Subtype Of Adenocarcinoma Research Articles

Minimally invasive determination of pancreatic ductal adenocarcinoma (PDAC) subtype by means of circulating cell-free RNA.

Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor-informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype-specific, protein-coding cell-free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal-like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence.

Explainable 18F-FDG PET/CT radiomics model for predicting EGFR mutation status in lung adenocarcinoma: a two-center study

PurposeTo establish an explainable 18F-FDG PET/CT-derived prediction model to identify EGFR mutation status and subtypes (EGFR wild, EGFR-E19, and EGFR-E21) in lung adenocarcinoma (LUAD).MethodsBaseline 18F-FDG PET/CT images of 478 patients with LUAD from 2 hospitals were collected. Data from hospital A (n = 390) was randomly split into a training group (n = 312) and an internal test group (n = 78), with data from hospital B (n = 88) utilized for external test. Further, a total of 4,760 handcrafted radiomics features (HRFs) were extracted from PET/CT scans. Candidates for the prediction model were constructed by cross-combinations of 11 feature selection methods and 7 classifiers. The optimal model was determined by combining the results of cross-center data validation and model visualization (Yellowbrick). The predictive performance was assessed via receiver operating characteristic curve, confusion matrix and classification report. Four explainable artificial intelligence technologies were used for optimal model interpretation.ResultsSex and SUVmax were selected as clinical risk factors, which were then combined with 8 robust PET/CT HRFs to establish the models. The optimal performance was obtained by combining a light gradient boosting machine classifier with random forest feature selection method achieving an optimal performance with a macro-average AUC of 0.75 in the internal test group and 0.81 in the external test group.ConclusionThe explainable EGFR mutation status prediction model have certain clinical practicability and good generalization performance, which may help in the timely selection of treatment options and prognosis prediction in patients with LUAD.

Identifying Clusters of Curatively-Treated Esophageal Cancer Patients Using Patient-Reported Outcome Measures at Three Months from Discharge: A Secondary Analysis from a Longitudinal Single Center Study.

This study aims to identify meaningful clusters based on Patient-Reported Outcome Measures (PROMs) in curatively-treated esophageal cancer patients at three months post-discharge. This secondary analysis of a longitudinal single-center study included 46 esophageal cancer patients who underwent curative surgery. Patients were selected based on their completion of PROMs surveys at three months post-discharge, were aged 18 years or older, and had undergone surgical resection (esophagectomy) with or without neoadjuvant chemotherapy and/or radiotherapy. The analysis utilized t-distributed Stochastic Neighbor Embedding (t-SNE) for dimensionality reduction and hierarchical clustering to analyze PROMs data collected three months post-discharge. Clustering was performed on physical, emotional, cognitive, and social functioning variables, symptom burden, and health literacy. Three distinct clusters were identified: Cluster 1 (n = 24) with higher functioning and moderate symptoms, Cluster 2 (n = 14) with moderate functioning, higher symptoms, and lower health literacy, and Cluster 3 (n = 8) with the highest functioning, lowest symptoms, and highest health literacy. Significant differences between squamous cell carcinoma and adenocarcinoma subtypes were observed across several PROMs domains, including critical health literacy, general health status/quality of life, nausea and vomiting, and insomnia. These clusters provide an exploratory framework for tailoring post-operative interventions to enhance patient recovery, which necessitates further confirmatory investigations, including outcomes such as complications and mortality, in the analysis. This study fills a research gap by demonstrating the utility of PROMs in identifying distinct recovery patterns in esophageal cancer patients post-surgery. The findings support the use of PROMs to guide personalized post-operative care, potentially improving patient outcomes and quality of life. Further research is needed to validate these findings in larger, diverse populations.

