Aberrant activation of Wnt/β-catenin signaling and dysregulation of metabolism have been frequently observed in lung cancer. However, the molecular mechanism by which Wnt/β-catenin signaling is ...regulated and the link between Wnt/β-catenin signaling and cancer metabolism are not fully understood. In this study, we showed that the loss of dual serine/threonine tyrosine protein kinase (DSTYK) led to the activation of Wnt/β-catenin signaling and upregulation of its target gene, lactate dehydrogenase (LDHA), and thus the elevation of lactate. DSTYK phosphorylated the N-terminal domain of β-catenin and inhibited Wnt/β-catenin signaling, which led to the inhibition of cell growth, colony formation and tumorigenesis in a lung adenocarcinoma mouse model. DSTYK was downregulated in lung cancer tissues, and its expression was positively correlated with the survival of patients with lung adenocarcinoma. Taken together, these results demonstrate that the loss of DSTYK activates Wnt/β-catenin/LDHA signaling to promote the tumorigenesis of lung cancer and that DSTYK may be a therapeutic target.
Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival ...and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m
intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m
IV day 1, or 25 mg/m
IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.
Precise point positioning (PPP) has received much attention in recent years for its low cost, high accuracy, and global coverage. Nowadays, PPP with ambiguity resolution and atmospheric augmentation ...is widely regarded as PPP-RTK (real-time kinematic), which weakens the influence of the long convergence time in PPP and regional service coverage in RTK. However, PPP-RTK cannot work well in urban areas due to limitations of non-line-of-sight (NLOS) conditions. Inertial navigation systems (INS) and vision can realize continuous navigation but suffer from error accumulation. Accordingly, the integration model of multi-GNSS (global navigation satellite system) and PPP-RTK/INS/vision with a cascading Kalman filter and dynamic object removal model was proposed to improve the performance of vehicle navigation in urban areas. Two vehicular tests denoted T01 and T02 were conducted in urban areas to evaluate the navigation performance of the proposed model. T01 was conducted in a relatively open-sky environment and T02 was collected in a GNSS-challenged environment with many obstacles blocking the GNSS signals. The positioning results show that the dynamic object removal model can work well in T02. The results indicate that multi-GNSS PPP-RTK/INS/vision with a cascading Kalman filter can achieve a positioning accuracy of 0.08 m and 0.09 m for T01 in the horizontal and vertical directions and 0.83 m and 0.91 m for T02 in the horizontal and vertical directions, respectively. The accuracy of the velocity and attitude estimations is greatly improved by the introduction of vision.
Early carcinomas of the esophagus are histologically classified as adenocarcinoma or squamous cell carcinoma and microscopically subdivided into mucosal and submucosal carcinomas depending on ...infiltration depth. The prevalence of lymph node metastasis in mucosal carcinoma remains low. However, lymph node metastases arise frequently from tumors with submucosal infiltration, with increasing prevalence in the deeper submucosal sublayers. According to current German guidelines, endoscopic resection is the recommended treatment in mucosal adenocarcinoma without histologic risk factors (lymphatic invasion 1, vascular invasion 1, >grade 2, R1‐margin). In superficial submucosal infiltration without histologic risk factors, endoscopic resection can be considered. In squamous cell carcinoma, endoscopic resection is indicated up to middle layer mucosal carcinoma. Beyond these criteria, surgical resection should be considered. The gold standard is a subtotal transthoracic esophagectomy with two‐field lymphadenectomy. Total esophagectomy is performed in cervical esophageal carcinoma and transhiatal extended gastrectomy in carcinoma of the cardia. Minimally invasive procedures show good oncologic results and reduce the morbidity of radical esophagectomy. Reduced morbidity might be an argument for surgical resection in borderline cases between endoscopic and surgical resection. In early squamous cell cancer, the combination of endoscopic resection and adjuvant chemoradiotherapy is a therapeutic option with promising results.
