Functional In Vitro Assessment of VEGFA/NOTCH2 Signaling Pathway and pRB Proteasomal Degradation and the Clinical Relevance of Mucolipin TRPML2 Overexpression in Glioblastoma Patients.

Glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high vascularization and its growth depends on the formation of new blood vessels. We have previously demonstrated that TRPML2 mucolipin channel expression increases with the glioma pathological grade. Herein by ddPCR and Western blot we found that the silencing of TRPML2 inhibits expression of the VEGFA/Notch2 angiogenic pathway. Moreover, the VEGFA/Notch2 expression increased in T98 and U251 cells stimulated with the TRPML2 agonist, ML2-SA1, or by enforced-TRPML2 levels. In addition, changes in TRPML2 expression or ML2-SA1-induced stimulation, affected Notch2 activation and VEGFA release. An increased invasion capability, associated with a reduced VEGF/VEGFR2 expression and increased vimentin and CD44 epithelial-mesenchymal transition markers in siTRPML2, but not in enforced-TRPML2 or ML2-SA1-stimulated glioma cells, was demonstrated. Furthermore, an increased sensitivity to Doxorubicin cytotoxicity was demonstrated in siTRPML2, whereas ML2-SA1-treated GBM cells were more resistant. The role of proteasome in Cathepsin B-dependent and -independent pRB degradation in siTRPML2 compared with siGLO cells was studied. Finally, through Kaplan-Meier analysis, we found that high TRPML2 mRNA expression strongly correlates with short survival in GBM patients, supporting TRPML2 as a negative prognostic factor in GBM patients.

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

Healthcare cost of HER2-positive and negative breast tumors in the United States (2012-2035).

BACKGROUND: In this study, we estimated the current and future costs related to the use of targeted agents in patients with HER2-positive and negative advanced breast cancer (BC), aimed at identifying the subgroup associated with the higher cost in the coming years. METHODS: We calculated the patient cost considering an ideal patient who received therapeutic sequences including all approved agents for HER2-positive or negative BC. The duration of treatment was estimated by the median Progression-Free Survival (PFS) reported in the phase III trials which have led to the approval of these drugs by the US Food and Drug Administration. The estimated number of BC patients in the US from 2012 to 2035 refers to data published by the World Health Organization. RESULTS: The per patient cost was $292,155 for HER2-positive and $224,955 for negative tumors, respectively. The total cost for HER2-positive patients was estimated for 2012 at $2,719,542,347, with an annual increase ranged from 4.3 (for 2035) to 7.7% (for 2020), leading to a total expense of $3,648,232,975 in 2035. Otherwise, the total cost for HER2-negative patients in 2012 was estimated as $8,376,028,459, with an increase of more than $2.5 billion from 2012 to 2035. The estimated cost for HER2-negative patients was $5.6 billion higher that for HER2-positive tumors, raising to $7.6 billion to 2035. CONCLUSIONS: Our data strongly suggest that cost-analyses should be carefully evaluated in the coming years, in particular in patients with HER2-negative tumors.

Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients: Recent insights and future challenges.

Anti-programmed death (PD)-1 agents pembrolizumab and nivolumab have recently obtained enthusiastic results in terms of progression-free survival (PFS), overall survival (OS) and tolerability in cancer patients. Despite these promising data, the high cost of these agents needs careful consideration. Indeed, the evaluation of cost-effectiveness analysis (CEA) and quality-adjusted life year (QALY), as well as different drug reimbursement modalities, will represent fundamental tools in order to guarantee the economic sustainability of health system and the access to care for all cancer patients. In this review, we discussed the recent results obtained by immunotherapy in cancer patients and we evaluated the economic impact of recently approved nivolumab and pembrolizumab in patients with advanced melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC).