Involvement of PAR-4 in Cannabinoid-Dependent Sensitization of Osteosarcoma Cells to TRAIL-Induced Apoptosis

The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface

The Challenge of Evaluating Response to Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic Neuroendocrine Tumors: The Present and the Future

The NETTER-1 study has proven peptide receptor radionuclide therapy (PRRT) to be one of the most effective therapeutic options for metastatic neuroendocrine tumors (NETs), improving progression-free survival and overall survival. However, PRRT response assessment is challenging and no consensus on methods and timing has yet been reached among experts in the field. This issue is owed to the suboptimal sensitivity and specificity of clinical biomarkers, limitations of morphological response criteria in slowly growing tumors and necrotic changes after therapy, a lack of standardized parameters and timing of functional imaging and the heterogeneity of PRRT protocols in the literature. The aim of this article is to review the most relevant current approaches for PRRT efficacy prediction and response assessment criteria in order to provide an overview of suitable tools for safe and efficacious PRRT

The antitumour activity of diorganotin(IV) complexes with adenine and glycylglycine

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Is it Possible to avoid rh-TSH test in Patients with Differentiated Thyroid Carcinoma by Using the Association between Ablation and Suppressive Thyroglobulin?

Background: The follow-up of differentiated thyroid cancers is based on neck ultrasonography and serum thyroglobulin assay (Tg), during l-T4 therapy and after recombinant human TSH administration; this test appears quite expensive, considering that only a small percentage of patients with undetectable Tg on TSH suppression therapy shows a response after TSH stimulation. Objectives: The aim of our study was to verify whether low levels of serum thyroglobulin at the time of remnant ablation (A-Tg) associated with undetectable thyroglobulin levels on TSH suppression (S-Tg), have sufficient negative predictive value for recurrence of disease, thus avoiding rh-TSH test in Differentiated Thyroid Cancer patients. Methods: we retrospectively enrolled 975 DTC patients treated with thyroidectomy+131-I remnant ablation showing undetectable S-Tg measured after 12 months follow-up. The availability of A-Tg and rh-TSH stimulated Tg (R-Tg) obtained 1 year later were considered as inclusion criteria. Patients with positive circulating Ab-Tg and/or histological dedifferentiation were excluded. Patients were subdivided in high and low risk of recurrence according to the criteria proposed by the European Thyroid Cancer Taskforce. Results: Using rh-TSH test as gold standard, the NPV for A-Tg<10 μg/L was 98.5% in group A (low risk patients) and 95.5% in group B (high risk patients); it significantly raised to 99.2% in group A (p-value 0.03) and 99.3% in group B (p-value 0.02) when the association between A-Tg<10 μg/L and S-Tg<0.6 μg/L was considered. When we evaluated the whole population the negative predictive value was 97% for A-Tg<10 μg/L alone, raising to 99.3% when associated with S-Tg<0.6 μg/L (p-value<0.008). Conclusion: our data confirmed the very high negative predictive value of the association between low levels of A-Tg and undetectable S-Tg in the early risk stratification of differentiated thyroid cancer patients, leading to avoid rh-TSH test with an important economic impact

Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study

Purpose: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. Methods: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. Results: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. Conclusion: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. Study registration: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1