Aggressive Features Research Articles

Enhanced Antiglioma Effect by a Vitamin D3-Inserted Lipid Hybrid Neutrophil Membrane Biomimetic Multimodal Nanoplatform.

Glioblastoma, the most prevalent malignant brain tumor, is a lethal threat to human health, with aggressive and infiltrative growth characteristics that compromise the clinical treatment. Herein, we developed a vitamin D3-inserted lipid hybrid neutrophil membrane biomimetic multimodal nanoplatform (designated as NED@MnO2-DOX) through doxorubicin (DOX)-loaded manganese dioxide nanoparticles (MnO2) which were coated with a vitamin D3-inserted lipid hybrid neutrophil membrane. It was demonstrated that in addition to chemotherapy and chemo-dynamic therapy efficacy, NED@MnO2-DOX exhibited great power to activate and amplify immune responses related to the cGAS STING pathway, bolstering the secretion of type I interferon-β and proinflammatory cytokines, promoting the maturation of DC cells and infiltration of CD8+T cells into the glioma tissue, thereby reversing the immunosuppressive microenvironment of glioma from a "cold" tumor to a "hot" tumor. The biomimetic multimodal nanoplatform has potential as a multimodal strategy for glioma-targeted treatment, especially holding considerable promise for the development of innate immune therapy for glioma.

Desmoid Fibromatosis Post-Cervical Spine Surgical Intervention

Abstract Desmoid tumors are rare benign tumors that show locally aggressive and invasive features leading to potential complications. They can be quite challenging for the treating surgeon if they occur adjacent to neurovascular structures. The etiology of these tumors is still unclear, but the incidence is higher in females and in patients with a history of trauma or surgical procedures raising the possibility of genetic and hormonal factors as well as post-traumatic or postoperative inflammatory changes promoting the formation of desmoid fibromatosis. We report a case of a 34-year-old Asian female who presented to our hospital with a history of difficulty in swallowing due to an enlarging lump on the left side of her neck. Patient had a past medical history of previous cervical spinal disc surgery due to a herniated disc. Diagnostic imaging showed a large soft tissue mass centered between the left common carotid artery and the cervical vertebrae displacing the trachea and esophagus to the right side. Biopsy was obtained and histopathological examination was suggestive of a desmoid tumor. Patient underwent surgical resection of the tumor but returned later with recurrence and had to undergo the surgery again to achieve full cure.

Machine learning-based selection of immune cell markers in osteosarcoma: prognostic determination and validation of CLK1 in disease progression

IntroductionOsteosarcoma (OS) is a malignancy of the bone that mainly afflicts younger individuals. Despite existing treatment approaches, patients with metastatic or recurrent disease generally face poor prognoses. A greater understanding of the tumor microenvironment (TME) is critical for enhancing outcomes in OS patients.MethodsThe clinical and RNA expression data of OS patients were extracted from the TARGET database. The single-cell RNA sequencing (scRNA-seq) data of 11 OS samples was retrieved from the GEO database, and analyzed using the Seurat package of R software. Copy number variation (CNV) was analyzed using the InferCNV software. The potential interactions between the different cells in the TME was analyzed with the CellChat package. A multi-algorithm-based computing framework was used to calculate the tumor-infiltrating immune cell (TIIC) scores. A prognostic model was constructed using 20 machine learning algorithms. Maftools R package was used to characterize the genomic variation landscapes in the patient groups stratified by TIIC score. The human OS cell lines MG63 and U2OS were used for the functional assays. Cell proliferation and migration were analyzed by the EdU assay and Transwell assay respectively. CLK1 protein expression was measured by immunoblotting.ResultsWe observed higher CNV in the OS cells compared to endothelial cells. In addition, there was distinct transcriptional heterogeneity across the OS cells, and cluster 1 was identified as the terminal differentiation state. S100A1, TMSB4X, and SLPI were the three most significantly altered genes along with the pseudo-time trajectory. Cell communication analysis revealed an intricate network between S100A1+ tumor cells and other TME cells. Cluster 1 exhibited significantly higher aggressiveness features, which correlated with worse clinical outcomes. A prognostic model was developed based on TIIC-related genes that were screened using machine learning algorithms, and validated in multiple datasets. Higher TIIC signature score was associated with lower cytotoxic immune cell infiltration and generally inferior immune response and survival rate. Moreover, TIIC signature score was further validated in the datasets of other cancers. CLK1 was identified as a potential oncogene that promotes the proliferation and migration OS cells.ConclusionA TIIC-based gene signature was developed that effectively predicted the prognosis of OS patients, and was significantly associated with immune infiltration and immune response. Moreover, CLK1 was identified as an oncogene and potential therapeutic target for OS.

