Efficacy of PD-1/PD-L1 blockade immunotherapy in recurrent/metastatic high-grade neuroendocrine carcinoma of the cervix: A retrospective study.

Although high-grade neuroendocrine carcinoma of the cervix (HGNECC) accounts for less than 1 % of all cervical cancers, it exhibits marked aggressiveness and resistance to radiation and chemotherapy. We retrospectively investigated the efficacy of immunotherapy for recurrent/metastatic HGNECC in a real-world setting. From September 2016 to December 2022, a total of 29 patients with HGNECC accepted PD-1/PD-L1 inhibitors; of these, six cases (20.7 %) were PD-L1 positive (combined positive score ≥1). According to their primary treatment, the patients were assigned to either a surgery group (n = 14) or a non-surgery group (n = 15). In the surgery group, four patients received anti-PD-1 therapy immediately after surgery, while six, two, one, and one patients started immunotherapy after the first, second, third, and forth recurrence, respectively. In the non-surgery group, seven patients started immunotherapy as part of their primary treatment, while the other four, two, and two patients received anti-PD-1 drugs as the second, third, and forth lines of treatment, respectively. The seven-patient group showed longer progression-free survival after immunotherapy (PFSi) and overall survival than those of their counterparts (P = 0.085 and 0.08, respectively), while this benefit was not observed in other subgroups. No significant correlation was observed between PD-L1 and PFSi expression. Interestingly, one patient with a high tumor mutation burden (TMB-H) had a long PFSi of 26 months and experienced no recurrence until the last follow-up. Based on these findings, we propose that PD-1/PD-L1 inhibitors may prolong the survival of patients with HGNECC who start immunotherapy as the first-line of treatment. This indicates that early immunotherapy may be a better choice for this challenging malignancy. Moreover, the predictive role of TMB-H in immunotherapeutic outcomes requires further investigation.

Oncologic and Perioperative Outcomes of Robot-Assisted Versus Conventional Laparoscopy for the Treatment of Clinically Uterine-Confined High-Grade Adenocarcinoma.

OBJECTIVE: The aim of this study was to compare oncologic and perioperative outcomes of robot-assisted laparoscopy (RA) and conventional laparoscopy (LSC) in apparent clinically uterine-confined, high-grade adenocarcinoma. METHODS: A retrospective review was conducted to identify patients with newly diagnosed high-grade uterine adenocarcinoma treated at our institution between 1 January 2009 and 30 June 2021. Exclusion criteria included bulky extrauterine disease, no lymph node assessment, or synchronous tumors. Clinicopathologic details were obtained from medical records. Postoperative complications were classified using the Memorial Sloan Kettering Cancer Center Surgical Secondary Events system, and statistical analysis was performed using appropriate tests. RESULTS: Of 901 patients identified, 748 (83%) underwent RA and 153 (17%) underwent LSC. Median age was 65 years (range 25-92) and median body mass index was 30 kg/m2 (range 15-60). Overall, 650 patients (72%) had 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I disease. Forty-one patients (4.6%) converted to laparotomy-26 (3.5%) from RA versus 15 (9.8%) from LSC (p = 0.02). Postoperative complications occurred in 81 patients (9.0%), with no significant differences in type or rate between groups. Median operative time was 192 mins (range 88-936) for RA versus 168 mins (range 90-372) for LSC (p = 0.002). Median follow-up was 52 months (range 1-163) for RA and 66 months (range 7-165) for LSC. Four-year progression-free survival (PFS) and disease-specific survival (DSS) were similar between groups. Multivariate analysis showed stage, histology, peritoneal cytology, and lymphovascular invasion predicated a decrease in PFS and DSS. CONCLUSIONS: RA demonstrated comparable oncologic outcomes to LSC in patients with high-grade endometrial carcinoma, with no significant difference in postoperative complications or long-term survival.

Value of 11C-Methionine PET Imaging in High-Grade Gliomas: A Narrative Review.

