Molecular Characteristics Of Tumor Research Articles

Distribution and Clinicopathological Features of Mott Cells (Plasma Cells Containing Russell Bodies) in Gastric Cancer: Presence of Mott Cells Is Associated with Favorable Prognosis

Gastric cancer (GC) is still one of the leading causes of cancer-related mortality. We previously reported the relationship between histological heterogeneity of tumor cells and molecular features in GC. The tumor microenvironment also has a crucial role in GC progression and therapeutic resistance. In this study, we focused on the tumor microenvironment, especially inflammatory cells in GC. Using GC tissue slides, we investigated the distribution and clinicopathological significance of inflammatory cell counts including eosinophils, neutrophils, lymphocytes, and plasma cells. Additionally, we investigated the relationship between Mott cells (plasma cells containing Russell bodies) and clinicopathological features. In neoplastic gastric mucosa, a high number of plasma cells was associated with low T-grade, early stage, and good prognosis. We then focused on Mott cells and found that their presence in neoplastic gastric mucosa was associated with lower T and N grades, early stage, and Helicobacter pylori infection and was inversely associated with CD44 and EGFR expression. Additionally, the presence of Mott cells was associated with good prognosis in advanced GC and was an independent favorable prognostic predictor. The presence of Mott cells in GC might be one useful prognostic predictor, and Mott cells might have an important role in the carcinogenesis of H. pylori infection.

Understanding causes of racial/ethnic survival disparity in 47,178 patients with colorectal cancer: A quantitative evaluation of molecular, socioeconomic, and clinical covariates.

20 Background: A disparity in overall survival (OS) of colorectal cancer (CRC) patients based on self-reported race has been observed. Separately, differing frequencies of driver gene mutations among racial groups have been observed. The contribution of these molecular differences to disparity in outcomes is not well understood. We conducted a systematic investigation of molecular, socioeconomic (SES) and clinical covariates to quantitate the degree to which each influences the OS disparity. Methods: The Foundry software platform was used to query electronic health records to identify CRC patients and extract clinical and molecular data. The relative contribution of each variable to OS disparity was determined using mediation analysis consisting of sequential multivariate Cox regression models. Results: 47,178 patients with CRC diagnosed between 1973 and 2023 with self-reported race were identified. Relative to Non-Hispanic white (NHW), African American (AA) had worse OS (HR=1.16, P= 1.5E-6), while Asians and Hispanics had better OS (HR=0.66, P=4.2E-13 and HR=0.86, P=3.4E-6, respectively). The magnitude of disparity between AA and NHW was greater in metastatic disease (HR 1.2, P=1.7E-4). Among 7,628 patients with clinical molecular testing, five genes differed significantly in mutation frequencies; APC (54% NHW, 62% AA, 57% Hispanics, 46% Asian, FDR= 0.01), KRAS (45%, 58%, 50%, 44%, FDR=8.4E-9), PIK3CA (17%, 23%, 17%, 12%, FDR=0.006) were higher in AA, while BRAF (8%, 3%, 4%, 7%, FDR=2.4E-8), KIT (4%, 1%, 2%, 3%, FDR=0.013) were higher in NHW. In multivariate analysis mutations of BRAF (HR= 1.9, P=1.2E-8), KRAS (HR= 1.39, P=1.7E-7), and APC (HR= 0.81, P= 5E-4) were significantly associated with OS as was national area deprivation index (HR= 1.07, P=0.004), marital status (HR= 1.16, P=0.03), performance status (HR= 1.42, P= 5.3E-29), disease stage (HR= 1.502, P=4.4E-26), right sided tumors (HR= 1.23, P=0.003), tumor differentiation (HR= 1.22, P=0.004) and MSI-high (HR= 0.37, P=1.8E-7). Mediation analysis identified neighborhood SES as the greatest contributor to disparity (38%), followed by primary tumor side (10%), and molecular characteristics (MSI-status, KRAS and BRAF mutations, 10%). After including all covariates, 39% of disparity remained unaccounted. Conclusions: Systematic evaluation of a large cohort from a single institution confirmed substantial racial disparity in survival and frequencies of driver mutations. SES factors have the largest contribution but account only for forty percent of the disparity, with tumor molecular features also contributing. Molecular characteristics should be incorporated in multicentric studies of racial survival disparity. Future clinical studies should ideally account for genetic ancestry and molecular features when evaluating chemotherapy outcomes.

