Small Adenocarcinoma Research Articles

Histopathological features of prostatic carcinoma in a Southwest tertiary institution in Nigeria

Background: The diagnosis of prostatic adenocarcinoma is often straightforward, in some cases there may be benign lesions that mimic prostatic cancer histologically. This study aimed to describe the morphological features of prostatic carcinoma from laboratory specimens. Methods: This was a retrospective study using histologically diagnosed cases of prostatic carcinoma from prostatectomy and trucut biopsy specimens. The histological sub-typing of the tumors according to WHO classification scheme of 2003 was done. The tumors were graded and scored using Gleason’s scoring scheme revised and modified at the consensus conference of the international society of urological pathology (ISUP), in 2005. Results: Prostate cancer constituted 18.7% of all malignant tumors and 4.4% of all neoplastic diseases. The majority of cases were small acinar adenocarcinoma 275 (73.7%). Others include pseudo-hyperplastic variant 47 (12.6%), atrophic variant 35 (9.3%), foamy gland carcinoma 16 (4.2%) and signet ring/colloid carcinoma 1(0.2%). More than half were classified as well-differentiated Gleason prognostic group A tumors. There was a statistically significant association between the age of the patient and the Gleason histologic grade and the histologic grade and histologic variant p<0.05. Conclusions: Prostatic carcinoma was thought to be a malignancy associated with elderly men but people of younger age less than fifty years are now diagnosed with the malignancy. Accurate diagnosis with the right grade and scores will go a long way in the management of the malignancy.

A RARE CASE OF COEXISTING BLADDER SMALL CELL NEUROENDOCRINE CARCINOMA AND PROSTATE ADENOCARCINOMA: CASE REPORT AND LITERATURE REVIEW

Objective: We present a case of synchronous malignancies of rare bladder small cell neuroendocrine carcinoma (SCNC) and prostate adenocarcinoma and provide literature review of bladder SCNC. Case(s) presentation: A 72-year-old male smoker presented with 3 months history of gross hematuria. Ultrasonography showed a large hypoechoic mass in the right bladder. TURBT was performed and histopathology of the TURBT specimen showed a high-grade papillary urothelial carcinoma. Abdominal contrast-enhanced computed tomography (CECT) demonstrated an isodense heterogenous undefined mass, with irregular border at right anterolateral side of bladder wall. Radical cystoprostatectomy, bilateral radical lymph node dissection and bilateral ureterocutaneostomy was performed. Histopathology and immunohistochemical examination after radical cystoprostatectomy revealed bladder small cell neuroendocrine carcinoma coexisting with prostate adenocarcinoma (Gleason score 3+3=6, group 1). The patient eventually succumbed to disease after having symptomatic disease progression and metastatic disease five months after the surgery. Discussion: Bladder SCNC is a rare malignancy with an incidence of 1–9/1,000,000 reported. This tumor has an aggressive clinical course with high incidence of metastasis, and it tends to confer dismal prognosis. No specific clinical symptom exists. Histopathological recognition and immunohistochemistry is required to differentiate this rare entity. Conclusion: Clinicians and pathologists should be alert to the possibility of bladder SCNC despite extremely scarce incidence. Keywords: Bladder cancer, small cell neuroendocrine carcinoma, synchronous malignancy, case report.

Common issues and solutions in intraoperative frozen pathological diagnosis of small pulmonary nodules

With the development of chest CT screening, surgically resected lung tumors have shifted from predominantly large masses to predominantly small nodules. The intraoperative frozen diagnosis of pulmonary small nodules faces many challenges, such as the accurate understanding about the concepts of adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic adenocarcinoma, as well as their differential diagnosis with small size invasive adenocarcinoma, benign tumors (such as bronchiolar adenoma, sclerosing pneumocytoma, etc.), metastatic tumors and so on. This study summarizes some common problems encountered in the intraoperative frozen diagnosis of small pulmonary nodules in daily practice, focusing on the diagnosis and differential diagnosis of adenocarcinoma, in order to make the accurate intraoperative frozen diagnosis of small pulmonary nodules and diminish misdiagnosis.

