Tumor Invasion Research Articles

Blastic plasmacytoid dendritic cell neoplasm: Two case reports

BACKGROUND Blastic plasmacytoid dendritic cell tumor (BPDCN) is a rare and highly invasive lymphohematopoietic tumor that originates from plasmacytoid dendritic cells. BPDCN has an extremely poor prognosis. Skin lesions are usually the first manifestation of BPDCN, although the tumor may also invade the bone marrow, lymph nodes, peripheral blood, and other parts of the body, leading to several other manifestations, requiring further differentiation through skin biopsy and immunohistochemistry. CASE SUMMARY In the present paper, the cases of 2 patients diagnosed with BPDCN are discussed. The immunohistochemistry analysis of these 2 patients revealed positivity for CD4, CD56, and CD123. Currently, no standard chemotherapy regimen is available for BPDCN. Therefore, intensive therapy for acute lymphoblastic leukemia was applied as the treatment method for these 2 cases. CONCLUSION Although allogeneic bone marrow transplantation could be further effective in prolonging the median survival the ultimate prognosis was unfavorable. Future treatment modalities tailored for elderly patients will help prolong survival.

Protein Tyrosine Kinase 7 (PTK7) in Breast Cancer: A Retrospective Analysis of Tumour Expression and Association with Clinical Outcome

Protein tyrosine kinase 7 (PTK7), originally known as colon carcinoma kinase (CCK4), is an evolutionary conserved, catalytically defective transmembrane receptor involved in Wnt signalling. PTK7 has been identified as a potential therapeutic target, and a PTK7 antibody drug conjugate (PF-06647020; cofetuzumab pelidotin) has been investigated in phase I clinical trials for triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer. PTK7 protein expression was evaluated in 1136 early-stage invasive breast tumours by immunohistochemistry. In addition, PTK7 mRNA expression in the METABRIC (n = 1980) and the TCGA breast cancer cohorts (n = 1082) was evaluated. Associations between PTK7 expression and clinicopathological criteria and patient outcome were determined. No association between PTK7 protein expression and breast cancer-specific survival was observed; however, PTK7 mRNA expression in the METABRIC cohort was associated with breast cancer-specific survival (p < 0.001). PTK7 protein and mRNA expression were associated with breast cancer-specific survival of patients with a poor prognostic Nottingham Prognostic Index (NPI) and a moderate prognostic NPI, respectively. Taken together, these data indicate that PTK7 expression is associated with patient outcome in subgroups of breast cancer patients.

Possibilities and limitations of magnetic resonance imaging in the diagnostics of endocervical adenocarcinomas

BACKGROUND: In recent decades, the incidence of cervical adenocarcinomas has increased from 5% to 20%. Endocervical adenocarcinomas are characterized by a more aggressive course and early metastasis. Owing to the difficulties in the cytological diagnosis of cervical adenocarcinoma, early radiation diagnostics and staging subsequently play a key role. Very few studies have examined the use of magnetic resonance imaging in diagnosing cervical adenocarcinomas. AIM: To determine the diagnostic informativeness of magnetic resonance imaging in the staging of cervical adenocarcinomas according to the T-criterion and assessing the depth of tumor invasion into the stroma of the cervix and clarify the semiotic signs of adenocarcinoma and features of tumor growth in the uterus. MATERIALS AND METHODS: In total, 123 patients diagnosed with cervical cancer (C53), who underwent diagnosis and treatment between 2020 and 2023, were examined. The examination results of 22 (18%) patients with cervical adenocarcinoma were analyzed. The average patient age was 56 years. A multiparametric magnetic resonance examination of the pelvic organs was performed on 22 patients using tomographs with a magnetic field strength of 1.5 T. Moreover, 14 (64%) patients underwent surgery including extirpation of the uterus and appendages with pelvic lymphadenectomy. The information value of magnetic resonance imaging was evaluated in 11 patients, whose first stage was surgical treatment. RESULTS: In this study, cervical adenocarcinoma was detected in 18% among all cases of cervical cancer. The information value of magnetic resonance imaging in assessing the local prevalence of endocervical adenocarcinoma according to the T-criterion was as follows (main value with the corresponding 95% confidence interval): sensitivity, 77.78% (39.99%–97.19%); specificity, 50.00% (1.26%–98.74%); positive predictive value, 87.50% (62.64%–96.69%); negative predictive value, 33.33% (7.30%–76.04%); and accuracy, 72.73% (39.03%–93.98%). The information value of magnetic resonance imaging in assessing the depth of tumor invasion into the cervical stroma was as follows: odds ratio, 3.500 (0.145%–84.694%); sensitivity, 85.7% (0.757%–0.993%); specificity, 33.3% (0.018%–0.0648%); positive predictive value, 75% (0.673%–0.883%); negative predictive value, 50% (0.027%–0.972%). CONCLUSIONS: The results of this study showed that magnetic resonance imaging is a good tool with high diagnostic informativeness in detecting endocervical cervical adenocarcinoma. The four macrostructures of tumor growth in endocervical adenocarcinoma identified during magnetic resonance imaging data analysis indicate locally aggressive tumor growth and a high frequency of endometrial dropouts. This finding will allow radiologists to structure a descriptive picture, including the verified cervical adenocarcinoma, to enhance methods of developing a treatment plan for the patient.

