Early Adenocarcinoma Research Articles

Differences between Survival Rates and Patterns of Failure of Patients with Lung Adenocarcinoma and Squamous Cell Carcinoma Who Received Single-Fraction Stereotactic Body Radiotherapy.

We investigated the survival and patterns of failure in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) in early stage non-small cell lung cancer (NSCLC) treated with single-fraction stereotactic body radiation therapy (SF-SBRT) of 27-34 Gray. A single-institution retrospective review of patients with biopsy-proven early stage ADC or SCC undergoing definitive SF-SBRT between September 2008 and February 2023 was performed. The primary outcomes were overall survival (OS) and disease-free survival (DFS). The secondary outcomes included local failure (LF), nodal failure (NF), and distant failure (DF). Of 292 eligible patients 174 had adenocarcinoma and 118 had squamous cell carcinoma. There was no significant change in any outcome except distant failure. Patients with ADC were significantly more likely to experience distant failure than patients with SCC (p = 0.0081). In conclusion, while SF-SBRT produced similar LF, NF, DFS, and OS, the higher rate of distant failure in ADC patients suggests that ongoing trials of SBRT and systemic therapy combinations should report their outcomes by histology.

Abstract A001: Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

Abstract Abstract: The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data. Citation Format: Chunyang Bao. Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A001.

The role of adenocarcinoma subtypes and immunohistochemistry in predicting lymph node metastasis in early invasive lung adenocarcinoma

BackgroundIdentifying lymph node metastasis areas during surgery for early invasive lung adenocarcinoma remains challenging. The aim of this study was to develop a nomogram mathematical model before the end of surgery for predicting lymph node metastasis in patients with early invasive lung adenocarcinoma.MethodsIn this study, we included patients with invasive lung adenocarcinoma measuring ≤ 2 cm who underwent pulmonary resection with definite pathology at Qilu Hospital of Shandong University from January 2020 to January 2022. Preoperative biomarker results, clinical features, and computed tomography characteristics were collected. The enrolled patients were randomized into a training cohort and a validation cohort in a 7:3 ratio. The training cohort was used to construct the predictive model, while the validation cohort was used to test the model independently. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. The prediction model and nomogram were established based on the independent risk factors. Recipient operating characteristic (ROC) curves were used to assess the discrimination ability of the model. Calibration capability was assessed using the Hosmer–Lemeshow test and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA).ResultsThe overall incidence of lymph node metastasis was 13.23% (61/461). Six indicators were finally determined to be independently associated with lymph node metastasis. These six indicators were: age (P < 0.001), serum amyloid (SA) (P = 0.008); carcinoma antigen 125 (CA125) (P = 0. 042); mucus composition (P = 0.003); novel aspartic proteinase of the pepsin family A (Napsin A) (P = 0.007); and cytokeratin 5/6 (CK5/6) (P = 0.042). The area under the ROC curve (AUC) was 0.843 (95% CI: 0.779–0.908) in the training cohort and 0.838 (95% CI: 0.748–0.927) in the validation cohort. the P-value of the Hosmer–Lemeshow test was 0.0613 in the training cohort and 0.8628 in the validation cohort. the bias of the training cohort corrected C-index was 0.8444 and the bias-corrected C-index for the validation cohort was 0.8375. demonstrating that the prediction model has good discriminative power and good calibration.ConclusionsThe column line graphs created showed excellent discrimination and calibration to predict lymph node status in patients with ≤ 2 cm invasive lung adenocarcinoma. In addition, the predictive model has predictive potential before the end of surgery and can inform clinical decision making.

Organ preservation with durvalumab-based immunotherapy in combination with chemoradiation as definitive therapy for early stage, cT1, and cT2N0 esophageal adenocarcinoma with indication for radical surgery: A prospective, multicenter study of the FLOT-AIO Gastric Cancer Group (IKF-t057/PRESTO trial).

