The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related ...anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRAL
neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRAL
neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.
Kidney cancer has been increasing 1.7% annually. Renal cell carcinoma is the most common kidney cancer and it can metastasize. Our aim was to analyze patients treated with stereotactic body radiation ...therapy of renal cell carcinoma metastases.
A total of 58 patients (73 lesions) were treated from 2004 to 2016. Patients were candidates for analysis if a maximum of 3 metastases were diagnosed and the primary tumor was resected. Toxicity was classified according to Common Terminology Criteria for Adverse Events version 3.
All patients had renal cell carcinoma, in particular the clear cell type in 82.7%. A total of 39 metastases (53.4%) were located in the lungs and 19 (26%) were in the lymph nodes. Less common were metastases to bone (9.5% of cases), the liver (4.1%) and the adrenal gland (6.8%). Median followup was 16.1 months (range 3.5 to 157.1). The local control rate at 12 and 18 months was 90.2% and 90.2%, respectively. The progression-free survival rate at 12 and 18 months was 46.2% (95% CI 32.2-59) and 35% (95% CI 21.4-48.9), respectively. On univariate and multivariable analyses metachronous and single metastases predicted better progression-free survival. Systemic therapy before stereotactic body radiation therapy predicted improved local control in clear cell cases.
Stereotactic body radiation therapy can be considered a safe approach and it provides effective local control of oligometastatic renal cell carcinoma. However, future prospective studies are necessary to evaluate the impact on survival and quality of life.
to find clinical features that can predict prognosis in patients with oligometastatic disease treated with stereotactic body radiotherapy (SBRT)
Patients with less than 5 metastases in less than 3 ...different body sites were included in the analysis. Various clinical and treatment parameters were analyzed to create a Cox proportional hazard model for Overall Survival (OS). Subsequently, significant variables were used to create a score
997 patients were analyzed. Median OS was 2.61 years, 1 and 3 years OS was respectively 85% and 43%. Location of the primary tumor, performance status, site of irradiated metastases, presence of extratarget non irradiated lesions and RT dose were significant prognostic factors for OS. These parameters were used to create a score and to distinguish three different classes, with median OS of 5.67 years in low risk, 2.47 years in intermediate risk and 1.82 years in high risk group.
moving from easily accessible clinical parameters, a score was created to help the physician's decision about the better treatment or combination of treatments for the individual patient.
Alzheimer disease (AD) is the most common form of neurodegenerative dementia. Amyloid-β deposition, neurofibrillary tangle formation, and neuro-inflammation are the major pathogenic mechanisms that ...in concert lead to memory dysfunction and decline of cognition. Palmitoylethanolamide (PEA) is the naturally occurring lipid amide between palmitic acid and ethanolamine. Despite its clear role in inflammation and pain control, only limited in vitro evidence exist about a role for PEA in neurodegenerative diseases. Here we describe the neuroprotective activities of PEA in mice injected intracerebroventricularly with amyloid-β 25-35 (Ab25-35) peptide (9 nmol). We used spatial and non-spatial memory tasks to evaluate learning and memory dysfunctions. Ab25-35 injection significantly impaired spontaneous alternation performances, water maze spatial reference and working-like memory, and novel object recognition test. PEA was administered once a day (3-30 mg/kg, subcutaneously), starting 3 h after Ab25-35, for 1 or 2 weeks. PEA reduced (10 mg/kg) or prevented (30 mg/kg) behavioral impairments induced by Ab25-35 injection. PEA failed to rescue memory deficits induced by Ab25-35 injection in peroxisome proliferator-activated receptor-α (PPAR-α) null mice. GW7647 (2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid; 5 mg/kg per day), a synthetic PPAR-α agonist, mimicked the effect of PEA. Acute treatment with PEA was ineffective. According with the neuroprotective profile of PEA observed during behavioral studies, experimental molecular and biochemical markers induced by Ab25-35 injection, such as lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, and caspase3 activation, were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, unrevealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.