Coating Dormant Collagenase-Producing Bacteria with Metal-Anesthetic Networks for Precision Tumor Therapy.

Tumor malignancy highly depends on the stiffness of tumor matrix, which mainly consists of collagen. Despite the destruction of tumor matrix is conducive to tumor therapy, it causes the risk of tumor metastasis. Here, metal-anesthetic network-coated dormant collagenase-producing Clostridium is constructed to simultaneously destruct tumor matrix and inhibit tumor metastasis. By metal-phenolic complexation and π-π stacking interactions, a Fe3+-propofol network is formed on bacterial surface. Coated dormant Clostridium can selectively germinate and rapidly proliferate in tumor sites due to the ability of carried Fe3+ ions to promote bacterial multiplication. Intratumoral colonization of Clostridium produces sufficient collagenases to degrade tumor collagen mesh and the loaded propofol restrains tumor metastasis by inhibiting tumor cell migration and invasion. Meanwhile, the delivered Fe3+ ions are reduced to the Fe2+ form by intracellular glutathione, thereby inducing potent Fenton reaction to trigger lipid peroxidation and ultimate ferroptosis of tumor cells. In addition to a satisfactory safety, a single intratumoral injection of coated dormant Clostridium not only effectively retards the growth of established large primary tumors, but also significantly suppresses distal lung metastasis in two different orthotopic tumor models. This work proposes a strategy to develop advanced therapeutics for malignant tumor treatment and metastasis prevention.

In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis

In addition to residual tumor cells, surgery-induced inflammation significantly contributes to tumor recurrence and metastasis by recruiting polymorphonuclear neutrophils (PMNs) and promoting their involvement in tumor cell proliferation, invasion and immune evasion. Efficiently eliminating residual tumor cells while concurrently intervening in PMN function represents a promising approach for enhanced postoperative cancer treatment. Here, a chitosan/polyethylene oxide electrospun fibrous scaffold co-delivering celecoxib (CEL) and doxorubicin-loaded tumor cell-derived microparticles (DOX-MPs) is developed for postoperative in-situ treatment in breast cancer. This implant (CEL/DOX-MPs@CP) ensures prolonged drug retention and sustained release within the surgical tumor cavity. The released DOX-MPs effectively eliminate residual tumor cells, while the released CEL inhibits the function of inflammatory PMNs, suppressing their promotion of residual tumor cell proliferation, migration and invasion, as well as remodeling the tumor immune microenvironment. Importantly, the strategy is closely associated with interference in neutrophil extracellular trap (NET) released from inflammatory PMNs, leading to a substantial reduction in postoperative tumor recurrence and metastasis. Our results demonstrate that CEL/DOX-MPs@CP holds great promise as an implant to enhance the prognosis of breast cancer patients following surgery.

MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients.