11C-Methionine (MET) is a widely utilized amino acid tracer in positron emission tomography (PET) imaging of primary brain tumors. 11C-MET PET offers valuable insights for tumor classification, facilitates treatment planning, and aids in monitoring therapeutic response. Its tracer properties allow better delineation of the active tumor volume, even in regions that show no contrast enhancement on conventional magnetic resonance imaging (MRI). This review focuses on the role of MET-PET in brain glioma imaging. The introduction provides a brief clinical overview of the problems of high-grade and recurrent gliomas. It discusses glioma management, radiotherapy planning, and the difficulties of imaging after chemoradiotherapy (pseudoprogression or radionecrosis). The mechanism of MET-PET is described. Additionally, the review encompasses the application of MET-PET in the context of primary gliomas, addressing its diagnostic precision, utility in tumor classification, prognostic value, and role in guiding biopsy procedures and radiotherapy planning.

A High-Grade Glioma, Not Elsewhere Classified in an Older Adult with Discordant Genetic and Epigenetic Analyses.

The World Health Organization's (WHO) classification of central nervous system (CNS) tumors is continually being refined to improve the existing diagnostic criteria for high-grade gliomas (HGGs), including glioblastoma. In 2021, advances in molecular analyses and DNA methylation profiling were incorporated to expand upon the diagnostic criteria for HGG, including the introduction of high-grade astrocytoma with piloid features (HGAP), a new tumor entity for which a match to the HGAP class in DNA methylation profiling is an essential criterion. We present an equivocal case of a 72-year-old male with an HGG exhibiting features of both HGAP and glioblastoma, but which did not conform to any existing 2021 WHO classification of CNS tumor entities. This "no match" in DNA methylation profiling resulted in a final diagnosis of HGG not elsewhere classified (NEC), for which standard treatment options do not exist.

Ovarian Cancer Patient-Derived Organoids Used as a Model for Replicating Genetic Characteristics and Testing Drug Responsiveness: A Preliminary Study.

This study aimed to explore the role of ovarian cancer patient-derived organoids (PDOs) in their replicating genetic characteristics and testing drug responsiveness. Ovarian cancer PDOs were cultured in Matrigel with a specialized medium. The successful rate and proliferation rate were calculated. Morphology, histology, and immunohistochemistry (IHC) (PAX8, P53, and WT1) were used to identify the tumor characteristics. Gene sequencing, variant allele frequency (VAF), and copy number variation were used to explore the mutation profile. The sensitivity to chemodrugs (carboplatin, paclitaxel, gemcitabine, doxorubicin, and olaparib) was conducted. Successful generation of organoids occurred in 54% (7/13) of attempts, encompassing 4 high-grade serous carcinomas (HGSC), 1 mucinous carcinoma (MC), 1 clear cell carcinoma (CCC), and 1 carcinosarcoma. The experiments used six organoids (3 HGSC, 1 CCC, 1 MC, and 1 carcinosarcoma). The derived organoids exhibited spherical-like morphology, and the diameter ranged from 100 to 500 µm. The histology and IHC exhibited the same between organoids and primary tumors. After cryopreservation, the organoid's growth rate was slower than the primary culture (14 days vs 10 days, P < 0.01). Targeted sequencing revealed shared DNA variants, including mutations in key genes, such as BRCA1, PIK3CA, ARID1A, and TP53. VAF was similar between primary tumors and organoids. The organoids maintained inherited most copy number alterations. Drug sensitivity testing revealed varying responses, with carcinosarcoma organoids showing higher sensitivity to paclitaxel and gemcitabine than HGSC organoids. Our preliminary results showed that ovarian cancer PDOs could be successfully derived and histology, mutations, and diverse copy numbers of genotypes could be faithfully captured. Drug testing could reveal the individual PDO's responsiveness to drugs. PDOs might be as valuable resources for investigating genomic biomarkers for personalized treatment.

Primary murine high-grade glioma cells derived from RCAS/tv-a diffuse glioma model reprogram naive T cells into immunosuppressive regulatory T lymphocytes.

High-grade gliomas (HGGs) and glioblastomas (GBMs) are the most aggressive and lethal brain tumors. The current standard of care (SOC) includes gross safe surgical resection followed by chemoradiotherapy. The main chemotherapeutic agents are the DNA-alkylating agent temozolomide (TMZ) and adjuvants. Due to the outdated therapeutic protocols and lack of specific treatments, there is an urgent and rising need to improve our understanding of tumor biology and design more effective therapeutic strategies. In vitro models are essential for investigating glioma biology and testing novel therapeutic approaches. While using commercially available and patient-derived glioma cell lines for in vitro studies is common practice, they exhibit several limitations, including failing to maintain the genetic and phenotypic diversity of primary tumors, undergo genetic drift over time, and often lacking the invasive and stem-like characteristics of patient tumors. These limitations can lead to inconsistent and non-reproducible results, hampering translational research progress. In this study, we established a novel primary murine HGG cell line, isolated from an immunocompetent HGG-bearing RCAS/T-va mouse. We characterized the transcriptome and phenotype to ensure that this cell line resembles the nature of HGGs and retains the ability to reprogram primary murine T lymphocytes.

