NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma.

NRF2 (NFE2L2) is a transcription factor mainly for regulating cellular antioxidant response and therefore promotes tumor progression. The target genes of NRF2 also play important roles in cellular processes including glucose metabolism, de novo serine synthesis, iron metabolism, etc. Here, by modulating NRF2 expression in lung adenocarcinoma (LUAD) cells, we showed that NRF2 regulated EGF expression at protein level. Furthermore, EGF was identified as a ubiquitinated protein. We predicted three deubiquitinases of EGF, and OTUD4 had the highest correlation with NRF2 in LUAD among the three. OTUD4 expression was reduced upon NRF2 knocking-down and recovered upon NRF2 rescuing in A549 cells. Then a potential binding site for NRF2 in OTUD4 promoter was searched out. By binding with OTUD4 promoter, NRF2 transcriptionally activated OTUD4, thus promoted EGF deubiquitination and enhanced its stability. More importantly, OTUD4 and NRF2 expression was found being correlated in LUAD patients. The data collectively revealed a novel mechanism of NRF2 regulating on EGF stability through OTUD4 in LUAD.

Limited resection is comparable to lobectomy for tumor size ≤ 2 cm pulmonary invasive mucinous adenocarcinoma.

OBJECTIVES: Invasive mucinous adenocarcinoma (IMA) has a rare incidence with better prognosis than nonmucinous adenocarcinoma. We aimed to investigate the prognosis between limited resection and lobectomy for patients with clinical stage IA IMA ≤ 2 cm. METHODS: Data were taken from two cohorts: In Shanghai Pulmonary Hospital (SPH) corhort, we identified 403 patients with clinical stage IA IMA who underwent surgery. In the SEER corhort, 480 patients with stage T1 IMA who after surgery were included. Recurrence-free survival (RFS) for SPH corhort, lung cancer-specific survival (LCSS) for the SEER corhort and overall survival (OS) for both corhort were compared between patients undergoing lobectomy and limited resection by Log-rank and Cox proportional hazard regression model. RESULTS: In SPH corhort, patients who underwent limited resection had equivalent prognosis than those underwent lobectomy (5-year RFS: 79.3% versus. 82.6%, p = 0.116; 5-year OS: 86.2% versus. 88.3%, p = 0.235). However, patients with IMA > 2 to 3 cm had worse prognosis than those with IMA ≤ 2 cm (5-year RFS: 73.7% versus. 86.1%, p = 0.007). In the analysis of IMA > 2 to 3 cm subgroup, multivariate analysis showed that limited resection was an independent risk factor of RFS (hazard ratio, 2.417; 95% confidence interval, 1.157-5.049; p = 0.019), while OS (p = 0.122) was not significantly different between two groups. For IMA ≤ 2 cm, limited resection was not a risk factor of RFS (p = 0. 953) and OS (p = 0.552). In the SEER corhort, IMA ≤ 2 cm subgroup, limited resection was equivalent prognosis in LCSS (p = 0.703) and OS (p = 0.830). CONCLUSIONS: Limited resection could be a potential surgical option which comparable to lobectomy in patients with clinical stage IA IMA ≤ 2 cm.

Development of the semi-dry dot-blot method for intraoperative detecting micropapillary component in lung adenocarcinoma based on proteomics analysis.

BACKGROUND: Micropapillary (MIP) component was a major concern in determining surgical strategy in lung adenocarcinoma (LUAD). We sought to develop a novel method for detecting MIP component during surgery. METHODS: Differentially expressed proteins between MIP-positive and MIP-negative LUAD were identified through proteomics analysis. The semi-dry dot-blot (SDB) method which visualises the targeted protein was developed to detect MIP component. RESULTS: Cellular retinoic acid-binding protein 2 (CRABP2) was significantly upregulated in MIP-positive LUAD (P < 0.001), and the high CRABP2 expression zone showed spatial consistency with MIP component. CRABP2 expression was also associated with decreased recurrence-free survival (P < 0.001). In the prospective cohort, the accuracy and sensitivity of detecting MIP component using SDB method by visualising CRABP2 were 82.2% and 72.7%, which were comparable to these of pathologist. Pathologist with the aid of SDB method would improve greatly in diagnostic accuracy (86.4%) and sensitivity (78.2%). In patients with minor MIP component (≤5%), the sensitivity of SDB method (63.6%) was significantly higher than pathologist (45.4%). CONCLUSIONS: Intraoperative examination of CRABP2 using SDB method to detect MIP component reached comparable performance to pathologist, and SDB method had notable superiority than pathologist in detecting minor MIP component.