Proopiomelanocortin (POMC) is a polypeptide hormone precursor that is expressed in the brain and in peripheral tissues such as in the pituitary gland, immune system, and skin. In the brain, POMC is ...processed to form several peptides including alpha-melanocyte stimulating hormone (α-MSH). alpha-MSH is expressed in the hypothalamic arcuate nucleus and in the nucleus tractus solitarius of the brainstem where it has a crucial role in the regulation of metabolic functions. Specifically, α-MSH is an anorexigenic peptide. Its production and maturation processes have been shown to be regulated according to the metabolic condition of the organism. This review summarizes our current knowledge on α-MSH processing including its maturation and degradation processes and pharmacological aspects of its manipulation.
The ONE SHOT trial is the first phase I/II prospective, multicenter, single-arm study assessing the efficacy and safety of a single-dose SBRT for men with localized prostate cancer. Aim of this paper ...is to present the phase I results of a 19 Gy single fraction urethra-sparing SBRT with real-time electromagnetic tracking.
Emerging evidence suggests that epigenetic mechanisms are involved in different brain functions such as the development of the nervous system and normal neuronal function. At the same time, it has ...been proposed that several neurological diseases are in part, caused by aberrant epigenetic modifications. Nevertheless, the mechanisms underlying pathological alterations in the brain genome are not completely understood.
Post-transcriptional histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are a family of proteins involved in both physiological and pathological conditions by regulating the status of chromatin histone acetylation. It is now becoming clear that epigenetic regulatory mechanisms may also play a major role in epilepsy; modulation of chromatin structure through histone modifications has emerged as an important regulator of gene transcription in the brain and altered histone acetylation seems to contribute to changes in gene expression associated with epilepsy and the epileptogenic process. Histone modification is crucial for regulating neurobiological processes such as neural network function, synaptic plasticity, and synaptogenesis which also contribute to the pathophysiology of epilepsy.
The role of epigenetics in epilepsy development is a new and emerging research area; the present article reviews the recent findings on the role played by HDACs and the possible function of different histone modifications in epilepsy and epileptogenesis. Inhibitors of HDACs (HDACIs) have been tested in different experimental models of epilepsy with some success. We also review the results from these studies, which indicate HDACIs as potential new therapeutic agents for the treatment of human epilepsy.
Purpose
For patients with oligometastatic/oligorecurrent/oligoprogressive lymph node metastases from PCa, metastases-directed therapy is an emerging strategy. The aim of this retrospective study was ...to evaluate the oncological outcome and pattern of recurrence in patients treated with stereotactic body radiation therapy (SBRT) to lymph node metastases.
Methods
In this multi-institutional analysis, patients with a maximum of five lymph node metastases from PCa treated with SBRT were included. Primary endpoints of the analysis were local control (LC), out-of-field nodal progression-free survival (NPFS), overall progression-free survival (PFS), and overall survival (OS).
Results
109 patients and 155 lymph node metastases were evaluated. Patients’ median age was 70.8 years (range 51–84) and median PSA before SBRT was 1.88 ng/ml (range 0.3–45.5 ng/ml). The dose delivered to the target ranged from 25 to 48 Gy in 4–7 fractions; median BED
1.5
Gy
was 198 Gy (range 108.3–432 Gy). With a median follow-up of 16 months, LC rates at 1 and 3 years were 93% and 86%, respectively. In-field progression of disease was observed in 11 (7%) lesions. One- and 3‑year NPFS was 59% and 29%, and median NPFS was 15 months. Rates of OS at 1 and 3 years were 100% and 95%. The median time to administration of a systemic treatment after SBRT was 7.8 months (1.7–54.8).
Conclusion
SBRT is an effective and well-tolerated treatment option in the management of lymph node metastases from PCa. Prospective trials are necessary to better select patients who benefit most from this ablative focal treatment and better define the recurrence patterns.
