tbuckley/cabot-search huggingface dataset:
Exploring the diagnostic potential of cerebrospinal fluid (CSF) IL-10:IL-6 ratio in patients with primary central nervous system lymphoma (PCNSL).
Authors: Sofia Singh, Aastha Takkar Kapila, Gaurav Prakash, Vivek Lal, Vishali Gupta, Ranjana Walker Minz, karthik Vinay Mahesh
Journal: Journal of Clinical Oncology (2024)

e14041 Background: Primary Central Nervous System Lymphomas (PCNSL) present significant diagnostic challenges due to their aggressive nature. Current diagnostic methods include neuroimaging, CSF cytology, FDG-PET scans, and biopsies. Building upon the success of the IL-10:IL-6 ratio as a diagnostic biomarker in intraocular lymphoma, this study investigates its potential in PCNSL diagnosis. CSF IL-10:IL-6 ratio emerges as a promising, easily accessible biomarker for early PCNSL detection. Methods: Fifteen histopathologically confirmed PCNSL patients were compared with fifteen CNS inflammatory condition patients and ten patients with other CNS malignancies. Detailed clinical assessments were conducted, and IL-10:IL-6 levels were measured in serum and CSF using Flow cytometry. Results: The CSF IL-10:IL-6 Ratio was elevated (&gt; 1) compared to serum levels in PCNSL patients in contrast to other control groups. The mean age ± SD of PCNSL patients was 55.47 ± 17.29, with a male-to-female ratio of 8:7. The mean (SD) for CSF IL-10:IL-6 ratio in PCNSL was 3.35 (3.88), while the mean (SD) for serum IL-10:IL-6 ratio was 0.438 (1.54). The statistical analysis revealed a significant difference (P = 0.0058 &lt; 0.05). Conversely, comparing the CSF IL-10:IL-6 ratio with serum levels in controls with CNS inflammatory conditions and CNS malignancies showed no statistical significance (P &gt; 0.05). Conclusions: Elevated CSF IL-10 and CSF IL-10/IL-6 ratios suggest their potential as early diagnostic markers for large B cell PCNSL. The IL-10:IL-6 ratio holds promise as a novel, easily accessible biomarker in readily available body fluids for PCNSL diagnosis.
HLA class-I antigen presentation machinery (APM) alterations mediate immune evasion in lung cancer brain metastases.
Authors: Noelia Vilariño, Miguel Lopez De Rodas, Kishu Ranjan, Adrien Costantini, Maria Villalba, Benjamin Y. Lu, Caro Kravitz, Ernest Nadal, Sarah B. Goldberg, Don Nguyen, Kurt A. Schalper
Journal: Journal of Clinical Oncology (2024)

e14014 Background: Although ~30% of patients with lung cancer brain metastasis (LBM) achieve intracranial response with immune checkpoint inhibitors (ICI), most have primary resistance, and those who initially respond develop rapid disease progression. The biological factors contributing to this unfavorable clinical scenario are poorly understood and could include distinct immunologic properties of tumors colonizing the brain. Using annotated tumor/patient cohorts, spatially resolved protein analysis, and in vitro models, we investigated the role of HLA class-I APM defects and interferon (IFN)-γ pathway in LBM. Methods: Using multiplex quantitative immunofluorescence, we measured the levels and spatial distribution of HLA class-I APM markers (β2M, tapasin, calreticulin, ERp57, TAP1, and TAP2), IFN-γ signaling (pSTAT1 and IRF-1), and tumor-infiltrating lymphocytes (TILs) (CD8, CD4, and FOXP3) in 56 LBM, 41 primary lung tumors (PLT), and 10 lung-extracranial metastases (ECM) represented in tissue microarrays. A subset of paired LBM/PLT samples from the same patients were also included (n=8). The spatial analysis of the markers was conducted using fluorescence co-localization and single-cell segmentation strategies. Associations between the markers, clinicopathological characteristics, and survival were studied. Protein expression of β2M and IFN-γ-sensitive markers (total STAT1, pSTAT1, IRF1, and PD-L1) before and after treatment with human recombinant IFN-γ was assessed using Western blot in cultured primary lung H2030 adenocarcinoma cells and their in vivo selected brain metastatic counterpart H2030-BrM3. Results: LBM showed significantly lower β2M, TAP2, and tapasin protein levels than PLT. However, LBM also showed higher expression of pSTAT1 and comparable levels of IRF-1 relative to PLT. Similar results were seen in paired LBM/PLT samples, but not in ECM samples. Tumors with low β2M showed reduced CD8+, CD4+, and FOXP3+ TILs. In LBM no significant association between β2M and IFN-γ pathway markers or major clinicopathologic and molecular patient/tumor features were found. LBM samples from patients progressing after radiotherapy and/or chemotherapy showed significantly lower β2M levels. Reduced β2M expression was associated with shorter overall survival in PLT but not in LBM. The brain metastatic H2030-BrM3 cell line showed lower β2M expression both at baseline and after IFN-γ treatment compared with their parental H2030 counterpart. Conclusions: HLA class-I APM downregulation is a prominent feature of LBM, is independent of local adaptive/inducible IFN-γ stimulation, and is associated with unfavorable clinical features. These findings support that HLA class-I APM deficiency plays a major role in immune evasion and immunotherapy resistance in patients with LBM.
GEMINI-Gastric: A phase 2 study of novel treatment combinations in patients with locally advanced unresectable or metastatic gastric cancers.
Authors: Lin Shen, Kohei Shitara, Jen-Shi Chen, Do-Youn Oh, Anastasia Jiang, Silver Liu, Zhi Dong, Qian Zhu, Rakesh Kumar, Sun Young Rha
Journal: Journal of Clinical Oncology (2024)

