Tumor Foci Research Articles

Establishment of an orthotopic model of endometrial cancer

The purpose of this study was to establish a model of uterine carcinoma in female laboratory rats by transplanting Guerin carcinoma directly into the uterine horn. Material and Methods. Fifteen nonlinear white laboratory rats weighing 250 ± 25 g served as the subjects of surgical intervention. all operative interventions were performed under xylazine-zoletil anesthesia. Female white laboratory rats were laparotomized under aseptic conditions using anesthesia. the incision length was 2 cm, and a tumor suspension containing 2.5-3.5×106 cells was injected into the lumen of the right uterine horn using an intravenous catheter with a 22G injection port (0.9 × 25 mm). tumor cells were counted using the ADAMIILS cell analyzer (Nano Entek, Korea). the tumor progression was monitored for 21 days. after euthanizing the animals under ether anesthesia, median longitudinal histological sections, 5–7 μm thick, were made from the tumor node and stained with hematoxylin-eosin and Van-Gizon using standard techniques. Results. Following the transplantation of Guerin’s carcinoma cell suspension, a tumor node of approximately 25 mm in diameter was identified macroscopically in the region of the inferior aspect of the right uterine horn. additionally, the presence of haemorrhagic effusion was documented in the abdominal cavity and tumor screenings. at light microscopy, areas of neutrophilic infiltration, significant narrowing of the lumen of the uterine horn with signs of involution, and prismatic epithelium of papillary structures were observed. the tumor cell features characteristic of Guerin’s carcinoma are preserved in the tumor node induced in the uterus, with a cytoplasmic-nuclear ratio that remains close to 1:1. the shapes of the nuclei vary, but the irregular ovoid shape remains dominant, and pathological mitotic figures are observed. the tumor stroma includes cytoplasmic branched connections connecting the tumor conglomeration. Conclusion. therefore, according to the morphological description, the presented experimental model demonstrates the possibility of intrauterine growth of Guerin’s carcinoma in animals and is most similar to the localization of the tumor focus in patients with gynecological cancer.

Computational Pathology-Enabled Residual Tumor Estimation is a Prognostic Factor for Overall Survival in Anal Squamous Cell Carcinoma.

Anal squamous cell carcinoma (SCC) incidence has increased, and treatment has shifted from surgery to chemoradiotherapy (CRT), with salvage abdominoperineal resection (APR) being reserved for persistent/recurrent cases. This study evaluates the utility of different Tumor Regression Scoring Systems (TRSS) in predicting survival in anal SCC patients, using pathologists' observations and digital pathology. Cases managed surgically from 2005 to 2019 were collected. Residual tumor was assessed by multiple methods (gross tumor size, largest focus of tumor on H&E slide, average of residual tumor in all submitted H&E slides, JES, Chirieac, Schneider, Hermann, CAP scoring system). Three expert pathologists individually estimated ("eyeballed") the residual tumor % based on residual tumor/tumor bed (single representative H&E slide). The QuPath software was used to measure tumor volume on the same slide. American Joint Committee on Cancer (AJCC) 8th staging, and outcome data were retrieved from electronic medical records. The study involved 48 participants, predominantly female (56%), with a median age of 57. Most were Caucasian. HPV-positive was present in 77% of those assessed (17/22). Initial treatment included chemoradiation (CRT), followed by APR (79%) or pelvic exenteration (21%). Complications (13%), persistent disease (33%), and recurrence (54%) led to surgical interventions. 51% had moderately differentiated SCC, whereas 42% were poorly differentiated. Lymphovascular invasion (44%), perineural invasion (38%), and lymph node metastasis (13%) were present. Distant metastasis was rare (2%). Median overall survival was 3.2 years. Positive margins (HR 4.12, 95% CI 1.83, 9.28) and larger tumor size (HR 1.02 95% CI 1.01, 1.03) were associated with an increased hazard of death. Most residual tumor measurement methods were not significantly associated with overall survival. Interobserver agreement (based on "eyeballing") was moderate (kappa 0.4). Computational pathology-based residual tumor percentage was the only method significantly associated with outcome, with each 10% increase in the residual tumor percentage corresponding to a 1.23-fold higher hazard death (95% CI 1.03, 1.46; p=0.024). This study highlights computational pathology's important role in predicting outcomes in anal SCC treated with CRT and surgery. Specifically, the computational assessment of the residual tumor percentage proves to be a strong predictor of overall survival, outperforming other established TRSS methods.

