Sublobar resection for adenocarcinoma in situ and minimally invasive adenocarcinoma diagnosed by intraoperative frozen section (ECTOP-1019): a study protocol of prospective, single-arm, multicenter, phase III study.

Background: Our previous retrospective study revealed that sublobar resection was appropriate for adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) diagnosed by intraoperative frozen section (FS). However, high-level evidence-based medical data confirming this treatment are still lacking. The aim of the ongoing study is to confirm the efficacy and safety of sublobar resection for AIS and MIA diagnosed by FS. Methods: Since October 2023, we have initiated a prospective, single-arm, multicenter, confirmatory phase III trial in China. We plan to enroll a total of 390 patients diagnosed as AIS or MIA by intraoperative FS and who will undergo sublobar resection. The primary endpoint is five-year recurrence-free survival; the secondary endpoints are five-year overall survival, the concordance rate between FS and final pathology, adverse events, proportion of local recurrence and metastasis, the completion rate of sublobar resection and R0 resection. Discussion: Surgical strategies for small-sized lung cancer that contains ground glass opacity lesions are still controversial. This study will deliver new evidence on the efficacy and safety of sublobar resection without lymph node dissection for cT1N0M0 non-small cell lung cancer (NSCLC) which are diagnosed as AIS or MIA by FS. Trial Registration: ClinicalTrials.gov identifier: NCT06031181.

Dissecting the clinicopathologic, genomic, and prognostic significance of anaplastic lymphoma kinase rearrangement in resected lung adenocarcinoma.

OBJECTIVES: The ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD). METHODS: We retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathologic characteristics, molecular profiles, and outcomes was explored. RESULTS: Among 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and nonsmokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (eg, TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in patients with stage I who did not receive adjuvant chemotherapy whereas it was associated with prolonged RFS in patients with stage II and III who received adjuvant chemotherapy. Notably, 6 patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. In addition, the administration of ALK inhibitors significantly improved postrecurrence survival in patients positive for ALK. CONCLUSIONS: ALK positivity was associated with specific aggressive pathologic features and inferior RFS in stage I LUAD. Patients positive for ALK seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for patients with ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

Ten-Year Survivals of Right Thoracic vs Left Thoracic Approach for Esophageal Cancer.

BACKGROUND: Esophagectomy can be performed using various surgical techniques. The aim of this study was to understand the impact of surgery on long-term survival for esophageal cancer. METHODS: Between May 2010 and July 2012, 300 patients with esophageal cancer were randomly assigned to undergo esophagectomy with either a left or right thoracic approach. Disease-free survival (DFS) and overall survival (OS) were compared based on the per-protocol principle among 286 patients with esophageal squamous cell carcinoma determined by postoperative pathologic results (146 in the right and 140 in the left thoracic arms). RESULTS: The median DFS was 92 months in the right thoracic arm and 41 months in the left thoracic arm (hazard ratio, 0.73; 95% CI, 0.54-0.99; P = .045), with a cumulative 10-year DFS of 47.6% and 37.5%, respectively. The median OS was 136 months in the right thoracic arm and 99 months in the left thoracic arm (hazard ratio, 0.75; 95% CI, 0.54-1.04; P = .081), with cumulative 10-year OS of 52.4% and 43.7%, respectively. DFS and OS were comparable between the 2 arms for patients without lymph node metastasis. Conversely, for patients with lymph node metastasis, 10-year DFS was 32.7% and 21.4%, respectively (P = .018), and 10-year OS of the right and left thoracic arms was 37.9% and 25.9%, respectively (P = .012). CONCLUSIONS: Compared with the left thoracic approach, patients who underwent esophagectomy through the right thoracic approach had better 10-year survival rates, and the survival benefit was significant for those with lymph node metastasis.

Prediction of Spread Through Air Spaces (STAS) By Intraoperative Frozen Section for Patients with cT1N0M0 Invasive Lung Adenocarcinoma: A Multi-Center Observational Study (ECTOP-1016).

OBJECTIVE: To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. BACKGROUND: Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. METHODS: We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. RESULTS: This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. CONCLUSIONS: This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.

Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages.

Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Protocol for a single-arm, multicenter, prospective, confirmatory phase III trial of wedge resection for invasive ground glass opacity-featured lung cancer with a size ≤2 cm and a consolidation tumor ratio between 0.25 and 0.5 (ECTOP-1020 study).

Background: Segmentectomy is the current standard treatment for ground glass opacity (GGO)-featured lung cancer patients with a tumor size ≤2 cm and a consolidation tumor ratio (CTR) between 0.25 and 0.5. However, compared with wedge resection, segmentectomy destroys the patient's hilar structure and consumes more lung parenchyma. A recent study demonstrated that wedge resection could yield comparable results for this group of patients. Methods: This study aimed to confirm the noninferiority of wedge resection over standard surgery in invasive GGO-featured lung cancer patients with a size ≤2 cm and a CTR between 0.25 and 0.5, as measured by 5-year overall survival (OS). The primary endpoint is 5-year OS. The secondary endpoints are 5-year recurrence-free survival (RFS), the R0 resection rate, pulmonary function, recurrence and metastasis sites, and adverse events after surgery. During the trial period, 286 patients are enrolled from six Chinese institutions. Discussion: The primary results of this study will be actively disseminated through manuscript publications and conference presentations. This prospective study will evaluate the surgical efficacy and safety of wedge resection for small (tumor size ≤2 cm with a CTR between 0.25 and 0.5) invasive GGO-featured lung cancer and will support the standardization of this surgical strategy. Trial Registration: This trial has been registered on ClinicalTrial.gov (No. NCT06102161).

Resected lung adenocarcinoma with lymph node metastasis: is ground glass opacity component a prognostic factor?

Background: Ground glass opacity (GGO)-featured lung adenocarcinoma generally has excellent prognosis, and here is rarely the occurrence of lymph node metastasis. We conducted a retrospective cohort study to explore the prognostic impact of GGO component in node-positive lung adenocarcinomas. Methods: A total of 669 patients with pathologic N1/N2 lung adenocarcinoma receiving R0 resection and systemic lymph node dissection from 2008 to 2015 were reviewed, including 635 solid and 34 part-solid lesions. Propensity score matching (PSM) was performed to compare survival outcomes of solid and part-solid lesions, in order to determine the prognostic value of GGO component. Cox proportional hazard model was performed to identify significant prognostic factors for resected node positive lung adenocarcinoma. Results: About 5.1% (34 of 669) of resected node-positive lung adenocarcinoma presented as part-solid nodules on computed tomography (CT) images in this cohort. The median nodule size on CT of the 34 part-solid lesions was 31 mm (range, 15-68 mm), median solid component size on CT was 24 mm (range, 12-62 mm), and median consolidation/tumor ratio was 0.8 (range, 0.64-0.95). After 1:4 PSM, 136 patients and 34 patients were matched from the solid and part-solid groups. No significant difference in either recurrence-free survival (RFS) (P=0.71) or overall survival (OS) (P=0.82) was found between the solid and part-solid groups. Multivariable Cox regression showed that pN stage was the strongest prognostic factor for RFS and OS. GGO component was not an independent prognostic factor toward for RFS [P=0.75; hazard ratio (HR) =0.93; 95% confidence interval (CI): 0.59-1.46] or OS (P=0.53; HR =1.19; 95% CI: 0.69-2.05). Conclusions: A minority of resected node-positive lung adenocarcinoma presents as GGO component on CT. The presence of GGO component does not predict better prognosis in node-positive lung adenocarcinoma.

The Overlooked Cornerstone in Precise Medicine: Personalized Postoperative Surveillance Plan for NSCLC.