Classification of histological subtypes of non-small cell lung cancer using computerized tomography texture analysis

Objective: This study aimed to differentiate between the two main histological subtypes of non-small cell lung cancer using a non-invasive technique, computerized tomography texture analysis. Method: We included 53 patients. All patients were histopathologically proven non-small cell lung cancer cases. All patients underwent thorax CT scans. In CT images, the differences present in the texture features of adenocarcinoma and squamous cell carcinoma, which are the two main histological subtypes of non-small cell lung cancer, were determined by the consensus of two radiologists for computerized tomography-based texture analysis. Results: A total of 44 texture features were extracted, including 12 first-order features and 32 second-order features derived from gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), neighborhood gray-level different matrix (NGLDM), and gray-level zone length matrix (GLZLM) features in 51 CT images. None of the evaluated texture parameters were statistically significant. However, in patients with squamous cell lung cancer, the values of Intensity Histogram, NGTDM Complexity, and Intensity Based Robust Mean Absolute Deviation higher from adenocarcinoma patients and had the highest area under the curve in roc analyses (0.727, 0.664, 0.666 respectively) Conclusion: Intensity Histogram, NGTDM Complexity, and Intensity Based Robust Mean Absolute Deviation features can be used to differentiate between the subtypes of non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma. These features were highly associated with the high intratumoral heterogeneity of squamous cell lung cancer.

Deep learning-based characterization of pathological subtypes in lung invasive adenocarcinoma utilizing 18F-deoxyglucose positron emission tomography imaging

SummaryObjectiveTo evaluate the diagnostic efficacy of a deep learning (DL) model based on PET/CT images for distinguishing and predicting various pathological subtypes of invasive lung adenocarcinoma.MethodsA total of 250 patients diagnosed with invasive lung cancer were included in this retrospective study. The pathological subtypes of the cancer were recorded. PET/CT images were analyzed, including measurements and recordings of the short and long diameters on the maximum cross-sectional plane of the CT image, the density of the lesion, and the associated imaging signs. The SUVmax, SUVmean, and the lesion's long and short diameters on the PET image were also measured. A manual diagnostic model was constructed to analyze its diagnostic performance across different pathological subtypes. The acquired images were first denoised, followed by data augmentation to expand the dataset. The U-Net network architecture was then employed for feature extraction and network segmentation. The classification network was based on the ResNet residual network to address the issue of gradient vanishing in deep networks. Batch normalization was applied to ensure the feature matrix followed a distribution with a mean of 0 and a variance of 1. The images were divided into training, validation, and test sets in a ratio of 6:2:2 to train the model. The deep learning model was then constructed to analyze its diagnostic performance across different pathological subtypes.ResultsStatistically significant differences (P < 0.05) were observed among the four different subtypes in PET/CT imaging performance. The AUC and diagnostic accuracy of the manual diagnostic model for different pathological subtypes were as follows: APA: 0.647, 0.664; SPA: 0.737, 0.772; PPA: 0.698, 0.780; LPA: 0.849, 0.904. Chi-square tests indicated significant statistical differences among these subtypes (P < 0.05). The AUC and diagnostic accuracy of the deep learning model for the different pathological subtypes were as follows: APA: 0.854, 0.864; SPA: 0.930, 0.936; PPA: 0.878, 0.888; LPA: 0.900, 0.920. Chi-square tests also indicated significant statistical differences among these subtypes (P < 0.05). The Delong test showed that the diagnostic performance of the deep learning model was superior to that of the manual diagnostic model (P < 0.05).ConclusionsThe deep learning model based on PET/CT images exhibits high diagnostic efficacy in distinguishing and diagnosing various pathological subtypes of invasive lung adenocarcinoma, demonstrating the significant potential of deep learning techniques in accurately identifying and predicting disease subgroups.

P4.07E.02 Genomic Profiling of Pre-invasive and Early-Stage Lung Adenocarcinoma Delineates Gene Signatures of Different Adenocarcinoma Subtypes

P4.07E.02 Genomic Profiling of Pre-invasive and Early-Stage Lung Adenocarcinoma Delineates Gene Signatures of Different Adenocarcinoma Subtypes

Preoperative markers for identifying CT ≤2 cm solid nodules of lung adenocarcinoma based on image deep learning.