The association between human papillomavirus and lung cancer: A Mendelian randomization study

BackgroundTo investigate the causal relationship between human papillomavirus (HPV) and lung cancer, we conducted a study using the two-sample Mendelian randomization (TSMR). MethodData from genome-wide association studies (GWAS) were analyzed with HPV E7 Type 16 and HPV E7 Type 18 as exposure factors. The outcome variables included lung cancer, small cell lung cancer, adenocarcinoma and squamous cell lung cancer. Causality was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods. Heterogeneity testing, sensitivity analysis, and multiple validity analysis were also performed.. ResultsThe results showed that HPV E7 Type 16 infection was associated with a higher risk of squamous cell lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0149). HPV E7 Type 18 infection significantly increased the risk of lung adenocarcinoma (OR = 0.71; 95% CI: 0.38–1.31; p = 0.0079) and lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0292). No significant causal relationship was found between HPV E7 Type 16 and lung adenocarcinoma, lung cancer, or small cell lung carcinoma, and between HPV E7 Type 18 and squamous cell lung cancer or small cell lung carcinoma. ConclusionsThis study has revealed a causal relationship between HPV and lung cancers. Our findings provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer.

TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern

A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors’ database. Among the 16 TPPP-BRD9 fusion-positive GBC cases, most were females (F:M = 7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p < 0.001), all with gastro-pancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC) morphology: 3 cases (27% vs. 4.6% in the reference database, p = 0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remaining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a “syringoid” appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubular-spindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC morphology and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.

Differentiating small (< 2 cm) pancreatic ductal adenocarcinoma from neuroendocrine tumors with multiparametric MRI-based radiomic features.

To assess MR-based radiomic analysis in preoperatively discriminating small (< 2 cm) pancreatic ductal adenocarcinomas (PDACs) from neuroendocrine tumors (PNETs). A total of 197 patients (146 in the training cohort, 51 in the validation cohort) from two centers were retrospectively collected. A total of 7338 radiomics features were extracted from T2-weighted, diffusion-weighted, T1-weighted, arterial phase, portal venous phase and delayed phase imaging. The optimal features were selected by the Mann-Whitney U test, Spearman's rank correlation test and least absolute shrinkage and selection operator method and used to construct the radiomic score (Rad-score). Conventional radiological and clinical features were also assessed. Multivariable logistic regression was used to construct a radiological model, a radiomic model and a fusion model. Nine optimal features were identified and used to build the Rad-score. The radiomic model based on the Rad-score achieved satisfactory results with AUCs of 0.905 and 0.930, sensitivities of 0.780 and 0.800, specificities of 0.906 and 0.952 and accuracies of 0.836 and 0.863 for the training and validation cohorts, respectively. The fusion model, incorporating CA19-9, tumor margins, pancreatic duct dilatation and the Rad-score, exhibited the best performance with AUCs of 0.977 and 0.941, sensitivities of 0.914 and 0.852, specificities of 0.954 and 0.950, and accuracies of 0.932 and 0.894 for the training and validation cohorts, respectively. The MR-based Rad-score is a novel image biomarker for discriminating small PDACs from PNETs. A fusion model combining radiomic, radiological and clinical features performed very well in differentially diagnosing these two tumors. A fusion model combining MR-based radiomic, radiological, and clinical features could help differentiate between small pancreatic ductal adenocarcinomas and pancreatic neuroendocrine tumors. Preoperatively differentiating small pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine tumors (PNETs) is challenging. Multiparametric MRI-based Rad-score can be used for discriminating small PDACs from PNETs. A fusion model incorporating radiomic, radiological, and clinical features differentiated small PDACs from PNETs well.

An open-label phase 1 study to investigate SGNCEACAM5C/SAR445953 in adults with advanced solid tumors (SGNCEA5C-001).

