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1.
Cancer Discov ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947663

RESUMO

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast DCIS, and in pre-invasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx pre-invasive to invasive NSCLC lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models, revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in pre-invasive disease, providing fuel for selection early in cancer evolution.

2.
Thorac Cancer ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33939309

RESUMO

BACKGROUND: Little is known about the prognostic advantage of sex for pulmonary adenocarcinoma among Chinese patients. In this study, we aimed to investigate the true sex differences in prognosis by adjusting for confounders and to explore whether the differences were time-varying. METHODS: We identified 4438 lung adenocarcinoma patients who underwent surgery at a regional Cancer Center of China from 2008 to 2016, retrospectively. Sex, age group, smoking history, year of diagnosis and pathological stage were collected. Time-dependent Cox regression models with inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of sex and account for confounders. Landmark analyses were conducted to assess survival before, and after, five years. RESULTS: Of these patients, 1761 (39.7%) were men and 2677 (60.3%) were women. Median follow-up time was 52.6 months. After IPTW adjustment, women were found to have significantly better survival than men varying with time in both crude and IPTW models (hazard ratio [HR] [t] = 0.453*1.015t , where t is the length of time from treatment and its unit is month, p < 0.001). Women had significantly better survival than men within 0-5 years after surgery (HR = 0.763, 95% CI: 0.649-0.897, p = 0.001), whereas there was no difference after five years (HR = 1.135, 95% CI: 0.803-1.605, p = 0.472). In subgroup analysis, women in the 61-71+ age group, in the more than 20 year packs group, pathological stage 0-IB group, and 2013-2016 diagnosis period group revealed the same prognostic pattern. CONCLUSIONS: Compared with men, women had better survival after surgical resection of lung adenocarcinoma, especially those who were older and nonsmokers or heavy-smokers and were pathological stage 0-IB in early years, while the advantage for women diminished with time.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33829316

RESUMO

INTRODUCTION: Ground glass opacity (GGO) nodules were found incidentally by computed tomography (CT) scan in some teenagers, which turned out to be lung cancer. The purpose of this study is to summarize the characteristics of teenage patients with GGO featured lung adenocarcinoma. METHODS: Patients aging from 13 to 20 who were incidentally diagnosed with lung cancer were reviewed between February 2015 to December 2020. The clinical, radiological and pathological characteristics were analyzed. RESULTS: Totally 12 patients were included. All of them were diagnosed as GGO featured lung cancer through CT scan, with no presenting symptom. The median surveillance before surgery was 5.5 months, and none of these GGO lesions enlarged or altered in the property during the surveillance. The mean tumor diameter was 0.93 ± 0.25 cm. Ten patients underwent wedge resection by video-assisted thoracoscopic surgery (VATS), 9 of which were minimally invasive adenocarcinoma (MIA) and 1 of which were invasive adenocarcinoma (IAC) in the pathological analysis. One patient underwent VATS left-upper sublobectomy, pathologically diagnosed as MIA and 1 patient underwent VATS left-upper lobectomy with systematic mediastinal lymphadenectomy, pathologically diagnosed as IAC. The median postoperative hospital stay was 3 days. All patients survived without recurrence during a median follow-up of 12.5 months. CONCLUSIONS: GGO nodules could be a sign of early-stage teenage lung adenocarcinoma. We proposed a screening strategy with long intervals based on a baseline CT scan for the teenage population, and a treatment strategy for diagnosed teenage patients.

5.
Ann Thorac Surg ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33839135

RESUMO

BACKGROUND: Recent studies on the favorable prognosis of ground-glass opacities (GGO) featured lung adenocarcinoma compared with solid nodules were limited to small tumors measuring ≤3.0 cm. This study aimed to investigate whether GGO component could predict better prognosis in patients with large subsolid lesions exceeding 3cm compared with small solid nodules within the same clinical T category. METHODS: From 2010 to 2015, a total of 1010 patients with completely resected clinical N0 lung adenocarcinoma were enrolled, including 860 solid lesions and 150 subsolid lesions exceeding 3cm. To analyze the prognostic significance of GGO component, propensity score matching adjusting solid component size was performed. RESULTS: After propensity score matching, 144 pairs of patients were finally analyzed. The mean size of the solid component was 23.7mm in the GGO group and 24.4mm in the solid group(p=0.450). The GGO group had significantly better overall survival and recurrence-free survival (p=0.011 and p=0.003, respectively), which were also validated in patients with solid-predominant lesions. Subgroup analysis showed the GGO group was associated with better prognosis in each clinical T category. CONCLUSIONS: The prognosis of patients with GGO lesions exceeding 3cm was better than that of patients with small solid lesions even within the same clinical T category. Clinical T classification incorporating GGO component may provide better prognostic prediction for patients with lung cancer exceeding 3cm.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33444769

RESUMO

We discuss the optimal timing of surgery for lung cancer, and propose 3 surgical strategies for pre- and minimally invasive lung adenocarcinoma to avoid "overdiagnosis" and "overtreatment." Benign disease should not be treated as malignancy, pre- and minimally invasive disease should not be treated as invasive disease, and indolent malignancy should not be treated as aggressive malignancy.