Neoadjuvant chemotherapy induces phenotypic mast cell changes in high grade serous ovarian cancer.

BACKGROUND: High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes. METHODS: Hematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR. RESULTS: Hematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells. CONCLUSIONS: Enhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target.

Analysis of ATP7A Expression and Ceruloplasmin Levels as Biomarkers in Patients Undergoing Neoadjuvant Chemotherapy for Advanced High-Grade Serous Ovarian Carcinoma.

Ovarian cancer (OC), particularly high-grade serous carcinoma (HGSC), is a leading cause of gynecological cancer mortality due to late diagnosis and chemoresistance. While studies on OC cell lines have shown that overexpression of the ATP7A membrane transporter correlates with resistance to platinum-based drugs (PtBMs) and cross-resistance to copper (Cu), clinical evidence is lacking. The functionality of ceruloplasmin (CP), the main Cu-transporting protein in the blood, is dependent on, among other things, ATP7A activity. This study investigated ATP7A expression and CP levels as potential biomarkers for predicting responses to PtBMs. We included 28 HGSC patients who underwent neoadjuvant chemotherapy (NACT). ATP7A expression in ovarian and peritoneal tissues before NACT and in peritoneal and omental tissues after NACT was analyzed via qPCR, and CP levels in ascites and plasma were measured via ELISA before and after NACT. In total, 54% of patients exhibited ATP7A expression in pretreatment tissue (ovary and/or peritoneum), while 43% of patients exhibited ATP7A expression in tissue after treatment (peritoneum and/or omentum). A significant association was found between higher ATP7A expression in the peritoneum before NACT and an unfavorable CA-125 elimination rate constant k (KELIM) score. Patients with omental ATP7A expression had significantly higher plasma mean CP levels before NACT. Plasma CP levels decreased significantly after NACT, and higher CP levels after NACT were associated with a shorter platinum-free interval (PFI). These findings suggest that the ATP7A transporter and CP have the potential to serve as predictive markers of chemoresistance, but further research is needed to validate their clinical utility.

[A lightweight recurrence prediction model for high grade serous ovarian cancer based on hierarchical transformer fusion metadata].

High-grade serous ovarian cancer has a high degree of malignancy, and at detection, it is prone to infiltration of surrounding soft tissues, as well as metastasis to the peritoneum and lymph nodes, peritoneal seeding, and distant metastasis. Whether recurrence occurs becomes an important reference for surgical planning and treatment methods for this disease. Current recurrence prediction models do not consider the potential pathological relationships between internal tissues of the entire ovary. They use convolutional neural networks to extract local region features for judgment, but the accuracy is low, and the cost is high. To address this issue, this paper proposes a new lightweight deep learning algorithm model for predicting recurrence of high-grade serous ovarian cancer. The model first uses ghost convolution (Ghost Conv) and coordinate attention (CA) to establish ghost counter residual (SCblock) modules to extract local feature information from images. Then, it captures global information and integrates multi-level information through proposed layered fusion Transformer (STblock) modules to enhance interaction between different layers. The Transformer module unfolds the feature map to compute corresponding region blocks, then folds it back to reduce computational cost. Finally, each STblock module fuses deep and shallow layer depth information and incorporates patient's clinical metadata for recurrence prediction. Experimental results show that compared to the mainstream lightweight mobile visual Transformer (MobileViT) network, the proposed slicer visual Transformer (SlicerViT) network improves accuracy, precision, sensitivity, and F1 score, with only 1/6 of the computational cost and half the parameter count. This research confirms that the proposed algorithm model is more accurate and efficient in predicting recurrence of high-grade serous ovarian cancer. In the future, it can serve as an auxiliary diagnostic technique to improve patient survival rates and facilitate the application of the model in embedded devices.

