Mean Progression-free Survival Research Articles

Real-world outcomes of sacituzumab govitecan in breast cancer.

e13137 Background: Sacituzumab govitecan (Trodelvy), a novel antibody-drug conjugate, has emerged as a promising treatment option, in patients with metastatic triple-negative breast cancer (mTNBC). It gained FDA approval for unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies based on ASCENT trial which demonstrated that progression-free survival (PFS) and overall survival (OS) was significantly longer with sacituzumab govitecan than with single-agent chemotherapy. Hence, here in our current study, we further explore the outcomes of patients on sacituzumab govitecan in the setting of mTNBC. Methods: A single-center retrospective analysis was conducted on 21 women (aged 30-80 years old) with mTNBC breast cancer treated with sacituzumab govitecan over a span of 4 years. Baseline characteristics, pre-sacituzumab govitecan treatment PFS correlations, PFS and OS of sacituzumab govitecan were assessed and compared with the ASCENT trial. Results: A total of 21 women, comprising 10 African American, 10 Caucasian, and 1 Asian were evaluated over a span of 4 years. In our study with an average population of 50.6 years, the overall mean (± standard error of the mean) observed was 5.00 months (SEM 1.02) for PFS and 8.33 months (SEM 1.62) for OS. Patients with brain metastasis (n=8) and without brain metastasis (n=13) exhibited a mean of 5.99 months (SEM 2.23) and 4.40 months (SEM 0.97) for PFS respectively whereas 8.34 months (SEM 2.28) and 8.33 months (SEM 2.29) for OS respectively. The average number of previous treatment exposures in this subset was 5.6, with a mean PFS of 11.33 months (SEM 3.64) for prior treatment before initiation of sacituzumab govitecan. Conclusions: Our data reflects a similar interpretation with ASCENT trial study for mean PFS, however with a lower mean OS. In our study, the mean PFS from 8 patients who had brain metastasis closely matched with the patients without brain metastasis and the median PFS of the trial, thus suggesting potential consideration of sacituzumab govitecan in patients with active brain metastasis, as the patients with brain metastasis were excluded from the primary endpoint analysis in the ASCENT trial. No correlation was observed between the mean PFS of the prior line of therapy before sacituzumab govitecan and sacituzumab govitecan’s mean PFS. Overall, sacituzumab govitecan represents a significant advancement in breast cancer treatment and offers hope for patients with mTNBC.

Effectiveness and safety of computed tomography-guided high-dose-rate brachytherapy in treating recurrent hepatocellular carcinoma not amenable to repeated resection or radiofrequency ablation

PurposeTo assess the efficacy and safety of computed tomography (CT)-guided high-dose-rate HDR) brachytherapy in treating recurrent hepatocellular carcinoma (HCC) not amenable to repeated resection or radiofrequency ablation. Materials and methodsFrom January 2010 to January 2022, 38 patients (mean age, 70.1 years; SD ± 9.0 years) with 79 nodular and four diffuse intrahepatic HCC recurrences not amenable to repeated resection or radiofrequency ablation underwent CT-guided HDR brachytheapy in our department. Tumor response was evaluated by cross-sectional imaging 6 weeks after CT-guided HDR brachytherapy and every 3 months thereafter. Local tumor control (LTC), progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier curves (KPCs). Severity of procedure-related complications (PRCs) was classified as recommended by the Society of Interventional Radiology (SIR). ResultsPatients were available for MRI evaluation for a mean follow-up of 33.1 months (SD, ±21.6 mm, range 4–86 months; median 29 months). Patients had a mean of 2.3 (SD, ±1.4) intrahepatic tumors. Mean tumor diameter was 43.2 mm (SD, ±19.6 mm). 13 of 38 (34.2%) patients showed local tumor progression after CT-guided HDR brachytherapy. Mean LTC was 29.3 months (SD, ±22.1). Distant tumor progression was seen in 12 patients (31.6%). The mean PFS was 20.8 months (SD, ±22.1). Estimated 1-, 3-, and 5-year PFS rates were 65.1%, 35.1% and 22.5%, respectively. 13 patients died during the follow-up period. Mean OS was 35.4 months (SD, ±21.7). Estimated 1-, 3-, and 5-year OS rates were 91.5%, 77.4% and 58.0%, respectively. SIR grade 1 complications were recorded in 8.6% (5/38) and SIR grade 2 complications in 3.4% (2/58) of interventions. ConclusionCT-guided HDR brachytherapy is a safe and efficient therapeutic option for managing large or critically located HCC recurrences in the remaining liver after prior hepatic resection.

