High-grade Tumors Research Articles

An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

RAD51 High-Expressed Hepatocellular Carcinomas Are Associated With High Cell Proliferation

IntroductionRAD51 is a pivotal DNA repair gene managing double-stranded DNA break recognition and repair. RAD51 high expression was associated with adverse outcomes in other cancer types. This study aims to investigate the tumor microenvironment and immune landscape in the RAD51 high-expressed Hepatocellular Carcinoma (HCCs). MethodsA total of 467 patients from two large independent cohorts with clinical and transcriptomic data were obtained. The cohort was dichotomized based on the median RAD51 gene expression. xCell and Gene Set Enrichment Analysis (GSEA) were used. ResultsRAD51 high-expressed HCCs were associated with worse recurrence-free, progression-free, disease-specific, and overall survival (all P < 0.05). While RAD51 high-expressed HCCs were associated with intratumoral heterogeneity, homologous recombination deficiency, and fraction altered scores, mutation or neoantigens were not increased in this group. xCell analysis demonstrated inconsistent immune cell infiltration between two cohorts. Cytolytic activity as well as GSEA with immune-related gene sets also demonstrated inconsistent results between two cohorts as well. On the other hand, RAD51 expression was significantly increased in higher-grade tumors, larger tumors, and higher clinical stages. RAD51 high-expressed HCCs were found to have elevated proliferation score. Furthermore, GSEA exhibited significant enrichment of all the cell proliferation–related gene sets in the Hallmark collection, including E2F targets, G2M checkpoint, Mitotic spindle, MYC targets, and MTORC1 signaling consistently in both cohorts (all false discovery rate < 0.25). ConclusionsRAD51 high-expressed HCCs were associated with worse survival and with increased cell proliferation and were not necessarily associated with immune infiltration or inflammation.

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

55 Influence of gender on immunosurveillance in a novel mouse model of clear cell renal cell carcinoma

Abstract Background Renal Cell Carcinoma (RCC) is a cancer that exhibits sex dimorphism. Males have twice the incidence rate of their female counterparts and more than twice the mortality rate. They frequently present with larger, higher-grade tumors, greater metastatic spread, and earlier diagnosis of disease. Many hormonal, genetic, and environmental reasons have been explored, however a considerable amount of uncertainty remains. Methods Here, we explored the immunologic differences using a novel syngeneic mouse model of ccRCC. Tumors were orthotopically implanted by sub-renal capsular injection in immunocompetent WT C57Bl/6 and immunodeficient mice NOD/Scid/Gamma (NSG) mice, and tumor growth was longitudinally monitored using ultrasound imaging. At necropsy, liver and lung metastases were quantified and immune populations in the tumor and peripheral blood were analyzed by flow cytometry. Results In the immune-competent model, female mice had lower tumor penetrance as well as delayed tumor growth compared to male mice. In contrast, in the immune-deficient model female mice had similar tumor penetrance and growth rates as males suggesting that the female immune system may be protective against tumor development. No metastases were seen in either sex in the immune-competent model, whereas both lung and liver masses were found in the immune-deficient model suggesting the immune system is critical for restricting metastatic development. Interestingly, increased lung metastases were observed in females compared with male counterparts in NSG mice, suggesting that perhaps hormonal or other non-adaptive immunity-mediated mechanisms can promote metastatic seeding into the lungs. Flow cytometry characterization revealed higher peripheral B- and T-cells in females, with a higher CD8/CD4 T-cell ratio. Tumors from females had more activated and cytotoxic CD8 T cells and were more frequently metastatic to the lung compared to male mice. Conclusions Our findings suggest sex-related immunologic differences in immunosurveillance and metastatic tropism that warrants further interrogation. DOD CDMRP Funding: yes

53 Associations between body composition, ClearCode34, and clinical outcomes in localized clear cell renal cell carcinoma

