Malignant Tumors Research Articles

Comprehensive analysis of clinical features, mRNA splicing, and immunological role of REEP5 in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy within the digestive system, characterized by high incidence and mortality rates. The biological role of REEP5 in ESCC progression remains poorly understood, despite its associations with various diseases, potentially accelerating tumor malignancy. We retrieved RNA-seq data and clinical information from 179 ESCC patients from the Gene Expression Omnibus (GEO) and 93 patients from The Cancer Genome Atlas (TCGA) databases. Bioinformatics analyses were conducted to explore the biological functions of REEP5 in ESCC, its role in the tumor microenvironment, and its prognostic value. Additionally, utilizing single-cell RNA-seq (scRNA-seq) data from 3 ESCC patients in the GEO database, we performed cluster analyses to investigate cell-specific expression differences of REEP5 between cancerous and adjacent non-cancerous tissues. Molecular biology experiments were also conducted to validate REEP5 expression disparities between tumor and non-tumor tissues. Compared to normal tissues, REEP5 was significantly enriched in ESCC tissues. High REEP5 expression was closely associated with poor prognosis in ESCC patients. Gene Ontology (GO) analysis revealed strong correlations between REEP5 and processes such as mRNA splicing and protein stabilization. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicated positive correlations between REEP5 and mRNA spliceosome assembly and disassembly. Pearson correlation analysis demonstrated positive associations between REEP5 and cancer-inhibitory immune checkpoints CTLA-4, TIM-3, and HVEM. Single-cell clustering and CIBERSORT analysis showed that REEP5 expression was closely related to T-cell infiltration in ESCC, with significant enrichment effects observed in CD8+ T-cell infiltration. REEP5 expression is closely correlated with the pathological and molecular pathology of ESCC, potentially playing a crucial role in Mast cell or T-cell-mediated immune responses in ESCC. Therefore, REEP5 holds promise as a novel therapeutic target for ESCC.

MRI and CT imaging characteristics in parotid tumors with false-negative fine-needle aspirations

BackgroundsPreoperative imaging, particularly with magnetic resonance imaging (MRI) and computed tomography (CT) scans, plays a crucial role in distinguishing between benign and malignant parotid gland tumors, while the reliability of Ultrasound-Guided Fine Needle Aspiration (FNA) in diagnosing these masses remains a topic of debate.MethodsThis two-center retrospective analysis was conducted on 347 patients with parotid gland tumors who had FNA and preoperative imaging (CT or MRI). All patients underwent surgery and final histopathological examination was available, along with complete medical records between January 2008 and May 2023.ResultsAmong the 347 patients, 318 (92%) had benign and 10 (3%) had malignant tumors based on FNA, with 19 (5%) unsatisfactory specimens. Final histological diagnosis revealed 303 (87%) benign and 44 (13%) malignant lesions, with a false-negative rate of 10.6% for FNA. Multivariate analysis identified irregular shape and invasion as independent predictors of malignancy in patient with benign or unsatisfactory FNA results. The odds ratio for irregular shape was 3.06 and for invasion was 12.73.ConclusionImaging characteristics, such as irregular shape and invasion may indicate towards malignant parotid tumors, even in patients with false-negative benign findings in FNA.

A phase II study of ME2136 (Asenapine Maleate) plus standard antiemetic therapy for patients, including diabetic patients, receiving cisplatin-based chemotherapy.

Olanzapine combined with the neurokinin-1 receptor antagonist, palonosetron and dexamethasone is the standard treatment for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). However, the use of olanzapine poses challenges in patients with diabetes mellitus (DM) due to the potential risk of hyperglycemia. ME2136, antipsychotic similar to olanzapine, is associated with a lower risk of hyperglycemia. This study investigated the antiemetic efficacy and safety of ME2136 for HEC. This single-arm phase 2 study examined the safety and efficacy of ME2136 5mg for 4days in combination with triplet-combination antiemetic therapy. Two cohorts were established for the safety assessment: DM and non-DM. Eligible patients had malignant tumors and were receiving cisplatin-based chemotherapy for the first time. The primary endpoint was the complete response (CR) rate, defined as the percentage of patients without vomiting and not requiring rescue medications in the delayed phase (24-120h). Between December 2020 and January 2022, 40 patients were enrolled, with 20 in each cohort. All patients were included in the safety analysis and 35 in the efficacy analysis. The CR rate in the delayed phase was 71.4% [60% CI 63.1-78.6%] for all patients, 66.7% in the DM cohort, and 76.5% in the non-DM cohort. No treatment-related adverse events ≥ grade 3, including hyperglycemia, were reported. ME2136, when combined with standard triplet-combination antiemetic therapy, is expected to exert similar antiemetic effects to the standard treatment for CINV due to HEC. Currently, ME2136-02 trial is underway to examine the safety and efficacy of triplet-combination antiemetic therapy and a 5-day treatment with ME2136. This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020. Clinical trial registration: This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020.