Non-small cell lung cancer recurrence after curative-intent surgery remains a challenge despite advancements in treatment. We review postoperative surveillance strategies and their impact on overall survival, highlighting recommendations from clinical guidelines and controversies. Studies suggest no clear benefit from more intensive imaging, whereas computed tomography scans reveal promise in detecting recurrence. For early-stage disease, including ground-glass opacities and adenocarcinoma in situ or minimally invasive adenocarcinoma, less frequent surveillance may suffice owing to favorable prognosis. Liquid biopsy, especially circulating tumor deoxyribonucleic acid, holds potential for detecting minimal residual disease. Clinicopathologic factors and genomic profiles can also provide information about site-specific metastases. Machine learning may enable personalized surveillance plans on the basis of multi-omics data. Although precision medicine transforms non-small cell lung cancer treatment, optimizing surveillance strategies remains essential. Tailored surveillance strategies and emerging technologies may enhance early detection and improve patients' survival, necessitating further research for evidence-based protocols.

The evolution of the treatment of non-small cell lung cancer: A shift in surgical paradigm to a more individualized approach.

Surgical treatment is an integral part of the comprehensive therapeutic methods for lung cancer, especially for early-stage non-small cell lung cancer (NSCLC). With a deeper understanding of the disease, we found that lung cancer is more commonly detected in young females. For regions of Asia, more lung cancer has been detected in early-stage GGO-dominant non-smokers. Therefore, surgical strategies have also been reformed commensurate with the shift of the disease spectrum. However, the pursuit of lung-sparing individualized approaches has raised worldwide attention. Suitable surgical treatment within the curative time window is recommended to maximize the long-term benefit. This article summarizes the shift in surgical treatment for small NSCLCs and hopes to enlighten further innovations to fill in the gaps between the unmet needs and a more individualized approach.

Segmentectomy versus lobectomy for ground-glass opacity dominant cT1N0 invasive lung adenocarcinoma.

Background: The Japan Clinical Oncology Group (JCOG) 1211 suggested that segmentectomy should be considered as standard treatment for clinical T1N0 (cT1N0) ground glass opacity (GGO). However, over half of patients in JCOG1211 had pre-/minimal invasive adenocarcinoma. This study aims to retrospectively investigate the long-term survival of GGO featured cT1N0 invasive lung adenocarcinoma undergoing segmentectomy or lobectomy. Methods: This study screened patients with primary cT1N0 lung adenocarcinoma who received segmentectomy or lobectomy from 2010-2020. Prior computed tomography (CT) scans before surgery of all patients were reviewed and the inclusion was confirmed according to tumor diameter and consolidation tumor ratio (CTR). GGO nodules between 2-3 cm with CTR ≤0.5 or ≤2 cm with CTR between 0.25-0.5 were finally included. Patients with pathologically diagnosed pre-/minimally invasive lung adenocarcinoma were excluded. Long-term survivals between segmentectomy group and lobectomy group were compared after propensity score matching (PSM). Recurrence and postoperative complication events were also analyzed. Results: In total, 617 patients were enrolled, 159 received segmentectomy and 458 received lobectomy. Clinicopathological characteristics were well distributed between two groups. With a median follow-up time of 61.1 months (IQR: 42.3-71.7 months), after PSM, the 5-year overall survival rate was 98.8% (97.9-99.6%) for lobectomy and 99.3% (98.2-99.8%) for segmentectomy (P=0.42), the 5-year relapse-free survival rate was 95.3% (92.2-97.6%) for lobectomy and 95.2% for segmentectomy (92.3-98.7%) (P=0.81). The proportion of recurrence was 4.1% for lobectomy and 4.4% for segmentectomy (P=0.89). The proportion of grade 2 and above early postoperative complications was 9.6% for lobectomy and 8.8% for segmentectomy (P=0.86). Conclusions: For cT1N0 GGO featured invasive lung adenocarcinoma (2 cm < tumor diameter ≤3 cm, CTR ≤0.5 or tumor diameter ≤2 cm, 0.25< CTR ≤0.5), postoperative outcomes between segmentectomy group and lobectomy group were comparable. Concerning minimally invasive surgical strategy, segmentectomy should be confirmed as the standard surgical approach.

Segmentectomy for ground glass-dominant invasive lung cancer with tumour diameter of 2-3 cm: protocol for a single-arm, multicentre, phase III trial (ECTOP1012).