TPS4182 Background: A large proportion of patients (pts) with gastric cancer present with locally advanced or metastatic disease, which is linked with poor survival. Platinum- and fluoropyrimidine-based doublet chemotherapy (CTx) remains the standard of care in advanced gastric cancers. Based on recent clinical data, immuno-oncology (IO) agents plus CTx can improve overall survival (OS) in pts with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have human epidermal growth factor receptor 2 negative/low expression (HER2–) and have not been previously treated for advanced/metastatic disease. GEMINI-Gastric (NCT05702229) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of multiple novel IO + CTx combination therapies in this setting. Methods: Adults (≥18 years) with previously untreated HER2– locally advanced unresectable, or metastatic gastric or GEJ adenocarcinoma are eligible. Pts should have measurable target disease per RECIST v1.1 and an ECOG performance status of 0–1. The GEMINI-Gastric design allows assessment of multiple novel agents plus CTx in different substudies (Table). Novel agents include: volrustomig, an anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody (mAb); rilvegostomig, an anti-PD-1/TIGIT bispecific humanized IgG1 mAb; AZD0901, a claudin18.2-targeted antibody-drug conjugate; and AZD7789, an anti-PD-1/TIM-3 bispecific mAb. Co-primary endpoints are objective response rate and progression-free survival (PFS) at 6 months by investigator assessment per RECIST v1.1. Secondary endpoints include safety, duration of response, PFS, OS, PK, and immunogenicity. Sample sizes have been selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Europe, and Asia. Clinical trial information: NCT05702229 . [Table: see text]
Single center experience of IDH inhibitors in high-grade gliomas.
Authors: Catherine R. Garcia, Kaitlin N. Highsmith, Stephanie Knight, Vinay K. Puduvalli, Carlos Kamiya-Matsuoka
Journal: Journal of Clinical Oncology (2024)