The solid pattern is a highly malignant subtype of lung adenocarcinoma. In the current era of transitioning from lobectomy to sublobar resection for the surgical treatment of small lung cancers, preoperative identification of this subtype is highly important for patient surgical approach selection and long-term prognosis. A total of 1489 patients with clinical stage IA1-2 primary lung adenocarcinoma were enrolled. Based on patient clinical characteristics and lung imaging features obtained via deep learning, highly correlated diagnostic factors were identified through LASSO regression and decision tree analysis. Subsequently, a logistic model and nomogram were constructed. A restricted cubic spline (RCS) was used to calculate the optimal inflection point of quantitative data and the differences between the groups. The three-dimensional proportion of solid component (PSC), sex, and smoking status was identified as being highly correlated diagnostic factors for solid predominant adenocarcinoma. The logistic model had good prediction efficiency, and the area under the ROC curve was 0.85. Decision curve analysis demonstrated that the application of diagnostic factors can improve patient outcomes. RCS analysis indicated that the proportion of solid adenocarcinomas increased by 4.6 times when the PSC was ≥72%. A PSC of 72% is a good cutoff point. The preoperative diagnosis of solid-pattern adenocarcinoma can be confirmed by typical imaging features and clinical characteristics, assisting the thoracic surgeon in developing a more precise surgical plan.

Cancer Incidence among Marines and Navy Personnel and Civilian Workers Exposed to Industrial Solvents in Drinking Water at US Marine Corps Base Camp Lejeune: A Cohort Study.

Drinking water at US Marine Corps Base Camp Lejeune, North Carolina, was contaminated with trichloroethylene and other industrial solvents from 1953 to 1985. A cohort cancer incidence study was conducted of Marines/Navy personnel who began service and were stationed at Camp Lejeune () or Camp Pendleton, California () between 1975 and 1985 and civilian workers employed at Camp Lejeune () or Camp Pendleton () between October 1972 and December 1985. Camp Pendleton's drinking water was not contaminated with industrial solvents. Individual-level information on primary invasive cancers and in situ bladder cancer diagnosed between 1996 and 2017 was obtained from 54 US cancer registries. Proportional hazards regression was used to calculate adjusted hazard ratios (aHRs) comparing cancer incidence between the Camp Lejeune and Camp Pendleton cohorts, adjusted for sex, race, education, and rank (or blue-collar work), with age as the time variable. Precision of aHRs was evaluated using the 95% confidence interval (CI) ratio (CIR). Cancers among Camp Lejeune Marines/Navy personnel and civilian workers totaled 12,083 and 1,563, respectively. Cancers among Camp Pendleton Marines/Navy personnel and civilian workers totaled 12,144 and 1,416, respectively. Compared with Camp Pendleton, Camp Lejeune Marines/Navy personnel had aHRs with CIRs for all myeloid cancers (; 95% CI: 1.03, 1.49), acute myeloid leukemia (; 95% CI: 1.03, 1.85), myelodysplastic and myeloproliferative syndromes (; 95% CI: 1.07, 2.62), polycythemia vera (; 95% CI: 0.94, 2.11), and cancers of the esophagus (; 95% CI: 1.03, 1.56), larynx (; 95% CI: 0.98, 1.50), soft tissue (; 95% CI: 0.92, 1.59), and thyroid (; 95% CI: 1.03, 1.45). Lymphoma subtypes mantle cell and marginal zone B-cell and lung cancer subtypes adenocarcinoma and non-small cell lung cancer also had aHRs with CIRs . Compared with Camp Pendleton, Camp Lejeune civilian workers had aHRs with CIRs for all myeloid cancers (; 95% CI: 0.83, 2.36), squamous cell lung cancer (; 95% CI: 1.10, 2.41), and female breast (; 95% CI: 0.97, 1.52) and ductal cancer (; 95% CI: 1.02, 1.71). Increased risks of several cancers were observed among Marines/Navy personnel and civilian workers exposed to contaminated drinking water at Camp Lejeune compared with Camp Pendleton. https://doi.org/10.1289/EHP14966.

Proinflammatory Microenvironment in Adenocarcinoma Tissue of Colorectal Carcinoma.

