Distant Spread Research Articles

Unraveling the Heterogeneity of Deficiency of Mismatch Repair Proteins in Endometrial Cancer: Predictive Biomarkers and Assessment Challenges

Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024. This rise correlates with aging populations, the obesity epidemic, and changing reproductive patterns, including delayed childbearing. Despite the early diagnosis in 67% of cases, approximately 30% of cases present with regional or distant spread, leading to nearly 20% mortality rates. Unlike many cancers, EC mortality rates are escalating, outpacing therapeutic advancements until recently. One of the reasons for this was the lack of effective therapeutic options for advanced disease until recently. The introduction of immunotherapy has marked a turning point in EC treatment, particularly benefiting patients with defects in mismatch repair proteins (dMMRs). However, dMMR status alone does not ensure a favorable response, underscoring the need for precise patient selection. This review explores the pivotal role of mismatch repair proteins in EC, emphasizing their heterogeneity, the challenges in their assessment, and their potential as predictive biomarkers.

Radiomics Signatures Based on Computed Tomography for Noninvasive Prediction of CXCL10 Expression and Prognosis in Ovarian Cancer.

Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with malignant ascites and even observed widespread metastasis or distant spread. We aimed to develop and identify radiomics models according to computed tomography (CT) for preoperative prediction of CXCL10 expression and prognosis in patients with OC. Genomic data with CT images and corresponding clinicopathological parameters were extracted from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). To analyze the prognosis, we carried out the univariate Cox regression analysis (UCRA), multivariate Cox regression analysis (MCRA), and Kaplan-Meier (KM) analysis. For the data reduction, logistic regression, operator regression, least absolute shrinkage selection, radiomic feature construction, and feature selection were utilized. The predictive performance of the radiomic signatures was assessed using the analyses of the receiver operating characteristic (ROC) curve, decision curve (DCA), and precision-recall (PR) curve. To evaluate the correlation between the radiomic score (Rad-score) and CXCL10 expression, the Wilcoxon rank-sum test was applied. Three radiomics models effectively predicted CXCL10 expression levels (AUC = 0.791, 0.748, and 0.718 for the set of training; AUC = 0.761, 0.746, and 0.701 for the set of validation). A higher Rad-score significantly correlated with upregulated CXCL10 expression. CXCL10 expression can be predicted noninvasively and preoperatively via radiomic signatures based on contrast-enhanced CT images.

Changing Clinical Presentation of Pediatric Differentiated Thyroid Cancer in Poland: A Retrospective Cohort Study Spanning 45 Years.

Background: Differentiated thyroid carcinoma (DTC) in children is uncommon; clinical presentation over recent decades is incompletely characterized. Methods: This retrospective cohort study analyzed demographic and disease characteristics of consecutive juveniles with DTC treated from 1970 to 2015 at Poland's largest pediatric DTC referral center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, who had available records. Sex, age, histopathological characteristics, and DTC stage were documented. We aimed to identify changes in these variables over time and independent risk factors for lymph node or distant metastases. Trends in these variables were assessed using the Cochran-Armitage test and Spearman correlation. Multivariable logistic regression was performed to identify risk factors associated with lymph node or distant metastases. Results: 475 of 479 patients (99.2%) were included in the analysis; roughly half were age ≥15 years, 10%, <10 years. Papillary thyroid carcinoma (PTC) represented 88% of cases and follicular thyroid carcinoma (FTC) 11%. Tumors ≤2 cm constituted 56% of cases with relevant data; those >4 cm accounted for 12%. Multifocality was observed in 37% and extrathyroidal invasion in 22%. Lymph node metastases were noted in 59% and distant metastases in 16%. Over the observation period, significant trends among new cases included: increased proportion of adolescents >15 years; increased frequency of tumors ≤2 cm, decreased multifocality rates, and increased proportion of PTC versus FTC. Extrathyroidal invasion rates remained appreciable throughout, ranging from 17 to 28% during the 5-year study subperiods after 1990. Lymph node metastases significantly increased in frequency in the central neck, remaining consistently common in lateral sites; presence of distant metastases significantly decreased. In multivariable analysis, multifocality, extrathyroidal invasion, and tumor size were independently associated with lateral lymph node metastases and multifocality, larger tumor size, and N1b metastases with distant spread. Conclusions: Our observations of a rising proportion of diagnoses in adolescence, reductions in primary tumor size, and decreased frequency of multifocality and distant metastases may reflect increased detection of patients with less aggressive DTC at earlier disease stages. Nonetheless, we found persistently substantial rates of locoregionally advanced disease features (multifocality, extrathyroidal invasion, and lymph node metastases), which multivariable analyses suggested have significant associations with lateral lymph node and/or distant metastases.

Interaction between tumor stage and age on survival outcomes of patients with anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an aggressive, rare malignancy associated with rapid growth and metastasis, and a very poor prognosis. We investigated the clinical characteristics, survival outcomes and independent prognostic factors associated with anaplastic thyroid cancer. To assess to what extent the interaction between age and tumor stage affects mortality. A total of 622 patients diagnosed with anaplastic thyroid cancer, between 2010 and 2017 were enrolled in our study by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We analyzed demographics, clinical characteristics, overall mortality (OM) and cancer specific mortality (CSM) of ATC. Variables with a P value < 0.1 were incorporated into the multivariate cox model to determine the independent prognostic factors. Furthermore, we analyzed the interaction between age and tumor stage on mortality. In the multivariate analyses, the divorced/separated population had a lower OM [hazard ratio (HR) = 0.63, 95%CI: 0.42-0.94, P < 0.05] and CSM (HR = 0.61, 95%CI: 0.40-0.92, P < 0.05). OM was higher in tumors with direct extension only (HR = 6.26, 95%CI: 1.29-30.42, P < 0.05) and tumors with distant spread (HR = 5.73, 95%CI: 1.34-24.51, P < 0.05). CSM was also higher in tumors with direct extension (HR = 5.05, 95%CI: 1.05-24.19, P < 0.05) and tumors with distant spread (HR = 4.57, 95%CI: 1.08-19.29, P < 0.05). Mortality was not adversely affected by lymph node involvement. OM was lower in patients who received radiation (HR = 0.66, 95%CI: 0.53-0.83, P < 0.01), chemotherapy (HR = 0.63, 95%CI: 0.50-0.79, P < 0.01) or surgery (HR = 0.53, 95%CI: 0.43-0.66, P < 0.01). CSM was also lower in patient who received radiation (HR = 0.64, 95%CI: 0.51-0.81, P < 0.01), chemotherapy (HR = 0.62, 95%CI: 0.50-0.78, P < 0.01) or surgery (HR = 0.51, 95%CI: 0.41-0.63, P < 0.01). There was no significant interaction between age and tumor stage that affected mortality. In this large US SEER database retrospective study, we found the mortality to be higher in advanced stage tumors with direct extension and distant metastasis. However, patients who received aggressive therapy showed a better overall survival. The aim of our study is to emphasize the importance of detecting ATC at an early stage and provide aggressive therapy to these patients. Since advanced stage ATC is associated with a dismal prognosis, we emphasize the need for randomized control trials and development of novel therapies that will be used to treat ATC.

Incidence Trends in Upper Gastrointestinal Cancer in Young Adults: A Nationwide Time-Trend Analysis Using 2001-2019 US Cancer Statistics Databases.

