Grade Tumors Research Articles

Association of PD-L1 immunoexpression with tumor grade in colorectal adenocarcinoma

Globally, colorectal cancer (CRC) is the primary cause of cancer-related deaths, and in emerging countries, its prevalence is continuously increasing. With all the advancements in surgery and treatment, the outlook for CRC patients is still not good. Even with the use of standard prognostic markers, there are presently no effective prognostic techniques for colorectal cancer. The long-term survival of many malignancies has been significantly enhanced by immune checkpoint blockades (ICB), suggesting that the immune checkpoint mechanism is crucial in inhibiting tumor-specific immune responses in the tumor microenvironment. By inhibiting T effector cell activity, the "PD-1 (programmed cell death-1)"/PD-L1 (programmed cell death-ligand 1) axis contributes significantly to immune suppression control and allows tumor cells to evade the host's anti-tumor immune surveillance. While early study suggested that immunotherapy was not relevant for patients with colorectal cancer, more recent studies have demonstrated that immunotherapy was beneficial for a certain subset of patients. This suggests that the prognosis prediction of colorectal cancer may benefit from a thorough evaluation of the local immune response. This study set out to assess the association between PD-L1 immunoexpression and tumor grade in CRC. : This was a cross-sectional observational study. Paraffin blocks of total 64 cases were selected from the patients who were diagnosed as adenocarcinoma from resected samples received in the department of pathology at BSMMU from July 2021 to June 2023. Immuno-histochemical staining for PD-L1 was performed using 28-8 clone along with appropriate positive control. In this study, PD-L1 immuno-expression was found in 14(21.9%) out of 64 cases. However, no expression was found in rest of the 50 (78.1%) cases. This study showed association of PD-L1 expression with high grade (Grade-3) tumors. : Evaluation of expression of PD-L1 may emerge as a new marker and target for the immunotherapy of colorectal cancer.

Liver metastases in high-grade neuroendocrine neoplasms: A comparative study of hepatic tumor volume and biochemical findings in NET G3 versus NEC.

Abnormal liver blood tests and liver tumor burden are known prognostic factors in neuroendocrine neoplasms (NEN). However, the relationship between biochemical liver parameters and hepatic tumor load is largely unknown in NEN and in high-grade NEN (G3) specifically. The primary objective of this study was to correlate the biochemical parameters and liver tumor volume of patients with neuroendocrine tumors grade 3 (NET G3) or neuroendocrine carcinomas (NEC). We wanted to investigate whether patients with NET G3 with extensive liver involvement had less severely elevated laboratory liver parameters than NEC patients. In total, 46 patients with NEN were included, 31 had NEC and 15 NET G3. All patients had distant metastatic disease, with liver metastases being the most common (n = 39). Both laboratory results and semiautomatic volumetric measurements of liver tumor burden were obtainable for 34 patients at baseline and 26 patients at follow-up. Alkaline phosphatase (AP), gamma-GT (gGT), and lactate dehydrogenase (LDH) increased significantly between the two time periods (p < .01). In a regression model, liver tumor burden significantly affected several blood parameters, for example, increasing AP, gGT, LDH, and aspartate aminotransferase (ASAT) by a factor of 1.02-1.04 per unit increase (1% tumor burden; all p < .001). AP, gGT, and LDH were significantly lower in NET G3 (factor of 0.43-0.68) than in NEC. Here, we found that liver chemistries changed over the NEN disease course, correlated with hepatic tumor burden, and differed by histologic subtype. The current data can potentially guide treatment decisions, for example, with regard to integration of liver-directed therapies.

Planned and Unplanned Sarcoma Resections: Comparative Analysis of Local Recurrence, Metastasis, and Mortality

