Tumor Parenchyma Research Articles

Strong YKL-40 expression in the invasive tumor front of colorectal cancer–A pilot study

Тhe poor prognosis of patients initially diagnosed at an advanced stage of colorectal cancer (CRC) and the heterogeneity within the same tumor stage define the need for additional predictive biomarkers. Tumor buds are proposed as a poor prognostic factor for CRC, however, they are still not implemented into routine pathology reporting. In turn, the chitinase-3-like protein 1 (CHI3L1) also known as YKL-40, is regarded as a candidate circulating biomarker and therapeutic target in CRC. The aim of our study was to investigate tissue YKL-40 localization and tumor budding in CRC. Thirty-one CRC patients and normal colonic tissues were examined. The correlation between YKL-40 levels, tumor budding and clinocopathological parameters was evaluated by polychoric correlation analysis. The immunohistochemical assessment revealed high YKL-40 expression in CRC in contrast to normal mucosa. Specifically, intense YKL-40 staining was detected in the front of tumor invasion compared with tumor parenchyma and noncancerous tissue. We present novel data for increased YKL-40 expression in tumor buds within the front of tumor invasion. We assume that the combination of this morphological parameter with the tissue level of the pleotropic YKL-40 glycoprotein could serve as a future prognostic biomarker for CRC stratification and treatment.

Consensus guidelines for the management of pineal region tumours for low- and middle-income countries.

Pineal region tumours are rare and mainly arise at a younger age. They can be categorized into various types: germ cell tumours (GCT), pineal parenchymal tumours (PPT), meningiomas, gliomas, pineoblastoma, pineal parenchymal tumours of intermediate differentiation, papillary tumours of the pineal region, and SMARCB1- mutant desmoplastic myxoid tumour. Within GCT, germinomas are the most prevalent, comprising the majority of tumours in this region, while nongerminomatous GCTs are also present. In rare instances, metastases from other sites may manifest. These tumours often lead to obstructive hydrocephalus and commonly exhibit symptoms related to mass effect, including headache, nausea, vomiting, and impaired gait stability. Different subtypes of pineal region tumours exhibit distinct radiological characteristics, thus imaging remains the primary diagnostic tool. Histologic diagnosis necessitates biopsy, unless in cases of germ cell tumours, particularly germinomas, which can be identified through elevated levels of tumour markers like alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in both cerebrospinal fluid (CSF) and serum. While benign tumours might be effectively treated with radical resection alone, malignant tumours demand additional chemotherapy and radiotherapy following surgical removal.

Understanding and Managing Pineal Parenchymal Tumors of Intermediate Differentiation: An In-Depth Exploration from Pathology to Adjuvant Therapies.

Pineal parenchymal cell tumors constitute a rare group of primary central nervous system neoplasms (less than 1%). Their classification, especially the intermediate subtype (PPTIDs), remains challenging. A literature review was conducted, navigating through anatomo-pathological, radiotherapy, and neurosurgical dimensions, aiming for a holistic understanding of these tumors. PPTIDs, occupying an intermediate spectrum of malignancy, reveal diverse histological patterns, mitotic activity, and distinct methylation profiles. Surgical treatment is the gold standard, but when limited to partial removal, radiotherapy becomes crucial. While surgical approaches are standardized, due to the low prevalence of the pathology and absence of randomized prospective studies, there are no shared guidelines about radiation treatment modalities. Surgical removal remains pivotal, demanding a personalized approach based on the tumor extension. This review underscores the considerable variability in treatment approaches and reported survival rates within the existing literature, emphasizing the need for ongoing research to better define optimal therapeutic strategies and prognostic factors for PPTIDs, aiming for further and more detailed stratification among them.

Looking through the imaging perspective: the importance of imaging necrosis in glioma diagnosis and prognostic prediction - single centre experience.

