Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study

Abstract

Purpose

Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome.

Methods

Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors.

Results

DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45–2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02–4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR.

Conclusions

Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

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Epicardial fat is a negative predictor of spine volumetric bone mineral density and trabecular bone score in acromegaly

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Delaying time to first nocturnal void may have beneficial effects on reducing blood glucose levels

Abstract

Experimental studies disrupting sleep and epidemiologic studies of short sleep durations indicate the importance of deeper and longer sleep for cardiometabolic health. We examined the potential beneficial effects of lengthening the first uninterrupted sleep period (FUSP) on blood glucose. Long-term data (≥3 months of treatment) were derived from three clinical trials, testing low-dose (10–100 µg) melt formulations of desmopressin in 841 male and female nocturia patients (90 % of which had nocturnal polyuria). We performed post hoc multiple regression with non-fasting blood glucose as dependent variable and the following potential covariates/factors: time-averaged change of FUSP since baseline, age, gender, race, ethnicity, baseline glucose, baseline weight, change in weight, patient metabolic status (normal, metabolic syndrome, type II diabetes), dose, follow-up interval, and time of random glucose sampling. Increases in FUSP resulted in statistically significant reductions in blood glucose (p = 0.0131), even after controlling for all remaining covariates. Per hour increase in time to first void was associated with glucose decreases of 1.6 mg/dL. This association was more pronounced in patients with increased baseline glucose levels (test of baseline glucose by FUSP change interaction: p < 0.0001). Next to FUSP change, other statistically significant confounding factors/covariates also associated with glucose changes were gender, ethnicity, metabolic subgroup, and baseline glucose. These analyses indicate that delaying time to first void may have beneficial effects on reducing blood glucose in nocturia patients. These data are among the first to suggest that improving sleep may have salutary effects on a cardiometabolic measure.

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Endogenous trans -zeatin content in plants with different metal-accumulating ability: a field survey

Abstract

A field survey was conducted to evaluate soil metal pollution and endogenous trans-zeatin content in the leaves of plants growing at six sites in a metal-polluted area located in Gejiu, Yunnan, China. Five plant species were collected, and the physicochemical properties and concentrations of five metals in the soil were analyzed. The trans-zeatin content in plant leaves was measured by high-performance liquid chromatography. Based on the Nemerow pollution index, the six sites were classified into four levels of pollution (i.e., low, medium, high, and severely high). The degree of soil metal pollution was cadmium (Cd) > arsenic (As) > lead (Pb) > zinc (Zn) > copper (Cu). The leaf trans-zeatin content in Pteris vittata (an arsenic hyperaccumulator) increased significantly by 98.6 % in soil with a severely high level of pollution compared with soil at a low level of pollution. However, in non-hyperaccumulators Bidens pilosa var. radiata and Ageratina adenophora, a significant decrease in leaf trans-zeatin content of 35.6 and 87.6 %, respectively, was observed. The leaf trans-zeatin content in Artemisia argyi also decreased significantly by 73.6 % in high metal-polluted soil compared with that in medium metal-polluted soil. Furthermore, significant correlations were observed between leaf trans-zeatin content in Pteris vittata and As, Pb, and Cd concentrations in the soil; however, either no correlation or a negative one was observed in the other plant species. Therefore, a high content of trans-zeatin in the leaves of Pteris vittata may play an important role in its normal growth and tolerance to metals.

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Sexual function in young women with type 1 diabetes: the METRO study

Abstract

Purpose

The aim of this study was to evaluate the prevalence and risk factors associated with female sexual dysfunction (FSD) in young women with type 1 diabetes treated with different intensive insulin regimens.

Methods

Type 1 diabetic women aged 18–35 years were included in this study if they had stable couple relationship and no oral contraceptive use. All women were asked to complete the Female Sexual Function Index (FSFI) and other validated multiple-choice questionnaires assessing sexual-related distress (Female Sexual Distress Scale, FSDS), quality of life (SF-36 Health Survey), physical activity (International Physical Activity Questionnaire), depressive symptoms (Zung Self-Rating Depression Scale, SRDS) and diabetes-related problems (Diabetes Integration Scale ATT-19). FSD was diagnosed according to a FSFI score higher than 26.55 and a FSDS score lower than 15.