SIX1 expression and its clinicopathological significance: difference between classic and follicular variant papillary thyroid carcinoma

BackgroundPapillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, representing the majority of thyroid cancer cases. Most patients with PTC have an excellent prognosis following treatment, yet approximately 10% face mortality within ten years, primarily due to lymph node metastasis (LNM) or local recurrence. The SIX1 gene, a member of the SIX gene superfamily, encodes a transcription factor integral to the development of certain tissues during embryogenesis. The impact of SIX1 in different subtypes of PTC has not been studied previously.ObjectiveThe purpose of this study was to investigate the expression of SIX1 protein in PTC and to explore its relationship with clinical behavior in two subtypes of PTC: classic PTC (C-PTC) and follicular variant PTC (FV-PTC).Materials and methodsUsing immunohistochemistry, the study analyzed 125 primary PTC cases, including 85 cases of C-PTC and 40 cases of FV-PTC.ResultsThe study found significant positive associations between high SIX1 expression and several adverse clinical features across the PTC samples. High SIX1 expression was linked with increased tumor size, multifocal tumors, LNM, high-grade tumor features, advanced tumor stage, lymphovascular invasion, perineural invasion, and extrathyroidal extension (ETE). Within the classic PTC subgroup, high SIX1 expression showed significant positive correlations with Tumor size (P = 0.04), Multifocality (P = 0.02) and High-grade features (P = 0.03). In the follicular variant subgroup, high SIX1 expression was significantly associated with Lymph node metastasis (LNM) (P = 0.001), Lymphovascular invasion (P = 0.03), ETE (P = 0.003) and tumor stage (P = 0.007).ConclusionsThe findings of this study indicate that SIX1 expression is a marker of poor prognosis in PTC, suggesting that its high expression is linked with more aggressive tumor characteristics and advanced disease stages. Importantly, the impact of SIX1 expression varies between C-PTC and FV-PTC, predicting distinct prognostic factors in each subtype. This suggests that SIX1 could be utilized not only as a prognostic biomarker but also in developing subtype-specific therapeutic strategies for PTC patients.

BUD23 promote the cell proliferation ability by affecting the PPAR signaling pathways: evidence from the online dataset and cell experiment

IntroductionProstate cancer is a major public health challenge for men worldwide, being the second most common cancer diagnosis and the fifth leading cause of cancer-related deaths among men. The etiology of prostate cancer is multifactorial, with age, genetic predispositions, and lifestyle factors playing critical roles. The role of the peroxisome proliferator-activated receptors (PPARs) in prostate cancer remains complex and not fully elucidated.MethodsTranscriptomic data from The Cancer Genome Atlas (TCGA) were utilized for this study. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). A prognosis-prediction model was constructed using Cox regression and LASSO analysis. Functional experiments, including Western blotting, quantitative PCR (qPCR), Cell Counting Kit-8 (CCK-8) assays, and EdU incorporation assays, were performed to validate the role of BUD23 in prostate cancer.ResultsSignificant differences were observed in the immune microenvironment and HLA gene expression profiles between high and low PPAR expression groups in prostate cancer. The high PPAR group exhibited a less active immune microenvironment with higher fractions of immunosuppressive T regulatory cells (Tregs). A robust prognostic model identified key genes, including BUD23, associated with patient survival. Elevated BUD23 expression was correlated with more aggressive clinical features such as advanced pathological stages, nodal metastasis, and higher Gleason scores. Knockdown of BUD23 in PC-3 and LNCaP prostate cancer cell lines significantly inhibited cell proliferation. Western blotting and qPCR confirmed effective BUD23 knockdown, and CCK-8 and EdU assays demonstrated reduced cell proliferation. BUD23 knockdown resulted in significant reductions in PPAR-α, PPAR-β, and PPAR-γ protein levels, suggesting a regulatory axis between BUD23 and PPARs in prostate cancer.ConclusionThe study highlights the distinct roles of PPARα, PPARβ/δ, and PPARγ in prostate cancer progression and their potential as therapeutic targets. Elevated BUD23 expression is associated with aggressive prostate cancer features and patient survival, making it a potential prognostic biomarker. The knockdown of BUD23 not only inhibited cell proliferation but also reduced the expression of PPAR-related proteins, indicating a potential regulatory axis between BUD23 and PPARs. These findings suggest that targeting BUD23 could modulate PPAR signaling and inhibit tumor growth in prostate cancer.