Tenosynovial giant cell tumor (TGCT) is a rare, locally invasive soft tissue tumor arising from the synovium of joints, bursa and tendon sheaths and is associated with the overexpression of the colony-stimulating factor 1 (CSF-1) gene. Pimicotinib is an orally available, highly selective and potent small molecule CSF-1 receptor (CSF-1R) inhibitor with robust efficacy and safety profile in patients with TGCT and is under development in multiple diseases. In an open-label Phase I study in patients with TGCT not amenable to surgery, pimicotinib showed superior efficacy and safety. In this article, we elucidate the rationale and study design of the multi-region Phase III MANEUVER trial (NCT05804045), which is designed to assess the efficacy and safety of pimicotinib in patients with TGCT not amenable to surgical resection in Asia, North America and Europe.

Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression.

Cancer remains a significant global health concern. Breast cancer is a multifaceted and prevalent disease influenced by several factors, among which estrogen receptors (ERs) and the extracellular matrix (ECM) play pivotal roles. ERs, encompassing ERα and ERβ, exert significant diversity on tumor behavior, cell signaling, invasion, and metastatic potential, thus guiding breast cancer prognosis. Understanding the multifunctional connections between ERs and ECM that mediate the dynamics of tumor microenvironment is vital for unraveling the complexity of breast cancer pathobiology and identifying novel therapeutic targets. This critical review delves into the intricate nature of ERs, emphasizing their structural isoforms and the consequential impact on breast cancer outcomes. A detailed examination of ER-mediated cell signaling pathways reveals how differential expression of ERα and ERβ isoforms influence breast cancer cell behavior. The functional ERs-matrix interactions emerge as a pivotal factor in modulating epigenetic mechanisms of breast cancer cells, orchestrating changes in cellular phenotype and expression patterns of matrix modulators. Specifically, ERα isoforms are shown to regulate ECM signaling cascades, while the effects of ECM components on ERα activity highlight a bidirectional regulatory axis. The diversity of ERβ isoforms is also highlighted, illustrating their distinct contribution to ECM-mediated cellular responses. This review underscores the complex interplay between ERα/β isoforms and the ECM, shedding light onto the potential therapeutic strategies targeting these interactions to improve breast cancer management.

A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers

Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.

Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives

Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo’s development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process.

Abstract A061: DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly challenging disease with a poor prognosis due to lack of diagnostic biomarkers and high tumor heterogeneity. Therefore, it is crucial to meticulously examine the intricate molecular mechanisms in PDAC. We previously identified DKK3 (Dickkopf-3) as a novel factor promoting organ regeneration during pancreatitis and established a previously unknown link between DKK3 and the Wnt and Hedgehog signaling. Given that pancreatitis is a significant risk factor for pancreatic cancer, we were motivated to investigate the potential role of DKK3 in PDAC development. We utilized PDAC mouse models driven by LSL-KrasG12D/+; Ptf1aCre/+ with wildtype, homozygous/heterozygous DKK3 deletion in both epithelial and stromal compartment while employing in vitro and ex vivo systems to examine the stage and compartment-specific roles of the same. Through a comprehensive and time-resolved analysis of tumor characteristics, we discovered that the loss of DKK3 led to rapid oncogenic transformation, marked by a significant increase in metaplasia and desmoplasia starting at an early stage (10 weeks). Ex vivo acinar-to-ductal metaplasia assay and rescue experiments with wildtype and DKK3-null acinar cells revealed that secreted DKK3 operates as a tumor suppressive roadblock in PDAC-initiating steps. This advanced preneoplastic stage translated into accelerated progression toward invasive tumors at 36 weeks, a shortened overall survival, and a higher liver metastasis incidence in the DKK3-null animals at the endpoint. Interestingly, transcriptomic analyses further validated our observation and revealed the involvement PI3-AKT signaling pathway as an underlying mechanism. Further characterization of isolated tumor cells confirmed our observations, revealing prominent mesenchymal features and enhanced migratory capacities upon loss of DKK3. Interestingly, DKK3-null PDACs exhibited a pronounced stroma remodeling with a myofibroblastic cancer-associated fibroblast-enriched environment, as well as an immunosuppressive stroma with abundant regulatory T cells and cytotoxic T cell depletion, as substantiated by coculture experiments. Intriguingly, while displaying similar phenotypic features to DKK3-null tumors, Dkk3+/- heterozygotes exhibited the most aggressive outcome. To further dissect this finding, we conducted a set of in silico approaches and immunostainings revealing persistent stromal DKK3 expression in DKK3- proficient PDACs. This suggested a possible dual role of DKK3 that could operate either as a friend or a foe depending on its spatiotemporal expression in PDAC. In line, in vitro systems demonstrated a distinct oncogenic effect of DKK3 on endpoint tumor cells, particularly promoting malignant cell migration. In summary, we propose that epithelial DKK3 exerts cell-autonomous tumor suppressive functions during the onset of PDAC, while stromal DKK3 acts as an oncogenic cue driving cancer progression. These findings highlight DKK3 as a promising biomarker and a novel therapeutic target for PDAC tumors. Citation Format: Dharini Srinivasan, Frank Arnold, Elodie Roger, Anna Härle, Michael K Melzer, Chantal Allgöwer, Patrick C Hermann, Lukas Perkhofer, Johann Gout, Alexander Kleger. DKK3 in pancreatic cancer – Elucidating the roles of a double-edged sword [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A061.

