Grade 3 Research Articles

Skin Rash in metastatic Hormone Sensitive Prostate Cancer Patients Treated with Apalutamide: A Retrospective Multicenter Study in Korea

PurposeSkin rash is a common adverse event in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with apalutamide. This study aims to investigate the incidence rate of skin rash and the predictive value of inflammation markers for skin rash in real-world Korean patients. Materials and MethodsWe conducted a retrospective analysis of patients with prostate cancer (PCa) who received apalutamide across 18 institutions in Korea, with a follow-up period of at least three months. A total of 218 patients were evaluated. ResultsAmong the 214 patients analyzed, 78 (36.4%) developed a skin rash. The severity of the rash was classified as grade 1 (G1) in 27 patients (12.6%), grade 2 (G2) in 29 patients (13.5%), and grade 3 (G3) in 22 patients (10.3%). The median time to onset of any skin rash was 65.5 days (interquartile range, IQR 31.0-88.0). There were no significant differences in inflammation markers before apalutamide administration between patients who developed a rash and those who did not. However, the Monocyte-to-Lymphocyte Ratio (MLR) and Systemic Immune-Inflammation Response Index (SIRI) were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (p=0.006, p=0.013, respectively) before apalutamide treatment. After 3 months, Platelet-to-Lymphocyte Ratio (PLR) and SIRI were significantly higher in the G2 plus G3 group compared to the no rash plus G1 group (p=0.010, p=0.025, respectively) ConclusionIn a real-world cohort of Korean patients, skin rash occurred in 36.4% of cases, with a median time to onset of 65.5 days. Grade 3 skin rash developed in 10.3% of cases. While MLR and SIRI were significantly higher in the G2 plus G3 group, these markers cannot be considered reliable predictors due to a low area under the curve (AUC < 0.7) before apalutamide treatment. However, increased levels of PLR, SII, and SIRI could potentially be useful for monitoring for the risk of severe rash development in these patients.

Artificial intelligence-enabled electrocardiogram for left ventricular diastolic dysfunction and long-term risk of new-onset atrial fibrillation

Abstract Background Heart failure (HF) and atrial fibrillation (AF) are intertwined, sharing common risk factors and influencing each other in a reciprocal manner. While left ventricular diastolic dysfunction (LVDD) stands as a hallmark of HF's hemodynamic profile, its direct correlation with heightened AF risk remains uncertain. Our recent validation of an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm for LVDD detection has opened new avenues. Yet, whether AI-ECG-detected LVDD correlates with long-term AF risk remains unexplored. Methods We performed a retrospective study among all patients with a comprehensive LVDD assessment from the test population of the AI-ECG LVDD study between September 2001 and June 2022. Patients with prior documented AF according to health records or previous ECG were excluded. Patients were classified by AI-ECG as normal diastolic function (DF), grade 1 (G1), grade 2 (G2), or grade 3 (G3) LVDD. We assessed the risk of AF across AI-ECG LVDD grade, with normal DF as reference, with competing risk models. Results Of 97,023 patients free of AF at baseline, 63,533 (65.4%), 10,776 (11.1%), 18,940 (19.5%), and 3,774 (3.9%) were classified as normal DF, G1-LVDD, G2-LVDD, and G3-LVDD, respectively. Worse AI-ECG LVDD was associated with older age, lower left ventricular ejection fraction (LVEF), and higher rates of HF, diabetes, hypertension, chronic pulmonary disease, renal failure, and cardiovascular disease (p-of-trend&amp;lt;0.001 for all). Over a median follow-up of 4.8 years (interquartile range 1.8-9.2 years), new-onset AF occurred in 6,795 (7.0%) patients. In multivariable survival analysis, adjusted to multiple risk factors including LVEF and clinical HF, G2 and G3 LVDD, representing patients with high filling pressures, were independently associated with a higher AF-risk [G2-LVDD: adjusted hazard ratio (aHR) 1.64 (95% confidence interval (95%CI) 1.52-1.73), G3-LVDD: aHR 2.24 (95%CI 2.02-2.48)]. Conclusion The AI-ECG LVDD algorithm independently predicts long-term AF risk, regardless of LVEF and clinical HF status, highlighting its potential for identifying high-risk populations and guiding proactive monitoring and management.

Evaluation of spexin levels in euthyroid patients with Hashimoto thyroiditis and its relation to autoimmunity.