Imaging Features in BMPR2 Mutation-associated Pulmonary Arterial Hypertension.

Background Germline mutation in the BMPR2 gene is common in patients with pulmonary arterial hypertension (PAH). However, its association with imaging findings in these patients is, to the knowledge of the authors, unknown. Purpose To characterize distinctive pulmonary vascular abnormalities at CT and pulmonary artery angiography in patients with and without BMPR2 mutation. Materials and Methods In this retrospective study, chest CT scans, pulmonary artery angiograms, and genetic test data were acquired for patients diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH) between January 2010 and December 2021. Perivascular halo, neovascularity, centrilobular ground-glass opacity (GGO), and panlobular GGO were evaluated at CT and graded on a four-point severity scale by four independent readers. Clinical characteristics and imaging features between patients with BMPR2 mutation and noncarriers were analyzed using the Kendall rank-order coefficient and the Kruskal-Wallis test. Results This study included 82 patients with BMPR2 mutation (mean age, 38 years ± 15 [SD]; 34 men; 72 patients with IPAH and 10 patients with HPAH) and 193 patients without the mutation, all with IPAH (mean age, 41 years ± 15; 53 men). A total of 115 patients (42%; 115 of 275) had neovascularity, and 56 patients (20%; 56 of 275) had perivascular halo at CT, and so-called frost crystals were observed on pulmonary artery angiograms in 14 of 53 (26%) patients. Compared with patients without BMPR2 mutation, patients with BMPR2 mutation more frequently showed two distinctive radiographic manifestations, perivascular halo and neovascularity (38% [31 of 82] vs 13% [25 of 193] in perivascular halo [P < .001] and 60% [49 of 82] vs 34% [66 of 193] in neovascularity [P < .001], respectively). "Frost crystals" were more frequent in patients with BMPR2 mutation compared with noncarriers (53% [10 of 19] vs 12% [four of 34]; P < .01). Severe perivascular halo frequently coexisted with severe neovascularity in patients with BMPR2 mutation. Conclusion Patients with PAH with BMPR2 mutation showed distinctive features at CT, specifically perivascular halo and neovascularity. This suggested a link between the genetic, pulmonary, and systemic manifestations that underly the pathogenesis of PAH. © RSNA, 2023 Supplemental material is available for this article.

Characterization of the evolution trajectory and immune profiling of new histologic patterns in lung adenocarcinoma.

In lung adenocarcinoma (LUAD), the appearance of morphologically diverse tumor regions, termed histological patterns, is closely associated with disease progression and lymph node metastasis. However, the molecular characteristics of the histological patterns in LUAD and the underlying molecular evolutionary mechanisms between the histological patterns in primary tumors and lymph node metastases are poorly understood. Here, we re-analyzed the large TCGA-LUAD dataset and depicted a comprehensive profiling of the genome and transcriptome across the histological patterns in LUAD. Tumor phylogenetic trajectory analysis suggested that the complex glands is more apt to metastasize to the lymph node. Further deconvolution of the tumor microenvironment demonstrated that the complex glands had a higher infiltration of cancer-associated fibroblasts (CAFs). Single-cell transcriptome profiling of complex glands pattern identified a novel CAF subtype co-expressing fibroblast activation protein-alpha (FAP) and stimulator of interferon genes (STING). Moreover, our data demonstrated that FAP is an important downstream effector of STING in CAFs. In summary, our results provide the basis for the development of innovative therapeutic guidelines and intervention strategies for LUAD patients.

Identification of filigree pattern increases the diagnostic accuracy of micropapillary pattern on frozen section for lung adenocarcinoma.

