Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation

[Abstract] Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Concentrations of ghrelin are controversial in liver cirrhosis. Our aim was to study fasting ghrelin and their response to an oral glucose tolerance test (OGTT) in liver failure patients and normal subjects. Methods We included 16 patients with severe liver failure prior to liver transplantation. As a control group we included 10 age- and BMI-matched healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min, respectively. Results Fasting ghrelin (median and range) were statistically significantly lower for patients compared to the controls, 527 (377–971) pg/ml vs. 643 (523–2163) pg/ml, P = 0.045, for patients and controls, respectively. The area under the curve for total ghrelin post-OGTT were lower in end-stage liver failure patients than in the control group, 58815 (44730–87420) pg/ml min vs. 76560 (56160–206385) pg/ml min, for patients and controls, respectively, P = 0.027. Conclusions Ghrelin levels are significantly decreased both fasting and post-OGTT in patients with liver failure candidates for transplantation. Decreased ghrelin levels could contribute to anorexia in patients with cirrhosis.Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI070413Xunta de Galicia; PS07/12Xunta de Galicia; PGIDT05PXIC91605PNXunta de Galicia; INCITE08ENA916110E

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.Ana Catarina Ferreira and Sandro Da Mesquita are recipients of PhD fellowships by the Fundação para a Ciência e Tecnologia (FCT, Portugal)/FEDER. Fernanda Marques is an assistant researcher IF/ 00231/2013 of the Fundação para a Ciência e Tecnologia (FCT, Portugal). This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the project: EXPL/NEUOSD/2196/2013 (to Marques F). The authors thank Nadine Santos for the helpful comments on the manuscript

Adjuvant Therapy in Women With Early Stage Uterine Serous Carcinoma: A Multi-institutional Study

OBJECTIVE: Uterine serous carcinoma is a rare but aggressive subtype of endometrial adenocarcinoma. Our objective was to compare adjuvant treatment strategies for patients with early stage uterine serous carcinoma. METHODS: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or any mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher\u27s exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free and overall survival. RESULTS: There were 737 patients included. Most patients had Stage IA disease (75%), 49% of which had no myometrial invasion. Only 164 (24%) tumors had lymphatic/vascular space invasion. Adjuvant treatment varied: 22% received no adjuvant therapy, 17% had chemotherapy alone, 19% had cuff brachytherapy, 35% had cuff brachytherapy with chemotherapy, and 6% underwent pelvic radiation. Adjuvant treatment was significantly associated with a decreased risk of recurrence (p = 0.04). Compared with no adjuvant therapy, patients who received brachytherapy or brachytherapy/chemotherapy had improved recurrence-free survival (HR 0.59, 95% CI 0.40-0.86; HR 0.65, 95% CI 0.49-0.88, respectively) and overall survival (HR 0.53, 95% CI 0.35-0.79; HR 0.49, 95% CI 0.35-0.69, respectively). Improved survival with brachytherapy and brachytherapy/chemotherapy persisted on multivariable analyses. Chemotherapy alone was also associated with improved overall survival compared with no adjuvant treatment (HR 0.55, 95% CI 0.37-0.81). CONCLUSIONS: Adjuvant therapy was associated with a decreased risk of recurrence relative to observation alone. Adjuvant cuff brachytherapy with and without chemotherapy was associated with improved survival outcomes in patients with early stage uterine serous carcinoma

Closed-form analytical expressions for the potential fields generated by triangular monolayers with linearly distributed source strength

The solution of the mixed boundary value problem of potential theory involves the computation of the potential field generated by monolayer and double layer source distributions on surfaces at which boundary conditions are known. Closed-form analytical expressions have been described in the literature for the potential field generated by double layers having a linearly distributed strength over triangular source elements. This contribution presents the corresponding expression for the linearly distributed monolayer strength. The solution is shown to be valid for all observation points in space, including those on the interior, edges and vertices of the source triangle

Palbociclib plus letrozole in estrogen receptor-positive advanced/recurrent endometrial cancer: Double-blind placebo-controlled randomized phase II ENGOT-EN3/PALEO trial

Purpose. The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recur-rent endometrial cancer. Patients and methods. Thi s placebo-controlled double-blind, randomized phase II screening trial (NCT02730429) enrolled women with measurable/evaluable estrogen receptor-positive endometrioid endome-trial cancer that was primary metastatic or had relapsed after >= 1 prior systemic therapy. Patients were randomized in a 1:1 ratio, stratified by number of prior chemotherapy lines, measurable versus evaluable non- measurable disease, and prior medroxyprogesterone/megestrol acetate treatment, to receive oral letrozole 2.5 mg on days 1-28 plus either oral palbociclib 125 mg or placebo on days 1-21, repeated every 28 days until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression- free survival (PFS). Results. Among 77 patients randomized between February 16, 2017, and December 21, 2018, 73 were treated (36 with palbociclib-letrozole, 37 with placebo-letrozole). Median follow-up was 21.9 (95 % CI, 16.7 to 22.3) months. Median PFS was 8.3 (95 % CI, 4.6 to 11.2) versus 3.1 (95 % CI, 2.7 to 6.8) months, respectively. In a landmark analysis at 12 months the PFS hazard ratio was 0.57 (95 % CI, 0.32 to 0.99; P = .044). Grade >= 3 adverse events were more common with palbociclib-letrozole (67 %) than placebo-letrozole (30 %), most commonly neutropenia (44 % v 0 %, respectively) . Conclusion. These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned. Clinical trial information. NCT02730429 (c) 2024 Published by Elsevier Inc

Validation analysis of the novel imaging-based prognostic radiomic signature in patients undergoing primary surgery for advanced high-grade serous ovarian cancer (HGSOC)

