Log-rank Test Research Articles

Dose-averaged linear energy transfer within the gross tumor volume of non-small-cell lung cancer affects the local control in carbon-ion radiotherapy

Background and purposeHigh linear energy transfer (LET) radiation exhibits stronger tumor-killing effect. However, the correlation between LET and the therapeutic efficacy in Carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) is currently not clear. This study aimed to investigate the relationship between the dose-averaged LET (LETd) distribution within tumor and local recurrence for LA-NSCLC treated with CIRT. Methods and materialsAn analysis of 62 consecutive patients with LA-NSCLC who underwent CIRT from 2018 to 2022 was conducted. The LETd distribution was calculated based on their treated plans, and the correlation between local recurrence and LETd, relative biological effectiveness (RBE)-weighted doses (DRBE) and clinical factors was investigated. Receiver operating characteristic (ROC) curve, log-rank test, and Cox regression analysis were performed based on that. Results16 patients were defined as local recurrence. Overall survival (OS) and local control (LC) at 24 months were 76.9 % and 73.2 %, respectively. The mean LETd in internal gross tumor volume (iGTV) in the local recurrence group was 48.7 keV/µm, significantly lower than the mean LETd of 53.2 keV/µm in the local control group (p = 0.016). No significant difference was observed in DRBE between the local recurrence and local control groups. ROC curve analysis indicated that a percentage of 88 % of volume in iGTV receiving at least 40 keV/µm (V40keV/μm) is the optimal threshold for predicting local recurrence (Area under curve (AUC) = 0.7636). The log-rank test and Cox regression analysis revealed that the LETd value covering 98 % volume of iGTV (LETd98%) was a significant risk factor for LC (p = 0.020). ConclusionsOur study revealed an association between LETd distribution and local recurrence in patients with LA-NSCLC. These findings suggest that lower LETd may increase the probability of local recurrence. We suggest that LETd distribution within iGTV should be routinely assessed in CIRT for lung cancer.

Development of A Deep Learning Algorithm for Paneth Cell Density Quantification for Inflammatory Bowel Disease

Alterations in ileal Paneth cell (PC) density have been described in gut inflammatory diseases such as Crohn's disease (CD) and could be used as a biomarker for disease prognosis. However, quantifying PCs is time-intensive, a barrier for clinical workflow. Deep learning (DL) has transformed the development of robust and accurate tools for complex image evaluation. Our aim was to use DL to quantify PCs for use as a quantitative biomarker. A retrospective cohort of whole slide images (WSI) of ileal tissue samples from patients with/without inflammatory bowel disease (IBD) was used for the study. A pathologist-annotated training set of WSI were used to train a U-net two-stage DL model to quantify PC number, crypt number, and PC density. For validation, a cohort of 48 WSIs were manually quantified by study pathologists and compared to the DL algorithm, using root mean square error (RMSE) and the coefficient of determination (r2) as metrics. To test the value of PC quantification as a biomarker, resection specimens from patients with CD (n=142) and without IBD (n=48) patients were analysed with the DL model. Finally, we compared time to disease recurrence in patients with CD with low versus high DL-quantified PC density using Log-rank test. Initial one-stage DL model showed moderate accuracy in predicting PC density in cross-validation tests (RMSE=1.880, r2=0.641), but adding a second stage significantly improved accuracy (RMSE=0.802, r2=0.748). In the validation of the two-stage model compared to expert pathologists, the algorithm showed good performance up to RMSE=1.148, r2=0.708. The retrospective cross-sectional cohort had mean ages of 62.1 years in the patients without IBD and 38.6 years for the patients with CD. In the non-IBD cohort, 43.75% of the patients were male, compared to 49.3% of the patients with CD. Analysis by the DL model showed significantly higher PC density in non-IBD controls compared to the patients with CD (4.04 versus 2.99 PC/crypt). Finally, the algorithm quantification of PCs density in patients with CD showed patients with the lowest 25% PC density (Quartile 1) have significantly shorter recurrence-free interval (p=0.0399). The current model performance demonstrates the feasibility of developing a DL-based tool to measure PC density as a predictive biomarker for future clinical practice. This study was funded by the National Institutes of Health (NIH).

Long-term follow-up MR imaging in children with transverse myelitis

BackgroundWe recently described magnetic resonance imaging (MRI) features of children with transverse myelitis (TM) at first event with important and unique differences depending on the underlying disease entity. ObjectiveTo study the resolution of lesions over time in children with TM due to MOG-antibody associated disorders (MOGAD), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) or double seronegative TM. Patients and methodsIn this prospective study, 78 children from 29 different medical centres with TM as part of MOGAD (n=34), MS (n=20), NMOSD (n=5) and in double seronegative children (n=19) were included. A grading system consisting of 4 grades (grade 0 = complete resolution; grade 3 = no resolution at all) was used to compare the degree of lesion resolution over time in the different disease entities. Time to lesion resolution was evaluated by Kaplan-Meier statistics and log-rank test. ResultsSignificant differences of the interval between first MRI until resolution of lesions were observed between the four disease entities. The most rapid and complete resolution was seen in MOGAD, followed by double seronegative, MS and NMOSD. Median periods until total resolution (grade 0) were 191 days (MOGAD), 750 days (double seronegative), 1117 days (MS), while none of the patients with NMOSD reached a complete resolution during the observation period. The better prognosis of MOGAD compared to MS was independent of sex, age, oligoclonal bands and cell count in the multivariate Cox analysis (P<0.001). ConclusionChildren with TM and antibodies to MOG show a faster resolution of radiological lesions compared to children with MS and NMOSD.