Abstract A002: A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC)

Abstract Introduction: Advances in adjuvant chemotherapy with 5-fluorouracil, irinotecan, and oxaliplatin (FFX) have improved survival for patients (pts) with resectable PDAC yet few are cured by the current standard of care. Neoadjuvant FFX may lead to early control of micrometastasis and enhance cure rates for this aggressive malignancy. Methods: We performed a single-arm phase-2 clinical trial for resectable PDAC evaluating 6 months of perioperative modified (m) FFX (NCT02047474). Patients underwent baseline pancreatic protocol CT and were reviewed for resectability by a multidisciplinary panel. Enrolled pts received 6 cycles of neoadjuvant mFFX followed by surgery and 6 cycles of adjuvant mFFX. The primary endpoint was a ≥ 66% 12-month progression-free survival (PFS). Additional endpoints included overall survival (OS), circulating tumor DNA (ctDNA), tumor molecular features and tumor Keratin 17 levels. Whole blood was prospectively collected and processed to stored plasma (median volume 5.4 mL, range: 2.6 – 10.2) for retrospective ctDNA analysis using a personalized, tumor-informed ctDNA assay (SignateraTM). Survival rates were estimated by Kaplan-Meier. Results: Forty-six pts enrolled with 63 months median follow up, median age of 65 [R 46–80], 36 (78%) were ECOG 0, 30 (65%) had an endobiliary stent and no pts had staging laparoscopy. All pts started mFFX, and 37 pts (80%) completed all 6 preop cycles. Thirty-three pts (72%) underwent surgery with 3 pts developing investigator-assessed progression during neoadjuvant mFFX. Six pts were unresectable intraoperatively, and 27 pts (59%) underwent resection per protocol (25 R0, 2 R1). Ten additional pts underwent surgery off protocol. The 12-month PFS was 78% (95% CI: 64.2–94.4), median PFS and OS were 36.5 months (95% CI: 16.6–74.5) and 37.2 months (95% CI 17.5–not reached), respectively. Two-year OS was 59% (95% CI: 45.8–74.7). Baseline ctDNA was detected in 16/22 (73%) pts, and after 6 cycles of mFFX ctDNA was detected in 3/17 (18%) of pts. Patients with a positive ctDNA test 4 weeks post-resection had worsened PFS (HR 34.0, 95% CI: 2.6-4758.6; P = 0.006) and OS (HR: 11.7, 95% CI: 1.5–129.9; P = 0.021) compared to ctDNA negative. Mutational signature analysis revealed predominant signatures to be COSMIC signatures SBS1 and SBS5 (age related), and SBS15 (mismatch repair deficiency associated) which was associated with improved OS. Using Keratin 17 as a biomarker of the basal molecular subtype, either in diagnostic needle aspirates or surgical specimens, we found that high K17 expression was associated with worse survival. Conclusion: The perioperative mFFX clinical trial for resectable PDAC met its primary endpoint with a promising survival rate, and R0 resection rate of 93%. These findings warrant further evaluation in a randomized clinical trial. Most pts with detectable ctDNA at baseline experience ctDNA clearance after 6 cycles of neoadjuvant mFFX. In the post-operative setting, ctDNA positivity was strongly associated with recurrence. Signature SBS15 and low K17 were associated with improved OS. Citation Format: Michael Cecchini, Ronald Salem, Marie Robert, Suzanne Czerniak, Moein Rajaei, Jeffrey Townsend, Ondrej Blaha, Daniel Zelterman, Jaykumar Thumar, Jeremy Kortmansky, Wajih Zaheer, Neal Fischbach, Justin Persico, Stacey Stein, Sajid Khan, Charles Cha, Kevin Billingsley, John Kunstman, Sumedha Chowdhury, Robert Tseng, Carlos Mauricio, Deanne Yugawa, Luisa Escobar-Hoyos, Kimberly Johung, Christina Wiess, Erik Spickard, Vasily N. Aushev, George Laliotis, Adham Jurdi, Minetta C. Liu, Jill Lacy. A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC) [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 A002.

Updates on WHO 5th edition classification, molecular characteristics and tumor microenvironment of adrenocortical carcinomas.