Abstract Background Emerging evidence suggests that pre-surgical body composition is a prognostic factor for cancer outcomes. Lower skeletal muscle quantity and radiodensity have been associated with renal cell carcinoma (RCC) outcomes in other studies, while reports of the relationship between visceral adipose tissue and RCC outcomes have been inconsistent. Mechanisms underlying these associations are unclear but may relate to tumor biology. We leveraged a large molecular epidemiology study of localized clear cell renal cell carcinoma (ccRCC) patients to examine how pre-surgical body composition features were associated with survival post-nephrectomy as well as ClearCode34 status, a previously validated prognostic gene expression signature. Methods The RESOLVE study at Memorial Sloan Kettering Cancer Center is a retrospective study of 1,239 patients with stage I-III ccRCC undergoing nephrectomy without systemic therapy. Pre-surgical CT scans at the third lumbar vertebrae were segmented for the cross-sectional areas and radiodensities of skeletal muscle, subcutaneous adipose and visceral adipose tissues using Automatica software. Formalin-fixed, paraffin-embedded tumor tissue samples were available for 929 patients, which were sent to the University of North Carolina at Chapel Hill and assayed for gene expression. RNA was extracted from these samples and analyzed using the Nanostring nCounter system on a custom panel of 356 genes, including the 34 genes used in the ClearCode34 assay. Of the 929 patients with tumor tissue available, gene expression data from 837 patients (90.1%) passed RNA extraction and data QC. Samples were classified into either ccA or ccB ClearCode34 classes using a reference data set and PAM (prediction analysis of microarrays) centroid-based classification. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) within five years of diagnosis using Cox proportional hazards models for both body composition variables and ClearCode34 subtype. We also estimated odds ratios (ORs) and 95% CIs for associations between ClearCode34 subtype and body composition with logistic regression. All multivariable models were adjusted for age, sex, and all body composition variables. Results Of the 837 patients in our analytic sample, 219 (26%) had ccB tumors. Men, patients with high stage or grade tumors, and patients with chronic kidney disease prior to nephrectomy were more likely to present with ccB tumors. Lower skeletal muscle density (SMD) was significantly associated with lower five-year DFS [HR (95% CI) per 10 HU decrease in SMD: 1.7 (1.2, 2.3)]. While no other body composition features were significantly associated, we also observed non-significantly increased HRs for VATI and VATD [HR (95% CIs): 1.3 (0.8, 2.0) and 1.5 (0.9, 2.7), respectively]. ClearCode34 subtype was significantly associated with five-year DFS, where patients with ccB tumors had poorer DFS [HR (95% CI): 1.7 (1.1, 2.5)] compared to patients with ccA tumors. Notably, we observed no significant associations between any body composition feature and ClearCode34 in univariable analyses. However, in multivariable models that accounted for all body composition variables simultaneously as well as age and sex, lower SMD emerged as significantly associated with ccB subtype [OR (95% CI) per 10 HU decrease in SMD: 1.3 (1.0, 1.7)]. Conclusions Our findings suggest that the associations observed between body composition features and clinical outcomes in ccRCC may be related to tumor biology. Lower pre-surgical SMD, which may represent myosteatosis and metabolic dysregulation in ccRCC patients, was associated with both decreased five-year DFS and an increased likelihood of presenting with a more aggressive ccB tumor. Future studies should investigate body composition features related to ccRCC prognosis and additional markers of tumor biology, such as immune-related gene expression patterns, to extend these findings.

A 10-Year Retrospective Cohort Study of Endometrial Cancer Outcomes and Associations with Lymphovascular Invasion: A Single-Center Study from Germany.

This 10-year retrospective cohort study at a single-center clinic in Germany aimed to analyze the outcomes of endometrial cancer patients and explore the impact of lymphovascular invasion (LV) on patient outcomes and disease-free survival (DFS). Identifying correlations among demographic data, tumor characteristics, treatment modalities, and survival outcomes could enhance patient management and improve survival rates. The study encompassed patients diagnosed and treated for endometrial cancer from January 2010 to December 2020. Clinical and pathological data were extracted from medical records for 311 patients, focusing on variables such as age, histological type, tumor grade, type of surgical treatment, and adjuvant therapies. Survival analysis was conducted using the Kaplan-Meier method and multivariate Cox proportional hazard models to identify factors independently associated with survival. The study demonstrated that lymphovascular invasion significantly impacted survival outcomes on Kaplan-Meier analysis (log-rank p-value = 0.0058). Patients with LV showed a marked decrease in DFS compared to those without LV invasion, with a median DFS of 3.2 years and a hazard ratio of 2.18 (95% CI: 1.56-3.04, p < 0.001). Furthermore, high-grade tumors and p53 positivity were strongly associated with reduced DFS, with hazard ratios of 1.93 (p = 0.001) and 2.11 (p < 0.001), respectively. Patients with distant metastasis exhibited the most significant decline in survival, with a hazard ratio of 5.56 (95% CI: 2.45-10.18, p < 0.001). Despite comprehensive surgical and adjuvant therapies, these high-risk factors dictated poorer outcomes. The presence of lymphovascular invasion, high-grade tumors, and genetic markers like MSI and p53 are pivotal in predicting the course of endometrial cancer. This study underscores the necessity for aggressive management strategies in patients exhibiting these high-risk features to potentially improve prognosis and survival outcomes. The findings advocate for enhanced therapeutic strategies tailored to the biological behavior of the tumor, thereby aiming to elevate the overall survival rates for women diagnosed with endometrial cancer.