e14036 Background: IDH inhibitors have shown to improve progression free survival in low grade gliomas. Antitumor effect in high-grade gliomas is not well known, with conflicting views regarding the role of IDH mutations in high-grade gliomas and the potential for resistance to DNA-damage-inducing therapies. We present the outcomes of high-grade gliomas that were treated in our institution with IDH inhibitors. Methods: We performed a retrospective review of patients with gliomas treated with FDA approved IDH inhibitors (ivosidenib and enasidenib) in the past 5 years at our institution (January 1 st 2019- January 1 st 2024). Our search identified 32 patients of which 11 were identified as high-grade gliomas (both oligodendrogliomas and astrocytomas). Institutional Review Board PA17-0222 was used for this study. Results: Eleven high grade, IDH-mutant glioma patients treated with IDH inhibitors were identified with a median age at diagnosis of 31 years; 63.6% of these patients were men. Over 63% of patients were categorized as WHO grade 3 and 36.4% as grade 4 tumors. Over 63% of patients were astrocytoma (4 out of 7 patients with WHO grade 4 astrocytoma) while the rest were oligodendrogliomas. All patients underwent initial resection and had received radiation plus at least one prior line of systemic therapy prior to starting an IDH inhibitor. Over 72% were started on IDH-inhibitor therapy after 3 or more recurrences; previous lines of systemic therapy included temozolomide, bevacizumab, and lomustine. Five patients were treated with more than 1 cycle of IDH inhibitor, 2 patients with 8 cycles, and 1 patient with 18 cycles. Of the 11 treated patients, four had progression while on an IDH inhibitor, of which one patient died. IDH inhibitors were discontinued in two patients (due to headaches and abnormal liver enzymes). Median survival and progression free survival after IDH inhibitors were not reached. Conclusions: IDH inhibitors were started on patients with high-grade astrocytoma and oligodendroglioma after multiple recurrences and after receiving DNA-damage-inducing therapies. Prolonged responses were observed in 3 patients (one oligodendroglioma and two WHO grade 3 astrocytomas). Further investigation is needed to establish the role for IDH inhibitors in the treatment of high-grade gliomas.
Extra-adrenal paraganglioma demographic data: A NCDB study.
Authors: Michael Peterson, Brianna Eillen Ramos, Jasika Grover, Noureen Nakshbandi, Peter T. Silberstein, Craig Heise, Beau Hsia
Journal: Journal of Clinical Oncology (2024)

e16293 Background: Extra-adrenal paragangliomas are rare neuroendocrine tumors that form near blood vessels and nerves outside of adrenal glands. Despite their rare occurrence, these tumors have higher rates of malignancy and varying survival rates compared to other paragangliomas. To better understand its epidemiology, there may be clinical value in analyzing the diagnostic trends of these tumors. This study utilized information provided by the National Cancer Database (NCDB) to examine the demographic factors of patient populations diagnosed with extra-adrenal paragangliomas. Methods: A retrospective cohort analysis using the 2004–2020 National Cancer Database (NCDB) included 133 patients with a histologically-confirmed diagnosis of extra-adrenal paraganglioma (ICD-O-3 code 8693). Demographic factors (age, sex, race, Hispanic status, educational attainment, insurance status, facility type, distance from facility, and Charles/Deyo score) were analyzed by descriptive statistics. Incidence trends were interpreted via regression analysis. Results: In the NCDB, 133 patients were identified with a confirmed diagnosis of extra-adrenal paraganglioma between 2004 and 2020. This database suggested a relatively stable number of patients diagnosed per year (R² = 0.022). Men (67%) were more likely to be diagnosed than women (35%), with an average age at diagnosis of 45.7 years (SD = 17.7, range = 11-83). Patients were most commonly non-Hispanic (88%), White (68%), and had a primary site of diagnosis in the retroperitoneum (35%). Treatment was primarily surgical resection (84%) followed by radiation (17%) and chemotherapy (8%). Most patients did not receive palliative care (98%). A majority of patients (77%) had a Charlson-Deyo comorbidity score of 0, with a 2 year survival rate of 92%, a 5 year survival rate of 79%, and a 10 year survival rate of 50%. Most patients were privately insured (65%) and received treatment in an academic research facility (56%). Many individuals lived in large metropolitan counties with a population larger than 1 million (56%), and resided a mean distance of 41.6 miles (SD = 74.4, range = 0.8 - 559.3) from the treatment facility. Conclusions: To the best of our knowledge, this is the first analysis of extra-adrenal paragangliomas utilizing the NCDB, and thus addresses a significant lack of knowledge on the subject. The majority of patients are non-Hispanic White men, with a primary site of diagnosis in the retroperitoneum. This is the first time that the socioeconomic factors of extra-adrenal paraganglioma patients have been described in the literature: patients tend to be privately insured, live in large metropolitan counties, and have 10 survival rate of 50%. Continued research is necessary to gain a deeper insight on the impact of socioeconomic and demographic factors that influence the diagnosis, treatment, and survivability of extra-adrenal paraganglioma patients.
Exploring the association of smoking status with clinical outcomes in patients with mPDAC treated on a clinical trial of maintenance niraparib plus immune checkpoint blockade.
Authors: Srishti Rathore, Kim Anna Reiss, Ursina R. Teitelbaum, William Joseph Chapin
Journal: Journal of Clinical Oncology (2024)