Clinical and prognostic effects of microvascular density and FOXP3 positive T cells in breast cancer

There are conflicting data regarding the prognostic effect of microvascular density (MVD) in breast cancer and its molecular subtypes. It is thought that high levels of FOXP3 + T cells in breast cancer are associated with poor prognosis. However, data regarding FOXP3 show significant variability in the literature. In our study, we aim to measure MVD and FOXP3 + T cells in breast cancer cases and investigate their relationship with each other and their effects on breast cancer patients’ clinical and prognostic features. In our study, the results of 207 female breast cancer patients whose excisional tumoral tissue was obtained are presented. The study evaluated the findings under a light microscope using antibodies against CD34 for measuring MVD and FOXP3 for measuring FOXP3-positive T cells. CD34 ≥ 17 was categorized as high MVD, and CD34 < 17 was classified as low MVD. FOXP3 + cell count ≥ 20/mm2 was categorized as high FOXP3 positivity and < 20/mm2 as low FOXP3 positivity. The SPSS program (version 22) was used to evaluate the results statistically, and p < 0.05 was considered significant. The median age was 54.0 (27–86) years, and the median follow-up period was 60.0 (IQR: 42.6–86.5) months. In the high MVD group, a higher progesterone receptor (PR) positivity rate was detected (p = 0.035). High FOXP3 positivity was significantly associated with high nuclear grade (p = 0.003). High FOXP3 positivity was significantly associated with PR negativity and high Ki67 values ​​(p = 0.009, p = 0.012, respectively). No statistically significant correlation was found between MVD elevation and FOXP3 positivity (r = 0.063, p = 0.36). A weakly significant positive correlation was detected between high Ki67 and FOXP3 positivity (r = 0.0146, p = 0.04). A weak inverse correlation was detected between high FOXP3 positivity and PR percentage values ​​(r=-0.182, p = 0.01). While there was no significant difference in disease-free survival in cases with high MVD and high FOXP3 + T cells compared to groups with low levels, the results were not mature enough because the median values ​​in overall survival could not be reached. A significant correlation was found between high FOXP3 positivity and some aggressive tumor features; no effect on survival was detected. In contrast to literature data on luminal A breast cancer, high MVD in the luminal B (HER2-) subgroup was associated with a lower risk of recurrence. Our study is the first in the literature to evaluate the relationship between MVD measured using CD34 and FOXP3 positive T cells in breast cancer. Our study found no correlation between MVD and FOXP3 positivity, while literature data show significant correlations in some other cancers.

Evaluation of Breast Cancer Gene Type 1 (BRCA1) Protein Levels in Cancer Tissue Using Surface-Enhanced Raman Spectroscopy.

