Pathological Stage Research Articles

Early diagnostic value of ECT whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer.

This research was aimed at investigating the early diagnostic value of emission computed tomograph (ECT) whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer. Case data of 86 lung cancer patients were categorized into lung cancer with bone metastasis (LCWBM, 46 cases) and lung cancer without bone metastasis (LCWOBM, 40 cases) groups according to the presence or absence of bone metastasis. Patients' general information were collected. ECT whole-body bone imaging was used to detect bone metastases and the grading of the extent of disease (EOD) in both groups, and electrochemiluminescence was utilized to detect the serum levels of PINP and β-CTX. Spearman correlation analysis was employed to evaluate the correlation between EOD grading and PINP and β-CTX levels. Logistic univariate and multivariate regression was implemented to analyze the risk factors of bone metastasis of lung cancer. Receiver operating characteristic (ROC) curve was applied to analyze the diagnostic efficacy of the single test of ECT whole-body bone imaging, PINP, or β-CTX and the combination of the three tests. The differences in pathological type, clinical stage and EOD grading, the number of positive ECT cases, and the expression levels of PINP and β-CTX between the LCWBM and LCWOBM groups were statistically significant. In LCWBM patients with different EOD grading, the trends of the expression of PINP and β-CTX were grade 3 > grade 2 > grade 1 and grade 0. Further correlation analyses revealed that EOD grading showed a significant positive correlation with the PINP and β-CTX expression levels. Univariate logistic regression analysis demonstrated that adenocarcinoma, TNM stage IV, ECT positivity, and high expression of PINP and β-CTX were associated with bone metastasis of lung cancer, and multivariate logistic regression analysis indicated that ECT positivity, high expression of PINP and β-CTX were independent risk factors for bone metastasis of lung cancer. The area under the curve (AUC) of ECT, PINP, and β-CTX alone for the diagnosis of bone metastasis of lung cancer were 0.872, 0.888, and 0.874, respectively, and the AUC for the combined diagnosis of the three was 0.963, which was greater than that of any one of the individual indices, with a sensitivity of 86.96% and a specificity of 97.50% at a Youden index of 0.845. ECT whole-body bone imaging combined with PINP and β-CTX has high diagnostic value for bone metastasis of lung cancer.

Organ-confined pT2 ISUP4/5 vs. nonorgan confined pT3/4 ISUP2 vs. ISUP3 prostate cancer: Differences in biochemical recurrence-free survival after radical prostatectomy

BackgroundTo test for differences in organ-confined pathological tumor stage (pT) and intermediate International Society of Urological Pathologists (ISUP) grade vs. nonorgan confined pT stage and high ISUP grade and biochemical recurrence (BCR) after radical prostatectomy (RP). MethodsRelying on a tertiary-care database, prostate cancer patients undergoing RP between January 2014 and December 2021 were stratified according to their combination of pT stage and ISUP grade in RP specimens (pT2 ISUP4/5 vs. pT3/4 ISUP2 vs. pT3/4 ISUP3). As Active Surveillance is recommended in ISUP1, these patients were excluded. Moreover, patients with pT2 ISUP2/3 are known for their good prognosis and pT3/4 ISUP4/5 patients for their poor prognosis. Therefore, these patients were also excluded from analyses. Kaplan–Meier survival analyses and multivariable Cox regression models addressed BCR after RP. ResultsOf 215 RP patients, 29 (13%) exhibited pT2 ISUP4/5 vs. 122 (57%) pT3/4 ISUP2 vs. 64 (30%) pT3/4 ISUP3 pathology. In survival analyses, 3-year BCR-free survival rates were 95% in pT2 ISUP4/5 vs. 88% in pT3/4 ISUP2 vs. 65% in pT3/4 ISUP3 patients (P < 0.001). In multivariable Cox regression models addressing BCR, pT3/4 ISUP3 pathology was associated with higher BCR rate relative to pT2 ISUP4/5 pathology (hazard ratio 3.42, 95% confidence interval 1.07-10.94; P = 0.039), but not pT3/4 ISUP2 pathology (P = 0.6). ConclusionCompared to prostate cancer patients with pT2 ISUP4/5 pathology, the combination of pT3/4 ISUP3 pathology is associated with higher risk of BCR after RP. In consequence, patients with pT3/4 ISUP3 pathology should be considered for a closer postoperative follow-up.

Proposed Ninth Edition TNM Staging System for Lung Cancer: Guide for Radiologists.

