Background
This study aimed to clarify differences in the prognostic impact of tumor spread through air spaces (STAS) in lobectomy versus sublobar resection (SR). The study also investigated the ...frequency and significance of STAS in residual lung segments.
Methods
This study identified 752 patients with p-stage 1A non-small cell lung cancer (NSCLC) from 2010 to 2012. Recurrence-free survival (RFS) and overall survival (OS) were compared. For proactive simulation of SR, 100 consecutive lobectomy specimens of p-stage 1A NSCLC were selected.
Results
The study found STAS in 182 (28.7%) of 634 lobectomy cases and 43 (36.4%) of 118 SR cases. Multivariable analysis showed that STAS was not a prognostic factor in the lobectomy group, but showed a significantly worse prognostic effect for the SR group (RFS,
P
< 0.001; OS,
P
< 0.001). In 9 of 100 simulated cases, STAS occurred in residual lung segments. The patients with T1c category disease had a significantly increased risk for the development of STAS in residual lung segments (
P
= 0.033).
Conclusions
For patients with p-stage 1A lung cancer who have undergone SR, STAS is a prognostic indicator of poor outcomes. The presence of STAS does occasionally exist in the residual lung segments.
BACKGROUND: Schistosoma japonicum is one of the major causative agents of schistosomiasis. The pairing of males and females leads to female sexual maturation and maintains this mature state. However, ...the mechanisms by which pairing facilitates sexual maturation are yet to be investigated. METHODS: Parasites isolated from single- and double-sex cercariae-infected mice were analyzed by Solexa to uncover pair-regulated miRNA profiles. To reveal the biological functions of differentially expressed miRNAs among the samples, we predicted the target genes of these differentially expressed miRNAs and compared the gene expression between 23-d-old female schistosomula from double-sex infections (23DSI) and 23-d-old female schistosomula from single-sex infections (23SSI) by analyzing digital gene expression profiling (DGE). KEGG pathway analysis was used to investigate the relevant biological processes of these target genes to understand the significance of differentially expressed miRNAs after pairing. RESULTS: The differentially expressed miRNA profiles of female 18- and 23-d post-single- and double-sex infections were analysed by Solexa. Similar miRNA profiles were observed in 18SSI and 18DSI, with the presence of identically expressed high-abundance miRNA, such as miRNA-1, miRNA-71b-5p and let-7. By contrast, in 23DSI and 23SSI, most of these high-abundance miRNAs were down-regulated. Furthermore, among all samples, bantam was distinctly up-regulated in 23 DSI, and miR-1, miR-71, miR-7-5p, and miR-7 were distinctly up-regulated in 23SSI. The transcriptomes of 23DSI and 23SSI revealed that the predicted target genes of miRNA-1, miRNA-71, miRNA-7, and miR-7-5p were associated with the ribonucleoprotein complex assembly and microtubule-based process. Conversely, the predicted target genes of bantam were related to the embryo development, development of primary sexual characteristics and regulation of transcription. KEGG pathway analysis revealed that in unpaired females, the highly-expressed miRNA-1, miRNA-71, miRNA-7, and miR-7-5p only inhibited the limited pathways, such as proteasome and ribosome assembly. Meanwhile, in paired mature females, highly-expressed bantam inhibited more biological pathways, such as the citrate cycle, glycolysis, fatty acid biosynthesis and RNA degradation. CONCLUSIONS: The differentially expressed miRNAs between 23SSI and 23DSI and their different functions indicated that more genes or metabolic pathways in paired mature females were inhibited than those in unpaired ones. The results suggested that after pairing, specific miRNAs regulated gene expression to lead to female sexual maturation.
Our study aimed to validate the clinicopathological characteristics and prognosis of lung adenocarcinoma (ADC) with a filigree pattern and to further investigate the relationship between the filigree ...pattern and the classical micropapillary (MP) pattern. We retrospectively reviewed the clinical and pathologic characteristics of 461 Chinese patients with completely resected ADC (stage I, 310; stage II, 44; stage III, 107). The filigree pattern was more likely to be observed in ADC with a higher stage (p = 0.003) and the classical MP pattern (p < 0.001). Patients with filigree-predominant ADC showed poor survival, similar to those with classical MP-predominant ADC. Multivariate analysis confirmed that the presence of the filigree pattern was an independent prognostic factor for recurrence-free survival (hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.50–2.68; p < 0.001) and overall survival (OS; HR, 1.83; 95% CI, 1.34–2.50; p < 0.001). Patients with both classical MP-positive and filigree-positive ADC had the worst survival compared with those with the filigree pattern or classical MP pattern alone. In stage I, ADC with both the filigree and classical MP patterns had a higher incidence of micrometastasis than ADC with the filigree pattern or classical MP pattern alone. Lymph node micrometastasis indicated poor survival in patients with ADC with the filigree pattern or classical MP pattern. Similar clinicopathologic features between patients with the filigree pattern and the classical MP pattern support the inclusion of the filigree pattern in the MP category. Recognition of the filigree pattern could provide helpful prognostic information, especially for stage I ADC.