Stromal softness confines pancreatic cancer growth through lysosomal-cathepsin mediated YAP1 degradation

The progression and malignancy of many tumors are associated with increased tissue stiffness. Conversely, the oncogenically transformed cells can be confined in soft stroma. Yet, the underlying mechanisms by which soft matrix confines tumorigenesis and metastasis remain elusive. Here, we show that pancreatic cancer cells are suppressed in the soft extracellular matrix, which is associated with YAP1 degradation through autophagic-lysosomal pathway rather than Hippo signal mediated proteasome pathway. In the soft stroma, PTEN is upregulated and activated, which consequently promotes lysosomal biogenesis, leading to the activation of cysteine-cathepsins for YAP1 degradation. In vitro, purified cathepsin L can directly digest YAP1 under acidic conditions. Lysosomal stress, either caused by chloroquine or overexpression of cystatin A/B, results in YAP1 accumulation and malignant transformation. Likewise, liver fibrosis induced stiffness can promote malignant potential in mice. Clinical data show that down-regulation of lysosomal biogenesis is associated with pancreatic fibrosis and stiffness, YAP1 accumulation, and poor prognosis in PDAC patients. Together, our findings suggest that soft stroma triggers lysosomal flux-mediated YAP1 degradation and induces cancer cell dormancy.Graphical

Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%.

Compact Molecular Conformation of Prodrugs Enhances Photocleaving Performance for Tumor Vascular Growth Inhibition.

Highly spatiotemporal-resolved photomodulation demonstrates promise for investigating key biological events in vivo and in vitro, such as cell signaling pathways, neuromodulation, and tumor treatment without side effects. However, enhancing the performance of photomodulation tools remains challenging due to the limitations of the physicochemical properties of the photoactive molecules. Here, a compact, stable intramolecular π-πstacking conformation forming between the target molecule (naproxen) and the perylene-based photoremovable protecting group is discovered to confine the motion of the photolabile bond and then enhance the photocleavage quantum yield. In conjunction with a red-absorbing photosensitizer, the photocleavage wavelength is extended to the red region via triplet-triplet annihilation. In particular, the triplet lifetime of the prodrug can be extended via the linked steric hindrance to improve the conversion yield via TTA. Using the new photomodulation tool, it is precisely photoreleased cyclooxygenase-2 inhibitors for tumor vascular growth suppression in vivo. In combination with cisplatin, over 90% efficient inhibition of malignant breast tumors is observed via the synergistic tumor treatment strategy. These findings provide a new concept for the rational design of efficient photocleavage and have implications for photomodulating cell signaling pathways in tumor therapy, as well as laying a solid foundation for the development of phototherapeutic approaches.

Radiomics-Based Machine Learning with Natural Gradient Boosting for Continuous Survival Prediction in Glioblastoma

(1) Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with an aggressive disease course that requires accurate prognosis for individualized treatment planning. This study aims to develop and evaluate a radiomics-based machine learning (ML) model to estimate overall survival (OS) for patients with GBM using pre-treatment multi-parametric magnetic resonance imaging (MRI). (2) Methods: The MRI data of 865 patients with GBM were assessed, comprising 499 patients from the UPENN-GBM dataset and 366 patients from the UCSF-PDGM dataset. A total of 14,598 radiomic features were extracted from T1, T1 with contrast, T2, and FLAIR MRI sequences using PyRadiomics. The UPENN-GBM dataset was used for model development (70%) and internal validation (30%), while the UCSF-PDGM dataset served as an external test set. The NGBoost Survival model was developed to generate continuous probability estimates as well as predictions for 6-, 12-, 18-, and 24-month OS. (3) Results: The NGBoost Survival model successfully predicted survival, achieving a C-index of 0.801 on internal validation and 0.725 on external validation. For 6-month OS, the model attained an AUROC of 0.791 (95% CI: 0.742–0.832) and 0.708 (95% CI: 0.654–0.748) for internal and external validation, respectively. (4) Conclusions: The radiomics-based ML model demonstrates potential to improve the prediction of OS for patients with GBM.

