Invasive Adenocarcinoma Research Articles

High expression of eukaryotic elongation factor 1-alpha-2 in lung adenocarcinoma is associated with poor prognosis.

Eukaryotic elongation factor 1 alpha 2 (eEF1A2) encodes an isoform of the alpha subunit of the elongation factor 1 complex and is responsible for the enzymatic delivery of aminoacyl tRNA to the ribosome. Our proteomic analysis has identified eEF1A2 as one of the proteins expressed during malignant progression from adenocarcinoma in situ (AIS) to early invasive lung adenocarcinoma. The expression level of eEF1A2 in 175 lung adenocarcinomas was examined by immunohistochemical staining in relation to patient prognosis and clinicopathological factors. Quantitative PCR analysis and fluorescence in situ hybridization (FISH) were performed to evaluate the amplification of the eEF1A2 gene. Relatively high expression of eEF1A2 was observed in invasive adenocarcinoma (39/144 cases) relative to minimally invasive adenocarcinoma (1/10 cases) or AIS (0/21 cases). Among invasive adenocarcinomas, solid-type adenocarcinoma (15/32 cases, 47%) showed higher expression than other histological subtypes (23/92, 25%). Patients with eEF1A2-positive tumors had a significantly poorer prognosis than those with eEF1A2-negative tumors. Of the five tumors that were eEF1A2-positive, two cases showed amplified genomic eEF1A2 DNA, which was confirmed by both qPCR and FISH. These findings indicate that eEF1A2 overexpression occurs in the course of malignant transformation of lung adenocarcinomas and is partly due to eEF1A2 gene amplification.

Correlation between common driver gene variations and clinicopathological typing in lung adenocarcinoma

Objective: To correlate the common driver gene variations in primary lung adenocarcinoma with their clinical characteristics and histopathological subtypes. Methods: There were 4 995 cases of primary lung adenocarcinoma diagnosed at Weifang People's Hospital of Shandong Province from January 2015 to December 2021 which were retrospectively analyzed. Among them 1 983 cases were evaluated for their histopathological subtype; 3 012 were analyzed for the correlation of their histopathological subtypes and corresponding driver gene variations, including invasive non-mucinous adenocarcinoma (INMA) and invasive mucinous adenocarcinoma (IMA), and morphologically, poorly-differentiated, moderately-differentiated and well-differentiated adenocarcinomas. Next-generation sequencing was used to detect variations in EGFR, KRAS, ALK, RET, ROS1, MET, HER2, or BRAF driver genes. Results: There were 2 384 males and 2 611 females. EGFR and ALK variations were more commonly found in female patients aged 60 years or older, with EGFR mutation rate in clinical stage Ⅰ (25.80%) significantly higher than in other stages (P<0.05). KRAS mutations were more commonly detected in male smokers aged 60 years or older, HER2 mutations were more commonly in patients younger than 60 years, and RET mutations were more commonly in non-smokers (all P<0.05). No correlation was found between ROS1, MET, and BRAF gene variations and their clinical characteristics (P>0.05). For the histopathological subtypes, among the 1 899 cases of acinar adenocarcinoma, EGFR mutation rate was the highest (67.30%) compared to the other genes. Exon 21 L858R and exon 19 del were the main mutation sites in IMA and INMA, with a higher mutation rate at exon 20 T790M (11.63%) in micropapillary adenocarcinoma. In IMA, KRAS had the highest overall mutation rate (43.80%), with statistically significant difference in mutation rates of exon 2 G12D and exon 2 G12V in acinar adenocarcinoma, solid, and IMA (P<0.05). KRAS mutation at various sites were higher in poorly differentiated groups compared to moderately- and well-differentiated groups (P<0.05). HER2 mutations were more commonly observed in acinar adenocarcinoma, papillary, and micropapillary adenocarcinoma of INMA. BRAF mutation was higher in micropapillary adenocarcinoma compared with other types (P<0.05). Conclusions: Variations in EGFR, ALK, KRAS, HER2, and RET in primary lung adenocarcinoma are associated with patients' age, smoking history, and clinical stage, and driver gene mutations vary among different histopathological subtypes. EGFR mutations are predominant in INMA, while KRAS mutations are predominant in IMA.

Primary mucinous gland lesions of fallopian tube: a clinicopathological analysis of fourteen cases

Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.