Hashimoto thyroiditis (HT) is chronic lymphocytic thyroiditis. Cytokines and chemokines such as tumor necrosis factor-alpha, interferon-gamma, and interleukin-1 beta originating from immune cells are involved in the etiopathogenesis of HT. Spexin (SPX) is a recently identified novel peptide hormone consisting of 14 amino acids and has been demonstrated in follicle epithelial cells in thyroid tissue. SPX has been shown to affect the inflammatory response and play a role in its regulation in various diseases. There is a need for markers for diagnosis and treatment of HT patients with negative antibody levels. We found that there is no study in the literature that investigates the HT and the role of spexin in this inflammatory process. Forty-five patients aged 18 to 70 years with HT or newly diagnosed HT and 42 healthy subjects as the control group were included in the study. Patients in the HT group were divided into 3 categories according to ultrasound findings. Mild heterogeneity was called grade 1 (G1), moderate heterogeneity was called grade 2 (G2), and high heterogeneity was called grade 3 (G3). Laboratory parameters and anthropometric measurements of all patients participating in the study were performed, and SPX was measured by the ELISA method. There was no significant difference between the HT and control groups in terms of SPX levels (P = .27). In HT subgroup analysis, SPX levels were found to be borderline statistically significantly higher in the G2 group, where antibody levels were higher compared to other groups (P = .061). In our study, we evaluated SPX levels in HT patients, which has never been done before in the literature. We found high SPX levels in HT patients with high antibody levels. Multicenter studies with high case series, especially at the tissue level, are needed to fully explain the role of SPX in HT immunoetiopathogenesis and to understand immune-checkpoint pathways more clearly.

Optimising outcomes for frail patients with oesophagogastric (OG) cancers: The impact of dose reduction and comprehensive geriatric assessment.

303 Background: Delivery of appropriate management of elderly patients with OG malignancies in the palliative setting remains challenging and unpredictable. Incidence of OG cancers increases markedly with age, and there are growing numbers of elderly, frail and medically complex patients referred to oncology services for treatment. An adaptive approach to their management is required, tailored to their complex medical needs. The GO2 study sought to optimise chemotherapy delivery in this cohort and demonstrated that upfront dose reductions do not reduce progression-free survival in OG cancers. We analysed the treatment and outcome of elderly patients undergoing first-line palliative chemotherapy at our centre, with or without comprehensive geriatric assessment (CGA). Methods: We retrospectively analysed the records of patients over the age of 75 treated at our centre between May 2011 and March 2023. Progression-free survival (PFS) was calculated from the date of treatment initiation to date of radiological progression, or 19 th March 2024 if patients had not progressed. Overall survival (OS) was calculated from treatment initiation to date of death per the electronic health record, or 19 th March 2024 if patients had not died. Grade 3 (G3) toxicities and dose reductions (DRs) were identified from medical records. Statistical analyses were performed using R v4.3.3. Results: 82 patients were included in the analysis. Overall median PFS was 6.5 months (1-107 months) and median OS was 10 months (1-107 months). Patients who qualified for chemotherapy with immunotherapy had improved PFS (median 16 months, range 2-27 months) and OS (median 16 months, range 10-27 months). G3 toxicities were increased in patients without upfront DR (44% vs. 30%). The most significant predictor for survival in multivariate analysis was performance status (PS), which was associated with worse PFS (hazard ratio 2.66, range 1.35–5.35, p = 0.004), and OS (hazard ratio 6.13, range 2.79–13.44, p &lt; 0.001). Age was not associated with survival. Consistent with the GO2 trial, there was no association between upfront DR and PFS (p = 0.13) or OS (p = 0.72). 38% of patients underwent CGA as part of their workup for chemotherapy. These patients were more likely to have upfront DR (61% vs. 47%). In this cohort, G3 toxicity rates were comparable in patients with PS 0-1 who underwent CGA (39% vs. 35%). In patients with PS ≥ 2, G3 toxicity rates were higher in those who did not undergo CGA (67% vs. 30%). Conclusions: Upfront DR in elderly patients is safe and does not impact survival but does reduce the burden of toxicity. PS, rather than age, is a better predictor of survival and treatment outcome. CGA may help mitigate toxicity burden in patients with poor performance status.

Outcomes of proton therapy to infradiaphragmatic sites in pediatric patients with Hodgkin lymphoma.