Early carcinomas of the esophagus (adenocarcinoma or squamous cell carcinoma) are subdivided into mucosal and submucosal carcinomas. The prevalence of lymph node metastasis in mucosal carcinoma remains low, but it occurs frequently in tumors with submucosal infiltration This review discusses the appropriate selection of surgery, endoscopy, or chemoradiation for the treatment of early carcinomas of the esophagus based on their degree of submucosal infiltration.
Background Thoracoscopic lobectomy for lung cancer has been widely accepted, but thoracoscopic segmentectomy remains controversial because of the complexity of the procedure and of the fear of ...increased local recurrence. This study compared outcomes between thoracoscopic segmentectomy and thoracoscopic lobectomy in patients with small-sized (≤2 cm) stage IA non-small cell lung cancer. Methods Between March 2006 and August 2011, 39 thoracoscopic segmentectomies and 81 thoracoscopic lobectomies were performed in 120 patients with small-sized (≤2 cm) stage IA lung cancer. Clinicopathologic factors, local recurrence rate, and survival rate were compared. Results The two groups were similar in age, sex, pulmonary function, and tumor size. There were no conversions from video-assisted thoracoscopic surgery to open or from segmentectomy to lobectomy. There were no in-hospital deaths. The two groups had a similar incidence of postoperative complications. Local recurrence rates were similar after thoracoscopic segmentectomy (5.1%) and thoracoscopic lobectomy (4.9%). No significant difference was observed in 5-year overall or disease-free survivals after thoracoscopic segmentectomy or thoracoscopic lobectomy. Multivariate Cox regression analyses showed tumor size was the only independent prognostic factor for disease-free survival. Conclusions Thoracoscopic segmentectomy is a safe option and provides comparable oncologic results to thoracoscopic lobectomy for small (≤2 cm) peripheral stage IA non-small cell lung cancer. Tumor size is an independent prognostic factor of disease-free survival for stage IA patients with small-sized lesions.
Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain ...elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad‐Cre, KrasG12D, and P53f/f). In studying the molecular mechanism, ZNF251 was found to inhibit the expression of dual‐specificity phosphatase 6, a negative regulator of ERK activation, by directly binding to its promoter region. Taken together, our data indicate the tumor‐promoting effects of ZNF251 in lung cancer and suggest that ZNF251 is a therapeutic target.
ZNF251 promotes lung cancer by activating ERK signaling.
Abstract
Background:
Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has limited ...outcome. New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches.
Methods:
We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017. Patient samples were sequenced using a 324-gene platform with licensed technologies. In this study, we focused on clinically relevant genomic alterations (CRGAs), which are previously proven to be pathogenic alterations, to identify the pathology-specific mutational patterns, prognostic signatures of TCs and TNENs.
Results:
The mutational profiles between TCs and TNENs were diverse. The genetic alterations that ranked highest in TCs were in
CDKN2A, TP53, ASXL1, CDKN2B, PIK3C2G, PTCH1,
and
ROS1
, while those in TNENs were in
MEN1, MLL2, APC, RB1
, and
TSC2
. Prognostic analysis showed that mutations of
ROS1, CDKN2A, CDKN2B, BRAF,
and
BAP1
were significantly associated with worse outcomes in TC patients, and that mutation of
ERBB2
indicated shortened disease-free survival (DFS) and overall survival (OS) in TNEN patients. Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control, chromatin remodeling/DNA methylation, phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) signaling.
Conclusion:
We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.