A Simple Morphometric Analysis of Preoperative Therapy Response for Esophageal Adenocarcinoma.

Histologic assessment of tumor regression grade (TRG) on esophagogastrectomy specimens after neoadjuvant therapy is an excellent predictor of local recurrence rate and long-term survival in esophageal adenocarcinomas. Although several grading systems exist globally, the modified Ryan system suggested by the College of American Pathologists (CAP) is widely used in North America. Most systems rely on quantitative percentage estimation of the residual tumor with or without additional qualitative descriptors, which is relatively subjective with poor interobserver agreement. To test a morphometric-based approach using the microscopic objective lens to estimate the size of the largest focus of the residual tumor. A total of 69 esophageal specimens post neoadjuvant therapy were evaluated. Tumor size was morphometrically determined by the microscopic field, using an Olympus microscope with ×10/×22 eyepieces. Residual viable tumor was categorized into 4 groups, using ×2, ×4, and ×10 objectives: less than or equal to an ×10 field; larger than an ×10 field but less than or equal to an ×4 field; larger than an ×4 field but less than an ×2 field; and larger than or equal to an ×2 field. Morphometric measurements significantly correlated with the CAP treatment effect scores. There was no significant difference in overall survival between larger than or equal to ×2 and ×2 to ×4 groups; however, a 3-tier system (TRG1: ≤ ×10, TRG2: > ×10 and ≤ ×4, and TRG3: > ×4) showed significant survival differences (P = .01). Significant differences in the percentage of lymphovascular and perineural invasion, advanced TNM stage, and lymph node metastasis were identified among the 3 groups. The proposed 3-tier morphometric approach based on microscopic field size is a simple and easy-to-use method, which helps stratify patients into 3 groups with distinct histopathologic features and overall survival.

Dissection of RET p.M918T-driven progression of hereditary vs. sporadic medullary thyroid cancer.

Whether inherited in the context of multiple endocrine neoplasia 2B at germline level or acquired in a lifetime, all RET p.M918T (RET c.2753T>C) mutations should activate the RET tyrosine kinase receptor alike, with similar degrees of medullary thyroid cancer (MTC) progression when disparities in disease onset and multifocal growth are accounted for. This cross-sectional analysis of RET p.M918T-driven progression of hereditary MTC (33 patients) vs. sporadic MTC (36 patients) sought to explore this hypothesis. Patients with hereditary disease were significantly younger at thyroidectomy (medians of 10 vs. 57 yrs.) and featured significantly more often multifocal growth (69 vs. 14%) with more thyroid tumor foci (medians of 2 foci vs. 1 focus) than patients with sporadic disease. Although the former had 3.6-fold smaller primary thyroid tumor diameters (medians of 5 vs. 18mm) and twice as many neck nodes dissected (medians of 66.5 vs. 32 nodes) than the latter, extrathyroid tumor extension (42 vs. 36%), node metastasis (64 vs. 77%), distant metastasis (33 vs. 17%), and biochemical cure rates (45 vs. 35%) were fairly comparable, as was the number of dissected node metastases (medians of 7 vs. 8 involved nodes). Sensitivity analyses, with breakdown of patients by tumor multifocality and nodal status, corroborated these findings. RET p.M918T-driven progression of MTC is similar in hereditary and sporadic disease, barring earlier development and more frequent multifocal growth of hereditary MTC. This makes a compelling case for referral of patients with RET p.M918T-driven MTCs to specialist surgical centers.

If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide.

Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor Tcells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

Efficacy of the combination of lenvatinib with pembrolizumab in patients with advanced renal cell carcinoma