AIMS: The presence of micropapillary (MIP) in early-stage lung adenocarcinoma is associated with a poorer prognosis, especially in patients undergoing sublobectomy. However, data on the sensitivity of frozen section (FS) evaluation of MIP is still limited. We included the concept of a filigree pattern on FS to assess its effect on the diagnostic sensitivity and specificity of MIP, and to verify its prognostic value in stage T1 lung adenocarcinoma. METHODS: A panel of five pathologists evaluated 125 patients with T1 lung adenocarcinoma from January to February 2014 as a study cohort, and 151 patients from January to February 2020 as a validation cohort. The diagnostic accuracy of the filigree and classical micropapillary (cMIP) pattern on FS was investigated. RESULTS: The diagnostic sensitivity of the MIP pattern on FS increased from 43.2% to 65.3% and 56.8% to 81.1% in the study cohort and validation cohort, respectively, and both with good specificity. Filigree not only increased the sensitivity of identifying MIP when there was an absence of cMIP, but also increased the sensitivity when the presence of a minor amount of cMIP. The almost perfect agreement among five pathologists was reached on cMIP and substantial agreement was reached on the filigree in the two cohorts. Moreover, the cMIP and filigree were both correlated with poorer recurrence-free survival (pcMIP = 0.003; pfiligree = 0.032) and overall survival (pcMIP = 0.004; pfiligree = 0.005). CONCLUSIONS: The identification of a filigree may improve the diagnostic sensitivity of the MIP pattern on FS. FS was feasible for the detection of filigree and cMIP patterns in stage T1 lung adenocarcinomas.

A clinicopathological study of lung adenocarcinomas with pure ground-glass opacity > 3 cm on high-resolution computed tomography.

OBJECTIVES: This study aimed to discuss whether a diameter of 3 cm is a threshold for diagnosing lung adenocarcinomas presenting with radiological pure ground-glass mass (PGGM, pure ground-glass opacity > 3 cm) as adenocarcinomas in situ or minimally invasive adenocarcinomas (AIS-MIAs). Another aim was to identify CT features and patient prognosis that differentiate AIS-MIAs from invasive adenocarcinomas (IACs) in patients with PGGMs. METHODS: From June 2007 to October 2015, 69 resected PGGMs with HRCT and followed up for ≥ 5 years were included in this study and divided into AIS-MIA (n = 13) and IAC (n = 56) groups. Firth's logistic regression model was performed to determine CT characteristics that helped distinguish IACs from AIS-MIAs. The discriminatory power of the significant predictors was tested with the area under the receiver operating characteristics curve (AUC). Disease recurrence was also evaluated. RESULTS: Univariable and multivariable analyses identified that the mean CT attenuation (odds ratio: 1.054, p = 0.0087) was the sole significant predictor for preoperatively discriminating IACs from AIS-MIAs in patients with PGGMs. The CT attenuation had an excellent differentiating accuracy (AUC: 0.981), with the optimal cut-off value at -600 HU (sensitivity: 87.5%; specificity: 100%). Additionally, no recurrence was observed in patients manifesting with PGGMs > 3 cm, and the 5-year recurrence-free survival and overall survival rates were both 100%, even in cases of IAC. CONCLUSIONS: This study demonstrated that PGGMs > 3 cm could still be AIS-MIAs. When PGGMs are encountered in clinical practice, the CT value may be the only valuable parameter to preoperatively distinguish IACs from AIS-MIAs. KEY POINTS: • Patients with pure ground-glass opacity > 3 cm in diameter are rare but can be diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. • The mean CT attenuation is the sole significant CT parameter that differentiates invasive adenocarcinoma from adenocarcinoma in situ or minimally invasive adenocarcinoma in patients with pure ground-glass opacity > 3 cm. • Lung adenocarcinoma with pure ground-glass opacity > 3 cm has an excellent prognosis, even in cases of invasive adenocarcinoma.

Recognition of filigree pattern expands the concept of micropapillary subtype in patients with surgically resected lung adenocarcinoma.

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.

Clinicopathological and prognostic analyses of 86 resected pulmonary lymphoepithelioma-like carcinomas.