e16302 Background: Previous research has hinted at a positive association between smoking history and outcomes in non-small cell lung cancer patients being treated with immune checkpoint blockade (Wang L. et al., 2021)(Cortellini A. et al., 2021). The PARPVAX trial (NCT03404960) assessed the efficacy of maintenance niraparib plus either nivolumab (Arm A) or ipilimumab (Arm B) in platinum-sensitive patients with mPDAC (Reiss KA. et al., 2022). We investigated whether there was an association between patient smoking history and outcomes on this trial. Methods: Patients treated on NCT0340960 were categorized by smoking status (binary; never/any smoking history). We performed multivariable Cox proportional hazards models for PFS and OS with a pre-specified set of covariates that underwent negative backward selection until the ratio of events to degrees of freedom in the model was less than 10 to avoid overfitting. Models were also performed within each arm in an exploratory fashion to determine if differences were observed between treatment groups. Results: Overall, 42% (Arm A) and 58% (Arm B) of patients had any history of smoking. Any smoking history was significantly associated with improved OS in the multivariate model (HR = 0.45 [0.24 – 0.86]; P = 0.015). The multivariate PFS analysis demonstrated a 37% reduction in the hazard of progression or death, but the result was not statistically significant (HR = 0.63 [0.37 – 1.09]; P = 0.10). When separated by treatment arm, any smoking history had a significant association with PFS (HR = 0.32 [0.14 – 0.73]; P = 0.007) and OS (HR = 0.30 [0.11 – 0.80]; P = 0.016) in Arm B but not Arm A. Conclusions: Our ad hoc analysis of outcomes by smoking status in a population of patients with advanced PDAC undergoing experimental maintenance treatment with PARPi and ICB suggests that a smoking history may be associated with improved outcomes, particularly in patients who received anti-CTLA4 therapy. Sample size greatly limited adjustment for potential confounders and these results are hypothesis generating only. [Table: see text]
Survival outcomes associated with treatment modalities in stage 4 gallbladder neuroendocrine tumors: A nationwide analysis.
Authors: Nouman Aziz, Shahzaib Ahmad, Mohammad Arfat Ganiyani, Ahmad Ozair, Muhammad Zeeshan Sarwar, Diya Jayram, Hadin Darain Khan, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

e16295 Background: Gallbladder neuroendocrine tumors (GNETs) are rare, heterogeneous, and aggressive tumors of the gallbladder. GNETs usually present in the elderly ( &gt; 60 years) and there are no clear clinical guidelines to treat stage 4 GNETs due to rarity. We evaluated therapeutic options for stage 4 GNETs. Methods: We included stage 4 GNETs diagnosed between 2004-2020 in the National Cancer Database. Treatment was stratified into combination therapy (Comb) - surgery (Sx) and chemotherapy (CT), Sx alone and CT alone. Survival outcomes were expressed as Kaplan-Meier curves and Cox proportional hazard model adjusting for age, Charlson-Deyo score (CDS) and sociodemographic variables like sex, race, ethnicity, insurance status, and facility location. We expressed survival outcomes as median overall survival (mOS, 95% CI) and time-dependent survival as hazard ratio (HR, 95% CI). Results: Of 242 patients with stage 4 GNETs, the median age was 64 years (range 29-90+ years), 62.4% were female, 66.9% had CDS of 0, 22.4% had CDS of 1, 10.8% had CDS ≥2, 98.7% had poorly differentiated tumor (grade 3 or 4), 70.3% were White, 85.9% were non-Hispanic, median size of the primary tumor was 10.7 cm (range 0.8-14.1 cm) and 47.8% were treated at academic or research program. 46 (19.0%) patients received Comb, 171 (70.7%) received CT and 25 (10.3%) patients received Sx alone. The mOS was 11.5 months (9.3-18.4), 9.4 months (7.9-11.2), 4.2 months (2.3-6.3) for Comb, CT and Sx, respectively (P &lt; 0.001). Pairwise log-rank revealed no significant differences between Comb and CT groups (P = 0.07). In univariate Cox analysis, CDS ≥2 showed HR of 1.6 (1.0-2.4; p = 0.04), Sx showed HR of 1.7 (1.1-2.7; P = 0.02), and Medicare had HR of 1.35 (1.02-1.78; p = 0.037). However, on multivariate analysis, uninsured patients (HR = 5.16; 95% CI 1.50-17.7; P = 0.009) and those receiving Sx alone (HR = 2.09; 95% CI 1.27-3.46; P = 0.004) had unfavorable outcomes. Conclusions: The combination of primary site surgery with CT improves survival in stage 4 GNETs as compared to resection alone. However, there is no significant difference in survival in combination therapy and CT. We emphasize the need for robust prospective studies comparing the efficacy of chemotherapy, neoadjuvant and adjuvant chemotherapy for stage 4 GNETs.[Table: see text]
Hydrogenated oxide material-based hyperthermia and radiotherapy: A new treatment option for esophageal squamous carcinoma.
Authors: Yuexin Yang, Jun Liang, Jun Jiang
Journal: Journal of Clinical Oncology (2024)