DLAT promotes triple-negative breast cancer progression via YAP1 activation

ABSTRACT Background Breast cancer (BC) is the most prevalent malignant tumor in women globally. Triple-negative breast cancer (TNBC) represents the most malignant and invasive subtype of BC. New therapeutic targets are urgently needed for TNBC owing to its receptor expression characteristics, which render it insensitive to traditional targeted and endocrine therapies for BC. The role and mechanisms of dihydrolipoamide S-acetyltransferase (DLAT) as a crucial molecule in glycometabolism and cuproptosis-related biological processes in tumors remain to be explored. Methods DLAT expression was investigated using bioinformatics methods and quantitative real-time polymerase chain reaction. Subsequently, the MTT assay, colony formation assay, and migration-invasion assay were performed to validate the effect of DLAT on TNBC cell viability, proliferation, and migration. Cytoplasmic-nuclear separation experiments, western blot analysis, and co-immunoprecipitation assays were performed to elucidate the underlying molecular mechanisms. Results This study revealed a robust correlation between elevated DLAT expression in BC and unfavorable prognosis in patients, with higher expression of DLAT compared to other subtypes in TNBC. Functional cytology experiments indicated that DLAT plays a tumor-promoting role in TNBC. Mechanistic studies showed that DLAT directly interacts with YAP1, leading to the dephosphorylation and activation of YAP1 and its increased nuclear translocation, thereby transcriptionally activating and regulating downstream oncogenes, promoting the malignant phenotype of TNBC. Rescue experiments indicated that DLAT promotes the malignant behavior of TNBC through a YAP1-dependent pathway. Conclusions Our research unveiled the significant involvement of DLAT in TNBC, along with the potential for modulating DLAT/YAP1 activity as a targeted treatment strategy for TNBC.

Tissue pool of hypersegmented neutrophils in patients with precancerous and tumor diseases of the larynx and laryngopharynx

The presence of neutrophils in a tumor often correlates with an unfavorable prognosis, however, there is still no clear answer about the role of tumor-associated neutrophils and the relationship of their morphofunctional features with the prognosis of the course of the disease. The aim of the study was to evaluate the structural features of tissue neutrophil nuclei in the pathological zone in patients with precancerous changes and malignant neoplasms in the larynx. Eight people with precancerous changes in the larynx, 18 patients with localized cancer of the larynx (stages II and III of the tumor process and the absence of metastases – T2- 3N0M0), and 12 patients with advanced cancer (stage III of tumor diseases and regional metastases – T3N1- 2M0) were examined. Blood slides and smear prints of tissue biopsies from three localizations were examined: 1 – zones of the pathological focus; 2 – boundaries between the pathological focus and conditionally healthy tissue; and 3 – conditionally healthy tissue. In the blood of patients with precancerous changes in the larynx and cancer patients, the main part of neutrophils was represented by cells with a 4-segment nucleus, and the number of hypersegmented forms (5 or more segments) was higher than in the blood of healthy volunteers (p 0.002). The same type of changes in smear prints of biopsies from different areas of the pathological focus in patients with precancerous and malignant neoplasms were revealed: as they approached the pathological focus, an increase the cells with 4-5 or more segments was observed. The content of hypersegmented forms was maximum in the pathological focus. Only in patients with a widespread tumor process, neutrophils with a 4-segment nucleus dominated the immediate environment of the tumor. As the tumor spreads and metastases form, the proportion of hypersegmented cells increases in the population of intra-tumor neutrophils. It is very likely that the morphological features of tissue neutrophils in different zones of the pathological focus reflect their functional heterogeneity, and hypersegmetation of nuclei can be considered as a potential predictor of the development and progression of the tumor process.