BACKGROUND: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. The present study aims at investigating clinicopathological features and prognostic characteristics of the resected pulmonary LELC. METHODS: Patients with resected pulmonary LELC were identified in our hospital from December 2008 to December 2018. Data of these patients were retrospectively reviewed, clinicopathological features and prognostic characteristics were analyzed subsequently. RESULTS: In total, 86 patients were enrolled in the study, including 39 (45.3%) males and 47 (54.7%) females. Most of the serum tumor markers were normal. Immunohistochemical staining result showed frequent differentiation traits of epithelial tissue such. Positive PD-L1 (15 of 19, 78.9%) and PD-1 (13 of 17, 76.5%) were also common, but cancer-related genetic mutation was scarce (1 of 47, 2.1%). Survival analyses demonstrated that the N stage (p = .011) and extent of resection (p = .023) were identified as independent predictive factors for overall survival. CONCLUSIONS: Pulmonary LELC is a distinctive subtype of lung cancer with several exclusive traits, such as the trend to happen among nonsmoking young people, epithelial origin of tumor differentiation, frequent expression of the immune checkpoint, and scarce presence of driver mutation. In addition, pulmonary LELC was apt to get a favorable outcome, especially in cases diagnosed and treated in the early stage.

Prognostic Impact of Tumor Spread Through Air Spaces in Sublobar Resection for 1A Lung Adenocarcinoma Patients.

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.

Critical role of molecular test in early diagnosis of gastric tuberculosis: a rare case report and review of literature.

BACKGROUD: Early diagnosis of gastric tuberculosis is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of gastric tuberculosis, we present a case of gastric tuberculosis secondary to pleural and pulmonary tuberculosis. CASE PRESENTATION: A 26-year-old woman complained gastric pain for 1 month but showed no other symptoms, who had no previous exposure to tuberculosis.Gastric stromal tumor was originally suspected. However, the pathology of her gastroscopic biopsy of the gastric lesion showed granulomatous lesions and caseating necrosis. Gene sequencing of the biopsy specimen identified deoxyribonucleic acid fragment of Mycobacterium tuberculosis. Chest computed tomography scan revealed nodular shadows in the lesser curvature soft tissue of the stomach, patchy densities and calcified nodular shadows in the upper right lung, bilateral pleural thickening, and calcified pleural nodules. Thus, the diagnosis was gastric tuberculosis secondary to pulmonary and pleural tuberculosis. The patient was hospitalized and treated with the antituberculosis therapy for 1 week. After discharged from the hospital, the patient continued routine antituberculosis therapy for 18 months and was follow-up was normal.Literature search found 22 cases of gastric tuberculosis reported from 2000 to 2016. Review of the 22 cases suggested that polymerase chain reaction has been increasingly used in the recent years in addition to the conventional histopathological and bacteriological approaches. CONCLUSION: Clinical presentation of gastric tuberculosis is not specific.When granuloma or caseation is detected on biopsy in patients who are suspected of having gastric malignancy or acid peptic diseases, polymerase chain reaction for Mycobacterium tuberculosis could be used as an available and sensitive diagnostic test in addition to pathology, acid-fast bacilli smear staining and culture.

SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer.

FAS-associated protein with death domain (FADD) is the pivotal adaptor protein, which transmits apoptotic signals mediated by the death receptors. Here we report that high FADD protein level predicts poor prognosis of non-small cell lung cancer (NSCLC) patients and its protein level is mainly regulated by the 26S proteasome. We also found that ubiquitin ligase SPOP (speckle-type POZ protein) binds to FADD and mediates its degradation, which can be blocked by MG132 treatment. Notably, SPOP inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity and its target genes expression via FADD. These results reveal the function of SPOP-FADDNFκB axis in NSCLC cells, which is associated with prognosis of NSCLC patients.

Intraoperatively measured tumor size and frozen section results should be considered jointly to predict the final pathology for lung adenocarcinoma.

Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section. We retrospectively reviewed 1,111 lung adenocarcinomas from January to March 2016 to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of adenocarcinoma in situ or minimally invasive adenocarcinoma diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts (first: April to June 2016, second: January to March 2015) were included to confirm the results. The overall concordance rate between frozen section and final diagnosis was 92%. Most frozen section errors were underestimation. The sensitivity of frozen section diagnosis for minimally invasive adenocarcinoma (74%) was significantly lower than others. Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (<1 cm: 2%, reference; 1-1.4 cm: 15%, odds ratio, 5.678; > 1.5 cm: 18%, odds ratio, 5.878; P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason. Our study suggests that adenocarcinoma in situ or minimally invasive adenocarcinoma ≥1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error. Frozen section diagnosis of adenocarcinoma in situ or minimally invasive adenocarcinoma should be considered cautiously for tumors ≥1 cm to avoid potentially insufficient resection.

