tbuckley/cabot-search huggingface dataset:
Effect of sodium thiosulfate anhydrous on cisplatin-induced ototoxicity in pediatric cancers: Turkish compassionate use treatment protocol—Updated results.
Authors: Emel Cabi Unal, Nurdan Tacyildiz, Cengiz Canpolat, Eda Ataseven, Ayse Cigdem Sivrice, Betul Sevinir, Dilvin celik Ates, Tolga Tuncel
Journal: Journal of Clinical Oncology (2024)

e15075 Background: Cisplatin induced ototoxicity (CIO), with permanent hearing loss is observed in &gt;60% pediatric patients in Turkey. PEDMARK (Sodium Thiosulfate anhydrous) reduced the risk of CIO cases with non-metastatic solid tumors observed in Phase 3 studies (SIOPEL 6 &amp; COG ACCL0431). We aimed to evaluate the investigational product PEDMARK provided for pediatric cases via a National Compassionate Use Treatment Protocol (CUP) in Turkey. Methods: Patients (1 month to &lt;18 years) with a localized, nonmetastatic solid tumor, standard-risk hepatoblastoma (HBB), nasopharyngeal carcinoma (NPC) and medulloblastoma MB whose treatment plans were including cisplatin were eligible. PEDMARK was administered intravenously 6 hours after each cisplatin dose infusion. Adverse events, demography, pre and post- hearing were recorded from 21OCT2019-21SEPT2022. Results: The CUP enrolled 12 patients, 8 HBB, 3 NPC and 1 MB in 3 years, from 6 academic institutions. HBB patients' median age was 1year (3mos-3 yrs). All pts had newly diagnosed HBB PRETEXT 3 (n = 5) with a median baseline AFP OF 54.000. 3 NPC age 13-17 yrs, MB 6yrs of age. All patients had Brock Grade 0 on hearing tests prior to treatment Patients received a median 0f 6 cycles (range 4-6) of cisplatin and PEDMARK. Patients with hearing tests available post-treatment (n=11), all maintained Brock Grade 0. At a median of 0.8mos post-treatment, CR were observed in all patients except one HBB with progressive disease. All CRs wer sustained 18.8 mos. AEs in 2 patients were Grade 1-2 nausea/vomiting, no Grade &gt;3 AEs were reported. Conclusions: PEDMARK was well tolerated, provided via a Turkish CUP to reduce the CIO in pediatric patients with nonmetastatic solid tumors. No hearing loss was observed/ detected post-treatment and the tumor outcomes were consistent with the Phase 3 studies. This is very encouraging.
Metabolic disorders in patients diagnosed with colorectal cancer.
Authors: Julia A. Levy, Nicole C. Lorona, Biljana Gigic, Christopher I. Li, Jennifer Ose, David Shibata, Erin M. Siegel, Adetunji T. Toriola, Cornelia M Ulrich, Sheetal Hardikar, Jane C. Figueiredo
Journal: Journal of Clinical Oncology (2024)