Lung cancer continues to be the primary cause of cancer-related deaths globally. Precise staging is imperative for the development of successful treatment approaches and improvement of patient outcomes. Traditionally, lung cancer staging has depended on the TNM staging system, and the International Association for the Study of Lung Cancer (IASLC) has recently recommended modifications. The updated classification for the ninth edition of the TNM staging system (TNM-9), slated to take effect in January 2025, is derived from a thorough analysis of a newly established large international database of lung cancer cases compiled by the IASLC. Proposed changes in TNM-9 include the following: (a) The mediastinal nodal category (N2) was split into single-station (N2a) and multiple-station (N2b) subcategories, and (b) multiple extrathoracic metastatic lesions (M1c) were split into single organ system (M1c1) and multiple organ systems (M1c2) subcategories. Considering these revisions, adjustments have been made to the established stage groups. In terms of pathologic nodal staging, patients in the post-neoadjuvant ypN category demonstrated worse prognosis than those in the similar non-neoadjuvant pN category. Understanding the fundamental changes introduced in TNM-9 enables radiologists to precisely determine the clinical stage of lung cancer and enhance therapeutic approaches.

Prognostic Value and Therapeutic Significance of CCL Chemokines in Gastric Cancer.

Gastric cancer is one of the most common malignant tumours of the gastrointestinal tract, which has a significant negative impact on human health. CCL chemokines play important roles in a variety of tumor microenvironments; nevertheless, gastric cancer has surprisingly limited associations with CCL chemokines. In our study, we comprehensively utilized bioinformatics analysis tools and databases such as cBioPortal, UALCAN, GEPIA, GeneMANIA, STRING, and TRRUST to clarify the clinical significance and biology function of CCL chemokines in gastric cancer. The mRNA expression levels of CCL1/3/4/5/7/8/14/15/18/20/21/22/26 were up-regulated, while the mRNA expression levels of CCL2/11/13/16/17/19/23/24/25/28 were down-regulated. The chemokine significantly associated with the pathological stage of gastric cancer is CCL2/11/19/21. In gastric cancer, the expression level of CCL chemokines was not associated with disease-free survival, but low expression of CCL14 was significantly associated with longer overall survival. Therein, associated with the regulation of CCL chemokines are only 10 transcription factors (RELA, NFKB1, STAT6, IRF3, REL, SPI1, STAT1, STAT3, JUN and SP1). The major biological process and functional enrichment of CCL chemokines are to induce cell-directed migration. These results may indicate that CCL chemokines may be immunotherapeutic targets and promising prognostic biomarkers for gastric cancer.

Overestimation of clinical N-staging in microsatellite instable gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics

Abstract Background Microsatellite instable (MSI) gastric cancers exhibit reduced lymph node (LN) metastasis and improved survival compared to microsatellite stable (MSS) counterparts. However, to our longstanding observation, clinical N-staging (cN) is frequently overestimated in MSI cases. The clinical implications and underlying mechanisms of this discrepancy warrant further investigation. Materials and methods We conducted a comprehensive review of clinicopathological data from a 141 MSI and 1119 MSS gastric cancer patients. Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were assessed using qPCR and immunohistochemistry. High-parameter flow cytometry was employed to analyze subsets of CD8+ T cells within the tumors. Results Multivariate analysis revealed that MSI status was an independent prognostic factor, alongside the LN ratio and AJCC8 pathology staging. MSI gastric cancers exhibited a reduced LN ratio, particularly at advanced T-staging, compared to MSS counterparts, while maintaining an equivalent LN yield. Overestimation of cN by computed tomography preoperatively was frequent in MSI gastric cancers but was more commonly underestimated in MSS counterparts. VEGF-C and VEGFR-3 expression were lower in MSI tumors. MSI gastric cancers showed an increased total number of CD8+ T cells, albeit with a lower proportion of effector memory cells expressing CD45RA (EMRA) and CD8+ CXCR4+ T cells, compared to MSS counterparts. Conclusion Frequent overestimation of clinical N-staging in MSI gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics and should be cautiously interpreted, as it might misguide therapeutic options.