The aim of the study was to investigate the diagnostic value of imaging necrosis (Imnecrosis) in grading, predict the genotype and prognosis of gliomas, and further assess tumor necrosis by dynamic contrast-enhanced MR perfusion imaging (DCE-MRI). We retrospectively included 150 patients (104 males, mean age: 46 years old) pathologically proved as adult diffuse gliomas and all diagnosis was based on the 2021 WHO central nervous system (CNS) classification. The pathological necrosis (Panecrosis) and gene mutation information were collected. All patients underwent conventional and DCE-MRI examinations and had been followed until May 31, 2021. The Imnecrosis was determined by two experienced neuroradiologists. DCE-MRI derived metric maps have been post-processed, and the mean value of each metric in the tumor parenchyma, peritumoral and contralateral area were recorded. There was a strong degree of inter-observer agreement in defining Imnecrosis (Kappa = 0.668, p < 0.001) and a strong degree of agreement between Imnecrosis and Panecrosis (Kappa = 0.767, p < 0.001). Compared to low-grade gliomas, high-grade gliomas had more Imnecrosis (85.37%, p < 0.001), and Imnecrosis significantly increased with the grade of gliomas increasing. And Imnecrosis was significantly more identified in IDH-wildtype, 1p19q-non-codeletion, and CDKN2A/B-homozygous-deletion gliomas. Using multivariate Cox regression analysis, Imnecrosis was an independent and unfavorable prognosis factor (Hazard Ratio = 2.113, p = 0.046) in gliomas. Additionally, extravascular extracellular volume fraction (ve) in tumor parenchyma derived from DCE-MRI demonstrated the highest diagnostic efficiency in identifying Panecrosis and Imnecrosis with high specificity (83.3% and 91.9%, respectively). Imnecrosis can provide supplementary evidence beyond Panecrosis in grading, predicting the genotype and prognosis of gliomas, and ve in tumor parenchyma can help to predict tumor necrosis with high specificity.

The role of tumor parenchyma and brain cortex signal intensity ratio in differentiating solitary fibrous tumors and meningiomas

BackgroundSolitary fibrous tumors (SFT) and meningiomas (MA) have similar clinical and radiographic presentations but require different treatment approaches and have different prognoses. This emphasizes the importance of a correct preoperative diagnosis of SFT versus MA.ObjectiveIn this study, investigated the differences in imaging characteristics between SFT and MA to improve the accuracy of preoperative imaging diagnosis of SFT.MethodsThe clinical and imaging data of 26 patients with SFT and 104 patients with MA who were pathologically diagnosed between August 2017 and December 2022, were retrospectively analyzed. The clinical and imaging differences between SFT and MA, as well as between the various pathological grades of SFT, were analyzed.ResultsAge, gender, cystic change, flow void phenomenon, yin-yang sign, lobulation, narrow base, tumor/cortex signal ratio (TCSR) > 1.0 in T1-weighted imaging (T1WI), TCSR ≥ 1.1 in T2-weighted imaging (T2WI), peritumoral edema, and absence of dural tail sign varied between SFT and MA. As per the receiver operating characteristic (ROC) curve analysis, TCSR > 1 in T1WI has the maximum diagnostic accuracy for SFT. Cranial or venous sinus invasion had a positive effect on SFT (Grade III, World Health Organization (WHO) grading).ConclusionAmong the many radiological and clinical distinctions between SFT and MA, TCSR ≥ 1 exhibits the highest predictive efficacy for SFT; while cranial or venous sinus invasion may be a predictor of WHO grade III SFT.

Positive correlation between the nuclear expression of GPER and pGLI3 in prostate cancer tissues from patients with different Gleason scores.

Prostate cancer (PCa) is the most prevalent cause of death in the male population worldwide. The G Protein-Coupled Estrogen Receptor (GPER) has been gaining relevance in the development of PCa. Hedgehog (Hh) pathway activation is associated with aggressiveness, metastasis, and relapse in PCa patients. To date, no studies have evaluated the crosstalk between the GPER and the Hh pathway along different group grades in PCa. We conducted an analysis of paraffin-embedded tissues derived from patients with different prognostic grade of PCa using immunohistochemistry. Expression and correlation between GPER and glioma associated oncogene homologue (GLI) transcriptional factors in the parenchyma and stroma of PCa tumors were evaluated. Our results indicate that GPER is highly expressed in the nucleus and increases with higher grade groups. Additionally, GPER's expression correlates with pGLI3 nuclear expression across different grade groups in PCa tissues; however, whether the receptor induces the activation of GLI transcriptional factors, or the latter modulate the expression of GPER is yet to be discovered, as well as the functional consequence of this correlation.