Results

The overall prevalence of FSD in diabetic and control women was 20 and 15 %, respectively (P = 0.446). Compared with the continuous subcutaneous insulin infusion group and control women, diabetic women on multiple daily injections (MDI) had lower global FSFI score (P = 0.007), FSDS score (P = 0.045) and domains such as arousal (P = 0.006), lubrication and satisfaction scores (P < 0.001 for both). In the multiple regression analysis, only the mental component summary (P = 0.047) and the SRDS score (P = 0.042) were independent predictors of FSFI score in the overall diabetic women.

Conclusion

Young women with type 1 diabetes wearing an insulin pump show a prevalence of sexual dysfunction similar to that of healthy age-matched women, but sexual function was significantly impaired in diabetic women on MDI therapy. Depression and the mental health status were independent predictors for FSD in diabetic women.

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DPP-4 (CD26) inhibitor sitagliptin exerts anti-inflammatory effects on rat insulinoma (RINm) cells via suppressing NF-κB activation

Abstract

Dipeptidyl peptidase-4 (CD26), a cell surface glycoprotein, is expressed by a variety of cells. It has been shown that dipeptidyl peptidase-4 (CD26) is involved in T cell activation. Nonetheless, its role in inflammatory effects in islet β cells has not been well investigated. In this study, we used sitagliptin, a classic inhibitor of dipeptidyl peptidase-4 (CD26), to research the effect of dipeptidyl peptidase-4 (CD26) on the activation of NF-κB, the expression of inflammatory cytokines, and cell apoptosis in rat insulinoma cells. Results showed that dipeptidyl peptidase-4 (CD26) was expressed on the surface of rat insulinoma cells. Lipopolysaccharide-induced NF-κB activation and expression of inflammatory cytokines were suppressed by sitagliptin treatment in rat insulinoma cells. Furthermore, sitagliptin treatment reduced cell apoptosis stimulated by lipopolysaccharide. Taken together, this study showed for the first time that sitagliptin suppressed NF-κB activation and inflammatory cytokines expression in rat insulinoma cells, suggesting that the dipeptidyl peptidase-4 inhibitor may exert direct anti-inflammatory effects in islet β cells.

http://ift.tt/2cLGcjP

DPP-4 (CD26) inhibitor sitagliptin exerts anti-inflammatory effects on rat insulinoma (RINm) cells via suppressing NF-κB activation

Abstract

Dipeptidyl peptidase-4 (CD26), a cell surface glycoprotein, is expressed by a variety of cells. It has been shown that dipeptidyl peptidase-4 (CD26) is involved in T cell activation. Nonetheless, its role in inflammatory effects in islet β cells has not been well investigated. In this study, we used sitagliptin, a classic inhibitor of dipeptidyl peptidase-4 (CD26), to research the effect of dipeptidyl peptidase-4 (CD26) on the activation of NF-κB, the expression of inflammatory cytokines, and cell apoptosis in rat insulinoma cells. Results showed that dipeptidyl peptidase-4 (CD26) was expressed on the surface of rat insulinoma cells. Lipopolysaccharide-induced NF-κB activation and expression of inflammatory cytokines were suppressed by sitagliptin treatment in rat insulinoma cells. Furthermore, sitagliptin treatment reduced cell apoptosis stimulated by lipopolysaccharide. Taken together, this study showed for the first time that sitagliptin suppressed NF-κB activation and inflammatory cytokines expression in rat insulinoma cells, suggesting that the dipeptidyl peptidase-4 inhibitor may exert direct anti-inflammatory effects in islet β cells.

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Mesothelial cells interact with tumor cells for the formation of ovarian cancer multicellular spheroids in peritoneal effusions

