RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyperrecombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers. Cancer Res; 71(13); 4598-607. Ó2011 AACR.
Heparin increased the haematoma formation, but did not change the incidence of free-flap failure. Thus, the intravenous low-dose heparin use does not affect microvascular flap survival.
Programmed cell death protein-1 (PD-1) blockade therapy has improved outcomes in the treatment of advanced cancers. The therapy is well-tolerated, although it occasionally causes immune-related adverse events (irAEs). Thyroid dysfunction is one of the most common irAEs seen. Our aim was to clarify the clinical characteristics of thyroid dysfunction induced by PD-1 blockade and its association with the therapeutic effect of the treatment in advanced cancers. A total of 174 patients who received nivolumab or pembrolizumab for metastatic or unresectable advanced cancers were included in this retrospective study. The patients were divided into two groups: The thyroid dysfunction group and the euthyroid group. In the present study, the clinical characteristics, the association with anti-thyroid antibodies, as well as the progression-free survival (PFS) and overall survival (OS) were estimated. An adjusted Cox proportional hazard regression model was used to evaluate prognostic factors for OS and PFS. This study showed that 25 out of 150 patients (16.7%) developed immune-related thyroid dysfunction. Hypothyroidism occurred in the early stage of the clinical course (median: 12 weeks); subsequently, 9 of the 25 patients underwent a transient period of hyperthyroidism, all with mild symptoms. The presence of positive anti-thyroid antibodies at baseline was significantly higher in the thyroid dysfunction group (13/22) than in the euthyroid group (18/100, P=0.0002). Moreover, PFS (median: 66 vs. 27 weeks, hazard ratio (HR): 0.50, 95% CI: 0.26-0.89, P=0.02) and OS (median 156 vs. 59 weeks, HR: 0.34, 95% CI: 0.13-0.75, P=0.01) were significantly longer in the thyroid dysfunction group than in the euthyroid group. Multivariable analysis also revealed that thyroid dysfunction was an independent prognostic factor for OS (HR: 0.42, 95% CI: 0.16-0.97, P=0.04). These findings may enable the early recognition and appropriate management of thyroid dysfunction, and help in maximizing the therapeutic effect of PD-1 blockade.
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