8.
EMBO Mol Med ; 13(3): e12627, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33439550

RESUMO

Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.

9.
J Cancer Res Clin Oncol ; 147(3): 739-747, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33392661

RESUMO

OBJECTIVE: Recent studies have indicated that CD47, interacting with SIRP-α, conveys "don't eat me" signal in evasion of tumor cells and serves as a potential target for cancer immunotherapy. The purpose of this study was to investigate the clinical correlation of CD47 and uncover prognostic implications of CD47 and CD68 in non-small cell lung cancer (NSCLC). METHODS: The specimens from 384 patients with completely resected NSCLC were collected for immunohistochemical assays of CD47 and CD68. Cox multivariate proportion hazard analyses were conducted to confirm the independent prognostic value of CD47 and CD68. TCGA database and GSE37745 were used to identify the association between CD47 and immune cells. RESULTS: In 186 pairs of lung cancer and adjacent tissues, the RNA of CD47 was overexpressed in lung cancer tissues (P < 0.001). High expression of CD47 was associated with worse recurrence-free survival in RNA and protein level (P = 0.032 and P < 0.001, respectively). High expression of CD47 was significantly associated with large tumor size (P = 0.004), advanced pathologic TNM stage (P < 0.001), and histology (P = 0.003). Further analyses demonstrated that CD47 and CD68 predicted outcomes of patients independently. In addition, the expression of CD47 correlated with neutrophils, and did not correlated with B cells and CD4 + T cells in the TCGA database and GSE37745. CONCLUSION: Combined use of CD47 and CD68 exhibited excellent performance in predicting survival of patients with NSCLC. CD47 was a potential therapeutic target for immune therapy of lung cancer.


Assuntos
Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígeno CD47/biossíntese , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Ásia/epidemiologia , Antígeno CD47/genética , Antígeno CD47/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , RNA/genética , RNA/metabolismo
11.
Neoplasia ; 23(2): 222-233, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387960

RESUMO

Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/ß-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with ß-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/ß-catenin pathway and could serve as a potential therapeutic target in LUAD.

12.
J Thorac Oncol ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33307192

RESUMO

INTRODUCTION: The optimal extent of lymphadenectomy during esophagectomy remains unclear. In this trial, we aim to clarify whether three-field (cervical-thoracic-abdominal) lymphadenectomy improved patient survival over two-field (thoracic-abdominal) lymphadenectomy for esophageal cancer. METHODS: Between March 2013 to November 2016, 400 patients with middle and lower thoracic esophageal cancer were included, and randomly assigned to undergo esophagectomy with either three- or two-field lymphadenectomy at a 1:1 ratio. Analyses were done according to the intention-to-treat principle. The primary endpoint was overall survival (OS), calculated from the date of randomization to the date of death from any cause. RESULTS: emographic characteristics were similar in the two arms. The median follow-up time was 55 months (95% confidence interval [CI], 52-58). Overall survival were comparable between the two arms (hazard ratio [HR], 1.019, 95% CI, 0.727-1.428, P=0.912) , as well as the disease-free survival (DFS) (HR, 0.868, 95% CI, 0.636-1.184, P=0.371) .The cumulative 5-year OS was 63% in the three-field arm, as compared with 63% in the two-field arm; 5-year DFS were 59% and 53%, respectively. Based on whether the patients had mediastinal/abdominal lymph nodes metastasis or not, overall survivals were also comparable between the two arms. In this cohort, only advanced tumor stage (pTNM stage III-IV) was identified as the risk factor associated with reduced OS (HR, 3.330, 95% CI, 2.140-5.183, P<0.001). CONCLUSION: For patients with middle and lower thoracic esophageal cancer, there was no improvement in OS or DFS after esophagectomy with three-field lymphadenectomy over two-field lymphadenectomy.