Precise point positioning (PPP) is receiving increasing interest due to its cost-effectiveness, global coverage and high accuracy. However, its application in the urban environment is still full of ...challenges due to the satellite tracking sky-view. Thus, we presented a comprehensive positioning model by fusing the multi-GNSS (global navigation satellite system) combination, GNSS/INS (inertial navigation system) tightly coupled integration as well as the ionospheric and tropospheric augmentation in the undifferenced and uncombined PPP. The performance of this model in dual-frequency and single-frequency positioning was assessed with two experiments that denoted as T019 and T023, respectively, and both the experiments were carried out in a real urban environment. Particularly, the experiment T023 was carried out in the Second Ring Road of Wuhan city, which can be regarded as a typical downtown environment. Concerning the regional atmospheric augmentation, observations from 5 reference stations with an inter-station distance of about 40 km were also collected during the experimental time. The comparison between reference stations suggested that the regional tropospheric model had a precision of better than 0.6 cm in terms of zenith tropospheric delay, while the regional ionospheric model had a precision of around 0.5 total electron content unit in terms of Vertical Total Electron Content. It can be concluded that the GPS-only PPP can be improved significantly for urban vehicle navigation with these techniques, i.e., the multi-GNSS, INS tightly coupled integration and the atmospheric augmentation, through the positioning analysis, while INS tightly coupled integration makes the most contributions under the downtown environment, and the improvement of the regional atmospheric augmentation in single-frequency PPP is more significant since that single frequency is more sensitive to the ionospheric delay. In addition, it is proved that the regional atmospheric augmentation accelerates positioning convergence. The 3D positioning root-mean-square (RMS) with the comprehensive positioning model for dual frequency are 0.22 m and 0.77 m for T019 and T023, respectively. Concerning single-frequency PPP, the 3D RMS is 0.45 m and 1.17 m for T019 and T023, respectively. Moreover, taking the lane-level navigation under the downtown environment of T023 into consideration, we further presented the cumulative frequency of the horizontal positioning error less than 1 m, i.e.,
P
d
N
2
+
d
E
2
<
1
m
, and the best solution can be found with PPP by fusing all the techniques, in which
P
d
N
2
+
d
E
2
<
1
m
is 99.0% and 93.2% for dual frequency and single frequency, respectively.
Lessons Learned
The findings of this prospective, single‐arm, phase II study showed that neoadjuvant erlotinib was well tolerated and might improve the radical resection rate in patients with stage ...IIIA‐N2 epidermal growth factor receptor mutation‐positive non‐small cell lung cancer (NSCLC).
Erlotinib shows promise as a neoadjuvant therapy option in this patient population.
Next‐generation sequencing may be useful for predicting outcomes with preoperative tyrosine kinase inhibitors (TKIs) in patients with NSCLC.
Large‐scale randomized controlled trials investigating the role of TKIs in perioperative therapy, combining neoadjuvant and adjuvant treatments to enhance personalized therapy for patients in this precision medicine era, are warranted.
Background
Information on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in non‐small cell lung cancer (NSCLC) is scarce. We evaluated whether neoadjuvant erlotinib improves operability and survival in patients with stage IIIA‐N2 EGFR mutation‐positive NSCLC.
Methods
We conducted a prospective, single‐arm, phase II study. Patients received erlotinib 150 mg per day for 56 days in the neoadjuvant period. The primary endpoint was the radical resection rate.
Results
Nineteen patients were included in the final analysis. After erlotinib treatment, 14 patients underwent surgery. The radical resection rate was 68.4% (13/19) with a 21.1% (4/19) rate of pathological downstaging. The objective response rate was 42.1%; 89.5% (17/19) of patients achieved disease control, with a 10.3‐month median disease‐free survival among patients who underwent surgery. Among all 19 patients who received neoadjuvant therapy, median progression‐free survival (PFS) and overall survival were 11.2 and 51.6 months, respectively. Adverse events (AEs) occurred in 36.8% (7/19) of patients, with the most common AE being rash (26.3%); 15.8% experienced grade 3/4 AEs. Quality of life (QoL) improvements were observed after treatment with erlotinib for almost all QoL assessments. Effects of TP53 mutation on prognosis were evaluated in eight patients with adequate tissue samples. Next‐generation sequencing revealed that most patients had a TP53 gene mutation (7/8) in addition to an EGFR mutation. No TP53 mutation, or very low abundance, was associated with longer PFS (36 and 38 months, respectively), whereas high abundance was associated with short PFS (8 months).