TPS431 Background: The outcome of patients (pts) with adenocarcinomas of stomach and esophagogastric junction (GEJ) remains unsatisfactory (5-year survival rates of 24-84%), whereby surgical resection is considered as cornerstone of the curative treatment for pts with early stage esophageal adenocarcinoma (EGA), however, it is associated with mortality, morbidity and an impact on the patient’s quality of life. Recent investigations showed that in locally advanced stage EGA surgery with neoadjuvant chemoradiotherapy (CROSS trial) is beneficial over surgery alone. Further benefit was achieved for locally advanced EGA by perioperative treatment with FLOT acc. to FLOT4- trial data. Immuno-oncology (IO) therapy by using checkpoint inhibitors is approved in the palliative and adjuvant EGA situation. In this trial we aim for the organ preservation treatment of EGA pts with a combination of the anti PD-L1 antibody durvalumab- FLOT - and chemoradio-therapy. Methods: This is a multicenter, single arm, open-label, phase II trial including a total of 32 pts with T1-T2N0 EGA (including GEJ) with indication for radical surgery. Enrolled pts will receive immunotherapy with durvalumab (1500 mg Q4W) in parallel to 2 cycles FLOT (50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 calcium folinate and 2600 mg/m2 5FU, Q2W) induction followed by 3 cycles of mFOLFOX (85 mg/m2 oxaliplatin, 200 mg/m2 calcium folinate, 400 mg/m2 5FU bolus and 1600 mg/m2 5FU over 48h, Q2W) plus concomitant radiation (25 daily fractions with 2.0 Gy = Σ50Gy). 8 weeks after last treatment, pts will undergo tumor assessment by esophagogastroduodenoscopy with biopsies, endoscopic ultrasonography, and CT- or MRI-scans. Surgical resection would be offered only to pts in whom a locoregional persistence is confirmed. Pts with complete remission will enter the maintenance phase and will receive durvalumab monotherapy (1500 mg, Q4W) for a maximum of 12 cycles accompanied by regular tumor re-evaluation. Primary endpoint is the rate of cCR/pCR at time of re-evaluation. Secondary endpoints include rate of cCR/pCR at 1, 2 and 3 years, rate of salvage surgery, 90 day and 1 year mortality after start of treatment, safety and quality of life. In this exploratory trial a cCR/pCR rate of ≥75% would indicate that the study treatment should be further investigated, whereas a rate &lt; 55% indicates no further investigation. First patient was enrolled on 2023-08-28. Currently one patient is recruited. Clinical trial information: NCT05713838 .

Performance of dual-layer spectrum CT virtual monoenergetic images to assess early rectal adenocarcinoma T-stage: comparison with MR.

To evaluate the image quality and utility of virtual monoenergetic images (VMI) of dual-layer spectrum computed tomography (DLSCT) in assessing preoperative T-stage for early rectal adenocarcinoma (ERA). This retrospective study included 67 ERA patients (mean age 62 ± 11.1 years) who underwent DLSCT and MR examination. VMI 40-200 keV and poly energetic image (PEI) were reconstructed. The image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and tumor contrast of different energy levels were calculated and compared, respectively. Two radiologists independently assess the image quality of the VMIs and PEI using 5-point scales. The diagnostic accuracies of DLSCT and HR-MRI for ERA T-staging were evaluated and compared. The maximum noise was observed at VMI 40 keV, and noise at VMI 40-200 keV in the arterial and venous phases showed no significant difference (all p > 0.05). The highest SNR and CNR were obtained at VMI 40 keV, significantly greater than other energy levels and PEI (all p < 0.05). Tumor contrast was more evident than PEI at 40-100 keV in the arterial phase and at 40 keV in the venous phase (all p < 0.05). When compared with PEI, VMI 40 keV yielded the highest scores for overall image quality, tumor visibility, and tumor margin delineation, especially in the venous phase (p < 0.05). The overall diagnostic accuracy of DLSCT and HR-MRI for T-stage was 65.67 and 71.64% and showed no significant difference (p > 0.05). VMI 40 keV improves image quality and accuracy in identifying lesions, providing better diagnostic information for ERA staging. Low-keV VMI from DLSCT can improve tumor staging accuracy for early rectal carcinoma, helping guide surgical intervention decisions, and has shed new light on the potential breakthroughs of assessing preoperative T-stage in RC. • Compared with PEI, low-keV VIM derived from DLSCT, particularly at the 40 keV, significantly enhanced the objective and subjective image quality of ERA. • Using VMI 40 keV helped increase lesion detectability, leading to improved diagnostic accuracy for ERA. • Low-keV VMI from DLSCT has shed new light on the potential breakthroughs of assessing preoperative T-stage in RC.