Abstract C028: Decreased heterogeneity in immune interactions in oral cavity squamous cell carcinoma patients with recurrence

Abstract There have been improvements in clinical risk stratifications for oral cavity squamous cell carcinoma (OSCC) with the AJCC 8th edition staging system. Other studies suggest the addition of a metric of specific immune interactions in and around the tumor may be helpful to further stratify patients, with mixed findings. The advent of spatial imaging has allowed a global view for assessing tumor features in the context of all surrounding cell interactions. We hypothesize that the lack of architectural information could contribute to varied clinical outcomes in previous studies, such as tumor recurrence. This highlights how spatial technologies could aid in understanding the role of tissue architecture and its influence on biology and medicine. To study tissue remodeling spatially, we focused on multiplexed-ion beam imaging (MIBI), a spatial proteomics platform to visualize 40 immuno-onco proteins simultaneously. Our banked patient cohort consists of 20 recurrent and 49 non-recurrent OSCC primary surgery samples. Clinical metadata capturing pathologic stage, alcohol use, smoking history, survival data, and more were also collected. With our pathologist, we curated 290 field-of-views (FOVs) of matched primary tumors, uninvolved lymph nodes, and metastatic lymph nodes (if any). Downstream computational analysis using existing MIBI codebases augmented with in-house spatial analytics has revealed a robust spatial dataset. After using machine-learning algorithms to cell segment our images, we validated these assigned cells and marker staining to further annotate cell populations. When we analyzed direct cell interactions, there was a decrease in heterogeneity in immune interactions within recurrent patients compared to non-recurrent patients. To ascertain how the loss of these interactions affected recurrence prognosis, we investigated their prevalence within the tumor border vicinity. We hypothesize that the proximity and cell-cell interactions near the border will promote a tumor-suppressive environment. Utilizing centroid-to-centroid distance measurements, we distilled the top 30 cell-cell interactions within a 100-micron distance from the tumor border. Cell pairs involving macrophage tissue-resident memory cells and CD8 T memory resident cells were more abundant in recurrent patients, while pairs involving CD4 T regulatory and CD8 cells were found in non-recurrent patients. Reassuringly, cell pairings involving myeloid cells were upregulated in the recurrent cohort as expected. Interestingly, cancer-associated fibroblast cell pairings were upregulated indiscriminately in both patient sub- cohorts. This suggests that the impact of certain known immunosuppressive changes may contribute in varying amounts to disease control. Our data demonstrates differences in the architecture of tumors with known divergent outcomes, which suggests global tissue-level changes could be a predictive factor. Clinically, interrogating these interactions of interest could guide treatment escalation or de-escalation in the future. Citation Format: Connie J. Zhou, Jane Lee, Rebecca Jaszczak, Steven R. Long, Patrick K. Ha, Matthew H. Spitzer. Decreased heterogeneity in immune interactions in oral cavity squamous cell carcinoma patients with recurrence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C028.

Clinicopathological predictive factors in long-term survivors who underwent surgery for pancreatic ductal adenocarcinoma: A single-center propensity score matched analysis.

Long-term survivors (LTSs) after pancreatic resection of pancreatic ductal adenocarcinoma (PDAC) represent a particular subgroup of patients that remains poorly understood. The primary endpoint was to identify clinicopathological factors associated with LTSs after pancreatic resection for PDAC. This was a retrospective study of patients who had undergone pancreatic resection for PDAC. Long survival was defined as a patient who survived at least 60months. Patients were divided in two groups: LTS and short-term survivor (STS). The two groups were compared regarding epidemiological, clinical, and pathological data. Propensity score matching (PSM) was used to reduce selection bias with a 1:2 ratio. Multivariable analysis of significative predictive factors before and after PSM was done. Three hundred and thirty-three patients were enrolled: 46 (13.8%) in the LTS group and 287 (86.2%) in the STS group. Using PSM, 138 patients were analyzed: 46 in the LTS group and 92 in the STS group. At the multivariate analysis of significative predictive factor after PSM, adjuvant chemotherapy, well-differentiated tumors (G1), and R0 status were related to long-term survival (p=0.052, 0.010 and p=0.019, respectively). Kaplan-Meier survival curves confirmed these data. Additionally, Kaplan-Meier survival curves showed that pathological stage I was a favorable factor with respect to stage II, III, and IV. Long-term survival is possible after pancreatic cancer resection, even if in a small percentage. Significant predictors of long-term survival are administration of adjuvant chemotherapy, American Join Committee on Cancer stage I, well-differentiated tumor (G1), and R0 resection.

Exosomal PSM-E inhibits macrophage M2 polarization to suppress prostate cancer metastasis through the RACK1 signaling axis.