Protein kinase C iota promotes glycolysis via PI3K/AKT/mTOR signalling in high grade serous ovarian cancer.

BACKGROUND: Epithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation. METHODS AND RESULTS: Two high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC. CONCLUSION: Taken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.

[An MRI multi-sequence feature imputation and fusion mutual-aid model based on sequence deletion for differentiation of high-grade from low-grade glioma].

OBJECTIVE: To evaluate the performance of magnetic resonance imaging (MRI) multi-sequence feature imputation and fusion mutual model based on sequence deletion in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). METHODS: We retrospectively collected multi-sequence MR images from 305 glioma patients, including 189 HGG patients and 116 LGG patients. The region of interest (ROI) of T1-weighted images (T1WI), T2-weighted images (T2WI), T2 fluid attenuated inversion recovery (T2_FLAIR) and post-contrast enhancement T1WI (CE_T1WI) were delineated to extract the radiomics features. A mutual-aid model of MRI multi-sequence feature imputation and fusion based on sequence deletion was used for imputation and fusion of the feature matrix with missing data. The discriminative ability of the model was evaluated using 5-fold cross-validation method and by assessing the accuracy, balanced accuracy, area under the ROC curve (AUC), specificity, and sensitivity. The proposed model was quantitatively compared with other non-holonomic multimodal classification models for discriminating HGG and LGG. Class separability experiments were performed on the latent features learned by the proposed feature imputation and fusion methods to observe the classification effect of the samples in twodimensional plane. Convergence experiments were used to verify the feasibility of the model. RESULTS: For differentiation of HGG from LGG with a missing rate of 10%, the proposed model achieved accuracy, balanced accuracy, AUC, specificity, and sensitivity of 0.777, 0.768, 0.826, 0.754 and 0.780, respectively. The fused latent features showed excellent performance in the class separability experiment, and the algorithm could be iterated to convergence with superior classification performance over other methods at the missing rates of 30% and 50%. CONCLUSION: The proposed model has excellent performance in classification task of HGG and LGG and outperforms other non-holonomic multimodal classification models, demonstrating its potential for efficient processing of non-holonomic multimodal data.

Emerging and Biological Concepts in Pediatric High-Grade Gliomas.

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.

Tubal Cancer Clinical Management: Two Exceptional Scenarios and a Review of the Literature.

This article provides a literature review on tubal carcinoma to offer an updated insight into its preventative strategies, diagnosis, treatment and oncological surveillance. In addition to the search string utilized, the authors' focus extended to key scientific studies, consensus statements, guidelines and relevant case reports essential for the proper clinical management of the disease, providing a methodologically well-structured literature review combined with practical expertise in the oncological field. This article also includes two special clinical cases that emphasize the importance of understanding the physiopathology and the current state of the art in the anatomopathological advancements in tubal/ovarian/peritoneal carcinoma, often assimilated into a single clinical entity and to which many of the concepts extracted from the literature can apply.

Molecular Analysis of High-Grade Serous Ovarian Carcinoma Exhibiting Low-Grade Serous Carcinoma and Serous Borderline Tumor.

Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification.

Systemic inflammatory markers and volume of enhancing tissue on post-contrast T1w MRI images in differentiating true tumor progression from pseudoprogression in high-grade glioma.

Background: High-grade glioma (HGG) patients post-radiotherapy often face challenges distinguishing true tumor progression (TTP) from pseudoprogression (PsP). This study evaluates the effectiveness of systemic inflammatory markers and volume of enhancing tissue on post-contrast T1 weighted (T1WCE) MRI images for this differentiation within the first six months after treatment. Material and Methods: We conducted a retrospective analysis on a cohort of HGG patients from 2015 to 2021, categorized per WHO 2016 and 2021 criteria. We analyzed treatment responses using modified RANO criteria and conducted volumetry on T1WCE and T2W/FLAIR images.Blood parameters assessed included neutrophil/lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). We employed Chi-square, Fisher's exact test, and Mann-Whitney U test for statistical analyses, using log-transformed predictors due to multicollinearity. A Cox regression analysis assessed the impact of PsP- and TTP-related factors on overall survival (OS). Results: The cohort consisted of 39 patients, where 16 exhibited PsP and 23 showed TTP. Univariate analysis revealed significantly higher NLR and SII in the TTP group [NLR: 4.1 vs 7.3, p = 0.002; SII 546.5 vs 890.5p = 0.009]. T1WCE volume distinctly differentiated PsP from TTP [2.2 vs 11.7, p < 0.001]. In multivariate regression, significant predictors included NLR and T1WCE volume in the "NLR Model," and T1WCE volume and SII in the "SII Model." The study also found a significantly lower OS rate in TTP patients compared to those with PsP [HR 3.97, CI 1.59 to 9.93, p = 0.003]. Conclusion: Elevated both, SII and NLR, and increased T1WCE volume were effective in differentiating TTP from PsP in HGG patients post-radiotherapy. These results suggest the potential utility of incorporating these markers into clinical practice, though further research is necessary to confirm these findings in larger patient cohorts.