Abstract A014: Combinations of previously reported biomarkers achieve improved sensitivity and specificity of detection of early stage pancreatic ductal adenocarcinoma

Abstract A promising approach to the early detection of pancreatic ductal adenocarcinoma (PDAC) is surveillance among people at elevated risk for the disease using a blood test. Several groups have reported promising biomarkers, but no single biomarker delivers the rate of positively predicting cancers and of negatively predicting non-cancers needed for routine use. We hypothesized that combinations of previously reported PDAC biomarkers could contribute complementary detection across heterogeneous subgroups of patients and consequently improve biomarker performance. Blood plasma specimens from 427 individuals, grouped into a training set (n = 132) and a validation set (n = 295), were distributed to four different laboratories for analysis using their independently developed biomarker assays. We analyzed the training set to identify biomarker combinations that improved upon CA19-9 for identification of early stage PDAC relative to benign disease conditions, both for improved sensitivity while controlling for high specificity and improved specificity while controlling for high sensitivity. We then applied the biomarker combinations to the validation set to determine their performance. The combination of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 sensitivity with 0.98 specificity for CA19-9 to 0.71 sensitivity with 0.94 specificity (p &amp;lt; 0.001, 1000-fold bootstrap), and CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 specificity and 0.94 sensitivity for CA19-9 to 0.58 specificity and 0.89 sensitivity (p &amp;lt; 0.001, 1000-fold bootstrap). Notably, cross-laboratory biomarker combinations that did not include CA19-9 in the panel significantly improved upon CA19-9. The combination of CA199.STRA with the protein biomarker MUC5AC improved sensitivity over CA19-9 with 0.61 sensitivity and 0.94 specificity (p = 0.0002, 1000-fold bootstrap), and the combination of CA199.STRA and the protein biomarkers MUC5AC, THSP2, and ANG improved specificity over CA19-9 with 0.66 specificity and 0.88 sensitivity (p &amp;lt; 0.0001, 1000-fold bootstrap). By coordinating this biomarker study across independent laboratories, we have identified novel biomarker combinations that significantly increase the sensitivity and specificity of early stage PDAC detection and that demonstrate the future feasibility of surveillance for PDAC using combinations of serum assays. Citation Format: Brian Haab, Lu Qian, Ben Staal, Maneesh Jain, Johannes Fahrmann, Christine Worthington, Denise Prosser, Liudmila Velokokhatnaya, Camden Lopez, Runlong Tang, Mark Hurd, Gopalakrishnan Natarajan, Sushil Kumar, Lynette Smith, Samir Hanash, Surinder Batra, Anirban Maitra, Anna Lokshin, Ying Huang, Randall E. Brand, Liudmila Velokokhatnaya. Combinations of previously reported biomarkers achieve improved sensitivity and specificity of detection of early stage pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A014.

Incidence rates of Barrett’s esophagus and esophageal adenocarcinoma: a systematic review and meta-analysis