Ultrasound-Based Radiomics for Predicting the WHO/ISUP Grading of Clear-Cell Renal Cell Carcinoma

ObjectiveTo explore the performance of ultrasound image-based radiomics in predicting World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading of clear-cell renal cell carcinoma (ccRCC). MethodsA retrospective study was conducted via histopathological examination on participants with ccRCC from January 2021 to August 2023. Participants were randomly allocated to a training set and a validation set in a 3:1 ratio. The maximum cross-sectional image of the lesion on the preoperative ultrasound image was obtained, with the region of interest (ROI) delineated manually. Radiomic features were computed from the ROIs and subsequently normalized using Z-scores. Wilcoxon test and least absolute shrinkage and selection operator (LASSO) regression were applied for feature reduction and model development. The performance of the model was estimated by indicators including area under the curve (AUC), sensitivity and specificity. ResultsA total of 336 participants (median age, 57 y; 106 women) with ccRCC were finally included, of whom 243 had low-grade tumors (grade 1–2) and 93 had high-grade tumors (grade 3–4). A total of 1163 radiomic features were extracted from the ROIs for model construction and 117 informative radiomics features selected by Wilcoxon test were submitted to LASSO. Our ultrasound-based radiomics model included 51 features and achieved AUCs of 0.90 and 0.79 for the training and validation sets, respectively. Within the training set, the sensitivity and specificity measured 0.75 and 0.92, respectively, whereas in the validation set, the sensitivity and specificity measured 0.65 and 0.84, respectively. In the subgroup analysis, for the training and validation sets Philips AUCs were 0.91 and 0.75, Toshiba AUCs were 0.82 and 0.90, and General Electric AUCs were 0.95 and 0.82, respectively. ConclusionUltrasound-based radiomics can effectively predict the WHO/ISUP grading of ccRCC.

Immunohistochemistry for YAP1 N-terminus and C-terminus highlights metaplastic thymoma and high-grade thymic epithelial tumors by different staining patterns.

Metaplastic thymoma (MT), a rare subtype of thymic epithelial tumors (TETs), harbors YAP1::MAML2 fusions. Poroma, a skin tumor, also carries these fusions and exhibits a unique staining pattern for YAP1 immunohistochemistry (IHC), namely, a YAP1 N-terminus (YAP1[N])-positive but YAP1 C-terminus (YAP1[C])-negative pattern. In this context, MT was recently reported to lack YAP1(C) expression exclusively among TET subtypes. However, a lack of information about YAP1(N) expression in that study and another report that wild-type YAP1 expression was diminished in type B3 thymoma and thymic carcinoma warrants further studies for YAP1 expression in TETs. Thus, we immunohistochemically examined YAP1(N) and YAP1(C) staining patterns in our TET samples, including 14 cases of MT. In addition, 11 of the 14 MT cases were genetically analyzed with the formalin-fixed paraffin-embedded tissues if they harbored YAP1::MAML2 fusions. MT consistently exhibited YAP1(N)-positive and YAP(C)-negative staining, whereas type B3 thymoma and thymic carcinoma showed relatively heterogeneous staining patterns for YAP1(N) and YAP1(C) and were sometimes negative for both antibodies. Furthermore, a lower expression of YAP1 was found in type B3 compared to B2 thymomas. Among genetically analyzed 11 MT cases, 6 cases showed YAP1::MAML2 fusions, whereas the analysis failed in 5 very old cases due to poor RNA quality. These results indicate that IHC of both YAP1(N) and YAP1(C) is recommended to obtain staining patterns almost unique to MT. The biological significance of YAP1 in high-grade TETs warrants further investigation.

Optimal Management for Primary High Grade Ta Bladder Cancer: Role of re-staging TURBT and Intravesical Adjuvant Therapy.

This study aims to investigate the impact of risk group classification, restaging transurethral resection (re-TURBT), and adjuvant treatment intensity on recurrence and progression risks in high-grade Ta tumours in patients with non-muscle invasive bladder cancer (NMIBC). Data from a comprehensive bladder cancer database were utilized for this study. Patients with primary high-grade Ta tumours were included. Risk groups were classified according to AUA/SUO criteria. Tumour characteristics and patient demographics were analysed using descriptive statistics. Cox proportional hazard regression models were used to assess the effect of re-TURBT and other clinical/treatment-related predictors on recurrence- and progression-free survivals. The survivals by selected predictors were estimated using Kaplan-Meier method, and groups were compared by the log-rank test. Among 218 patients with high-grade Ta bladder cancer, those who underwent re-TURBT had significantly better 5-year recurrence-free survival (71.1% vs. 26.8%, p = 0.0009) and progression-free survival (98.6% vs. 73%, p = 0.0018) compared with those with initial TURBT alone. Full BCG treatment (induction and maintenance) showed lower recurrence risk, especially in high-risk patients. However, residual disease at re-TURBT did not significantly affect recurrence risk. This study highlights the significance of risk group classification, the role of re-TURBT, and the intensity of adjuvant treatment in the management of high-grade Ta tumours. A risk-adapted model is crucial to reduce the burden of unnecessary intravesical treatment and endoscopic procedures.