Raman spectroscopy is a chemical process that utilizes the interaction between light and matter to get significant insights into the structure or characteristics of matter. Raman spectroscopy techniques, such as quantitative evaluation, early diagnostic capabilities, and elucidation of the spectral properties of tissues, are excellent candidates for use in research. In cancer, changes in genes and proteins expressed by related genes are associated with a poor prognosis and aggressive tumor characteristics. Due to modifications and regulatory steps in protein translation, the results of the messenger RNA (mRNA) expression of genes may not correctly reflect the results of protein expression. For this reason, the mRNA and protein expressions of genes are studied in parallel in molecular studies on cancer. In our study, the breast cancer gene type 1 (BRCA1) gene, which is frequently studied in breast cancer and is relatively more difficult to measure by traditional methods due to its high molecular weight, was selected, and protein quantification was performed in tissue samples by Raman spectroscopy. With Raman spectroscopy, it is possible to obtain rapid and precise quantitative results even with a small amount of sample, so it is quite advantageous compared to traditional methods. In our study, we performed surface-enhanced Raman spectroscopy (SERS) to analyze the quantitative protein amount. SERS is a highly sensitive method for detecting compounds at low concentrations. For this purpose, magnetic nanoparticles modified with protein antibodies were used, and the target protein was withdrawn from the complex environment and transferred to an appropriate buffer environment. The calibration curve for BRCA1, which plots Raman intensity against concentration, was derived by calculating the average response reading from duplicate assays conducted under identical conditions. The BRCA1 protein levels of cells were determined from the regression curve of the BRCA1 protein. The relation between the concentration of BRCA1 protein and SERS spectrum intensity was determined to be logarithmic in the range of 300 µg·mL-1 to 292 ng·mL-1 (R2 = 0.9928, limit of detection = 10.41 µg·mL-1, and limit of quantitation = 31.24 µg·mL-1).

The Spectrum of B-cell and Plasma Cell Proliferations in Nodal T Follicular Helper Cell Lymphomas.

B-cell and plasma cell proliferations are frequently observed in nodal T follicular helper (nTfh) cell lymphomas and can present a diagnostic challenge. These proliferations can be monotypic or monoclonal and morphologically resemble lymphoma or plasmacytoma, but their clinical behavior is poorly defined. In this study, we reviewed 414 cases of nTfh lymphoma seen over the past decade at our institution. We identified 78 (19%) cases that exhibited B-cell or plasma cell proliferation detected by morphology, flow cytometry, immunohistochemistry, and/or molecular techniques. The B-cell/plasma cell proliferations occurred before (22%), concurrently with (50%), or after (28%) the diagnosis of nTfh lymphoma. We divided them into 3 categories: (1) focal or scattered B-immunoblastic proliferations recognized morphologically without a monotypic/monoclonal B-cell population (17%), (2) monotypic/monoclonal B-cell/plasma cells identified solely by flow cytometry or molecular clonality studies without morphologic confirmation (11%), and (3) unequivocal B-cell/plasma cell expansions recognized by morphologic assessment (72%). We further subdivided group 3 into proliferations associated with and possibly dependent on neoplastic Tfh cells versus those proliferations occurring in the absence of neoplastic Tfh cells and likely bona fide lymphomas. Follow-up biopsy specimens showed persistence of B-cell/plasma cell proliferations in various patient subcategories, with transformation to higher-grade B-cell proliferation or persistence without Tfh cells in some cases. In conclusion, our data support the notion that most B-cell and plasma cell proliferations associated with neoplastic Tfh clones have little impact on the clinical course of patients with nTfh lymphoma and likely do not constitute an independent B-cell lymphoma, especially those of small B cells of plasma cells. However, B-cell expansions exhibiting aggressive morphologic features may represent an independent B-cell lymphoma.

Immunohistochemical Expression of Cyclin D1 and p16 in Invasive Breast Carcinoma and Its Association with Clinicopathological Parameters.