Proton therapy (PT) has potential advantages in pediatric Hodgkin lymphoma (pHL). However, there are limited data on PT, specifically to infradiaphragmatic targets. We report on PT planning details, doses achieved to organs at risk (OARs), and clinical and toxicity outcomes for patients with pHL who received PT to infradiaphragmatic regions. This is a retrospective study including patients treated between 2011 and 2022. Demographic and clinical factors were collected, and toxicity was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Dosimetric and clinical factors associated with key outcomes were assessed via Cox regression. Photon plans were generated for all patients, and the paired t-tests or Wilcoxon signed rank sum tests were used for dosimetric comparisons. Twenty-one patients comprising 22 PT courses were included. Median follow-up was 5.0years, and mean age was 14.2years. Median dose was 21 Gray equivalent (GyE) over 14 fractions. Top acute grade 1 (G1) toxicities included fatigue (59%) and anorexia (36%). Rates of acute G2 and G3+ toxicity were 18% and 0%, respectively. After PT, no local or marginal failures occurred. Five percent experienced disease progression, who were all successfully salvaged, and all patients were alive and disease-free at last follow-up. No secondary malignancies developed. Compared to photon radiotherapy, PT achieved significantly lower doses to the bowels, stomach, spleen, pancreatic tail, liver, kidneys, and pelvic bones. PT is well-tolerated and leads to excellent oncologic and toxicity outcomes with long-term follow-up. PT confers dosimetric advantages when compared to photons.

Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

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.

Clinicopathological Features of Pediatric Insulinoma: A Single-Centre Study.

Aims/Background: Insulinoma is an extremely rare condition in pediatric patients. This study aims to examine the pathological and clinical characteristics of pediatric insulinoma. Methods: A retrospective, single-center study was conducted involving five pediatric patients diagnosed with insulinoma. The study involved evaluating the postoperative status of the patients during follow-up and analyzing their clinical manifestations, diagnostic work-up, pathological findings, and therapeutic approaches. Results: The study cohort comprised four males and one female, aged between 4 and 9 years. Common symptoms included dizziness and fatigue. The insulinomas were located in various parts of the pancreas: two in the head, one in the neck, one in the body, and one in the tail. After undergoing subtotal pancreatectomy, four patients experienced no side effects during a follow-up period of 41 to 153 months. One patient, who underwent an incomplete pancreatic resection, required ongoing postoperative treatment with 150 mg Creon due to pancreatic enzyme deficiency. Postoperative pathological results indicated that all cases were low-grade neuroendocrine tumours, classified as grade 1 (G1) or grade 2 (G2). Two cases exhibited capsule invasion, and one case showed microvascular invasion. Despite these invasions, no recurrences or metastases have been observed to date. Conclusion: Surgical resection is a viable treatment option for pediatric insulinoma, yielding a favorable prognosis. The presence of capsular and microvascular invasions does not seem to affect the overall prognosis in these cases.

Incidence of alopecia in brain tumour patients treated with pencil scanning proton therapy and validation of existing NTCP models

Background and purposeRadiation-induced alopecia (RIA) is one of the most frequent and upsetting cosmetic side effects after radiotherapy (RT) for brain cancer. We report the incidence of RIA in a cohort of brain tumours patients treated with Proton Therapy (PT) and externally validate published NTCP models of grade 2 (G2) RIA for their implementation in clinical practice. MethodsData for patients treated for brain tumours with scanning beam PT between 2018 and 2022 were extracted. Acute, late and permanent RIA events were evaluated according to CTCAE 5.0. Lyman-Kutcher-Burman (LKB) and multivariable logistic regression (MLR) published models were computed from the relative dose-surface histogram of the scalp. External validity of models was assessed in terms of discrimination and calibration. ResultsIn the 264 patients analysed, rates of any grade acute (≤90 days after PT completion), late (>90 days) and permanent RIA (persisting for> 12 months) were 61.8 %, 24.7 % and 14.4 %, respectively. In our independent cohort, LKB- and MLR-NTCP showed a good discrimination for G2 RIA (0.71≤ROC-AUC≤0.83) while model calibration was unsatisfactory possibly due to a different outcome evaluation between training and validation cohorts, as well as differences in clinical and treatment related variables between the two groups. ConclusionsDespite the reasonable sensitivity and specificity of the NTCP models for RIA in the validation cohort, our study emphasizes the significance of differences between the cohorts utilized for model development and validation. Specifically, variations in the reporting of clinical outcomes inevitably jeopardize the validation of NTCP models. A standardize and objective RIA scoring system is essential.