Objective: to re-evaluate the efficacy and safety of lenvatinib with pembrolizumab in unselected Russian renal cell carcinoma (RCC) patients, included in the phase IV study, in a median follow-up extended to 17.1 months. The primary end point was progression-free survival (PFS), secondary end points were overall survival (OS), objective response rate (ORR) and duration of response (DOR), disease control rate (DCR) and its duration, as well as safety.Materials and methods. The study included medical data of 165 patients with verified advanced RCC who received lenvatinib with pembrolizumab in 36 centers of the Russian Federation from 05.02.2018 to 25.07.2024. The median age was 60 (20–76) years, the male to female ratio was 2.3:1. The majority of patients had Karnofsky performance status ³80 % (74.6 %), clear cell RCC (93.3 %) without sarcomatoid differentiation (93.3 %), metachronous metastases (50.9 %) localized in >1 organ (75.2 %), were nephrectomized (63.0 %) and did not receive antitumor therapy (91.0 %). At the time of lenvatinib with pembrolizumab therapy start 40 patients (24.2 %) were classified into International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable prognostic group, 92 (55.8 %) in the intermediate prognostic group, and 33 (20.0 %) in the poor prognostic group. The median follow-up was 17.1 (1.5–72.9) months.Results. The median PFS achieved 24.0 (18.7–29.3) months, 17-month PFS 60.5 %. The median OS was 48.9 (18.5– 79.2) months, 17-month OS – 76.1 %. Objective response was registered in 46.0 % of patients including 2.4 % complete responders; the DCR was 92.1 %. The median DOR was 16.6 (2.1–72.9) months, duration of disease control –14.3 (2.1–72.9) months. Confirmed dynamics of change in the sum of tumor foci diameters was recorded in 152 patients, while the median change was –25 % (from –100 % to +29 %). Any decrease in the sum of tumor foci diameters occurred in 69.1 % of cases. The incidence of any adverse events (AE) was 78.2 %, severe AE – 24.2 %, and serious AE – 9.7 %. Immune-mediated AEs developed in 17.0 % of cases and AE grades 3–4 in 6.7 % of cases. Mortality from AEs was 1.2 %.Conclusion. Compared with the registration study, in real-world clinical practice in patients with advanced RCC the lenvatinib with pembrolizumab provides a lower ORR with comparable PFS and OS rates and demonstrates a satisfactory safety profile.

Abstract C050: Leveraging ECM deposition by CAF-like Ewing sarcoma tumor cells to target micrometastases with matrix-binding VHHs

Abstract Ewing sarcoma (EwS) is an aggressive bone and soft tissue tumor and EwS patients often succumb to their disease years after initial treatment due to relapses at metastatic sites. Novel therapeutic strategies are needed that can successfully eliminate microscopic residual disease foci that persist at the end of primary therapy. Extracellular matrix (ECM) proteins in the tumor microenvironment (TME) provide critical pro-survival and pro-invasion signals to tumor cells. Our published and unpublished data show that the glycoprotein tenascin-C (TNC) is enriched in EwS metastases and that TNC and other pro-tumorigenic ECM proteins are deposited by subpopulations of CAF-like tumor cells that are activated in response to tumor and TME-derived TGF-beta ligands. TNC is abundantly produced by multiple human tumors of epithelial and non-epithelial lineage but is otherwise rarely expressed outside of development and wound healing. Importantly, TNC is specifically enriched in metastatic lesions where it has been implicated as a mediator of metastatic competence and treatment resistance. In the current work we have tested whether the TNC-rich TME of disseminated EwS tumor foci could be leveraged to direct therapies to sites of residual micrometastatic disease. To achieve this, we generated monovalent and bivalent anti-human TNC VHHs (hTNC-VHH) using a mammalian expression platform. Camelid-derived hTNC-VHH sequences were sourced from published literature. VHHs are single domain heavy chain only antibody fragments with higher stability and tissue penetration than conventional monoclonal antibodies. Using EwS tumor spheroids in collagen-rich 3D culture, hTNC-VHH penetrated dense ECM matrices and bound through multiple cell layers in under 10 minutes. hTNC-VHH accumulated in TNC-positive but not TNC-knockout EwS spheroids and were retained beyond 96 hours. To assess their potential to drive protein and immune therapies to TNC-rich TMEs, we fused hTNC-VHH to immune modulating CD3- and CD28-activating VHHs. These hTNC-VHH-CD3/CD28-conjugates promoted immune cell activation and tumor cell death in PBMC-tumor co-culture assays as determined by CD25 flow cytometry and fluorescence microscopy, respectively. To assess in vivo localization, fluorescently-tagged hTNC-VHH were intravenously injected into mice that had been xenografted with EwS cells. Tissue microscopy confirmed selective binding of hTNC-VHH to small lung and liver EwS micrometastases in less than 4 hours. VHHs were not retained in non-tumor bearing organs including the brain and heart or in tumor-free lung and liver regions. Experiments are ongoing to assess anti-tumor efficacy and pharmacodynamics of hTNC-VHH conjugates in EwS xenografts. Together these findings suggest that the ECM-remodeling properties of CAF-like EwS cells can be exploited to recruit novel ECM-targeting protein therapeutics to micrometastases. If successful, this innovative approach could eradicate microscopic residual disease and prevent metastatic EwS recurrence. Citation Format: Emma D. Wrenn, Jason P. Price, Raymond O. Ruff, Nicolas M. Garcia, James M. Olson, Elizabeth R. Lawlor. Leveraging ECM deposition by CAF-like Ewing sarcoma tumor cells to target micrometastases with matrix-binding VHHs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C050.