Assessment of traumatic brain injury treatment guided by continuous monitoring of intracranial pressure and brain tissue oxygen partial pressure: A single-center pilot study

Severe traumatic brain injury (TBI) is a leading cause of death and disability. Monitoring intracranial pressure (ICP) is recommended, but the data on the outcomes are conflicting. Adding continuous brain tissue oxygen partial pressure (PbtO2) monitoring may have some benefit but the OXY-TC suggested it did not improve 6-month neurological outcomes. This single-center pilot randomized controlled study aimed to evaluate whether adding PbtO2 monitoring was feasible and could improve the prognosis of severe TBI. The participants were randomized into either an ICP alone or an ICP + PbtO2 group for 7 days, with treatment protocols based on existing guidelines. Clinical parameters were collected hourly. The primary outcome was the feasibility of using PbtO2 monitoring. The secondary outcomes were 6-month survival, analyzed by the log-rank test, the 3- and 6-month Glasgow Outcome Scale (GOS) scores, compared between groups by chi-squared test. Seventy patients were included (36 ICP, 34 ICP + PbtO2). The ICP + PbtO2 group had lower mean daily ICP (13.4 vs. 18.2 mmHg, P = 0.0024) and higher mean daily cerebral perfusion pressure (82.1 vs. 74.5 mmHg, P = 0.0055). The ICP + PbtO2 group had higher 6-month survival (79.4 % vs. 55.6 %, P = 0.0337) and more favorable outcomes at 3 months (67.6 % vs. 38.9 %, P = 0.0160) and 6 months (70.6 % vs. 41.7 %, P = 0.0149). Adding PbtO2 monitoring to ICP monitoring is feasible in patients with severe TBI and could maybe improve the intermediate-term outcomes. The results will serve to design larger trials.

In a prospective, multicenter study, the 31-GEP identified patients at increased risk of tumor recurrence and added significant prognostic value to AJCC staging

Cutaneous melanoma (CM) guidelines base management decisions on a patient’s American Joint Committee on Cancer (AJCC) tumor stage. However, limitations in staging accuracy suggest additional tools could improve risk-aligned patient management decisions. The 31-gene expression profile (GEP) test identifies patients with CM with low (Class 1A), intermediate (Class 1B/2A), or high (Class 2B) risk for sentinel lymph node (SLN) positivity, recurrence, metastasis, and death. In this multicenter, prospective study, we validated the 31-GEP for risk of recurrence and demonstrated the added value of 31-GEP to AJCC staging. Patients were included in the prospective CONNECTION study if they were tested with the 31-GEP from 2018 to the present (n=876). Survival was estimated using Kaplan-Meier analysis and 31-GEP stratification tested with the log-rank test. Cox regression was performed to identify predictors of recurrence. ANOVA was used to compare Cox models for the most accurate recurrence prediction. Patients with a Class 1A result had significantly higher 3-year recurrence-free survival than those with a Class 1B/2A or Class 2B result (98.5% vs. 80.8% vs. 63.0%, p&lt;0.001). The 31-GEP had higher sensitivity (75.0% vs. 37.5%) and negative predictive value (98.6% vs. 96.9%) than AJCC staging. Multivariable analysis demonstrated that Class 1B/2A (hazard ratio, HR=3.12, p=0.037) and Class 2B (HR=5.91, p=0.002) were significant predictors of recurrence in addition to stage IB (HR=4.02, p=0.02), IIA (HR=6.06, p=0.006), IIC (HR=17.14, p&lt;0.001), and III (HR=8.84, p&lt;0.001). Stage IIB (HR=4.63, p=0.057) was not significant. Comparing a staging-only model to a 31-GEP+staging model showed that adding 31-GEP to staging significantly improved prediction accuracy over staging alone (ANOVA: c2=10.58, p=0.005). In this prospective study, the 31-GEP stratified risk of recurrence, was a significant predictor of recurrence, and added significant predictive value to AJCC staging. The 31-GEP identifies patients at high risk of recurrence who should be managed more intensely, and adding 31-GEP to staging allows better risk-aligned care decisions, which can lead to improved patient outcomes.