Background: Sarcomas, a diverse group of malignant tumors arising from mesenchymal tissues, pose significant diagnostic and therapeutic challenges. This study compares the outcomes of planned resections (PEs) and unplanned resections (UEs) to inform better clinical practices. Methods: Data were analyzed from the Swiss Sarcoma Network (SSN), including patients with soft tissue and bone sarcomas treated at two major hospitals. This study utilized logistic regression and Cox regression models to examine the odds of UEs and their impact on local recurrence-free survival. Results: Among 429 patients registered by SSN members, 323 (75%) underwent PEs and 106 (25%) experienced UEs. PEs were associated with significantly larger tumors (94 mm vs. 47 mm, p &lt; 0.001) and higher-grade tumors (Grade 3: 50.5% vs. 37.4%, p = 0.03). Despite achieving superior resection margins (R0: 78.8% vs. 12.6%, p &lt; 0.001), PEs showed higher metastasis rates at follow-up (31.0% vs. 10.4%, p &lt; 0.001) and greater cancer-specific mortality (16.7% vs. 6.6%, p = 0.01). UEs, while linked to higher local recurrence, did not significantly affect metastasis-free survival (MFS) or overall survival (OS). Conclusions: PEs achieve superior immediate surgical outcomes but are linked to higher metastasis and cancer-specific mortality due to the advanced stage of tumors. UEs, while associated with higher local recurrence rates, do not significantly impact MFS or OS. Early detection, comprehensive diagnostics, and timely referrals to specialized sarcoma hubs are essential to avoid UEs and reduce metastatic risk. Future research should focus on developing diagnostic tools using individual tumor and patient characteristics to improve sarcoma management.

Prognostic impact of diagnostic and therapeutic time delays in breast cancer: an exploratory data analysis for patients at Parirenyatwa Hospital, Zimbabwe

Objective: This paper seeks to investigate factors related to time delays for diagnosis and treatment in breast cancer patients at Parirenyatwa Hospital in Zimbabwe and subsequently evaluate the effects of presentation and diagnosis delays on cancer stage. Methods: The study was done for 379 patients with histologically diagnosed invasive breast cancer, from 2015 through to 2029. The study sought to identify factors associated with the time delays ( months)using parametric and non-parametric methods, depending on whether underlying assumptions of such tests are met. A multiple logistic regression model was also used to analyse the association between factors, primary delay, secondary delay variables and cancer stage. Results: The median of the primary, secondary and treatment delay were found to be 7.6, 1 and 0.4 months respectively. Rural residence, Karnofsky Performance Score below 70%, hypertension comorbidity, tumor size (&gt;5cm) and well differentiated tumors (grade 1) were significant factors for delayed presentation. Longer primary delay times and post-menopausal status were associated with secondary delay. Advanced cancer stage at diagnosis and those on medical aid were more likely to have a delay in treatment onset. Conclusion: Primary and secondary delay were predictive of advanced disease using logistic regression. Keywords: Breast cancer; primary delay; secondary delay; treatment delay; Zimbabwe.

Peritumoral radiomics increases the efficiency of classification of pure ground-glass lung nodules: a multicenter study

PurposeWe aimed to evaluate the efficiency of computed tomography (CT) radiomic features extracted from gross tumor volume (GTV) and peritumoral volumes (PTV) of 5, 10, and 15 mm to identify the tumor grades corresponding to the new histological grading system proposed in 2020 by the Pathology Committee of the International Association for the Study of Lung Cancer (IASLC).MethodsA total of 151 lung adenocarcinomas manifesting as pure ground-glass lung nodules (pGGNs) were included in this randomized multicenter retrospective study. Four radiomic models were constructed from GTV and GTV + 5/10/15-mm PTV, respectively, and compared. The diagnostic performance of the different models was evaluated using receiver operating characteristic curve analysisResultsThe pGGNs were classified into grade 1 (117), 2 (34), and 3 (0), according to the IASLC grading system. In all four radiomic models, pGGNs of grade 2 had significantly higher radiomic scores than those of grade 1 (P < 0.05). The AUC of the GTV and GTV + 5/10/15-mm PTV were 0.869, 0.910, 0.951, and 0.872 in the training cohort and 0.700, 0.715, 0.745, and 0.724 in the validation cohort, respectively.ConclusionsThe radiomic features we extracted from the GTV and PTV of pGGNs could effectively be used to differentiate grade-1 and grade-2 tumors. In particular, the radiomic features from the PTV increased the efficiency of the diagnostic model, with GTV + 10 mm PTV exhibiting the highest efficacy.

Anti-phosphohistone H3 (PHH3) as a proliferation marker to assess mitotic activity and to grade neuroendocrine neoplasms of hepatopancreaticobiliary (HPB) system.