Discerning malignancy in adrenocortical tumors is clinically pivotal in the management of patients but has also been one of the most difficult areas in both clinical and pathology settings. The recently published WHO 5th edition "Endocrine and Neuroendocrine Tumours" recommends a diagnostic algorithm employing not only one but several proposed histopathological criteria-including the Weiss criteria and its revision and the Helsinki criteria-in addition to the Reticulin algorithm, the Ki-67 proliferative index, and others depending upon their histopathological features. On the other hand, the risk classification proposed by ENSAT (European Network of Study for Adrenal Tumors) in 2018 was primarily based on the Ki-67 proliferative index of carcinoma cells, especially focusing on whether or not postoperative or adjuvant chemotherapy could be administered. The recently reported results of the ADIUVO study, although preliminary, discuss the necessity of postoperative therapy with mitotane in patients with low-grade adrenocortical carcinomas (ACCs) after complete resection. In addition, recently reported comprehensive genetic analyses attempted to classify ACCs into four major molecular subtypes: (i) the Wnt/-catenin pathway, (ii) the p53/Rb1 pathway, (iii) the chromosomal maintenance/chromatin remodeling pathway, and (iv) the MMR (Mismatch repair) pathway. Among those, groups (i) and (ii) are more commonly detected in high-grade ACCs but it is also true that specific therapeutic targets based on the molecular characteristics of tumors have remained limited. In addition, possible effects of glucocorticoid excess in functional ACCs on the tumor microenvironment have also been examined, and the utility of immune checkpoint inhibitors is being explored at this juncture.

Prediction of WHO grade and methylation class of aggressive meningiomas: Extraction of diagnostic information from infrared spectroscopic data.

Infrared (IR) spectroscopy allows intraoperative, optical brain tumor diagnosis. Here, we explored it as a translational technology for the identification of aggressive meningioma types according to both, the WHO CNS grading system and the methylation classes (MC). Frozen sections of 47 meningioma were examined by IR spectroscopic imaging and different classification approaches were compared to discern samples according to WHO grade or MC. IR spectroscopic differences were more pronounced between WHO grade 2 and 3 than between MC intermediate and MC malignant, although similar spectral ranges were affected. Aggressive types of meningioma exhibited reduced bands of carbohydrates (at 1024cm-1) and nucleic acids (at 1080cm-1), along with increased bands of phospholipids (at 1240 and 1450cm-1). While linear discriminant analysis was able to discern spectra of WHO grade 2 and 3 meningiomas (AUC 0.89), it failed for MC (AUC 0.66). However, neural network classifiers were effective for classification according to both WHO grade (AUC 0.91) and MC (AUC 0.83), resulting in the correct classification of 20/23 meningiomas of the test set. IR spectroscopy proved capable of extracting information about the malignancy of meningiomas, not only according to the WHO grade, but also for a diagnostic system based on molecular tumor characteristics. In future clinical use, physicians could assess the goodness of the classification by considering classification probabilities and cross-measurement validation. This might enhance the overall accuracy and clinical utility, reinforcing the potential of IR spectroscopy in advancing precision medicine for meningioma characterization.

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Melanoma is a malignant tumor that most often affects the skin, but it can also occur in many other human organs. In recent decades, the frequency of melanoma cases continues to grow and it has now become a relatively common malignant neoplasm, which is a serious socio-economic problem. The vast majority of melanomas have a known primary site of their development, but approximately 3.2 % of all melanomas are first detected in distant locations without a known primary tumor. Melanoma is considered as a multi-factorial disease, which arises as a result of the interaction of the genetic sensitivity of the human body and the influence of the environment. The most important and potentially modifying environmental risk factor of malignant melanoma is exposure to UV rays due to their genotoxic effect. The most important human body risk factors are the number of melanocytic nevi, family history and genetic predisposition. Melanomas without a primary skin lesion have been poorly studied due to their rarity, although in recent years more information has become available regarding the clinical, molecular, and genetic characteristics of such tumors. The article presents the actual observation of the so-called primary melanoma of the lung with a detailed description of known clinical data, performed surgical intervention and pathomorphological examination. The obtained data were compared with the available information on similar cases, demonstrating high grade of agreement. However, the authors hesitate to draw a conclusion regarding the treatment of primary lung melanoma, because recently, in a high-tech study of a number of similar cases of lung melanoma, objective molecular-genetic evidence has been provided for the existence of primary hidden melanoma of the skin.

Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Patient-Derived Xenograft Models for Ovarian Cancer.

Patient-derived xenograft (PDX) models play a crucial role for in vivo research. They maintain the original molecular characteristics of the human tumor and provide a more accurate tumor microenvironment, which cannot be replicated by in vitro models. This chapter describes four different transplantation methods, namely, intra-bursal, intrarenal capsule, intraperitoneal, and subcutaneous, to develop PDX models for ovarian cancer research.

Advances in Molecular Pathology, Diagnosis and Treatment of Spinal Cord Astrocytomas.

Spinal cord astrocytoma (SCA) is a rare subtype of astrocytoma, posing challenges in diagnosis and treatment. Low-grade SCA can achieve long-term survival solely through surgery, while high-grade has a disappointing prognosis even with comprehensive treatment. Diagnostic criteria and standard treatment of intracranial astrocytoma have shown obvious limitations in SCA. Research on the molecular mechanism in SCA is lagging far behind that on intracranial astrocytoma. In recent years, huge breakthroughs have been made in molecular pathology of astrocytoma, and novel techniques have emerged, including DNA methylation analysis and radiomics. These advances are now making it possible to provide a precise diagnosis and develop corresponding treatment strategies in SCA. Our aim is to review the current status of diagnosis and treatment of SCA, and summarize the latest research advancement, including tumor subtype, molecular characteristics, diagnostic technology, and potential therapy strategies, thus deepening our understanding of this uncommon tumor type and providing guidance for accurate diagnosis and treatment.

Leveraging Patient-Derived Organoids for Personalized Liver Cancer Treatment.

Primary liver cancer (PLC) is a primary cause of cancer-related death worldwide, and novel treatments are needed due to the limited options available for treatment and tumor heterogeneity. 66 surgically removed PLC samples were cultured using the self-developed 2:2 method, and the final success rate for organoid culture was 40.9%. Organoid performance has been evaluated using comprehensive molecular measurements, such as whole-exome and RNA sequencing, as well as anticancer drug testing. Multiple organoids and their corresponding tumor tissues contained several of the same mutations, with all pairs sharing conventional TP53 mutations. Regarding copy number variations and gene expression, significant correlations were observed between the organoids and their corresponding parental tumor tissues. Comparisons at the molecular level provided us with an assessment of organoid-to-tumor concordance, which, in combination with drug sensitivity testing provided direct guidance for treatment selection. Finally, we were able to determine an appropriate pharmacological regimen for a patient with ICC, demonstrating the clinical practicality in tailoring patient-specific drug regimens. Our study provides an organoid culture technology that can cultivate models that retain most of the molecular characteristics of tumors and can be used for drug sensitivity testing, demonstrating the broad potential application of organoid technology in precision medicine for liver cancer treatment.

Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma.

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (p = 0.001) and were more frequently classified high-grade than low-grade MTC (p < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p = 0.005). RET mutations, in particular RET-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET, 46.9% vs. 12.7% mutated in RET-M918T; p < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Role of Tumor Molecular Profiling With FoundationOne®CDx in Advanced Solid Tumors: A Single-Centre Experience From Romania.

Background In the field of precision oncology, comprehensive genomic profiling tests play a very important role by providing a complex understanding of the molecular characteristics of malignant tumors. Therefore, next-generation sequencing (NGS) has become a valuable tool in various aspects of cancer care from diagnosis and monitoring to treatment selection and personalized cancer treatment. Our aim was to evaluate the role of tumor molecular profiling in tailored treatment selection. Methods In our study, we conducted a retrospective analysis to assess the practicality of utilizing NGS testing in patients with metastatic solid tumors. The genomic testing was performed on blood or tissue samples from a fresh biopsy, less than six months old, and the expression of programmed death-ligand 1 was evaluated by immunohistochemistry. Results A total of 75 tests were performed on 66 patients between 2019 and 2022, with a success rate of 80%. The most common pathologies were gastro-intestinal tract cancer (26%), breast cancer (14%), non-small cell lung cancer (11%), and pancreatic cancer(11%). There were 9% liquid biopsies and 91% tissue biopsies.From all 66 patients tested, 55 had at least one genetic alteration. The most frequent genetic alteration found was TP53 (n=32) followed by KRAS (n=15) and BRCA1/2 (n=12) mutations. There were nine patients tested (14%) that presented a high tumor mutational burden, and only one patient presented high microsatellite instability.There were 37 patients (56%) with actionable alterations found from which 14 received matched therapy and four patients were enrolled in clinical trials. The NGS testing played a significant role in determining the next therapeutic strategy in 20 out of 66 patients (30.3%). Conclusion From all the patients included in our analysis, 83% had at least one mutation that is known to be of pathogenic significance but only 23% received treatment selected by the analysis of the tumor's genome, and only 6% were included in a clinical trial. This moderate success of personalized medicine using NGS testing highlights the importance of evaluating the factors that could lead to further improvement.