Assessment of histogram analysis in distinguishing between low-grade and high-grade brainstem glioma.

This retrospective study was designed to evaluate the value of histogram analysis on the apparent diffusion coefficient (ADC) map in distinguishing between low-grade and high-grade brainstem glioma (BSG). In this article, we used the two VOI (volume of interest) placements of the entire tumour method and the entire solid part method, thus aiming to compare the diagnostic value between these two performances. A total of 28 patients (8 low-grade BSGs and 20 high-grade BSGs) with histological diagnosis of BSG. All victims underwent contrast-enhanced magnetic resonance imaging (MRI). We measured ADC histogram parameters (mean, median, SD, max, min, Kurtosis, Skewness, Entropy, Uniformity, and Variance) and calculated the ratios between tumour and normal brain parenchyma parameters in two methods. Independent samples test, Mann-Whitney U test, and ROC curve were used to determine each value's cut-off point, sensitivity, and specificity. Among the method of VOI placing the entire tumour, the values of ADC_min, rADC_mean, rADC_median, and rADC_min are significantly different between these two neoplasms with cut-off values (sensitivity %, specificity %) of 776 x10-6 m2/s (62.5%, 90%), 2.1765 (62.5%, 95%), 2.1588 (50%, 100%), 1.0535 (100%, 50%), respectively. On the other hand, the method of VOI placing the entire solid part of the tumour showed significantly different in ADC_mean, ADC_median, ADC_min, rADC_mean, rADC_median, rADC_min at the cut-off values (sensitivity%, specificity %) of 1491 x10-6 m2/s (62.5%, 95%), 1438.9 x10-6 m2/s (62.5%, 90%), 862.5 x10-6 m2/s (75%, 100%), 2,112 (62.5%, 95%), 1.9748 (62.5%, 90%), 1.3735 (87.5%, 90%), respectively. The ADC histogram analysis is a promising approach to distinguishing low-grade BSG and high-grade BSG. The entire solid part VOI placement has a superior value compared to the whole tumour VOI placement. The rADC_mean showed the best performance in differentiating between these two entities, followed by ADC_min, rADC_mean, rADC_median, ADC_mean, and ADC_median.

Defining Melanoma Immune Biomarkers-Desert, Excluded, and Inflamed Subtypes-Using a Gene Expression Classifier Reflecting Intratumoral Immune Response and Stromal Patterns.

The spatial distribution of tumor infiltrating lymphocytes (TILs) defines several histologically and clinically distinct immune subtypes-desert (no TILs), excluded (TILs in stroma), and inflamed (TILs in tumor parenchyma). To date, robust classification of immune subtypes still requires deeper experimental evidence across various cancer types. Here, we aimed to investigate, define, and validate the immune subtypes in melanoma by coupling transcriptional and histological assessments of the lymphocyte distribution in tumor parenchyma and stroma. We used the transcriptomic data from The Cancer Genome Atlas melanoma dataset to screen for the desert, excluded, and inflamed immune subtypes. We defined subtype-specific genes and used them to construct a subtype assignment algorithm. We validated the two-step algorithm in the qPCR data of real-world melanoma tumors with histologically defined immune subtypes. The accuracy of a classifier encompassing expression data of seven genes (immune response-related: CD2, CD53, IRF1, and CD8B; and stroma-related: COL5A2, TNFAIP6, and INHBA) in a validation cohort reached 79%. Our findings suggest that melanoma tumors can be classified into transcriptionally and histologically distinct desert, excluded, and inflamed subtypes. Gene expression-based algorithms can assist physicians and pathologists as biomarkers in the rapid assessment of a tumor immune microenvironment while serving as a tool for clinical decision making.