Abstract

Epithelial ovarian cancer (EOC) dissemination is primarily mediated by the shedding of tumor cells from the primary site into ascites where they form multicellular spheroids that rapidly lead to peritoneal carcinomatosis. While the clinical importance and fundamental role of multicellular spheroids in EOC is increasingly appreciated, the mechanisms that regulate their formation and dictate their cellular composition remain poorly characterized. To investigate these important questions, we characterized spheroids isolated from ascites of women with EOC. We found that in these spheroids, a core of mesothelial cells was encased in a shell of tumor cells. Analysis further revealed that EOC spheroids are dynamic structures of proliferating, non-proliferating and hypoxic regions. To recapitulate these in vivo findings, we developed a three-dimensional co-culture model of primary EOC and mesothelial cells. Our analysis indicated that, compared to the OVCAR3 cell line, primary EOC cells isolated from ascites as well as mesothelial cells formed compact spheroids. Analysis of heterotypic spheroid microarchitecture revealed a structure that grossly resembles the structure of spheroids isolated from ascites. Cells that formed compact spheroids had elevated expression of β1 integrin and low expression of E-cadherin. Addition of β1 integrin blocking antibody or siRNA-mediated downregulation of β1 integrin resulted in reduced tightness of the spheroids. Interestingly, the loss of MUC16 and E-cadherin expression resulted in the formation of more compact spheroids. Therefore, our findings support the heterotypic nature of spheroids from malignant EOC ascites. In addition, our data describe an unusual link between E-cadherin expression and less compact spheroids. Our data also emphasize the role of MUC16 and β1 integrin in EOC spheroid formation.

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Radikale Zystektomie vs. Radiochemotherapie zur Behandlung des Blasenkarzinoms im Stadium T2–4a N0 M0

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Patient-Centered Communication Intervention in Advanced Cancer

This study describes the effectiveness of a combined intervention that included oncologist communication training and coaching for patients with advanced cancer and caregivers in improving patient-centered communication.

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Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes

Summary

Objective

Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-hour plasma glucose (2hG) during the oral glucose tolerance test (OGTT).

Design/Participants/Measurements

We studied 1380 non-diabetic subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study using the second visit (2000-2004) as baseline when serum levels of FGF21 and other adipokines were measured. Glycaemic status was assessed by OGTT. Incident diabetes was defined as fasting glucose level (FG) ≥ 7 mmol/L or 2hG ≥ 11.1 mmol/L or use of anti-diabetic agents, at subsequent visits.

Results

123 participants developed diabetes over 9.0 years (median). On multivariable logistic regression analysis, FGF21 (p=0.003), adipocyte-fatty acid binding protein (p=0.003) and adiponectin (p=0.035) were independent predictors of incident diabetes. FGF21 had the best change in log likelihood when added to a diabetes prediction model (DP) based on age, family history, smoking, hypertension, BMI, dyslipidaemia and FG. It also improved the area under ROC curve (AUROC) of diabetes prediction (DP) from 0.797 to 0.819 (P=0.0072), rendering its performance comparable to the "DP + 2hG" model (AUROC=0.838, P=0.19).

Conclusions

As a biomarker for diabetes prediction, serum FGF21 appeared to be superior to other adipokines and, on its own, could be considered as an alternative to the OGTT.

This article is protected by copyright. All rights reserved.

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Oral Cavity and Allergy: Meeting the Diagnostic and Therapeutic Challenge

Abstract

Allergic reactions of the oral mucosa are associated with diverse symptoms and can severely affect patients' quality of life. Oral mucosa changes such as stomatitis or lichenoid reactions can be the first evidence of a contact allergy, with oral lichenoid reactions after contact with dental restorations, especially amalgam fillings, being among the most common clinical reactions. Additives in foods and oral hygiene products may also cause allergic mucosal reactions. Subjective symptoms, such as pain, burning feeling, or dryness of the oral mucosa, as well as cheilitis or lip and facial swelling, may not only have an allergic component but may also be associated with other diseases that have to be excluded. A complete and thorough clinical examination of the oral mucosa is the first step in the diagnosis of a contact allergy. A detailed history of the patient's oral care products, drugs, and dental materials is both essential and helpful for the clinician. As a result of the presence of mucosal changes, a patch test can be used for the diagnosis of contact allergy of delayed type. Although the patch test is the standard diagnostic tool for such types of contact allergy, proper interpretation of patch-test results and their clinical relevance can be challenging. As the number of patients with allergies resulting from different materials increases over the years, and a larger number of different dental materials are found to induce an allergy, it is essential for dentists to be aware of the possible allergic reactions to dental materials. Thus, we aimed to develop a systematic approach for contact allergy of the oral cavity, focusing not only on clinical manifestations and diagnosis but also on management and prediction of the risk of oral allergic reactions. A multidisciplinary approach for patients with an oral allergy is essential, with participation of physicians of different specialties, including dentists, allergists and dermatologists.