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Production Slows Bladder Cancer Progression in an Intravesical Murine Model

Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

The multifaceted therapeutical role of low-density lipoprotein receptor family in high-grade glioma.

The diverse roles of the low-density lipoprotein receptor family (LDLR) have been associated with many processes critical to maintaining central nervous system (CNS) health and contributing to neurological diseases or cancer. In this review, we provide a comprehensive understanding of the LDLR's involvement in common brain tumors, specifically high-grade gliomas, emphasizing the receptors' critical role in the pathophysiology and progression of these tumors due to LDLR's high expression. We delve into LDLR's role in regulating cellular uptake and transport through the brain barrier. Additionally, we highlight LDLR's role in activating several signaling pathways related to tumor proliferation, migration, and invasion, engaging readers with an in-depth understanding of the molecular mechanisms at play. By synthesizing current research findings, this review underscores the significance of LDLR during tumorigenesis and explores its potential as a therapeutic target for high-grade gliomas. The collective insights presented here contribute to a deeper appreciation of LDLR's multifaceted roles and implications for physiological and pathological states, opening new avenues for tumor treatment.

A bioengineered tumor matrix-based scaffold for the evaluation of melatonin efficacy on head and neck squamous cancer stem cells

Head and neck squamous cell carcinoma (HNSCC) presents a significant challenge worldwide due to its aggressiveness and high recurrence rates post-treatment, often linked to cancer stem cells (CSCs). Melatonin shows promise as a potent tumor suppressor; however, the effects of melatonin on CSCs remain unclear, and the development of models that closely resemble tumor heterogeneity could help to better understand the effects of this molecule. This study developed a tumor scaffold based on patient fibroblast-derived decellularized extracellular matrix that mimics the HNSCC microenvironment. Our study investigates the antitumoral effects of melatonin within this context. We validated its strong antiproliferative effect on HNSCC CSCs and the reduction of tumor invasion and migration markers, even in a strongly chemoprotective environment, as it is required to increase the minimum doses necessary to impact tumor viability compared to the non-scaffolded tumorspheres culture. Moreover, melatonin exhibited no cytotoxic effects on healthy cells co-cultured in the tumor hydrogel. This scaffold-based platform allows an in vitro study closer to HNSCC tumor reality, including CSCs, stromal component, and a biomimetic matrix, providing a new valuable research tool in precision oncology.