The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrateenhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for theirmalignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus,has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits. This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors. This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways. In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Diagnosis and Management of Malignant Epithelial Nail Unit Tumors

Background: Malignant epithelial nail unit tumors pose significant diagnostic and therapeutic challenges due to their clinical presentation often mimicking benign conditions and due to the need to preserve as much nail unit function as possible during surgery. Early detection is crucial, even if none of these tumors represent a life-threatening disease. Objectives: This review focus on squamous cell carcinoma, verrucous carcinoma, eccrine porocarcinoma, onychocytic carcinoma, basal cell carcinoma, malignant onychopapilloma, malignant onycholemmal cyst and onycholemmal carcinoma. Methods: Existing literature on the aforementioned tumors has been revised and synthesized. Results: Clinical presentation, pathology, diagnostic procedures, risk factors and the challenges associated with surgical management have been described in detail. Conclusions: Malignant epithelial tumors of the nail unit require careful evaluation and management due to their complex presentation. Early detection and an informed surgical approach are essential to improve patient outcomes and minimize complications.

Combined microscopic transoral and endoscopic endonasal approach for a clival chordoma: A case report and literature review

Background: Chordomas are primary bone tumors derived from the embryonic notochord. They represent 1–4% of all malignant bone tumors. They have a predominantly extra-axial location, arising in the clival region in 35% of reported cases. The prognosis is generally poor, and radical resection remains the first-line treatment. This study aims to describe a case of a clival chordoma that was resected through a combined microscopic transoral and endoscopic endonasal approach, with excellent clinical outcomes. Case Description: A 24-year-old woman with low cranial nerve symptomatology was admitted for a two-stage surgical approach. An occipital-cervical fixation was performed in the first stage, while a combined endonasaltransoral resection was performed later for tumor resection. Conclusion: Microscopic transoral and endoscopic endonasal approaches offer advantages for treating clival chordomas, with careful consideration of anatomical constraints and potential for postoperative recurrence being essential in approach selection.

Unusual Presentation of Myeloid Sarcoma as Thigh Mass

IntroductionMyeloid sarcoma (MS) is a tumor containing myeloid blasts, with or without maturation, involving any anatomical site other than the bone marrow. It can occur de novo or following a hematological malignancy. CaseWe report a 6-year-old female who presented with fever and a rapidly enlarging left thigh mass. The initial provisional diagnosis considered was tubercular hip arthritis with an abscess, but imaging investigations suggested neoplastic swelling. A biopsy of the mass showed a malignant small-round cell tumor. Bone marrow aspiration revealed the diagnosis of acute myeloid leukemia without the presence of blasts in the peripheral smear. ConclusionMS is a rare malignancy. The diagnosis is often delayed due to a lack of clinical suspicion and the absence of blasts in peripheral blood. This report aims to enhance the awareness of pediatric nurse practitioners that MS should also be considered as a differential for an extremity mass.

Survival of pediatric patients with ependymoma in a tertiary cancer center in Rio de Janeiro, Brazil

IntroductionEpendymoma is the third most frequent central malignant nervous system tumor in the pediatric age group. There is scarce data in the literature on survival of these patients, especially in upper and lower middle-income countries. We aimed to describe the clinical and demographic characteristics, treatment, and outcome of pediatric patients with ependymoma admitted to a public cancer hospital.MethodsRetrospective analysis of medical records of patients with ependymoma, admitted to the Pediatric Oncology department (0-20 years) during the period of 2000-2022. Data on patient, disease characteristics, and treatment were analyzed. Overall survival (OS) was calculated using the Kaplan-Meier method.ResultsSeventy-two patients were evaluated; median age at diagnosis was 6.5 years (range: 1-20), 63% were male, 54% of the tumors were in the posterior fossa (PF-EPN), 45% were classified as WHO grade 3, and 68% were operated on in other institutions before referral. Regarding treatment, 72% underwent radiotherapy and 33% of patients underwent chemotherapy. Almost 70% percent of the patients had relapses. The median follow-up time was 5.2 years (Range: 0,1-21,4). The OS in 5 years was 67%. Totally resected tumors had OS in 5 years of 88% (p: 0.028).ConclusionThe results achieved in this series show a survival gap between UMIC and HIC. Relapses occurred mainly in the first ten years and then reached a plateau, with the majority of patients experiencing endocrinological and neurological sequelae.