Background and AimsBarrett’s esophagus (BE) surveillance is commonly performed to detect early dysplasia and esophageal adenocarcinoma (EAC). However, high-quality incidence rates for the development of dysplasia and EAC in patients with BE are limited. This study aims to perform a systematic review and meta-analysis to provide an updated incidence rates for the development of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC in a population of patients with BE undergoing endoscopic surveillance. MethodsWe performed a systematic search of EMBASE and Medline from inception to September 2022 to identify studies reporting the incidence rates of LGD, EAC, or HGD/EAC as an outcome in patients with non-dysplastic BE (NDBE), LGD, or HGD. Respective pooled incidence rates were estimated using a meta-analysis. ResultsTwenty-five studies were included in this meta-analysis comprising 2,587 patients with a combined follow-up of 218,351 person-years. For patients with NDBE, pooled incidence rates for progression to LGD, HGD, EAC, and HGD/EAC were 4.29, 0.52, 0.21, and 0.57 per 100 person-years, respectively. For patients with LGD, pooled incidence rates were 3.18 (HGD), 1.16 (EAC), and 5.05 (HGD/EAC) per 100 person-years. For those with HGD, the pooled incidence rate for EAC was 14.16 per 100 person-years. ConclusionsProgression to EAC and HGD/EAC remained low for patients with NDBE. Patients with confirmed LGD (≥2 pathologists) may be more likely to develop EAC, prompting a need to assess current BE surveillance strategies in this group.

Endoscopic Characteristics of Early Gastroesophageal Junction Adenocarcinomas and Assessment for Invasion Depth: A Case Series Study.

Early-stage gastroesophageal junction (GEJ) adenocarcinoma can be challenging to diagnose and treat promptly using endoscopy. This study aims to summarize the endoscopic characteristics of early GEJ adenocarcinoma and investigate their correlation with pathological grade and invasion depth. This retrospective case series study evaluated patients with early GEJ adenocarcinoma who underwent endoscopic or surgical resection at First Affiliated Hospital of Dalian Medical University between January 2016 and December 2022. A total of 71 patients were included in the analysis, with 59 males and a median age of 67 years. The majority of the lesions were located on the posterior side of the GEJ (40.8%) or the lesser curvature side (29.6%). Siewert II lesions accounted for 71.8% of cases, with most occurring on the posterior side (49.0%) and Siewert III lesions mostly occurring on the lesser curvature side (42.9%). Siewert I lesions accounted for only 7.0%, and all originated from Barrett mucosa. Paris classification of Is (P = .015) or IIc (P = .015), lesion size ≥12 mm (P = .017), red color with subsquamous extension (P = .038), and disordered microsurface with local fusion (P < .001) were independently and positively correlated with pathological grade and invasion depth by multivariable ordinal logistic regression. The posterior side and lesser curvature of the GEJ are the high-incidence sites of GEJ adenocarcinoma. Both forward and backward views during endoscopy should be combined to detect the lesion. Endoscopic characteristics such as Is or IIc morphology, larger size, red color with subsquamous extension, and disordered microsurface with local fusion may indicate a higher pathological grade and deeper invasion.

Comparison of Clinicopathological Characteristics of Patients with Early and Late-onset Colorectal Adenocarcinoma: A Cross-sectional Study

Introduction: Colorectal Cancer (CRC) has been primarily considered a disease of the elderly, but recent data have shown an alarming rise among young people. It has also been suggested that young age is associated with aggressive histopathological characteristics and advanced stages of the disease at diagnosis. Aim: To assess and compare the clinical and pathological characteristics of patients with rectal cancer diagnosed at ages over and below 45 years. Materials and Method: This prospective cross-sectional study was conducted between January 2020 and August 2022 in the Departments of Surgical, Medical, Radiation Oncology, Surgical Gastroenterology, and General Surgery at All India Institute of Medical Sciences (AIIMS) Rishikesh, Uttarakand, India. All patients underwent a biopsy from the representative site for histological documentation of the disease. They then underwent treatment (surgery/chemotherapy/radiotherapy) as required. All the data were categorised into two groups: an early-onset group (age &lt;45 years) and a late-onset group (≥45 years). A comparison of the clinicopathological characteristics (age, gender, comorbidities, tumour subsite, clinical presentation, clinical stage, etc.), pathological data (grade and differentiation of tumour, as per World Health Organisation (WHO) grading system), and serum Carcinoembryonic Antigen (CEA) levels between the two groups was performed. The association between categorical variables was investigated using the Chi-square test. The mean difference was assessed using an independent t-test. A p-value of 0.05 or below was considered statistically significant. Results: A total of 51 patients with rectal cancer, 35 males and 16 females, were included in the study. The mean age was 44.73±16.47 years. Out of the total of 51 (100%) patients, lower rectum involvement was seen in 22 (43.1%) patients, followed by 7 (13.7%) patients each with ascending colon and sigmoid involvement resepectively. However, the Chi-square test showed no statistically significant association of location involved with age groups (χ2 =9.09; p=0.16). Out of 51 (100%) adenocarcinoma patients in total, three patients each under 45 years of age had signet cell adenocarcinoma and mucinous adenocarcinoma (χ2 =7.07; p=0.029). Among the total of 51 (100%) patients, moderately differentiated lesions were seen in 17 (33.3%) patients, poorly differentiated lesions were seen in 15 (29.4%) patients, and well-differentiated lesions were seen in 10 (19.6%) patients (χ2 =13.01; p=0.005). Conclusion: Younger patients tended to have larger tumours that were of a higher grade and had signet ring or mucinous histopathology. The social and clinical implications of these findings are to be explored.