Abstract PO5-25-04: Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab

Abstract Background: Immune checkpoint inhibitors (ICIs) offer new treatment possibilities for women with triple-negative breast cancer (TNBC) – one of the most challenging breast cancer subtypes. The PD-1 inhibitor pembrolizumab (pembro; Keytruda®) is approved in metastatic TNBC (mTNBC) patients with PD-L1(+) tumors, and for neoadjuvant treatment (NAT) in stage II/III TNBC [1, 2]. Residual cancer burden (RCB) after NAT is highly prognostic, with pathologic complete response (pCR, RCB 0) anticipating long-term survival [3]. In mTNBC, pembro plus chemotherapy in the 1st-line improves progression free survival (PFS), but durable responses are rare. Optimizing ICI use in TNBC thus remains an unmet need, and defining easily assessable markers of response is crucial. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are peripheral blood surrogates of tumor inflammation and have prognostic and predictive value in TNBC [4-8]. Elevated NLR (≥ 5) and PLR (≥ 200) correlate with worse outcomes upon ICIs in melanoma and non-small-cell lung cancer [9, 11-14]; however, this has not been studied in breast cancer [9, 10]. We evaluated the relationship of baseline NLR and PLR with pembro responses in TNBC patients. Methods: We retrospectively reviewed data from TNBC patients who completed pembro between 10/2/20 - 6/1/23 at Weill Cornell. Patients on NAT who did not complete treatment were excluded. RCB score (pCR/0, 1, 2, 3) was calculated from surgical resection pathology reports using the MD Anderson RCB Calculator [15, 16]. Baseline laboratory data were obtained from clinical records. Associations between NLR and PLR with RCB levels were examined using the non-parametric Kruskal-Wallis test (if >2 levels), the Wilcoxon rank sum test (if 2 levels), or the Spearman’s rank correlation. NLR and PLR were also correlated with PFS (measured from pembro start date to date of progression) in metastatic patients. PFS data for metastatic patients without interval imaging since pembro initiation were censored at the date of data analysis, and PFS was not calculated for patients who received only 1 cycle of pembro. Results: We identified 63 eligible patients: 24 were excluded due to lack of TNBC diagnosis (n=20), or because they only received adjuvant pembro (n=4). Of the 39 remaining patients, 5 did not complete NAT and 2 had missing data, leaving 32 evaluable patients (17 in the NAT cohort and 15 in the mTNBC cohort). Overall, the median age was 51 years, and 16% were Hispanic, 11% Asian, 57% non-Hispanic, 24% Black, and 65% Non-Black. Neoadjuvant cohort: The pCR rate was 30%. Patients with both NLR ≥ 5 and PLR ≥ 200, had a pCR rate of 0%; in patients with NLR < 5 or PLR < 200, pCR rate was 43%. Median NLR in pCR vs. non-pCR groups was 1.91 [IQR: 1.72- 2.73] vs. 2.44 [IQR: 1.97- 5.24] (p=0.3), with trends towards significance when NLR was compared between RCB levels >1 (2.67; IQR: 2.05, 6.49) vs. RCB levels ≤1 (1.91; IQR: 1.63, 2.58) (p=0.14). Mean PLR was higher in patients with RCB 2-3 (409) compared to those with pCR or RCB 1 (167) (p=0.146). Metastatic cohort: The overall mean PFS was 7.8 months. Visceral metastases were seen in 80% of patients (17% liver, 33% brain). In patients with brain mets, baseline NLR and PLR were higher than in the overall cohort (NLR, 4.86 vs. 2.78; PLR, 429 vs. 186). Conclusions: Our study is the first to evaluate NLR and PLR as response biomarkers in TNBC patients receiving pembro and is the first report of our real-world data of TNBC patients on pembro. In our neoadjuvant cohort, higher baseline NLR and PLR correlated with higher RCB levels, with a trend towards statistical significance. Further investigation and correlation of NLR and PLR with tumor microenvironment features will help to clarify these relationships. Citation Format: Ashley Schreier, Roberta Zappasodi, Inna Serganova, Laura Munoz Arcos, Xi Kathy Zhou, Massimo Cristofanilli, Eleni Andreopolu. Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab [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 PO5-25-04.

Re-188 lipiodol in hepatocellular carcinoma with portal vein thrombosis: a pilot study using novel chelating agent N-DEDC and its comparison with (A)HDD.

Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]. Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study. Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70 years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6 ± 0.37 GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups. Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same.

Prognostic significance of alterations in fibrinogen level and fibrinogen-to-lymphocyte ratio after radiotherapy on survival outcomes in glioblastoma.

Fibrinogen (FIB) plays an important role in tumor initiation, progression, and metastasis, but its clinical significance in glioblastoma has not been studied. We intend to explore the prognostic value by retrospectively analyzing the changes in FIB and fibrinogen-to-lymphocyte ratio (FLR) in glioblastoma patients before and after radiotherapy, and study the impact of radiotherapy on them. This study retrospectively included 104 patients who were newly diagnosed with glioblastoma between February 2017 and February 2022 and analysed their clinical data from before to after radiotherapy. The cut-off values for FLR and FIB were calculated using a receiver operating characteristic curve. For inter-group comparisons, the Mann-Whitney U or t-test was applied. The prognostic importance of FIB and FLR was evaluated using the Kaplan-Meier curve and the Cox regression model. Spearman correlation coefficients were calculated to evaluate the association of FIB and FLR with radiotherapy-related dose-volume parameters. The mean progression-free survival (PFS) and overall survival (OS) of the high FIB and high FLR groups were significantly lower than those of the low FIB and low FLR groups (P<0.05). Larger planning target volume (PTV), mean brain dose, and mean brainstem dose were independent prognostic factors for poor PFS and OS in patients with glioblastoma. FLR was a unique and very accurate predictor for the prognosis of glioblastoma, and FIB rise after radiation was a predictive sign of poor survival. Both PTV volume and dose volume for involved organs could significantly affect the FIB and FLR values in patients with glioblastoma.