Low Expression of Mitochondrial Ribosomal Protein S5 is Associated With Poor Prognosis in Patients With Clear Cell Renal Cell Carcinoma

Mitochondrial ribosomal protein S5 (MRPS5) is abnormally expressed in various tumor tissues and may be a key molecule for the regulation of tumors. Our aim is to investigate the relationship between the expression of MRPS5 in clear cell renal cell carcinoma (ccRCC) and the prognosis of patients. MRPS5 expression in fresh tumoral tissues and peritumoral tissues of patients with ccRCC was examined by quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemical staining, respectively. MRPS5 expression level in paraffin-embedded tumoral tissue samples with ccRCC was evaluated by immunohistochemical scoring criteria. The relationship between the expression of MRPS5 and the clinicopathological parameters and prognosis of patients with ccRCC was analyzed statistically. The expression of MRPS5 mRNA and protein in fresh tumoral tissues was lower than that in peritumoral tissues. Among 160 paraffin-embedded tumoral tissue samples, 99 cases (61.9%) showed high expression and 61 cases (38.1%) showed low expression of MRPS5. The expression level of MRPS5 was significantly correlated with T classification, TNM stage, and Fuhrman grade. Kaplan-Meier method and log-rank test indicated that patients with low MRPS5 expression had significantly poorer overall survival and recurrence-free survival than high MRPS5 expression. Multivariate analysis revealed that MRPS5 expression was an independent predictor of overall survival and recurrence-free survival, respectively. MRPS5 low expression was a risk factor for the prognosis of patients. The expression level of MRPS5 is significantly correlated with the postoperative survival status, which has the potential to be used as a novel prognostic biomarker for patients with ccRCC.

Demographic, Disease, and Treatment Characteristics of Primary Tracheal Cancers

Abstract Background Primary tracheal cancers (PTCs) are rare neoplasms underreported in the literature. No consensus guidelines exist for the treatment of these cancers and multimodal management of these cancers has not been adequately explored for cases diagnosed over the past 2 decades. Methods The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with PTC. Cox proportional hazards and log-rank testing was used to assess the association between demographic and treatment variables and 5-year cause-specific survival (CSS). Results Among the 689 identified patients, age &lt; 65 years at diagnosis (hazard ratio [HR] 0.64, p &lt; 0.001), non-squamous cell carcinoma (SCC) histology (HR 0.22, p &lt; 0.001), and treatment with surgery (HR 0.43, p &lt; 0.001) were all associated with increased 5-year CSS. Regarding disease histology, patients with adenoid cystic carcinomas (ACCs) had increased 5-year CSS compared with those with neither SCC nor ACC histology and those with SCC histology (83.4% [76.0%, 90.8%] versus 50.3% [42.5%, 58.1%] and 28.8% [23.2%, 34.4%]; p &lt; 0.001) based on univariate analysis. Despite the improved CSS associated with surgery, 55% of the identified cohort did not undergo surgery, with only 5.5% of these patients having ACC compared with 58% having SCC (p &lt; 0.001). Conclusions Age &lt; 65 years, ACC histology, and treatment with surgery were associated with improved 5-year CSS among patients with PTC, although the significant proportion of this group not receiving surgery represents an opportunity for improved outcomes.

THE IMPACT OF VASCULAR RISK FACTORS ON CEREBRAL AMYLOID ANGIOPATHY: A COHORT STUDY IN HEREDITARY CAA AND A SYSTEMATIC REVIEW IN SPORADIC CAA

Background: Cerebral amyloid angiopathy (CAA) has a remarkably variable disease course, even in monogenetic hereditary forms. Our aim was to investigate the prevalence of vascular risk factors and their effect on disease onset and course in Dutch-type hereditary (D-)CAA and sporadic CAA. Methods: We performed a cohort study in D-CAA to investigate the association between vascular risk factors (hypertension, hypercholesterolemia, smoking and alcohol use) and age of intracerebral hemorrhage (ICH) onset and time of ICH recurrence with survival analyses. In addition, we performed a systematic review to assess the prevalence of vascular risk factors and their effect on clinical outcome in sporadic CAA. We searched PubMed, Embase, Web of Science and COCHRANE Library, from 1987-2022 and included cohorts with ≥10 patients. We created forest plots, calculated pooled estimates and reported variability (heterogeneity plus sampling variability) and risk of bias. Results: We included 70 participants with D-CAA (47% women, mean age 53y). Sixteen (23%) had hypertension, 15 (21%) hypercholesterolemia, 45 (64%) were smokers and 61 (87%) used alcohol. We found no clear effect of vascular risk factors on age of first ICH (log-rank test hypertension: p=0.35, hypercholesterolemia: p=0.41, smoking: p=0.61 and alcohol use: p=0.55) or time until ICH recurrence (log-rank test hypertension: p=0.71, hypercholesterolemia: p=0.20 and smoking: p=0.71). We identified 25 out of 1234 screened papers that assessed the prevalence of risk factors in CAA and 6 that reported clinical outcomes. The pooled prevalence estimates of hypertension was 62% (95%CI:55%-69%), diabetes 17% (95%CI:14%-20%), dyslipidemia 32% (95%CI:23%-41%), and tobacco use 27% (95%CI:18%-36%). One study reported study diabetes and hypertension to be associated with a lower risk of recurrent ICH, whereas another study reported hypertension to be associated with an increased risk. All other studies showed no association between vascular risk factors and clinical outcome. High quality studies focusing on vascular risk factors were lacking. Conclusions: In patients with D-CAA and sporadic CAA the prevalence of vascular risk factors is high. Although this suggests an opportunity for prevention, there is no clear association between these risk factors and CAA-related ICH onset and recurrence.