Conclusion
Neoadjuvant erlotinib was well tolerated and may improve the radical resection rate in this patient population. Next‐generation sequencing may predict outcomes with preoperative TKIs.
经验获取
• 本次前瞻性单组 II 期研究结果显示，埃罗替尼新辅助治疗在 IIIA‐N2 期表皮生长因子受体突变阳性非小细胞肺癌 (NSCLC) 患者中的耐受性良好，可以提高根治性切除率。
• 在此患者群体中，埃罗替尼显示出了作为新辅助治疗选择的希望。
• 对于预测 NSCLC 患者的手术前酪氨酸激酶抑制剂 (TKI) 结果而言，下一代测序可能十分有用。
• 为了在这个精准医疗的时代提高患者的个性化治疗水平，开展旨在调查 TKI 在围术期治疗(新辅助治疗与辅助治疗相结合)中作用的大规模随机对照试验很有必要。
摘要
背景。关于表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 作为非小细胞肺癌 (NSCLC) 的新辅助治疗的信息十分匮乏。我们对埃罗替尼新辅助治疗能否改进 IIIA‐N2 期 EGFR 突变阳性 NSCLC 患者的可手术性和生存期进行了评估。
方法。我们进行了一项前瞻性单组 II 期研究。在新辅助治疗期间，患者每天服用埃罗替尼 150 mg，连续给药 56 天。主要终点是根治性切除率。
结果。最终分析中包含 19 名患者。在埃罗替尼治疗之后，14 名患者接受手术。根治性切除率为 68.4% (13/19)，病理性降级率为 21.1% (4/19)。客观反应率为 42.1%；89.5% (17/19) 的患者病情得到控制，在接受手术的患者中，中位无病生存期为 10.3 个月。在所有接受新辅助治疗的 19 名患者中，中位无进展生存期 (PFS) 和总体生存期分别为 11.2 个月和 51.6 个月。36.8% (7/19) 的患者出现不良反应 (AE)，最常见的 AE 为皮疹 (26.3%)；15.8% 的患者出现 3/4 级 AE。对于几乎所有的生存质量 (QoL) 评估，在治疗后均观察到了 QoL 改善。我们针对 8 名具有适当组织样本的患者评估了 TP53 突变对预后的影响。下一代测序显示，除 EGFR 突变之外，大多数患者均有 TP53 基因突变 (7/8)。无 TP53 突变或极低丰度与较长的 PFS(分别为 36 个月和 38 个月)相关，而高丰度与短 PFS(8 个月)相关。
结论。埃罗替尼新辅助治疗在此患者群体中的耐受性良好，可以提高根治性切除率。下一代测序可以预测手术前 TKI 的结果。
早期非小细胞肺癌患者的生存率有待提高。含实体或微乳头成分、伴脉管侵犯或伴气道播散的浸润性腺癌患者属于复发风险高危人群，需要探索包括根治性手术切除在内的系统治疗方案。而现有指南不推荐IA期患者行术后辅助化疗。本文将综述上述病理高危因素在IA期肺腺癌患者中的研究进展以及辅助化疗在IA期复发风险高危人群中的作用。 The survival rate needs to be improved in ...early stage non-small cell lung cancer patients. The risk of recurrence is relatively high in invasive adenocarcinoma patients with a solid or micropapillary component, lymphovascular invasion or tumor spread through air spaces. Systemic treatment options including radical surgical resection should be explored for this population. Adjuvant chemotherapy is not recommended for patients in stage IA in current guidelines. This article is a review on the research progress of the above pathological high-risk factors and the role of adjuvant chemotherapy in patients with pathological high-risk factors in stage IA lung adenocarcinoma.
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