Invasive breast cancer (IBC) is a significant health concern globally, contributing to substantial morbidity and mortality among women. Dysregulated cellular proliferation, a hallmark of malignancy, involves molecular pathways modulated by proteins such as cyclin D1 and p16. Understanding their roles in IBC pathogenesis and their association with prognostic parameters is crucial for refining treatment strategies. This retrospective study included 50 female IBC patients who underwent modified radical mastectomy. Histopathological evaluation and immunohistochemical staining for cyclin D1 and p16 were conducted. Associations between protein expression and clinicopathological parameters were analyzed using statistical tests. Cyclin D1 was expressed in 76% of cases, significantly associated with lower tumor grade and lower Ki-67 proliferation index. It also correlated with luminal A/B molecular subtypes. p16 expression was observed in 48% of cases, significantly associated with higher tumor grade, higher Ki-67 index, and triple-negative/Her-2 neu-enriched subtypes. Co-expression of cyclin D1 and p16 was noted in 60% of cases. No significant association was found between protein expression and other parameters. Cyclin D1 and p16 exhibit potential as prognostic markers in IBC. Cyclin D1 expression correlates with less aggressive tumor features and luminal subtypes, suggesting a favorable prognosis and potential predictive value for CDK4/6 inhibitor therapy. Conversely, p16 expression associated with aggressive phenotypes, indicating poor prognosis. Further studies are warranted to validate these findings and explore their clinical implications. Integrating these biomarkers into clinical practice may enhance risk stratification and treatment decisions, ultimately improving outcomes for IBC patients.

CK2B is a Prognostic Biomarker and a Potential Drug Target for Hepatocellular Carcinoma.

Although casein kinase II subunit beta (CK2B) was previously reported to be involved in human cancers, such as hepatocellular carcinoma (HCC), there has been no systematic assessment of CK2B in HCC. To assess the potential function of CK2B as a prognostic biomarker and possible druggable target in HCC. The Cancer Genome Atlas database was accessed to investigate the potential oncogenic and prognostic roles of CK2B in HCC. Diverse analytical methods were used to obtain a fuller understanding of CK2B, including CIBERSORT, The Tumor Immune Estimation Resource (TIMER), gene set enrichment analyses (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene ontology (GO). Furthermore, the Comparative Toxicogenomic Database (CTD) was used to identify potential drugs to treat CK2B-overexpressing HCC. Patents for these drugs were reviewed using Patentscope® and Worldwide Espacenet®. Upregulated CK2B expression was markedly associated with more aggressive pathological features, including G3, G4 (vs. G1, G2), and T2, T3 (vs. T1). Kaplan-Meier survival curves indicated that patients with HCC with higher expression of CK2B had worse overall survival (P = 0.005), progression-free interval (P = 0.001), and disease-specific survival (P = 0.011). GO and KEGG analysis revealed that CK2B dysregulation affects mitotic chromosome condensation, protein stabilization and binding, regulation of signal transduction of p53 class mediator, and cancer-related pathways. GSEA identified six well-known pathways, including MAPK, WNT, Hedgehog, and TGFβ signaling pathways. Finally, CTD identified six compounds that might represent targeted drugs to treat HCC with CK2B overexpression. A review of patents indicated these compounds showed promising anticancer results; however, whether CK2B interacts with these drugs and improves drug outcomes for patients with HCC was not confirmed. CK2B is a biomarker for HCC prognosis and could be a potential new drug target. Moreover, the association between infiltrating immune cells and CK2B in the HCC tumor microenvironment might provide a solid basis for further investigation and a potent strategy for immunotherapy of HCC.

Histopathologic And Clinical Features of Bethesda III-VI Nodules Harboring Isolated RAS Mutations.