Clinicopathologic Features and Outcomes of Endoscopic Submucosal Dissection for Foveolar-Type Adenocarcinoma of the Stomach.

Foveolar-type adenocarcinoma of the stomach is a rare variant of gastric cancer. The clinicopathological features and outcomes of endoscopic submucosal dissection (ESD) for gastric foveolar-type adenocarcinoma remain unclear. This study included 1,161 patients who underwent ESD for single early gastric cancers (EGCs) (78 foveolar-type adenocarcinomas and 1,083 well-differentiated [WD] adenocarcinomas). The clinicopathological features and short- and long-term outcomes of ESD for gastric foveolar-type adenocarcinomas were reviewed and compared with those for WD EGCs. Gastric foveolar-type adenocarcinomas were larger and more likely to exhibit an elevated macroscopic appearance than WD EGCs. Foveolar-type adenocarcinomas exhibited higher rates of lymphatic invasion, histological heterogeneity, and lateral margin involvement than WD EGCs. The en bloc R0 and curative resection rates of foveolar-type adenocarcinoma were 85.9% and 76.9%, respectively. Both foveolar-type adenocarcinoma rates were significantly lower than those of WD EGCs (95.8% and 91.3%, respectively). Lateral margin involvement accounted for 55.6% of the non-curative resection cases of foveolar-type adenocarcinoma. Among patients who underwent curative ESD for foveolar-type adenocarcinoma, no recurrence occurred during the median 62.3 months of follow-up. No lymph node metastases were detected in patients with foveolar-type adenocarcinoma who underwent additional surgery following ESD. The overall and disease-specific survival rates of patients with foveolar-type adenocarcinoma were comparable to those of patients with WD EGC. Gastric foveolar-type adenocarcinomas have distinct clinicopathological features among WD EGCs. Given favorable long-term outcomes after curative resection, ESD can be indicated for early gastric foveolar-type adenocarcinomas.

The usefulness of traction-assisted endoscopic papillectomy for ampullary early tumors(with video)

