, CD57+ and CD68+ cells were counted using semi-quantification of natural killer (NK) cells and macrophages. Fer expression in stromal cells was negatively associated with Fuhrman grade, pathological tumor stage and metastasis (P<0.001). Fer expression in stromal cells was negatively associated with CD68+ macrophage density, whereas it was positively associated with CD57+ NK cell density. Kaplan-Meier estimators indicated that decreased stromal Fer expression was a predictive marker of decreased cause-specific survival rate (P<0.001). Furthermore, low expression of Fer was identified as being an independent marker of decreased cause-specific survival using multivariate analysis (hazard ratio, 7.4; 95% confidence interval, 1.7-33.0; P<0.001). The results of the present study suggested that low Fer expression in stromal cells is associated with increased malignant aggressiveness and decreased survival in patients with RCC. CD57+ NK cell and CD68+ macrophage regulation in cancer-stromal tissue is considered to affect RCC pathology.