Though thyroid tumors possessing isolated RAS mutations are generally considered to be indolent, the oncologic outcomes of tumors evaluated with comprehensive molecular testing have not been well characterized. We performed a retrospective cohort study of 368 consecutive patients with Bethesda III - VI thyroid nodules at a single institution (2016 to 2021) who underwent molecular testing with Thyroseq v3. Patients with isolated RAS mutations were identified, and those with isolated BRAF V600E-mutated cancers were used as comparators. Outcomes of interest included rate of malignancy, high-risk histopathologic features, and structural disease recurrence. A total of 50 (14%) patients had an isolated RAS-mutated nodule, of which 41 underwent surgery (median age 43 years, 83% female). The malignancy rate on final pathology was 46%, while 32% of patients had NIFTP and 22% of patients had benign histopathology. In comparison, the isolated BRAF-mutated cohort (86 [24%] patients, median age 45 years, 68% female) had a 100% rate of malignancy. Only 2 (11%) of the isolated RAS patients with malignant histopathology had lymph node metastasis, compared to 34 (39%) of the BRAF cohort (p=0.016). Over a median follow up of 5 years, no patients with isolated RAS mutations had a structural recurrence compared to 5 (6%) patients in the isolated BRAF cohort. Bethesda III-VI thyroid nodules with isolated RAS mutations have a low rate of aggressive histopathologic features and are unlikely to recur. Thyroid lobectomy may be sufficient treatment for these tumors.

Tissue Expression and Plasma Soluble PD-L1 Levels in Patients With Endometrial Cancer.

The prognostic role of tissue PD-L1 expression in endometrial cancer (EC) remains controversial. Moreover, its value in guiding anti-PD1/PD-L1 immunotherapy is questionable. The eventual role of soluble PD-L1 (sPD-L1), released by cancer tissue and circulating immune cells, is largely unexplored. In this pilot study, we investigated the expression of PD-L1 in cancer cells and tumor stroma infiltrating inflammatory cells (TIICs), in parallel with sPD-L1 levels in the plasma of 19 patients with early-stage endometrioid EC, before and after hysterectomy. Cancer cell membrane staining was noted in 5/19 (26.3%) cases (range=1-5%; median 1% of the cancer cell population). IICs showed positive reactivity in 14/19 (73.7%) cases. sPD-L1 plasma levels ranged from 53-408 pg/ml and 113-557 pg/ml, respectively, in the plasma of patients before and after hysterectomy (p=0.01). High PD-L1 expression by IIC was marginally associated with a high histology grade (p=0.08). High sPD-L1 levels before surgery were significantly associated with ICC PD-L1 expression (p=0.0007), high histology grade (p=0.04), and marginally with T2-stage (p=0.08). sPD-L1 is easily detectable in the plasma of EC patients and may be associated with aggressive clinical features and PD-L1-expressing immune cells infiltrating the tumor stroma. sPD-L1 plasma levels in EC patients undergoing immunotherapy can be further tested as a biomarker for therapeutic stratification.

Circular RNA 14580 promotes papillary thyroid cancer progression by interacting with CTSW/fibrosis singling pathway.

Papillary thyroid cancer (PTC) is an increasingly prevalent endocrine malignancy, with a subset exhibiting aggressive features such as lymphatic metastasis and resistance to iodine therapy. Recent studies suggest that circular RNAs (circRNAs) play a significant role in PTC pathology. High throughput circRNA sequencing identified circRNA_14580 as notably upregulated in PTC tissues. This circRNA is implicated in crucial tumorigenic processes, including apoptosis, proliferation, and migration of PTC cells. Mechanistic investigations reveal that circ_14580 interacts with cathepsin W (CTSW), a key player in PTC-associated fibrosis. Notably, silencing circ_14580 diminishes the activation and collagen production of cancer-associated fibroblasts (CAFs), highlighting its role in modulating the tumor microenvironment. These findings underscore circ_14580 as a critical oncogene in PTC and suggest that targeting the circ_14580/CTSW/fibrosis axis could offer novel therapeutic strategies for controlling PTC progression.

