Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

The mechanistic target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AkT)/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis) and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs.

Emerging antibodies for the treatment of pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC. Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment. This review will underline the most important targeted pathways by mAbs involved in this disease, including EGFR, HER-2, IGF-1 R, VEGF/VEGFR, NOTCH, WNT and immune checkpoints. Expert opinion: Despite the promising results of preclinical and phase I trials, the addition of mAbs to standard chemotherapy or in association with other target agents seems not to confirm these results in the following phase II and III trials in pancreatic cancer patients. However, an improved patient selection before treatment based on molecular characteristics in association with reliable predictive biomarkers can identified more efficacious treatment approaches, minimizing toxicity profile of these drugs.

Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.

Effects of 24/7 palliative care consultation availability on the use of emergency department and emergency medical services resources from non-oncological patients: a before-and-after observational cohort study.

OBJECTIVES: The non-oncological population is relatively under-represented among end-of-life (EOL) patients managed by palliative care (PC) services, and the effects of different PC delivery models are understudied in this population.This retrospective observational study on routinely collected data aimed at evaluating the effects of the extension from workday-only to 24/7 mixed hands-on and advisory home PC service on emergency department (ED) access and emergency medical services (EMS) interventions needed by non-oncological patients during their last 90 days of life, and their probability to die in hospital. METHODS: A before-and-after design was adopted comparing preimplementation and postimplementation periods (2018-2019 and 2021-22).We used a difference-in-differences approach to estimate changes in ED access and EMS intervention rates in the postintervention period through binomial negative regression. The oncological population, always exposed to 24/7 PC, was used as a control. A robust Poisson regression model was adopted to investigate the differences regarding hospital mortality. The analyses were adjusted for age, sex and disease grouping by the system involved. Results were reported as incidence rate ratios (IRRs) and ORs. RESULTS: A total of 2831 patients were enrolled in the final analysis.After the implementation of 24/7 home PC, both ED admissions (IRR=0.390, p<0.001) and EMS interventions (IRR=0.413, p<0.001) dropped, as well as the probability to die in hospital (OR=0.321, p<0.001). CONCLUSIONS: The adoption of a 24/7 mixed hands-on and advisory model of home PC could have relevant effects in terms of ED access and EMS use by non-oncological EOL patients under PC. TRIAL REGISRATION NUMBER: NCT05640076.

Prognostic Value of 68Ga-DOTANOC PET/CT SUVmax in Patients with Neuroendocrine Tumors of the Pancreas.

UNLABELLED: This study was performed to investigate the role of (68)Ga-DOTANOC SUVmax as a potential prognostic factor in patients with pancreatic neuroendocrine tumor (pNET). METHODS: Among the patients who underwent (68)Ga-DOTANOC PET/CT, we retrospectively collected the data of those who had G1 or G2 pNET (2010 World Health Organization classification), presented with disease on PET/CT and CT, and had at least 6 mo of follow-up. Patients with multiple endocrine neoplasia were excluded. RESULTS: Overall, 43 patients were included. No significant differences in SUVmax were observed with respect to sex, tumor syndrome, stage, World Health Organization classification, or Ki-67. During follow-up (median, 20 mo), 11 patients (35.6%; median, 33 mo; interquartile range, 20-48 mo) had stable disease and 32 (74.4%; median, 19 mo; interquartile range, 14-26 mo) had progressive disease. SUVmax at 24 mo of follow-up was significantly higher (P = 0.022) in patients with stable disease than in patients with progressive disease. The best SUVmax cutoff ranged from 37.8 to 38.0. The major risk factors for progression included an SUVmax of no more than 37.8 (hazard ratio, 3.09; P = 0.003), a Ki-67 of more than 5% (hazard ratio, 2.89; P = 0.009), and medical therapy alone (hazard ratio, 2.36; P = 0.018). Advanced stage (IV) (P = 0.026), an SUVmax of less than 37.8 (P = 0.043), and medical therapy alone (P = 0.015) were also confirmed at multivariate analysis. Median progression-free survival was 23 mo. Significant differences in progression-free survival were observed in relationship to Ki-67 (median, 45 mo for Ki-67 ≤ 5% and 20 mo for Ki-67 > 5%; P = 0.005), SUVmax (<37.8 vs. >38.0: 16.0 vs. 27.0 mo; P = 0.002), and type of therapy (medical vs. peptide receptor radionuclide therapy: 16.0 vs. 26.0 mo; P = 0.014). CONCLUSION: (68)Ga-DOTANOC SUVmax is a relevant prognostic factor in patients with G1 and G2 pNET, and its routine use will improve disease characterization and management in these patients, who may present with atypical cases showing heterogeneous clinical behavior.