Spatial whole exome sequencing reveals the genetic features of highly-aggressive components in lung adenocarcinoma

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes, especially the highly aggressive components.Based on a cohort of 5,933 patients, this study observed that in different tumor size groups, LUAD with MIP/SOL components showed a different prevalence, and patients with ALK alteration or TP53 mutations had a higher probability of developing MIP/SOL components. To control individual differences, this research used spatial whole-exome sequencing (WES) via laser-capture microdissection of five patients harboring these five coexistent components and identified genetic features among different histologic components of the same tumor. In tracing the evolution of components, we found that titin (TTN) mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by a cohort of 146 LUAD patients undergoing bulk WES. Functional analysis revealed that TTN mutations enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation.Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

The Battle for Accuracy: Identifying the Most Effective Grading System for Lung Invasive Mucinous Adenocarcinoma.

The prognostic analysis of lung invasive mucinous adenocarcinoma (IMA) is deficient due to the lack of a universally recommended histological grading system, leading to unregulated treatment approaches. We aimed to examine the clinical trajectory of IMA and assess the viability of utilizing the existing grading system for lung invasive non-mucinous adenocarcinoma in the context of IMA. We retrospectively collected clinicopathological data from 265 IMA patients. Each case re-evaluated the tumor grade using the following three classification systems: the 4th Edition of the World Health Organization classification system, the International Association for the Study of Lung Cancer (IASLC) grading system, and a two-tier grading system. We performed a comparative analysis of these grading systems and identified the most effective grading system for IMA. The study comprised a total of 214 patients with pure IMA and 51 patients with mixed IMA. The 5-year overall survival (OS) rates for pure IMA and mixed IMA were 86.7% and 57.8%, respectively. All three grading systems proved to be effective prognostic classifiers for IMA. The value of area under the curve at 1-, 3-, and 5-year OS was highest for the IASLC grading system compared with the other grade systems and the clinical stage. The IASLC classification system was an independent prognostic predictor (p=0.009, hazard ratio 2.243, 95% confidence interval 1.219-4.127). Mixed IMA is more aggressive than pure IMA, with an OS rate on par with that of high-grade pure IMA. The IASLC grading system can better indicate prognosis and is recommended for lung IMA.

BATF-dependent Th17 cells act through the IL-23R pathway to promote prostate adenocarcinoma initiation and progression.

The role of Th17 cells in prostate cancer is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. In this study, we aimed to characterize the role of Batf-dependent Th17 cells in prostate cancer by crossbreeding Batf knockout mice with mice conditionally mutant for Pten. We found that Batf knockout mice had changes in the morphology of prostate epithelial cells compared with normal mice, and Batf knockout mice deficient in Pten (called Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (called Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of nuclear factor-κB signaling. Moreover, Batf- mice showed significantly reduced interleukin 23 (IL-23)-IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared with Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL-23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared with control immunoglobulin G-treated mice. In human prostate tumors, BATF messenger RNA level was positively correlated with IL-23A and IL-23R but not RORC. Our novel findings underscore the crucial role of IL-23-IL-23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting prostate cancer initiation and progression. This finding highlights the BATF-IL-23R axis as a promising target for the development of innovative strategies for prostate cancer prevention and treatment.

Clinicopathological analysis of bronchiolar adenoma combined with lung adenocarcinoma: Report of eight cases and literature review.

To investigate the clinicopathological characteristics and potential diagnostic pitfalls of bronchiolar adenoma (BA) combined with lung adenocarcinoma (LUAD) in the same lesion. We analyzed eight cases of BA combined with LUAD from our hospital pathology department between July 2020 and January 2022, and summarized their clinical data, radiological features, histopathological characteristics and immunohistochemical phenotypes. Upon macroscopic examination, the lesions were characterized by gray-white or gray-brown solid nodules with well-defined borders, measuring 0.6-1.8cm in maximum diameter. The incidence of proximal-type BA (6/8) was higher than that of distal-type BA (2/8), and they combined with different stages of LUAD, including adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and invasive mucinous adenocarcinoma (IMA). Immunohistochemistry showed that cytokeratin 5/6 and P40 were positive in the continuous basal cell layer in BA, but only scattered positive basal cells were seen at the junction of BA and LUAD. TTF-1 was positive in proximal-type BA ciliated cells in five cases and in LUAD cells in seven cases, and weakly positive in some basal cells. One case of IMA and mucinous cells of BA were TTF-1 negative. There was partially positive Napsin-A expression in BA luminal cells and LUAD cells of all cases except IMA. There is no obvious boundary when BA and LUAD are in the same lesion. The luminal epithelial cells in the area where the two components migrate toward each other are atypical and lack a continuous underlying basal cell layer. Microscopic diagnosis should be aided by immunohistochemistry.

