"On/off"-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX.

Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions. In this study, we address these challenges by designing a "on/off" switchable crosslinked paclitaxel (PTX) nanocarrier, BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct "on/off" switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The "off" state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the "on" state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.

The Coexistence of Genetic Mutations in Thyroid Carcinoma Predicts Histopathological Factors Associated With a Poor Prognosis: A Systematic Review and Network Meta-Analysis.

PURPOSE: Genetic mutations may play an important role in the progression and invasion of thyroid carcinoma (TC), and their coexistence may result in mutational synergy. The presence of the BRAFV600E mutation, as well as mutations affecting the TERT promoter, RAS, CHEK2 and RET/PTC, may all have an impact on prognosis. The aim of this study was to explore whether synergy between the coexistent mutations predicts histopathological prognostic factors that influence disease outcome. METHODS: A comprehensive literature search of PubMed, Embase and the Cochrane Library, from their inception until January 2020. Primary outcomes included: disease stage, lymph node metastasis, extrathyroidal extension and distant metastasis; while, secondary outcomes included: tumor recurrence, mortality, invasion of thyroid capsule, multiplicity, presented as an odds ratio (OR) with 95% credible intervals (CrI). RESULTS: 27 publications (comprising 9 active intervention arms), involving 8,388 TC patients, were selected. Network meta-analytic estimates of active interventions contrasted with other active interventions, with random effects, were calculated. In terms of outcomes focus on overall TC, BRAFV600E + TERT co-mutation ranked highest for diseases stage (OR = 5.74, 95% CrI: 3.09-10.66), as well as lymph node metastasis, extrathyroidal extension (5.74, 4.06-8.10), tumor recurrence (7.21, 3.59-14.47), and invasion of the thyroid capsule (3.11, 1.95-4.95). BRAFV600E + TERT co-mutation ranked secondary in distant metastasis, mortality, and multiplicity that ranked highest was TERT+RAS or RAS. When we were limited to the study of patients with papillary TC (PTC), BRAFV600E + TERT always ranked highest for primary outcomes: disease stage (6.39, 3.13-13.04), lymph node metastasis, extrathyroidal extension (5.80,3.89-8.64) and distant metastasis (7.33, 3.00-17.89), while BRAFV600E + TERT again ranked highest in secondary outcomes: tumor recurrence (7.23,3.37-15.51), mortality (9.26, 3.02-28.42), invasion of thyroid capsule (3.20,2.01-5.11), and multiplicity. CONCLUSIONS: In this molecular marker mutation-based systematic review and network meta-analysis, we found that coexistent BRAFV600E + TERT genetic co-mutations predicted poor histopathological prognosis, including progression, invasion, and metastasis, especially in PTC. For the overall TC, the BRAFV600E + TERT + RAS triple mutations may have a greater impact on the prognosis, and further research should related to potentially important features. This study is registered with PROSPERO, number CRD42019143242.

Clinical Analysis of Preoperative Anti-thyroglobulin Antibody in Papillary Thyroid Cancer Between 2011 and 2015 in Beijing, China: A Retrospective Study.

The anti-thyroglobulin antibody (TgAb) has been suggested to be more common in patients with papillary thyroid cancer (PTC). Here, we performed a retrospective study investigated the correlation between TgAb level and PTC in Chinese patients between 2011 and 2015. Patients with goiter who underwent thyroidectomy and received a confirmed pathological diagnosis were enrolled into the study. Clinical characteristics and preoperative thyroglobulin antibody (TgAb) level data were collected from all enrolled patients. Based on the preoperative TgAb test results, patients were divided into a TgAb negative (TgAb-) group (<60 IU/mL) and a TgAb positive (TgAb+) group (≧60 IU/mL). Of the 4,046 patients, 671 patients were TgAb+ while 3,375 patients were TgAb-. There were 535 (79.7%) patients with PTC in the TgAb+ group, and 2,154 (63.8%) patients with PTC in the TgAb- group. The prevalance of PTC was significantly higher in TgAb+ patients than in TgAb- patients. TgAb+ patients were stratified into four groups based on the TgAb titer. The prevalence of PTC did not increase with TgAb titer. No significant difference in TgAb level was noted in patients with different clinicopathologies, including TNM stage, lymph node metastasis, and multifocal carcinoma. Regression analysis suggested a higher risk of PTC malignancy among TgAb+ patients. Preoperative TgAb level ≥60 IU/mL might be associated with a higher risk of PTC. However, there was no titer-dependent association between elevated TgAb titer and PTC malignancy.

Association of obesity with the clinicopathological features of thyroid cancer in a large, operative population: A retrospective case-control study.

We aimed to investigate the association between excess body mass index (BMI) and papillary thyroid cancer (PTC) in an operative population, and the impact of higher BMI on clinicopathological aggressiveness of PTC.Charts of 10,844 consecutive patients with thyroid nodules undergoing partial or total thyroidectomy between 1993 and 2015 were reviewed. Patients diagnosed with PTC were stratified in 4 groups: BMI < 18.5 (underweight), 18.5 ≤ BMI < 24 (normal-weight), 24 ≤ BMI < 28 (overweight) and BMI ≥ 28(obese). The impacts of high BMI on prevalence and clinicopathological parameters of PTC were retrospectively analyzed in both univariate and multivariate binary logistic regression analysis.For every 5-unit increase in body mass, the odds of risk-adjusted malignance increased by 36.6%. The individuals who were obese and overweight were associated with high risk of thyroid cancer [odds ratio (OR)= 1.982, P < .001; OR= 1.377, P < .001; respectively] compared to normal weight patients, and this positive association was found in both genders. Obesity was independent predictors for tumors larger than 1 cm (OR = 1.562, P < .001) and multifocality (OR = 1.616, P < .001). However, there was no difference in cervical lymph node (LN) metastasis among BMI groups. Crude analysis showed BMI was associated with advanced tumor-node-metastasis (TNM) stage (relative risk, approximately 1.23 per 5 BMI units, P < .001), but this association disappeared after adjusting for confounding factors.Obesity was significantly associated with the risk of PTC in a large, operative population. Higher BMI was significantly associated with larger tumor size and multifocal tumor.