The world health organization (WHO) classification of neuroendocrine neoplasms (NENs, i.e. neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs)) of the gastrointestinal system involves grading of these tumors by mitotic count (i.e. H and E mitotic index or Haematoxylin and Eosin mitotic index [HE-MI] and Mindbomb E3 ubiquitin protein ligase 1 labelling index (MIB1-LI) into Grade 1 (G1), Grade 2 (G2), or Grade 3 (G3). However, the assessment of HE-MI and MIB1-LI is hindered by several factors that contribute to discordance between these two grading methods. Clinical data demonstrate the dependency of prognosis on grade. The objective of this study was to compare the grading of NENs of the hepatopancreatobiliary (HPB) system using Anti-phosphohistone H3 mitotic index (i.e. PHH3-MI), HE-MI and MIB1-LI. In a cohort of 140 NENs selected from January 2011 to August 2019, the concordance and correlation between HE-MI, MIB1-LI and PHH3-MI grading methods were analysed using Cohen's weighted kappa (κ) statistics and Spearman's correlation (ρ), respectively. Receiver operating characteristic (ROC) curve and cut-off analyses were done to determine optimal PHH3-MI cut-off values to grade NENs. The rates of discordance between HE-MI vs. MIB1-LI, PHH3-MI vs. MIB1-LI and PHH3-MI vs. HE-MI were 52% (κ =0.416), 29% (κ =0.64) and 41% (κ =0.508), respectively. There was a significant correlation between the grading methods. PHH3-MI had good overall sensitivity and specificity at cut-offs 2 and 17 in distinguishing between G1 vs. G2, and G2 vs. G3 tumors, respectively. PHH3 immunolabeling allowed for quick and easy identification of mitotic figures (MF). It had the highest concordance with MIB1-LI. At cut-off values of 2 and 17, there was good overall sensitivity and specificity. The interobserver agreement was excellent.

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.

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.

MiRNA Expression Profiling in G1 and G2 Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine neoplasms pose a growing clinical challenge due to their rising incidence and variable prognosis. The current study aims to investigate microRNAs (miRNA; miR) as potential biomarkers for distinguishing between grade 1 (G1) and grade 2 (G2) pancreatic neuroendocrine tumors (PanNET). A total of 33 formalin-fixed, paraffin-embedded samples were analyzed, comprising 17 G1 and 16 G2 tumors. Initially, literature-based miRNAs were validated via real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), confirming significant downregulation of miR-130b-3p and miR-106b in G2 samples. Through next-generation sequencing, we have identified and selected the top six miRNAs showing the highest difference between G1 and G2 tumors, which were further validated. RT-qPCR validation confirmed the downregulation of miR-30d-5p in G2 tumors. miRNA combinations were created to distinguish between the two PanNET grades. The highest diagnostic performance in distinguishing between G1 and G2 PanNETs by a machine learning algorithm was achieved when using the combination miR-106b + miR-130b-3p + miR-127-3p + miR-129-5p + miR-30d-5p. The ROC analysis resulted in a sensitivity of 83.33% and a specificity of 87.5%. The findings underscore the potential use of miRNAs as biomarkers for stratifying PanNET grades, though further research is warranted to enhance diagnostic accuracy and clinical utility.

IMG-34. THE UTILITY OF [18F]FET PET IMAGING IN PAEDIATRIC CNS TUMOURS: A SINGLE INSTITUTION EXPERIENCE IN SYDNEY, AUSTRALIA