Objective Endoscopic papillectomy(EP) is a minimally invasive treatment for early ampullary tumors. However, the optimal method is unclear. The aim of this study is to explore the efficacy and safety of traction-assisted EP treatments for ampullary early tumors. Methods We retrospective analyzed the patients with ampullary adenoma or early adenocarcinoma underwent endoscopic papillectomy between January 2010 and August 2023, including patient characteristics, lesion size, papilla type, pathological diagnosis and lesion surrounding conditions, en-bloc resection rate, complete resection rate, procedure time, complications, recurrences. Results During the study period, a total of 106 patients with ampullary adenoma or early adenocarcinoma underwent EP. The number of patients in traction group (clip combined with dental floss traction, CDT-EP) and non-traction group (hot snare papillectomy, HSP or endoscopic mucosal resection, EMR) were 45 and 61 respectively. The traction group has a higher en-bloc resection rate and complete resection rate than the non-traction group (92.86% vs. 68.85%, p = 0.003; 90.48% vs. 60.66%, p = 0.001), and the procedure time is slightly shorter[(1.57 ± 1.93)min vs. (1.98 ± 1.76)min, p = 0.039]. The complications and recurrence in the traction group were lower than those in the non-traction group (7.14% vs. 19.72%, p = 0.076; 7.14% vs. 11.78%, p = 0.466), and all complications were successfully treated by endoscopy or conservative medical treatment. There was no statistical difference between the two groups in terms of patient characteristics, papilla type, pathological diagnosis and lesion surrounding conditions (p > 0.050), but there were differences in lesion size[(13 ± 1.09)mm vs. (11 ± 1.65)mm, p = 0.002]. The recurrence rate of the traction group is lower than that of the non-traction group, but the difference is not significant(7.14% vs. 13.11%, p = 0.335), and the non-traction group mainly has early recurrence. Further analysis shows that the size of the lesion, whether en-bloc resection or not, and the method of resection as independent risk factors for incomplete resection (OR = 1.732, p = 0.031; OR = 3.716, p = 0.049; OR = 2.120, p = 0.027). Conclusions CDT- EP, HSP and EMR are all suitable methods for the treatment of ampullary adenoma or early adenocarcinoma. Assisted traction technology can reduce the operation difficulty of large and difficult to expose lesions, thereby improving the efficacy and safety of EP.

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma

ObjectiveEarly gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in...

Diagnostic value of plasma circular RNA based on droplet digital polymerase chain reaction in lung adenocarcinoma.

Plasma circular (circ)RNAs detected by droplet digital polymerase chain reaction (ddPCR) may be ideal markers for liquid biopsy. However, ddPCR detection of circRNAs in plasma for diagnosis of lung adenocarcinoma has been rarely reported. An RNA sequencing analysis was performed in plasma from patients with early lung adenocarcinoma and healthy individuals. Droplet digital PCR was used to verify the differentially expressed genes. The copy numbers of circle RNALZIC (circLZIC)and circle RNACEP350 (circCEP350) in the plasma of lung adenocarcinoma patients were significantly higher than in plasma of healthy people, and the copy numbers in postoperative plasma of the same patients were significantly lower than those in preoperative plasma. CircLZIC and circCEP350 alone and in combination had diagnostic value in lung adenocarcinoma and early lung adenocarcinoma. CircLZIC and circCEP350 had more binding sites with multiple microRNAs. Their target genes were enriched in several signaling pathways. The copy numbers of circLZIC and circCEP350 were higher in plasma of lung adenocarcinoma patients than in plasma of healthy controls, significantly correlated with tumor size and TNM stage, and closely related to the occurrence and development of tumors. These circRNAs may serve as molecular markers for the diagnosis of lung adenocarcinoma.

Abstract A177: In vivo TuBa-seq growth profiling identifies a differential role of the Tbx2 subfamily in oncogene-negative versus Kras-driven lung cancers