Intensity of survivin expression linked to features of aggressive relapsed/refractory diffuse large B-cell lymphoma.

SPiReL is a phase II clinical trial evaluating combination immunotherapy, pembrolizumab and cyclophosphamide, with maveropepimut-S, in survivin-expressing relapsed/refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL). We describe baseline tumor survivin expression and associations with clinico-pathological variables in 25 participants. The median number of survivin-expressing cells was 99%, and the intensity of survivin expression within tumors was heterogeneous by semi-quantitative immunohistochemistry assessment. Tumors with higher numbers of cells expressing 2+/3+ survivin were associated with characteristics of poor outcome, (Lactate dehydrogenase and cell-of-origin). Greater total baseline tumor area was associated with lower proportions of 1+ cells and greater proportions of 2+/3+ cells. High intensity survivin expression is associated with aggressive clinical features supporting a pathobiological role in R/R DLBCL. Future prognostic models incorporating survivin as a clinical biomarker require assessment of intensity, overall expression and should include potential threshold effects of survivin in DLBCL pathobiology.

Integrating HRMAS-NMR Data and Machine Learning-Assisted Profiling of Metabolite Fluxes to Classify Low- and High-Grade Gliomas.

Diagnosing and classifying central nervous system tumors such as gliomas or glioblastomas pose a significant challenge due to their aggressive and infiltrative nature. However, recent advancements in metabolomics and magnetic resonance spectroscopy (MRS) offer promising avenues for differentiating tumor grades both in vivo and ex vivo. This study aimed to explore tissue-based metabolic signatures to classify/distinguish between low- and high-grade gliomas. Forty-six histologically confirmed, intact solid tumor samples from glioma patients were analyzed using high-resolution magic angle spinning nuclear magnetic resonance (HRMAS-NMR) spectroscopy. By integrating machine learning (ML) algorithms, spectral regions with the most discriminative potential were identified. Validation was performed through univariate and multivariate statistical analyses, along with HRMAS-NMR analyses of 46 paired plasma samples. Amongst the various ML models applied, the logistics regression identified 46 spectral regions capable of sub-classifying gliomas with accuracy 87% (F1-measure 0.87, Precision 0.82, Recall 0.93), whereas the extra-tree classifier identified three spectral regions with predictive accuracy of 91% (F1-measure 0.91, Precision 0.85, Recall 0.97). Wilcoxon test presented 51 spectral regions significantly differentiating low- and high-grade glioma groups (p < 0.05). Based on sensitivity and area under the curve values, 40 spectral regions corresponding to 18 metabolites were considered as potential biomarkers for tissue-based glioma classification and amongst these N-acetyl aspartate, glutamate, and glutamine emerged as the most important markers. These markers were validated in paired plasma samples, and their absolute concentrations were computed. Our results demonstrate that the metabolic markers identified through the HRMAS-NMR-ML analysis framework, and their associated metabolic networks, hold promise for targeted treatment planning and clinical interventions in the future.

Cell and gene therapy in neuro-oncology.

The majority of primary brain tumors are gliomas, among which glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 18-24 months, and despite extensive research it remains incurable, thus novel therapies are urgently needed. The current standard of care is a combination of surgery, radiation, and chemotherapy, but still remains ineffective due to the invasive nature and high recurrence of gliomas. Gene therapy is a versatile treatment strategy investigated for multiple tumor types including GBM. In gene therapy, a variety of vectors are employed to deliver genes designed for different antitumoral effects. Also, over the past decades, stem cell biology has provided a new approach to cancer therapies. Stem cells can be used as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. Stem cell-based therapy allows targeted therapy that spares healthy brain tissue as well as establishes a long-term antitumor response by stimulating the immune system and delivering prodrug, metabolizing genes, or even oncolytic viruses. This chapter describes the latest developments and the current trends in gene and cell-based therapy against GBM from both preclinical and clinical perspectives, including different gene therapy delivery systems, molecular targets, and stem cell therapies.