Abstract 2388: Artificial neural network based ensemble models for single-arm glioblastoma trials: A new historical control adjustment method

Abstract Background: Despite a long history of poor decision making leading to repeated failed phase 3 trials, phase 2 single-arm studies continue to be common in glioblastoma (GBM). With the drawback of inflated false positive rate in current adjustment method for historical control data as concurrent controls, the new statistical methods and validation approach will be needed for adequate covariate adjustment in the GBM single-arm trial data. Methods: The systematic review was performed to extract the summary-level external data of survival outcomes (mean progression-free survival, mPFS, and PFS at 6 months, PFS6) and prognostic factors (age, gender, extent of resection, KPS, methylation status, and treatment history) from published randomized clinical trials for the standard of care (SOC) treatment in GBM. Four models of the standard, bootstrap aggregating, random subspaces, and random patches models were developed to construct a powerful predictive tool by comprising a series of connections producing survival outputs as a function of prognostic inputs using (1) artificial neural network (ANN) method and (2) linear method (Fig1). The root mean square errors (RMSEs) were calculated to evaluate the model performance using the five-fold cross-validation approach with the effects of ensemble size. The predictive survival outcomes among prognostic factors were calculated to evaluate the relative importance of factors. Results: We identified 19 Phase 2 and 3 clinical trials in glioblastoma and two survival outcomes and seven prognostic factors (Table 1). ANN models have less prediction error and therefore better performance on the test set than linear models. Presumably, the relationships in the data are highly nonlinear, and thus linear models cannot capture these relationships (Table 2). Bagging models typically outperform their standard counterparts for both ANNs and linear models. Ensemble methods can capture many trends within the data by manipulation of the training set and are therefore less prone to biases of individual models exacerbated by the small sample size. The previous treatment history and methylation status were the top two influential prognostic factors for both mPFS and PFS6, followed by the extent of resection and mean age (Fig2). With the examination of the ANN parameters of sample size, learning rate, training hyperparameters, it could be observed that there is no clear change in error when increasing sample size beyond 10 (Fig3). Conclusions: High failure rate of phase 3 glioblastoma trials emphasizes the need for greater reliability of earlier studies in phase 2 single-arm trials. The proposed statistical and epidemiologic approach based on the ensemble-based ANN models will be an effective tool to lead to better decision with phase 2 single-arm trials, which may give better chance to appropriately advance to phase 3 trials with higher predictive power. Citation Format: Wonsuk Yoo, Tortsen Ullrich, Nader Sanai. Artificial neural network based ensemble models for single-arm glioblastoma trials: A new historical control adjustment method [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2388.

Clinical outcomes of patients with CIC-rearranged sarcoma: a single institution retrospective analysis

PurposeCIC-rearranged sarcomas represent a type of undifferentiated small round cell sarcoma (USRCS) characterized by poor survival, rapid development of chemotherapy resistance, and high rates of metastasis. We aim to contribute to the growing body of knowledge regarding diagnosis, treatment, clinical course, and outcomes for these patients.MethodsThis case series investigates the clinical courses of ten patients with CIC-rearranged sarcoma treated at the Johns Hopkins Hospital from July 2014 through January 2024. Clinical data were retrospectively extracted from electronic medical records.ResultsPatients ranged from 10 to 67 years of age at diagnosis, with seven patients presenting with localized disease and three with metastatic disease. Tumors originated from soft tissues of various anatomic locations. Mean overall survival (OS) was 22.1 months (10.6–52.2), and mean progression-free survival (PFS) was 16.7 months (5.3–52.2). Seven patients received intensive systemic therapy with an Ewing sarcoma-directed regimen or a soft tissue sarcoma-directed regimen. Three patients experienced prolonged disease-free survival without systemic treatment.ConclusionMost patients in this case series demonstrated aggressive clinical courses consistent with those previously described in the literature, although we note a spectrum of clinical outcomes not previously reported. The diversity of clinical courses underscores the need for an improved understanding of individual tumor biology to enhance clinical decision-making and patient prognosis. Despite its limitations, this article broadens the spectrum of reported clinical outcomes, providing a valuable addition to the published literature on this rare cancer.

Effect of venetoclax plus chemotherapy on treatment-naive acute myeloid leukemia patients with moderate to poor cytogenetic profiles and the combination's influence on the expression of proteins of the anti-apoptoic family