Background
In 2016 we published a phase II study exploring safety and efficacy of Stereotactic Body Radiation Therapy (SBRT) delivered with Volumetric Modulated Arc Therapy (VMAT) and Flattening ...Filter Free (FFF) beams techniques in prostate cancer (PC) patients. We present herein the updated results on late toxicity and long‐term survival.
Methods
Patients enrolled in the study had a biopsy‐confirmed localized PC and the features of a low‐ or intermediate‐risk disease (National Comprehensive Network Criteria). The radiotherapy (RT) schedule consisted of 35 Gy delivered in five fractions every other day. Toxicities were registered according to the common toxicity adverse events v4.0. Biochemical recurrence was defined as an increase of prostate specific antigen after nadir, confirmed at least once. Local recurrence (LR) and distant metastases were detected either with Choline‐ or PSMA‐PET/CT scans.
Kaplan‐Meier curves for Biochemical Recurrence‐Free Survival (BFS), Local Control (LC), Distant Metastasis Free Survival (DMFS) and Cancer Specific Survival, were calculated by using MedCalc.
Results
Ninety patients were submitted to SBRT between February 2012 and March 2015. Fifty‐eight patients (64.5%) had a Gleason Score of 6, while 32 (35.5%) had a Gleason Score of 7. A late grade 1 Genito‐Urinary toxicity was observed in 54.5% of patients while a grade 2 in 3.3%. A late Gastro‐intestinal grade 1 toxicity was reported in 18.9% of patients, while a grade 2 in 2.2%. Erectile dysfunction was reported by 13% of patients No heavier toxicities were observed. At a median follow‐up of 102 months, 5‐ and 8‐year BFS were 93.0% and 84.4% respectively, 5‐ and 8‐year LC were 95.2% and 87.0% respectively, 5‐ and 8‐year DMFS were 95.3% and 88.4%, respectively.
Conclusions
This long‐term update confirms that SBRT is a valid therapeutic strategy for low‐intermediate risk PC. RT with VMAT and FFF warrants optimal results in terms of toxicity and disease control.
Stereotactic body radiation treatment represents an intriguing therapeutic option for patients with early-stage prostate cancer. In this phase II study, stereotactic body radiation treatment was ...delivered by volumetric modulated arc therapy with flattening filter free beams and was gated using real-time electromagnetic transponder system to maximize precision of radiotherapy and, potentially, to reduce toxicities.
Patients affected by histologically proven prostate adenocarcinoma and National Comprehensive Cancer Network (NCCN) intermediate class of risk were enrolled in this phase II study. Beacon transponders were positioned transrectally within the prostate parenchyma 7 to 10 days before simulation computed tomography scan. The radiotherapy schedule was 38 Gy in 4 fractions delivered every other day. Toxicity assessment was performed according to Common Terminology Criteria for Adverse Events (CTCAE), v4.0.
Thirty-six patients were enrolled in this study. Median initial prostate-specific antigen was 7.0 ng/mL (range: 2.3 to 14.0 ng/mL). Median nadir-prostate-specific antigen after treatment was 0.2 ng/mL (range: 0.006 to 4.8 ng/mL). A genitourinary acute toxicity was observed in 21 patients (dysuria grade G 1: 41.7%, G2: 16.7%). Gastrointestinal acute toxicity was found in 9 patients (proctitis G1: 19.4%, G2: 5.6%). Late toxicity was mild (genitourinary toxicity G1: 30.6%; G2: 8.3%; gastrointestinal toxicity G1: 13.9%; G2: 19.4%). At a median follow-up time of 41 months, 3 biochemical recurrences were observed (2 local recurrences, 1 distant metastasis). Three-year biochemical recurrence-free survival was 89.8% (International Society of Urologic Pathology Grade Group 2: 100%, Grade Group 3: 77.1%, P=0.042).
Ultrahypofractionated radiotherapy, delivered with flattening filter free-volumetric modulated arc therapy and gated by electromagnetic transponders, is a valid option for intermediate-risk prostate cancer.
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