Background Predictive models based on radiomics features are novel, highly promising approaches for gynaecological oncology. Here, we wish to assess the prognostic value of the newly discovered Radiomic Prognostic Vector (RPV) in an independent cohort of high-grade serous ovarian cancer (HGSOC) patients, treated within a Centre of Excellence, thus avoiding any bias in treatment quality. Methods RPV was calculated using standardised algorithms following segmentation of routine preoperative imaging of patients (n = 323) who underwent upfront debulking surgery (01/2011-07/2018). RPV was correlated with operability, survival and adjusted for well-established prognostic factors (age, postoperative residual disease, stage), and compared to previous validation models. Results The distribution of low, medium and high RPV scores was 54.2% (n = 175), 33.4% (n = 108) and 12.4% (n = 40) across the cohort, respectively. High RPV scores independently associated with significantly worse progression-free survival (PFS) (HR = 1.69; 95% CI:1.06–2.71; P = 0.038), even after adjusting for stage, age, performance status and residual disease. Moreover, lower RPV was significantly associated with total macroscopic tumour clearance (OR = 2.02; 95% CI:1.56–2.62; P = 0.00647). Conclusions RPV was validated to independently identify those HGSOC patients who will not be operated tumour-free in an optimal setting, and those who will relapse early despite complete tumour clearance upfront. Further prospective, multicentre trials with a translational aspect are warranted for the incorporation of this radiomics approach into clinical routine

Retinoblastoma with and without Extraocular Tumor Extension: A Global Comparative Study of 3435 Patients

PURPOSE: To study the treatment and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). DESIGN: Multicenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naive patients. Cases with microscopic orbital extension detected postenucleation were excluded from the study. PARTICIPANTS: \ud A total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE. INTERVENTION: Chemotherapy, enucleation, exenteration, radiotherapy. MAIN OUTCOME MEASURES: Systemic metastasis and death. RESULTS: Of the 3435 RB patients included in this study, 309 (9%) were from low-income countries (LIC), 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from LIC, 197 (6%) lower-middle income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (P = 0.0001). The outcomes were statistically significant for RB-EOE compared with RB-w/o-EOE: systemic metastasis (32% vs. 4% respectively; P = 0.0001) and metastasis-related death (63% vs. 6% respectively; P = 0.0001). Multimodal treatment was the most common form of treatment (n = 177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n = 97; 30%). Adjuvant external beam radiotherapy (EBRT) after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan–Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk of death from RB-EOE was greater in patients aged >4 years than <2 years (hazard ratio, 2.912; P < 0.001) and for unimodal (surgery or intravenous chemotherapy) and bimodal (surgery and intravenous chemotherapy) treatment than trimodal treatment (surgery, intravenous chemotherapy, and EBRT) (hazard ratio, 2.023; P = 0.004 and hazard ratio, 1.819; P = 0.027, respectively). CONCLUSIONS: Retinoblastoma with extraocular tumor extension is associated with a higher risk of metastasis and death. Patients with RB-EOE are likely to benefit from trimodal treatment (intravenous chemotherapy, surgery, and EBRT) rather than treatment protocols excluding EBRT. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article

Molecular mechanisms of vaspin action: from adipose tissue to skin and bone, from blood vessels to the brain

Visceral adipose tissue derived serine protease inhibitor (vaspin) or SERPINA12 according to the serpin nomenclature was identified together with other genes and gene products that  were specifically expressed or overexpressed in the intra abdominal or visceral adipose tissue  (AT) of the Otsuka Long-Evans Tokushima fatty rat. These rats spontaneously develop visceral  obesity, insulin resistance, hyperinsulinemia and ‐glycemia, as well as hypertension and thus represent a well suited animal model of obesity and related metabolic disorders such as type  2 diabetes.  The follow-up study reporting the cloning, expression and functional characterization of  vaspin suggested the great and promising potential of this molecule to counteract obesity induced insulin resistance and inflammation and has since initiated over 300 publications, clinical and experimental, that have contributed to uncover the multifaceted functions and molecular mechanisms of vaspin action not only in the adipose, but in many different cells, tissues and organs. This review will give an update on mechanistic and structural aspects of vaspin with a focus on its serpin function, the physiology and regulation of vaspin expression, and will summarize the latest on vaspin function in various tissues such as the different adipose tissue depots as well as the vasculature, skin, bone and the brain

EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy

Background Overexpression of the EVI1 (ecotropic viral integration site 1) oncogene has recently been implicated as a prognostic factor in breast cancer (BC), particularly in triple-negative BC (TNBC). In this study we aimed to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy. Methods EVI1 expression was determined by immunohistochemistry using H-score as a cumulative measurement of protein expression in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 was analyzed as a continuous variable and dichotomized into low or high based on median expression. Endpoints were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Results Of the 993 tumors analyzed, 882 had available subtype information: 50.8% were HR + /HER2-, 15% HR + /HER2 + , 9.8% HR-/HER2 + , and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5–291.4). High EVI1 expression was significantly associated with smaller tumor size (p = 0.002) but not with BC subtype. Elevated EVI1 levels were not significantly associated with therapy response and survival in the entire cohort or within BC subtypes. However, TNBC patients with high EVI1 showed a trend towards increased pCR rates compared to low group (37.7% vs 27.5%, p = 0.114; odds ratio 1.60 (95%CI 0.90–2.85, p = 0.110) and numerically better DFS (HR = 0.77 [95%CI 0.48–1.23], log-rank p = 0.271) and OS (HR = 0.76 [95% 0.44–1.31], log-rank p = 0.314) without reaching statistical significance. Conclusion EVI1 was not associated with response to neoadjuvant therapy or patient survival in the overall cohort. Further analyses are needed to verify our findings especially in the pathological work-up of early-stage HER2-negative BC patients