Viral capsid-mediated efficient cell labeling of micron-sized magnetic particles for highly sensitive long-term in vivo tumor cells MRI tracking

As a contrast agent, micron-sized iron oxide particles (MPIO) offer major advantages for monitoring tumor cells in vivo—applications crucial for studies of tumorigenesis and metastasis. However, labeling tumor cells with MPIO is often dependent on phagocytosis, which limits the labeling efficiency of the cells and thus affects in vivo tumor cell tracking. To address this issue, we prepared a virus-like particle (VLP) consisting of the SV40 VP1 protein modified on the surface of a MPIO (vMPIO). The vMPIO can enter cells via a pathway similar to that of viral infection (caveolae-dependent endocytosis pathway). This approach increased the number of vMPIO in individual labeled cells, which in turn enhances magnetic resonance imaging (MRI) signal intensity and the number of vMPIO in daughter cells. These vMPIO-labeled cells can be detected by MRI in vitro and in vivo even in very small numbers (≤10 cells). Furthermore, vMPIO-labeled cells were successfully applied to long-term tracing of tumor tissue and detection of early metastatic lesions. This VLP-mediated MPIO labeling strategy (vML) not only enables highly sensitive in vivo MRI but also introduces a useful technical tool for investigating tumor invasion and early metastasis.

Prediction of axillary lymph node metastasis using a magnetic resonance imaging radiomics model of invasive breast cancer primary tumor

BackgroundThis study investigated the clinical value of breast magnetic resonance imaging (MRI) radiomics for predicting axillary lymph node metastasis (ALNM) and to compare the discriminative abilities of different combinations of MRI sequences.MethodsThis study included 141 patients diagnosed with invasive breast cancer from two centers (center 1: n = 101, center 2: n = 40). Patients from center 1 were randomly divided into training set and test set 1. Patients from center 2 were assigned to the test set 2. All participants underwent preoperative MRI, and four distinct MRI sequences were obtained. The volume of interest (VOI) of the breast tumor was delineated on the dynamic contrast-enhanced (DCE) postcontrast phase 2 sequence, and the VOIs of other sequences were adjusted when required. Subsequently, radiomics features were extracted from the VOIs using an open-source package. Both single- and multisequence radiomics models were constructed using the logistic regression method in the training set. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and precision of the radiomics model for the test set 1 and test set 2 were calculated. Finally, the diagnostic performance of each model was compared with the diagnostic level of junior and senior radiologists.ResultsThe single-sequence ALNM classifier derived from DCE postcontrast phase 1 had the best performance for both test set 1 (AUC = 0.891) and test set 2 (AUC = 0.619). The best-performing multisequence ALNM classifiers for both test set 1 (AUC = 0.910) and test set 2 (AUC = 0.717) were generated from DCE postcontrast phase 1, T2-weighted imaging, and diffusion-weighted imaging single-sequence ALNM classifiers. Both had a higher diagnostic level than the junior and senior radiologists.ConclusionsThe combination of DCE postcontrast phase 1, T2-weighted imaging, and diffusion-weighted imaging radiomics features had the best performance in predicting ALNM from breast cancer. Our study presents a well-performing and noninvasive tool for ALNM prediction in patients with breast cancer.

Towards imaging the immune state of cancer by PET: Targeting legumain with 11C-labeled P1-Asn peptidomimetics carrying a cyano-warhead

PurposeM2-type tumor-associated macrophages (TAM) residing in the tumor microenvironment (TME) have been linked to tumor invasiveness, metastasis and poor prognosis. M2 TAMs suppress T cell activation, silencing the recognition of the cancer by the immune system. Targeting TAMs in anti-cancer therapy may support the immune system and immune-checkpoint inhibitor therapies to fight the cancer cells. We aimed to develop a PET tracer for the imaging of M2 TAM infiltration of cancer, using activated legumain as the imaging target. Basic proceduresTwo P1-mimicking inhibitors with a cyano-warhead were labeled with carbon-11 and evaluated in vitro and in vivo with a CT26 tumor mouse model. Target expression and activity were quantified from RT-qPCR and in vitro substrate conversion, respectively. The co-localization of legumain and TAMs was assessed by fluorescence microscopy. The two tracers were evaluated by PET with subsequent biodistribution analysis with the dissected tissues. Parent-to-total radioactivity in plasma was determined at several time points after i.v. tracer injection, using reverse phase radio-UPLC. Main findingsLegumain displayed a target density of 40.7 ± 19.1 pmol per mg total protein in tumor lysate (n = 4) with high substrate conversion and colocalization with M2 macrophages in the tumor periphery. [11C]1 and [11C]2 were synthesized with >95 % radiochemical purity and 12.9–382.2 GBq/μmol molar activity at the end of synthesis. We observed heterogeneous tumor accumulation in in vitro autoradiography and PET for both tracers. However, excess unlabeled 1 or 2 did not compete with tracer accumulation. Both [11C]1 and [11C]2 were rapidly metabolized to a polar radiometabolite in vivo. Principal conclusionsThe legumain tracers [11C]1 and [11C]2, synthesized with high radiochemical purity and molar activity, accumulate in the legumain-positive CT26 tumor in vivo. However, the lack of competition by excess compound questions their specificity. Both tracers are rapidly metabolized in vivo, requiring structural modifications towards more stable tracers for further investigations.