Adjuvant therapy and recurrence risk in non-myoinvasive high-grade (stage IC) endometrial cancer: A systematic review and meta-analysis.

OBJECTIVE: To summarize practice patterns and outcomes among patients with non-myoinvasive high-grade (formerly stage IA, now stage IC) endometrial cancer. METHODS: We conducted a systematic search using MEDLINE, Embase, Cochrane, Web of Science, and ClinicalTrials.gov databases from inception to May 8, 2024 to identify studies reporting on treatment and outcomes of non-myoinvasive high-grade endometrial cancer. We included full-text English reports of patients undergoing adjuvant therapy or surveillance for polyp- or endometrium-confined high-grade endometrial cancer without myometrial invasion containing data on recurrence or survival outcomes. Two reviewers independently screened studies; a third reviewer resolved disagreements. Data were extracted using a standardized form. The primary outcome was recurrence risk. Random-effects meta-analysis was used to summarize binomial proportions and to compare outcomes by adjuvant treatment strategy. RESULTS: A total of 29 studies were included, representing 2770 unique patients. Overall, 49.0 % of patients were managed with observation and 37.9 % with chemotherapy. Most patients (92.5 %) had serous histology. Of 23 studies with data on recurrence, 13.7 % of patients recurred, with a meta-analysis estimate recurrence risk of 11 % (95 % confidence interval [CI]: 8-15 %). Across 13 studies reporting on recurrence by receipt of chemotherapy versus no chemotherapy, comparative meta-analysis showed similar likelihood of recurrence (8.0 % versus 13.2 %; odds ratio 0.73, 95 % CI: 0.38-1.42). Comparative meta-analyses for (1) adjuvant therapy versus observation and (2) observation or vaginal brachytherapy versus chemotherapy and/or external beam radiation therapy demonstrated no statistically significant difference in recurrence risk. Sensitivity analyses results, including those limiting to studies of patients with serous histology (12 studies) or complete surgical staging (10 studies), were overall consistent with the primary analysis. Survival data was inconsistently reported and not amenable to meta-analysis. CONCLUSION: Among patients with non-myoinvasive high-grade endometrial cancer, recurrence risk was 11 % and use of adjuvant therapy was not associated with reduced recurrence risk. Prospective study of this population is warranted.

Routine Urology Consultation and Follow-up After Pediatric Blunt Renal Trauma is Likely Unnecessary.

INTRODUCTION: This study examines the outcomes of high-grade renal trauma in pediatric patients and evaluates the intervention rate. In our hospital, we routinely consult urology on all high-grade injuries. We anticipated minimal intervention, casting doubt on the need for routine urology consultation and follow-up. METHODS: We conducted a retrospective review at a single pediatric trauma center from January 2018 to June 2023, focusing on patients with severe (grade III-V) renal injuries. Data collected included demographics, trauma-related variables, hospital course, interventions, and follow-up. When the grade was not readily available in the electronic medical record, we had a board-certified pediatric radiologist review the imaging and provide the grade. Follow-up was included only if it was with a pediatric urologist. RESULTS: There were 92 patients that met our inclusion criteria. Of these, 47 were grade III, 32 were grade IV, and 13 were grade V. Six (6.5%) patients required inpatient renal stent procedures. Follow-up occurred in 55/92 (60%) patients with a pediatric urologist. Follow-up by grade is as follows: 22/47 (47%) grade III, 22/32 (69%) grade IV, and 11/13 (85%) grade V. Overall 5.8% of patients required antihypertensive medications and this was more likely as injury grade increased. All stents were removed outpatient and there were 3 (3.3%) additional outpatient interventions, all in patients that were symptomatic. CONCLUSION: Given the low prevalence of interventions after discharge, routine consultation and follow-up with urology is likely unnecessary in the absence of an inpatient urologic procedure during the index hospitalization. Patients with high-grade injuries should instead follow up with a trauma clinic or general provider with urology follow-up based on symptoms. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: Level III.