It is well-established that understanding the mechanism of prostate cancer (PCa)-associated metastasis is paramount for improving its prognosis. Metastasis is known to involve the communication between tumor-associated macrophages (TAMs) and tumor cells. Exosomes are crucial in mediating this intercellular communication within the tumor microenvironment. Nonetheless, the role of exosomal proteins in PCa metastasis is not yet fully understood. Here, we investigated the mechanisms of prostate cancer-derived exosomal PSM-E on regulating macrophage M2 polarization to suppress tumor invasion and metastasis. PSM-E levels in exosomes were detected by transmission electron microscopy and Western blotting analysis. The diagnostic value of urine-derived exosomal PSM-E in PCa were evaluated by LC-MS/MS, correlation analysis, and ROC curves analysis. The mechanisms underlying the inhibitory effect of exosomal PSM-E on the M2 polarization of macrophages was investigated by co-IP, IHC staining, and PCa tumorigenesis model, etc. RESULTS: We revealed that exosomal PSM-E is upregulated in exosomes derived from the serum and urine of PCa patients. Clinically, an elevated exosomal PSM-E expression in urine is significantly correlated with an advanced pathological tumor stage and a high Gleason score. Our research also revealed that exosomal PSM-E inhibits prostate cancer cell proliferation, invasion, and metastasis by suppressing macrophage polarization in vitro and in vivo. Furthermore, we provided compelling evidence that exosomal PSM-E inhibits M2 polarization of macrophages by recruiting RACK1 and suppressing the FAK and ERK signaling pathways, consequently suppressing PCa invasion and metastasis. Furthermore, we found that the protease-associated domain of PSM-E and the fourth tryptophan-aspartate repeat of RACK1 are crucial for the interaction between PSM-E and RACK1. Notably, exosomes carrying PSM-E from PCa urine could potentially serve as a biomarker for PCa, and targeting exosomal PSM-E may represent a strategy for preventing tumor progression in this patient population.

Worse Clinical and Survival Outcomes in Breast Cancer Patients Living in Puerto Rico Compared to Hispanics, Non-Hispanic Blacks, and Non-Hispanic Whites from Florida.

Herein, we report the characterization of four cohorts of breast cancer patients including (1) non-Hispanic Whites in Florida, (2) non-Hispanic Blacks in Florida, (3) Hispanics in Florida, and (4) Hispanics in Puerto Rico. Data from female breast cancer patients were collected from cancer registry (n = 9361) and self-reported patient questionnaires (n = 4324). Several statistical tests were applied to identify significant group differences. Breast cancer patients from Puerto Rico were least frequently employed and had the lowest rates of college education among the groups. They also reported more live births and less breastfeeding. Both Hispanic groups reported a higher fraction experiencing menstruation at age 11 or younger (Floridian Hispanics [38%] and Puerto Ricans [36%]) compared to non-Hispanic Whites (20%) and non-Hispanic Blacks (22%). Non-Hispanic Black and Puerto Rican women were significantly older at breast cancer diagnosis than their non-Hispanic White and Floridian Hispanic counterparts. The Puerto Rican and non-Hispanic Black groups more frequently had pathology stage T2 or higher primary breast tumors at diagnosis (non-Hispanic Whites [29%], non-Hispanic Blacks [39%], Floridian Hispanics [33%], Puerto Ricans [46%]). The Puerto Rican (73%, 95% CI [66, 82]) and non-Hispanic Black (79%, 95% CI [75, 84]) groups demonstrate reduced 5-year survival compared to non-Hispanic Whites (89%, 95% CI [86, 92]) and Floridian Hispanics (89%, 95% CI [86, 90]). These findings demonstrate that Puerto Rican breast cancer patients suffer significant breast cancer health disparities relative to non-Hispanic Whites and Hispanics from Florida similar to the disparities observed for non-Hispanic Blacks. Future work must seek to better understand and address these disparities.