Automated Quantitative Analysis of CT Perfusion to Classify Vascular Phenotypes of Pancreatic Ductal Adenocarcinoma

CT perfusion (CTP) analysis is difficult to implement in clinical practice. Therefore, we investigated a novel semi-automated CTP AI biomarker and applied it to identify vascular phenotypes of pancreatic ductal adenocarcinoma (PDAC) and evaluate their association with overall survival (OS). Methods: From January 2018 to November 2022, 107 PDAC patients were prospectively included, who needed to undergo CTP and a diagnostic contrast-enhanced CT (CECT). We developed a semi-automated CTP AI biomarker, through a process that involved deformable image registration, a deep learning segmentation model of tumor and pancreas parenchyma volume, and a trilinear non-parametric CTP curve model to extract the enhancement slope and peak enhancement in segmented tumors and pancreas. The biomarker was validated in terms of its use to predict vascular phenotypes and their association with OS. A receiver operating characteristic (ROC) analysis with five-fold cross-validation was performed. OS was assessed with Kaplan–Meier curves. Differences between phenotypes were tested using the Mann–Whitney U test. Results: The final analysis included 92 patients, in whom 20 tumors (21%) were visually isovascular. The AI biomarker effectively discriminated tumor types, and isovascular tumors showed higher enhancement slopes (2.9 Hounsfield unit HU/s vs. 2.0 HU/s, p &lt; 0.001) and peak enhancement (70 HU vs. 47 HU, p &lt; 0.001); the AUC was 0.86. The AI biomarker’s vascular phenotype significantly differed in OS (p &lt; 0.01). Conclusions: The AI biomarker offers a promising tool for robust CTP analysis. In PDAC, it can distinguish vascular phenotypes with significant OS prognostication.

Tumor margin irregularity degree is an important preoperative predictor of adverse pathology for clinical T1/2 renal cell carcinoma and the construction of predictive model.

To explore the critical role of the tumor margin irregularity degree (TMID) of renal tumors in predicting adverse pathology of patients with clinical T1/2 (cT1/2) renal cell carcinoma (RCC). A total of 821 patients with cT1/2 RCC undergoing nephrectomy in the Second Hospital of Tianjin Medical University between January 2017 and December 2020 were reviewed. The tumor margin irregularity (TMI) was classified into renal mass with locally raised protrusion and smooth margin called 'lobular', sharply and unsmooth nodular margin called 'spiculation', blurred margins between tumor and renal parenchyma or a completely irregular and non-elliptical shape. The ratio between the number of irregular cross-sections (X) and the number of total cross-sections from top to bottom occupied (Y) was defined as TMID (X/Y). The logistic regression was performed to determine the independent predictors of adverse pathology, and the Kaplan-Meier curve and log-rank test were used to analyze the survival outcomes. Among 821 cT1/2 RCC patients, 245 (29.8%) had adverse pathology. The results of the univariate and multivariate logistic regressions showed that the age, tumor size, hemoglobin, and TMID were the independent predictors of adverse pathology. Incorporation of TMID could increase the discrimination of the predictive model with the area under curve (AUC) of ROC curves increasing from 0.725 to 0.808. Patients with adverse pathology or higher TMID both had significantly shorter recurrence-free survival (RFS). The nomogram model incorporated with TMID for predicting adverse pathology could increase its discrimination, calibration, and clinical application values, compared with the models without TMID.

Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.

The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma. Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Improving the diagnosis of ductal carcinoma in situ with microinvasion without immunohistochemistry: An innovative method with H&E-stained and multiphoton microscopy images.