Cancer-promoting proinflammatory microenvironment influences colorectal cancer (CRC) development. We examined the biomarkers of inflammation, intestinal differentiation, and DNA activity correlated with the clinical parameters to observe progression and prognosis in the adenocarcinoma subtype of CRC. Their immunohistology, immunoblotting, and RT-PCR analyses were performed in the adenocarcinoma and neighboring healthy tissues of 64 patients with CRC after routine colorectal surgery. Proinflammatory nuclear factor kappa B (NFκB) signaling as well as interleukin 6 (IL-6) and S100 protein levels were upregulated in adenocarcinoma compared with nearby healthy colon tissue. In contrast to nitrotyrosine expression, the oxidative stress marker 8-Hydroxy-2'-deoxyguanosine (8-OHdG) was increased in adenocarcinoma tissue. Biomarkers of intestinal differentiation β-catenin and mucin 2 (MUC2) were inversely regulated, with the former upregulated in adenocarcinoma tissue and positively correlated with tumor marker CA19-9. Downregulation of MUC2 expression correlated with the increased 2-year survival rate of patients with CRC. Proliferation-related mammalian target of rapamycin (mTOR) signaling was activated, and Ki67 frequency was three-fold augmented in positive correlation with metastasis and cancer stage, respectively. Conclusion: We demonstrated a parallel induction of oxidative stress and inflammation biomarkers in adenocarcinoma tissue that was not reflected in the neighboring healthy colon tissue of CRC. The expansiveness of colorectal adenocarcinoma was confirmed by irregular intestinal differentiation and elevated proliferation biomarkers, predominantly Ki67. The origin of the linked inflammatory factors was in adenocarcinoma tissue, with an accompanying systemic immune response.

Abstract PR-16: Evaluating direct KRASQ61H inhibition in pancreatic cancer models

Abstract KRASQ61 mutations are associated with the worst prognosis among the various KRAS mutational subtypes of pancreatic ductal adenocarcinoma (PDAC). RMC-7977 is a RAS(ON) multi-selective noncovalent inhibitor with broad spectrum activity against oncogenic RAS mutants and wild-type RAS. The related investigational agent RMC-6236 is currently undergoing clinical trials. Binary complexes of CypA: RMC-7977 bind equipotently to multiple KRAS mutational subtypes however RMC-7977 is less potent at inhibiting growth in KRASQ61H-mutant cell lines. In contrast, RM-047 is a preclinical RAS(ON) Q61H-selective inhibitor tool compound. We evaluated direct KRASQ61H inhibition using both RMC-7977 and RM-047 in cell culture models. We found that in KRASQ61H-rescued RASless mouse embryonic fibroblasts (MEFs), RM-047 inhibited ERK activity and suppressed growth more potently than RMC-7977. Conversely, in a panel of KRASQ61H-mutant PDAC cell lines, RM-047 was less potent than RMC-7977 in two out of three KRASQ61H-mutant PDAC cell lines. Furthermore, we discovered that ERK activity rapidly rebounded with treatment in KRASQ61H-mutant PDAC cell lines, whereas ERK activity remained suppressed in KRASQ61H-rescued RASless MEFS lacking WT RAS alleles. Our analysis of DepMap data indicated that among the KRAS mutational subtypes frequently found in pancreatic cancer, KRASQ61H is the least dependent on KRAS for survival. This suggests that in a KRASQ61H-mutant PDAC setting, additional factors such as WT RAS expression may mediate growth. From our KRAS drug-anchored CRISPR loss-of-function screens, we found that the loss of EGFR sensitized cells to KRAS inhibition, particularly in a KRASQ61H-dependent context. Therefore, we combined erlotinib, an FDA-approved EGFR inhibitor, with either RM-047 or RMC-7977, and found that the addition of erlotinib prevented ERK rebound activity and synergized with RM-047 or RMC-7977 to reduce growth in KRASQ61H-mutant PDAC cell lines. These data provide insights into mechanisms by which KRASQ61H-mutant PDAC may be less dependent on KRAS for survival and further support the clinical evaluation of combined EGFR and RAS(ON) inhibition as a potential therapeutic strategy in the treatment of PDAC patients harboring KRASQ61H mutations. Citation Format: Szu-Aun Long, Amber M Amparo, Haley Todd, Grace Goodhart, Syed A Ahmad, Andrew M Waters. Evaluating direct KRAS inhibition in pancreatic cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-16.