AB085. Trans-cortical trans-ventricular approach to pineal tumors: a case series.

Attributing to its deep-seated location, surrounded by significant vessels, surgical management of pineal gland lesions is still considered a challenge. Various surgical approaches are employed to access these lesions, based on patient-specific risks and benefits. Each approach has its merits and demerits. In this study, we aim to narrate our experience with trans-cortical trans-ventricular (TT) approach for pineal tumor resection. We aim to outline the procedure details, safety, efficacy, and treatment outcome of TT. This is a single-center, consecutive case series. All patients with pineal gland tumors who underwent surgical intervention, namely biopsy or resection using TT approach from 2000 to 2023 were included. Data for the patient characteristics, intraoperative details and complications were collected from the hospital's database. Mean [standard deviation (SD)] and frequency (proportions) were calculated for continuous and discrete variables, respectively. We identified 13 patients, mean age 24 (SD: 13) years in our case series. Of them, 8 (61.5%) were male. Most common presenting complains were headaches (69%), nausea/vomiting (38.5%), seizure (23%), and visual deficit (23%). Most patients, 60%, had high grade tumor and average size of tumors were 43.5 mm (SD: 18.45 mm). Pilocytic astrocyotma (23%) and pineal parenchymal tumor of intermediate differentiation (23%) were the most common diagnoses. In total, nine patients had pineal gland lesion biopsy done using TT approach along with the cerebrospinal fluid (CSF) diversion. Of them, four had tumor resection done using the same approach. Whereas four patients had primary excision done using TT approach. There were no intra-operative complications. Two patients had post-operative seizures which were treated with anti-epileptics. We did not identify any long-term sequalae attributed to this approach. We presented our data regarding the safety, efficacy, and outcomes of trans-cortical trans-ventricular approach for pineal tumor surgical management. Utilizing this novel approach for pineal lesion resection can be a great addition to surgeons' armamentarium. This unique approach allows to access the tumor for biopsy/resection and perform CSF diversion procedure, simultaneously. Moreover, the same incision can be used for the second/redo surgery.

Single Nucleotide Polymorphisms in APE1, hOGG1, RAD51 Genes and their Association with Radiotherapy Induced Toxicity among Head and Neck Cancer Patients.

Radiotherapy (RT) is a crucial treatment for head and neck cancer however, it causes adverse reactions to the normal tissue and organs adjacent to target tumor. The present study was carried out to investigate possible association of single nucleotide polymorphism in DNA repair genes with toxicity effects of radiotherapy on normal tissue. Three hundred and fifty head and neck cancer patients receiving radiotherapy treatment were enrolled in this study. The adverse after effects of radiotherapy on the normal tissue in the form of skin reactions were recorded. Single nucleotide polymorphisms of APE1 (rs1130409), hOGG1 (rs1052133) and Rad51 (rs1801320, rs1801321) genes were studied by polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing methods and their association with development of severe radio-toxicity effects was evaluated logistic regression analysis. The 172G/T polymorphism of Rad51 was 2.85 times higher and significantly associated with skin reactions (OR=2.85, 95% CI: 1.50-5.41; p=0.001) and severe oral mucositis (OR=4.96, 95% CI: 2.40-10.25; p<0.0001). These results suggested that the polymorphic nature of Rad51 is responsible for risk of radiotherapy adverse effects in HNC patients. The variant 326Cys and heterozygous 326Ser/Cys genotype of hOGG1 was significantly associated with high tumor grade (OR=3.16 95% CI: 1.66-5.99; p=0.0004, and OR=3.97 95% CI: 2.15-7.34; p=<0.0001 respectively). The homozygous variant 172TT genotype of Rad51 showed positive association with poor response of both tumor and nodes towards radiotherapy treatment (p=0.007 and p=0.022). Interpretation of our results revealed significant association of rs1801321 SNP of Rad51 with development of adverse toxicity reactions in normal tissue of head and neck cancer patients treated with radiotherapy.

A Novel Oncogenic Role of Disulfidptosis-related Gene SLC7A11 in Anti-tumor Immunotherapy Response to Human Cancers.