Integrated whole-exome and bulk transcriptome sequencing delineates the dynamic evolution from preneoplasia to invasive lung adenocarcinoma featured with ground-glass nodules.

The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma insitu (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.

Clinicopathologic and molecular landscape of invasive mucinous adenocarcinoma of the lung.

8037 Background: Invasive mucinous adenocarcinoma (IMA), accounting for 2–10% of lung adenocarcinomas, often mimics pneumonia with multicentric opacities in multiple lobes and both lungs. Notable for its microscopic skip lesions leading to tumor spread through air spaces (STAS), IMA is still under-researched in terms of its comprehensive clinical and genetic characteristics in large, multicenter studies. Methods: Primary lung cancer cases were obtained from the Tempus database, categorized into either IMA or non-IMA, and compared by patient, clinical, biopsy, and molecular characteristics. The normalization of RNA-seq data involved computing transcripts per million (TPM), performing log2 transformations, and adjusting for assay and batch effects. Significantly up- and down-regulated genes were defined as false discovery rate q-values &lt; 0.05 and |log2(fold change)| &gt; 0.5. Results: The study analyzed 18,857 cases, with 655 (3.5%) in the IMA group and 18,202 (96.5%) in the non-IMA group. The IMA group predominantly consisted of older individuals (median age 70 vs. 68; p&lt;0.001), had fewer smokers (63% vs. 73%; p&lt;0.001), and included more individuals of Hispanic or Latino ethnicity (4.3% vs. 2.7%; p=0.007). This group was more likely to be diagnosed with early-stage cancer and less likely to have stage 4 cancer at diagnosis (stage 1: 23% vs. 14%, stage 2: 18% vs. 7.3%, stage 3: 23% vs. 17%, stage 4: 36% vs. 62%; p&lt;0.001). They exhibited significantly lower tumor mutational and neoantigen burdens (median 3.1 vs. 4.6 mutations/Mb and 6 vs. 9 neoantigens/Mb, respectively; both p&lt;0.001), fewer positive PD-L1 statuses (27% vs. 58%; p&lt;0.001), and different immune cell infiltration patterns (Table). Gene expression analysis revealed 416 upregulated and 258 downregulated genes in the IMA group compared to the non-IMA group. Conclusions: This analysis underscores the unique clinicopathologic and molecular characteristics of IMAs. An improved understanding of IMA’s biological behavior could lead to the development of more effective, personalized treatment strategies. [Table: see text]

Double lung transplantation in patients with metastatic lung-limited non-small cell lung carcinoma (NSCLC): A case series.

8643 Background: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. Double lung transplantation (DLT) may offer curative treatment for metastatic lung-limited NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 02/2024 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study cohort A (NCT05671887). Exclusion criteria includes presence of extrapulmonary disease. Results: Six patients with stage IVA NSCLC who underwent lung transplantation were included. Five (83.3%) patients underwent double lung, and one (16.7%) patient single lung transplantation. Four (66.7%) patients had invasive mucinous, and two (33.3%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-71; one (16.7%) was Asian, five (83.3%) were White, four (66.7%) were male, and three (50%) had a history of smoking. One (16.7%) patient had a past medical history of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). The median pretransplant treatment lines were 2 (1-5). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C &gt; T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 28, 18, 8, 8, 5, and 4-month posttransplant follow-up. Conclusions: Six patients underwent DLT successfully without significant complications. All patients were alive and in good health. Ongoing DREAM study will continue to investigate the role of DLT in metastatic lung-limited NSCLC patients (especially in pN0). Clinical trial information: NCT05671887 .