Objective: This was an open-label observational assessment aimed to evaluate whether venetoclax (VEN) plus chemotherapy could enhance the therapeutic benefits for treatment-naive acute myeloid leukemia (AML) patients with adverse cytogenetic profiles. Methods: A total of 38 adult patients (including 11 patients with moderate risk stratification and 27 patients with high risk stratification) who were treated at the Affiliated Hospital of Inner Mongolia Medical University from April 2019 to May 2022 were enrolled in this study. Patients were randomized into two cohorts according to the random number method to receive single intensive chemotherapy (18/38) alone or VEN+intensive chemotherapy (20/38), respectively. The chemotherapy cohort received 2 cycles of induction chemotherapy (idarbicin or daunorubicin plus cytarabine), followed by 6 cycles of consolidation chemotherapy (cytarabine), while the treatment for the VEN + chemotherapy cohort consisted of the same chemotherapy as above plus oral VEN. Heparinized bone marrow samples were obtained from patients at enrollment de novo and post chemotherapy. The expressions of MCL-1 and BCL-2 were detected by Western blot analysis. Results: Patients with VEN+chemotherapy showed an objective response rate (ORR) of 90.0% (18/20), compared with 55.6% (10/18, P=0.012) of the chemotherapy group. Meanwhile, the VEN + chemotherapy cohort gained more benefits in progression-free survival (PFS) and overall survival (OS) than the chemotherapy cohort (mean PFS: 27.1 months versus 17.9 months, P=0.038; mean OS: 32.2 months versus 21.3 months, P=0.004). For patients with moderate risk stratification, there were no differences in the ORR and PFS between the chemotherapy cohort and the VEN + chemotherapy cohort: the ORR was 80.0% (4/5) versus 100% (6/6, P=0.251), and the PFS was 27.9 months versus 32.0 months (P=0.582). Moreover, the ORR was 85.7% (12/14) for the VEN+chemotherapy cohort and 46.2% (6/13) for the chemotherapy cohort in the high risk profile (P=0.029). The PFS of the VEN+chemotherapy cohort was superior to the chemotherapy cohort in the high risk profile (mean PFS: 23.7 months versus 11.1 months, P=0.002). Meanwhile, in the chemotherapy cohort, there were no difference in the PFS between FAB-M5 patients and non-FAB-M5 patients; the mean PFS was 20.0 months versus 15.5 months (P=0.298) for the two groups. Nevertheless, FAB-M5 patients were inferior to non-FAB-M5 patients in PFS in the VEN + chemotherapy arm (mean PFS: 19.6 months versus 30.2 months, P=0.031). The most frequent grade 4 hematological toxicities (therapy related) were leukopenia and thrombopenia. Grade 3/4 hematological adverse events in patients treated with VEN+chemotherapy were not increased compared with those who received chemotherapy. Western blot showed VEN continuously decreased the expression of BCL-2 proteins in both FAB-M5 and non-FAB-M5 patients, but obviously increased the expression of MCL-1 proteins only in FAB-M5 patients. Conclusions: VEN combined with intensive chemotherapy have yielded high ORR and survival advantages for de novo AML patients with poor cytogenetics profiles. The high-expression of MCL-1 may drive resistance to VEN.

A real-world evaluation of tislelizumab in patients with head and neck cancer.

Various studies support the use of programmed cell death protein 1 (PD-1) blockades, also known as immune checkpoint inhibitors (ICIs), to treat head and neck cancer (HNC). Tislelizumab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody with a high affinity and specificity for PD-1. However, the "real-world" clinical evidence of tislelizumab for HNC is limited. In this study, the medical records of 39 patients with head and neck squamous cell carcinoma (HNSCC) or nasopharyngeal carcinoma (NPC) who received tislelizumab between January 2021 and March 2022 were reviewed retrospectively. Tislelizumab was administered to 15 patients during neoadjuvant therapy (Group 1), five patients during adjuvant therapy (Group 2), 14 patients during consolidation therapy (Group 3), and five patients during salvage therapy (Group 4). The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). The median age of enrolled patients was 55 (range, 28-83) years. The median follow-up time was 27.1, 26.1, 28.6, and 20.9 months for Groups 1, 2, 3, and 4, respectively. The mean PFS and OS of Groups 1, 2, 3, and 4 were 21.5 and 22.8; 24.1 and 24.2; 26.9 and 28.1; and 13.9 and 17.1 months, respectively. In Groups 1 and 4, the objective response rate (ORR) was 86.7% and 60%, respectively. Meanwhile, except for one (2.6%) patient with grade 4 enteritis, the other observed non-haematological adverse events (AEs) were ≤ grade 2. Tislelizumab demonstrated promising efficacy and tolerability in patients with HNSCC or NPC in a real-world setting, consistent with previous reports.

Intrathecal chemotherapy for leptomeningeal disease in high-grade gliomas: a systematic review.

Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which further complicates treatment approaches. Intrathecal (IT) chemotherapy has surfaced as a potential strategy to bypass the blood-brain barrier and address the challenges posed by disseminated disease. Here, we present a review of the safety and efficacy of IT chemotherapy in the treatment of LMD secondary to HGG. A systematic review following PRISMA guidelines was conducted searching PubMed and Embase from January 1995 to September 2022 using specified terms related to IT chemotherapy for LMD. Included articles involved patients diagnosed with LMD from HGG, treated with intrathecal chemotherapy, and provided survival data. Data, including demographics, tumor characteristics, treatment, and survival information, were collected and independently extracted. A total of 68 patients across 10 clinical studies were diagnosed with LMD from HGG and included in the review. Among these patients, the average age at diagnosis was 44.2years. GBM was the most common tumor type (n = 58, 85.3%). A majority of the patients presented with recurrent disease (n = 29, 60.4%). The review encompassed various IT chemotherapy regimens, including mafosfamide, thio-TEPA, 5-fluoro-2'-deoxyuridine (FdUrd), methotrexate (MTX), and cytarabine; however, dosages and frequencies were inconsistently reported. The mean progression-free survival (PFS) and overall survival (OS) for this cohort were 7.5months and 11.7months, respectively. Common side effects of IT chemotherapy included headaches, nausea, and vomiting, with more severe complications such as myelotoxicity, disseminated intravascular coagulopathy, meningitis, and gastrointestinal toxicity reported in some cases. LMD continues to be an uncommon complication associated with HGG with a poor prognosis. This article provides an overview of the presently available literature on IT chemotherapy for LMD secondary to HGG, and their respective treatment protocols with overall survival attributes. Additional research is warranted to ascertain how to maximize the potential efficacy of IT chemotherapy as a treatment option.