INTRODUCTION: Previous studies demonstrated that wedge resection is sufficient for ground glass-dominant lung adenocarcinoma (LUAD) with tumour diameter ≤2 cm, however, the optimal surgical type for ground glass-dominant LUAD with tumour diameter of 2-3 cm remains unclear. The purpose of this trial is to investigate the safety and efficacy of segmentectomy for ground glass-dominant invasive LUAD with tumour size of 2-3 cm. METHODS AND ANALYSIS: We initiated a phase III trial to investigate whether segmentectomy is suitable for ground glass-dominant invasive LUAD with tumour size of 2-3 cm. This trial plans to enrol 307 patients from multiple institutions including four general hospitals and two specialty cancer hospitals over a period of 5 years. The primary endpoint is 5 year disease-free survival. Secondary endpoints are lung function, 5 year overall survival, the site of tumour recurrence and metastasis, segmentectomy completion rate, radical segmentectomy (R0 resection) completion rate and surgery-related complications. ETHICS AND DISSEMINATION: This trial has been approved by the Ethics Committee of Fudan University Shanghai Cancer Centre (reference 2212267-18) and by the institutional review boards of each participating centre. Written informed consent is required from all participants. The study results will be published in a peer-reviewed international journal. TRIAL REGISTRATION NUMBER: NCT05717803.

The 2023 American Association for Thoracic Surgery (AATS) Expert Consensus Document: Management of subsolid lung nodules.

OBJECTIVE: Lung cancers that present as radiographic subsolid nodules represent a subtype with distinct biological behavior and outcomes. The objective of this document is to review the existing literature and report consensus among a group of multidisciplinary experts, providing specific recommendations for the clinical management of subsolid nodules. METHODS: The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an international, multidisciplinary expert panel composed of radiologists, pulmonologists, and thoracic surgeons with established expertise in the management of subsolid nodules. A focused literature review was performed with the assistance of a medical librarian. Expert consensus statements were developed with class of recommendation and level of evidence for each of 4 main topics: (1) definitions of subsolid nodules (radiology and pathology), (2) surveillance and diagnosis, (3) surgical interventions, and (4) management of multiple subsolid nodules. Using a modified Delphi method, the statements were evaluated and refined by the entire panel. RESULTS: Consensus was reached on 17 recommendations. These consensus statements reflect updated insights on subsolid nodule management based on the latest literature and current clinical experience, focusing on the correlation between radiologic findings and pathological classifications, individualized subsolid nodule surveillance and surgical strategies, and multimodality therapies for multiple subsolid lung nodules. CONCLUSIONS: Despite the complex nature of the decision-making process in the management of subsolid nodules, consensus on several key recommendations was achieved by this American Association for Thoracic Surgery expert panel. These recommendations, based on evidence and a modified Delphi method, provide guidance for thoracic surgeons and other medical professionals who care for patients with subsolid nodules.

Ten-Year Follow-Up of Lung Cancer Patients with Resected Stage IA Invasive Non-Small Cell Lung Cancer.

OBJECTIVE: The purpose of this study was to assess 10-year follow-up outcomes after surgical resection in patients with stage IA invasive non-small cell lung cancer (NSCLC) based on postoperative pathological diagnosis. METHODS: Patients with stage IA invasive NSCLC who underwent resection between December 2008 and December 2013 were reviewed. Patients were categorized into the pure-ground glass opacity (pGGO), mixed-ground glass opacity (mGGO), and solid groups based on consolidation to tumor ratio (CTR). Postoperative survival and risk of recurrence and developing secondary primary lung cancer were analyzed in each group. RESULTS: Among the 645 stage IA invasive NSCLC, the 10-year overall survival and recurrence-free survival rate was 79.38% and 77.44%, respectively. The 10-year overall survival for pGGO, mGGO, and solid group of patients was 95.08%, 86.21%, and 72.39%, respectively. The respective recurrence-free survival rate was 100%, 89.82%, and 65.83%. Multivariable Cox regression analysis associated tumor size and GGO components with recurrence and younger age, and tumors with GGO components were associated with longer overall survival. The cumulative incidence curve indicated no recurrence of GGO lung cancer ≥ 5 years postoperatively. Our cohort indicated that the number and stations of dissected lymph node did not influence long-term prognosis of IA invasive NSCLC. CONCLUSIONS: Recurrence of invasive stage IA NSCLC with GGO was more prevalent in patients with tumor size >1 cm and CTR > 0.5, occurring within 5 years after surgery. This will provide important evidence for follow-up strategies in these patients.