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.

Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A.

Valoctocogene roxaparvovec is an adeno-associated virus vector serotype 5 (AAV5)-mediated gene therapy approved for severe haemophilia A (HA). To report the safety and efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795). Males ≥18 years with severe HA (factor VIII [FVIII] ≤1 international unit [IU]/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6×1013vg/kg; n=7) and 6 (4×1013vg/kg; n=6) years. In the last year, one participant in each cohort reported treatment-related adverse events (AEs): grade 1 (G1) hepatomegaly (6×1013), and G1 splenomegaly and G1 hepatic steatosis (4×1013). During all follow-up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6×1013 (n=5) and 4×1013 (n=4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was -0.001 and -0.07IU/dL/week for the 6×1013 and 4×1013 cohorts, respectively. Two participants (6×1013) resumed prophylaxis in year 7: one after a non-treatment-related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity. The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis.

Primary Presacral Neuroendocrine Tumors Presented by Lumbosacral Pain: a Case Report

Primary presacral neuroendocrine tumors (NETs) are exceedingly rare and often present with extensive metastases, posing significant challenges for clinical management. We report a case of a presacral neuroendocrine tumor in a 68-year-old male who presented with lumbosacral pain. Enhanced MRI revealed a soft tissue mass at the sacrococcygeal region, while whole-body enhanced 18F-PET/CT identified small intratumoral vessels and involvement of the adjacent rectal posterior wall, mesorectal fascia, presacral fascia, and sacrococcygeal bones, accompanied by multiple lymph node metastases and widespread metastases to the lungs, liver, and bones. A CT-guided biopsy confirmed the diagnosis of a grade 2 (G2) neuroendocrine tumor. Given the tumor's extensive metastasis and aggressive nature, surgical intervention was deemed unsuitable, and the patient was treated with sulfatinib. Sulfatinib shows significant potential in managing advanced neuroendocrine tumors, providing an effective therapeutic option for patients with such complex and high-risk conditions.

Effect of synthetic CT on dose-derived toxicity predictors for MR-only prostate radiotherapy.

Toxicity-driven adaptive radiotherapy (RT) is enhanced by the superior soft tissue contrast of magnetic resonance (MR) imaging compared with conventional computed tomography (CT). However, in an MR-only RT pathway synthetic CTs (sCT) are required for dose calculation. This study evaluates 3 sCT approaches for accurate rectal toxicity prediction in prostate RT. Thirty-six patients had MR (T2-weighted acquisition optimized for anatomical delineation, and T1-Dixon) with same day standard-of-care planning CT for prostate RT. Multiple sCT were created per patient using bulk density (BD), tissue stratification (TS, from T1-Dixon) and deep-learning (DL) artificial intelligence (AI) (from T2-weighted) approaches for dose distribution calculation and creation of rectal dose volume histograms (DVH) and dose surface maps (DSM) to assess grade-2 (G2) rectal bleeding risk. Maximum absolute errors using sCT for DVH-based G2 rectal bleeding risk (risk range 1.6% to 6.1%) were 0.6% (BD), 0.3% (TS) and 0.1% (DL). DSM-derived risk prediction errors followed a similar pattern. DL sCT has voxel-wise density generated from T2-weighted MR and improved accuracy for both risk-prediction methods. DL improves dosimetric and predicted risk calculation accuracy. Both TS and DL methods are clinically suitable for sCT generation in toxicity-guided RT, however, DL offers increased accuracy and offers efficiencies by removing the need for T1-Dixon MR. This study demonstrates novel insights regarding the effect of sCT on predictive toxicity metrics, demonstrating clear accuracy improvement with increased sCT resolution. Accuracy of toxicity calculation in MR-only RT should be assessed for all treatment sites where dose to critical structures will guide adaptive-RT strategies. Patient data were taken from an ethically approved (UK Health Research Authority) clinical trial run at Guy's and St Thomas' NHS Foundation Trust. Study Name: MR-simulation in Radiotherapy for Prostate Cancer. ClinicalTrials.gov Identifier: NCT03238170.

Total toxicity burden as a practical tool to quantify the overall severity of multiple adverse events in clinical trials.