Lymph Node Micrometastasis Prognosticates Survival for Patients with Stage 1 Bronchogenic Adenocarcinoma.

BACKGROUND: This study aimed to investigate the significance of lymph node micrometastasis (LNMM) in the lung cancer nodal categories. METHODS: Between 1 January 2009 and 31 December 2013, 589 patients with suspected c-stage 1 and p-T1-2aN0-1M0 lung adenocarcinoma were enrolled in this study. The study evaluated LNMM with cytokeratin (AE1/AE3) and transcription factor-1 (TTF1) (8G7G3/1) expression by immunohistochemistry. Recurrence-free survival (RFS) and overall survival (OS) were compared among the T1-2aN0-1M0 patients stratified by the new N categories. RESULTS: From 589 patients, 7892 removed lymph nodes were examined, and LNMM was observed in 55 (9.3%) of the patients. The patients without LNMM or N1 had the best RFS (5-year rate: 80% vs 25%; P < 0.001) and OS (5-year rate: 87% vs 43%; P < 0.001), followed by the patients with LNMM, compared with those in the N1 category (RFS: 5-year rate, 25% vs 8%; P = 0.010; OS: 5-year rate, 43% vs 20%; P = 0.009). Similarly, this trend was observed when patients were subdivided into the T1 and T2a categories. Multivariate analysis showed that the new N categories with the addition of LNMM were an independent prognostic factor. This result also was noticed in all subgroups. CONCLUSIONS: The findings showed LNMM to be clinically significant as a risk factor for lung cancer. Clinicians should consider LNMM when estimating N categories to determine prognosis and the best treatment strategy.

The predictive value of CT-based radiomics in differentiating indolent from invasive lung adenocarcinoma in patients with pulmonary nodules.

OBJECTIVES: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are assumed to be indolent lung adenocarcinoma with excellent prognosis. We aim to identify these lesions from invasive adenocarcinoma (IA) by a radiomics approach. METHODS: This retrospective study was approved by institutional review board with a waiver of informed consent. Pathologically confirmed lung adenocarcinomas manifested as lung nodules less than 3 cm were retrospectively identified. In-house software was used to quantitatively extract 60 CT-based radiomics features quantifying nodule's volume, intensity and texture property through manual segmentation. In order to differentiate AIS/MIA from IA, least absolute shrinkage and selection operator (LASSO) logistic regression was used for feature selection and developing radiomics signatures. The predictive performance of the signature was evaluated via receiver operating curve (ROC) and calibration curve, and validated using an independent cohort. RESULTS: 402 eligible patients were included and divided into the primary cohort (n = 207) and the validation cohort (n = 195). Using the primary cohort, we developed a radiomics signature based on five radiomics features. The signature showed good discrimination between MIA/AIS and IA in both the primary and validation cohort, with AUCs of 0.95 (95% CI, 0.91-0.98) and 0.89 (95% CI, 0.84-0.93), respectively. Multivariate logistic analysis revealed that the signature (OR, 13.3; 95% CI, 6.2-28.5; p < 0.001) and gender (OR, 3.5; 95% CI, 1.2-10.9; p = 0.03) were independent predictors of indolent lung adenocarcinoma. CONCLUSION: The signature based on radiomics features helps to differentiate indolent from invasive lung adenocarcinoma, which might be useful in guiding the intervention choice for patients with pulmonary nodules. KEY POINTS: • Based on radiomics features, a signature is established to differentiate adenocarcinoma in situ and minimally invasive adenocarcinoma from invasive lung adenocarcinoma.

Development and validation of a nomogram to estimate the pretest probability of cancer in Chinese patients with solid solitary pulmonary nodules: A multi-institutional study.

OBJECTIVES: To develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN). MATERIALS AND METHODS: A primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC). RESULTS: The mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83-0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability. CONCLUSIONS: We developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests.

Clinical and radiological features of synchronous pure ground-glass nodules observed along with operable non-small cell lung cancer.