Background:
Limited resection has gradually become an acceptable treatment for lung adenocarcinomas (ADCs) presenting as ground-glass nodules (GGNs). However, its role in lung ADCs presenting as pure ...solid nodules (PSN) remains unclear. In this study, we aimed to identify potential candidates for limited resection in lung ADCs presenting as PSN.
Methods:
We retrospectively reviewed 772 patients from seven hospitals with lung ADCs ⩽2 cm, presenting as PSN on computed tomography scans, who had undergone surgery between 2009 and 2013. Histological subtypes were listed in 5% increments. To investigate the value of histological subtypes in surgical decision making, five pathologists prospectively evaluated the feasibility of identifying histological subtypes using frozen section (FS) in two cohorts.
Results:
The percentage of micropapillary (MIP) subtype had a striking impact on recurrence-free survival (RFS) and overall survival (OS) for lung ADCs ⩽2 cm presenting as PSNs. In multivariable Cox analysis, segmentectomy was significantly associated with worse RFS and OS in patients with MIP >5% than lobectomy, but not in those with MIP ⩽5%. With wedge resection, worse RFS and OS were observed in patients with MIP >5% and those with MIP ⩽5% than lobectomy. The sensitivity and specificity for detecting MIP by FS were 74.2% and 85.6%, respectively, with substantial inter-rater agreement.
Conclusion:
Segmentectomy and lobectomy had similar oncological outcomes in patients with lung ADCs ⩽2 cm presenting as PSN with MIP ⩽5%. Randomized trials are necessary to validate the feasibility of intraoperative FS to choose candidates for segmentectomy.
Background:
Grading system for resected invasive pulmonary adenocarcinoma proposed by the International Association for the Study of Lung Cancer (IASLC) was validated as a strong prognostic ...indicator. Nonetheless, the efficacy of utilizing such grading system in prognostic assessment of patients receiving neoadjuvant therapy still needs elucidating.
Methods:
A retrospective study was conducted including patients with resected adenocarcinoma following neoadjuvant chemotherapy or targeted therapy from August 2012 to December 2020 in Shanghai Pulmonary Hospital. All the surgical specimens were re-evaluated and graded. The prognostic value of the grading system was further validated.
Results:
Ultimately, a total of 198 patients were enrolled in this study, and subdivided into three cohorts according to the grading system. There were 13 (6.6%), 37 (18.7%), and 148 (74.7%) patients belonging to Grades 1, 2, and 3, respectively. IASLC grading system demonstrated significant power in prognosis differentiation of the entire cohort recurrence-free survival (RFS), p < 0.001; overall survival (OS), p < 0.001 and the neoadjuvant chemotherapy and targeted therapy cohorts separately, and was further verified as a significant prognostic indicator for RFS and OS in multivariable Cox analysis. Since the majority of the patients (84.8%) did not achieve major pathologic response (MPR), representing a wide spectrum of survival, the prognostic value of grading system in non-MPR cohort was further evaluated. Similar results were also obtained that IASLC grading system was assessed significant in univariable analysis of RFS (p < 0.001) and univariable analysis of OS (p = 0.001).
Conclusions:
The prognostic efficacy of pathological evaluation of the residual proportion of pulmonary adenocarcinoma post-neoadjuvant therapy using IASLC grading system was preliminarily verified. Such grading system might assist prognostic evaluation of neoadjuvant cohort other than traditional pathological parameters.
Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I ...interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.
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•High-throughput screening identifies brivanib as a cGAS activity-enhancing compound•Brivanib targets cGAS to boost its activation by enhancing its DNA binding affinity•Brivanib enhances platinum-induced type I IFN responses in tumor cells•Brivanib and cisplatin synergistically control tumors by boosting CD8+ T cell
Liu et al. identify brivanib as a cGAS activity-enhancing compound and provide a proof-of-concept for sensitizing platinum-based chemotherapy by boosting cGAS-mediated antitumor immunity. Brivanib may serve as a drug candidate for sensitizing platinum-based chemotherapeutics in cancer treatment and intervention of cGAS-related diseases.
The prognostic analysis of limited resection vs. lobectomy in stage IA small cell lung cancer (SCLC) remains scarce.
Using the Surveillance, Epidemiology, and End Results registry (SEER) database, we ...identified patients who were diagnosed with pathological stage IA (T1a/bN0M0) SCLC from 2004 to 2013. The overall survival (OS) and lung cancer-specific survival (LCSS) rates of patients with different treatment schemes were compared in stratification analyses. Univariable and multivariable analyses were also performed to identify the significant predictors of OS and LCSS.
In total, we extracted 491 pathological stage IA SCLC patients, 106 (21.6%) of whom received lobectomy, 70 (14.3%) received sublobar resection and 315 (64.1%) received non-surgical treatment, respectively. There were significant differences among the groups based on different treatment schemes in OS (log-rank
< 0.0001) and LCSS (log-rank
< 0.0001). Furthermore, in subgroup analyses, we did not identify any differences between sublober resection group and lobectomy group in OS (log-rank
= 0.14) or LCSS (log-rank
= 0.4565). Patients with four or more lymph node dissection had better prognosis. Multivariable analyses revealed age, laterality, tumor location, and N number were still significant predictors of OS, whereas age, tumor location, and N number were significant predictors of LCSS.