Abstract B079: Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases

Abstract Keratin 17 (K17), an intermediate filament protein typically expressed during embryonic development, is a hallmark of one of the most aggressive pancreatic ductal adenocarcinoma (PDAC) subtypes. Its expression is also associated with poor patient survival and resistance to first-line therapies. However, the mechanistic roles of K17 in malignancy remain largely unexplored. Here, we demonstrate that K17 expression and disassembly enhance tumor growth, increase metastatic potential, and shorten overall survival. Using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) stratified by K17 phosphorylation status, we found that increased K17 phosphorylation correlated with worse survival. Mass spectrometry of untreated PDAC patient samples identified a phosphorylation hotspot at serines 10-13, which is conserved across species and type I keratin proteins. We found that K17 phosphorylation, mediated by the PKC/MEK/RSK pathway, led to increased disassembly and nuclear translocation in pancreatic cancer cells. Mice with phosphomimetic mutations at the serine hotspot showed increased metastases and decreased survival compared to wild-type and phosphorylation-resistant K17. Lastly, detergent-soluble nuclear K17 promoted metastasis- related genes in both patient and murine tumors. These findings suggest that disassembly of K17 mediated by phosphorylation at serines 10-13 is sufficient to promote metastases and decrease overall survival in PDAC. This opens the door for further investigation into K17 phosphorylation as a novel therapeutic target to enhance PDAC patient survival, especially in those with more aggressive, chemoresistant subtypes. Citation Format: Deanne E Yugawa, Ryan Kawalerski, Mariana Torrente Gonçalves, Chun-Hao Pan, Robert Tseng, Lucia Roa-Pena, Cindy V Leiton, Luke A Torre-Healy, Taryn Boyle, Sumedha Chowdhury, Natasha T Snider, Kenneth R Shroyer, Luisa F Escobar-Hoyos. Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B079.

The role of local ablative therapy in patients with advanced invasive mucinous adenocarcinoma of the lung

PurposeInvasive mucinous adenocarcinoma (IMA) of the lungs is a rare subtype of lung adenocarcinoma with a limited understanding of its prognosis, particularly in advanced stages. This study aimed to assess the prognosis of patients with advanced IMA by focusing on treatment modalities.MethodsThis single-center retrospective study evaluated 33 patients with IMAs diagnosed with advanced-stage disease or disease progression after curative treatment between 2011 and 2021. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). OS and PFS were calculated from the date of the diagnosis of advanced IMA.ResultsThe study cohort included 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Treatment modalities included conventional chemotherapy in 24 patients (72.7%), targeted therapy in seven (21.2%), immunotherapy in 13 (39.4%), and local ablative therapy (LAT) in 13 (39.4%). The median OS was 32 months (95% confidence interval [CI], 2.9–61.0), with LAT significantly associated with improved OS compared to non-LAT treatment (not reached vs. 11.3 months, p = 0.001). However, there was no significant difference in OS based on conventional chemotherapy (p = 0.396), targeted therapy (p = 0.655), or immunotherapy (p = 0.992). In multivariate analysis, LAT remained an independent prognostic factor for OS (hazard ratio, 0.125; 95% CI, 0.026–0.608; p = 0.01). PFS was 8.6 months (95% CI, 3.6–13.7), with no significant differences observed among the treatment modalities.ConclusionOur findings suggest that LAT may provide favorable survival outcomes in patients with advanced IMA.

Impact of lung adenocarcinoma subtypes on survival and timing of brain metastases.