3156 Background: Phase I clinical trials (CT) report adverse events (AEs) using the Common Terminology Criteria for AEs (CTCAE) version 5.0. If multiple qualitatively AEs are recorded in a trial, this results into manifold AE counts. Total toxicity burden (TTB) is defined for each patient as the sum of the highest grade of each AE divided by the number of AEs recorded [Thall, 2003]. We computed the TTBs for five groups of drugs studied in phase I trials. Methods: Pts treated from 2016 to 2022 in the phase I CT unit at MD Anderson Cancer Center were included. Clinical baseline prognostic factors [ECOG, age, Carlson comorbidity index (CCI)] were included and analyzed. AEs according to the CTCAE v5.0 were collected and simplified into 21 categories per trial and patient. Treatments were divided into: Cytotoxic agents (Chemo), Targeted Therapy (TT), Immune checkpoint inhibitors (ICI), Chimeric antigen receptor T cells (CART), or Cytokines (CYT). Using regimen-related AEs for evaluable patients, mean (SD) TTB for each treatment group was computed using each patent’s worst grade as the severity weight for each type of AE. Results: A total of 1322 evaluable pts from an initial sample of 2,350 were collected. Median age was 61 years (range, 19-92), 75.6% ECOG PS 1, median CCI was 8, and all pts were treated in a phase I/II CT. A total of 1782 AEs were treatment related and 3071 AEs were not treatment related. 715 evaluable pts (54.1%) had at least one treatment-related AE, and 902 patients (68.2%) had at least one treatment unrelated AE. A total of 265 (20.0%) grade 1 (G1) treatment-related AEs, 231 (17.5%) G2, 184 (13.9%) % G3, and 29 (2.2%) G4, and one G5 was reported. The most frequent G≥3 AEs overall were Neutropenia (N=54), Anemia (N=52), and low platelets (N=35). The most frequent G≥3 AEs per treatment group were Neutropenia (10%), Anemia (15%), and increased AST/ALT (13%) in group Chemo, Neutropenia (8%), Low platelets (9%), and Anemia (9%) in group TT, Increased AST/ALT (10%), Anemia (5%), and Pain (5%) in group ICI, Neutropenia (10%), Anemia (10%), and Low platelets (5%) in group CART, and Nausea/Vomit (3%), Pneumonitis (1%), and Infection (1%) in group CYT. Mean TTBs for the five treatment groups were 2.7 (SD=3.3) for Chemo, 2.9 (SD=3.6) for TT, 1.7 (SD=1.9) for IO, 5.9 (SD=5.1) for CART, and 0.8 (SD=1.8) for CYT. Corresponding G≥3 treatment-related AE rates were 21.7%, 21.0%, 12.2%, 52.4%, and 6.4% in the five treatment groups. It appears that CART is the most toxic treatment group based on TTBs and conventional analysis based on G&gt;3. These results suggest that propensity score-based comparisons of mean TTB to correct for selection bias using prognostic variables are warranted. Conclusions: TTB is a useful tool to quantify the mean severity of qualitatively different types of adverse events experienced by patients in a clinical trial, and mean TTB may be compared between treatment groups.

New drugs to prevent oxaliplatin-induced peripheral neuropathy: A double-blind, randomized study.

3568 Background: Postoperative adjuvant chemotherapy for colorectal cancer reduces postoperative recurrence; however, it often causes undesirable adverse events. Oxaliplatin, the mainstay of postoperative adjuvant chemotherapy is particularly likely to cause chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSR) that may make it difficult to continue treatment. Various agents have been tested for prevention or treatment of CIPN caused by oxaliplatin, but none have proven effective. Reactive oxygen species contribute oxaliplatin-induced PN; therefore, super oxide dismutase (SOD) could potentially suppress them, but its very short serum half-life has made clinical application difficult. We developed a lecithinized human copper/zinc SOD (Cu/Zn-SOD) (PC-SOD) in which four phosphatidylcholine derivative molecules are bound covalently to each SOD dimer. Compared with SOD, PC-SOD enhanced stability in plasma and stronger tissue affinity, and exerts therapeutic effects in animal models of several diseases, including CIPN. Methods: This double-blind, randomized study included 90 patients with stage II/III colorectal cancer. All patients were slated to receive 12 cycles of mFOLFOX6. In each cycle, patients received PC-SOD or a placebo immediately before oxaliplatin. The primary endpoint of this study was the number of cycles before NCI-CTCAE Grade 2 (G2) CIPN occurred. One of the secondary endpoints was the number of cycles before DEB-NTC G2 PN occurred. Results: Forty-three patients received PC-SOD. No serious adverse events were observed that could be related to PC-SOD. The incidence of neutropenia, diarrhea, stomatitis, and malaise were lower in the study group, but the differences were not significant. Additionally, 3 patients (7.0%) in the study group and 11 (23.4%) in the placebo group had HSR. Although there was no difference in the number of cycles between the two groups until NCI-CTCAE G2 PN occurred, the study group had a significantly greater number of cycles before DEB-NTC G2 PN compared to the placebo group (P=0.08). The study group had a significantly greater number of cycles before NCI-CTC G1 PN (P=0.01) and HSR (P=0.03) compared to the placebo group. The number of cycles before HSR or NCI-CTCAE G2 PN occurred was greater in the study group , but the difference was not significant. The average total oxaliplatin dose was higher in the study group but the difference was not statistically significant. Conclusions: The primary endpoint did not occur; however, the study group had a significantly greater number of cycles before DEB-NTC G2 PN. Notably, the study group also had a significantly greater number of cycles before HSR. These results show that PC-SOD may suppress HSR as well as PN, both of which limit administration of oxaliplatin. Thus, this drug is expected to improve not only patient quality of life, but also the prognosis of patients. Clinical trial information: 2031210466.