TPS3160 Background: Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (1-3). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (4,5). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods: SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. 1. Bordry 2021. 2. Chakrabarti 2022. 3. Merle 2022. 4. Baudat 2023. 5. Baudat 2024. Clinical trial information: NCT06131840 .

The journey of patients with lung cancer: The gap between symptom onset and treatment.

e23119 Background: Prompt access to health care services is a priority in public health policies. The aim of this study was to map the journey of patients (pts) diagnosed with lung cancer (LC) and determine the time interval (TI) from symptom onset (SO) to treatment initiation and assess the impact on survival. Methods: A retrospective cohort study was conducted at the University Hospital of Larissa. Pts’ demographic and disease-related data were captured from medical records. The TI from SO to first doctor visit (StD), SO to first oncologist visit (StO), diagnosis to treatment initiation (DtT) and SO to treatment initiation (StT) were estimated. Overall survival (OS) was defined as the TI between treatment initiation and the date of death or the date of last follow-up. OS were estimated using the Kaplan–Meier analysis and the comparisons were computed with the log-rank test. Results: Overall, 251 sequential pts with metastatic LC were included in the study. Pts’ mean age was 71 years (range 35-88). The majority were men (82%) and 24%, 32%, 28% and 16% were diagnosed with small cell lung cancer (SCLC), squamous cell (SCC), adenocarcinoma (ADC) and large cell (LCC) LC, respectively. The median StD and StO was 32 (0-212) days and 102 (11-608) days, respectively. No difference was detected across genders, age ( &gt; or &lt; 70), family history of cancer or not, and area of residence (rural, urban). The median StT and DtT was 123 (30-851) days and 26 (1-105) days, respectively, with this time intervals being shorter among pts with SCLC compared to pts with non-small cell LC (NSCLC) ( p: 0.006 and p&lt; 0.001, respectively). Pts with sort StT intervals had significantly improved OS, compared to pts with longer StT intervals (SCLC p:0.044, NSCLC p:0.004). Conclusions: To the best of our knowledge, this is the first study aiming to determine specific TI from SO to treatment initiation for pts with LC in Greece and assess the potential impact on OS. Our data revealed a substantially prolonged StT (~4months) that is associated with worse survival rates. This indicates a need to improve public awareness of LC symptoms, enable pts’ access to specialized health care services and facilitate earlier diagnosis and treatment.

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

Clinical Efficacy Analysis of Wedge Resection of Pulmonary in Patients with Small Volume Invasive Lung Adenocarcinoma

With further understanding and research into non-small cell lung cancer with tumours ≤2 cm in maximum diameter, segmental lung resection is able to achieve the same long-term prognosis as lobectomy. However, there are few studies on the prognostic effect of wedge resection on small volume invasive lung adenocarcinoma with an invasion depth of 0.5 to 1.0 cm. Therefore, this study focuses on the clinical efficacy and prognosis of wedge resection in patients with small-volume invasive lung adenocarcinoma. A retrospective analysis of the medical records of 208 patients who underwent surgery in the Department of Thoracic Surgery of the Affiliated Provincial Hospital of Anhui Medical University from February 2016 to December 2017 was made, and the postoperative pathological results confirmed small volume invasive lung adenocarcinoma. According to their surgical methods, they were divided into lobectomy group (n=115), segmentectomy group (n=48) and wedge resection group (n=45). Kaplan-Meier survival curve estimation and Cox proportional risk regression model were used to explore the influence of different surgical methods on the prognosis of patients with small volume invasive lung adenocarcinoma. The wedge resection group had better perioperative outcomes compared with the segmentectomy group and lobectomy group, with statistically significant differences in intraoperative bleeding (P=0.036), postoperative drainage (P<0.001), operative time (P=0.018), postoperative time with tubes (P=0.001), and postoperative complication rate (P=0.006). There were no significant differences when comparing the three groups in terms of survival rate (lobectomy group vs segmentectomy group, P=0.303; lobectomy group vs wedge resection group, P=0.742; and segmentectomy group vs wedge resection group, P=0.278) and recurrence-free survival rate (lobectomy group vs segmentectomy group, P=0.495; lobectomy group vs wedge resection group, P=0.362; segmentectomy group vs wedge resection group, P=0.775). Univariate and multivariate survival analyses showed that consolidation tumor ratio (CTR) was the prognostic factor of overall survival and revurrence-free survival for patients with small-volume invasive lung adenocarcinoma (P<0.05). Wedge resection in patients with small volume invasive lung adenocarcinoma can achieve long-term outcomes similar to segmentectomy and lobectomy. When the CTR≤0.5, wedge resection is preferred in such patients.

