Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers.

The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib and pralsetinib has led to a paradigm change in the treatment of RET-altered lung and thyroid cancers through a higher response rate and a more tolerable safety and toxicity profile than multi-kinase inhibitors. Recently, selpercatinib has received a tissue-agnostic FDA approval for all RET-fusion-positive cancers, and pralsetinib has shown pan-cancer activity as well. Given the anticipated increase in the use of both drugs across multiple tumor types, it is crucial to recognize the possible side effects and approaches for their optimal management in order to maximize the clinical benefit for treated patients. In this review, we underscore potential toxicities associated with selective RET inhibitors and discuss strategies to mitigate them.

The immune landscape of undifferentiated pleomorphic sarcoma.

Introduction: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. Material and methods: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. Results: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001). Conclusion: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

Hypotensive activity of terpenes found in essential oils.

The cardiovascular activity of essential oils has been reported. Some studies showed that the main chemical components of these oils contribute to their pharmacological activity. Therefore, the cardiovascular activity of four monoterpenes and one sesquiterpene was evaluated in the present work. In non-anaesthetized normotensive rats, (+)-alpha-pinene, (-)-beta-pinene, (+/-)-citronellol and (+/-)-linalool (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-35 +/- 3)%, (-46 +/- 4)%, (-48 +/- 2)% and (-40 +/- 2)%, respectively; n=6] and tachycardia [maximal effect: (13 +/- 4)%, (16 +/- 7)%, (21 +/- 1)% and (19 +/- 3)%, respectively; n=6] while (-)-a-bisabolol (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-47 +/- 8)%, n=6] and bradycardia [maximal effect: (-57 +/- 3)%]. In conclusion, these results demonstrated that all terpenes tested had hypotensive activity in rats and that the pharmacological effect of the terpene alcohols was more effective than that of the terpene hydrocarbons.