Abstract C030: Timing of melanoma brain metastasis seeding dictates the immunomodulatory effect and efficacy of systemic anti-CD40 agonist therapy

Abstract Introduction: Melanoma brain metastasis (MBM) affects nearly 50% of patients with advanced melanoma. Despite progress in systemic therapies, particularly immune checkpoint inhibitors, intracranial responses remain highly variable. The CD40/CD40L axis and its pleiotropic effects on the anti-tumoral immune response has the potential to improve MBM treatment. Our aim was to investigate whether the timing of MBM seeding, in a two-site mouse model of MBM, impacts the intracranial efficacy of anti-CD40 agonism (aCD40). Methods: 2 x 105 B16F1-cOVA murine melanoma cells were subcutaneously (s.c.) injected in the right flank in C57BL/6 mice (5F, 5M). After 3 days, 1 x 105 B16F1-cOVA cells were intracerebrally (i.c.) injected into the right striatum under stereotaxic guidance (early MBM’ cohort). A separate cohort of C57BL/6 mice (5F, 5M) had s.c. injection of B16F1-cOVA cells, followed by an i.c. injection of B16F1-cOVA cells after 5 days (‘late MBM’ cohort). In both experimental cohorts, the mice were randomly allocated to receive either an aCD40 antibody or an isotype IgG antibody (control) intraperitoneally on days 4 (D4) and 7 (D7) post-i.c. injection (D0). S.c. tumor volume and survival data were serially collected. Separately, tumor-bearing mice treated with either aCD40 or IgG (n = 4 per early/late MBM groups) were euthanized day 9 (D9) post-i.c. injection and tissues (blood, brain tumor [BT], and flank tumor [FT]) were collected for immune profiling by spectral flow cytometry. Results: The early MBM cohort showed a significant s.c. tumor response to aCD40 therapy with a mean D9:D4 s.c. tumor volume ratio of 2.81 (SD±2.05) vs 16.51 (±13.10) in the IgG group (unpaired t-test; p=0.0497). The late MBM cohort showed no significant difference in s.c. tumor response between aCD40 or IgG (D9:D4 ratio 1.52±1.00 vs 1.20±0.83; p=0.5999). Survival increased in early MBM following aCD40 vs IgG (median 20 days vs 13 days; logrank test, p=0.0078), which was not replicated in late MBM (median 21 days vs 19 days; p=0.7717). Systemic aCD40 led to reduced circulating B cells, most expressing CD11b, and increased monocytes, compared to IgG treatment. In the BT, there were higher infiltration of CD8 T cells (normalized to microglia), including OVA+ CD8 T cells, and CD4 T cells in early MBM treated with aCD40 vs IgG. Systemic aCD40 induced more infiltrating SIRP1a+ cDC2 cells than XCR1+ cDC1 cells and vice versa in the IgG group, in both the BT and FLT. Meanwhile, infiltrating B cells were predominantly CD11b+ in aCD40 groups in the BT, regardless of MBM timing. Conclusion: Systemic aCD40 therapy improved survival of MBM-bearing mice, with a shorter interval between s.c. and i.c. implantation; an effect abrogated by later MBM seeding. Systemic aCD40 therapy induced specific changes in the BT infiltrative immune profile, which may explain the distinct response between the early and late BM cohorts. These findings have implications on the experimental modelling of MBM and provide insight into variability of MBM response to immunomodulating therapies. Citation Format: Vinton W. T. Cheng, Victoria R. Breza, Beata Chertok, Natasha D. Sheybani, Timothy N. J. Bullock, Richard J. Price. Timing of melanoma brain metastasis seeding dictates the immunomodulatory effect and efficacy of systemic anti-CD40 agonist therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C030.

Radiomics-based predictive model for preoperative risk classification of gastrointestinal stromal tumors using multiparametric magnetic resonance imaging: aretrospective study.

The aim of this study was to develop and assess aradiomics model utilizing multiparametric magnetic resonance imaging (MRI) for the prediction of preoperative risk assessment in gastrointestinal stromal tumors (GISTs). An analysis was performed retrospectively on agroup of 121 patients who received ahistological diagnosis of GIST. They were then divided into two sets, with85 in the training set and 36 in the validation set through random partitioning. Radiomics features from five MRI sequences, totaling 600 per patient, were extracted and subjected to feature selection utilizing arandom forest algorithm. The discriminatory efficacy of the models was evaluated through receiver operating characteristic (ROC) and precision-recall (P-R) curve analyses. Model calibration was assessed via calibration curves. Subgroup analysis was performed on GISTs with apathological maximum diameter equal to or less than 5 cm. Furtherly, Kaplan-Meier (K-M) curves and log-rank tests were used to compare the differences in survival status among different groups. Cox regression analysis was employed to identify independent prognostic factors and to construct aprognostic prediction model. The clinical model (ModelC) displayed limited predictive efficacy in the context of GIST. Conversely, aradiomics model (ModelR) incorporating five parameters exhibited robust discriminative capabilities across both the training and validation sets, yielding area under the ROC curve (AUC) values of 0.893 (95% confidence interval [CI]: 0.807-0.949) and 0.855 (95% CI: 0.732-0.978), respectively. The F1max scores derived from the P‑R curves were 0.741 and 0.842 for the training and validation sets, respectively. Noteworthy was the exclusion of the two-dimensional tumor diameter and tumor location when constructing ahybrid model (ModelCR) that amalgamated radiomics and clinical features. ModelR demonstrated asubstantially enhanced discriminative capacity in the training set compared with ModelC (p < 0.005). The net reclassification improvement (NRI) corroborated the superior performance of ModelR over ModelC, thereby enhancing diagnostic accuracy and clinical applicability. Patients in the high-risk group had significantly worse recurrence-free survival (RFS, p < 0.001) and overall survival (OS, p = 0.004), and the radiomics signature is an independent risk factor for RFS. The extended model incorporating the radiomics signature outperformed the baseline model in terms of risk assessment accuracy (p < 0.001). Our investigation underscores the value of integrating radiomics analysis in conjunction with machine learning algorithms for prognostic risk stratification in GIST, presenting promising implications for informing clinical decision-making processes as well as optimizing management strategies.