Abstract CT077: An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress)

Abstract Background Patients (pts) with recurrent or metastatic solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), gastric adenocarcinoma (GC), and pancreatic ductal adenocarcinoma (PDAC), have limited treatment options with short PFS and OS despite recent advances (Bordry 2021; Chakrabarti 2022; Merle 2022). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is highly expressed across multiple solid tumors, such as CRC, GC, PDAC, and NSCLC. Restricted normal tissue expression and efficient lysosomal trafficking of CEACAM5 highlight its potential as an anticancer target. SGN-CEACAM5C is a novel investigational antibody-drug conjugate (ADC) directed to CEACAM5 composed of the humanized immunoglobulin G (IgG1) anti-CEACAM5 monoclonal antibody tusamitamab chemically conjugated to 8 molecules of the topoisomerase 1 inhibitor 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT). SGN-CEACAM5C selectively binds to CEACAM5 present on the cell surface and is internalized via the endo-lysosomal pathway, with subsequent release of the payload through enzymatic cleavage. Release of the cytotoxic payload induces DNA damage, cell cycle arrest in S phase, and apoptosis in tumor cells. In vitro bystander activity was observed against tumor cells without CEACAM5 surface expression. SGN-CEACAM5C is highly active in multiple patient-derived xenograft models, including CRC, GC, and NSCLC, across various levels of CEACAM5 expression (Baudat 2023; Baudat 2024). These preclinical findings justify evaluation of SGN-CEACAM5C in a clinical trial setting. Methods SGNCEA5C-001 (NCT06131840) is a phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of SGN-CEACAM5C in adults with select advanced solid tumors. This study consists of dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion (Part C). Eligible pts are adults ≥18 years of age with confirmed metastatic or unresectable solid tumor malignancy, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an ECOG PS of 0-1, and 1 of the following tumor types: CRC, GC/gastroesophageal junction adenocarcinoma (GEJ), PDAC, NSCLC (squamous/non-squamous), or SCLC. Primary endpoints include incidence of AEs, laboratory abnormalities, dose modifications due to AEs, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of PK parameters, incidence of antidrug antibodies, objective response rate and best response per RECIST v1.1 by investigator, duration of response, PFS, and OS. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part A in North America. Citation Format: Funda Meric-Bernstam, Cesar A. Perez, Nehal Lakhani, Meredith Pelster, Justin Call, Suzanne McGoldrick, Tianhua Wang, Brigitte Demers, Amita Patnaik. An open-label phase 1 study to investigate SGN-CEACAM5C in adults with advanced solid tumors (SGNCEA5C-001, Trial in Progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT077.

Abstract 6243: Rapid autopsy reveals the interplay of tumor heterogeneity at genomic, transcriptomic, and spatial dimensions