Magnetic resonance imaging-based radiomics for predicting infiltration levels of CD68+ tumor-associated macrophages in glioblastomas.

Tumor-associated macrophages (TAMs) are important biomarkers of tumor invasion and prognosis in patients with glioblastoma. We combined the imaging and radiomics features of preoperative MRI to predict CD68+ macrophage infiltration. Clinical, MRI image, and pathology data of 188 patients with glioblastoma were analyzed. Overall, 143 patients were included in the training (n = 101) and validation (n = 42) sets, whereas 45patients were included in an independent test set. The optimal cut-off value (14.8%) was based on the minimum p-value formed by the Kaplan-Meier survival analysis and log-rank tests which divided patients into groups with high CD68+ TAMs(≥ 14.8%) and low CD68+ TAMs (< 14.8%). Regions of interest and radiomics features extraction were based on contrast-enhanced T1-weighted images (CE-T1WI) and T2WI. Multi-parameter stepwise regression was used to create the clinical, radiomics, and combined models, each evaluated using the receiver operating characteristic curve. Decision curve analysis was used to assess the clinical applicability of the nomogram. Aclinical model based on the minimum apparent diffusion coefficient (ADCmin) revealed an area under the curve (AUC) of 0.768, 0.764, and 0.624 for the training set, validation set, and test set, respectively. The 2D radiomics model, based on two features, revealed an AUC of 0.783, 0.724, and 0.789 for the training, validation, and test sets, respectively. The 3D radiomics model, based on three features, revealed AUCs of 0.823, 0.811, and 0.787 for the training, validation, and test sets, respectively. The combined model, with ADCmin and radiomics features, showed the best performance, with AUCs of 0.865, 0.822, and 0.776 for the training, validation, and test sets, respectively. The calibration curve of the combined model nomogram showed good agreement between the estimated and actual probabilities. The combined model constructed using ADCmin, aquantitative imaging parameter, combined with five key radiomics features can be used to evaluate the extent of CD68+ macrophages before surgery.

Peri-Ampullary Tumour; An Unusual Cause of Upper Gastrointestinal Bleeding

Periampullary tumors are cancers that arise in the region of the around the ampulla of Vater, where the bile duct and pancreatic duct converge and empty into the small intestine. This region is very critical for digestive enzyme and bile secretions. This may be associated with slow disease progression, age related changes delayed onset of symptoms and lack of screening and diagnostic facilities. These tumours can be challenging to diagnose and manage due to their proximity to several vital structures. Upper gastrointestinal bleeding may be a rare clinical presentation following tumoral ulceration, erosion into blood vessels or nearby structures or secondary complications like pancreatitis or portal hypertension. Identifying the anatomical origin of these malignancies is usually a herculean task. This will require prompt oesophagogastroduodenoscopy and imaging to determine the source and appropriate management. This is especially true given the region's transitional character, closeness to various structures, and overlapping features among them. We present periampullary tumour an unusual cause of upper gastrointestinal bleeding in a resource limited setting. A52 year old Nigerian male was admitted at the Usmanu Danfodiyo University Teaching Hospital, Sokoto for evaluation following a 3 months history of progressive weight loss, generalized body weakness and a burning and occasionally colicky, persistent, non-radiating epigastric pain, loss of appetite, easy fatiguability, occasional dizziness and recurrent non-projectile post-prandial non-billous vomiting. Though he had no hematemesis, he had history of passage of malaena. The patient was fully conscious on admission, pale, wasted with a markedly tender epigstric region. He was tachycardic with a minimal elevation in blood pressure level of 138/94mmHg. He had an international normalized ratio (INR) of 1.0. Oesophagogastroduodenoscopy was performed which showed a polypoid fungating mass at the1st extending to the 2nd part of the duodenum. A Computerized Tomogram scan of the abdomen showed a diffuse circumferential duodenal wall thickening of 1st and 2nd parts (more in 2nd part) with reduction in luminal calibre of duodenum and mildly dilated pancreatic, common bile, common hepatic ducts. Multiple biopsies were taken for histology which showed moderately differentiated aadenocarcinoma. Surface epithelium composed of columnar epithelial cells which can be seen in the top right of the image below with an invasive tumour, seen infiltrating the lamina propria in the lower left. He went on to have an exploratory laparotomy with triple bypass involving a side to side gastrojejunal anastomosis and cholecystojejunostomy and entero-enterotomy folowing which he went on to receive chemotherapy. As of the time of this write up the patient has recuperated well following his treatment.