Upper gastrointestinal (UGI) cancers, comprising malignancies of the esophagus, stomach, duodenum, pancreas, liver, biliary tract, and gallbladder, are the second leading cause of cancer-related mortality in the United States and are associated with significant comorbidities. Recent studies show a disproportionate rise in pancreatic and stomach cancer among young adults. This study aims to use a nationwide, population-based cohort to (i) evaluate the trend of all UGI cancer as an aggregate and (ii) examine the role of demographics, histology, and tumor stage in UGI cancer incidence among young adults. Individuals diagnosed with UGI cancer in the United States from 2001 to 2019 were identified and obtained from the Surveillance, Epidemiology, and End Results-National Program of Cancer Registries database. The primary outcomes were incidence rates of UGI cancer (calculated per 100,000, age-adjusted to the year 2000 US population), stratified by sex and age (< 55 years for young adults and ≥ 55 years for older adults). Trends, annual percentage change, and average annual percentage change were calculated using the parametric method. Sensitivity analysis was performed according to primary site and histology; further analysis examining race and cancer stage was performed in the young adult subgroup. A total of 2,333,161 patients with UGI cancer were identified. Most cases were male, and 14.3% were < 55 years of age. Incidence of UGI cancer increased most in women younger than 55 years, driven primarily by pancreatic and stomach cancers, as well as neuroendocrine tumor and gastrointestinal stromal tumor histology. African American race and localized tumors and malignancy with distant spread are also contributing to the disparate increase among young women. UGI mortality rates have not changed significantly in young adults. The overall incidence rate of upper gastrointestinal cancer is increasing significantly in young women compared with men. Increased endoscopic procedures and disparate exposure to risk factors are likely contributing to these trends.

Assessment of Immunoreactivity Patterns in the Excised Cervical Lymph Nodes of Oral Squamous Cell Carcinoma

Introduction: Epidermoid carcinoma (oral squamous cell carcinoma [OSCC]) comprises approximately 80% of the malignancies of the oral cavity, which is also responsible for the morbidity and mortality due to the distant spread of the neoplastic cells. The regional draining lymph node has been considered an anatomic barrier to the systemic dissemination of malignant cells. It has been postulated that the microscopic architectural pattern of a regional lymph node (RLn) represents the immunologic reactivity in that node and the host response. Morphological assessment of the regional nodes aids in a better understanding of the immune response and its correlation with the stage of the tumour. Materials and Methods: A total of 51 head-and-neck dissection cases were assessed for immunomorphological patterns and the degree of tumour involvement in positive lymph nodes. 49 lymph nodes were in the early stage (TNM Stage l and ll) and 71 lymph nodes were in the advanced stage(TNM stage lll and lV). A total of 595 lymph nodes were histologically evaluated and were categorised into metastatic and non-metastatic nodes showing four different patterns: lymphocyte predominance (LP) pattern, germinal centre predominance (GCP) pattern, sinus histiocytosis (SH) pattern and lymphocyte-depleted pattern. Results: The most frequently encountered pattern of lymph nodes was of LP (436 nodes), followed by GCP (61 nodes), SH (36 nodes) and lymphocyte depleted (18 nodes), respectively. Out of 595, 120 nodes were positive for metastasis, indicating that as the stage advances, the GCP type predominates (the predominant immunomorphological pattern shifts from LP to GCP), facilitating metastasis. Conclusion: Immunomorphological changes in the RLns of OSCCs seem to be pivotal factors that serve as an important prognostic indicator. Whereas the cell-mediated immune response represented by LP and SH appears to resist the metastasis process, the humoral response reflected by GCP favours metastasis.

Breast Cancers Detected during a Decade of Screening with Digital Breast Tomosynthesis: Comparison with Digital Mammography.