Association of low muscle strength with incident pneumonia in older patients with heart failure.

Patients with heart failure (HF) are at an increased risk of developing pneumonia, leading to a high mortality. A decrease in muscle strength due to aging or concomitant disease may contribute to the development of pneumonia in older adults. We sought to investigate the relationship between low muscle strength and pneumonia incidence in older patients hospitalized for worsening HF. We carried out a sub-analysis of the FRAGILE-HF, a prospective multicenter observational study, including 1266 consecutive older (≥65 years) patients hospitalized with HF (mean age 80.2±7.8 years; 57.4% male; left ventricular ejection fraction 46±17%) and information of incident pneumonia observed after discharge. Patients were followed up for two years post-discharge. A total of 88 patients (7.0%) developed pneumonia after discharge, with an incidence of 42.7 per 1,000 person-years. A total of 893 patients with low muscle strength, defined as handgrip strength <28kg for men and <18kg for women according to international criteria, were more likely to develop pneumonia than those with normal muscle strength (p <0.001; log-rank test). Low muscle strength was a significant predictor of incident pneumonia (adjusted hazard ratio with 95% confidence interval: 2.65 [1.31-5.35], p=0.007). Furthermore, the mortality rates were 43.2% in patients who developed pneumonia and 19.3% in those who did not, indicating a heightened risk of death following the onset of pneumonia (adjusted hazard ratio: 4.25 [2.91-6.19], p<0.001). In older patients hospitalized for HF, low muscle strength was associated with incident pneumonia after discharge.

Efficacy of Monopolar Radiofrequency or Microwave Ablation in Intrahepatic Cholangiocarcinoma: A Retrospective Multicenter Study from Association des Gastro-Entérologues Oncologues (AGEO)

Background: Several locoregional treatments approaches, including thermoablation, have been tested for the treatment of intrahepatic cholangiocarcinoma (ICC) and have shown encouraging results. However, data are heterogeneous in terms of tumor number, size, and ablation technique. Objective: The aim of this study was to investigate the efficacy and prognostic factors in ICC treated by monopolar radiofrequency (RF) or microwave ablation (MW). Methods: This was a retrospective study including patients treated with RF or MW for ICC in six participating centers. DFS and OS were evaluated by the Kaplan–Meier method and prognostic factors by log-rank test and Cox modeling. Results: From January 2015 to October 2023, 24 patients with 31 nodules were treated with RFA or MW. Overall, 70% had chronic liver disease, with 50% at cirrhosis stage. The median size of lesions was 17 mm (6–35 mm). After a median follow-up of 33 months (5–85), the median DFS was 10.5 months. The median OS was 40.8 months. On univariate and multivariate analysis, only lesion size &gt; 17 mm was associated with a poor OS (HR 3.09; IC [1.02; 9.37] (p = 0.04). Conclusions: Monopolar radiofrequency or microwave ablation is an alternative to surgery for small ICCs. Tumors &lt; 17 mm were associated with better OS.

Adverse events after nivolumab and ipilimumab combined immunotherapy in advanced renal cell carcinoma: a multicentre experience in Poland.

Immune checkpoint inhibitors (ICIs) have been employed in the adjuvant and metastatic setting of renal cell carcinoma (RCC) treatment. Among ICIs, combined immunotherapy has the highest risk for immune-related adverse events (irAEs). We aimed to document the incidence of irAEs in RCC patients treated with nivolumab and ipilimumab as data from the European population remain limited. We analysed data from 88 RCC patients treated with nivolumab + ipilimumab between May 2022 and June 2024 across six high-volume oncology units in Poland. We reviewed irAEs and estimated their impact on survival parameters via univariate and multivariate Cox proportional hazards regression models, along with log-rank tests. With a median follow-up of 11.3 months, the median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 12.8 months (6.3-19.3). A total of 74 irAEs were recorded in 50 patients. The most frequent events were endocrine (n = 20, 27%), hepatic (n = 15, 17%), general (n = 12, 13.6%), and cutaneous (n = 11, 12.5%). The occurrence of irAEs was associated with a 60% lower risk of disease progression (hazard ratio 0.44, 95% confidence interval 0.2-0.87, p = 0.018) without impacting OS and higher disease control rate (n = 45, 90% vs. n = 24, 63.2%, p = 0.004). In contrast, patients with hepatotoxicity had poorer outcomes, with a 2.6-fold greater risk of death (p = 0.05). IrAEs may serve as a predictive factor for the efficacy of the nivolumab + ipilimumab regimen in RCC patients. Special attention is needed for hepatotoxicity, as it can significantly impact survival outcomes.