OGC SO15 - Utility of radiological re-staging following neo-adjuvant chemotherapy and its impact on oncological outcomes in resectable gastric adenocarcinoma

Abstract Background The current perioperative chemotherapy regimen that comprises the multimodal treatment strategy for gastric cancer consists of Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel. Despite improvement in outcomes at a population level, real-world data suggests that ≤40% of patients show a poor/no response to the neoadjuvant phase of treatment. Identification of these poor/non-responders may facilitate a re-evaluation of their treatment strategy and prevent potentially futile surgery. Radiological re-staging following neoadjuvant treatment is routinely performed despite its debatable accuracy and benefits. This study aimed to define the accuracy of radiological re-staging and its impact on survival following neoadjuvant treatment for resectable GC. Method Patients with resectable gastric cancer who completed 4 cycles of neoadjuvant FLOT and underwent resectional surgery with curative intent between 2018 and 2022 were retrospectively identified. All patients were clinically staged with gastroscopy, CT and staging laparoscopy. The index radiological/clinical stage at diagnosis was compared to the radiological re-staging following neoadjuvant treatment. Patient were re-staged with either a CT or PET-CT. Both were then compared with the final pathological stage to assess for correlation between the radiological and pathological stage. A survival analysis was then performed to evaluate the impact of radiological-pathological staging discrepancy on overall survival Results A total of 65 consecutive patients met the inclusion criteria of this study. On comparison of the index clinical stage with the radiological re-stage post-neoadjuvant treatment, 71% had concordant stages, 25% were downstaged, and 4% were upstaged. On comparison of the index clinical stage with the final pathological stage, 35% had concordant stages, 38% were upstaged and 27% were down staged (Cohen kappa = -0.224, 95% CI -0.390, -0.058). Discrepancy between clinical stage and radiological re-stage did not influence survival. However, discrepancy between clinical and pathological stage highlighted survival differences where upstaged patients had reduced survival (p = 0.018). Conclusion The accuracy of clinical staging compared to final pathological staging in the setting of aggressive tumour biology remains undefined. Radiological re-staging following neoadjuvant treatment proves to be an unreliable tool for assessing treatment response and does not predict long-term survival outcomes. These findings highlight the importance of accurate staging and the need for more precise methods of evaluating treatment response. This may enhance decision-making, individualise treatment regimens, and improve patient outcomes.

Integrated cerebellar radiomic-network model for predicting mild cognitive impairment in Alzheimer's disease.

Pathological and neuroimaging alterations in the cerebellum of Alzheimer's disease (AD) patients have been documented. However, the role of cerebellum-derived radiomic and structural connectome modeling in the prediction of AD progression remains unclear. Radiomic features were extracted from magnetic resonance imaging (MRI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n=1319) and an in-house dataset (n=308). Integrated machine learning models were developed to predict the conversion risk of normal cognition (NC) to mild cognitive impairment (MCI) over a 6-year follow-up. The cerebellar models outperformed hippocampal models in distinguishing MCI from NC and in predicting transitions from NC to MCI across both cohorts. Key predictors included textural features in the right III and left I and II lobules, and network properties in Vermis I and II, which were associated with cognitive decline in AD. Cerebellum-derived radiomic-network modeling shows promise as a tool for early identification and prediction of disease progression during the preclinical stage of AD. Altered cerebellar radiomic features and topological networks were identified in the subjects with mild cognitive impairment (MCI). The cerebellar radiomic-network integrated models outperformed hippocampal models in distinguishing MCI from normal cognition. The cerebellar radiomic model effectively predicts MCI risk and can stratify individuals into distinct risk categories. Specific cerebellar radiomic features are associated with cognitive impairment across various stages of amyloid beta and tau pathology.

OGC O01 - Stomach Cancer Elective Surgery Morbidity and Mortality at 90-Days (HOLD Study): A Prospective, International Collaborative Cohort Study

Abstract Background Data on multinational 90-day mortality and morbidity rates after surgery for gastric cancer is limited in the literature. This study aimed to understand the 90-day mortality and morbidity outcomes according to GASTRODATA Registry for elective gastric cancer surgery patients and identify risk factors. Method We conducted an international prospective study on ≥18 years patients undergoing elective surgery for gastric cancer with curative intent from 01 April 2022 to 30 September 2022. Known metastatic disease, concurrent secondary cancers, gastrointestinal stromal tumour (GIST) and Siewert type I/II oesophagogastric junction malignancies were excluded. Univariate and multivariate logistic regression was used to identify variables associated to 90-day outcome. Results 380 collaborators from 47 countries submitted data on 1538 patients. Mean age was 64.2 years and 58.5% were males. 90-day morbidity rate was 38.2% (n=587) and mortality rate was 2.9% (n=45). Pre-operative higher CCI or ASA score, pre-operative weight loss &amp;gt;10%, and surgical determinants such as type of gastric resection, positive specimen margin, number of harvested lymph nodes, longer surgery duration and post operative pathological IV staging (p value&amp;lt;0.05) were identified as predictors of postoperative severe complications and mortality. Conclusion Elective gastric cancer surgery has a 90-day morbidity of 38.2% and 90-day mortality of 2.9%, globally. This study identified several factors associated with higher morbidity and exemplified the importance of a unified language on surgical morbidity, pre-habilitation and ongoing audits to enhance patient outcomes.