Background Digital breast tomosynthesis (DBT) has been shown to help increase cancer detection compared with two-dimensional digital mammography (DM). However, it is unclear whether additional tumor detection will improve outcomes or lead to overdiagnosis of breast cancer. Purpose This study aimed to compare cancer types and stages over 3 years of DM screening and 10 years of DBT screening to determine the effect of DBT. Materials and Methods A retrospective search identified breast cancers detected by using screening mammography from August 2008 through July 2021. Data collected included demographic, imaging, and pathologic information. Invasive cancers 2 cm or larger, human epidermal growth factor 2-positive or triple-negative tumors greater than 10 mm, axillary nodes positive for cancer, and distant organ spread were considered advanced cancers. The DBT and DM cohorts were compared and further analyzed by prevalent versus incident examinations. False-negative findings were also assessed. Results A total of 1407 breast cancers were analyzed (142 with DM, 1265 with DBT). DBT showed a higher rate of cancer depiction than DM (5.3 vs four cancers per 1000, respectively; P = .001), with a similar ratio of invasive cancers to ductal carcinomas in situ (76.5%:23.5% [968 and 297 of 1265, respectively] vs 71.1%:28.9% [101 and 41 of 142, respectively]). Mean invasive cancer size did not differ between DM and DBT (1.44 cm ± 0.93 [SD] vs 1.36 cm ± 1.14, respectively; P = .49), but incident DBT cases were smaller than prevalent cases (1.2 cm ± 1.0 vs 1.6 cm ± 1.4, respectively; P < .001). DBT and DM had similar rates of invasive cancer subtypes: low grade (26.5% [243 of 912] vs 29% [28 of 96], respectively), moderate grade (57.2% [522 of 912] vs 51% [49 of 96], respectively), and high grade (16.1% [147 of 912] vs 20% [19 of 96], respectively) (P = .65). The proportion of advanced cancers was lower with DBT than DM (32.6% [316 of 968] vs 43.6% [44 of 101], respectively; P = .04) and between DBT prevalent and incident screening (39.1% [133 of 340] vs 29.1% [183 of 628], respectively; P = .003). There was no difference in interval cancer rates (0.14 per 1000 with DM and 0.2 per 1000 with DBT; P = .42) for both groups. Conclusion DBT helped to increase breast cancer detection rate and depicted invasive cancers with a lower rate of advanced cancers compared with DM, with further improvement observed at incident rounds of screening. © RSNA, 2024 See also the editorial by Kim and Woo in this issue.

Findings of Endoscopic US and CT of Esophageal Disease.

Various diseases can affect the esophagus. Endoscopic ultrasound (EUS), which provides precise information about the layers of the esophageal wall, is the primary approach used to investigate esophageal diseases. However, CT is one of the most important imaging modalities for diagnosing esophageal diseases as it can elucidate mediastinal involvement, adjacent lymphadenopathy, and distant disease spread. These two modalities complement each other in the diagnosis of esophageal diseases. Although radiologists may be unfamiliar with EUS procedures and their interpretation, understanding them aids in the differential diagnosis of esophageal conditions. This pictorial essay illustrates the EUS and CT findings of various esophageal diseases originating in the esophageal wall.

Rare Metastasis of Cutaneous Leiomyosarcoma to the Inguinal Region: Case report and Literature review

Introduction: Cutaneous leiomyosarcoma (CLM) is a rare malignancy arising from smooth muscle cells in the skin. It constitutes 2%-3% of all cutaneous soft tissue sarcomas and is known for its propensity for local recurrence and distant metastasis. Common metastatic sites include the lungs, liver, and brain. Diagnosis involves clinical examination and histopathological analysis, while management typically involves surgical excision, with adjunctive therapies like radiation and chemotherapy often considered due to its aggressive nature. Metastasis rates are reported as 12% for dermal and 51% for subcutaneous CLM. Case Report: A 40-year-old female with a history of excised leiomyosarcoma on the right buttock presented with a large, painful mass in the right inguinal region. Imaging revealed a substantial subcutaneous mass with significant local invasion and inguinal lymphadenopathy. Histopathological examination confirmed metastatic leiomyosarcoma. The patient showed anemia and elevated white blood cell count. Literature Review: Various cases reveal that CLM typically presents as nodular masses, primarily managed by surgical excision. Metastasis is rare but can occur, particularly in subcutaneous tumors. Inguinal region metastasis is highly unusual, with most cases showing spread to distant organs or regional lymph nodes. Imaging and histopathological findings are crucial for diagnosis. Discussion: CLM, while less metastatic compared to other sarcomas, requires vigilant monitoring due to its potential for local recurrence and distant spread. Metastasis to the inguinal region is exceptionally rare, highlighting the need for ongoing research to better understand such anomalies. Conclusion: CLM generally has a better prognosis than other sarcomas, but early detection of recurrence and metastasis is crucial. The rare occurrence of inguinal region metastasis emphasizes the importance of comprehensive surveillance and further research to understand this phenomenon better.