Improvement of long-term treatment results in oligometastatic colorectal cancer patients by using a combined approach

Purpose of the study. To improve the treatment results of patients suffering from CRC with oligometastatic lesion by determining the most effective combination of treatment methods.Patients and methods. The results of treatment of 71 patients with oligometastases of colorectal cancer were analyzed. All patients were divided into 2 groups depending on the treatment methods. The first group included 35 patients who underwent simultaneous removal of the primary tumor and metastatic foci at the first stage of complex treatment. The second group includes clinical data on 36 patients who underwent primary lesion removal at the first stage of complex treatment followed by drug antitumor therapy.Results. In the primary tumor removal group, the response was received in 3 (8.3 %) cases, stabilization was achieved in 14 (38.9 %) cases, and progression of the tumor process was detected in 19 (52.8 %) cases. The median disease-free survival was 9.2 ± 3.2 months. One-year, two- and three-year survival rates in the group of simultaneous removal of the primary tumor and oligometastases and in the group of primary tumor removal were 97.1 %, 88.6 %, 77.1 % and 100 %, 80.5 %, 72.2 %, respectively. The overall survival rate in the group of simultaneous removal of the primary tumor and oligometastases was 63 ± 3.9 months, in the group of primary tumor removal – 58 ± 3.8 months.Conclusion. In the presented clinical study, a comparative assessment of the effectiveness of the treatment of patients with colorectal cancer with oligometastases was carried out, depending on the option of an integrated approach. The results obtained turned out to be multidirectional – the response to treatment and progression were obtained in 54.3 % and 45.7 % of cases in the group of simultaneous removal of the primary tumor and oligometastases versus 47.2 % and 52.8 % of cases in the group of removal of the primary tumor without oligometastases, respectively. The median recurrence-free survival was shorter in the group of primary tumor removal without metastases. Complete removal of the primary tumor and oligometastases can significantly increase the overall survival rates of patients.

Retro and prospective analysis of complex treatment of a patient with a polyostotic form of osteoclastoma of the maxillofacial region: clinical observation

In global literature there is not sufficient information on the course of the polyostotic form of osteoclastoma and methods of its treatment. For this reason, the analysis of this clinical case may be interesting for oncologists, maxillofacial surgeons and dentists of various specialties, who can reveal both the onset and recurrence of the disease. A characteristic feature of the course of this disease is the relapse of neoplasms with localization of foci in various parts of the upper and lower jaw. A clinical case of polyostotic form of jaw osteoclastoma and patient`s management tactics from 2006 to 2024 are described in the article. The disease was first diagnosed in 2006, when a neoplasm was revealed in the right part of the lower jaw. The neoplasm was removed by resection and mandibular defect was replaced by a carbon implant with further prosthesis. In 2011 a new neoplasm was detected on the left side in the frontal part of the upper jaw. At the same time a relapse of the disease was diagnosed with a new tumor focus in the lower jaw on the right. Surgical treatment was performed. Firstly, the neoplasm in the frontal area of the upper jaw was removed with replacement of the defect with a resection prosthesis. And secondly, a removal of the tumor on the lower jaw with resection of the chin within healthy tissues and replacement of the defect with an implant made of carbon-carbon material "Uglecon M" were performed. In 2023 the patient was invited to the dental hospital of the Clinical Multidisciplinary Medical Center of E.A. Vagner Perm State Medical University for dispensary observation and evaluation of the results of the treatment. The obtained results indicate the need for medical follow-up of patients after surgery for osteoblastoclastoma. The effectiveness of jaw implants made of carbon-carbon composite material " Uglecon M" was proved as well.