RETROSPECTIVE ANALYSIS OF GLIOBLASTOMA OUTCOMES

Background Glioblastoma (GBM) is one of the most aggressive brain cancers, with a median overall survival (OS) of about 15 months. This retrospective study focuses on 144 GBM cases treated over 12 years in our clinic in Romania, analyzing factors affecting progression-free survival (PFS) and OS, including genetic markers and treatment modalities. Methods This study involved patients treated between 2012 and 2024 at the National Institute of Neurology and Neurovascular Diseases in Bucharest. The cohort included 144 patients, with variables such as age, gender, tumor location, IDH mutation status, Karnofsky Performance Status (KPS), and genetic markers (MGMT methylation and EGFR amplification) analyzed. Survival outcomes were evaluated using Kaplan-Meier curves and log-rank tests. Results - Patient Demographics: The cohort included 64 males (44.4%) and 80 females (55.6%) with a mean age of 60.7 years. - Tumor Characteristics: The most common tumor location was the frontal lobe (31.9%), followed by multilobular GBM (26.3%). Right-side tumors were more prevalent (51.3%). - Genetic Markers: MGMT promoter was methylated in 46 patients (31.9%), and EGFR was amplified in 76 patients (52.7%). - Treatment Modalities: 105 patients (72.9%) received chemotherapy with temozolomide (TMZ), and 116 patients (80.5%) underwent radiotherapy. - Survival Outcomes: Median PFS was 5 months, and median OS was 8.5 months. Kaplan-Meier survival curves indicated significantly increased OS in patients with MGMT methylation undergoing chemotherapy (p&lt;0.005) and radiotherapy (p&lt;0.005). Similarly, OS was significantly higher in patients without EGFR amplification receiving chemotherapy (p&lt;0.005) and radiotherapy (p&lt;0.005). Conclusion The study emphasizes the importance of MGMT methylation and EGFR amplification in predicting survival outcomes in GBM patients. Immediate postoperative adjuvant therapy significantly improves PFS and OS. The findings underscore the need for coordinated care and timely access to adjuvant therapies to enhance survival rates in GBM patients. Second surgical interventions also showed a survival benefit, highlighting their potential role as salvage therapy in recurrent GBM cases.

Predicting the prognosis of Wilms tumor by peripheral blood cells: a real-world study of more than 30years.

Despite established excellent treatment strategies for Wilms tumor (WT), effective prognostic evaluation methods were lacking. This study aims to examine prognostic factors for WT through real-world peripheral blood cell profiling. Basic data and pre-treatment laboratory indices from WT and non-WT children underwent Wilcoxon test analysis. Chi-square tests assessed the correlation between blood cells and the overall survival (OS) and event-free survival (EFS) of WT. Further the Log-rank test and multivariate Cox were used to identify independent prognostic factors for OS. Traditional accepted factors were included in multi-Cox and the nomogram was constructed to further validate the outcome. Blood cells significantly differed between WT and non-WT groups (P < 0.05). Univariate analysis revealed that NLR above 1.380, stage IV, M below 0.325 × 103/μL were linked with lower OS, and PLR below 94.632, LB above 3.570 × 103/μL, stage IV, M above 0.325 × 103/μL,age ≤ 3years were meaningful for higher EFS (P < 0.05). While in the multifactorial COX, only M (HR:0.220, HR95%CI: 0.080 ~ 0.620, P = 0.004 and HR: 0.437, HR95%CI: 0.202 ~ 0.947, P = 0.036, respectively) and stage IV (HR: 7.890, HR95%CI: 1.650 ~ 37.770, P = 0.010 and HR: 3.720, HR95%CI: 1.330 ~ 10.408, P = 0.012, respectively) were independent prognostic factors for OS and EFS. These two variables also were significant after including recognized risk factors, and were demonstrated the predictability via nomogram. OS and EFS were poorer in WT children with M below 0.325 × 103/μL, suggesting the potential as a prognostic predictor for WT.

Prolonged survival in women with Hepatocellular Carcinoma: a French observational study.

Less than 25% of hepatocellular carcinoma (HCC) occurs in women, in whom prognosis could be better. Due to the lack of date in Europe, this study aims to assess survival of patients with HCC according sex in a tertiary French liver center. Every patient diagnosed with a first diagnosis of HCC presented at our weekly multidisciplinary tumor board between 2013 and 2017 were included. Baseline characteristics of patients and tumors were compared according sex using the Mann-Whitney test for Continuous variables and the Fisher or Chi-square test for dichotomous variables. Survival analyses according sex were conducted using the Kaplan-Meier method, the log-rank test, Cox models and a propensity score. 694 patients were included, of whom 130 (18.7%) were women. Among them, 587 (86%) had cirrhosis, mainly compensated (Child A 62.7%), and related to alcohol (48.7%), HCV (27.2%), and/or metabolic-associated fatty liver disease (25.8%). HCC was unifocal in 54% of cases, with a mean main nodule size of 37 mm. Curative treatment was administered in 45.4% of cases (percutaneous ablation 93%). Compared to men, women diagnosed with HCC were older (73 vs. 65 years, p < 0.001), were more frequently HCV-infected (40% vs. 24%, p = 0.0003) and presented more often with a solitary HCC (63% vs. 52%, p = 0.020). After a median follow-up of 57 months, overall survival was significantly longer in women both in multivariate analysis (aHR 1.39 (CI95%: 1.07-1.81) p=0.014) and using a propensity score (HR 1.51 (1.13-2.02, p=0.005)). Despite being diagnosed at an older age, women with HCC exhibit significant better overall survival.