e15618 Background: Colorectal cancer (CRC) is the third most common cancer globally and ranks second as a cause of cancer-related death. As survival rates among CRC patients continue to rise, addressing accompanying metabolic comorbidities is becoming increasingly important. This study aims to explore the prevalence of metabolic comorbidities and metabolic syndrome among CRC patients, as well as their impact on survival. Methods: The ColoCare Study is a prospective cohort study conducted across seven U.S. and European sites. Data from a single site, Cedars-Sinai Medical Center in Los Angeles, California was analyzed. Adults with newly diagnosed stage I-IV CRC and available medical records were eligible. Basic demographic information and medical history, including hypertension, hyperlipidemia, and diabetes mellitus (DM) diagnosis at or before CRC diagnosis were collected by manually reviewing electronic medical records. Additionally, BMI was calculated using patients' weight and height at the time of diagnosis and classified according to the CDC’s published ranges. Patients were considered to have metabolic syndrome if they met three or more of the following criteria: hypertension, hyperlipidemia, DM, or obesity. Overall survival rates for patients with each metabolic condition were compared. Results: A total of 295 patients (58.3% male, 41.7% female, mean age at diagnosis = 58.3) were identified. 172 were non-Hispanic White (58.3%), 52 were Hispanic/Latino (17.6%), 36 (12.2%) were Asian, 27 (9.2%) were Black, and 8 (1.8%) were unknown/other. Metabolic conditions were prevalent in the cohort: hypertension affected 33.9%, hyperlipidemia affected 21.4%, and DM affected 13% of patients. Additionally, over half of the patients (56.6%) were overweight or obese. Individuals meeting criteria for metabolic syndrome (8.8%) had lower survival rates compared to those without this condition (73.1% vs. 81.4%). Similarly, patients with DM had lower survival rates compared to their counterparts without DM (72.5% vs. 82.0%). Patients with hypertension, hyperlipidemia, and elevated BMI did not have significantly different survival rates compared to patients without such conditions. Conclusions: Our study highlights the prevalence of metabolic comorbidities, specifically metabolic syndrome and DM, among CRC patients and emphasizes how these factors can impact patient outcomes post-diagnosis. This information is valuable for physicians when considering lifestyle changes or treatment strategies following CRC diagnosis. Further, it highlights the importance of coordination between oncologists and primary care providers to effectively manage metabolic diseases in CRC patients.
Molecular profiling using next generation sequencing with high-purity enrichment of circulating tumor cells.
Authors: Jaesung Choi, Aejin Jeong, Sehwan Park, Hanbyeol Kim, Sehyung Pak, Min-Ji Song, Jungwon Kim, Hai-Chon Lee
Journal: Journal of Clinical Oncology (2024)

e15054 Background: In the field of liquid biopsy, coupled with next generation sequencing (NGS), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) can serve as an alternative substrate to tumor tissue for mutation detection and companion diagnostic purpose. Emerging evidence suggests that complementary sequential CTCs and ctDNA profiling offers promising benefits for prognosis and treatment. In contrast to well-established ctDNA extraction methods, the process of isolation of intact CTCs for NGS analysis has not yet been fully elucidated. Here we show that isolation and harvesting of viable CTCs using CytoGen's Smart Biopsy™ System achieves high CTC purity for NGS analysis in breast cancer and non-small cell lung cancer (NSCLC). Methods: Targeted panel sequencing for CTC was developed to detect representative mutated genes using the Oncomine™ Comprehensive Assay Plus (501 genes) and the Oncomine™ Pan-Cancer Cell-Free Assay (52 genes). Analytical validation was performed with breast cancer cells MDA-MB-231 (50 to 5 cells) and NSCLC cells H358 (10 and 5 cells) which were spiked into 5 mL of healthy blood to mimic CTCs. CytoGen's Smart Biopsy™ System was applied to isolate the CTCs. Subsequently, CD45 depletion and whole genome amplification were performed. Sequencing was performed on Ion S5™ XL Systems using an Ion 550™ chip kit. The sequencing data were then analyzed using the Ion Torrent software with the default configurations. Results: As a result of targeted panel sequencing with Oncomine™ Comprehensive Assay Plus, representative breast cancer mutation genes (BRAF, KRAS, TP53, NF2 and NOTCH3) were detected in at least 20 MDA-MB-231 cells. In the results using Oncomine™ Pan-Cancer Cell-Free Assay, mutated genes (BRAF, KRAS and TP53) were successfully detected in as few as 5 MDA-MB-231 cells and, in addition, KRAS mutation was detected even with only 5 H358 cells. These results suggest that CytoGen's Smart Biopsy™ System could be applied to detect representative mutated genes in clinical breast cancer and NSCLC patient samples with detection technology that require high sensitivity and specificity. Conclusions: Molecular analysis of CTCs is a challenge since CTCs are very rare in the blood and there are technical limitations in isolating CTCs with sufficient purity for NGS analysis. In this study, we developed the process for NGS analysis on very small number of high-purity CTCs using CytoGen's Smart Biopsy™ System. Taken together with the results from our ongoing clinical trials, this process could provide information for the diagnosis and appropriate treatment of breast cancer and NSCLC patients.
Flushing fluid of post-bronchoscopic biopsy as a novel liquid biopsy specimen for genome profiling in advanced lung cancer.
Authors: Zhanhong Xie, YongQing Wu, Yingbo Xie, Yu Chen, Junjun Li, Bing Li, Chengzhi Zhou, Ming Liu, Xinqing Lin, Xiaohong Xie
Journal: Journal of Clinical Oncology (2024)