Abstract BACKGROUND MRI remains the standard imaging modality in paediatric CNS tumours. Whilst Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F-FET) is a well-established tool in adult central nervous system (CNS) tumours, established data on its diagnostic utility and impact on clinical management in children and adolescents remain limited. METHODS Single centre retrospective review of database of all paediatric and adolescent patients (age 0-19years) who underwent 18F]FET-PET imaging with cross referencing of patient electronic medical records. Conducted at the Children’s Hospital at Westmead in Sydney, Australia. RESULTS 116 patients underwent 18F-FET PET imaging between October 2012 and January 2024. 28 patients had additional comparative fluorodeoxyglucose (FDG) CNS dedicated PET imaging. Primary indications for FET PET imaging included differentiating between a neoplastic versus non-neoplastic process (23.3%), identifying active residual tumour (14.7%), characterising tumour grade in patients including in those with the known tumour predisposition syndromes (6%), distinguishing between progression pseudo-progression (2.5%) and providing additional localisation or biopsy guidance (8.6%). Malignant transformation, gliomatosis and extent of disease was also noted as indications. 15 patients were able to avoid a biopsy or invasive surgery. Nearly 60% of FET PET imaging was considered clinically useful with the management of 52/112 (46%) patients being supported or changed. Management changes included change second look surgery, change of radiation field, change of treatment and access to a clinical trial. Only 3 scans were reported to have technical challenges in resolution or poor spatial correlation with MRI. Further analysis is currently being conducted, reviewing standard uptake values (SUV’s) of histologically proven low/high grade tumours and T2 enhancing/non-enhancing lesions. CONCLUSIONS This small study demonstrated the clinical benefit and utility of 18F-FET PET imaging in paediatric CNS tumours. Our experience has demonstrated significant surgical and diagnostic advantage in tumour localisation as well as avoiding surgery where able.

Expression of hormone receptors and human epidermal growth Factor2/Neu in female breast cancer patients

Overexpression of HER2/neu and estrogen receptors (ER) and/or progesterone receptors (PR) are reported to be inversely associated with breast cancer (BC). The relationship between hormone receptors and HER2/neu is attenuated by age and numerous other clinical factors. Here, we examined the link between hormone receptors and HER-2/neu in terms of an additional variable, such as the histological grades of breast tumors in women. A total of 240 breast cancer samples were obtained from the Department of Histopathology at the University of Lahore Teaching Hospital in Lahore, Punjab. Immunohistochemistry (IHC) was used to examine the expression of hormone receptors and HER-2/neu. Using the χ2 and fisher exact test, the association between hormone receptors and HER-2/neu in various age groups and histological grades was investigated. Patients that were included in this study had ages between 30 and 90 years, with a mean age of 51.89 ± 12.01 years, and were mostly having grade 1 tumors. The most prevalent type of breast cancer was invasive ductal carcinoma (95.83%). It was found that the ER, PR, and HER-2/neu were more expressive in older (above 45) and grade 1 tumors as compared to younger (≤45) and higher-grade tumor patients. HER-2 was negatively correlated with hormonal receptors in women aged >45 years old with grade-1 tumors. Hormonal receptor (ER/PR) expression is associated with HER-2/neu expression not only in older age (>45) but also in grade 1 tumors. This correlation between HER2/neu and hormone receptors that improves with age and tumor grade is useful for predicting outcomes and, likely, for guiding therapy choices.

Prognostic indicators of recurrence after surgical resection in non-pancreatic gastrointestinal neuroendocrine tumors.

e16287 Background: The incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has continued to increase over the last two decades. In patients with locoregional disease, surgical resection of the primary tumor without additional therapies is considered standard of care. The frequency and risk factors associated with recurrence and survival in patients with non-pancreatic GI-NETs are poorly defined. We aimed to evaluate clinical and pathological factors associated with recurrence and survival in patients with resected non-pancreatic GI-NETs. Methods: We conducted a retrospective review of patients who presented to the Johns Hopkins Hospital between 2000-2019 with locoregional small bowel, colon, appendiceal, and rectal neuroendocrine tumors who underwent surgical resection with curative intent. We collected clinical and pathological data including tumor primary site, tumor differentiation, grade using Ki-67 labeling index (grade 1, 2, or 3), margin involvement, perineural or vascular invasion, time of recurrence, patterns of recurrence, and death. Patients with metastatic disease at the time of diagnosis and insufficient follow up were excluded. Results: A total of 133 patients met inclusion criteria. Most patients had tumors originating from the small bowel (n = 87, 66%), followed by the appendix (n = 19, 15%), rectum (n = 18, 14%), and colon (n = 7, 5%). With a median follow-up of 35 months, 23 patients (17%) had tumor progression after curative-intent surgery, with the liver (n = 13, 57%) as the most common site. In the majority of patients, tumors were well-differentiated (n = 118, 97%) and grade 1 (n = 78, 75%). Intermediate/high grade tumors (grade 2/3) occurred in 26 (25%) of patients. Median progression-free survival was 226 months (18.8 years). Age (greater than 60) and intermediate/high grade tumors (grade 2 or 3) were associated with worse overall survival HR = 5.5 (95% CI: 1.5, 19.6), p = 0.009, and HR = 3.3 (95% CI: 1.1, 10.2), p = 0.034, respectively. Tumor grade (2 or 3) and positive nodes were associated with worse progression-free survival HR = 4.5 (95% CI: 2.0, 10.1), p = 4e-04, and HR = 3.1 (95% CI: 1.4, 6.8), p = 0.009, respectively. Conclusions: A significant number of patients (17%) with non-pancreatic GI-NETs had tumor progression after curative-intent surgery. Risk factors for recurrence include intermediate/high-grade tumors and positive lymph nodes. Further studies are needed to evaluate the role of adjuvant therapy in patients at higher risk of recurrence following surgical resection for non-pancreatic GI-NETs.