Efficacy of systemic treatments in patients with metastatic lung invasive mucinous adenocarcinoma.

e20609 Background: Invasive mucinous adenocarcinoma (IMA) is a relatively rare histological subtype of lung adenocarcinomas that differs in its clinical behavior, radiologic features, histopathological, and genomic characteristics than invasive non-mucinous adenocarcinomas (INMA). Methods: We retrospectively investigated medical records of patients diagnosed with lung IMA at four oncology centers in Turkey. Patients who were ≥18 years of age, pathologically diagnosed with lung IMA, and who received at least one course of treatment for metastatic or inoperable disease were included in the study. Results: Forty-one patients were included in the study. The median follow-up was 16.6 months. Among the included patients, 24 (58.5%) were male, 17 (38.5%) were female, and their average age was 62. Six (14.6%) patients had a targetable mutation. Three (7.3%) patients were epidermal growth factor receptor (EGFR), two (4.8%) anaplastic lymphoma kinase (ALK) mutation, and one (2.4%) neurotrophic tyrosine receptor kinase (NTRK2) fusion. Most patients (83.1%) had received platinum-based chemotherapy as a first-line treatment. Of the patients who received cytotoxic chemotherapy, 9 (25.7%) had a partial response, 14 (40%) had a stable response, and 12 (34.3%) had progression. The median PFS was 8.24 months (95% CI: 5.9-10.5 months), and the median OS was 20.4 months (95% CI: 14.4-26.3 months) in all study populations. In those receiving cytotoxic chemotherapy, median PFS and OS were 8.11 months (95% CI: 5.02-11.2) and 17.5 months (95% CI: 11.7-23.3 months), respectively. While the PFS of two EGFR-positive patients were similar at 18.9 months and 20.6 months, the third patient's PFS was quite prolonged (66.5 months). The ALK-positive patients receiving brigatinib and crizotinib PFS were 15.8 months and 2.73 months, respectively. The PFS of the patient receiving entrectinib was only two months. Among the entire patient population, only one patient used oxaliplatin and capecitabine combination (XELOX) as chemotherapy. In this patient, who progressed after four cycles of gemcitabine and platinum first-line treatment, a partial response and 7.23 months PFS were achieved with second line XELOX. Conclusions: Standard-of-care treatments have the same efficacy in IMA and INMA patients. Targetable mutation is less common in IMA patients compared to INMA. 5-FU-based chemotherapies also appear to be effective in lung IMA patients.

Artificial intelligence-based prediction model of malignant lung nodules for preoperative planning.

8034 Background: The histopathological prediction of malignant lung nodules is crucial for preoperative planning, but it always remains not precise until the detailed pathological evaluation is performed after the surgery. Thus, to define the histology types (in situ adenocarcinoma (AIS), microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA)) of pulmonary adenocarcinoma appearing as lung nodules before the operation and reduce unnecessary invasive diagnosis and treatment operations, we developed a classification model of based on CT images. Methods: Patients who were diagnosed with pulmonary adenocarcinoma (tumor diameter ≤ 3cm) at Nanfang Hospital, Southern Medical University, China, were retrospectively enrolled, including detailed pathology results, computed tomography (CT) images, and basic information. Through training the model proposed in our previous study, we proposed a new model for defining histopathological types. Then, we used this data to train and compare the diagnostic efficacy of our model with another previously reported deep learning (DL) model (that was a segmentation - classification model with the 3D Unet++ - ResNet-50 combined model) and machine learning (ML) model (that was a traditional model Grey Level Co-occurrence Matrices (GLCM) as the feature extractor and the support vector machine (SVM) as the classifier) in the same method. Results: A total of 2061 patients (with 395 of AIS, 334 of MIA and 1332 of IA) were retrospectively enrolled from January 2019 to April 2022. The data from 2/3 of the patients were randomly selected for training and another 1/3 for verifying. Through training and verifying, our model shows much better diagnostic efficacy, with areas under receiver operating characteristic (ROC) curves with 95% confidence interval (CI) of 0.97(0.96, 0.98), comparing with those of the ML model of 0.77(0.73, 0.81) and the DL model of (0.90(0.88, 0.92). The heatmap visualization of the proposed model shows the classification ability with prediction probabilities of our model clearly and understandably. Conclusions: In this study, we developed a novel artificial intelligence multi-task learning model to precisely predict the pathology type of malignant lung nodules with satisfying diagnostic efficacy, which might provide a new and reliable way for preoperative planning of lung nodules. Further external verifying should be done in the future. In addition, prediction of the growth patterns of pulmonary adenocarcinoma could be more helpful in addition to predicting histopathological types.