e15038 Background: Tumour tissue is the primary substrate for molecular testing in advanced NSCLC. However, obtaining sufficient tissue samples from biopsy for molecular testing can often be challenging. Flushing fluid of post-bronchoscopic biopsy, which contains tumor-derived DNA, may serve as a supplement for genotyping. The aim of this study is to assess the efficacy and precision of detecting gene alterations in flushing fluid samples and evaluate their clinical potential. Methods: Flushing fluid, matched tissue (TIS), and whole blood were prospectively collected from 25 patients with stage III-IV NSCLC between June 2022 and December 2023. Ten milliliters of flushing fluid and whole blood were used to prepare flushing fluid supernatant (FFS) and plasma (PLA), respectively. Capture-based targeted sequencing of TIS, FFS and PLA samples was performed using a universal oncology panel. Results: In this cohort of 25 patients, there was a male predominance (22 out of 25) and the mean age was 60.2 years. The majority of patients were diagnosed with lung adenocarcinoma (23 out of 25), and smokers outnumbered non-smokers (16 out of 25). Furthermore, 18 out of 25 patients presented with metastatic disease at diagnosis. The performance of three sample types regarding key quality control indices was evaluated first. FFS exhibited a maximum allelic fraction similar to TIS, while PLA showed a significantly lower than TIS and FFS. Subsequently, we compared the positive detection rates, with TIS, FFS, and PLA achieving respective rates of 100%, 96%, and 80%. A total of 495 mutation events were detected from the three samples (FFP:209, FFS:196, PLA:90), Among these, 161 were concordant between TIS and FFS samples, and 72 were concordant between TIS and PLA samples. The sensitivity and positive predictive value (PPV) of detecting eight established driver alterations in NSCLC were compared using TIS as the gold standard with the two liquid biopsies. FFS demonstrated superior sensitivity and PPV compared to PLA (80.5% vs. 56.1%, 97% vs. 88.5%) and showed equivalent performance for EGFR mutation. Furthermore, estimates of tumor mutational burden (TMB) based on TIS and FFS were highly correlated (Pearson r= 0.97). Conclusions: Our study demonstrated that FFS performs comparably to matched TIS and superiorly to PLA for genotyping advanced NSCLC. FFS emerges as a valuable specimen source, especially in patients with insufficient tumor tissue.
Acute severe ulcerative colitis trials: the past, the present and the future
Authors: Sailish Honap, Vipul Jairath, Bruce E Sands, Parambir S Dulai, Silvio Danese, Laurent Peyrin-Biroulet
Journal: Gut (2024)

Acute severe ulcerative colitis (ASUC), characterised by bloody diarrhoea and systemic inflammation, is associated with a significant risk of colectomy and a small risk of mortality. The landmark trial of cortisone in 1955 was pivotal for two reasons: first, for establishing the efficacy of a drug that remains a first-line therapy today and, second, for producing the first set of disease severity criteria and clinical trial endpoints that shaped the subsequent ASUC trial landscape. Trials in the 1990s and at the turn of the millennium established the efficacy of infliximab and ciclosporin, but since then, there has been little progress in drug development for this high-risk population. This systematic review evaluates all interventional randomised controlled trials (RCTs) conducted in patients hospitalised with severe UC. It provides an overview of the efficacy of treatments from past to present and assesses the evolution of trial characteristics with respect to study populations, eligibility criteria and study designs over time. This review details ongoing RCTs in this field and provides a perspective on the challenges for future clinical trial programmes and how these can be overcome to help deliver novel ASUC therapies.
Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of <i>ARID1A</i> Mutant Cancers
Authors: Patricia J. Keller, Elizabeth J. Adams, Rentian Wu, Alexandre Côté, Shilpi Arora, Nico Cantone, Rosana Meyer, Jennifer A. Mertz, Victor Gehling, Jike Cui, Jacob I. Stuckey, Avinash Khanna, Feng Zhao, Zehua Chen, Ziyang Yu, Richard T. Cummings, Mohammed Taimi, Nehal J. Lakhani, Drew Rasco, Martin Gutierrez, Linda Duska, Michael Devitt, Ronda Rippley, Julian Levell, Jennifer Truong, Jing Wang, Kaiming Sun, Patrick Trojer
Journal: Cancer Research (2024)