Factors associated with surgical intervention in Native American patients with hepatocellular carcinoma.

e16279 Background: Hepatocellular carcinoma (HCC) is the prevailing type of primary liver cancer, exhibited at a higher frequency in individuals afflicted by chronic liver conditions. Past literature has demonstrated the impact certain socioeconomic factors have on the prognosis of HCC. Native American patients often face late-stage cancer diagnoses and have the lowest survival rates among racial and ethnic groups. While surgery offers potential for cure, factors related to surgical interventions in liver cancer for Native American patients remain largely unexplored. Through the NCDB, this study analyzed factors associated with surgical intervention and survival trends in Native American patients with HCC. Methods: The National Cancer Database (NCDB) was used to identify Native American patients diagnosed with Hepatocellular Carcinoma from 2004 to 2019 using the histology code 8170 and race code 03 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 27, and statistical significance was set at α = 0.05. Results: Of 1193 Native American patients included in this sample, 172 (14.4%) patients received surgical treatment for HCC, while 1021 (85.6%) patients did not receive surgical treatment for HCC. Native American patients who received surgery for HCC experienced a greater mean overall survival (90 months) when compared to the mean overall survival (24 months) in HCC Native American patients who did not receive surgical treatments (p &lt; 0.001). When controlling for age, year of diagnosis, stage, grade, facility type and income status, receiving surgery showed an independent decrease in hazard (HR = 0.245; p &lt; 0.05). HCC Native American patients who received surgery were more likely to be treated an at academic facility, have stage I disease, and have less aggressive tumors (grade) (p &lt; 0.05). Native American patients who did not receive surgery were more likely to be older (62 vs 60 years old), have larger tumors, and have brain, bone, lung, and liver metastases (p &lt; 0.05). No associations of surgical versus non-surgical treatment were seen in Charlson-Deyo score, urban or rural residence, and primary payor at diagnosis. Conclusions: Native American patients with HCC who received surgical intervention experienced improved overall survival compared to non-surgical treatment groups. Native American patients undergoing surgical intervention more often received care at academic or private institutions and had lower stages of HCC. These results follow previous trends, where cancer patients receiving adequate surgical intervention generally survive longer. Further research is needed to examine other treatment differences among Native American patients and how these findings compare across other disadvantaged groups.

Targeting Chemoresistance in Advanced Bladder Cancers with a Novel Adjuvant Strategy.

Advanced urinary bladder cancer is characterized by rapid progression and development of therapy resistance. About 30% of the patients are diagnosed with high-grade tumors (grade > T2a). A typical nonsurgical treatment is systemic chemotherapy using cisplatin (C) and gemcitabine (G). However, treatment failure and subsequent disease progression are common in treated patients, and adjuvant therapies are not significantly effective. The therapeutic potential of a molecular hybrid of ursolic acid (UA), a pentacyclic-triterpene conjugated to N-methyl piperazine (UA4), was tested on both naïve (WT) and gemcitabine-resistant (GemR) variants of two human invasive bladder cancer cell lines, 5637 and T24. UA4 killed 5637 (4 µmol/L), T24 (4 µmol/L) WT, and GemR cells in vitro at equal potency. Pretreatment with UA4 followed by G synergistically killed WT and GemR cells by >50% compared with G followed by UA4. Oral gavage of UA4 (100 mg/kg) inhibited WT and GemR tumor growth in athymic mice. UA4 + G was more effective against GemR tumors than either drug alone. Studies revealed cytotoxic autophagy as a mechanism of UA4 cytotoxicity. UA4 induced moderate apoptosis in T24 but not in 5637 cells. Mitochondrial integrity and function were most affected by UA4 because of high levels of reactive oxygen species, disruption of mitochondrial membrane, and cell cycle arrest. These effects were enhanced in the UA4 + G combination. UA4 was well-tolerated in mice, and oral gavage led to a serum level >1 µmol/L with no systemic toxicity. These results show the potential of UA4 as a nontoxic alternative treatment for high-grade bladder cancer.