The protein Solute Carrier Family 7 Member 11 (SLC7A11) plays a pivotal role in cellular redox homeostasis by suppressing disulfidptosis, which restricts tumor growth. Yet, its relevance in prognosis, immunity, and cancer treatment efficacy is not well understood. We conducted a comprehensive analysis of the expression of SLC7A11 across 33 cancer types, employing datasets from public databases. Methods, such as Cox regression and survival analyses assessed its prognostic significance, while functional enrichment explored the biological processes tied to SLC7A11. The association between SLC7A11 expression, immune cell infiltration, and immune-related gene expression was also scrutinized. Notably, SLC7A11 expression was more pronounced in cancerous compared to normal samples and correlated with higher tumor grades. Increased SLC7A11 expression was linked to poor outcomes, particularly in liver hepatocellular carcinoma (LIHC). This protein's expression also showcased significant relationships with diverse molecular and immune subtypes. Additionally, a prognostic nomogram was devised, integrating SLC7A11 expression and clinical variables. High SLC7A11 levels corresponded with cell growth and senescence pathways in various cancers and with lipid and cholesterol metabolism in LIHC. Furthermore, potential therapeutic compounds for LIHC with high SLC7A11 were identified. Real-time PCR (qPCR) and Western blot were conducted to explore the expression of SLC7A11 in tumor tissues and cancer cell lines. In summation, this study emphasizes the prognostic and immunological importance of SLC7A11, spotlighting its potential as a therapeutic target in LIHC.

AB006. The use of magnetic resonance spectroscopy in the differential diagnosis of paediatric intracranial tumours.

Despite different intracranial tumour subtypes varying largely in their prognoses and recommended treatment regimens, they can have markedly similar appearances on standard radiology, especially in paediatric patients where they tend to occur in the midline. There is a need for a non-invasive, accurate method of determining tumour diagnosis to help expedite treatment planning. Existing studies have found magnetic resonance spectroscopy (MRS) to have value in diagnosing intracranial tumours in adults. The aim of this study was to investigate whether MRS could be accurate in diagnosing and grading paediatric intracranial tumours. The hospital database was retrospectively searched for paediatric intracranial tumour patients ≤18 years that had 1.5 T MRS data available. Medical and demographic data were collected from existing records including MRS metabolites N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), and final histopathologic diagnosis. MRS metabolites were then statistically compared against final histopathologic diagnosis. In total, 166 patients were included. In the overall cohort, the tumour to control tissue Cr ratio was significantly higher in grade 1 than grade 4 tumours (P=0.03), and tumour Cho/Cr was significantly higher in grade 4 than grade 1 tumours (P=0.004). When analyzing tumour subtypes, control tissue Cr was significantly higher in embryonal/germ cell tumours than glial tumours (P=0.044). Binary logistic regression models including MRS metabolite ratios and age, sex, and tumour location covariates could diagnose grade 4 tumours [area under the curve (AUC) =0.857], and grade 1 tumours (AUC =0.766) with reasonable accuracy. This study suggests that MRS has benefits in the non-invasive diagnosis of paediatric intracranial tumours, in particular, identifying low- and high-grade tumours. Future advances in MRS technology, and larger cross-sectional studies will be necessary to improve the clinical integration of MRS for accurate non-invasive paediatric intracranial tumour diagnosis.

Clinical, Prognosis, and Treatment Effect Features Analysis of Metachronous and Synchronous UTUC and BUC

ObjectiveTo provide a comprehensive understanding of the clinical features of patients with synchronous and metachronous upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) and inform surgical and postoperative adjuvant treatment planning. Patients and MethodA total of 292 consecutive patients with synchronous and metachronous UTUC-BUC were retrospectively enrolled and were categorized into three groups: (1) UTUC metachronous BUC (N = 185, UTUC-mBUC), (2) BUC-metachronous UTUC (N = 43, BUC-mUTUC), (3) synchronous UTUC-BUC (N = 64, sUTUC-BUC). We compared pathological characteristics and survival data among groups with Wilcoxon's rank sum tests, Pearson's chi-squared, and the Kaplan–Meier method. ResultsIn the sUTUC-BUC group, a higher proportion of patients exhibited UTUC tumors with grade G3 (56%, P = .001) and stage T4 (6%, P < .001) than group UTUC-mBUC (G3 = 16%, T4 = 0%). The proportion of patients with variant histology subtype in group sUTUC-BUC was higher than that of metachronous UTUC-BUC, involving squamous (P = .003), adenoid (P = .012), and sarcomatoid (P < .001) differentiation. It was also observed that the maximum diameter of the UTUC tumor of group sUTUC-BUC (median = 3.5) was significantly larger than group UTUC-mBUC (median = 2.5, P = .002) and group BUC-mUTUC (median = 2.2, P < .001). Notably, sUTUC-BUC has an increased risk of cancer-specific death compared with UTUC-mBUC (P < .001) and BUC-mUTUC (P < .001). On multivariable Cox regression, synchronous UTUC-BUC was an independent predictor of both RFS (P < .001; vs. UTUC-mBUC: HR 0.555, P = .004; vs. BUC-mUTUC: HR 0.279, P < .001) and CSS (P < .001, HR 29.737). Moreover, sUTUC-BUC showed a better response to intravesical therapy and chemotherapy with higher cancer-specific survival (P < .001) and recurrence-free survival (P = .034). ConclusionsThe prognosis and pathological characteristics among different metachronous and synchronous UTUC and BUC were diverse. The synchronous UTUC-BUC group showed variant histology subtype, high-grade tumors, advanced tumors, multifocal UTUC, worse cancer-specific survival, but better response to intravesical therapy and chemotherapy.