Prediction of the pathological subtypes by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma (ECTOP-1015): a prospective multicenter study.

BACKGROUND: This study aims to assess the diagnostic accuracy of the intraoperative frozen section (FS) in determining the pathological subtypes among patients diagnosed with cT1N0M0 invasive lung adenocarcinoma. MATERIALS AND METHODS: This was a prospective, multicenter (seven centers in China) clinical trial of Eastern Cooperative Thoracic Oncology Projects (ECTOP-1015). Patients with cT1N0M0 invasive lung adenocarcinoma were enrolled in the study. Pathological images obtained from FS and final pathology (FP) were reviewed by at least two pathologists. The primary endpoint was the concordance between FS and FP diagnoses. The interobserver agreement for identifying pathological subtypes on FS was evaluated among three pathologists. RESULTS: A total of 935 patients were enrolled. The best sensitivity of diagnosing the predominant subtype was 78.2% in the evaluation of the acinar pattern. The presence of an acinar pattern diagnosed by FS was an independent factor for the concordance between FS and FP ( P =0.007, 95% confidence interval: 2.332-4.736). Patients with tumor size >2 cm measured by pathology showed a better concordance rate for the predominant subtype (81.6% vs. 74.6%, P =0.023). The presence of radiological ground glass opacity component did not affect the diagnosis accuracy of FS for the predominant subtype (concordance rate: 76.4% vs. 75.2%, P =0.687). Patients with ground glass opacity component showed better accuracy of the identification in the presence of lepidic pattern-predominant adenocarcinoma (82.1% vs. 71.0%, P =0.026). Substantial agreement between the FS diagnosis from three pathologists for the predominant pathological pattern was revealed with κ=0.846. CONCLUSIONS: This is the largest prospective trial evaluating FS diagnosing pathological subtype in cT1N0M0 invasive lung adenocarcinoma. A favorable concordance in the assessment of the pathological subtypes between FS and FP was observed, indicating the feasibility of utilizing accurate intraoperative pathological diagnoses from FS in guiding surgical strategies. A combination of radiology could improve the precision of FS.

The Use of Generative Adversarial Network and Graph Convolution Network for Neuroimaging-Based Diagnostic Classification.

Functional connectivity (FC) obtained from resting-state functional magnetic resonance imaging has been integrated with machine learning algorithms to deliver consistent and reliable brain disease classification outcomes. However, in classical learning procedures, custom-built specialized feature selection techniques are typically used to filter out uninformative features from FC patterns to generalize efficiently on the datasets. The ability of convolutional neural networks (CNN) and other deep learning models to extract informative features from data with grid structure (such as images) has led to the surge in popularity of these techniques. However, the designs of many existing CNN models still fail to exploit the relationships between entities of graph-structure data (such as networks). Therefore, graph convolution network (GCN) has been suggested as a means for uncovering the intricate structure of brain network data, which has the potential to substantially improve classification accuracy. Furthermore, overfitting in classifiers can be largely attributed to the limited number of available training samples. Recently, the generative adversarial network (GAN) has been widely used in the medical field for its generative aspect that can generate synthesis images to cope with the problems of data scarcity and patient privacy. In our previous work, GCN and GAN have been designed to investigate FC patterns to perform diagnosis tasks, and their effectiveness has been tested on the ABIDE-I dataset. In this paper, the models will be further applied to FC data derived from more public datasets (ADHD, ABIDE-II, and ADNI) and our in-house dataset (PTSD) to justify their generalization on all types of data. The results of a number of experiments show the powerful characteristic of GAN to mimic FC data to achieve high performance in disease prediction. When employing GAN for data augmentation, the diagnostic accuracy across ADHD-200, ABIDE-II, and ADNI datasets surpasses that of other machine learning models, including results achieved with BrainNetCNN. Specifically, in ADHD, the accuracy increased from 67.74% to 73.96% with GAN, in ABIDE-II from 70.36% to 77.40%, and in ADNI, reaching 52.84% and 88.56% for multiclass and binary classification, respectively. GCN also obtains decent results, with the best accuracy in ADHD datasets at 71.38% for multinomial and 75% for binary classification, respectively, and the second-best accuracy in the ABIDE-II dataset (72.28% and 75.16%, respectively). Both GAN and GCN achieved the highest accuracy for the PTSD dataset, reaching 97.76%. However, there are still some limitations that can be improved. Both methods have many opportunities for the prediction and diagnosis of diseases.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Clinicopathologic features, concurrent genomic alterations, and clinical outcomes of patients with KRAS G12D mutations in resected lung adenocarcinoma.