Abstract Lung adenocarcinoma (LUAD) is a complex cancer driven by diverse combinations of oncogenic and tumor suppressive events. The TBX2 subfamily genes, including TBX2, TBX3, TBX4, and TBX5, are known to play a crucial role in lung development as master transcriptional regulators. Our previous clinical and in vitro studies found that their expression is significantly suppressed in LUADs, suggesting a potential tumor suppressor role through modulating tumor methylation patterns in early tumorigenesis. However, the role of TBX2 subfamily genes in other cancer types is paradoxical, with both oncogenic and tumor suppressive effects being reported. Herein, we employed the Tumor Barcoding with Ultradeep Sequencing (Tuba-seq) and CRISPR/Cas9-mediated genome editing technologies to investigate the putative tumor suppressive role of TBX2 genes functionally and quantitatively and their downstream targets in genetically engineered mouse models of LUAD. Lung tumors were initiated by intratracheal intubation with pooled lentiviral-Cre vectors targeting each gene independently with two different sgRNAs per gene. To enable the unique identification of each tumor and its corresponding sgRNA, we utilized Lenti-sgRNA/Cre vectors harboring barcodes specific to each targeted gene. Initial assessment of tumor burden was carried out through fluorescence microscopy, lung weight measurements, and histological analysis. To simultaneously determine the number of neoplastic cells corresponding to each gene knockout, the barcoded region was amplified from genomic DNA extracted from bulk tumor-bearing lung samples and sequenced. Quantification of tumor sizes was carried at 6 and 20 weeks after tumor initiation. Hyperplasia, adenomas, and/or early adenocarcinomas within the lungs were detected among different genetic backgrounds and throughout the study time intervals. Specifically, the inactivation of Tbx2, Tbx3, Tbx4, Tbx5, and Cdh2, increased tumor initiation and growth in the oncogene-negative mouse model (n=8). However, strikingly, inactivation of Tbx3, Tbx4, and Cdh2 suppressed tumorigenesis in a KRAS-driven genetic background while Tbx2, Tbx5, and Tnfaip3, consistently exhibited tumor suppressive effects (n=9). Further investigation is needed to understand these newly discovered interactions between the TBX2 subfamily critical developmental pathway and Ras signaling in modulating lung cancer progression. These insights emphasize the importance of considering tumor suppressor phenotypic heterogeneity and their context-dependent roles when developing targeted therapeutic approaches for lung adenocarcinoma and other cancers. Citation Format: Athar Khalil, Mira Rahm, Zachary Faber, Madeline Bedrock, Xiangzhen Wei, Bindi Patel, Christopher Mcfarland. In vivo TuBa-seq growth profiling identifies a differential role of the Tbx2 subfamily in oncogene-negative versus Kras-driven lung cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A177.

Endoscopic papillectomy could be rewarding to patients with early stage duodenal ampullary carcinoma?

There is currently no consensus on the use of endoscopic papillectomy (EP) for early stage duodenal ampullary adenocarcinoma. This study aimed to evaluate the feasibility of EP for patients with early stage duodenal ampullary adenocarcinoma. Patients who underwent EP for ampullary adenocarcinomas were investigated. Complete and clinical complete resection rates were evaluated. Clinical complete resection was defined as either complete resection or resection with positive or unknown margins but no cancer in the surgically resected specimen, or no recurrence on endoscopy after at least a 1-year follow-up. Adenocarcinoma developed in 30 patients (carcinoma insitu [Tis]: 21, mucosal tumors [T1a(M)]: 4, tumors in the sphincter of Oddi [T1a(OD)]: 5). The complete resection rate was 60.0% (18/30) (Tis: 66.7% [14/21], T1a[M]: 50.0% [2/4], and T1a[OD]: 40.0% [2/5]). The mean follow-up period was 46.8 months. The recurrence rate for all patients was 6.7% (2/30). The clinical complete resection rates of adenocarcinoma were 89.2% (25/28); rates for Tis, T1a(M), and T1a(OD) were 89.4% (17/19), 100% (4/4), and 80% (4/5), respectively. EP may potentially achieve clinical complete resection of early stage (Tis and T1a) duodenal ampullary adenocarcinomas.

Prognostic Factor in Completely Resected Early Stage Lung Adenocarcinoma Manifesting as Radiological Solid Lesions

Prognostic Factor in Completely Resected Early Stage Lung Adenocarcinoma Manifesting as Radiological Solid Lesions

Investigation of risk factors for metachronous recurrence in patients with early gastric adenocarcinoma by miRNA–mRNA integral profiling

The mechanism of metachronous recurrence (MR) after performing endoscopic treatment for early gastric adenocarcinoma (GAC) and eradicating Helicobacter pylori (H. pylori) is unknown. To elucidate the mechanism and risk factors of MR, we analyzed gene expression at multiple locations of the gastric mucosa. We selected each five patients with MR and without MR (control), after early GAC treatment and eradication of H. pylori. Mucosal tissue was collected from four sites in the stomach of each patient as biopsy specimens for mRNA sequencing, gene set enrichment analysis, and microRNA (miRNA) sequencing. We also performed correlation analysis and target prediction on pathways. As a result, endoscopically, the MR group had more intestinal metaplasia and enlarged folds. A total of 384 mRNAs presented changes in expression and 31 gene sets were enriched in the MR group. Immune-related pathways were enriched in the entire stomach, and the IFN-α response had the highest enrichment score. Additionally, 32 miRNAs revealed changes in their expression. Correlation analysis and target prediction with genes in the gene set of IFN-α response revealed that 10 miRNA–mRNA pairs presented a significant correlation. Immune-related pathways with miRNAs in the gastric mucosa after H. pylori eradication may be a risk factor for MR.