Organoid co-culture models of the tumor microenvironment promote precision medicine.

In recent years, the three-dimensional(3D) culture system has emerged as a promising preclinical model for tumor research owing to its ability to replicate the tissue structure and molecular characteristics of solid tumors in vivo. This system offers several advantages, including high throughput, efficiency, and retention of tumor heterogeneity. Traditional Matrigel-submerged organoid cultures primarily support the long-term proliferation of epithelial cells. One solution for the exploration of the tumor microenvironment is a reconstitution approach involving the introduction of exogenous cell types, either in dual, triple or even multiple combinations. Another solution is a holistic approach including patient-derived tumor fragments, air-liquid interface, suspension 3Dculture, and microfluidic tumor-on-chip models. Organoid co-culture models have also gained popularity for studying the tumor microenvironment, evaluating tumor immunotherapy, identifying predictive biomarkers, screening for effective drugs, and modeling infections. By leveraging these 3Dculture systems, it is hoped to advance the clinical application of therapeutic approaches and improve patient outcomes.

Clinical and Molecular Characteristics of Gonadotroph Pituitary Tumors According to the WHO Classification

Since 2017, hormone-negative pituitary neuroendocrine tumors expressing the steroidogenic factor SF1 have been recognized as gonadotroph tumors (GnPT) but have been poorly studied. To further characterize their bio-clinical spectrum, 54 GnPT defined by immunostaining for FSH and/or LH (group 1, n = 41) or SF1 only (group 2, n = 13) were compared and studied for SF1, βFSH, βLH, CCNA2, CCNB1, CCND1, caspase 3, D2R, and AIP gene expression by qRT-PCR. Immunohistochemistry for AIP and/or D2R was performed in representative cases. Overall, patients were significantly younger in group 1 (P = 0.040 vs group 2), with a similar trend excluding recurrent cases (P = 0.078), and no significant difference in gender, tumor size, invasion or Ki67. SF1 expression was similar in both groups but negatively correlated with the patient’s age (P = 0.013) and positively correlated with βLH (P < 0.001) expression. Beta-FSH and AIP were significantly higher in group 1 (P = 0.042 and P = 0.024, respectively). Ki67 was unrelated to gonadotroph markers but positively correlated with CCNB1 (P = 0.001) and negatively correlated with CCND1 (P = 0.008). D2R and AIP were strongly correlated with each other (P < 0.001), and both positively correlated with SF1, βFSH, βLH, and CCND1. AIP immunopositivity was frequently observed in both groups, with a similar median score, and unrelated to Ki67. D2R immunostaining was best detected with a polyclonal antibody and mostly cytoplasmic. This study indicates that hormone-negative GnPT tend to occur in older patients but do not significantly differ from other GnPT in terms of invasion or proliferation. It also points out the current limits of D2R immunostaining in such tumors.

Unique characteristics of the tumor immune microenvironment in young patients with metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) remains a common and highly morbid disease, with a recent increase in incidence in patients younger than 50 years. There is an acute need to better understand differences in tumor biology, molecular characteristics, and other age-related differences in the tumor microenvironment (TME). 111 patients undergoing curative-intent resection of colorectal liver metastases were stratified by age into those <50 years or >65 years old, and tumors were subjected to multiplex fluorescent immunohistochemistry (mfIHC) to characterize immune infiltration and cellular engagement. There was no difference in infiltration or proportion of immune cells based upon age, but the younger cohort had a higher proportion of programmed death-ligand 1 (PD-L1)+ expressing antigen presenting cells (APCs) and demonstrated decreased intercellular distance and increased cellular engagement between tumor cells (TCs) and cytotoxic T lymphocytes (CTLs), and between TCs and APCs. These trends were independent of microsatellite instability in tumors. Age-related differences in PD-L1 expression and cellular engagement in the tumor microenvironment of patients with mCRC, findings which were unrelated to microsatellite status, suggest a more active immune microenvironment in younger patients that may offer an opportunity for therapeutic intervention with immune based therapy.