Ductal carcinoma in situ with microinvasion (DCISM) is a challenging subtype of breast cancer with controversial invasiveness and prognosis. Accurate diagnosis of DCISM from ductal carcinoma in situ (DCIS) is crucial for optimal treatment and improved clinical outcomes. However, there are often some suspicious small cancer nests in DCIS, and it is difficult to diagnose the presence of intact myoepithelium by conventional hematoxylin and eosin (H&E) stained images. Although a variety of biomarkers are available for immunohistochemical (IHC) staining of myoepithelial cells, no single biomarker is consistently sensitive to all tumor lesions. Here, we introduced a new diagnostic method that provides rapid and accurate diagnosis of DCISM using multiphoton microscopy (MPM). Suspicious foci in H&E-stained images were labeled as regions of interest (ROIs), and the nuclei within these ROIs were segmented using a deep learning model. MPM was used to capture images of the ROIs in H&E-stained sections. The intensity of two-photon excitation fluorescence (TPEF) in the myoepithelium was significantly different from that in tumor parenchyma and tumor stroma. Through the use of MPM, the myoepithelium and basement membrane can be easily observed via TPEF and second-harmonic generation (SHG), respectively. By fusing the nuclei in H&E-stained images with MPM images, DCISM can be differentiated from suspicious small cancer clusters in DCIS. The proposed method demonstrated good consistency with the cytokeratin 5/6 (CK5/6) myoepithelial staining method (kappa coefficient = 0.818).

Lymph Node-Targeted Vaccine Boosting of TCR T-cell Therapy Enhances Antitumor Function and Eradicates Solid Tumors.

T-cell receptor (TCR)-modified T-cell therapies have shown promise against solid tumors, but overall therapeutic benefits have been modest due in part to suboptimal T-cell persistence and activation in vivo, alongside potential tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and function of TCR T cells through combination with Amphiphile (AMP) vaccination including cognate TCR T peptides. AMP modification improves lymph node targeting of conjugated tumor immunogens and adjuvants, thereby coordinating a robust T cell-activating endogenous immune response. AMP vaccine combination with TCR T-cell therapy led to complete eradication and durable responses against established murine solid tumors refractory to TCR T-cell monotherapy. Enhanced antitumor efficacy was correlated with simultaneous in vivo invigoration of adoptively transferred TCR T cells and in situ expansion of the endogenous antitumor T-cell repertoire. Long-term protection against tumor recurrence in AMP-vaccinated mice was associated with antigen spreading to additional tumor-associated antigens not targeted by vaccination. AMP vaccination further correlated with pro-inflammatory lymph node transcriptional reprogramming and increased antigen presenting-cell maturation, resulting in TCR T-cell expansion and functional enhancement in lymph nodes and solid tumor parenchyma without lymphodepletion. In vitro evaluation of AMP peptides with matched human TCR T cells targeting NY-ESO-1, mutant KRAS, and HPV16 E7 illustrated the clinical potential of AMP vaccination to enhance human TCR T-cell proliferation, activation, and antitumor activity. Taken together, these studies provide rationale and evidence to support clinical evaluation of combining AMP vaccination with TCR T-cell therapies to augment antitumor activity.

Epidemiological Characteristics and Prognosis Model of Pineal Region Tumors: A Retrospective Analysis Based on the SEER Database

BackgroundPineal region tumor is a rare intracranial tumor, and its special location leads to its own characteristics. This study aimed to provide some insight to the medical practice for the care of pineal region tumor. It investigated key epidemiological characteristics and survival prognosis of pineal tumors based the epidemic data from SEER database. MethodsData of pineal region tumor patients from 1975 to 2019 were extracted from the SEER database and divided all data into three pathologic groups: "Germ cell tumors (GCTs)", "Pineal parenchymal tumors (PPTs) " and "Others". Patients’ overall survival (OS) was analyzed using the Kaplan-Meier (K-M) method. Prognostic effect of patient’s characteristics on OS was explored via the Cox proportional hazard model. Analyses results were presented in tables and figures including K-M plots, forest plot and nomogram. A calibration curve was used to verify that the nomogram. All analyses were performed for all patients overall and by pathological group using SPSS and R language. ResultsBased on pre-defined the inclusion and exclusion criteria, 628 patients were included in this study, 440 (70.1%) males and 188 (29.9%) females. The majority of patients was between 0-19 years; 225 (35.8%) of patients’ pathological type was germinoma. Age, surgery, behavioral codes and pathology were significant factors of OS. A calibration curve was used to verify that the nomogram had a good prediction effect. ConclusionAn intuitive nomogram was developed and verified. It can predict the prognosis of patients with pineal tumors.