Diagnostic challenges in the assessment of thyroid neoplasms using nuclear features and vascular and capsular invasion: a multi-center interobserver agreement study.

The diagnosis of thyroid neoplasms necessitates the identification of distinct histological features. Various education/hospital centers located in cities across Indonesia likely result in discordances among pathologists when diagnosing thyroid neoplasms. This study examined the concordance among Indonesian pathologists in assessing nuclear features and capsular and vascular invasion of thyroid tumors. Fifteen pathologists from different centers independently assessed the same 14 digital slides of thyroid tumor specimens. All the specimens were thyroid neoplasms with known BRAFV600E and RAS mutational status, from a single center. We evaluated the pre- and post-training agreement using the Fleiss kappa. The significance of the training was evaluated using a paired T-test. Baseline agreement on nuclear features was slight to fair based on a 3-point scoring system (k = 0.14 to 0.28) and poor to fair based on an eight-point system (k = -0.02 to 0.24). Agreements on vascular (κ = 0.35) and capsular invasion (κ = 0.27) were fair, whereas the estimated molecular type showed substantial agreement (κ = 0.74). Following the training, agreement using the eight-point system significantly improved (p = 0.001). The level of concordance among Indonesian pathologists in diagnosing thyroid neoplasm was relatively poor. Consensus in pathology assessment requires ongoing collaboration and education to refine diagnostic criteria.

Spatial transcriptomics reveals tumor-derived SPP1 induces fibroblast chemotaxis and activation in the hepatocellular carcinoma microenvironment

BackgroundThe tumor microenvironment (TME) exerts profound effects on tumor progression and therapeutic efficacy. In hepatocellular carcinoma (HCC), the TME is enriched with cancer-associated fibroblasts (CAFs), which secrete a plethora of cytokines, chemokines, and growth factors that facilitate tumor cell proliferation and invasion. However, the intricate architecture of the TME in HCC, as well as the mechanisms driving interactions between tumor cells and CAFs, remains largely enigmatic.MethodsWe analyzed 10 spatial transcriptomics and 12 single-cell transcriptomics samples sourced from public databases, complemented by 20 tumor tissue samples from liver cancer patients obtained in a clinical setting.ResultsOur findings reveal that tumor cells exhibiting high levels of SPP1 are preferentially localized adjacent to hepatic stellate cells (HSCs). The SPP1 secreted by these tumor cells interacts with the CD44 receptor on HSCs, thereby activating the PI3K/AKT signaling pathway, which promotes the differentiation of HSCs into CAFs. Notably, blockade of the CD44 receptor effectively abrogates this interaction. Furthermore, in vivo studies demonstrate that silencing SPP1 expression in tumor cells significantly impairs HSC differentiation into CAFs, leading to a reduction in tumor volume and collagen deposition within the tumor stroma.ConclusionsThis study delineates the SPP1-CD44 signaling axis as a pivotal mechanism underpinning the interaction between tumor cells and CAFs. Targeting this pathway holds potential to mitigate liver fibrosis and offers novel therapeutic perspectives for liver cancer management.