BACKGROUND: In light of the ongoing clinical development of KRAS G12D-specific inhibitors, we sought to investigate the clinicopathologic, co-occurring genomic features and outcomes of patients with KRAS G12D-mutant lung adenocarcinoma. METHODS: 3828 patients with completely resected primary lung adenocarcinomas were examined for KRAS mutations between 2008 and 2020. The association between KRAS G12D and clinicopathologic features, molecular profiles, and outcomes was investigated. RESULTS: 65 patients (1.7%) with KRAS G12D-mutant lung adenocarcinoma were identified. KRAS G12D mutation was more frequent in males, former/current smokers, radiologic solid tumors, and invasive mucinous adenocarcinoma. TP53 and STK11 were the two most frequent concomitant mutations in the KRAS G12D group. KRAS G12D mutation did not appear to be a prognostic factor in resected stage I-III lung adenocarcinomas, while KRAS non-G12D mutation was related to worse survival, especially in stage I tumors. KRAS G12D mutations were associated with positive but low (1-49%) PD-L1 expression compared to negative (<1%), while KRAS non-G12D mutation was associated with high PD-L1 expression (≥50%). TP53 co-mutation indicated higher PD-L1 expression, while STK11 co-mutation had a negligible impact on PD-L1 expression. Furthermore, data mining of MSK datasets from cBioPortal revealed that KRAS G12D and SKT11 co-mutation were associated with a diminished response to immunotherapy. CONCLUSIONS: KRAS G12D-mutant lung adenocarcinoma harbored unique clinicopathologic and genomic characteristics. Despite not being prognostic in resected lung adenocarcinoma, KRAS G12D might be a valuable biomarker in combination with certain co-mutations for identifying relevant subgroups of patients that could eventually influence treatment regimens.

Prognostic value of KRAS G12V mutation in lung adenocarcinoma stratified by stages and radiological features.

OBJECTIVE: KRAS G12V is one of the most common KRAS mutation variants in lung adenocarcinoma (LUAD), and yet its prognostic value is still unrevealed. In this study, we investigated the clinicopathologic characteristics and prognostic value of the KRAS G12V mutation in LUAD. METHODS: Data of 3829 patients who underwent LUAD resection between 2008 and 2020 were collected. Mutations were classified as wild-type, G12V, or non-G12V. The clinicopathologic characteristics, postoperative outcomes, and recurrence pattern were analyzed among groups. RESULTS: In total, 3554 patients were wild-type and 275 patients harbored a KRAS mutation: 60 patients with G12V (22.2%) and 215 patients with non-G12V (77.8%). The KRAS G12V mutation was more frequent in male patients, older patients (≥60 years), former/current smokers, those patients with radiologic solid nodules, and those with highly invasive histologic subtypes. Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. Multivariate analysis demonstrated that the KRAS G12V mutation was an independent prognostic factor in stage Ⅰ tumors, whereas the KRAS non-G12V mutation was not. KRAS G12V was associated with early recurrence and locoregional recurrence. CONCLUSIONS: The KRAS G12V mutation was associated with aggressive clinical-pathologic phenotype and early recurrence. To note, this mutation exhibited a significantly worse prognosis in patients with part-solid and stage Ⅰ lung adenocarcinoma. Meanwhile, the prognostic significance of KRAS G12C and G12V variants was comparable.