Abstract B015: Toxin-producing bacterial therapy limits tumor growth in autochthonous mouse models of pancreatic ductal adenocarcinoma

Abstract Treating pancreatic ductal adenocarcinoma (PDAC) with systemic chemotherapeutic drugs has remained a challenge, due in part to the hypovascularized and poorly perfused nature of PDAC tumors, impeding the accumulation of systemically delivered drugs. Several clinical trials aimed at improving drug delivery in PDAC, through targeting of ECM components (HALO-301) or stromal angiogenic signaling (IPI-926-03) have unfortunately not been effective. However, the features that have interfered with systemic therapy in PDAC are potential advantages for the use of bacterial therapies, as bacteria can actively migrate through tissues, thrive in hypoxic microenvironments, and benefit from local immune suppression. Recent developments in the field of synthetic biology have made it possible to engineer complex logic circuits into bacteria, enabling the production of anticancer therapies directly within the tumor parenchyma. Furthermore, live bacteria, once colonized within the tumor niche, are capable of providing a stable source of anticancer compounds directly, rather than relying on repeated systemic doses. We have therefore worked to develop novel bacterial strains and demonstrate preclinical efficacy of a novel strain of therapeutic bacteria for targeting PDAC. We began by testing a range of bacteria-produced toxins and identified the pore-forming protein theta toxin as having the greatest effect in both 2D cell culture and PDAC explant (tissue slice) models. We then engineered a non-toxic probiotic bacteria, E. coli Nissle 1917, to produce either theta toxin or GFP. To assess preclinical efficacy, we performed intratumoral injections of live GFP- and theta-expressing bacteria into the “KPC” genetically engineered mouse model (Kras LSL.G12D/+; Tp53 LSL.R172H/+; PdxCre tg/+). While GFP-producing bacteria did not induce a change in tumor growth kinetics, treatment with theta toxin-producing bacteria demonstrated prolonged stabilization of tumor growth, increasing the median survival to 34 days compared to ~12 days for vehicle- or gemcitabine-treated controls and 18.5 days for GFP-producing bacteria without additional therapy. Strikingly, while there was minimal spread of bacteria to non-tumor tissues, we observed translocation of the bacteria to macro- and micro- metastatic lesions and distant papillomas following injection of the primary pancreatic tumor, indicating a mechanism for targeting both known and unknown metastases following local administration. Histological analyses demonstrated that diffuse populations of bacteria co-localized with regions of cell death, but that bacterial presence and evidence of increased cell death was not observed in healthy tissues, such as the lung, liver, intestine, and diaphragm. Additionally, bacterial treatment, independent of the payload, led to a modest influx of anti-tumor immune populations, suggesting potential synergy with immunotherapies. Together these data demonstrate potent preclinical activity of cytotoxic bacterial therapy as a novel strategy to circumvent the challenges of systemic treatment of PDAC. Citation Format: Amanda R. Decker-Farrell, Stephen A. Sastra, Tetsuhiro Harimoto, Marie C. Hasselluhn, Fangda Li, Rosa Vincent, Carmine F. Palermo, Edward R. Ballister, Tal Danino, Kenneth P. Olive. Toxin-producing bacterial therapy limits tumor growth in autochthonous mouse models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B015.

Prognostic effect of programmed cell death ligand 1/programmed cell death 1 expression in cancer stem cells of human oral squamous cell carcinoma.