Adaptively learning visual model of surgical resection images via coarse-to-fine–grained strategy for pathological invasiveness prediction in indeterminate stage IA lung adenocarcinoma.

1563 Background: Indeterminate nodules with high risk of malignancy are suggested to receive video-assisted thoracoscopy biopsy. Frozen section assists surgeons to decide surgical strategies for stage IA lung adenocarcinoma (LUAD) intraoperatively, which is time-consuming and may misdiagnosis due to limited sampling and poor tissue quality. Methods: We prospectively enrolled stage IA LUAD patients underwent complete resection between June 2020 and September 2023 in Guangdong Provincial People's Hospital (GDPH), Affiliated Hospital of Guangdong Medical University, Meizhou People's Hospital. All the resected lung nodules were finally diagnosed as pre-invasive lesion (PIL), minimally invasive adenocarcinoma (MIA) or invasive lung adenocarcinoma (IAC) by FFPE pathological diagnosis. Images of the whole section of the lung nodules were taken by smartphones under natural lighting condition in operating theaters without shadowless surgical lights. Patients received preoperative anti-cancer therapy and with low-quality tumor section images were excluded. Images of nodules section, FS reports, FFPE diagnosis and clinical information were prospectively collected. Predictive artificial intelligence (AI) model was developed by a three-step process, which first predict the IAC and non-IAC region at coarse level, and identify fine level features through the high-risk region. The coarse and fine labels were then coordinated through risk ranking loss to reach a final predictive result. Results: We prospectively enrolled 1516 patients with 1638 indetermined lung nodules from preoperative chest CT following the inclusion and exclusion criteria, with 2438 images acquired from intraoperative nodule sections. The included patients have median age of 57 years old and 38.6% male patients. The pathological diagnosis for included lung nodules are 122 PIL nodules, 502 MIA nodules and 1014 stage IA LUAD. A multi-task artificial intelligence based on Coarse-to-Fine-Grained Strategy has been established to classify the indetermined lung nodules during the surgery. For binary classification, AI model reach an AUC of 0.86 in differentiation between IAC or non-IAC. For 3-classification level, AI model reach an AUC of 0.87 in differentiation between PIL, MIA or IAC. We further defined the IAC nodules into G1, G2 and G3 according to IASLC lung adenocarcinoma grading system. For 5-classification level, AI model reach an AUC of 0.86 in differentiation between PIL, MIA, IAC-G1, IAC-G2 and IAC-G3. Conclusions: Our AI models based on images of intraoperative surgical resection could effectively classify indetermined lung nodules, which can assist thoracic surgeons diagnose the nodules rapidly during the surging and decide the following surgical strategies. Clinical trial information: ChiCTR2300075999 .

Deciphering lung adenocarcinoma evolution: Integrative single-cell genomics identifies the prognostic lung progression associated signature.

We employed single-cell analysis techniques, specifically the inferCNV method, to dissect the complex progression of lung adenocarcinoma (LUAD) from adenocarcinoma insitu (AIS) through minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IAC). This approach enabled the identification of Cluster 6, which was significantly associated with LUAD progression. Our comprehensive analysis included intercellular interaction, transcription factor regulatory networks, trajectory analysis, and gene set variation analysis (GSVA), leading to the development of the lung progression associated signature (LPAS). Interestingly, we discovered that the LPAS not only accurately predicts the prognosis of LUAD patients but also forecasts genomic alterations, distinguishes between 'cold' and 'hot' tumours, and identifies potential candidates suitable for immunotherapy. PSMB1, identified within Cluster 6, was experimentally shown to significantly enhance cancer cell invasion and migration, highlighting the clinical relevance of LPAS in predicting LUAD progression and providing a potential target for therapeutic intervention. Our findings suggest that LPAS offers a novel biomarker for LUAD patient stratification, with significant implications for improving prognostic accuracy and guiding treatment decisions.