A phase 1 study of mebendazole with bevacizumab and irinotecan in high-grade gliomas.

High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG. To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group. Patients between 1 and 21years of age with HGG were enrolled in a 3+3 design to escalating doses of mebendazole in combination with bevacizumab (10mg/kg/dose) and irinotecan (150mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles. Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50mg/kg/day (n=3), 100mg/kg/day (n=4), and 200mg/kg/day (n=3). One subject assigned to 100mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n=3) and lymphopenia (n=4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4months, respectively. Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

Diffuse Midline H3 K27-Altered Gliomas in the Spinal Cord: A Systematic Review

Background: Gliomas account for 80-90% of all intramedullary spinal cord tumors (IMSCTs). Though rare compared to brain tumors, spinal cord gliomas can cause significant morbidity and mortality. Diffuse midline gliomas (DMGs) with H3 K27M-mutation, first introduced in the 2016 WHO classification, are high-grade tumors with aggressive behavior and poor prognosis. The 2021 updated WHO classification renamed them "diffuse midline glioma, H3 K27-altered" to include other molecular changes. Limited single-institution data on spinal cord DMGs (DMGSCs) hinder comprehensive understanding and optimal treatment protocols. In this review, we summarize clinical and molecular features, management strategies, and survival impact in patients with DMG-SCs.&#x0D; Project Methods: A systematic review was performed following the (PRISMA) guidelines. PubMed, Ovid EMBASE, Scopus, and Web of Science were searched. Clinical characteristics, treatment protocols, and outcomes were analyzed.&#x0D; Results: A total of 26 studies with 259 patients were included. Most patients were male (63%), diagnosed at a mean age of 32 years (range, 4-72), and tumors were predominately located in the cervical (32%) or thoracic (43%) regions of the spinal cord. Primary management included surgical resection (97%), radiotherapy (78%), and chemotherapy (62%). Most common combination of treatment included surgical resection, radiotherapy, and chemotherapy (47%). The mean overall and progression free survival were 25 (range, 0.1-48) and 14 (range, 0.1-25) months, respectively. Gene alterations included p53 mutation (61%), loss of ATRX (46%), Olig- 2 positive (100%), and GFAP positive (80%). The mean Ki-67/MIB-1 was 23% (12-40%).&#x0D; Conclusion/Impact: DMG-SCs affect mostly the adult population and appear to resemble adult DMGs in terms of molecular features, management, and prognosis.

Stimulating thyroglobulin to TSH ratio predict long-term efficacy of 131I therapy in patients with differentiated thyroid cancer after total thyroidectomy: a retrospective study.

This study utilized the stimulated thyroglobulin (sTg) to thyroid stimulating hormone (TSH) ratio to predict the long-term efficacy of 131I therapy in patients with moderate-to-high-risk differentiated thyroid cancer (DTC). This study retrospectively analyzed 960 DTC patients with a median follow-up time of 30 months (6-92 months). The median age was 44 years. All patients underwent total thyroidectomy, lymph node dissection, and at least one 131I therapy. Patients were subjected to a final efficacy evaluation according to American Thyroid Association's 2015 guidelines. Patients were grouped according to their TSH levels before the initial 131I therapy and the final efficacy evaluation, and factors influencing TSH levels and final efficacy were analyzed. Construction of nomograms using independent risk factors affecting long-term outcomes. The cut-offs of sTg and sTg/TSH ratios were calculated for different long-term outcomes. Progression-free survival (PFS) of patients was analyzed by making Kaplan-Meier survival according to the cut-offs of sTg and sTg/TSH ratio. TSH (mU/L) levels were more concentrated at 60-90 in females (71.5%) and 30-60 in males (39.0%), while patients with younger age, more lymph node metastases, shorter time interval between surgery and the first 131I therapy, and lower dose of levothyroxine sodium taken prior to the first 131I therapy would have higher TSH levels (All P < 0.05).Patients who are male, have primary tumor involvement of the strap muscles, lymph node metastasis, distant metastasis, and higher sTg and sTg/TSH are more likely to have poor long-term outcomes (All P < 0.05).The cut-offs of sTg and sTg/TSH for long-term efficacy were 7.515 and 0.095. STg, sTg/TSH, tumor size, lymph node metastasis, and distant metastasis were shown to be independent risk factors for long-term efficacy. The mean PFSs were longer for patients who had sTg/TSH ≤ 0.095 and/or sTg≤7.515 ug/L. For patients with moderate-to-high-risk DTC, when sTg>7.515 ug/L and/or sTg/TSH > 0.095 before the first 131I therapy, patients are more likely to have a poor long-term efficacy after full 131I therapy. This means that this group of patients may require further surgical treatment or targeted drug therapy after 131I therapy.

