Targeting the Mevalonate Pathway for Treating Lung Cancer.

The mevalonate (MVA) pathway is a key metabolic pathway involved in various important cellular functions. Its downstream products are critical for cell-signaling, cell membrane integrity, protein synthesis, and cellular respiration. The rate-limiting enzyme of this pathway is targeted by statins, a class of medications best known for their lipid-lowering effects. Many studies have shown that a variety of cancerous cells have a dysregulated MVA pathway. Lung cancer is responsible for a third of all cancer-related deaths worldwide. As our understanding of the molecular mechanisms driving the pathogenesis of lung cancer improves, newer therapeutics have been proposed. However, these medications have not had the expected benefits for all subtypes of lung cancer. Therefore, there exists a significant role in identifying medications with safe profiles, which can potentially be used in managing various types of lung cancer. Herein, we review whether there is a role in utilizing statins to target the MVA pathway in treating lung cancer.

Extended-arch repair for acute type-A aortic dissection: perioperative and mid-term results.

OBJECTIVES: Extended-arch techniques offer the potential to comprehensively treat acute type-A aortic dissection (ATAAD), but add surgical complexity compared to the standard hemiarch technique. This study describes both perioperative and mid-term outcomes following the introduction of an extended-arch technique for ATAAD. METHODS: Ours is a retrospective single-centre observational study of 95 consecutive patients with ATAAD from 2011 to 2016. The decision to perform extended-arch or hemiarch repair was individualized based on clinical and radiological features. Extended-arch repair was defined as replacement of the ascending aorta and arch with reimplantation of head vessels with or without distal endovascular extension. Clinical follow-up was 100% complete. Cross-sectional double-oblique measurements were performed for aortic remodelling analysis. RESULTS: Extended-arch (n = 28) and hemiarch (n = 67) repair resulted in a in-hospital mortality of 10% (n = 3) and 10%, (n = 7), and permanent neurological deficit rate of 7% and 12%, respectively. At a mean imaging follow-up duration of 2.7 ± 1.5 years, false lumen thrombosis was achieved in 57% and 9% of patients undergoing extended-arch and hemiarch repair, respectively. Rate of growth in the proximal descending aorta was 0.7 ± 2.3 mm/year in the extended-arch group vs 2.7 ± 3.9 mm/year in the hemiarch group. At a mean clinical follow-up time of 3.0 ± 1.6 years, open surgical aortic reoperation was 0% in the extended-arch group and 22% in the hemiarch group. CONCLUSIONS: Extended-arch repair of ATAAD can be introduced in the acute setting without increase in perioperative mortality or morbidity. At mid-term follow-up, extended-arch for ATAAD improves aortic remodelling and reduces the need for open surgical reoperation.

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.