Prolonged Response to Dabrafenib/Trametinib in Grade 3 Metastatic Pancreatic Neuroendocrine Tumor (NET G3) with BRAF V600E Mutation

PurposeTreatment of metastatic pancreatic neuroendocrine tumors (pancNETs), particularly grade 2 (G2) and grade 3 (G3), often presents a dilemma in choosing from multiple similarly efficacious therapies. Data on targeted therapies for these tumor types is limited, and this report presents BRAF-targeted therapy as a therapeutic option for metastatic pancNET G3.MethodsThis is a case report of a patient with G3 pancNET metastatic to the liver, lung, lymph node, and scalp (soft tissue) treated with dabrafenib/trametinib (D/T) in the presence of a BRAF V600E mutation detected in tumor tissue.ResultsThis patient has demonstrated an ongoing partial response to therapy at all involved sites for nearly 15 months with minimal side effects attributable to D/T.ConclusionDabrafenib/trametinib therapy for BRAF-mutated metastatic pancNETs provides a novel treatment option and, especially in the G3 setting, should be considered a first-line option. Tumor testing for actionable mutations should be undertaken at the time of diagnosis and/or progression to identify novel therapeutic avenues in these rare tumors.

Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance.

Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.

Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study

AimsWHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. Materials and methodsPatients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. Results84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection.Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27–1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27–0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy–60Gy), 45.8% of adjuvant RT was delivered using IMRT.At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. ConclusionSurgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

Abstract PO3-17-11: The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data Study

Abstract Background: The Oncotype Dx (ODX) genomic risk score (RS) has become an essential tool in clinical practice for guiding adjuvant chemotherapy decisions in early-stage hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Since some of the genes evaluated in the genomic RS tests are proliferation-related, the use of the test is less clear in tumors with low proliferation, such as histologic grade 1 tumors or those with a low Ki67-index. In contrast to common understanding, however, ODX RS is determined more strongly by estrogen-related features and only weakly by proliferation markers. Methods: This multicentric real-world data (RWD) study aimed to evaluate the usefulness of (ODX) in patients with grade 1 (G1) HR+, HER2-negative BC. The study population consisted of patients treated between 2009 and 2020 across nine Brazilian cancer centers. Key endpoints included the prevalence of high genomic RS in the histologic grade 1 cohort, recurrence rates based on genomic risk, and invasive disease-free survival (IDFS). Results: A total of 651 patients with HR+, HER2-negative BC who underwent Oncotype Dx testing were evaluated. Among 651 patients evaluated, 128 had HG1 tumors, constituting the focus of this analysis. The majority of patients were aged over 50 years (59.4%), had breast carcinoma of non-special type (75.8%), and Ki67 index lower than 20% (77%). Tumor stage distribution revealed 28.1% T1b, 50% T1c, and 14% T2 cases. Additionally, 74.2% were classified as N0, 9.4% as N1mic, and 16.4% as N1. According to the binary categorization based on Adjuvant! algorithm, 92.2% of patients (n=118) had a low clinical risk. ODx analysis showed that 21.9% had a low RS, 74.2% had an intermediate RS, and only 3.1% had a high RS. Among the few patients with a high genomic RS, only one patient did not receive adjuvant chemotherapy. With a median follow-up of 38.3 months, three patients experienced recurrence, all of whom had an intermediate RS. Among these cases, two patients were younger than 50 years, had low clinical risk, and a genomic RS of 18-24; both had locoregional recurrences. The third patient, aged over 50 years, had high clinical risk, a RS of 12, and had a distant recurrence. The recurrence rates according to Ki67 index were 1.1% for patients with Ki67 index &amp;lt; 20% and 7.1% for those with Ki67 index ≥ 20%. Notably, no recurrences were observed in the high genomic risk group. The estimated 5-year IDFS rate was 96.9% (95% CI 88.2% - 99.2%). Conclusion: In the context of G1 BC and low clinical risk, the utility and cost-effectiveness of ODX may be limited. These findings emphasize the importance of carefully assessing clinical risk when selecting patients for genomic RS tests, thereby optimizing resource utilization. Longer follow-up is planned for this RWD cohort. Citation Format: Renata Colombo Bonadio, Leandro Oliveira, Daniel Batista, Daniela Rosa, Artur Katz, Max Mano, Daniele Assad-Suzuki, Daniel Argolo, Solange Sanches, Rafael Kaliks, Débora Gagliato, Thais Megid, Daniel Musse, Tatiana Correa, Andrea Shimada, Romualdo Barroso-Sousa, Marcelle Cesca, Débora Gaudêncio, Larissa Moura, Julio Araujo, José Bines, Laura Testa. The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data Study [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 PO3-17-11.