Integrated multiomics analysis identified comprehensive crosstalk between diverse programmed cell death patterns and novel molecular subtypes in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with increasing global prevalence and is one of the leading causes of cancer-related mortality in the human population. Developing robust clinical prediction models and prognostic stratification strategies is crucial for developing individualized treatment plans. A range of novel forms of programmed cell death (PCD) plays a role in the pathological progression and advancement of HCC, and in-depth study of PCD is expected to further improve the prognosis of HCC patients. Sixteen patterns (apoptosis, autophagy, anoikis, lysosome-dependent cell death, immunogenic cell death, necroptosis, ferroptosis, netosis, pyroptosis, disulfidptosis, entotic cell death, cuproptosis, parthanatos, netotic cell death, alkaliptosis, and oxeiptosis) related to PCD were collected from the literatures and used for subsequent analysis. Supervised (Elastic net, Random Forest, XgBoost, and Boruta) and unsupervised (Nonnegative Matrix Factorization, NMF) clustering algorithms were applied to develop and validate a novel classifier for the individualized management of HCC patients at the transcriptomic, proteomic and single-cell levels. Multiple machine learning algorithms developed a programmed cell death index (PCDI) comprising five robust signatures (FTL, G6PD, SLC2A1, HTRA2, and DLAT) in four independent HCC cohorts, and a higher PCDI was predictive of higher pathological grades and worse prognoses. Furthermore, a higher PCDI was found to be correlated with the presence of a repressive tumor immune microenvironment (TME), as determined through an integrated examination of bulk and single-cell transcriptome data. In addition, patients with TP53 mutation had higher PCDI in comparison with TP53 WT patients. Three HCC subtypes were identified through unsupervised clustering (NMF), exhibiting distinct prognoses and significant biological processes, among the three subtypes, PCDcluster 3 was of particular interest as it contained a large proportion of patients with high risk and low metabolic activity. Construction and evaluation of the Nomogram model was drawn based on the multivariate logistic regression analysis, and highlighted the robustness of the Nomogram model in other independent HCC cohorts. Finally, to explore the prognostic value, we also validated the frequent upregulation of DLAT in a real-world cohort of human HCC specimens by qPCR, western blot, and immunohistochemical staining (IHC). Together, our work herein comprehensively emphasized PCD-related patterns and key regulators, such as DLAT, contributed to the evolution and prognosis of tumor foci in HCC patients, and strengthened our understanding of PCD characteristics and promoted more effective risk stratification strategies.

Unusual presentation of incidental atypical carcinoid tumor masquerading as carcinoid tumorlets arising from diffuse neuroendocrine cell hyperplasia (DIPNECH): A case report

Introduction: Carcinoid tumorlets are usually incidental findings in lung excisions. These neuroendocrine proliferations should be less than 5 mm, and resemble typical carcinoid (TC) lacking necrosis and elevated mitotic activity. We report a case of atypical carcinoid (AC) presenting as multiple tumors all measuring less than 5 mm, mimicking carcinoid tumorlets. Case Report: Our patient underwent a right upper lobectomy for multifocal invasive lepidic adenocarcinoma. Multiple nodules of neuroendocrine cells less than 5 mm in greatest dimension were noted within the lobectomy. Unlike carcinoid tumorlets, these nodules showed >2 mitotic figures per square millimeter and punctate necrosis. The ACs masqueraded as multiple microscopic tumor foci (greater5 mm) resembling “carcinoid tumorlets” in adjacent background lung tissue next to the adenocarcinoma. However, increased mitoses and punctate necrosis were diagnostic of AC. A background of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was noted, appeared to be a precursor lesion to AC, and demonstrated the DIPNECH’s preneoplastic potential to evolve directly into an AC. Conclusion: The rare possibility of AC in “tumorlet”-appearing multiple micronodules should be considered in presence of elevated mitotic activity and necrosis in background of DIPNECH.

Artificial intelligence-based automated determination in breast and colon cancer and distinction between atypical and typical mitosis using a cloud-based platform.