The relationship between cancer stem cells (CSCs) in oral squamous cell carcinoma (OSCC) and programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) remains unclear. Therefore, the present study aimed to clarify the association between the CD44v3high/CD24low immunophenotype of CSCs in OSCC and PD-L1/PD-1 co-expression, and to assess the prognostic effect of CSCs in terms of immune checkpoint molecules. Formalin-fixed, paraffin-embedded tissue samples and clinicopathological data from 168 patients with OSCC were retrospectively retrieved. Immunohistochemical staining and reverse transcription quantitative polymerase chain reaction were applied to a tissue microarray of the invasive front of each case. Semi-automated cell counting was used to assess CD44v3, CD24, PD-L1 and PD-1 expression by immunohistochemistry (IHC) using a digital image analysis program. Associations between immunological markers and clinicopathological variables were estimated. Patients with the CSC immunophenotype CD44v3high/CD24low, and patients with a high PD-L1/PD-1-positive cell density in the tumor parenchyma and stroma had significantly lower survival rates. Furthermore, patients with the CSC immunophenotype (CD44v3high/CD24low) and high PD-L1/PD-1 co-expression had even lower survival rates (P<0.01, log-rank test). Notably, there was a positive correlation between CD44v3 and PD-L1 expression (τ=0.1096, P=0.0366, Kendall rank correlation coefficient) and a negative correlation between CD24 and PD-1 expression (τ=-0.1387, P=0.0089, Kendall rank correlation coefficient). Additionally, the high CD44v3 expression group, as determined by IHC, exhibited significantly decreased expression of U2 small nuclear RNA auxiliary factor 1 (U2AF1) at the mRNA level compared with that in the low CD44v3 expression group (P<0.001, Mann-Whitney U test), and U2AF1 and PD-L1 mRNA expression exhibited a significant negative correlation (τ=-0.3948, P<0.001, Kendall rank correlation coefficient). In conclusion, CSCs in OSCC may evade host immune mechanisms and maintain CSC stemness via PD-L1/PD-1 co-expression, resulting in unfavorable clinical outcomes.

Imaging diagnosis and differential diagnosis of extraskeletal osteosarcoma

ObjectiveThe aim of this study was to investigate the clinical, imaging and pathological features of extraskeletal osteosarcoma (EOS) and to improve the understanding of this disease and other similar lesions.MethodsThe data for 11 patients with pathologically confirmed extraosseous osteosarcoma, including tumour site and size and imaging and clinical manifestations, were analysed retrospectively.ResultsSix patients were male (60%), and 5 were female (40%); patient age ranged from 23 to 76 years (average age 47.1 years). Among the 11 patients, 7 had clear calcifications or ossification with different morphologies, and 2 patients showed a massive mature bone tumour. MRI showed a mixed-signal mass with slightly longer T1 and T2 signals in the tumour parenchyma. Enhanced CT and MRI scans showed enhancement in the parenchyma. Ten patients had different degrees of necrosis and cystic degeneration in the mass, 2 of whom were complicated with haemorrhage, and MRI showed “fluid‒fluid level” signs. Of the 11 patients, five patients survived after surgery, and no obvious recurrence or metastasis was found on imaging examination. One patient died of lung metastasis after surgery, and 2 patients with open biopsy died of disease progression. One patient died of respiratory failure 2 months after operation. 2 patients had positive surgical margins, and 1 had lung metastasis 6 months after operation and died 19 months after operation. Another patient had recurrence 2 months after surgery.ConclusionThe diagnosis of EOS requires a combination of clinical, imaging and histological examinations. Cystic degeneration and necrosis; mineralization is common, especially thick and lumpy mineralization. Extended resection is still the first choice for localized lesions. For patients with positive surgical margins or metastases, adjuvant chemoradiotherapy is needed.

The possibilities of immunohistochemistry for assessing the pathogenetic mechanisms of action of compounds with a suspected antitumor effect. Part I. General indicators of the process activity