Broad-spectrum antibiotic use and risk of early-onset colorectal cancer.

e15653 Background: The incidence of early-onset colorectal cancer (eoCRC) diagnosed under age 50 is rising in the United States, but the underlying causes are largely unknown. Use of broad-spectrum antibiotics can induce intense gut dysbiosis, which is strongly implicated in CRC carcinogenesis. Emerging evidence supports a link between broad-spectrum antibiotic use and CRC. We evaluated the associations between oral broad-spectrum antibiotic use and risk of eoCRC. Methods: We conducted a nested case-control study within Kaiser Permanente Southern California (KPSC). Cases were persons aged 15-49 years with invasive colorectal adenocarcinoma diagnosis between 2009-2021; controls were matched at 10:1 ratio on age, sex at birth, and length of KPSC membership. Those with less than 15 years of prior membership at diagnosis date or controls’ index date were excluded to allow evaluation of exposure up to 15 years prior. We extracted all study data, including use of antibiotics by drug type and days of prescriptions, from KSPC’s electronic medical records. Conditional logistic regression was used to evaluate antibiotic use from three etiologic periods: 10-15, 5-10, and 2-5 years prior to diagnosis/index date, adjusting for potential confounders (narrow-spectrum antibiotics use, clinical and lifestyle risk factors, race/ethnicity, body mass index) with a crude p-value &lt; 0.10. Analyses were conducted overall and separately for colon cancer. Results: A total of 310 cases (mean age at diagnosis 44.5 years, 52% female, 33% non-Hispanic White) and 2,976 controls were included. In the 10-15 years prior to diagnosis/index date, 65% of cases and 62% of controls used broad-spectrum antibiotics. Broad-spectrum antibiotic use was not associated with eoCRC overall [OR = 1.15 (95% CI: 0.88-1.49)]. An increased risk was suggested for &gt; 3 months of cumulative use: OR = 1.07 (0.81-1.42) for ≤1 month; 1.26 (0.87-1.84) for 1-3 months; and 1.59 (0.95-2.65) for &gt; 3 months. The association between exposure and colon adenocarcinoma was: OR = 1.26 (0.91-1.72) for any use; OR = 1.17 (0.83-1.64) for ≤1 month; and OR = 1.50 (0.99-2.27) for &gt; 1 month. No association was observed between broad-spectrum antibiotic use within 5-9.9 years or 2-4.9 years prior to diagnosis and risk of eoCRC overall or for the colon site. Conclusions: Our findings suggest a possible association between cumulative longer-term use of broad-spectrum antibiotics and increased risk of eoCRC. The etiologic window for assessing antibiotic exposure appears to be relevant. Larger studies with long-term follow-up are needed to confirm these findings.

The clinical, radiological, postoperative pathological, and genetic features of nodular lung adenocarcinoma: a real-world single-center data.

The preoperative differential diagnosis of nodular lung adenocarcinoma has long been a challenging issue for thoracic surgeons. This study aimed to explore differential diagnosis of nodular lung adenocarcinoma by comprehensively analyzing its clinical, computed tomography (CT) imaging, and postoperative pathological and genetic features. The clinical, CT imaging, and postoperative pathological features of different classifications of nodular lung adenocarcinoma were retrospectively analyzed through univariate and multivariate statistical methods. There were 132 patients with nodular lung adenocarcinoma enrolled. Firstly, compared with ground-glass nodular lung adenocarcinoma, solid nodular lung adenocarcinoma was more common in women [odds ratio (OR), 3.662; 95% confidence interval (CI): 1.066-12.577] and older adults (OR, 1.061; 95% CI: 1.007-1.119), and CT signs were mostly lobulation (OR, 4.957; 95% CI: 1.714-14.337) and spiculation (OR, 8.214; 95% CI: 2.740-24.621); the mean CT (CTm) value of solid nodular lung adenocarcinoma was significantly higher than that of ground-glass nodular lung adenocarcinoma, and the optimal diagnostic threshold was -267.5 Hounsfield units (HU). Secondly, the maximum diameter of nodule size (NSmax) of invasive adenocarcinoma (IAC) was significantly greater than that of minimally IAC (MIA; OR, 6.306; 95% CI: 1.191-33.400) or atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS; OR, 189.539; 95% CI: 4.720-7,610.476), and the optimal diagnostic threshold between IAC and MIA was 1.35 cm; the CTm value of IAC was significantly higher than that of MIA, and the optimal diagnostic threshold was -460.75 HU. Thirdly, lepidic-predominant adenocarcinoma (LPA) manifest more commonly as pure ground-glass nodule (pGGN; OR, 6.252; 95% CI: 1.429-27.358) or mixed ground-glass nodule (mGGN; OR, 4.224; 95% CI: 1.223-14.585). Moreover, the mutation rate of epidermal growth factor receptor (EGFR) in IAC was 70.69% (41/58). The EGFR mutation rates of mGGNs (OR, 8.794; 95% CI: 1.489-51.933) and solid nodules (SNs; OR, 12.912; 95% CI: 1.597-104.383) were significantly higher than that of pGGNs. Furthermore, compared with those of micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), or invasive mucinous adenocarcinoma (IMA), there were significantly higher EGFR mutation rates in acinar-predominant adenocarcinoma/papillary-predominant adenocarcinoma (APA/PPA; OR, 55.925; 95% CI: 4.045-773.284) and LPA (OR, 38.265; 95% CI: 2.307-634.596). Different classifications of nodular lung adenocarcinoma have their own clinicopathological and CT imaging features, and the latter is the main predictor.