Lung cancer is a devastating disease, with brain metastasis being one of the most common distant metastases of lung adenocarcinoma. This study aimed to investigate the prognostic characteristics of individuals with brain metastases originating from invasive lung adenocarcinoma of distinct pathological subtypes, providing a reference for the management of these patients. Clinical data from 156 patients with lung adenocarcinoma-derived brain metastases were collected, including age, sex, smoking status, Karnofsky Performance Status scores, pathological subtype, lymph node metastasis, tumor site, treatment mode, T stage, and N stage. Patients were classified into two groups (highly differentiated and poorly differentiated) based on their pathological subtypes. Propensity score matching was used to control for confounding factors. The prognostic value of pathological subtypes was assessed using Kaplan-Meier analysis and Cox proportional hazards regression modeling. Kaplan-Meier analysis indicated that patients in the moderately to highly differentiated group had better prognoses. Multivariate analysis revealed that being in the poorly differentiated group was a risk factor for poorer prognosis. Thoracic tumor radiation therapy, chemotherapy, and surgery positively influenced the time interval between lung cancer diagnosis and brain metastasis. The pathological subtypes of lung adenocarcinoma-derived brain metastases are associated with patient prognosis. Patients in the poorly differentiated group have worse prognoses compared to those in the moderately to highly differentiated group. Therefore, patients in the poorly differentiated group may require more frequent follow-ups and aggressive treatment.

Survival Analysis, Clinical Characteristics, and Predictors of Cerebral Metastases in Patients with Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related deaths. While liver metastasis is common, brain metastasis (BM) is rare, occurring in 0.1% to 14% of cases. Risk factors for BM include lung metastasis at diagnosis, rectal cancer, and mutations in RAS and KRAS genes. Due to its rarity, guidelines for BM screening and treatment are limited. The aim of this study is to identify the clinical characteristics and predictors of BM at the time of the initial diagnosis of CRC. We evaluated patients ≥18 years old with metastatic colorectal cancer and brain metastases at diagnosis from the SEER database (2010-2021). A retrospective cohort study was conducted to analyze overall survival and predictive factors for brain metastasis, utilizing multivariate logistic regression, Kaplan-Meier survival analysis, and the Cox proportional hazards models, with p-values < 0.05 considered significant. Out of 24,703 patients with metastatic colorectal cancer (mCRC), 228 (0.92%) had brain metastasis (BM) at diagnosis. BM was more prevalent in average-onset mCRC (≥50 years) compared to early-onset (<50 years) (1% vs. 0.55%, p = 0.004). Certain factors, such as older age and adenocarcinoma subtype, were associated with BM. Additionally, Asians/Pacific-Islanders (HR 1.83 CI: 1.01-3-33, p = 0.045) and American Indians/Alaska Natives (HR 4.79 CI 1.15-19.97, p = 0.032) had higher mortality rates, while surgical treatment and chemotherapy were linked to decreased mortality. Patients with BM had significantly worse overall survival (6 months vs. 21 months, p < 0.001). BM in mCRC is uncommon, but it is associated with significantly worse outcomes, including markedly reduced overall survival. Our study highlights several critical factors associated with the presence of BM, such as older age and specific racial/ethnic groups, which may inform risk stratification and early-detection strategies. Our findings emphasize the need for heightened awareness and screening for BM in high-risk mCRC patients, as well as the inclusion of these patients in clinical trials to explore tailored therapeutic approaches aimed at improving survival and quality of life.

Outcome of Minimally Invasive and Open Pancreatoduodenectomy in Patients with Intestinal- and Pancreatobiliary Subtype Ampullary Cancer: An International Multicenter Cohort Study.

To compare minimally invasive and open pancreatoduodenectomy in different subtypes of ampullary adenocarcinoma. Ampullary adenocarcinoma (AAC) is widely seen as the best indication for minimally invasive pancreatoduodenectomy (MIPD) due to the lack of vascular involvement and dilated bile and pancreatic duct. However, it is unknown whether outcomes of MIPD for AAC differ between the pancreatobiliary (AAC-PB) and intestinal (AAC-IT) subtypes as large studies are lacking. This is an international cohort study, encompassing 27 centers from 12 countries. Outcome of MIPD and open pancreatoduodenectomy (OPD) were compared in patients with AAC-IT and AAC-PB. Primary end points were R1 rate, lymph node yield, and 5-year overall survival (5yOS). Overall, 1187 patients after MIPD for AAC were included, of whom 572 with AAC-IT (62 MIPD, 510 OPD) and 615 with AAC-PB (41 MIPD and 574 OPD). The rate of R1 resection was not significantly different between MIPD and OPD for both AAC-IT (3.4% vs 6.9%, P=0,425) and AAC-PB (9.8% vs 14.9%, P=0,625). AAC-IT, more lymph nodes were resected with MIPD group (19 vs 16, P=0.007), compared to OPD. The 5y-OS did not differ after MIPD and OPD for both AAC-IT (56.8% vs 59.5%, P=0.827 and AAC-PB (52.5% vs 44.4%, P=0.357). The rates of surgical complication between MIPD and OPD did not differ between AmpIT and AmpPB. This international multicenter study found no differences in outcomes between MIPD and OPD for AAC-IT and AAC-PB. MIPD and OPD demonstrated comparable outcomes in oncological resection, survival and surgical outcomes for both subtypes of AAC.