Abstract Incomplete understanding of tumor heterogeneity across primary and metastatic sites often lead to ineffective cancer treatments. To comprehensively interrogate tumor heterogeneity at genomic, transcriptomic, and spatial levels, we established a novel rapid autopsy protocol to obtain multiregional tri-omic data consisted of whole exome sequencing, mRNA-sequencing, and multiplexed immunohistochemistry on primary and metastatic tumors and associated microenvironments (TMEs). We applied this protocol to six patients with various primary tumor types: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), urothelial cancer, and one mixed case with both NSCLC and SCLC. A total of 50 tumor samples with paired tri-omic data were obtained across 16 different primary and metastatic organs to interrogate heterogeneities underlying tumor evolution and treatment resistance mechanisms. We constructed mutation-based phylogeny trees to reveal structural differences in tumor evolution trajectories across patients and infer heterogeneous tumor antigen landscape. We uncovered highly entropic phylogenetic structures having unique variants gained at each metastasis as well as low entropic structures with high sharing across sites. The mixed case had a clonal sweep structure with two metastases developed prior to the rest of the metastasis. In this case, older clones were shown to have strong association with APOBEC mutation signatures, enhanced subclonal mutation burden and loss of human leukocyte antigen heterozygosity as mechanisms of immune evasion. Integrating transcriptome and spatial profiles, we revealed that tumor intrinsic expressions and extrinsic immune infiltration levels covary with tissue types rather than with mutation-based phylogenetic clusters. Across patients, samples that had high similarities in mutational landscape varied in their pro-tumor expression programs and the cellular composition of TMEs. In particular, lung samples across patients had the highest effector T cell population and major histocompatibility complex (MHC) class I, II presentations compared to other tissue types. Contrasting small cell carcinoma (SCC) and adenocarcinoma (Adeno) samples from lung tissues further revealed that SCC had more immunosuppressive TMEs with downregulation of MHC class II. Liver metastasis samples were further characterized to have the most aggressive phenotypes enriched in genomic instability measured by aneuploidy compared to other metastatic sites. In sum, we present a novel technology and computational framework that enables a three-dimensional profiling of tumor heterogeneity. This work suggests that single-site biopsies are insufficient to capture tumor heterogeneity and calls for multi-modal integrations to design treatments that can overcome tumor-specific resistance mechanisms. Citation Format: Ning Yao, Rami Vanguri, Juber Patel, Jayon Lihm, Andrew Fisher, Irene Jarchum, Shigeaki Umeda, Hao Li, Scott Ely, Travis Hollmann, Christine Iacobuzio-Donahue, Benjamin Greenbaum. Rapid autopsy reveals the interplay of tumor heterogeneity at genomic, transcriptomic, and spatial dimensions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6243.

Laparoscopic partial splenectomy in distal pancreatectomy may preserve splenic function.

Splenectomy is known to carry a risk of infection with encapsulated organisms and associated sepsis. Current Australian guidelines recommend intensive vaccination schedules and long-term antibiotic therapy. We postulate that in some clinical scenarios where distal pancreatectomy (DP) and splenectomy is being performed, a partial splenectomy is feasible. This may preserve splenic function and help retain immunocompetence. Five patients underwent laparoscopic distal pancreatectomy with partial splenectomy (LDPPS). The DP is performed with proximal division and resection of the splenic artery and vein. The inferior portion of the spleen is removed en bloc with the distal pancreas with ligasure and linear cutting staplers. The line of demarcation on the spleen after the division of the splenic artery identifies the portion supplied by the short gastric vessels. Temporary clamping of the short gastrics during splenic parenchymal transection reduces blood loss. All operations were completed laparoscopically and within 4 h. The pathology of resected lesions includes a serous cystadenoma, a pseudocyst, an IPMN and two small medial pancreatic ductal adenocarcinomas. The benign lesions involved splenic vessels at the hilum, making Kimura or Warshaw procedures untenable. No patient required blood transfusion. One patient suffered a postoperative collection consistent with postoperative pancreatic fistula requiring a drain for 10 days. Follow-up ranged from 6 to 24 months. Following surgery, all patients had a perfused splenic remnant on imaging and benign blood films, which suggests retained splenic function. Preserving some spleen when performing distal pancreatectomy may provide long-term benefits for patients.

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives

Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.

Comprehensive profiling of serum glycosphingolipids to discover the diagnostic biomarkers of lung cancer and uncover the variation of glycosphingolipid networks in different lung cancer subtypes.