AB011. A propensity-score matched prospective study on the impact of tumour treating fields (TTF) on overall survival and quality of life in newly diagnosed WHO grade 4 astrocytoma patients.

World Health Organization (WHO) grade 4 astrocytoma is a high-grade brain tumour in adults. Tumour treating fields (TTF) has been shown to improve overall survival (OS). Few studies have explored quality-of-life (QoL) in these patients. This study aims to assess the QoL of TTF patients and OS. This was a prospective multicenter study of adult patients diagnosed with WHO grade 4 astrocytoma from 2018 to 2023 receiving TTF for >1 month after completing standard therapy. A propensity-score matched comparison with a 1:2 ratio with historical control was performed for OS analysis. The patients completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-30/BN20 questionnaires before TTF and at 3-month interval. Primary outcomes included OS, and secondary outcomes included QoL and TTF-associated adverse effects at 3 months. A total of 141 patients were reviewed, with TTF patients (n=47, 33%) and propensity-score matched controls (n=94). The mean duration of TTF use was 10±8 months. The mean age of the TTF group was 54±13 years, and for the control group 52±13 years. Sixty percent (n=28) were male, similar to the control group with 71% (n=67) (P=0.16). Seventy-two percent of TTF patients had preoperative Karnofsky Performance Scale (KPS) score ≥80, while controls had 70% (P=0.79). Five (11%) TTF patients and 8 (9%) controls were IDH1 mutant (P=0.70). Twenty (43%) TTF patients and 42 (45%) controls were O6-methylguanine-DNA methyltransferase promoter (pMGMT) methylated (P=0.81). Twenty-one (45%) of TTF patients and 55 (59%) of controls had gross total resection (P=0.72). After adjusting for independent predictors for OS, the median OS of the TTF group was 22.4 months [interquartile range (IQR): 18.6-26.5 months], significantly longer than the control group (17.2 months; IQR: 12.1-22.3 months) (log-rank test: P=0.01). Forty-seven TTF patients and 40 control patients completed EORTC questionnaires. There was no difference for EORTC functional and symptom scores between the TTF and control group [P=0.45, analysis of variance (ANOVA)] at 3 months. Thirty-two (67%) of TTF patients reported associated RTOG grade I scalp dermatitis. TTF for WHO grade 4 astrocytoma patients is an independent predictor for OS. QoL between the groups was similar, and overall QoL over time for TTF patients was not affected. TTF is a novel and effective outpatient treatment with minimal adverse effects.

Accuracy of an Artificial Intelligence System for Interval Breast Cancer Detection at Screening Mammography.

Background Artificial intelligence (AI) systems can be used to identify interval breast cancers, although the localizations are not always accurate. Purpose To evaluate AI localizations of interval cancers (ICs) on screening mammograms by IC category and histopathologic characteristics. Materials and Methods A screening mammography data set (median patient age, 57 years [IQR, 52-64 years]) that had been assessed by two human readers from January 2011 to December 2018 was retrospectively analyzed using a commercial AI system. The AI outputs were lesion locations (heatmaps) and the highest per-lesion risk score (range, 0-100) assigned to each case. AI heatmaps were considered false positive (FP) if they occurred on normal screening mammograms or on IC screening mammograms (ie, in patients subsequently diagnosed with IC) but outside the cancer boundary. A panel of consultant radiology experts classified ICs as normal or benign (true negative [TN]), uncertain (minimal signs of malignancy [MS]), or suspicious (false negative [FN]). Several specificity and sensitivity thresholds were applied. Mann-Whitney U tests, Kruskal-Wallis tests, and χ2 tests were used to compare groups. Results A total of 2052 screening mammograms (514 ICs and 1548 normal mammograms) were included. The median AI risk score was 50 (IQR, 32-82) for TN ICs, 76 (IQR, 41-90) for ICs with MS, and 89 (IQR, 81-95) for FN ICs (P = .005). Higher median AI scores were observed for invasive tumors (62 [IQR, 39-88]) than for noninvasive tumors (33 [IQR, 20-55]; P < .01) and for high-grade (grade 2-3) tumors (62 [IQR, 40-87]) than for low-grade (grade 0-1) tumors (45 [IQR, 26-81]; P = .02). At the 96% specificity threshold, the AI algorithm flagged 121 of 514 (23.5%) ICs and correctly localized the IC in 93 of 121 (76.9%) cases, with 48 FP heatmaps on the mammograms for ICs (rate, 0.093 per case) and 74 FP heatmaps on normal mammograms (rate, 0.048 per case). The AI algorithm correctly localized a lower proportion of TN ICs (54 of 427; 12.6%) than ICs with MS (35 of 76; 46%) and FN ICs (four of eight; 50% [95% CI: 13, 88]; P < .001). The AI algorithm localized a higher proportion of node-positive than node-negative cancers (P = .03). However, no evidence of a difference by cancer type (P = .09), grade (P = .27), or hormone receptor status (P = .12) was found. At 89.8% specificity and 79% sensitivity thresholds, AI detection increased to 181 (35.2%) and 256 (49.8%) of the 514 ICs, respectively, with FP heatmaps on 158 (10.2%) and 307 (19.8%) of the 1548 normal mammograms. Conclusion Use of a standalone AI system improved early cancer detection by correctly identifying some cancers missed by two human readers, with no differences based on histopathologic features except for node-positive cancers. © RSNA, 2024 Supplemental material is available for this article.