e16127 Background: Radiotherapy (RT) is the mainstay of esophageal squamous carcinoma (ESCC) treatment, and hyperthemia could exert synergistic effects to refractory diseases. Hydrogenated oxide material (HMO) is a newly developed photothermal agent, featured by selectively targeting tumors, high photothermal conversion efficiency under 1064 nm near-infared (NIR) illumination and safe degradation. This study aims at investigating the combination effects of HMO-based hyperthermia and RT in ESCC. Methods: mEC25 murine ESCC cells were cultured and treated with RT alone (prescribed cumulative dose of 10Gy), HMO-based hyperthermia (incubated with 100ug/ml HMO for 20min and irradiated with 1064nm NIR continuously for 15min) or combination therapy (RT followed by HMO-based hyperthermia). FLIR-One was applied to monitor temperature alterations in HMO-based hyperthermia. Flow cytometry was performed to detect apoptosis rates 24h after treatment. Results: The temperature was increased by 21.3[19.8-23.7]℃ after NIR irradiation. The apoptosis rates were 19.4%[19.4%, 19.5%], 43.8%[43.6%, 44.0%] and 61.4%[58.5%, 61.8%] in RT alone, HMO-based hyperthermia and combination therapy group respectively. Considerably low apoptosis rates were observed in HMO-incubation and NIR-irradiation only groups, which was 6.2% and 6.6% respectively, similar to that of treatment-naive cells. Conclusions: The combination of HMO-based hyperthermia and RT provided a promising treatment modality for ESCC, while its effects in rodent models and potentials in clinical practice merit further investigations.
Current trends in lung cancer brain metastases trials.
Authors: Edgar Petrosyan, Jawad Fares, Luis G. Fernandez, Daniel E. Oyon, William S. Gibson, Adam M. Sonabend, Maciej S. Lesniak
Journal: Journal of Clinical Oncology (2024)

e14006 Background: Brain metastases are the predominant central nervous system malignancy, primarily originating from lung cancer. In the era of precision medicine, enhanced control of extracranial disease is increasing the incidence of brain metastases, underscoring their status as a growing unmet need in modern Neurooncology. Methods: On December 12, 2023, we searched ClinicalTrials.gov for interventional and therapeutic clinical trials focusing on lung cancer brain metastases (LCBM). We gathered information on trial characteristics, including phase, study design, primary and secondary endpoints, status, enrollment criteria, size, duration, and results. Subsequently, the collected data was subjected to systematic analysis. Results: Among 198 identified trials, the majority were in early phases: 12% in phase I, 6% in phase I/II, and 60% in phase II. Only 27% of trials in phase II &amp; II/III were randomized, with 92% lacking blinding. Trials were concentrated in North America (36%) and Asia/Africa/Australia (33%), predominantly targeting non-small cell lung cancer (NSCLC) (82%). Patients with leptomeningeal metastases were included in only about 10.5% of the trials. Out of 44 completed trials, only 21 resulted in published original articles. Termination occurred in 38 trials, primarily due to insufficient participant enrollment. Tyrosine kinase inhibitors emerged as promising treatments for brain parenchymal and leptomeningeal NSCLC metastases. Conclusions: This study highlights critical deficiencies in LCBM trials, ranging from inadequate trial numbers and recruitment difficulties to the overwhelming focus on NSCLC trials, insufficient randomization and blinding, and a marked scarcity of trials involving patients with leptomeningeal metastases. Addressing these issues is pivotal for advancing the understanding and treatment of LCBM.