Glycosphingolipids are glycolipid complexes formed by an oligosaccharide chain covalently linked to a ceramide backbone and play important roles in the occurrence and metastasis of lung cancer. In this study, an UHPLC-HRMS method was developed for the comprehensive profiling of glycosphingolipids, with an in-house library constructed for data interpretation. Serum glycosphingolipids were profiled in 31 healthy controls (HCs) and 92 lung cancer patients with different pathologic subtypes. Over 1700 glycosphingolipids were detected in human serum based on the novel method. A total of 567 differential glycosphingolipids (adjusted P < 0.05, and fold change > 2) were found between lung cancer patients and HCs. Glycosphingolipids can be used as potential biomarkers for lung cancer diagnosis, with sensitivity much higher than that of traditional serum tumor markers. The levels of most glycosphingolipids in squamous cell carcinoma (Squa) were significantly lower than those in small cell lung cancer (SCLC) and adenocarcinoma (Aden). The highest Cer1P abundance in SCLC patients among the three different subtypes of lung cancer was thought to be related to the high malignancy and metastasis of SCLC. An artificial neural network (ANN) model was constructed for the discrimination of the three different subtypes of lung cancer, with accuracy higher than 93%. Beyond providing biomarkers and statistical models for the diagnosis of lung cancer and discrimination of lung cancer subtypes, this study uncovered the variation of glycosphingolipid networks in different subtypes of lung cancer and thereby provided a novel insight to study the pathogenesis of lung cancer and explore therapeutic targets.

Phase 1 Study of BXCL701, a Dipeptidyl Peptidase Inhibitor, in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Background and Significance: BXCL701 is an oral small molecule inhibitor of dipeptidyl peptidases (DPP)-primarily DPP8/9-that has been extensively studied in humans with metastatic castration-resistant prostate cancer (both small cell neuroendocrine and adenocarcinoma), non-small cell lung cancer, melanoma, non-Hodgkin's lymphoma, and GI malignancies. Inhibition of DPP8/9 triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß, bridging innate and adaptive immunity. Preclinical studies have demonstrated that BXCL701 may have direct induction of apoptosis in AML cells through activation of CARD8 and subsequent activation of inflammatory cytokines and Gasdermin D. Mouse model studies demonstrated a reduction in AML blasts and AML tumor size when treated with BXCL701. We hypothesize that BXCL701 can be safe and effective in patients with relapsed/refractory AML or patients with relapsed/refractory MDS with blasts ≥ 10%. Study Design and Methods: This is a Phase 1 single center investigator-initiated trial of BXCL701 in patients with relapsed/refractory AML or relapsed/refractory MDS with blasts ≥10% (ClinicalTrials.gov Identifier: NCT05703542). In the lead-in stage, we will use a 3 + 3 design with 4 dose levels of BXCL701 (0.2 mg, 0.4 mg, 0.6 mg and 0.8 mg). Doses of BXCL701 will be given on Days 1-3, Days 8-10, Days 15-17, and Days 22-24 on a 28-day cycle. The primary objective is to evaluate the safety of BXCL701 in the AML or MDS with ≥ 10% blasts. Secondary objectives include determining the maximum tolerated dose or recommended phase 2 dose, pharmacokinetics, and to estimate response, duration of response and overall survival. Exploratory endpoints include: pharmacodynamic profiling, T-cell response, inhibitory effect on DPP8/9, and evaluation of potential biomarkers such as Copy Number Variants and mRNA levels of DPP8, DPP9, FAP, Caspase-1, Pro-caspase-1, NLRP1, and CARD8. Major eligibility criteria include: ≥18 years of age, relapsed or refractory AML or relapsed or refractory MDS with ≥10%.refractory to at least 4 cycles of hypomethylating agent, ECOG performance status ≤2, adequate renal function (CrCl ≥30 mL/min), adequate liver function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN), WBC &amp;lt;25,000/µL on Day 1 Cycle 1 (hydroxyurea permitted), no symptomatic CNS disease, no active viral or bacterial infections, and &amp;gt;100 days from allogeneic bone marrow transplant with no active graft versus host disease. Patients on gliptin therapy are not permitted on the study due to drug interaction; patients are also excluded if they have a history of orthostatic hypotension or uncontrolled hypertension. There will be a second phase of the study that will evaluate BXCL701 in combination with a hypomethylating agent (decitabine or azacytidine) and venetoclax. Dose selection of BXCL701 in the combination stage will be based on the data from the single agent study. Conclusion: The trial is currently open and continuing to enroll.