AB032. The effect of high-dose dexamethasone on systemic immune-inflammation index (SII) in patients with brain tumor, a retrospective study in tertiary hospital in Indonesia.

Inflammation plays an important role in proliferation, migration, and invasion of tumor cells; therefore, many research has been done to investigate inflammation parameters including systemic immune-inflammatory index (SII). Dexamethasone, a strong anti-inflammatory, is still widely used as the main treatment in vasogenic edema. High-dose administration (16 mg/day) is recommended in patients with brain tumors with increased intracranial pressure. We performed this retrospective study to determine SII profile, dexamethasone use, and the effect of high-dose dexamethasone on SII in patients with brain tumors. We performed a retrospective study on patients with brain tumors in 2022-2023 period who were treated with intravenous high-dose dexamethasone. Patient demographics, clinical characteristics of the brain tumor, concurrent infection, as well as dexamethasone dose and duration were recorded. Platelet, neutrophil, and lymphocyte count obtained prior to dexamethasone administration, and on the fifth to seventh day were also collected. SII was calculated by the following formula: neutrophil × platelet counts/lymphocyte. Data were then analyzed using Microsoft Excel 2019 and SPSS 29.0.2.0. We enrolled 56 patients with brain tumors, age 47±13.5 years, 78.6% were female, 69.6% had malignant brain tumors (brain metastases and high-grade primary brain tumors) and 26.8% had concurrent infection. High-dose dexamethasone was administered with average dose of 16.8±3.3 mg/day for average duration of 4.8±1.8 days. SII was significantly higher in malignant compared to benign brain tumors both in prior and after dexamethasone administration (P=0.02, P=0.01). SII was significantly higher in metastasis brain tumor compared to primary brain tumor (P=0.005). High-dose dexamethasone significantly increased SII and decreased lymphocyte count (P=0.006, P=0.04). SII was found higher in malignant brain tumor and brain metastasis. High-dose dexamethasone was administered with average dose of 16.81±3.37 mg/day for average duration of 4.78±1.84 days. SII was found to be higher after high-dose dexamethasone, due to a decrease of lymphocyte counts in peripheral blood.

Management considerations and treatment outcomes for newly diagnosed prostate cancer in advanced age patients (≥80 years): real-world data from a single urological center over a 10-year period.

There is ongoing debate regarding prostate cancer (PCa) screening in advanced age males, leading to treatment decisions often based on tumor staging and life expectancy. A critical gap in clinical evidence and tailored guidelines for the advanced age with PCa persists. This study aims to compare survival outcomes of various treatment approaches in this demographic. We analyzed data from a large urological center for advanced age patients suspected of having PCa between 2012 and 2022. We collected clinical and pathological characteristics and evaluated treatment modalities, including palliative therapy and definitive therapy. Propensity score matching (PSM) analysis was implemented to reduce bias between treatment modalities. Kaplan-Meier and multivariate Cox proportional hazard regression analyses were conducted to evaluate progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Out of 4,333 suspected patients, 376 individuals aged 80 years and older underwent prostate biopsy. The overall detection rate of PCa was 78.7%, with a high prevalence of high-grade tumors [International Society of Urological Pathology (ISUP) grade ≥2]. Most patients (86.5%) received palliative therapy, while 13.5% underwent definitive therapy. Patients in the definitive therapy group had lower prostate-specific antigen (PSA) values, lower tumor stage, and Charlson Comorbidity Index (CCI), longer life expectancy, and a higher Geriatric 8 (G8) score compared to the palliative therapy group. The median OS for the entire cohort was 72.0 months, with 70.0 months for palliative therapy and 96.0 months for definitive therapy. Multivariable analyses identified lymphatic and bone metastasis, as well as definitive therapy, as independent prognostic factors for PFS, CSS, and OS. Advanced age patients, although a small group, have distinct characteristics, including higher PSA levels, positive biopsy rates, and pathological grading and staging. In medically fit elderly patients, especially those with localized PCa and a life expectancy of ≥5 years, definitive therapy could improve survival outcomes.