Pathomic and bioinformatics analysis of clinical-pathological and genomic factors for pancreatic cancer prognosis.

Pancreatic cancer exhibits a high degree of malignancy with a poor prognosis, lacking effective prognostic targets. Utilizing histopathological methodologies, this study endeavors to predict the expression of pathological features in pancreatic ductal adenocarcinoma (PAAD) and investigate their underlying molecular mechanisms. Pathological images, transcriptomic, and clinical data from TCGA-PAAD were collected for survival analysis. Image segmentation using unsupervised machine learning was employed to extract features, perform clustering, and establish models. The prognostic value of pathological features and associated clinical risk factors were evaluated; the correlation between pathological features and molecular mechanisms, gene mutations, and immune infiltration was analyzed. By clustering 45 effective pathological features, we divided PAAD patients into two groups: cluster 1 and cluster 2. Significant associations with poor prognosis were found for cluster 2 in both the training group (n = 113) and validation group (n = 75) (p = 0.006), with pathological stages II-IV identified as potential synergistic risk factors (HR = 2.421, 95% CI = 1.263-4.639, p = 0.008). Subsequently, through multi-omics correlation analysis, we further revealed a close association between cluster 2 and the oxidative phosphorylation mechanism. Within the cluster 2 group, 28 oxidative phosphorylation genes exhibited reduced expression, CDKN2A gene mutations were upregulated, and there was significant downregulation of Tregs infiltration and related immune gene expression. The pathomic model constructed using machine learning serves as a valuable prognostic target for PAAD. The histopathological features cluster 2 are closely associated with the downregulation of oxidative phosphorylation levels and Tregs immune infiltration.

OGC SO22 - Accuracy of CT and FDG/PET clinical staging within a dedicated multidisciplinary service for patients with oesophago-gastric cancer

Abstract Background Accurate staging for oesophago-gastric cancer is important in ensuring correct treatment pathways, avoiding unnecessary surgery and providing prognostication for patients. Previously, cross sectional imaging in accurately providing tumour (T) and nodal (N) staging has been variable for upper GI malignancies, with usage of invasive investigations such as EUS to provide more specific local staging. With the increased utilisation of specialist multidisciplinary involvement and improved technology, we aimed to assess whether CT and PET imaging may be able to provide sufficiently accurate staging required for treatment decision making. Method All patients who underwent oesoophagogastric resections between January 2022 and March 2024 were identified from our surgical database. Patients were included if they had oesophago-gastric cancer, and underwent curative resection without neo-adjuvant treatment. Data collected included age, gender, location of primary tumour, CT/PET staging, and final histology. Outcomes assessed included rate of understaging in clinical and pathological T and N staging, and sensitivity and specificity of imaging in identifying presence of nodal disease. Results 38 patients were included in this analysis. For oesophageal and GOJ cancers, T stage under-reporting occurred in 6/27 (22%) patients, and N under-reporting in 7/27 (27%) patients. Radiological staging correlated with final pathological staging in 55% of T staging and 59% of N staging. Sensitivity (55.56%, 95% CI 21-86%) and specificity (72.2%, 95% CI 46.5-90.3%) for nodal disease on CT/PET was low, however no tumour or nodal under-staging would have impacted management. Gastric cancer staging accuracy assessment was limited by small numbers (n=12), however T under-staging occurred in 5/12 (42%) patients and N under-staging occurred in 5/11 patients (45%). Conclusion Involvement of dedicated radiology services in multidisciplinary care for oesophago-gastric cancer provides adequate radiological staging to guide treatment. Gastric cancer clinical staging requires laparoscopic and endoscopic assessment for accurate tumour assessment and management guidance. Radiological under-staging is less common in oesophageal and GOJ tumours than gastric cancer and has minimal impact on patient management.