Despite the wide arsenal of chemotherapeutic agents, the search and study of new compounds with an alleged antitumor effect is relevant. Morphological diagnostics of pathological processes occurring under the action of pharmacologically active substances is the most important component of preclinical research of compounds with an alleged antitumor effect. It is advisable to use information about the possible cytotoxic effect of candidates for antitumor drugs using an immunohistochemical method for studying organs and systems of experimental animals at different stages of the development of the tumor process by indirect markers of tumor progression activity. Morphological examination of parenchymal organs and tumor tissue in the dynamics of the development of malignant neoplasm is more informative and evidence-based than biochemical research. The aim of the study is to conduct a comparative analysis of markers of tumor process activity for more effective use of morphological and immunohistochemical research methods in the preclinical study of compounds with suspected antitumor activity to assess the prospects for their use with the detection of tumor process activity. The literature search was carried out using the Scopus, Web of Science, PubMed and eLIBRARY databases. The paper presents an overview of current molecular biological markers for assessing the activity of the malignant process in the experiment: Transforming Growth Factor beta 1 (TGF-β1), Ki-67, Tumor necrosis factor alpha (TNF-α), p53, Poly-ADP-ribose polymerase 1 (PARP-1) and Anti-8-Hydroxy-2'-deoxyguanosine (8-OHdG), beta III Tubulin, p120 Catenin, Beta Actin. The listed markers are indirect and can be used in a single mode only for screening studies of antitumor and antimetastatic activity in which a large number of compounds are sorted according to the principle of effectiveness. When conducting an in-depth study of the pharmacological activity of the leader compounds it is necessary to perform a comprehensive immunohistochemical study. Our analysis of the literature data confirms the importance of selecting optimal, sensitive, economically feasible and affordable markers, which in turn leads to the improvement of diagnostic panels and their standardization to simplify their transition into clinical practice.

Endoport-Guided Endoscopic Excision of Intraaxial Brain Tumors.

Transcortical approaches using a spatula-based retraction system have traditionally been used for the microsurgical resection of deep-seated intraventricular and parenchymal brain tumors. Recently, transparent cylindrical or tubular retractors have been developed to provide a stable corridor to access deeper brain lesions and perform bimanual microsurgical resection. The flexible endoports minimize brain retraction injury during surgery and, along with the superior vision of endoscopes, offer several advantages over standard microsurgery. In this chapter, we describe the surgical technique of the endoport-guided endoscopic excision of deep-seated intraaxial brain tumors. The endoscopic endoport technique that we use at our institution for the surgical management of intraventricular and intraparenchymal brain tumors has been described in detail with illustrative cases. Results from the literature review of intraventricular and intraparenchymal port surgery were analyzed, and the feasibility and safety of this technique were discussed. Surgical complication avoidance and management were highlighted. The port technique offers numerous potential advantages, including (1) reducing focal brain injury by distributing retraction forces homogenously, (2) minimizing white matter disruption and the risk of fascicle injury during cannulation, (3) ensuring the stability of the surgical corridor during the procedure, (4) preventing inadvertent expansion of the corticectomy and white fiber tract dissection throughout surgery, and (5) protecting the surrounding tissues against iatrogenic injuries caused by instrument entry and reentry. The endoport-assisted endoscopic technique is safe and offers an effective alternative option for the resection of intraventricular and intraparenchymal lesions.

Reconsideration of Surgical Indication for Prolactin-producing Pituitary Tumor Focusing on Visual Impairment.

Prolactin-producing pituitary tumor (PRLoma) is the most prevalent functional pituitary tumor. If the tumor becomes large, vision can be impaired. In contrast to other pituitary tumors, cabergoline (CAB) is extremely effective for PRLoma and has become the first-line treatment. In this study, we examined our experience with the pharmacological and surgical management of PRLomas with visual impairment (VI) to determine whether VI could be a surgical indication. Further, we discussed the function of surgery in situations where the gold standard of PRLoma treatment was CAB administration. Of the 159 patients with PRLomas (age, 13-77 [mean = 36.3] years; men, 29; women, 130) at Tokyo Women's Medical University Hospital from 2009 to 2021, 18 (age, 15-67 [mean = 35.8] years; men, 12; woman, 6) had VI (subjectively, 12; objectively, 6). They started CAB treatment immediately (maximum dose: 0.5 to 6 mg/week; average: 2.17 mg/week). VI improved in 16 patients (88.9%) but did not improve in 2 (11.1%) requiring surgeries. One of the two patients had a parenchymal tumor resistant to CAB, and the other had a cystic tumor due to intratumoral bleeding. Consequently, CAB is the first-line treatment for PRLomas with VI because of its significantly high rate of improvement. However, close and rigorous surveillance is necessary for cases resistant to CAB, and the correct decision is required regarding surgical interventions at proper timing and appropriate surgical approaches considering the purpose of surgery.