Surgery is an important component of multidisciplinary treatment for stage IA SCLC patients and sublober resection is not inferior to lobectomy for the specific patients.
Objective:
Neoadjuvant chemotherapy has increased the survival benefit of non-small cell lung cancer (NSCLC) patients. The effects of different neoadjuvant therapies are still controversial. We ...carried out the study to evaluate the efficacy and safety of neoadjuvant therapy.
Methods:
We performed a search of electronic databases (PubMed, Embase, MEDLINE, Cochrane) for randomized controlled trials (RCTs) comparing neoadjuvant treatment. After literature screening and data extraction, efficacy, and safety were analyzed by the Bayesian network meta-analysis (NMA).
Results:
A total of 19 RCTs were included, covering 3276 patients and six kinds of neoadjuvant therapies, including immunotherapy, targeted therapy, chemotherapy drugs and radiotherapy. Erlotinib, the first-generation epidermal growth factor receptor tyrosine inhibitors (EGFR TKIs), neoadjuvant targeted therapy is best for improving overall survival (OS) and progression-free survival (PFS), which is superior to other neoadjuvant therapy, such as neoadjuvant chemotherapy with platinum drugs hazard ratio (HR) 0.39, 95% confidence intervals (CIs) 0.16–0.96, neoadjuvant chemoradiotherapy (HR 0.37, 95% CI 0.14–0.96) and neoadjuvant chemotherapy with non-platinum drugs (HR 0.25, 95% CI 0.07–0.90). OS of all neoadjuvant therapies is superior to surgery alone, but only neoadjuvant chemotherapy with platinum drugs showed a significant advantage (HR 0.76, 95% CI 0.59–0.93). Besides, for the stage IIIA N2 NSCLC patients, no significant difference was found between neoadjuvant therapies.
Conclusions:
Targeted neoadjuvant therapy is the best treatment for prolonging PFS. The neoadjuvant chemotherapy with platinum drugs was associated with the better OS benefits for patients with NSCLC, compared with surgery alone. There is no significant difference in the efficacy of neoadjuvant therapy for the stage IIIA N2 NSCLC.
Lung cancer is the leading cause of cancer-related death worldwide. Cancer immunotherapy has shown great success in treating advanced-stage lung cancer but has yet been used to treat early-stage lung ...cancer, mostly due to lack of understanding of the tumor immune microenvironment in early-stage lung cancer. The immune system could both constrain and promote tumorigenesis in a process termed immune editing that can be divided into three phases, namely, elimination, equilibrium, and escape. Current understanding of the immune response toward tumor is mainly on the "escape" phase when the tumor is clinically detectable. The detailed mechanism by which tumor progenitor lesions was modulated by the immune system during early stage of lung cancer development remains elusive. The advent of single-cell sequencing technology enables tumor immunologists to address those fundamental questions. In this perspective, we will summarize our current understanding and big gaps about the immune response during early lung tumorigenesis. We will then present the state of the art of single-cell technology and then envision how single-cell technology could be used to address those questions. Advances in the understanding of the immune response and its dynamics during malignant transformation of pre-malignant lesion will shed light on how malignant cells interact with the immune system and evolve under immune selection. Such knowledge could then contribute to the development of precision and early intervention strategies toward lung malignancy.
Tumor spread through air spaces (STAS) has three morphologic subtypes: single cells, micropapillary clusters, and solid nests. However, whether their respective clinical significance is similar ...remains unclear.
We retrospectively reviewed 803 patients with resected non-small cell lung cancer (NSCLC) from January to December 2009. Recurrence-free survival (RFS) and overall survival (OS) were compared among patients stratified by STAS subtypes. We also performed a prospective study of NSCLC resection specimens to evaluate the influence of a prosecting knife on the presence of STAS subtypes during specimen handling (83 cases).
STAS was found in 370 NSCLCs (46%), including 47 single cell STAS (13%), 187 micropapillary cluster STAS (50%), and 136 solid nest STAS (37%). STAS-negative patients had significantly better survival than patients with micropapillary cluster STAS (RFS:
< 0.001; OS:
< 0.001) and solid nest STAS (RFS:
< 0.001; OS:
< 0.001), but similar survival compared with those with single cell STAS (RFS:
= 0.995; OS:
= 0.71). Multivariate analysis revealed micropapillary cluster (RFS:
< 0.001; OS:
< 0.001) and solid nest STAS (RFS:
= 0.001; OS:
= 0.003) to be an independent prognostic indicator, but not for single cell STAS (RFS:
= 0.989; OS:
= 0.68). Similar results were obtained in subgroup analysis of patients with adenocarcinoma. The prospective study of NSCLC specimens suggested that 18 cases were considered as STAS false-positive, and most were singe cell pattern (13/18, 72%).
Single cell STAS was the common morphologic type of artifacts produced by a prosecting knife. A precise protocol of surgical specimen handling is required to minimize artifacts as much as possible.
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