Abstract A055: Tumor muscle invasion promotes tumor heterogeneity and normal muscle reprogramming

Abstract Aggressive human prostate tumors traverse a contractile smooth muscle pseudo-capsule, in a process termed extracapsular extension (ECE), defining the pT3 pathologic stage associating with increased biochemical recurrence, bone metastases, and cancer-specific mortality. While T3 lesions can be detected by non-invasive mpMRI imaging, how the tumor invades into and through the contractile muscle is unknown. Using a mouse xenograft model system of ECE, we investigated the transcriptomic consequences of human tumor invasion into and through the contractile smooth muscle of the mouse diaphragm. Both human and mouse gene transcripts were documented and analyzed. Tumor cells were intraperitoneally injected into male NSG mice and 6 weeks later, three tumor compartments (pre-invasive, muscle-invasive, and super-invasive cells that had reached the superior diaphragm surface) were analyzed for differential bulk human and mouse gene expression. Whole genome transcriptomic sequencing and GO pathway analysis revealed that approximately 414 human genes were differentially expressed between the non- invasive, muscle-resident, and super-invasive tumor populations and at least 5 enriched pathways were involved. The unique expression gene patterns of muscle-resident tumor cells were reversible when compared to the pre-invasive and super-invasive expression patterns. Significant increases in g-H2AX and nuclear deformation were observed in the muscle-resident tumor clusters as compared to the non-invasive tumor mass. No differences in tumor cell proliferation, as detected by Ki67 staining, were found between the tumor clusters in the three compartments. Immunohistochemistry staining for a damage response cytokeratin (KRT6A) and integrin (CD49f) revealed heterogeneity within the muscle resident tumors as compared to the non- invasive cells. Taken together, these data suggest a hostile contractile muscle environment elicits specific responses by the invading tumor. Single cell analysis within each of the tumor compartments is currently underway to define the spatial heterogeneity of gene expression in invasive tumor cell clusters within the contractile muscle. A dynamic reciprocity of the tumor/muscle microenvironment is suggested by the analysis of the bulk transcriptomic sequencing demonstrating a significant increase in mouse muscle bio-synthetic gene transcription as a consequence of the human tumor penetrating the tissue. Taken together, these data indicate that human tumors, during the act of traversing the contractile muscle layer, respond to this unique microenvironment by transiently altering transcription, while sustaining nuclear damage which results in the reprogramming of the muscle. This new information suggests that novel tumor or muscle biomarkers might indicate early muscle invasion events and assist new high-resolution image analysis for precision diagnostic and/or therapeutic decisions. (Supported in part by P30 CA23074; F30 CA143924, UACC Team Science Award). Citation Format: Kendra D Marr, Beatrice S Knudsen, Rafael Sainz, Kelvin W Pond, Noel E Warfel, Belinda E Sun, Anne E Cress. Tumor muscle invasion promotes tumor heterogeneity and normal muscle reprogramming [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A055.

DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. Clinical traits and RNA-seq of HCC patients in TCGA were used for weighted gene co-expression network analysis, where one module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to non-tumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to TKIs. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH, we discovered that the E1A-associated protein p300 (EP300) binds to DGKH’s promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid (PA). In an immunocompetent mouse model, co-treatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, PA production and mTOR signaling. Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, inhibition of which may lead to more effective hepatocellular carcinoma treatment.

Pan-cancer landscape analysis of NOP58 and its oncogenic driving role in lung adenocarcinoma.

Despite improvements in treatment in recent years, patients with lung adenocarcinoma (LUAD) still face poor prognoses. In this study, we elucidated the potential role of NOP58 ribonucleoprotein in pan-cancer and validated its oncogenic significance in LUAD using bioinformatics and in vitro and in vivo functional assays. NOP58 was found to be overexpressed in various types of tumors. It had great precision for predicting 20 distinct cancer types using receiver operating characteristic curve (ROC) as well as significant connections with the prognoses in particular cancers. In LUAD, NOP58 expression was correlated substantially with the TNM stage, pathologic stage, smoking status, and effectiveness endpoints, when we analyzed its association with clinical characteristics in LUAD. Elevated NOP58 expression was shown as connected with Th2 cell infiltration while also negatively linked with infiltrating other immune cells, such as CD8 T, cytotoxic, and Th1. By inhibiting NOP58 within the LUAD cells, we found a decrease in cells' capability to proliferate, migrate, and invade. Knockdown of NOP58 inhibited tumor growth in mouse xenograft models. Furthermore, the tissue microarray study indicated that there was a greater expression of NOP58 in the tumor tissues compared to adjacent normal tissues in LUAD. Our findings revealed that NOP58 could be an outstanding bio-index for pan-cancer diagnosis and prognosis and an independent prognostic risk factor in LUAD.

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease.

Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.