13.
Chest ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33197404

RESUMO

BACKGROUND: Our previous study revealed that intraoperative frozen section (FS) could accurately differentiate invasive lung adenocarcinoma (LUAD) from pre-invasive lesions. However, few articles analyzed the clinical impact of FS errors such as underestimation of invasive adenocarcinomas, and whether complementary therapy was needed remains controversial. RESEARCH QUESTION: This study aims to investigate the prognosis of patients undergoing limited resection for invasive LUAD misdiagnosed as atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) by intraoperative FS. STUDY DESIGN AND METHODS: From 2012 to 2018, data on 3031 patients undergoing sublobar resection of AAH/AIS/MIA diagnosed by FS were collected. The concordance rate between FS and final pathology (FP) was evaluated. To assess the clinical significance of FS/FP discrepancy, patients with invasive adenocarcinomas in final pathology were identified for prognostic evaluation. RESULTS: When AAH, AIS and MIA were classified together as a group, the overall concordance rate between FS and FP was 93.7%, and 192 (6.3%) patients got an upgraded diagnosis from the FP. Misdiagnosed invasive adenocarcinomas consisted of 94 (48.9%) lepidic predominant adenocarcinoma, 77 (40.1%) acinar predominant adenocarcinoma, 19 (9.9%) papillary predominant adenocarcinoma, one solid predominant pattern and one invasive mucinous adenocarcinoma. Among these patients, no positive N1, N2 lymph node was found. Moreover, the 5-year recurrence-free survival was still 100% even the final pathology turned out to be invasive adenocarcinoma. INTERPRETATION: Patients undergoing limited resection of invasive LUAD misdiagnosed as AAH/AIS/MIA by FS had excellent prognosis. Sublobar resection guided by FS diagnosis would be adequate for these underestimated invasive LUAD.

14.
J Neurosci Res ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197957

RESUMO

Alzheimer's disease (AD) is a serious neurodegenerative disease in people of age 65 or above. The detailed etiology and pathogenesis of AD have not been elucidated yet. In this study, the hippocampi of 2- and 6-month-old triple transgenic Alzheimer's disease male mice and age-sex-matched wild-type (WT) mice were analyzed by using targeted metabolomics approach. Compared with WT mice, 24 and 60 metabolites were found with significant differences in 2- and 6-month-old AD mice. Among these, 14 metabolites were found common while 10 metabolites showed consistent variable trends in both groups. These differential metabolites are found associated with amino acid, lipid, vitamin, nucleotide-related base, neurotransmitter and energy metabolisms, and oxidative stress. The results suggest that these differential metabolites might play a critical role in AD pathophysiology, and may serve as potential biomarkers for AD. Moreover, the results highlight the involvement of abnormal purine, pyrimidine, arginine, and proline metabolism, along with glycerophospholipid metabolism in early pathology of AD. For the first time, several differential metabolites are found to be associated with AD in this study. Targeted metabolomics can be used for rapid and accurate quantitative analysis of specific target metabolites associated with AD.

15.
Thorac Cancer ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33210466

RESUMO

BACKGROUND: 99m Tc bone scintigraphy (BS) is still the most common approach for the evaluation of bone metastasis in China. The purpose of this study was to investigate the necessity of BS as part of a routine preoperative workup for patients with cT1N0 subsolid lung cancer. METHODS: This was a prospective multicenter clinical trial (NCT03689439). Patients with cT1N0 subsolid nodules who were candidates for surgical resection were consecutively enrolled into the study. BS was performed preoperatively. The surgical plan could be changed if a positive result was detected. The primary endpoint was the incidence rate of the surgical plan being changed because of positive BS results. The secondary endpoint was the rate of positive BS findings and the rate of related complications. RESULTS: From November 2018 to July 2019, 691 patients were enrolled into the study. None of the patients had positive BS results and no surgical plans were changed by BS findings. There were 222 male and 469 female patients. The average age was 54.8 ± 3.7 years old. The average tumor diameter was 14.9 ± 4.2 mm. There were 282 patients with pure GGO nodules and 409 with part-solid nodules. A total of 470 patients had a single nodule, while 221 patients had multifocal lesions. The number of patients whose pathological diagnosis was invasive adenocarcinoma, minimally invasive adenocarcinoma, adenocarcinoma in situ and mucinous adenocarcinoma was 357, 293, 32 and nine, respectively. The number of patients who underwent lobectomy, segmentectomy and wedge resection was 234, 199 and 258, respectively. CONCLUSIONS: 99m Tc bone scintigraphy is unnecessary in the preoperative workup for patients with cT1N0 subsolid lung cancer. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: In this prospective study of 691 patients with cT1N0 subsolid lung cancer, no surgical plans were affected by positive bone scan findings. WHAT THIS STUDY ADDS: We suggest physicians consider canceling BS from preoperative workup for cT1 subsolid lung cancer patients. Clinical trial registry number: NCT03689439.