AB019. Detailed analysis of DNA hydroxymethylation observed with the malignant progression of IDH-mutant gliomas.

Gliomas vary in prognosis with World Health Organization (WHO) grade. Low-grade gliomas can undergo malignant progression (MP), becoming aggressive high-grade tumors, worsening prognosis. This is prevalent in isocitrate dehydrogenase-mutant (IDH-mt) gliomas like astrocytoma and oligodendroglioma, but the mechanism of MP is still not fully understood. High-grade IDH-mt gliomas have been reported to exhibit TET-mediated DNA hydroxymethylation, which is suggested to potentially influence gene expression. We hypothesized that hydroxymethylation in specific regions could be implicated in triggering MP. We collected glioma tumor samples over a decade, using WHO 2021 classification to study IDH-mt astrocytoma grade 2 progression to grades 3 or 4, indicating MP. Samples from five patients, demonstrating MP, were analyzed for DNA hydroxymethylation status across more than 850,000 genomic locations using the oxidative bisulfite process and Infinium EPIC methylation array. This was complemented by RNA sequencing for gene expression analysis and its correlation with hydroxymethylation, and motif-enrichment analysis to infer transcription factor involvement in hydroxymethylation-based gene regulation. Additionally, to delve into the fundamental causes of hydroxymethylation, we exposed an IDH-mt glioma cell line to hypoxic conditions and systematically explored the genomic locations where hydroxymethylation occurred. Our comprehensive analysis identified a significant overlap of hydroxymethylated genomic regions across samples during MP, with a notable enrichment in open sea and intergenic regions (P<0.001). These regions were significantly associated with cancer-related signalling pathways. Integration with RNA sequencing data revealed 91 genes with significant correlations between hydroxymethylation and gene expression, implying roles in cell cycle regulation and antineoplastic functions. Furthermore, motif-enrichment analysis suggested the potential regulatory role of KLF4 in these processes. The cell culture results revealed that a certain similarity exists between the hydroxymethylation patterns observed during MP and those in glioma cells cultured under hypoxic conditions. This study elucidates the importance of region-specific DNA hydroxymethylation in the MP of IDH-mt astrocytomas, suggesting its potential impact on gene expression relevant to cancer malignancy. Our findings propose a complex interplay between hydroxymethylation and gene regulation, which may offer new insights into the mechanisms driving glioma progression and highlight potential targets for therapeutic intervention.

AB037. Association between systemic immune-inflammation index with hypercoagulable state in primary brain tumor: a retrospective study in Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

Hypercoagulable state is considered a common complication in brain tumors, which increases the risk of thromboembolic events, leading to mortality and morbidities. Detecting hypercoagulability typically requires expensive tests, such as D-dimer and fibrinogen, which are not accessible in many healthcare facilities in Indonesia. The systemic immune-inflammation index (SII) is known as an inflammation marker that contributes to hypercoagulability in many conditions. SII tests are more affordable and widely available, but there is still not much study that investigates the association between SII and hypercoagulable state in primary brain tumors. This preliminary study aimed to find an association between SII with hypercoagulable state in primary brain tumor conditions. We collected data from inpatients diagnosed with primary brain tumors from 2021 to 2023 in Dr. Cipto Mangunkusumo Hospital. Hypercoagulable states were established from high D-dimer serum testing (>660 µg/L). SII was calculated by the following formula: neutrophil counts × platelet counts/lymphocyte counts. Both D-dimer and SII were collected at first admission to the hospital. The receiver operating characteristic (ROC) curve were used to determine the SII cut-off value. Bivariate and multivariate logistic analyses were performed to confirm the association with the incidence of hypercoagulable state. This study enrolled 65 patients with primary brain tumors, 73.8% subjects with hypercoagulable state. A total of 61.5% were female, mean age 47.54±2.02 years. High-grade tumors exhibited a higher prevalence than low-grade tumors (53.8% vs. 46.2%). SII cut-off value determined at 1,343.50 (sensitivity 56.9%, specificity 57.1%). We found no significant association between SII and hypercoagulable state. Multivariate analyses show that duration of brain tumor before 6 months (P=0.04), and history of brain tumor surgery (P=0.02) were significantly associated with the incidence of hypercoagulable state in primary brain tumor. Based on the findings in this investigation, we find 73.8% subjects with hypercoagulable states in primary brain tumor. No significant relationship between high SII and hypercoagulable states but significant association of duration brain tumor before 6 months and history of brain tumor surgery with hypercoagulable state in primary brain tumor.