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Oral health and orofacial pain in older people with dementia: a systematic review with focus on dental hard tissues

Abstract

Objective

The aim of this review was to provide a systematic overview including a quality assessment of studies about oral health and orofacial pain in older people with dementia, compared to older people without dementia.

Methods

A systematic literature search was performed in PubMed, CINAHL, and the Cochrane Library. The following search terms were used: dementia and oral health or stomatognathic disease. The quality assessment of the included articles was performed using the Newcastle-Ottawa Scale (NOS).

Results

The search yielded 527 articles, of which 37 were included for the quality assessment and quantitative overview. The median NOS score of the included studies was 5, and the mean was 4.9 (SD 2.2). The heterogeneity between the studies was considered too large to perform a meta-analysis. An equivalent prevalence of orofacial pain, number of teeth present, decayed missing filled teeth index, edentulousness percentage, and denture use was found for both groups. However, the presence of caries and retained roots was higher in older people with dementia than in those without.

Conclusions

Older people with dementia have worse oral health, with more retained roots and coronal and root caries, when compared to older people without dementia. Little research focused on orofacial pain in older people with dementia.

Clinical relevance

The current state of oral health in older people with dementia could be improved with oral care education of caretakers and regular professional dental care.

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Computer Modelling of the Cervical Spine Movements in Cervical Dystonia

Condition:   Cervical Dystonia, Primary
Intervention:   Device: cone beam imagery of cervical spine
Sponsor:   Fondation Ophtalmologique Adolphe de Rothschild
Not yet recruiting - verified August 2016

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Immunotherapy in Breast Cancer- Paving New Roads?

Significant advances have been made in our understanding of the mechanisms of innate and adaptive immunity and the mechanisms by which tumors escape from the normal process of immune surveillance. However, effectively harnessing the power of the immune system to specifically target the tumor cells has proven quite difficult, in large part due to the fact that tumors are composed of patient's own cells, expressing antigens recognized as "self" and thus escaping the immune surveillance. For breast cancer treatment, the first successful inroads in immunotherapy came with the introduction of monoclonal antibodies against a membrane receptor for the epidermal growth factor receptor family (HER2). In 1998 the first monoclonal antibody against the Her 2 antigen was approved for clinical use (trastuzumab). Clinical trials combining trastuzumab with various chemotherapy regimens have consistently shown improvement in survival in both metastatic as well as early stage breast cancer. Another promising approach has been the development of anti HER 2 vaccines. More recently the discovery of immune modulating antibodies (checkpoint inhibitors) and their success in the treatment of cancers such as melanoma and renal cell carcinoma has lead to renewed interest in immune therapies in cancer in general and new clinical trials exploring the role of immune therapies in breast cancer.

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Inhibitors of Cancer Stem Cells

The cancer stem cell (CSC) theory is current strategy of cancer treatment. Cancers follow pathways of cancer stem cell such as Notch, Wnt and Hedgehog can be addressed with natural products or synthetic drugs to diminish the chance of new tumours. The cancer growth can also be suppressed by aiming the tumourigenic stem cells alone, instead of targeting at reducing complete tumour dimension. The recurrence of tumours after years of disease-free survival has prompted interest in the concept that cancers may have a stem cell basis. Current assumption holds that < 5% of the tumour mass may be chemo-resistant and radio-resistant, harbouring stem-like properties that impel tumour survival, development, and metastasis. There is intense an investigation to interpret CSCs based on self-renewal and multi-lineage differentiation. Nevertheless, no successful targeted therapies have reached the clinic. The ionophore antibiotic salinomycin that selectively kills breast CSCs seems to be a promising anticancer drug. Clinical trials conducted by the NIH (National Institute of Health) on several synthetic drugs demonstrate the current importance of the issue and predict a bright future for such molecular weapons against cancer.