Clinical features of oncohematological diseases in twins (literature review)

Relevance. According to the World Health Organization, the most common oncological diseases in childhood are hemoblastoses. In particular, acute leukemia ranks the first in the structure of malignant tumors, non-Hodgkin’s lymphomas – the third, Hodgkin lymphoma – the fifth in children aged 0 to 19 years. There is no convincing evidence of the inheritance of these diseases, but nevertheless, the literature describes cases of the development of the same disease with the same immunophenotype within the same family in mono- or dizygotic twins, which is one of the proofs of the persistence of preleukemic cells and the possibility of their migration from one twin to another during the antenatal development. These data allow us to study the features of oncogenesis in leukemia in twins, in particular monozygotic twins: the timing of tumor development, clinical features and molecular biological characteristics, as well as the response to therapy.Aim. To study the clinical and molecular-genetic features of hemoblastoses in twins.Materials and methods. When writing a literature review, we analyzed data in specialized medical databases PubMed, Scopus, Web of Science with the very first descriptions of the manifestations of tumors of the hematopoietic system in monozygotic twins from 1964 to 2023.Results. In the course of writing this literature review, we confirmed that the genetic component plays a significant role in the development of hemoblastoses. Studies on twins reveal genetic mutations that predispose to the development of malignant blood tumors, which in turn opens up new opportunities for the early diagnosis of hemoblastoses. The twin method allows for comparative clinical trials of different treatment approaches, which help to choose the optimal therapy and improve the prognosis of diseases.

Возможности использования профилирования экспрессии мРНК для прогноза прогрессирования локальных стадий колоректального рака

Progression assessment enables implementation of the colorectal cancer (CRC) tertiary prevention measures aimed at early detection and timely treatment of metastatic cancer. The study was aimed to develop a model of CRC progression using pathomorphological and molecular genetic characteristics of tumors. Relative expression of mRNAs of 63 genes from various functional groups was determined in the tumor specimens of 223 patients with stage T1–4N0–2M0 CRC. The median follow-up period was 42 months. Binary logistic regression models were constructed, in which likelihood of progression within 36 months after the CRC diagnosis was a target variable. Explanatory variables were as follows: tumor grade, angiolymphatic invasion, ratio of the number of metastatic lymph nodes to the total number of lymph nodes in the surgical specimen, patient’s age and tumor localization, as well as expression levels of genes CCNB1, Ki67, GRB7, IGF1, Il2, Il6, Il8, GATA3. Prediction accuracy of the model using clinical and morphological characteristics was 56.6%. Inclusion of CCNB1, Ki67, GRB7, IGF1, Il2, Il6, Il8, GATA3 expression profiles in the model increased accuracy to 80.6%. Thus, prediction of CRC progression for treatment personalization requires additional parameters beyond information acquired within the framework of conventional morphological TNM classification. The use of molecular markers as predictors significantly increases the CRC progression prediction accuracy. Further research is needed for validation and quality improvement of prognostic models.