Post-traumatic intraosseous sheath development of the extensor carpi radials brevis tendon: a case report

BackgroundComplications from closed treatment in children are rare but can include growth disturbances and deformities. This case report presents a unique, post-traumatic growth deformity in the distal radius, where the extensor carpi radialis brevis tendon developed an interosseous course.Case presentationA 49-year-old Caucasian male presented with chronic, dull pain in the radiodorsal aspect of the right wrist, worsened by weightbearing and terminal flexion and extension. The patient had a history of a distal radius fracture from a motor vehicle accident in adolescence, which was treated nonsurgically. Current X-rays showed a lucent process along the distal lateral radius without aggressive features. Magnetic resonance imaging revealed the extensor carpi radialis brevis tendon in an interosseous position within the distal dorsal lateral radius, with a longitudinal tear of the tendon. A noncontrast computed tomography scan confirmed a complete bone bridge along the tendon’s interosseous component, limiting potential surgical access. The patient, found to have a positive Antinuclear Antibody (ANA), was treated with prednisone and later with methotrexate and folic acid, which alleviated symptoms.ConclusionsThis case highlights a rare post-traumatic deformity following a distal radius fracture, where the extensor carpi radialis brevis tendon formed an intraosseous sheath. It underscores the importance of considering unique anatomical changes when planning surgical interventions. This is the first reported case of an interosseous tendon sheath development around a tendon postdistal radius fracture, expanding the spectrum of known complications.

Prognostic factors associated with worse outcomes following chemoradiation therapy in patients with anal carcinoma.

Chemoradiation therapy (CRT) is considered as the first line of treatment for patients with squamous cell carcinoma of the anal canal. Following initial CRT, patients who present with either persistent or locally recurrent disease are treated by surgical intervention. The aim of our study is to determine the prognostic factors associated with failure of CRT and overall mortality in patients with anal squamous cell carcinoma (SCC). We performed a 14-year analysis (2004-2017) of the National Cancer Database and included patients diagnosed with non-metastatic SCC of the anal canal who underwent CRT. Baseline patient characteristics including demographics, comorbidities and tumour characteristics were analysed. Outcome measures were needed for operative intervention after 4 months of initiation of CRT (failure of CRT) and 5-year overall mortality. Multivariate logistic regression analysis identified prognostic factors independently associated with failure of CRT. We included a total of 37 615 patients with anal SCC who received CRT. Predictors of operative intervention included male sex, higher Deyo-Charlson Comorbidity Index (DCCI) and higher primary tumour stage. The 5-year overall survival rate was 77.6%, and 2.4% of patients failed CRT, defined as requiring and undergoing surgical intervention within 4 months post-initiation of CRT. Median follow-up time was 47 (95% CI 24-84) months. Independent predictors of overall mortality within the first 5 years of diagnosis were increased age, male sex, Black race, non-insured status, higher DCCI, higher primary tumour grade, and higher primary tumour and lymph node stage. The 5-year survival rate was significantly lower in patients who underwent operative intervention compared to those who received CRT alone (57.4% vs. 78.1%; P < 0.01). Our study showed that male sex, younger age, DCCI of 1 and 3, and increased tumour size were predictive of CRT failure among patients with anal SCC. Increased age, male sex, Black race, non-insured status, increased DCCI, and more aggressive tumour characteristics were associated with increased 5-year overall mortality. More importantly, patients who failed CRT had worse 5-year overall survival. Our findings support increased emphasis on intensive surveillance for these high-risk patient cohorts.

Clonal hematopoiesis impacts frailty in newly diagnosed multiple myeloma patients: a retrospective multicenter analysis

Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5–1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated. In this study, high-depth targeted sequencing of peripheral blood from 76 NDMM patients revealed CHIP in 46% of them, with a variant allele frequency (VAF) ranging from ~ 1 to 34%. The most frequently mutated gene was DNMT3A, followed by TET2. More aggressive disease features were observed among CHIP carriers, who also exhibited higher proportion of high-risk stages (ISS and R-ISS 3) compared to controls. Longitudinal analyses at diagnosis and during follow-up showed a slight increase of VAFs (p = 0.058) for epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (TP53; p = 0.0123). A more stable frequency was observed among other genes, suggesting different temporal dynamics of CH clones. Adverse clinical outcomes, in term of overall and progression-free survivals, were observed in CHIP carriers. These patients also exhibited weakened immune T-cells and enhanced frailty, predicting greater toxicity and consequently shorter event-free survival. Finally, correlation analysis identified platelets count as biomarker for higher VAF among CHIP carriers, regardless of the specific variant. Overall, our study highlights specific biological and clinical features, paving the way for the development of tailored strategies for MM patients carrying CHIP.