Expression and clinical significance of PIKFYVE gene in hepatocellular carcinoma analyzed based on TCGA database and experimental validation

Objective: To investigate the expression and clinical significance of human FYVE finger-containing phosphoinositide kinase (PIKFYVE) in hepatocellular carcinoma (HCC) on the basis of cancer genome atlas (The cancer genome atlas, TCGA) database analysis and clinical samples experimental validation. Methods: Based on the data information of 424 clinical samples (including 374 cases of HCC tissues and 50 cases of nontumorous liver tissues) in the TCGA database, Cox regression analysis and Kaplan-Meier method were used to analyse the relationship between the PIKFYVE mRNA expression and the clinical characteristics, prognosis for survival of HCC patients. The relationship between the PIKFYVE gene and immune cell infiltration was examined by correlation analysis between the PIKFYVE gene and 24 immune cells. In addition, we analysed the correlation between the mRNA expression of PIKFYVE gene and RAC-alpha serine/threonine-protein kinase (AKT1), phosphatase and tensin homolog (PTEN), protein kinase C, alpha (PRKCA), inositol polyphosphate-5-phosphatase (INPP5D), phosphoinositide-3-kinase regulatory subunit 1(PIK3R1), Inositol Polyphosphate 4-phosphatase Type II (INPP4B) and phospholipase-C4 gene (PLCB4) in HCC tissues. Meanwhile, paraffin sections of highly differentiated, moderately differentiated, poorly differentiated, and nontumorous liver tissue in the Department of Pathology of the First Affiliated Hospital of Xinjiang Medical University were collected, each of which was 30 cases, and the histopathological observation was carried out by HE staining, and the expression levels of PIKFYVE and Ki67 proteins were verified by immunohistochemistry in each clinical sample. Results: The expression level of PIKFYVE gene in HCC tumours was significantly higher than that in normal liver tissues (P=0.000 2, P<0.01), and the overall survival of patients in the low PIKFYVE expression group was significantly longer than that in the high expression group (HR=1.57, 95%CI: 1.10～2.25, P=0.014). The results of Univariate Cox regression analysis showed that there was an effect of TNM stage, pathological stage, tumour status and residual tumour on Overall survival (OS) (P<0.05), and the expression level of PIKFYVE had an effect on OS survival (P<0.05); the PIKFYVE prognostic risk model score ratio was HR=1.533 (1.077-2.181, P=0.018). Multivariate Cox regression analysis showed a PIKFYVE prognostic risk model score ratio HR=1.481 (0.886-2.476, P=0.134) and an area under the Receiver Operating Characteristic curve of 0.640, which was greater than 0.5, suggesting that the PIKFYVE prognostic risk model has a predictive value in survival prediction. Correlation analysis showed that the expression level of PIKFYVE was highly correlated with immune cell infiltration and TP53 (P<0.01). The immunohistochemistry staining results showed that the expression of PIKFYVE in HCC tissues was significantly higher than that of nontumorous tissues (P<0.05), and there was a negative correlation with the degree of differentiation. Conclusion: PIKFYVE, as an independent risk factor for HCC, is expected to be developed as a clinical diagnostic biomarker for HCC, which will provide a reference for new drugs for the treatment of HCC.

Safety and feasibility of robotic surgery in geriatric patients with rectal cancer.

The incidence of rectal cancer is increasing in the elderly population, yet the safety of surgical interventions in this group, particularly robotic surgery, is still debated. This study aims to investigate the safety and short-term postoperative outcomes of robotic surgery in geriatric patients (aged ≥ 70years) with rectal cancer. Patients diagnosed with rectal cancer and undergoing robotic surgery between March 2021 and September 2023 were divided into two groups based on age: the elderly group (aged ≥ 70years) and the younger group (aged < 70years), totaling 108 patients. The study included 80 younger patients in group 1 and 28 elderly patients in group 2. The groups had similar gender distribution and tumor characteristics. The elderly group had higher ASA scores and lower albumin levels and underwent the Miles procedure more frequently. The stoma rate was higher in the elderly group. Operation duration, tumor diameter, lymph node dissection numbers, pathological stage, and other histopathological features were similar in the two groups. Postoperative outcomes like hospital stay, complication rates, anastomotic leakage, reoperation rates, unplanned readmissions, and mortality were comparable between the groups. Robotic surgery for rectal cancer in elderly patients is technically feasible and safe. Age should not be a determining factor in patient selection for robotic surgery or be considered a risk factor for postoperative complications.