Abstract C045: Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US

Abstract Background. Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the US, with a 5-year survival rate of approximately 12%. The occurrence of new pancreatic cancer cases has continued to rise in the last two decades, with the highest incidence observed in the Black and African American (BAA) population. While socioeconomic and environmental factors may contribute to observed racial disparities in the occurrence of pancreatic cancer, it is unclear whether there are molecular differences in pancreatic tumors across racially and ethnically diverse populations. The goal of this study was to identify key molecular differences between BAA and White patients’ pancreatic tumors. Methods. We analyzed 4620 de-identified records with a primary diagnosis of pancreatic ductal adenocarcinoma (PDAC) who underwent somatic NGS testing via a commercially available 595-648 gene DNA panel as well as whole transcriptome RNA-seq. Race was extracted from clinical records (e.g., order forms, patient records, etc.). Somatic mutations, microsatellite instability (MSI), and tumor mutational burden (TMB) were compared between White (n=3797) and BAA (n=452) samples by Chi-squared or Fisher’s Exact tests. False discovery rate (FDR) corrections were applied to pairwise comparisons. Results. The combined cohort had a median age of 68 years and 88% of records had stage 3 or 4 disease at the time of diagnosis. We found that alterations in TP53 (70% vs 62%, q=0.014) and KMT2C (6.9% vs 2.3% q&amp;lt;0.001) were at significantly higher frequencies in BAA vs White samples. Weakly significant differences were observed in BAA vs White samples based on alterations in KRAS (79% vs 74%, p=0.02), RNF43 (6% vs 3.7% p=0.022), and GNAS (0.2% vs 1.6%, p=0.022), all of which had q-values of 0.14 after FDR correction. When stratifying by detailed alterations, KRAS G12R was significantly more frequent in BAA than White (14% vs 10%, q=0.037), and GNAS R201H was more frequent in White vs BAA (0.9% vs. 0%, q=0.056) samples. Finally, when assessing biomarkers associated with immunotherapy response in solid tumors, we found that neither the frequency of TMB-H (≥ 10 mut/MB) nor MSI-high status were significantly different between BAA and White samples. Interestingly, in the subset of 676 PDAC patients who had PD-L1 IHC performed previously, BAA samples had a higher frequency of PD-L1 positivity compared with White samples (20% vs 12%, p=0.039). Conclusions. We assessed molecular differences between BAA and White patients’ tumors in the largest cohort of PDAC records reported to date. Our findings suggest that there are key molecular tumor characteristics which occur more frequently in BAA PDAC tumors. In particular, alterations in genes such as KMT2C, which were more frequent in our cohort of BAA tumors, are known contributors to pancreatic tumorigenesis and represent potential therapeutic targets. These findings highlight the importance of studying racially and ethnically diverse populations to better understand key molecular alterations. Citation Format: Emily Teslow, Minxuan Huang, Melissa Stoppler, Albert Levin, Ling Huang. Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C045.

MiRNA Expression Profiling in Human Breast Cancer Diagnostics and Therapy.

Breast cancer is one of the most commonly diagnosed cancer types worldwide. Regarding molecular characteristics and classification, it is a heterogeneous disease, which makes it more challenging to diagnose. As is commonly known, early detection plays a pivotal role in decreasing mortality and providing a better prognosis for all patients. Different treatment strategies can be adjusted based on tumor progression and molecular characteristics, including personalized therapies. However, dealing with resistance to drugs and recurrence is a challenge. The therapeutic options are limited and can still lead to poor clinical outcomes. This review aims to shed light on the current perspective on the role of miRNAs in breast cancer diagnostics, characteristics, and prognosis. We discuss the potential role of selected non-coding RNAs most commonly associated with breast cancer. These include miR-21, miR-106a, miR-155, miR-141, let-7c, miR-335, miR-126, miR-199a, miR-101, and miR-9, which are perceived as potential biomarkers in breast cancer prognosis, diagnostics, and treatment response monitoring. As miRNAs differ in expression levels in different types of cancer, they may provide novel cancer therapy strategies. However, some limitations regarding dynamic alterations, tissue-specific profiles, and detection methods must also be raised.

Chinese expert consensus on the application of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal neoplasms (2023 edition)

Circulating tumor cell (CTC), as a novel tumor marker, has the characteristics of non-invasive, dynamic monitoring and high accuracy, and provides precise molecular characteristics of tumors and helps understand the changes in tumor development. Therefore, CTC has important clinical value in the dynamic monitoring of tumor progression. In order to standardize and guide the application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, Gastric Cancer Group of Oncology Branch of Chinese Medical Association, Colorectal Cancer Professional Committee of Chinese Medical Doctor Association, Colorectal Cancer Professional Committee of Chinese Anti-Cancer Association, Gastric Cancer Professional Committee of Chinese Anti-Cancer Association, Digestive Tract Polyp and Precancerous Lesion Professional Committee of Chinese Anti-Cancer Association, jointly convened some domestic experts to discuss and formulate the Chinese expert consensus on the application of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal neoplasms (2023 edition). The consensus provides opinions on the detection technology and clinical application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, including the prediction of tumor prognosis, the monitoring of tumor recurrence and metastasis, the evaluation of treatment response, and the additional diagnostic value, providing guidance for clinical application.