Abstract PO2-16-07: Real-world eligibility for adjuvant CDK4/6 inhibitors among patients without genomic risk for chemotherapy: a GBECAM multicenter retrospective study

Abstract Background: Oncotype DX (ODX) is a genomic signature (GS) for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and positive (N1), hormone receptor positive (HR+), HER2 negative (HER2-) early breast cancer (eBC). ODX was not an inclusion criterion in the MonarchE but was one in the Natalee study, in which trials most patients received neo-adjuvant chemotherapy. We aim to evaluate the proportion of patients potentially eligible for adjuvant CDK4/6 inhibitors (CDK4/6i) without CT indication by genomic risk using real-world data from a large dataset of patients from various Brazilian institutions. Methods: Clinicopathologic and ODX information were reviewed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by genomic criteria were based on TAILORx and RxPONDER data. Projections of adjuvant CDK4/6i indication were based on the MonarchE and Natalee criteria. Results: Of 636 patients, 27.5%/51.8%/20.8% were T1mic-a-b/T1c/T2-3, respectively. 19.5% were grade 1 (G1), 66.9% G2 tumors and 12.9% G3. 74 (11.6%) were N1. The ODX indicated low (&amp;lt; 11), intermediate (11-25) and high ( &amp;gt;25) risk in 117 (18.4%), 408 (64.1%) and 111 (17.5%) patients, respectively. 408 patients (64.2%) had low clinical risk and 228 patients (35.8%) had high clinical risk disease. In the overall cohort, 439 (69%) did not have genomic indication for CT, 25 (3.9%) and 133 (21%) were eligible for adjuvant abemaciclib and ribociclib, respectively. Among patients eligible for adjuvant CDK4/6i, greater than 50% did not meet genomic criteria for recommendation of CT (Table 1). Conclusions: In times of rapid incorporation of both GES (as valuable treatment de-escalation tools) and adjuvant CDK4/6i, our results suggest that a meaningful proportion of patients could be eligible for adjuvant abemaciclib and/or ribociclib independently of CT indication. However, little is currently known about the role of these agents in patients not treated with chemotherapy because they were largely unrepresented in these studies. Proportion of patients eligible for adjuvant CDK4/6i in the overall and non-CT eligible population. CT: chemotherapy Citation Format: Leandro Oliveira, Thais Megid, Daniela Rosa, Daniele Assad-Suzuki, Daniel Argolo, Solange Sanches, Laura Testa, José Bines, Rafael Kaliks, Débora Gagliato, Romualdo Barroso-Sousa, Tatiana Correa, Andrea Shimada, Daniel Batista, Daniel Musse, Marcelle Cesca, Débora Gaudêncio, Larissa Moura, Julio Araujo, Renata Colombo Bonadio, Artur Katz, Max Mano. Real-world eligibility for adjuvant CDK4/6 inhibitors among patients without genomic risk for chemotherapy: a GBECAM multicenter retrospective study [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 PO2-16-07.