Rare giant ovarian metastasis arising from a small primary lung adenocarcinoma: a case report.

This intricate case report details an exceptionally rare incidence of ovarian metastasis originating from a primary lung adenocarcinoma (LUAD). The relative rarity of this metastatic pathway in medical literature indicates significant diagnostic challenges. This patient was initially found to have both the ovarian tumor and lung nodule and they were originally considered independent primary tumors, derived from radiological interpretations and biomarker profiling. Nevertheless, subsequent postoperative histopathological and immunohistochemical staining evaluations identified ovarian tumors as invasive adenocarcinoma metastasized from lung. The lung and ovary tumor both showed marked anaplastic lymphoma kinase gene (ALK) protein expression by immunohistochemistry. The molecular pathologic genetic testing for lung tumor also revealed ALK rearrangement positive. The complexity of this case underscores the essentiality of maintaining a high degree of diagnostic vigilance, particularly when confronting synchronous tumors. In addition, immunohistochemical staining plays an important role in diagnosing the ovarian neoplasm's metastatic nature and determining the primary site of metastatic adenocarcinoma. For lung cancer with ovary metastasis patients, the adopting an adaptable treatment approach responsive to evolving diagnostic evidence can improve the accuracy of diagnosis and avoid excessive treatment of patients.

A comprehensive multi-omics analysis exploring the correlation between NECTIN4 and tumor microenvironment profiles in bladder cancer.

74 Background: NECTIN4 is a transmembrane protein that is found in the adherent junctions and highly expressed in urothelial carcinoma (UC). NECTIN4 is a TIGIT ligand and the TIGIT-NECTIN4 interaction inhibits natural killer cell activity. Therefore, Enfortumab vedotin (EV), an antibody-drug conjugate targeting NECTIN4, potentially induces immunogenic cell death. In fact, an encouraging result has been recently reported from a clinical trial of combined EV and pembrolizumab as the first line treatment for platinum-ineligible UC patients. However, there has been no study exploring the correlation between NECTIN4 expression and tumor microenvironment (TME) so far. Methods: To explore the potential association between NECTIN4 and TME, we analyzed a comprehensive dataset of whole-exome and RNA-sequencing, immunohistochemistry, and clinicopathological record from 389 bladder cancers (BC) and 35 adjacent normal tissues, which enables us to evaluate the potential relationship between genetic and transcriptomic profile and TME. Results: NECTIN4 mRNA expression was positively correlated with NECTIN4 H-score, gender, T-stage, tumor grade, lymph vascular invasion and tumor mutation burden, and was negatively correlated with CD274 mRNA expression levels in BC. Our cohort included 44 patients (44/389 = 11.3%) who were diagnosed as having variant histology. NECTIN4 expression levels of samples with variant histology (especially small cell carcinoma, sarcomatoid and adenocarcinoma) were significantly lower compared to conventional BC. When we classified 378 patients into three groups according to H-score, 93 patients were included in low group (H-score:0), 202 patients in medium group (H-score:10-190) and 83 patients in high group (H-score:200-300). Overall survival was significantly worse in the low group compared to medium/high groups (p&lt;0.0001). CIBERSORTx analysis suggested increased proportions of M0 macrophages and neutrophils in low group. Gene set enrichment analysis identified that EMT-related programs and immune-related cytokines were activated in the low group. 45 platinum-refractory BC patients were treated with pembrolizumab and objective response rate was 57.1% in H-score high group, which was significantly higher compared to low/medium groups (p=0.0498). We also compared 73 immune check point related gene expression in H-score low and high groups and found that putative immune checkpoint gene expression was significantly different between the two groups, which collectively suggests that differential immune therapy strategies according to NECTIN4 expression levels would be beneficial for patients with BC. Conclusions: NECTIN4 expression levels are closely associated with tumor pathology and microenvironment. NECTIN4 expression levels may be a predictive marker that potentially contributes to the precision immune therapy in BC.