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Clinical Approaches to Immunotherapy in Non-Small Cell Lung Cancer: Current and Future Perspectives

Lung cancer is among the most prevalent and deadly cancers. Although the development of targeted drugs, erlotinib and crizotinib, has improved lung cancer management, survival rates of lung cancer patients have not shown significant improvement over the past decade. Better therapeutic options are required to treat lung cancer patients. Immunotherapy is a maturing and rapidly growing field, which has recently contributed many novel strategies for addressing cancer treatment. Here, we discuss the current state of cancer vaccines, immune checkpoint blockers, and adoptive cellular therapies, as novel clinical treatment strategies for non-small cell lung cancer. The durability of clinical activity in a subset of patients has led to a great deal of excitement and optimism.

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A New Era of Immunotherapy in Prostate Cancer

Prostate cancer was one of the first cancer types where FDA (Food and Drug Administration) approval was granted to a cancer vaccine, sipuleucel-T, in the metastatic setting for asymptomatic or minimally symptomatic patients. This marked the beginning of the era of immunotherapies in cancer and stimulated the interest to develop other immune-based novel agents. In addition to sipuleucel-T vaccine, pox viral-based vaccine and personalized peptide vaccine are also being investigated in prostate cancer. Other agents that modulate the tumor microenvironment to enhance the immune response against the prostate cancer cells is also being developed. Immune checkpoint inhibitors such as ipilimumab, anti-PD-1 monoclonal antibody (programmed cell death-1), and Indoleamine 2,3-dioxygenase (IDO) inhibitors have shown some promise in this field. However, similar to sipuleucel-T vaccine, the preliminary data reflects the efficacy of these to be limited to mCRPC patients with favorable risk factors without any visceral disease. More clinical trials are needed to identify the group of patients with mCRPC that would benefit from immunotherapy. In this article we review the role of immune-based therapies including vaccines and immune checkpoint inhibitors in mCRPC.

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Drug-Induced Tactile Hallucinations Beyond Recreational Drugs

Abstract

In monosymptomatic hypochondriacal psychosis (MHP), such as delusional infestation (DI), the patient has a fixed, false, encapsulated belief associated with tactile hallucinations (TH), most commonly formication, which is defined as cutaneous sensations of crawling, stinging, biting, etc., without evidence of infestation. Drug-induced TH should be considered in patients with suspected MHP. Although recreational drugs such as cocaine, amphetamines, and narcotics are well known to induce TH, many busy practicing dermatologists may not be familiar with other types of medications that can induce TH. A literature search for peer-reviewed articles was conducted in the PubMed, PsychInfo, Cochrane, and Embase databases. For each article, the medication(s) that induced TH was identified in a systematic way. The most commonly reported group of medications to induce TH was anti-Parkisonian agents, followed by antidepressants, prescription stimulants, antihypertensives (propranolol), and antiepileptics. In many cases, other types of hallucinations, such as visual and auditory, were present. Patients also commonly presented with psychiatric comorbidities. Although the conclusions that can be derived from this literature review are limited, it appears that certain medications that alter neurotransmitters, especially dopamine and, less convincingly, norepinephrine and serotonin, can be associated with TH. Drug-induced TH should also be considered in patients presenting with multiple types of hallucinations and patients with existing psychiatric comorbidity. Drug-induced TH, especially with an underlying psychiatric diagnosis that is separate from MHP, may be a more manageable disease entity compared with bona fide MHP.

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Influence of filtration velocity on DON variation in BAF for micropolluted surface water treatment

Abstract

Biological aerated filters (BAFs) are widely used for the treatment of micropolluted surface water. However, the biological process produces dissolved organic nitrogen (DON), which, as precursors of nitrogenous disinfection by-products, pose potential threats to drinking water safety. Therefore, to control DON in BAF effluent, it is necessary to study the influence of BAF operation parameters on DON production. In this study, the influence of filtration velocity in a BAF on DON production was investigated. Under different filtration velocity (0.5, 2, and 4 m/h) conditions, profiles of DON concentrations along the media layer were measured. The profile at a filtration velocity of 0.5 m/h showed a decreasing trend, and the ones under filtration velocities of 2 and 4 m/h fluctuated in a small range (from 0.1 to 0.4 mg/L). Moreover, the relatively high filtration velocities of 2 and 4 m/h resulted in a lower level of DON concentration. Additionally, 3D excitation-emission matrix fluorescence spectroscopy was used to characterize DON. It is found that the patterns of DON at a relatively high filtration velocity condition (4 m/h) were obviously different from the ones under low filtration velocity conditions (0.5 and 2 m/h).

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