Survival characteristics of Wilms Tumor, a reference developed from a longitudinal cohort study

BackgroundWilms tumor (WT) survival has been affected by the evolution in clinical and biological prognostic factors. Significant differences in survival rates indicate the need for further efforts to reduce these disparities. This study aims to evaluate the clinicopathological data impact on survival among patients after Wilm's diagnosis.MethodsThe study utilized the SEERStat Database to identify Wilms tumor patients, applying SEERStat software version 8.3.9.2 for data extraction. Selection criteria involved specific codes based on the International Classification of Diseases for Oncology (ICDO-3), excluding cases with unknown SEER stage, incomplete survival data, unknown size, or lymph node status. Statistical analyses, including Kaplan–Meier estimates and Cox regression models, were conducted using R software version 3.5. Standardized mortality ratios (SMR) were computed with SEER*Stat software, and relative and conditional survival analyses were performed to evaluate long-term survival outcomes.ResultsOf 2273 patients diagnosed with Wilms tumor, (1219 patients, 53.6% were females with an average age group of 3–8 years (50.2%). The overall mean survival after five years of diagnosis was 93.6% (2.6–94.7), and the overall mean survival rate was 92.5% (91.3–93.8) after ten years of diagnosis. Renal cancers were identified as the leading cause of death (77.3%), followed by nonrenal cancers (11%) and noncancer causes (11%). Additionally, robust relative survival rates of 98.10%, 92.80%, and 91.3% at one, five, and ten years, respectively, were observed, with corresponding five-year conditional survival rates indicating an increasing likelihood of survival with each additional year post-diagnosis. Univariate Cox regression identified significant prognostic factors: superior CSS for patients below 3 years (cHR 0.48) and poorer CSS for those older than 15 years (cHR 2.72), distant spread (cHR 10.24), regional spread (cHR 3.09), and unknown stage (cHR 4.97). In the multivariate model, age was not a significant predictor, but distant spread (aHR 9.22), regional spread (aHR 2.84), and unknown stage (aHR 4.98) were associated with worse CSS compared to localized tumors.ConclusionThis study delving into WT survival dynamics reveals a multifaceted landscape influenced by clinicopathological variables. This comprehensive understanding emphasizes the imperative for ongoing research and personalized interventions to refine survival rates and address nuanced challenges across age, stage, and tumor spread in WT patients.

MODL-09. IMAGE-BASED SCREENING IN MEDULLOBLASTOMA REVEALS TUMOR-SUPPRESSIVE EFFECTS OF THE NEUROPROTECTIVE AGENT URMC-12K

Abstract BACKGROUND Enhanced motility and the invasive behavior of medulloblastoma (MB) influence microenvironment interactions and may promote distant spread. Current drug screening focuses on cytotoxic agents, leaving subtle but potentially therapeutically relevant drug phenotypes associated with motility and invasiveness unrecognized. The serine/threonine kinase MAP4K4 is upregulated in MB and promotes invasiveness1,2. Toxicities associated with existing MAP4K4 inhibitors in the CNS prevented further pre-clinical evaluation. URMC-12k is a novel MAP4K inhibitor identified as a motor-neuron-protective agent in ALS. Using advanced imaging approaches, we investigated URMC-12k as a tumor-suppressive drug in MB and characterized its effects at the molecular, cellular, and tissue levels. METHODS We use cell-based 3D invasion assays and quantitative microscopy to assess tumor-restraining activities of URMC-12k, and machine learning to detect URMC-12k phenotypes associated with repressed motility. We use tissue and zebrafish larval models to explore URMC-12k effects on cell and tissue viability and anti-invasion efficacy. We determined URMC-12k targets in MB cells using phosphoproteomics. RESULTS URMC-12k outcompetes existing MAP4K4 inhibitors in repressing basal and growth-factor-induced matrix invasion with no detectable effects on vertebrate developmental processes. A computational model trained to detect morphological alterations in the actin cytoskeleton associated with cell dynamics established a firm correlation between the URMC-12k-repressed motile behavior and alterations in the tumor cell actin cytoskeleton. Quantitative imaging further revealed that URMC-12k promoted increased cell clustering and reduced deposition of extracellular vesicles. Phosphoproteomics identified proteins involved in cell adhesion organization and vesicle trafficking as potential molecular effectors targeted by URMC-12k. CONCLUSIONS URMC-12k effectively inhibits MB cell migration and displays no toxicities at effective concentrations. The regulation of cell-cell adhesion molecules and the deposition of extracellular vesicles revealed by URMC-12k are tumor-promoting, druggable mechanisms of MAP4Ks in MB. 1. 1Migliavacca, J., et al. Commun Biol5, (2022). 2. 2Tripolitsioti, D. et al. Oncotarget9, 23220–23236 (2018).