A Radiological-Radiomics model for differentiation between minimally invasive adenocarcinoma and invasive adenocarcinoma less than or equal to 3 cm: A two-center retrospective study

ObjectiveTo develop a Radiological-Radiomics (R-R) combined model for differentiation between minimal invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA) of lung adenocarcinoma (LUAD) and evaluate its predictive performance. MethodsThe clinical, pathological, and imaging data of a total of 509 patients (522 lesions) with LUAD diagnosed by surgical pathology from 2 medical centres were retrospectively collected, with 392 patients (402 lesions) from center 1 trained and validated using a five-fold cross-validation method, and 117 patients (120 lesions) from center 2 serving as an independent external test set. The least absolute shrinkage and selection operator (LASSO) method was utilized to filter features. Logistic regression was used to construct three models for predicting IA, namely, Radiological model, Radiomics model, and R-R model. Also, receiver operating curve curves (ROCs) were plotted, generating corresponding area under the curve (AUC), sensitivity, specificity, and accuracy. ResultsThe R-R model for IA prediction achieved an AUC of 0.918 (95 % CI: 0.889–0.947), a sensitivity of 80.3 %, a specificity of 88.2 %, and an accuracy of 82.1 % in the training set. In the validation set, this model exhibited an AUC of 0.906 (95 % CI: 0.842–0.970), a sensitivity of 79.9 %, a specificity of 88.1 %, and an accuracy of 81.8 %. In the external test set, the AUC was 0.894 (95 % CI: 0.824–0.964), a sensitivity of 84.8 %, a specificity of 78.6 %, and an accuracy of 83.3 %. ConclusionThe R-R model showed excellent diagnostic performance in differentiating MIA and IA, which can provide a certain reference for clinical diagnosis and surgical treatment plans.

Oncological Outcomes and Patterns of Recurrence after the Surgical Resection of an Invasive Intraductal Papillary Mucinous Neoplasm versus Primary Pancreatic Ductal Adenocarcinoma: An Analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant cystic neoplasms of the pancreas (CNPs), which can progress to invasive IPMN and pancreatic cancer. The available literature has shown controversial results regarding prognosis and clinical outcomes after the resection of invasive IPMN. This study aims to characterize the oncologic outcomes and metastatic progression pattern after the resection of non-metastatic invasive IPMN. Data were obtained from 24 clinical cancer registries participating in the German Cancer Registry Group of the Society of German Tumor Centers (ADT). Patients with invasive IPMN (n = 217) as well as PDAC (n = 5794) between 2000 and 2021 were included and compared regarding oncological outcomes. Invasive IPMN was significantly smaller in size (p < 0.001) and of a lower tumor grade (p < 0.001), with fewer lymph node metastases (p < 0.001), lymphangiosis (p < 0.001), and consequently a higher R0 resection rate (88 vs. 74%) compared to PDAC. Moreover, invasive IPMN was associated with fewer local (11 vs. 15%) and distant recurrences (29 vs. 46%) and metastasized more frequently in the lungs only (26% vs. 14%). Invasive IPMN was associated with a longer median OS (29 vs. 19 months) and DFS (31 vs. 15 months) compared to PDAC and stayed independently prognostic in multivariable analyses. These survival differences were most pronounced in early tumor stages. Interestingly, postoperative chemotherapy was not associated with improved overall survival in surgically resected invasive IPMN. Invasive IPMN is a rare pancreatic entity with increasing incidence in Germany. It is associated with favorable histopathological features at the time of resection and longer OS and DFS compared to PDAC, particularly before the locoregional spread has occurred. Invasive IPMNs are associated with lung-only metastasis. The benefit of postoperative chemotherapy after the resection of invasive IPMN remains uncertain.