Hepatic arterial infusion chemotherapy combined with systemic therapy sequentially or simultaneously for advanced hepatocellular carcinoma.

The goal of this study was to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with targeted therapy and PD-(L)1 blockade (triple therapy), either sequentially (SE) or simultaneously (SI), in the treatment of Barcelona Clinic Liver Cancer (BCLC) stageC hepatocellular carcinoma (HCC). From January1, 2018, to June1, 2022, 575patients with BCLC stageC HCC who underwent SE or SI triple therapy were retrospectively enrolled. Propensity score matching (PSM; 1:1) was performed to eliminate possible confounder imbalances across cohorts. We used the Kaplan-Meier method and a log-rank test to compare the overall survival (OS) and progression-free survival (PFS) rates between the SI and SE groups. The tumor response and the incidence of adverse events (AEs) were reported. After PSM, 182patients in each of the two groups were matched. The median OS in the SI group was significantly longer than that in the SE group (28.8 vs. 16.1months; P = 0.002), and the median PFS was significantly improved in the SI versus SE group (9.6 vs. 7.0months; P = 0.01). The objective response rate based on the mRECIST was higher in the SI group (58% vs. 37%; P < 0.001). The total incidences of grade3-4 AEs were 111/182 (60.9%) and 128/182 (70.3%) in the SE and SI groups, respectively. No grade5 AEs were reported in either group. Simultaneous HAIC plus targeted therapy and PD-(L)1 blockade significantly improved outcomes compared to the sequential regimen in patients with BCLC stageC HCC, with no unexpected AEs. The patients who received hepatic arterial infusion chemotherapy combined with targeted therapy and PD-(L)1 blockade simultaneously have a better prognosis than those who received it sequentially.

MS O11 - HPB Laparoscopic vs open liver resections for hepatocellular cancer in a tertiary care hepatobiliary unit; outcomes of cases over 10 years

Abstract Background Despite its established role in liver resection surgery, minimally invasive surgery is still not a favoured option in cases of hepatocellular cancer (HCC) due to perceived risks of intra- and post-operative surgical morbidity and poorer oncological outcomes. This study aims to look at the outcomes of liver resections performed for HCC cases over ten years comparing laparoscopic and open cohorts. Method A retrospective study including all liver resections for HCC cases performed in our tertiary care hepatobiliary unit between 2013 and 2022 (10 years) was conducted. Data on demographics, underlying degree of liver cirrhosis, types of liver resection and post-operative outcomes, including recurrence rates and resections margins were collected and reported using descriptive statistics. Survival analysis was performed with compared between these two groups with log rank test in GraphPad prism 10. Results 200 liver resections performed for HCC were grouped into laparoscopic and open cohorts containing 147 and 53 patients respectively. 21 (40%) laparoscopic cases had background liver cirrhosis as compared to 24 (16%) in open cases. Major liver resection comprised 9% and 43% of all cases and one and five patients had Grade B/C PHLF in laparoscopic and open groups. All 8 (4%) cases with 90-day mortality were from the open group. Negative resection margins (68% vs 71%), local recurrence (51% vs 47%) and overall survival (75 months vs 67 months (p=0.29)) were similar in laparoscopic and open groups, respectively. Conclusion Post-operative and oncological outcomes of liver resections for HCC were comparable in laparoscopic and open groups. Laparoscopic liver resections could be safely performed in patients with background liver cirrhosis.