Bevacizumab and gamma knife radiosurgery for first-recurrence glioblastoma

IntroductionGlioblastoma (GBM) is the most common central nervous system malignancy in adults. Despite decades of developments in surgical management, radiation treatment, chemotherapy, and tumor treating field therapy, GBM remains an ultimately fatal disease. There is currently no definitive standard of care for patients with recurrent glioblastoma (rGBM) following failure of initial management.ObjectiveIn this retrospective cohort study, we set out to examine the relative effects of bevacizumab and Gamma Knife radiosurgery on progression-free survival (PFS) and overall survival (OS) in patients with GBM at first-recurrence.MethodsWe conducted a retrospective review of all patients with rGBM who underwent treatment with bevacizumab and/or Gamma Knife radiosurgery at Roswell Park Comprehensive Cancer Center between 2012 and 2022. Mean PFS and OS were determined for each of our three treatment groups: Bevacizumab Only, Bevacizumab Plus Gamma Knife, and Gamma Knife Only.ResultsPatients in the combined treatment group demonstrated longer post-recurrence median PFS (7.7 months) and median OS (11.5 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total PFS (p=0.015), total OS (p=0.0050), post-recurrence PFS (p=0.018), and post-recurrence OS (p=0.0082) compared to patients who received either bevacizumab or Gamma Knife as monotherapy.ConclusionThis study demonstrates that the combined use of bevacizumab with concurrent stereotactic radiosurgery can have improve survival in patients with rGBM.

Type 2 Diabetes Mellitus and Non-Metastatic Colorectal Cancer: A Retrospective Study on Survival and Toxicity Profiles.

Being one of the most common cancers accounting for approximately 185 million cases globally, colorectal cancer (CRC) is one of the leading derivers of cancer-related mortalities. A high prevalence of Type 2 diabetes mellitus and CRC was noted, together with a causal link between diabetes and CRC development. Thereby, the goal of this study was to properly evaluate type 2 Diabetes mellitus in non-metastatic colorectal cancer patients, and to highlight its impacts on patient's outcome. Patients with non-metastatic colorectal cancer diagnosed between January 2016 and December 2020 were studied retrospectively. Patients were divided into two groups based on whether or not they had type II diabetes. The clinico-pathological, laboratory, treatment and survival data were gathered. A total of 318 patients were included in this study. The toxicity of the drugs used in CRC patients receiving the treatment protocols (169 in non-T2DM group and 39 in T2DM group), both groups reported close percentage of side effects and a similar frequency of drug toxicity occurrence as well as grade of toxicity, with the exception of neuropathy, which was more common in the T2DM group (33.3% vs 11.2%). As for prognosis, non-T2DM and T2DM patients had a mean progression free survival of (71.4 and 60.83 months, respectively) (p = 0.019). Overall survival was 73.1% for T2DM and 85.3% for non T2DM cases. The median overall survival was not reached for both groups in terms of overall survival. T2DM is considered a risk factor for poor survival among CRC patients. Treatment related toxicity is not affected by the presence or absence of diabetes, yet neuropathy needs further studies for diabetic patients receiving oxaliplatin.

Two-Day Fraction Gamma Knife Radiosurgery for Large Brain Metastasis.

We investigated how treating large brain metastasis (LBM) using two-day fraction gamma knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for two consecutive days, with a biologically effective dose (BED) equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy. Between November 2017 and December 2021, 42 patients (mean age: 68.3 years, range: 50-84 years, male: 29 [69.1%], female: 13 [30.9%]) with 44 tumors underwent two-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (NSCLC, N=16), small cell lung cancer (SCLC, N=7), colorectal cancer (N=7), breast cancer (N=3), gastric cancer (N=2), and other cancers (N=7). Twenty-one (50.0%) patients had a single LBM, nineteen (46.3%) had a single LBM and other metastasi(e)s, and two had two (4.7%) large brain metastases. At the time of the two-day fraction GKRS, the tumors had a mean volume of 23.1 cc (range: 12.5-67.4). on each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line. We obtained clinical and magnetic resonance imaging (MRI) follow-up data for 34 patients (81%) with 35 tumors, who had undergone two-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (P = 0.019) and lung cancer origin (P = 0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat SRS ranged from 15-878 days (median: 263±38 days, mean: 174±43) after the two-day fraction GKRS. Eight patients (18.2%) were still alive. Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS.

Major impact of prognosis by age and sex in patients with primary mediastinal large B‑cell lymphoma.