Racial disparities in the prevalence of extrathoracic metastases in lung cancer patients and survival: A SEER database study (2010–2019).

e20630 Background: Metastatic disease at the time of lung cancer diagnosis influences therapy choice and prognosis. Metastasis to the brain, bones, and liver may lead to higher morbidity. Differences in the prevalence of metastatic sites among patients (pts) of White (W) and Black (B) race and their association with overall survival need further elucidation. Methods: Utilizing the SEER database from 2010-2019, we identified W and B pts with metastatic small cell (SCLC), squamous cell (SQ-NSCLC), and adenocarcinoma (AD-NSCLC). Only pts with bone, brain, or liver metastasis (mets) at diagnosis were included. Metastatic site prevalence rates were determined. Cox proportional hazard ratios for survival were calculated while controlling for gender, ethnicity, other metastatic sites, chemotherapy, and radiation. Results: Total of 338,411 pts, 11.4% of B race. In SCLC, B pts had a higher prevalence of brain mets, while W pts demonstrated a higher prevalence of bone and liver mets. Survival between W and B pts with SCLC was comparable except for modest superior survival in B pts with liver mets. In SQ-NSCLC, metastatic disease for the 3 sites of interest was more prevalent in B pts, most notably in brain. However, survival did not differ. In AD-NSCLC, B pts were more likely to present with brain and liver mets. B pts with bone mets had inferior survival. Conclusions: Significant differences in patterns of mets at the time of lung cancer diagnosis between W and B pts exist. B pts with SCLC and liver mets had longer survival. Interestingly, B pts with bone mets and SQ-NSCLC had better survival while those with AD-NSCLC fared worse. Multiple factors, including socioeconomic, environmental/smoking patterns and access to healthcare, may have contributed. Further studies are needed. [Table: see text]

Sensitivity of endoscopic ultrasound-guided fine-needle aspiration cytology and biopsy for a diagnosis of pancreatic ductal adenocarcinoma: A comparative analysis.

The utility of endoscopic ultrasound fine-needle aspiration cytology (EUS-FNAC) or endoscopic ultrasound fine-needle aspiration biopsy (EUS-FNAB) for diagnosis of small and large pancreatic ductal adenocarcinomas (PDACs) remains in question. We addressed this by analyzing 97 definitively diagnosed cases of PDAC, for which both EUS-FNAC and EUS-FNAB had been performed. We subclassified the 97 solid masses into small (n = 35) or large (n = 62) according to the maximum tumor diameter (<24 mm or ≥24 mm) and compared the diagnostic sensitivity (truly positive rate) of EUS-FNAC and of EUS-FNAB for small and large masses. Diagnostic sensitivity of EUS-FNAC did not differ between large and small masses (79.0% vs. 60.0%; p = 0.0763). However, the diagnostic sensitivity of EUS-FNAB was significantly higher for large masses (85.5% vs. 62.9%; p = 0.0213). Accurate EUS-FNAC-based diagnosis appeared to depend on the degree of cytological atypia of cancer cells, which was not associated with quantity of cancer cells. The accuracy of EUS-FNAB-based diagnosis appeared to depend on cancer cell viability in large masses and cancer volume in small masses. Based on the advantages or disadvantages in each modality, both modalities play an important role in the qualitative diagnosis of PDAC as a complementary procedure.