Osteosarcoma with Pathological Fracture: A Rare Case Report

Introduction: Osteosarcoma is a primary malignant bone tumor originating from stem cells and is characterized by the proliferation of tumor cells that directly form immature bone or bone-like tissue. Osteosarcoma represents only 3% to 5% of all spinal malignancies. The aim of study is to discuss the importance of diagnostic investigation for a relatively rare case of spinal osteosarcoma. Case presentation: A 49 years old female came to the Emergency Unit, with a chief complaint of bilateral weakness of lower extremities for 1 year and worsening in 2 weeks. Upon examination, the initial diagnosis was mistaken for a spinal canal stenosis because metastatic bone disease from previous history of malignant melanoma. Subsequently, a decompression with stabilization fusion and biopsy is performed. Primary osteosarcoma was confirmed from histopathology results. Further chemotherapy is planned referring to confirmed primary osteosarcoma on histopathology. Discussion: Spinal osteosarcoma is very rare. Osteosarcoma occurs most frequently in the appendicular skeleton, especially the distal femur and proximal tibial metaphysis, which account for 90% of all cases. Primary osteosarcomas of the vertebral column are uncommon and occur dominantly in the vertebral body. Biopsy remains the gold standard of care for diagnosis. Conclusion: The performance of MRI and pathologic evaluation with immunohistochemistry is particularly important for the differential diagnosis of soft tissue tumors. Histopathologic analysis also plays an important role in differentiating from metastatic bone disease. An aggressive treatment plan and long-term follow-up are mandatory in managing this case. Keywords: osteosarcoma, spinal osteosarcoma, spinal canal stenosis, malignancy, pathological fracture, rare case.

Comparative Analysis of Treatment Patterns in DoD Beneficiaries With Malignant Central Nervous System Tumors: A Focus on Care Setting.

Malignant brain and other central nervous system tumors (MBT) are deadly and disproportionately affect younger men and women in the age range of most active-duty service members. Timely and appropriate treatment is important to both survival and quality of life of patients. Information on treatment factors across direct care (DC) and private sector care (PSC) networks may be important for provider training and staffing for the DoD. The aim of this study was to analyze treatment patterns for patients with MBT within the DoD's universal access Military Health System (MHS), comparing DC and PSC networks. The Military Cancer Epidemiology database was used to identify patients 18 years and older who were diagnosed with an MBT between 1999 and 2014 who received primary treatment. Differences in first treatment type and time from diagnosis to initial treatment between DC and PSC were assessed using chi-square and Wilcoxon-Mann-Whitney tests, respectively. Frequency of treatment initiation beyond the 28-day TRICARE Prime access standard for Specialty Care was also compared between care settings using chi-square and Fisher's exact tests. Then logistic regression models generated odds of treatment initiation beyond 28 days and 95% confidence intervals (CIs) associated with care setting. Kaplan-Meier survival curves and log-rank tests compared survival between DC and PSC. The study included 857 patients, with n = 540 treated in DC and n = 317 treated in PSC. The proportion of patients receiving each initial treatment type did not differ by care setting (P = .622). Median time from diagnosis to initial treatment (interquartile range) varied significantly between DC at 6 (0 to 25) days and PSC at 12 (0 to 37) days for all treatment types combined (P < .001). For all years combined, treatment was initiated beyond 28 days for 21% of patients using DC compared to 31% of patients using PSC (P = .001). The odds of treatment initiation beyond 28 days for a patient treated in PSC were 1.61 (95% CI, 1.11 to 2.33, P = .012) compared to patients treated in DC when controlling for demographic, military, tumor, and patient variables. Survival did not differ by care setting (P = 1.000). Based on the available data between 1999 and 2014, care setting was associated with differences in time to initial treatment and odds of treatment initiation beyond 28 days among DoD beneficiaries with MBT receiving care in the MHS. Information on these differences may help inform MHS leadership decisions on the most appropriate location for military provider training and staffing.

Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses

(1) Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Due to a lack of level 1 evidence, there is no clear consensus on the optimal extent of resection to improve overall survival. This umbrella review aggregates existing meta-analyses (MAs) to assess overall survival in patients undergoing subtotal resection (STR) versus gross total resection (GTR). (2) Methods: A systematic search of PubMed, Scopus, and Web of Science identified 441 studies, with four MAs meeting inclusion criteria. Data were analyzed using the metaumbrella R package, focusing on overall survival. Quality was assessed using AMSTAR2, with scores ranging from 0 to 11. The Ioannidis criteria were applied to evaluate the credibility of the evidence. (3) Results: The quality assessment rated all four studies highly, with a mean AMSTAR2 score of 10.25. The pooled analysis revealed a significant survival advantage for GTR over STR. However, the Ioannidis classification graded the evidence as Class III, indicating weak credibility. (4) Conclusions: GTR offers a slight survival benefit over STR in GBM patients, but the credibility of the evidence is weak, highlighting the need for further research.

One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma

Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.

Case Report: Facial fracture sequelae: the importance of using a specific customized implant (PSI) for orbital reconstruction

The reconstruction of orbital fracture sequelae is a major challenge due to concerns regarding surgical approach and implant stability. Few anatomical sites of such minute size have presented with as much variation in treatment as the orbital floor fractures and related sequelae. Our patient developed sequelae of an orbital fracture over the last 3 years, presenting with dystopia, ophthalmoplegia, and diplopia in the supra- and lateroversion and aesthetic impairment. The variety of implant materials for reconstruction after orbital fractures is extensive, and the decision as to which material to use continues to be debated. The continuing development of computer-aided diagnosis and management and the construction of stereolithographic models offer comparable reproduction of anatomical detail. This technology is described in relation to the planning of trauma surgery and sequelae and the planning of ablative surgery for malignant neoplasms of the head and neck. The use of specific 3D printed titanium implants for bone defects was first reported in cranial reconstruction in 2012, and several studies have reported their use in orbital fractures. The advantages of this implant were increased stiffness, preventing shape loss during placement, a precise fit, and decreased surgical time. However, in the existing literature, the one-piece implant done in this way was a precise fit; therefore, it is possible that navigation between intraoperative anatomical landmarks is lost. However, in cases where reconstruction is difficult, such as extensive orbital wall fractures and large orbital sequelae, the 3D printed implant has been helpful in decreasing surgical time and can be accessed by a limited surgical approach with a precise fit. Our clinical case involved a 37-year-old male patient who experienced severe physical aggression in 2020, amid the COVID-19 pandemic. At the time, due to the overwhelming healthcare demands and resource constraints imposed by the pandemic, immediate surgical intervention for the correction of the fracture was not feasible. As a result of this delay, the patient developed sequelae of the orbital fracture over the last 3 years.

Epithelioid solitary fibrous tumors from CNS and soft tissues: an unusual morphologic variant

BackgroundSolitary fibroous tumors (SFTs) are distinctive soft tissue tumors characterized by rearrangements of NAB2-STAT6 gene, which are associated with thin-walled, branching, “staghorn”-shaped vessels. SFTs are originally classified as a type of hemangiopericytoma (HPC). Classical SFTs are composed of spindle to ovoid cells arranged haphazardly or in fascicles. Rarely, SFTs exhibit unusual morphological variants such as fat formation, giant cells, dedifferentiation, or epithelioid variant. The epithelioid cell variant, which is composed almost entirely of epithelioid cells and arranged in solid or nest patterns, is extremely rare and frequently malignant.Case presentationIn this study, we reported three cases of epithelioid SFTs (ESFTs) located in extrathoracic sites (right lateral ventricle, right lumbar, left pelvis). All the subjects in this study were elderly, with a predominance of female patients, accounting for two out of the three cases, and only one case involved a male patient. The tumor cells were entirely composed of epithelioid cells and exhibited positive for CD34 and STAT-6 markers. Ultimately, the majority of cases (two out of three) were diagnosed as malignant SFTs.ConclusionThis study aims to enhance the awareness of ESFTs. In these cases, irrespective of the onset location, the arrangement patterns of tumor cells, such as papillary structures and the morphology of epithelial-like cells, conspicuously lack the hallmark histological characteristics of Solitary Fibrous Tumors (SFTs). Consequently, it requires differential diagnosis from a plethora of malignant neoplasms. Moreover, the elevated malignancy level of this cohort of cases poses substantial diagnostic challenges to pathologists, compounding the complexity of accurate interpretation.