Prognostic Significance of DSCC1, a Biomarker Associated with Aggressive Features of Breast Cancer

Background and Objectives: Invasive breast cancer (BC) was traditionally investigated visually, and no technique could identify the key molecular drivers of patient survival. However, essential molecular drivers of invasive BC have now been discovered using innovative genomic, transcriptomic, and proteomic methodologies. Nevertheless, few evaluations of the prognostic factors of BC in Saudi Arabia have been performed. Evaluating the biomarkers associated with the development of early-stage BC could help determine the risk of metastasis and guide treatment decisions. In a previous study, using large BC cohorts and artificial neural network techniques, DNA replication and sister chromatid cohesion 1 (DSCC1) was found to be one of the principal genes in invasive BC samples. To date, no studies have addressed the prognostic significance of DSCC1 in invasive BC and its association with aggressive tumor behavior. This research aimed to address this gap. Materials and Methods: The association of clinicopathological features and patient outcomes with DSCC1 expression at the mRNA level was assessed using the Molecular Taxonomy Breast Cancer International Consortium (METABRIC; n = 1980) and The Cancer Genome Atlas (TCGA; n = 854) cohorts. DSCC1 was also evaluated at the protein level using immunohistochemistry on samples from invasive BC patients (n = 100) presenting to King Abdul Aziz Specialist Hospital in Saudi Arabia. The association of clinicopathological parameters (including patient age, tumor grade, tumor size, and patient outcome) with protein level was also evaluated. Results: In both METABRIC and TCGA cohorts, high expression of DSCC1 was significantly associated with high histological grade, large tumor size, lymphovascular invasion positivity, and hormone receptor negativity (all p &lt; 0.001). A high DSCC1 mRNA level was associated with poor outcomes (p &lt; 0.001 for METABRIC, p = 0.23 for TCGA). At the protein level, high DSCC1 expression was associated with high histological grade (p = 0.001), lymph node presence (p = 0.008), hormone receptor negativity (p = 0.005), high Ki67 expression (p = 0.036), and shorter survival (p = 0.008). Conclusions: This study confirmed the prognostic significance of DSCC1 in invasive BC patients. DSCC1 could be a therapeutic target in BC cases with poor outcomes.

Spontaneous globe rupture from an intraocular melanotic schwannoma.

Melanotic schwannoma (MS) is a rare neoplasm composed of Schwann cells with melanosomes in various maturation stages. While MS is typically observed in spinal nerve roots or peripheral nerves, their involvement in intraocular structures is uncommon. Here, we present a case of spontaneous globe rupture as the presenting feature of intraocular extension of a MS. Enucleation was performed to remove the lesion. Confirmatory light microscopy and immunohistochemistry were used to properly diagnose and differentiate from conventional schwannoma and uveal malignant melanoma. The ocular tumor in our patient showed melanin pigmentation with positive melanocytic markers. The tumor revealed spindle and epithelioid cells proliferating in fascicles, which has previously been described for MS. No choroidal invasion, moderate nuclear pleomorphism, and a low mitotic rate were observed supporting a diagnosis of MS in our patient. With reports of MS with high recurrence and metastatic spread rates, there have been some suggestions that MS should be considered an aggressive malignancy. This case highlights a dramatic presentation of a rare ocular malignancy with some features of aggressiveness. Our case report endorses the importance of close monitoring for local recurrence or metastasis to prevent a poor outcome.

Prognostic significance of CD8 and TCF1 double positive T cell subset in microsatellite unstable gastric cancer

Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R2 = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC.

Unraveling the tumor-initiating cells in hepatocellular carcinoma

Aggressive features of hepatocellular carcinoma (HCC) are highly related to liver tumor-initiating cells (TICs), which are heterogeneous and plastic. In this issue of Cancer Cell, Yang etal. reveal the ability of CD49f-high TICs in shaping the tumor immunosuppressive microenvironment in HCC.