BRAFV600E mutation is highly prevalent in patients with papillary thyroid carcinoma (PTC), and TERT promoter (TERTp) mutation is strongly associated with cancer‐related mortality. However, predictive power of the two mutations remains inconclusive. We aimed to verify the prognostic effects of both mutations to assess the value of mutation detection for risk stratification in terms of PTC prognosis and tumour invasion, to guide PTC diagnosis and treatment. We conducted a literature search in the MEDLINE (PubMed), EMBASE, Web of Science and CENTRAL (Cochrane library) databases, from inception to February 2020. Basic characteristics, prognoses and clinicopathological features were collected from the included studies for further analysis. Twelve studies involving 4184 PTC patients were enrolled in our analysis. In total, 2412 (57.6%) of the patients carried either BRAFV600E or TERTp mutation, and 290 (6.9%) patients had both mutations. TERTp mutation was more common in patients with BRAFV600E mutation (RR = 1.75 [95% CI 1.44‐2.13]). Patients with both mutations had a worse prognosis compared with those with a single mutation (vs BRAFV600E only: RR = 5.34 [4.20‐6.78] vs TERTp only: RR = 2.12 [1.41‐3.19]). TERTp mutation alone independently increased the risk of a poor prognosis (RR = 2.90 [1.93‐4.35]) in terms of mortality (RR = 15.09 [7.75‐29.37]), disease persistence (RR = 4.00 [2.03‐7.90]), recurrence (RR = 4.34 [4.20‐6.78]), lymph node metastasis (RR = 1.57 [1.24‐1.99]) and distant metastasis (RR = 2.94 [1.13‐7.65]). We found that PTC patients with BRAFV600E mutation were more likely to have TERTp mutation. TERTp mutation was an independent predictive factor for poor prognosis of PTC patients, but the predictive value of BRAFV600E mutation remains inconclusive. Patients with both mutations have remarkably higher risks of adverse outcomes compared with those with a single mutation. PTC patients could benefit from mutation detection for aiding risk stratification (BRAF + TERT+ > BRAF − TERT+ > BRAF + TERT−).
Purpose D3 lymphadenectomy for right colon cancer improves oncological outcomes. This meta-analysis aimed to compare operation data, histopathological characteristics, perioperative conditions, and long-term survival after D3 and D2 lymphadenectomy in right hemicolectomy. Methods We searched PubMed, Embase, and the Cochrane Library for relevant articles (up to March 31, 2020). Random-effects and fixed-effects meta-analysis models were used. Review Manager (RevMan) version 5.3 and Stata version 15.1 were used for pooled estimates. Results After screening 714 articles, 7 articles with a total of 1368 patients were eligible for inclusion. Compared with D2, D3 lymphadenectomy improves results in terms of blood loss (weighted mean difference [WMD] = −20.63, 95% confidence interval [CI] −28.19 to −13.16, P < .01), harvested lymph nodes (WMD = 8.86, 95% CI 7.74 to 9.98, P < .01), 3-year overall survival (OS) (hazard ratio [HR] = 2.03, 95% CI 1.20 to 3.43, P < .01), 5-year OS (HR = 2.22, 95% CI 1.15 to 4.30, P = .02), and 5-year disease-free survival (DFS) (HR = 2.16, 95% CI 1.19 to 3.90, P = .01). There was no significant difference regarding operation time, anastomosis leakage, wound infection, overall morbidity, postoperative hospital stay, mortality, length of dissected colon, and 3-year DFS ( P >= .05). Conclusions It is suggested in this review that D3 lymphadenectomy is superior to D2 lymphadenectomy in terms of blood loss, harvested lymph nodes, 3-year OS, 5-year OS, and 5-year DFS. The conclusion must be drawn with caution due to the limited number of included studies. Further RCTs are needed for stronger evidence.
BackgroundPapillary thyroid carcinoma (PTC) is the most common thyroid malignancy, but little is known regarding PTC metabolic phenotypes and the effects of mitochondrial activity on PTC progression. The great potential of mitochondria-targeting therapy in cancer treatment promoted us to use tool compounds from a family of Mito-Fu derivatives to investigate how the regulation of mitochondrial respiration affected tumor progression characteristics and molecular changes in PTC.MethodsMito-Fu L20, a representative of 12 synthetic derivatives, was chosen for mitochondrial inhibition experiments. Sample sections from PTC patients were collected and processed to explore potential molecular alterations in tumor lymph node metastasis (LNM). In vitro analyses were performed using human PTC cell lines (K1 and TPC-1), with the human normal thyroid follicular cell line (Nthy) as a control. K1 cells were injected into nude mice to generate an animal model. The mice were injected with normal saline or Mito-Fu L20 at 20 or 50 mg/kg every other day; their body weights and tumor volumes were also measured over time. To elucidate the resulting metabolic phenotype, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), cellular adenosine triphosphate (ATP) levels and reactive oxygen species (ROS) production, and mitochondrial membrane potential. Wound healing and Transwell assays, cell cycle assays, real-time fluorescence quantitative PCR, Western blotting, and immunohistochemical staining were performed to explore glycolysis-dominant metabolism in PTC.ResultsCyclin D1 and mitochondrial complex IV were detected in tumor samples from PTC patients with LNM. Mito-Fu L20 showed dose-independent and reversible modulation of mitochondrial respiration in PTC. In addition to mitochondrial dysfunction and early apoptosis, G1/S phase arrest. Notably, reversible mitochondrial inhibition yielded durable suppression of tumor proliferation, migration, and invasion via the PI3K/Akt/FoxO1/Cyclin D1 pathway. In vivo experiments demonstrated that Mito-Fu L20 has a good safety profile and specific restorative effect on mitochondrial activity in the liver. In addition, Mito-Fu L20 showed antitumor effects, alleviated tumor angiogenesis, and improved thyroid function.ConclusionReversible inhibition of ATP production and durable suppression of PTC growth indicates that the downregulation of mitochondrial function has a negative impact on tumor progression and LNM via the PI3K/Akt/FoxO1/Cyclin D1 pathway. The results provide new insights into the antitumor potential and clinical translation of mitochondrial inhibitors.
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