Artificial intelligence (AI) technology in pathology has been utilized in many areas and requires supervised machine learning. Notably, the annotations that define the ground truth for the identification of different confusing process pathologies, vary from study to study. In this study, we present our findings in the detection of invasive breast cancer for the IHC/ISH assessment system, along with the automated analysis of each tissue layer, cancer type, etc. in colorectal specimens. Additionally, models for the detection of atypical and typical mitosis in several organs were developed using existing whole-slide image (WSI) sets from other AI projects. All H&E slides were scanned by different scanners with a resolution of 0.12-0.50μm/pixel, and then uploaded to a cloud-based AI platform. Convolutional neural networks (CNN) training sets consisted of invasive carcinoma, atypical and typical mitosis, and colonic tissue elements (mucosa-epithelium, lamina propria, muscularis mucosa, submucosa, muscularis propria, subserosa, vessels, and lymph nodes). In total, 59 WSIs from 59 breast cases, 217 WSIs from 54 colon cases, and 28 WSIs from 23 different types of tumor cases with relatively higher amounts of mitosis were annotated for the training. The harmonic average of precision and sensitivity was scored as F1 by AI. The final AI models of the Breast Project showed an F1 score of 94.49% for Invasive carcinoma. The mitosis project showed F1 scores of 80.18%, 97.40%, and 97.68% for mitosis, atypical, and typical mitosis layers, respectively. Overall F1 scores for the current results of the colon project were 90.02% for invasive carcinoma, 94.81% for the submucosa layer, and 98.02% for vessels and lymph nodes. After the training and optimization of the AI models and validation of each model, external validators evaluated the results of the AI models via blind-reader tasks. The AI models developed in this study were able to identify tumor foci, distinguish in situ areas, define colonic layers, detect vessels and lymph nodes, and catch the difference between atypical and typical mitosis. All results were exported for integration into our in-house applications for breast cancer and AI model development for both whole-block and whole-slide image-based 3D imaging assessment.

METTL3-induced lncARSR aggravates neuroblastoma tumorigenic properties through stabilizing PHOX2B

Neuroblastoma (NB), the most common extracranial solid tumor in pediatric patients, manifests with considerable variability across multiple primary sites. Despite this, the extent of genetic heterogeneity within these tumor foci and the identification of consistent oncogenic drivers remains largely unexplored. Of particular interest, genetic mutations in PHOX2B have been linked to familial cases of NB, yet the underlying molecular mechanisms are not fully delineated. In our research, we focus on unraveling the role of a novel functional long non-coding RNA (lncRNA) associated with PHOX2B in the context of NB. Using NB cell models with overexpressed PHOX2B, combined with lncRNA microarray analysis, we discovered that lncARSR is significantly upregulated in response to PHOX2B overexpression. Subsequent biological assays demonstrated that lncARSR promotes both the proliferation and metastasis of NB cells. Further molecular investigations revealed that lncARSR plays a crucial role in stabilizing PHOX2B expression within NB cells. Moreover, we identified that the expression of lncARSR is regulated by methylation through methyltransferase-like 3 (METTL3), which itself is positively correlated with PHOX2B expression. Rescue experiments underscored the functional importance of METTL3, lncARSR, and PHOX2B in NB cells. In summary, our findings provide new insights into the molecular functions of PHOX2B in the progression of neuroblastoma and propose a novel therapeutic target for this aggressive malignancy.

IDO1-mediated catabolism of tryptophan in gastric tumors: Its potential role in the axis of histopathology, differentiation and metastasis

BackgroundIndoleamine 2,3-Dioxygenase 1 (IDO1)-mediated tryptophan degradation, which is the rate-limiting enzyme of tryptophan/kynurenine pathway, may cause immune suppression in the tumor microenvironment, while potentiating proliferative and metastatic activity in the tumor focus, Phase studies of IDO1 inhibitors are ongoing, and our study aims to evaluate the potential contribution of IDO1 gene expression to the tryptophan/kynurenine pathway in tumor and tumor microenvironment foci in gastric cancer (GC) on a clinicopathological axis, MethodIn the case-control study design, the determination of tryptophan and its metabolites in the serum of 51 GC and 49 healthy controls was made using High Pressure Liquid Chromatography-Fluorescence Detector (HPLC-FD). IDO1 expression in a total of 102 tissues with tumor and tumor microenvironment was detected by quantitative PCR (q-PCR). ResultsIn gastric tumors, 3,25-fold decreased expression of IDO1 was detected according to the tumor microenvironment (p=0,05), IDO1 expression was found to be more than 2 times higher in signet ring cell carcinoma (SRCC) and poorly differentiated tumors without distant organ metastasis (p<0,05), In GC, tryptophan level was found to be 1,6 times lower than in control (AUC:0889; cut off≤21,57; p<0001), Low tryptophan level was found in advanced tumor stage compared to early stage and in the presence of perineural invasion compared to its absence (p<0,05) The level of kynurenine was found to be approximately 1,8 times lower in SRCC (p=0,04), ConclusionIncreased tryptophan accumulation in the gastric tumor and its microenvironment, when catabolized via IDO1, exhibits histological type, tumor differentiation, and metastasis-promoting effects more prominently in aggressive subtypes such as SRCC,