Proton therapy in pediatric neuro-oncology. Potential advantages and the relationship between cost and results

The aim of study: to analyze the accumulated experience and try to identify those clinical situations in which the use of protons will be economically and clinically more effective than photon radiation therapy. Material and methods. The articles devoted to the study of the evaluation and comparison of the effectiveness of proton and photon radiation beams in the treatment of tumors of the central nervous system and published over the past 25 years were searched in the Medline, Embase and the Cochrane Library databases. Results. the analysis of available publications has shown that accelerated protons do not improve survival rates and disease-free rates in all forms of brain tumors compared with photon therapy. However, protons can significantly increase the level of dose distribution conformity and reduce the dose to critical structures (pituitary gland, cochlea, eye lenses, hypothalamus), thus reducing the risk of hearing and visual impairment as well as hormonal and cognitive disorders. All this is critically important for potentially curable malignant tumors, such as medulloblastoma and germinoma, for low malignant potential tumors (grade 1–2 glioma) or tumors with decreased metastatic potential, since proton therapy compared to photon therapy reduces the risk of late side effects that worsen the quality of life of cured children. Conclusion. central nervous system tumors are one of the most common solid malignant neoplasms in children. Radiation therapy (RT) is recognized as an important therapeutic component of treatment and is often used in strategies for multimodal therapy of tumors of the central nervous system in children. Proton radiation therapy is one of the attractive methods of radiotherapy with minimal dose distribution to normal tissues and a decrease in the absorbed dose. The precision of protons reduces the risk of long-term side effects associated with this type of treatment and the induction of secondary malignancies, which is of particular importance for the quality of life.

Prognostic significance of Klotho expression in patients with renal cell carcinoma.

Various molecular markers have been investigated in renal cell carcinoma (RCC) without significant reliability. We analyzed Klotho (tumor suppressive protein) expression in RCC to investigate its association with tumor-stage, grade, disease-free-survival (DFS) and overall-survival (OS). Data of histologically confirmed patients of RCC with complete clinical follow-up were retrieved from Medical-Record-Library. Tissue sections of tumor and normal parenchyma were prepared from the blocks. Immunohistochemical studies for Klotho were done with commercially available kit (EPR6856, Ab181373; Abcam, Cambridge MA, USA). Klotho expression was scored between 0-3 and grouped into weak/absent (0, 1) and moderate/strong (2, 3). Tumors stages and grades were grouped into low stage (I and II) and high stage (III and IV) and into low grade (grade 1 and 2) and high grade (grade 3 and 4) according to WHO/ISUP grading. The histopathologists were blinded as to the clinical and follow-up data. Various prognostic factors were analyzed with respect to Klotho expression. Kaplan-Meier curves were created for DFS and OS. Fifty-four patients of mean age 55.15 ± 13.34 years and M:F ratio of 1.8:1 were included. Normal renal tissue had strong expression of Klotho in all. In tumor tissue 20 (37%) had negative, 7 (13%) had weak, 14 (25.9%) had moderate and 13 (24.1%) had strong Klotho expression. Significantly more patients had absent/weak Klotho expression with higher grade (16/24 (66.7%) vs 7/25 (28%); p = 0.007), higher stage (22/33 (66%) vs 5/21 (23.8%); p = 0.002), LVI (12/14 (85.7%) vs 2/14 (14.3%); p = 0.002), sinus-fat-invasion (16/21 (76.2%) vs 5/21 (23.8%); p = 0.002), renal-vein-involvement (14/18 (77.8%) vs 4/18 (22.2%); p = 0.004), necrosis (17/26 (65.3%) vs 9/26 (34.6%); p = 0.029) and metastasis (8/9 (88.9%) vs 1/9 (11.1%); p = 0.01). Median DFS and OS were significantly lower in patients with weak/absent Klotho expression (12 vs 23 months, p = 0.023 and 15 vs 33 months, p = 0.006 respectively). Kaplan-Meier curves showed lower estimated DFS and OS in patients with weak/absent expression. We conclude that Klotho expression in renal tumor could be a good prognostic marker in patients with RCC.

Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms

BackgroundHigh-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55).MethodsWe analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1.ResultsFrequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival.ConclusionsThis study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was &amp;gt;200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-14.

Limb salvage surgery for primary bone tumors: retrospective study in a tertiary care centre

Background: Limb salvage surgery is the standard of care for patients with primary bone tumors. The study retrospectively analyses a single center experience of use of endo-prosthesis for limb conservation in cases of primary bone tumors over a five-year period (2015-2020). Methods: Total of 34 histologically proven primary bone tumor were retrospectively studied which included 25 males and 9 females who received limb salvage surgery for bone tumors at department of surgical oncology, Rajiv Gandhi Government general hospital, Madras medical college, Chennai. Results: Median age at diagnosis was 23 years. Tumor localized to lower limb in 23 patients, and upper limb in 9 patients, pelvic bones in 3 cases. Tumors were malignant in 24 patients (70.4%) and benign in 10 patients (29.4%). The most common diagnosis was osteosarcoma17 patients (50%). The median resection length was 10 cm. High grade tumors (grade 2a and 2b and grade 3) was found in 14 cases (41.1%). 6 patients had prosthesis related complications. The mean follow-up was 5 years (range: 3-7). 27 (79.4%) patients of 34 were alive with the endo-prosthesis at the last follow-up. Conclusions: The custom mega prosthesis favored by us in most of the cases in limb sparing surgery for bone tumors results in satisfactory results in terms of local tumor control and limb function.

Predicting histological grade in symptomatic meningioma by an objective estimation of the tumoral surface irregularity

IntroductionPredicting the histopathologic grade of meningioma is relevant because local recurrence is significantly greater in WHO grade II–III compared to WHO grade I tumours, which would ideally benefit from a more aggressive surgical strategy. It has been suggested that higher WHO grade tumours are more irregularly-shaped. However, irregularity is a subjective and observer-dependent feature. In this study, the tumour surface irregularity of a large series of meningiomas, measured upon preoperative MRI, is quantified and correlated with the WHO grade. MethodsUnicentric retrospective observational study of a cohort of symptomatic meningiomas surgically removed in the time period between January 2015 and December 2022. Using specific segmentation software, the Surface Factor (SF) was calculated for each meningioma. SF is an objective parameter that compares the surface of a sphere (minimum surface area for a given volume) with the same volume of the tumour against the actual surface of the tumour. This ratio varies from 0 to 1, being 1 the maximum sphericity. Since irregularly-shaped meningiomas present proportionally greater surface area, the SF tends to decrease as irregularity increases. SF was correlated with WHO grade and its predictive power was estimated with ROC curve analysis. ResultsA total of 176 patients (64.7% females) were included in the study; 120 WHO grade I (71.9%), 43 WHO grade II (25.7%) and 4 WHO grade III (2.4%). A statistically significant difference was found between the mean SF of WHO grade I and WHO grade II–III tumours (0.8651 ± 0.049 versus 0.7081 ± 0.105, p < 0.0001). Globally, the SF correctly classified more than 90% of cases (area under ROC curve 0.940) with 93.3% sensibility and 80.9% specificity. A cutoff value of 0.79 yielded the maximum precision, with positive and negative predictive powers of 82.6% and 92.6%, respectively. Multivariate analysis yielded SF as an independent prognostic factor of WHO grade. ConclusionThe Surface Factor is an objective and quantitative parameter that helps to identify aggressive meningiomas preoperatively. A cutoff value of 0.79 allowed differentiation between WHO grade I and WHO grade II–III with high precision.