The effective prognostic factors for primary mediastinal large B-cell lymphoma (PMLBCL) vary among published studies. The aim of the present study was to explore the factors influencing the overall survival (OS) and progression-free survival (PFS) of patients with PMLBCL at a single institute in Taiwan. This retrospective study was conducted to analyze the prognostic impact of age, sex, disease stage, International Prognostic Index (IPI) score, treatment modality and initial response. A total of 72 patients with a median age of 28 years were included in the study. The mean OS and PFS were 171.40 and 159.77 months, respectively. Female sex, age ≤60 years, receiving radiotherapy (RT) and achieving a complete response were found to be associated with a significantly improved OS and PFS. In addition, high-intensity chemotherapy and an IPI score ≤1 were associated with longer OS, and early-stage disease was associated with a PFS superior to that of advanced-stage disease. The predictive value of IPI is limited in PMLBCL. Therefore, it is necessary to develop a novel prognostic system. The present study revealed the impact of sex on prognosis and, therefore, this factor should be considered in future prognostic evaluations. Since a complete post-treatment response was found to be important, high-intensity chemotherapy is recommended. However, low-intensity treatment followed by RT consolidation appears to be a feasible approach in elderly patients.

10236-NI-11 IMAGING FEATURES AND CONSIDERATION OF PROGRESSION PATTERN OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT

Abstract BACKGROUND Diffuse hemispheric gliomas, H3 G34-mutant (DHG-G34m) are newly recognized pediatric-type diffuse high-grade gliomas. We describe detail imaging features of seven cases of DHG-G34m and consider about progression pattern of DHG-G34m. RESULTS H3 G34R/V was detected by sanger sequencing in all tumors. Mean age of onset was 16.5 years (range: 10-26). Tumors were located on frontal (n=2), parietal (n=2), temporal lobe (n=1) and insular cortex (n=1), respectively. In one case, gliomatosis cerebri-like multiple lesions involving the cortex and basal ganglia occurred. Magnetic resonance imaging showed T2/FLAIR high lesions with poor contrast enhancement in all cases. All tumors harbored restriction of diffusion. Strong accumulation of methionine was observed in six cases. Tumors of these cases harbored T2/FLAIR high lesions in the deep white matter which showed methionine accumulation. All patients underwent surgery (total resection in one case, partial resection in five cases, and biopsy in one case) followed by radiation chemotherapy. The mean progression free survival was 9.9 months (range: 1.6-33.1 months). All recurrent tumors harbored diffuse infiltration along the white matter adjacent to surgical cavity, which was temporarily reduced by bevacizumab, but eventually invaded into cerebral peduncle via pyramidal tract and into contralateral brain via corpus callosum or anterior commissure in six cases. Extensive infiltration of tumor cells into the contralateral brain and brain stem was confirmed in the autopsy brain of one case. The mean overall survival was 21.6 months (range: 8.9-48.3 months). CONCLUSION DHG-G34m showed deep white matter infiltration from the time of initial onset, which made gross total resection difficult. Residual lesions extensively infiltrated along the white matter and eventually invaded the brainstem and contralateral brain, leading to death.

Different Mutations in SF3B1 Gene Have Specific Transcriptomic Characteristics in Myelodysplastic Neoplasms

Myelodysplastic neoplasms (MDS) are hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis, peripheral cytopenia, and increased tendency to leukemic transformation. Somatic mutations in spliceosome machinery occur in approx. 50% of MDS patients. Among these, up to 30% of MDS patients carry a mutation in SF3B1. According to the 2022 classification system, MDS-SF3B1 is now considered as separate MDS subtype. Mutated SF3B1 perturbs mitochondrial function, resulting in apoptosis and ineffective erythropoiesis. The most common mutation of SF3B1, K700E, accounts for 50% of the variants, with additional codons (such as 666 and 662) acting as hotspot sites. Different mutations seem to be associated with distinct clinicopathological features. However, the prognostic implication of different SF3B1 mutations in MDS remains controversial and needs further clarification. This study investigated differences in clinical and molecular features of MDS-SF3B1 with different types of SF3B1 mutations. To investigate a direct impact of different point mutations in SF3B1, the study was based on four isogenic NALM6 cell lines, the wildtype (wt) and three cell lines, each with different SF3B1 mutation (CRISPR/Cas9-edited K700E, K666N, and H662Q). To understand phenotypic manifestations of the mutations in the disease, we also analyzed clinical and transcriptional characteristics of 146 lower-risk MDS patients. Using RNA-seq in the cell lines and CD34+ BM patient cells (17 patients with no mutation, 11 patients with K700E SF3B1 mutation, 5 patients with K666N/E SF3B1 mutation), we investigated effects of different SF3B1 mutations on RNA splicing events and gene expression levels. Initially, outcome analysis confirmed the previously described observation that patients with a SF3B1 mutation have favorable outcomes compared to those with other splicing factor mutations. Further, the analysis showed that specific mutations in SF3B1 tend to lead to different prognoses; patients with K700E had longer survival compared to those with other SF3B1 mutations (mean progression-free survival was 64.8 vs. 29.1 months). Analysis of RNA splicing in NALM6 showed that K666N and H662Q mutations share similar characteristics whereas K700E mutation is more similar to wt-cells. Most significant changes were found in retained introns (RI); increased RI inclusion levels were detected in K666N/H662Q cells compared to K700E/wt cells. In patients, RI events were also strongly increased in K666N/E compared to K700E samples (Fig. 1). A significant overlap was identified between cell line and patient data; out of 173 genes with higher RI inclusion level in K666N-NALM6 cells, 77 genes had higher RI inclusion also in patients. Interestingly, 12 out of these 77 genes were related to mitochondrial functions (e.g., CREBZF, DDX1, MRPL23, MUTYH, and RAF1). RNA-seq data further showed significant alternations in gene expression levels in the four isogenic cell lines and also in patient samples with different mutations. Surprisingly, a more pronounced difference was detected in gene expression between patients with different SF3B1 mutations than between patients with no mutation and with any SF3B1 mutation (irrespective of its type), suggesting that specific SF3B1 mutations result in different phenotypes. Pathway analyses showed that deregulated genes in samples with K700E vs. other hotspot mutations were significantly enriched in electron transport, cell cycle, proliferation, quiescence, and HSC differentiation. Importantly, expression of multiple mitochondria-related genes was altered between K700E and K666N/H662Q NALM6 cells (334 genes, FDR &amp;lt; 0.01; Fig. 2), indicating different metabolic characteristics of the cells with non-K700E mutations. For example, several subunits of mitochondrial respiratory complexes I and IV were upregulated in K700E cells, pointing to differences in energetic metabolism. Altogether, our data support the hypothesis that only K700E mutation of SF3B1 may have a positive prognostic value and that other SF3B1 mutations may influence cells differently, specifically affecting their mitochondrial functions. Based on our results, we conclude that prognostic implication of different SF3B1 mutations in MDS will need additional refinements in future. Supported by AZV CR (NU20-03-00412), GA CR (20-19162S), and MH CZ-DRO (00023736).