Concomitant Botulinum Toxin Injections for Neurogenic Detrusor Overactivity and Spasticity-A Retrospective Analysis of Practice and Safety.

As multiple indications for botulinum toxin injections (BTIs) can coexist for neurological patients, there are to date no description of concomitant injections (CIs) to treat both spasticity and neurogenic detrusor overactivity incontinence (NDOI) in patients with spinal cord injuries (SCIs) and multiple sclerosis (MS). We therefore identified patients followed at our institution by health data hub digging, using a specific procedure coding system in use in France, who have been treated at least once with detrusor and skeletal muscle BTIs within the same 1-month period, over the past 5 years (2017-2021). We analyzed 72 patients representing 319 CIs. Fifty (69%) were male, and the patients were mostly SCI (76%) and MS (18%) patients and were treated by a mean number of CIs of 4.4 ± 3.6 [1-14]. The mean cumulative dose was 442.1 ± 98.8 U, and 95% of CIs were performed within a 72 h timeframe. Among all CIs, five patients had symptoms evocative of distant spread but only one had a confirmed pathological jitter in single-fiber EMG. Eleven discontinued CIs for surgical alternatives: enterocystoplasty (five), tenotomy (three), intrathecal baclofen (two) and neurotomy (one). Concomitant BTIs for treating both spasticity and NDOI at the same time appeared safe when performed within a short delay and in compliance with actual knowledge for maximum doses.

Mutation of SIVA, a candidate metastasis gene identified from clonally related bilateral breast cancers, promotes breast cancer cell spread in vitro and in vivo.

Metastasis is the most dreaded outcome after a breast cancer diagnosis, and little is known regarding what triggers or promotes breast cancer to spread distally, or how to prevent or eradicate metastasis effectively. Bilateral breast cancers are an uncommon form of breast cancers. In our study, a percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this "breast-to-breast" metastasis that might promote breast cancer distant spread. One somatic mutation acquired was SIVA-D160N that displayed pro-metastatic phenotypes in vivo and in vitro. Over-expression of SIVA-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA-D160N promoted invasion and anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA-D160N in 4T1 cells increased orthotopically implanted mammary gland tumor growth as well as liver metastasis. Clonally related bilateral breast cancers represented a novel system to investigate metastasis and revealed a role of SIVA-D160N in breast cancer metastasis. Further characterization and understanding of SIVA function, and that of its interacting proteins, may elucidate mechanisms of breast cancer metastasis, providing clinically useful biomarkers and therapeutic targets.

Abstract 2830: Intravital multiphoton microscopy of bone metastatic renal cell carcinoma