The association between histological subtypes and lymph node metastasis and prognosis in early esophageal cancer: a population-based study.

There is still a lack of high-level clinical evidence and uniform conclusions on whether there are differences in lymph node metastasis (LNM) and prognosis between early esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Patients with surgically resected, histologically diagnosed, pT1 EAC or ESCC in the Surveillance, Epidemiology and End Results registries database from 2004 to 2015 were included. Multivariable logistic regression, Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the histology and LNM or prognosis. A total of 570 early esophageal cancer patients were included. The LNM rates were 13.8% and 15.1% for EAC and ESCC ( P = 0.757), respectively. Multivariate logistic regression analysis showed no significant association between histological type and LNM (odds ratio [OR], 1.209; 95% CI, 0.538-2.715; P = 0.646). Moreover, the prognosis of early EAC and ESCC was shown to be comparable in both multivariate Cox regression (hazard ratio [HR], 1.483; 95% CI, 0.699-3.150; P = 0.305) and the multivariate competing risk model (subdistribution HR, 1.451; 95% CI, 0.628-3.354; P = 0.383). After propensity score matching, there were no significant differences between early EAC and ESCC in terms of LNM (10.6% vs.18.2%, P = 0.215), 5-year CSS (89.8% [95% CI, 81.0%-98.6%] vs. 79.1% [95% CI, 67.9%-90.3%], P = 0.102) and 5-year cumulative incidence of CSS (10.2% [95% CI, 1.4%-19.0%] vs. 79.1% [95% CI, 9.7%-32.1%], P = 0.124). The risk of LNM and prognosis of early ESCC and EAC are comparable, so the treatment choice for early esophageal cancer does not depend on the histologic type.

Artificial intelligence-based recurrence prediction outperforms classical histopathological methods in pulmonary adenocarcinoma biopsies

IntroductionBetween 10 and 50% of early-stage lung adenocarcinoma patients experience local or distant recurrence. Histological parameters such as a solid or micropapillary growth pattern are well-described risk factors for recurrence. However, not every patient presenting with such a pattern will develop recurrence. Designing a model which can more accurately predict recurrence on small biopsy samples can aid the stratification of patients for surgery, (neo-)adjuvant therapy, and follow-up. Material and MethodsIn this study, a statistical model on biopsies fed with histological data from early and advanced-stage lung adenocarcinomas was developed to predict recurrence after surgical resection. Additionally, a convolutional neural network (CNN)-based artificial intelligence (AI) classification model, named AI-based Lung Adenocarcinoma Recurrence Predictor (AILARP), was trained to predict recurrence, with an ImageNet pre-trained EfficientNet that was fine-tuned on lung adenocarcinoma biopsies using transfer learning. Both models were validated using the same biopsy dataset to ensure that an accurate comparison was demonstrated. ResultsThe statistical model had an accuracy of 0.49 for all patients when using histology data only. The AI classification model yielded a test accuracy of 0.70 and 0.82 and an area under the curve (AUC) of 0.74 and 0.87 on patch-wise and patient-wise hematoxylin and eosin (H&E) stained whole slide images (WSIs), respectively. ConclusionAI classification outperformed the traditional clinical approach for recurrence prediction on biopsies by a fair margin. The AI classifier may stratify patients according to their recurrence risk, based only on small biopsies. This model warrants validation in a larger lung biopsy cohort.

483P Genetic profiles and evolutionary trajectory of early stage lung adenocarcinoma (AAH, AIS, MIA and IAC) revealed by multiplex sequecing

483P Genetic profiles and evolutionary trajectory of early stage lung adenocarcinoma (AAH, AIS, MIA and IAC) revealed by multiplex sequecing