Abstract A050: Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer death world-wide. In the US, liver cancer has increased in incidence and mortality due to a growing population from South and Central America, which faces higher risk of disease in part due to aflatoxin exposure. Recently, we showed that the DELFI (DNA evaluation of fragments for early interception) approach using genome-wide cell free DNA (cfDNA) fragmentation profiles and machine learning can be used for detection of liver and other cancers. Having previously demonstrated that a DELFI classifier accurately detects HCC in populations from the US and Hong Kong, we evaluated the classifier in other clinically relevant cohorts worldwide. Here we show that approach generalizes to diverse populations, and that including other genomic and protein features from the same blood draw improves performance. We examined plasma samples from 377 individuals, including 244 individuals with HCC and 133 without cancer, including 85 with cirrhosis. Plasma samples were collected from individuals with or without HCC in a case-control study in Guatemala (n=203) and from a prospective collection in Romania (n=174) and cfDNA was analyzed by whole- genome sequencing at ∼10x coverage. The median DELFI scores using a locked classifier (Foda et al., Cancer Discovery, 2023) were higher in both cohorts for patients with cancer across all stages compared to individuals without cancer, regardless of the presence of cirrhosis. Using the locked model with a threshold that corresponded to 80% specificity in prior work, DELFI detected individuals with HCC with sensitivities of 90% and 69% in the two cohorts at specificities of 92% and 86%, respectively. For early-stage HCC within Milan Criteria for liver transplantation, sensitivities were 85% in the case-control cohort and 64% in the prospective cohort. In these cohorts, the fixed DELFI model outperformed AFP at the clinically used threshold of 20 ng/mL with a sensitivity in the combined cohorts of 78% at 91% specificity, compared to 63% sensitivity at 91% specificity for AFP. A combined approach using either DELFI at a threshold that corresponded to a 90% specificity in our previous study or AFP at the clinical threshold resulted in 82% sensitivity (74% in early stage) at 92% specificity and was superior to estimates of AFP and ultrasound for early-stage disease (63% sensitivity at 84% specificity). Individuals who tested positive with DELFI had a significantly shorter overall survival (p=0.002, log rank test), even amongst individuals at the earliest stage, while AFP alone did not stratify survival for patients with early-stage disease. Single-molecule analyses from low coverage WGS of cfDNA revealed genome-wide mutational profiles that were similar to those of HCC and in individuals from Guatemala that were characteristic of aflatoxin exposure. Overall, this work provides insight into the origins of cfDNA in populations at risk for HCC and validates our genome-wide fragmentome approach for non-invasive cancer detection that may facilitate liver cancer screening. Citation Format: Zachariah H Foda, Daniel Bruhm C Bruhm, Akshaya V Annapragada, Shashikant Koul, Sarah Short, Keerti Boyapati, Adrianna Bartolomucci, Vilmos Adleff, Nicholas A Vulpescu, Hope Orjuela, Andrei Sorop, Razvan Iacob, Liana Gheorghe, Simona Dima, Katherine A McGlynn, Manuel Ramírez-Zea, Jillian Phallen, John Groopman, Robert B Sharpf, Victor E Velculescu. Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A050.

Abstract B018: Plasma-based circulating tumor tissue modified viral (TTMV)-HPV DNA for detection of recurrent HPV-driven anal cancer

Abstract Purpose: Squamous cell carcinoma of the anus (SCCA) is primarily driven by human papillomavirus (HPV) infection. Up to 30% of patients experience recurrence, necessitating improved surveillance strategies. Liquid biopsies have shown promise as a tool in oncology. This study investigates the clinical performance of circulating tumor tissue modified viral (TTMV)- HPV DNA in the post-treatment surveillance of SCCA. Patients and methods: This central IRB-approved retrospective cohort study included 117 patients diagnosed with HPV-driven SCCA from seven U.S. centers who had ≥1 TTMV-HPV DNA tests (NavDx®, Naveris, Inc., Waltham, MA) performed between March 2020 and June 2024. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 were analyzed using droplet digital PCR. The diagnostic accuracy of TTMV-HPV DNA was evaluated by comparing test results with clinical evidence of SCCA recurrence determined through anoscopy, radiology, and/or tissue biopsy. Recurrence is defined as either a positive biopsy or subsequent salvage therapy. Results: Patients were primarily female (73%) with a median age 63 years. Median follow-up after initial treatment was 19 months. Forty-seven patients (40%) had pretreatment TTMV-HPV DNA testing, with a baseline detectability of 85.1% (40/47, 95% CI: 74.9–95.3). Of these, 24 were re-tested within 3 months post-treatment and 18 had undetectable TTMV-HPV DNA (75%). Those patients whose scores became undetectable had significantly longer recurrence-free survival than those whose scores remained detectable (log-rank test, p=0.01). One hundred and four patients (89%) underwent post-treatment testing, of which 91 provided relevant data for the analysis. Of these 91 patients, 27 (29.7%) experienced recurrence. Post-treatment testing demonstrated a per- patient sensitivity of 85.7% (24/28, 95% CI: 72.8-98.7). Of four patients with a false negative test, only one had biopsy-confirmed recurrence, whereas the remaining recurrences were not biopsied prior to starting salvage treatment. The positive predictive value of a single positive test was 97.6% (40/41; 95% CI: 92.8–100.0). One patient remains in active follow-up. Of the true positive post-treatment tests, 58% (14/24) predicted recurrence before clinical detection, with a median lead time of 59 days (range: 10–536). There were 141 negative post-treatment tests across 66 patients. This yielded a per-test specificity and negative predictive value of 99.3% (136/137, 95% CI: 97.8-100.0) and 97.2% (136/140, 95% CI: 94.9-99.9), respectively. Indeterminate TTMV-HPV DNA tests were rare (5/268,1.9%). However, clinically indeterminate findings (CIFs) were common, with 141 post-treatment CIFs identified across 52/117 patients (44.4%). TTMV-HPV DNA testing was able to correctly predict recurrence status in 94.3% of CIF cases. Conclusion: TTMV-HPV DNA testing is a sensitive and specific surveillance method for detecting early recurrence of HPV-driven SCCA. Citation Format: Shane Lloyd, Rafi Kabarriti, James Jabalee, Tyler Slater, Corbin Jacobs, Sean Inocencio, Michael Rutenberg, Chance Matthiesen, Kasha Neff, Gene-Fu F Liu, Tiffany M Juarez, Catherine DV Fitz, Stanley Liauw. Plasma-based circulating tumor tissue modified viral (TTMV)-HPV DNA for detection of recurrent HPV-driven anal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B018.