16.
ANZ J Surg ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33155410

RESUMO

BACKGROUND: The correlation of post-operative serum albumin level with the occurrence of anastomotic leakage (AL) in oesophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to evaluate the impact of post-operative serum albumin level on AL after transthoracic oesophagectomy. METHODS: Patients with ESCC who underwent transthoracic oesophagectomy between 2013 and 2017 in Fudan University Shanghai Cancer Center were included. The correlation of post-operative serum albumin level with the occurrence and short-term outcomes of AL was analysed. RESULTS: Patients with serum albumin level of <35 g/L on the first post-operative day were identified with higher frequency of AL in the whole study population (10.3% versus 6.1%; P < 0.001), intrathoracic anastomosis subgroup (7.1% versus 3.9%; P = 0.002) and cervical anastomosis subgroup (24.1% versus 16.0%; P = 0.042). Multivariate analysis showed that low albumin level was an independent risk factor of AL in the overall population (odds ratio (OR) 1.842; P < 0.001), intrathoracic anastomosis subgroup (OR 1.815; P = 0.006) and cervical anastomosis subgroup (OR 1.946; P = 0.013). In patients with AL, low albumin level was associated with poorer short-term outcomes. For patients with low albumin level on the first post-operative day, the probability of AL was significantly reduced if the level in the first post-operative week was improved to the normal range (5.9% versus 14.9%; P < 0.001). CONCLUSION: Serum albumin level on the first post-operative day was an independent predictor of AL in patients with ESCC receiving transthoracic oesophagectomy. Increase of albumin level to the normal range post-operatively could reduce the risk of AL.

18.
J Natl Cancer Inst ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33136163

RESUMO

BACKGROUND: Previous studies have indicated Coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate. METHODS: We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariate logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes. RESULTS: We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the UK and Europe, followed by the USA and Canada (35.7%) and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (odds ratio [OR] = 3.57; 95% CI = 1.80 to 7.06), male (OR = 2.10; 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00; 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariate analysis, only age greater than 65 years (OR = 3.16; 95% CI = 1.45 to 6.88) and being male (OR = 2.29; 95% CI = 1.07 to 4.87) were associated with increased risk of severe events. CONCLUSION: Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate when compared with that of COVID-19 patients without cancer. Age and gender appear to be risk factors associated with a poorer prognosis.

20.
J Cardiothorac Surg ; 15(1): 238, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907605

RESUMO

BACKGROUND: Uniportal video-assisted thoracoscopic surgery (U-VATS) has recently emerged as an alternative procedure for non-small cell lung cancer (NSCLC); however, whether U-VATS has advantages over multiportal VATS (M-VATS) remains unknown. METHODS: We performed a systematic review of two databases (Pubmed and Web of Science) to search comparative studies of U-VATS and M-VATS anatomical pulmonary resection for NSCLC. Operative time, blood loss, number of resected lymph nodes, drainage duration, length of postoperative stay, pain in postoperative day 1(POD1) and conversion rates were retrieved to estimate the comparison of outcomes. A subgroup analysis stratified by study type (propensity-matched analysis and randomized-controlled trial versus non-propensity matched analysis) was performed. RESULT: A total of 20 studies with 4142 patients were included in this meta-analysis. U-VATS was performed on 1869 patients, whereas the other 2173 patients underwent M-VATS. This meta-analysis showed that there was no significant difference in operative time (U-VATS: 146.48 ± 55.07 min versus M-VATS: 171.70 ± 79.40 min, P = 0.81), blood loss (74.49 ± 109.03 mL versus 95.48 ± 133.67 mL, P = 0.18), resected lymph nodes (17.28 ± 9.46 versus 18.31 ± 10.17, P = 0.62), conversion rate (6.18% versus 4.34%, P = 0.14), drainage duration (3.90 ± 2.94 days versus 4.44 ± 3.12 days, p = 0.09), length of postoperative stay (6.16 ± 4.40 days versus 6.45 ± 4.80 days, P = 0.22), and pain in POD1 (3.94 ± 1.68 versus 3.59 ± 2.76, p = 0.07). Subgroup analysis showed the value of PSM and RCT group consistency with overall value. CONCLUSION: This up-to-date meta-analysis shows that the perioperative outcomes of U-VATS and M-VATS anatomical pulmonary resection are equivalent. In addition, the differences in long-term outcomes of these two approaches are still unclear. Thoracic surgeons should pay more emphasize on providing high-quality and personalized surgical care for patients, to improve the survival ultimately.

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