Prognostic Significance of Monoclonal Paraproteinemia in Marginal Zone Lymphoma

Introduction and aim:Marginal zone lymphoma (MZL) is an indolent lymphoma which can progress with frequent relapses and transform to aggressive lymphoma. Therefore, the factors that affect prognosis are important fields of interest. This study was aimed to investigate the effect of immunoglobulin (Ig) paraproteinemia on MZL prognosis and survival. Material and method: Between January 2000 and June 2022, 73 patients who applied to Dokuz Eylül University Faculty of Medicine Hospital Department of Hematology, diagnosed with MZL, and continued their follow-up in our center were assessed. Patients whose paraproteinemia was investigated by immunofixation (SIFE), serum protein electrophoresis (SPEP), or free kappa and lambda free light chain (FLC) assays were included in the study. Demographic characteristics and laboratory data were retrospectively analyzed. Results: Ig paraproteinemia was ascertained in 20 patients which 11 of 20 was IgM type. The median follow-up was 58 (3-200) months. Median overall survival (OS) and progression free survival (PFS) were not reached. Mean OS and PFS were 169±8.5 and 146±10.6 months, respectively. Serum Ig paraproteinemia was detected in 20 of 73 patients (27.3%). Most were IgM- κ (9, 45%), followed by IgG-κ (7, %35), IgM-λ (2, %10), IgA-λ (1, %5), and IgA-κ (1, %5). The presence of Ig paraproteinaemia was significantly associated with advanced age (p&amp;lt;0.001), advanced disease stage (III-IV) (p=0.023), elevated ß2 microglobulin (ß2MG) level (p=0.001), decreased hemoglobin level (p=0.002), decreased albumin level (p&amp;lt;0.001), and bone marrow involvement (p=.026). Gender, elevated lactate dehydrogenase (LDH) level, and elevated Ki-67 were not significantly associated with the presence of Ig paraproteinaemia. In our cohort Ig paraproteinemia was shown in 35%, 10% and 55% of extranodal MZL, splenic MZL and nodal MZL respectively (p=0,009) which favors nodal MZL dominance. The prognostic value of Ig paraproteinaemia and other clinical outcomes are summarized in Table 1. The OS rate at 5 and 10 years was %87.2 and %81.9, respectively. The PFS rate at 5 and 10 years was %71.5 and %68.3 respectively. Patients with Ig paraproteinaemia has shorter OS compared to patients without any paraproteinemia (73,8 mo. vs 178,8 mo. p&amp;lt;0,05). This survival disadvantage was more pronounced in patients with IgM paraproteinemias. Kaplan-Meier survival curve analysis of PFS according to the occurrence of Ig paraproteinaemia are shown in Figure 1. Conclusion: Although MZL is an indolent lymphoma type and there are many prognostic factors affecting its prognosis, it may show relapsed or refractory disease course or histological transformation. 55% of our nodal MZL cohort had Ig paraproteinemia which is higher than all reported cohorts in the literature so far. Several studies have previously shown that Ig paraproteinemia may be a potential prognostic factor for NHL and MALT lymphoma 1-3. Ren et al. showed that Ig paraproteinemia was an independent prognostic predictor for MALT lymphoma 4. Epperla et al. showed that patients diagnosed with MZL with Ig paraproteinemia had inferior survival in comparation with no-M protein group 5. In conclusion, this study provides evidence that Ig paraproteinaemia and especially of IgM type shortens PFS and OS in patients with MZL. Thus, our study is the first in literature to show survival disadvantage for MZL patients specifically with IgM paraproteinemia and deserves confirmation with further studies.