Abstract Clear cell renal carcinoma (ccRCC) represents 80% of renal neoplasms, with bone as a major site for distant spread (35-40% of patients). These secondary lesions cause a variety of skeletal-related complications, including pain, spinal cord compression, hypercalcemia, mobility issues and fractures, posing a significant negative impact on patient quality of life and survival. Furthermore, bone is well-known as a site of therapy resistance, which confers to patients treated with systemic therapies significantly worse time-to-treatment failure and progression-free and overall survival compared to those without bone metastases. Because of the complexity of the bone microenvironment and the paucity of suitable models, preclinical investigation of bone metastasis and therapy response is challenging. Preclinical models of bone metastasis that integrate tissue engineering and advanced imaging techniques can facilitate the study of the mechanism of tumor progression and therapy response. We recently developed a window model amenable to intravital multiphoton microscopy (MPM) to longitudinally monitor human ccRCC lesions in tissue engineered bone constructs (TEBCs) in immunodeficient mice. TEBCs were generated by functionalizing polymeric polycaprolactone scaffolds with bone morphogenetic protein 7. Human ccRCC lesions, after implantation into the bone cavity, were longitudinally monitored for growth and niche development, using multi-parameter recording of collagen/bone matrix (SHG), bone surface (THG), blood vessels/stromal phagocytes (fluorescent dextran), and tumor cells (GFP). However, this model lacked key components of the immune system (including B and T-cells), which are of major interest in the study of tumor progression and (immune) therapy response. Therefore, we developed a tissue-engineered preclinical model that incorporate species-specific interactions between cancer and bone stromal cells, and account for an intact immune system. To this purpose, we optimized TEBC formation in C57BL/6 fluorescent reporter mice (Sp7-mCherry, osteoblasts; Trap-td-Tomato, osteoclasts; GFP, immune cells, αSMA-RFP fibroblasts; and Flk1-GFP, blood vessels), coupled to detection by intravital or ex vivo multiphoton microscopy analysis, to monitor the evolution and fate of the TEBC. Interestingly, the bone marrow in the core of the TEBC was replaced by a desmoplastic tissue with features like the foreign body response, including foreign body giant cells, which was not present in immunodeficient mice. By applying dual color GFP/αSMA-RFP mice, which expressed red fluorescence in activated fibroblasts, we confirmed the fibrotic nature of this core. To avoid its formation, we generated scaffold-free ossicle, by direct implantation of BMP7 and VEGF in the subcutaneous tissue. To conclude, we established a protocol for generating ectopic ossicles in immunocompetent mice. Citation Format: Stefan Maksimovic, Nina Constanza Boscolo, Sergio Barrios, Antonios Mikos, Matthew T. Campbell, Eleonora Dondossola. Intravital multiphoton microscopy of bone metastatic renal cell carcinoma [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 2830.

TGFβ signalling pathway impacts brain metastases profiles in locally advanced colorectal cancer

RationaleColorectal Cancer (CRC) represents the third most common type of cancer in Germany and the second most common cancer-related cause of death worldwide. Distant metastases are still the main limit for patient survival. While liver metastases as well as peritoneal carcinomatosis can often either be resected or treated with systemic therapy, little options remain for brain metastases. Additionally, a number of studies has already investigated hepatic, peritoneal, pulmonary as well as continuing distant metastases in colorectal cancer. Yet, with respect to tumor biology and brain metastases, little is known so far.Material and methodsTwo cohorts, M0 without distant spread and BRA with brain metastases were build. RNA was isolated from paraffin embedded specimen. Gene expression was performed by an RNA NanoString-Analysis using the nCounter® PanCancer Progression Panel by NanoString-Technologies (Hamburg, Germany). Results were analysed by principal component analysis, gene expression and pathway analysis using commonly available databases such as KEGG as benchmark for comparison.ResultsWe were able to determine a gene signature that provides a sophisticated group separation between M0 and BRA using principal component analysis. All genes with strong loading characteristics on principal component 1 were cross-referenced with the subsequently performed accurate gene set enrichment analysis (GSEA). The GSEA revealed a clear dysregulation of the TGFβ pathway in compared cohorts M0 and BRA. Interestingly, the targeted pathways analysis of the identified genes confirmed that in fact almost all strong loading genes of PC1 play a role in the TGFβ pathway.ConclusionOur results suggest the TGFβ pathway as a crucial player in the development of brain metastases in primary CRC. In some types of colorectal cancer, downregulation of the TGFβ pathway might hinder primary colorectal cancer to metastasize to the nervous system. While the paradoxical functioning of the TGFβ pathway is still not fully understood, these shed light on yet another clinical implication of this complex pathway.

Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) has an excellent prognosis using local treatment, whereas nodal follicular lymphoma (nFL), occasionally presenting with cutaneous spread, often requires systemic therapy. Distinction of the 2 diseases based on histopathology alone might be challenging. Copy number alterations (CNAs) have scarcely been explored on a genome-wide scale in PCFCL; however, they might serve as potential biomarkers during differential diagnosis and risk stratification. Low-coverage whole-genome sequencing is a robust, high-throughput method for genome-wide copy number profiling. In this study, we analyzed 28 PCFCL samples from 20 patients and compared the copy number profiles with a cohort of diagnostic samples of 64 nFL patients. Although the copy number profile of PCFCL was similar to that of nFL, PCFCL lacked amplifications of 18q, with the frequency peaking at 18q21.33 in nFL cases involving the BCL2 locus (PCFCL: 5.0% vs nFL: 31.3%, P = .018, Fisher exact test). Development of distant cutaneous spread was significantly associated with higher genomic instability including the proportion of genome altered (0.02 vs 0.13, P = .033) and number of CNAs (2 vs 9 P = .017), as well as the enrichment of 2p22.2-p15 amplification involving REL and XPO1 (6.3% vs 60.0%, P = .005), 3q23-q24 amplification (0.0% vs 50.0%, P = .004), 6q16.1-q23.3 deletion (6.3% vs 50.0%, P = .018), and 9p21.3 deletion covering CDKN2A and CDKN2B loci (0.0% vs 40.0%, P = .014, all Fisher exact test) in PCFCL. Analysis of sequential tumor samples in 2 cases harboring an unfavorable clinical course pointed to the acquisition of 2p amplification in the earliest common progenitor underlining its pivotal role in malignant transformation. By performing genome-wide copy number profiling on the largest patient cohort to date, we identified distinctive CNA alterations conceivably facilitating the differential diagnosis of PCFCL and secondary cutaneous involvement of nFL and potentially aiding the risk stratification of patients with PCFCL in the future.

Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.

Expert consensus on diagnosis and treatment of malignant pleural effusion caused by lung cancer

Malignant pleural effusion (MPE) can occur in nearly all types of malignant tumors, with lung cancer being the most prevalent cause. The presence of MPE indicates an advanced stage or distant spread of the tumor, significantly reducing the patient's life expectancy. Particularly, a substantial amount of pleural effusion can impede heart and lung function, impair blood oxygen perfusion levels in the body, and greatly diminish patients' quality of life. Even when systemic treatment has alleviated the primary lung tumor in some patients, effective control over MPE remains challenging and impacts clinical outcomes. Therefore, it is crucial to implement measures for reducing or managing MPE while ensuring standardized treatment for lung cancer. In recent years, significant advancements have been made in diagnosing and treating lung cancer complicated by MPE through extensive basic and clinical research. Based on existing evidence and China's clinical practice experience, relevant experts from the China Association of Health Promotion and Education and Cancer Rehabilitation and Palliative Treatment Professional Committee of China Anti-Cancer Association (CRPC) have summarized key aspects related to diagnosis and treatment consensus opinions for lung cancer complicated by MPE. This aims to establish standardized procedures that will serve as a reference for doctors' clinical practice.

Unusual metastases of papillary thyroid carcinoma: a case report and review of literature

Papillary thyroid carcinoma comprise approximately 80 % of all thyroid cancers. It has generally a good prognosis, and distant spread is rare. Common sites of distant metastasis include lung and bone. Whatever the pleural and breast metastasis are exceedingly rare. Their presence portends a dismal prognosis and a shorter median survival. We recently experienced a case of 60 -year-old women with pleural and breast metastasis of papillary thyroid carcinoma. We report this case with a review of the literature.

Identification of novel biomarkers in the early diagnosis of malignant melanoma by untargeted liquid chromatography coupled to high-resolution mass spectrometry-based metabolomics: a pilot study.

Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage, it has an excellent prognosis, but mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge. To identify novel blood-circulating biomarkers that may be useful in the diagnosis of MM to guide patient counselling and appropriate disease management. In this study, 105 serum samples from 26 healthy patients and 79 with MM were analysed using an untargeted approach by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to compare the metabolomic profiles of both conditions. Resulting data were subjected to both univariate and multivariate statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 patients with stage I MM. We successfully identified several lipidic metabolites differentially expressed in patients with stage I MM vs. healthy controls. Three of these metabolites were used to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample. These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in bodily fluids that could serve as potential early diagnostic markers for MM.