464. OUTCOMES AFTER CURATIVE RESECTION FOR GASTRO-ESOPHAGEAL JUNCTION ADENOCARCINOMA

Abstract Background Gastro-Esophageal Junction (GEJ) adenocarcinoma is becoming increasingly common in the west. Given the anatomical location of the junction there are several surgical approaches that can be used to treat these tumours, this is often guided by the sub-type of tumour, categorised using the Siewert classification. While overall survival for GEJ cancer tends to be poor compared with other solid organ cancers, changes in diagnosis and treatment have led to improvements in recent years. This study represents one of the largest retrospective reviews of its type to focus on the short- and long-term outcomes of patients undergoing curative resection for GEJ cancer. Methods Information was collected on 807 consecutive patients undergoing curative resection for gastro-esophageal junction adenocarcinoma between February 2010 and April 2023. The primary outcome was overall 5- and 10-year survival. Secondary outcomes included: disease free survival, survival based on surgical resection, 30- and 90-day mortality, post operative complications, oncology and pathology outcomes. For each outcome overall results and analysis comparing Siewert types was performed. Results 807 patients were included [319 type I cancers (39.5%), 401 type II (50%) and 87 type III (10.8%)]. Type I and II were predominantly managed with Esophagectomy (Type I = 100%, Type II = 97.5%). For Type III tumours 49% had esophagectomy and 51% had either a total or extended total gastrectomy. Siewert groups had comparable short-term outcomes, presented in table 1. Overall survival was 46% at 5 years and 37% at 10 years with no significant difference between Siewert types (p=0.24). Disease free survival was 55% at 5 years and 50% at 10 years with no significant difference between Siewert type (p=0.34). Conclusion The 3 Siewert classification subtypes of gastro-esophageal junction adenocarcinoma have similar short-term outcomes, overall and disease-free survival.

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

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. 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. 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 >2cm 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. 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.

MET exon 14 skipping mutations in non-small-cell lung cancer: real-world data from the Italian biomarker ATLAS database

Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS. Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry. From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively. Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14.

Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer.

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical strategies designed to exploit growth within the context of invasion are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early 3D invasion phenotypes in different molecular subtypes of KRAS-driven lung adenocarcinoma (LUAD). Combined live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix and transcriptomic profiling identified mutant LKB1-specific upregulation of BMP6. LKB1 loss increased BMP6 signaling, which induced the canonical iron regulatory hormone hepcidin. Intact LKB1 was necessary to maintain BMP6 signaling homeostasis and restrict ALK2/BMP6-fueled growth. Pre-clinical studies in a Kras/Lkb1-mutant syngeneic mouse model and in a xenograft model showed potent growth suppression by inhibiting the ALK2/BMP6 signaling axis with single agent inhibitors that are currently in clinical trials. Lastly, BMP6 expression was elevated in LKB1-mutant early-stage lung cancer patient tumors. These results are consistent with a model where LKB1 acts as a 'brake' to iron regulated growth and suggest that ALK2 inhibition can be used for patients with LKB1-mutant tumors.

Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favourable prognosis.

Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM-SBAs). Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death-ligand 1 (PD-L1) and mismatch repair proteins was performed in both SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein-Barr virus (EBV)-encoded RNAs by in-situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (9%) SB-MC was EBV-positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD-L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB-MC patients compared to NM-SBA cases (P = 0.02). SB-MCs represent a distinct histologic subtype, with peculiar features compared to NM-SBAs, including association with coeliac disease, dMMR, PD-L1 expression, and better prognosis.