Choice of surgical treatment approach in patients with metastatic colorectal cancer complicated by intestinal obstruction

BACKGROUND: Every year more than 1 million new cases of colorectal cancer are diagnosed worldwide, with approximately 30% patients already having distant metastases. Colorectal cancer is often complicated, which makes chemotherapy challenging or, in some cases, impossible, therefore worsening the prognosis. As the first step, such patients need to undergo surgical treatment, in order to eliminate existing complications. However, what volume of surgery remains a discussion point among ongologists: a colostomy or a cytoreductive r2 resection to remove the primary tumor. AIM: To analyze the results of complex treatment in patients with metastatic colorectal cancer and to optimize surgical treatment approaches. MATERIALS AND METHODS: We conducted a study in Samara regional clinical Oncology dispensary (Samara, Russia), which included patients with metastatic colorectal cancer complicated by intestinal obstruction. Before treatment, all patients were examined according with current clinical standards. Subsequently, the patients were divided into two groups: the first group included patients who underwent cytoreductive surgery (r2 resection to remove the primary lesion due to the presence of colonic obstruction), and the second group included patients who underwent palliative surgery (colostomy or a bypass anastomosis in order to eliminate intestinal obstruction without removing the primary tumor). RESULTS: We found that postoperative complications in patients who had undergone primary tumor removal were significantly more prevalent. At the same time, however, the number of complications at the stage of chemotherapy, combined with angiogenesis inhibitor therapy, was significantly greater than in the group of patients in whom primary lesion was not removed. Complications that arose during chemotherapy affected the number of chemotherapy cycles performed. Discontinuation of chemotherapy affected event-free and overall survival. CONCLUSION: Timely identification and elimination of existing complications by removing the primary tumor focus before chemotherapy is an important component of an individual approach in order to develop treatment optimal tactics for patients with metastatic colorectal cancer.

NIR‐II AIEgens nanosystem for fluorescence and chemiluminescence synergistic imaging‐guided precise resection in osteosarcoma surgery

AbstractOsteosarcoma (OS) is characterized by an unfavorable prognosis and high mortality rates, with the local recurrence attributed to residual lesions post‐surgery being a major reason for treatment failure. Precise and tumor‐specific resection guidance to minimize recurrence remains a significant challenge. In the present study, a nanosystem based on aggregation‐induced emission (AIE) molecules with emission in the second near‐infrared window is proposed for the synergistic fluorescence (FL) and chemiluminescence (CL) imaging‐guided surgical resection for the elimination of tumor foci. The designed AIE molecule, BBTD14, exhibits stable FL with a high quantum yield of up to 3.95%, which effectively matches the energy levels of CL high‐energy states, generating the longest emission wavelength of CL reported to date. Targeted tumor imaging‐guided surgery (IGS) is facilitated by FL and CL nanoprobes (FLNP and CLNP) constructed based on BBTD14. During OS surgery, the FLNP, with the stability of FL and a high targeting capability, was first intravenously used to guide the surgical removal of the main tumor. Subsequently, CLNP was locally incubated to facilitate rapid and accurate evaluation of residual tumors at the operative border. High signal‐to‐noise ratio CL imaging was achieved after spraying with hydrogen peroxide, thereby overcoming the limitations of intraoperative frozen sections. The proposed technique also significantly reduced the recurrence rates in OS mouse models and exhibited high marker specificity in ex vivo OS patient pathology samples, confirming its potential in clinical applications and providing a unique perspective for developing IGS.

NIR laser-activated phthalocyanine loaded lipid nanoparticles targeting M2 macrophage for improved photoacoustic imaging-guided photothermal therapy

The development of novel phototheranostic agents with significant potential in bioimaging-guided therapy is highly desirable for precise tumor therapy. Herein, NIR laser-activated ruthenium phthalocyanine (PcRu) loaded sub-30 nm targeting lipid nanoparticles (α-PcRu-NPs) were fabricated for photoacoustic imaging (PAI)-guided photothermal therapy (PTT). Due to the formation of J-type aggregation of PcRu in the core of the nanostructure, the α-PcRu-NPs exhibited high stability, efficient NIR absorption, reduced singlet oxygen generation, high photothermal activity, and intense photoacoustic signal. With the M2 macrophage target peptide (M2pep) modification and small size of α-PcRu-NPs, in vivo evaluations reveal that α-PcRu-NPs can specifically target and deeply penetrate the tumor foci. Under a high contrast PAI guidance with α-PcRu-NPs (744 nm, 0.35 μW), it also realizes superior photothermal therapy (PTT) for breast cancer under 670 nm laser irradiation (0.5 W/cm2). The prominent therapeutic efficacy of α-PcRu-NP-based PTT not only directly kills tumor cells, but also enhances the immune response by promoting dendritic cell maturation and increasing cytotoxic T cell infiltration. Thus, this work broadens the applications of phthalocyanine derivatives as phototheranostics in the PAI-guided PTT field.