18F]FDG PET/CT is useful in discriminating invasive adenocarcinomas among pure ground-glass nodules: comparison with CT findings-a bicenter retrospective study.

Predicting the malignancy of pure ground-glass nodules (GGNs) using CT is challenging. The optimal role of [18F]FDG PET/CT in this context has not been clarified. We compared the performance of [18F]FDG PET/CT in evaluating GGNs for predicting invasive adenocarcinomas (IACs) with CT. From June 2012 to December 2020, we retrospectively enrolled patients with pure GGNs on CT who underwent [18F]FDG PET/CT within 90days. Overall, 38 patients with 40 ≥ 1-cm GGNs were pathologically confirmed. CT images were analyzed for size, attenuation, uniformity, shape, margin, tumor-lung interface, and internal/surrounding characteristics. Visual [18F]FDG positivity, maximum standardized uptake value (SUVmax), and tissue fraction-corrected SUVmax (SUVmaxTF) were evaluated on PET/CT. The histopathology of the 40 GGNs were: 25 IACs (62.5%), 9 minimally invasive adenocarcinomas (MIA, 22.5%), and 6 adenocarcinomas in situ (AIS, 15.0%). No significant differences were found in CT findings according to histopathology, whereas visual [18F]FDG positivity, SUVmax, and SUVmaxTF were significantly different (P=0.001, 0.033, and 0.018, respectively). The size, visual [18F]FDG positivity, SUVmax, and SUVmaxTF showed significant diagnostic performance to predict IACs (area under the curve=0.693, 0.773, 0.717, and 0.723, respectively; P=0.029, 0.001, 0.018, and 0.013, respectively). In the multivariate logistic regression analysis, visual [18F]FDG positivity discriminated IACs among GGNs among various CT and PET findings (P=0.008). [18F]FDG PET/CT demonstrated superior diagnostic performance compared to CT in differentiating IAC from AIS/MIA among pure GGNs, thus it has the potential to guide the proper management of patients with pure GGNs.

Integrating IASLC grading and radiomics for predicting postoperative outcomes in stage IA invasive lung adenocarcinoma.

The International Association for the Study of Lung Cancer (IASLC) Pathology Committee introduced a histologic grading system for invasive lung adenocarcinoma (LUAD) in 2020. The IASLC grading system, hinging on the evaluation of predominant and high-grade histologic patterns, has proven to be practical and prognostic for invasive LUAD. However, there are still limitations in evaluating the prognosis of stage IA LUAD. Radiomics may serve as a valuable complement. To establish a model that integrates IASLC grading and radiomics, aimed at predicting the prognosis of stage IA LUAD. We conducted a retrospective analysis of 628 patients diagnosed with stage IA LUAD who underwent surgical resection between January 2015 and December 2018 at our institution. The patients were randomly divided into the training set (n=439) and testing set (n=189) at a ratio of 7:3. Overall survival (OS) and disease-free survival (DFS) were taken as the end points. Radiomics features were obtained by PyRadiomics. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO). The prediction models for OS and DFS were developed using multivariate Cox regression analysis, and the models were visualized through nomogram plots. The model's performance was evaluated using area under the curves (AUC), concordance index (C-index), calibration curves, and survival decision curve analysis (DCA). In total, nine radiomics features were selected for the OS prediction model, and 15 radiomics features were selected for the DFS prediction model. Patients with high radiomics scores were associated with a worse prognosis (p<0.001). We built separate prediction models using radiomics or IASLC alone, as well as a combined prediction model. In the prediction of OS, we observed that the combined model (C-index: 0.812±0.024, 3 years AUC: 0.692, 5 years AUC: 0.792) achieved superior predictive performance than the radiomics (C-index: 0.743±0.038, 3 years AUC: 0.633, 5 years AUC: 0.768) and IASLC grading (C-index: 0.765±0.042, 3 years AUC: 0.658, 5 years AUC: 0.743) models alone. Similar results were obtained in the models for DFS. The combination of radiomics and IASLC pathological grading proves to be an effective approach for predicting the prognosis of stage IA LUAD. This has substantial clinical relevance in guiding treatment decisions for early-stage LUAD.