BACKGROUND: It is common to observe synchronous pure ground-glass nodules (PGN) along with operable primary tumor on initial CT scans while clinical and radiological features of these PGNs remain unclear. METHODS: We included patients with primary tumor and PGNs detected between June 2010 and December 2013 retrospectively. The radiographic manifestations of all PGNs, pathologic findings of resected PGNs, and follow-up outcomes of unresected PGNs were analyzed to determine the predictors of malignant PGNs. RESULTS: Overall, 84 PGNs in 71 patients were included, of which 41 were resected at primary surgery and 43 were followed up. In resected group, there were 17 carcinomatous PGNs, 11 atypical adenomatous hyperplasia, and 13 benign lesions. In a follow-up group, 7 out of 43 PGNs grew, out of which four PGNs were diagnosed as adenocarcinoma and the remaining three PGNs were still followed up. In univariate analysis, size (P < 0.001), air bronchogram (P = 0.001), bubble lucency (P = 0.038), and pleural tag (P = 0.004) were the factors for malignant potential of PGNs. Multivariate analysis showed that size was an independent risk factor (P = 0.005), and the cut-off value was 9.4 mm. CONCLUSIONS: The initial size and imaging signs may be useful in assessing the malignant potential of synchronous PGNs before surgery. J. Surg. Oncol. 2016;113:738-744. © 2016 Wiley Periodicals, Inc.

[Expression of p63, p40 and CK5/6 in small cell lung cancer].

OBJECTIVE: To study the expression of squamous cell markers p63, p40 and CK5/6 in small cell carcinoma of lung (SCLC). METHODS: Immunohistochemical study for squamous cell markers (p63, p40 and CK5/6), neuroendocrine markers (chromogranin A, synaptophysin and CD56) and TTF1 was carried out in 283 cases of SCLC. The diagnostic value of these markers was evaluated. RESULTS: The expression rate of p63, p40 and CK5/6 were 20.7% (54/261), 7.9% (5/63) and 0.5% (1/221), respectively in the cases of SCLC studied. Amongst the squamous cell markers, CK5/6 had the lowest rate of positivity (P < 0.01). On the other hand, chromogranin A, synaptophysin and CD56 were positive in 61.8% (170/275), 85.5% (242/283) and 89.2% (248/278), respectively. The positivity rate for chromogranin A was lower than that for synaptophysin and CD56 (P < 0.01). TTF1 was expressed in 77.2% (217/281). CONCLUSIONS: p63 and p40 are expressed in a subset of SCLC. In contrast, CK5/6 is rarely positive in SCLC. An immunohistochemical panel of CK5/6, synaptophysin and CD56 is recommended for differential diagnosis of SCLC.

Hypoxia-Derived Exosomes Promote Lung Adenocarcinoma by Regulating HS3ST1-GPC4-Mediated Glycolysis.

OBJECTIVE: The diagnosis of lung adenocarcinoma (LUAD) is often delayed due to the typically asymptomatic nature of the early-stage disease, causing advanced-stage LUAD diagnosis in most patients. Hypoxia is widely recognized as a driving force in cancer progression. Exosomes originating from hypoxic tumor cells promote tumorigenesis by influencing glycolysis, migration, invasion, and immune infiltration. Given these insights, our study aimed to explore the role of hypoxia-derived exosomal long non-coding RNA (lncRNA) OIP5-AS1 in LUAD cell lines and mouse models. MATERIALS AND METHODS: Exosomes were meticulously isolated and authenticated based on their morphology and biomarkers. The interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4) was examined using immunoprecipitation. The influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on glycolysis was assessed in LUAD cell lines. The effect of the hypoxia-derived exosomal lncRNA OIP5-AS1 on cell proliferation and metastasis was evaluated using colony formation, cell viability, cell cycle, and apoptosis analyses. Its effects on tumor size were confirmed in xenograft animal models. RESULTS: Our study revealed the mechanism of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. We discovered that GPC4 promotes HS3ST1-mediated glycolysis and that the hypoxia-derived exosomal lncRNA OIP5-AS1 enhances glycolysis by regulating miR-200c-3p in LUAD cells. Notably, this lncRNA stimulates LUAD cell proliferation and metastasis and fosters LUAD tumor size via miR-200c-3p. Our findings underscore the potential role of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. CONCLUSIONS: The hypoxia-derived exosomal lncRNA OIP5-AS1 promotes LUAD by regulating HS3ST1-GPC4-mediated glycolysis via miR-200c-3p.