“Find Your Y”: histological differences in early stage (pT) and post-treatment (ypT) oesophageal adenocarcinoma with implications for salvage endoscopic resection

AimsCurrent guidelines offer limited strategies for managing recurrent/persistent oesophageal adenocarcinoma (EAC). Salvage endoscopic mucosal/submucosal resection (ER) shows promise in oesophageal squamous cell carcinoma, however its success in EAC is limited....

An aggressive Cushing's syndrome originating from a rare thymic neuroendocrine tumor, controlled successfully with fluconazole and octreotide therapy before surgery.

Cushing's syndromes (CSs) due to the thymic neuroendocrine tumors are rarely seen. Here, a case of ectopic CS originating from an atypical neuroendocrine tumor has been presented. A 49-year-old woman was hospitalized with symptoms of fatigue, chest pressure, dyspnea, muscle weakness, and resistant hypertension. There was marked hyperpigmentation in the whole-body surface suggestive of adrenocorticotropic hormone (ACTH) excess and there were physical features of CS. There was deep hypokalemia. Basal hormone profile, dexamethasone suppression tests, midnight cortisol, and 24-hour urine cortisol levels were suggestive of ectopic CS. The pituitary magnetic resonance imaging revealed a 5 mm cystic lesion and the patient refused inferior petrosal sinus sampling. Thorax computerized tomography showed an anterior mediastinal mass. A fluorodeoxyglucose-positron emission tomography showed the same mediastinal lesion (suvmax: 11.4), and no other tumor focus was detected. There was an aggressive cortisol excess causing acute respiratory distress syndrome, making it difficult to perform the surgery. We immediately started fluconazole and octreotide therapy and were successful in lowering the cortisol level. Then a complete resection of the tumor had been able to be surgically performed and tumor cells showed strong cytoplasmic immunopositivity with ACTH. A definitive diagnosis of "ACTH secreting atypical thymic carcinoid tumor" was rendered based on the histopathological and immunohistochemical features. There was only surrounding vessel invasion, and no lymphoid or other organ metastases were detected. As there were surrounding vessel invasions, a two-cycle regimen cisplatin-etoposide chemotherapy and radiotherapy were employed. After surgical and medical therapy, the cortisol and ACTH levels turned to normal. The patient is in biochemical and clinical remission and has no tumor recurrence yet. Ectopic ACTH-producing thymic carcinoids are rare but life-threatening tumors because of the underlying malignancy and severe hypercortisolemia. It is important to consider this disease and perform appropriate treatment at the right time. Today, surgery is the standard therapeutic modality if it is possible to perform, but there is not a clear and constant recommendation for nonsurgical therapeutic modalities. Further studies are needed for the optimal treatment strategies.

Metastatic Leiomyoma With Malignant Transformation Harboring RAB2A-PLAG1 Fusion-A Case Report and Review With Molecular Analysis.

Metastasizing leiomyoma is a rare condition characterized by the development of benign-appearing smooth muscle neoplasms at extrauterine sites in patients with a history of uterine leiomyoma. These lesions occur most commonly in the lung, with the abdominopelvic and mediastinal lymph nodes being other reported sites. Malignant transformation of metastasizing leiomyoma is extremely rare, with only a few cases described in the literature. We describe a case of metastasizing leiomyoma with malignant transformation in a middle-aged Asian lady, who developed pulmonary metastatic foci 12 years after surgical excision of the original uterine leiomyomata. Molecular analysis showed a common RAB2A-PLAG1 fusion gene and identical single nucleotide variants in both tumor foci, with significantly more pronounced segmental chromosomal copy number variations in one focus showing high-grade features. A comprehensive review of the literature lends support to the hypothesis that the original leiomyomata and the metastatic foci are clonally related, with high-grade features being associated with more complex genomic signatures.