Abstract Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.
FS-1502 in patients with HER2 high expression, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: An open-label, multicenter, phase II study.
Authors: Hongming Pan, Xiang-lin Yuan, Yu Zheng, Hui Peng, Hong Qiu, Jufeng Wang, Zhiwei Li, Shegan Gao, Zuoxing Niu, Jianwei Yang, Yifu He, Guowu Wu, Yiyi Yu, Ying Jieer, Yusheng Wang, Zhen Li, Jun Bai, Huilong Liu, Zhuli Wu, Xingli Wang
Journal: Journal of Clinical Oncology (2024)

e15000 Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]
Changes in serum ghrelin and resistin levels after sleeve gastrectomy versus one anastomosis gastric bypass: prospective cohort study
Authors: Fusun Ozmen, Tevfik T. Şahin, Anil Dolgun, M. Mahir Ozmen
Journal: International Journal of Surgery (2024)

Introduction: Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and adipokines, including ghrelin and resistin, are linked to obesity, studies analyzing the changes in fasting ghrelin and resistin levels in patients following one anastomosis gastric bypass (OAGB) are lacking. Aim: The authors aimed to investigate resistin and ghrelin levels before and after two commonly used bariatric procedures with different mechanisms of action: sleeve gastrectomy (SG) and OAGB. Patients and methods: Fasting serum ghrelin and resistin levels were evaluated by using ELISA in a nonrandomized, prospective cohort study for the pattern of changes in the preoperative period and 1 week, 1 month, 3 months and, 12 months after surgery in age and sex-matched patients with BMI ≥40 kg/m 2 undergoing either SG ( n =40) or OAGB ( n =40). Their relationships with demographic parameters such as body weight, BMI, presence of T2DM, HbA 1 C, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were also evaluated. Results: OAGB was superior in weight control compared to the SG group. There were significant differences in resistin and ghrelin levels between the OAGB and SG groups. Ghrelin decreased more in the SG group than the preoperative values. This change in ghrelin levels was more significant at 1 year after SG [preoperative mean (range) level of 334.2 (36.6–972.1) pg/ml decreased to 84 (9.1–227) pg/ml at 1 year] whereas in the OAGB group no significant change was observed [preoperative mean (range) level of 310 (146–548) pg/ml decreased to 264 (112–418) pg/ml at 1 year]. Resistin levels decreased in both groups, especially after 3 months and onward following both operations [the mean (range) resistin levels were 2.6 (0.87–5.4) ng/ml and decreased to 1.1 (0.5–2.4) ng/ml in the SG group vs 2.48 (0.89–6.43) ng/ml decreased to 0.72 (0.35–1.8) ng/ml in OAGB group at 1 year], which was in parallel with changes in HOMA-IR index, body weight, and BMI changes at 1st year. HOMA-IR index changes were similar, but more prominent after OAGB. OAGB was als3 three months and onward), and HOMA-IR changes. Conclusion: This is the first study to compare fasting ghrelin and resistin levels after OAGB and SG. Although similar changes were observed, ghrelin changes were more prominent after SG, whereas resistin were observed after OAGB. OAGB was superior in T2DM control, which was in parallel with weight loss, fasting resistin levels, and HOMA-IR changes suggesting a possible effect of resistin after OAGB in glucose metabolism and insulin resistance.
Primary central nervous system lymphomas: EHA–ESMO Clinical Practice Guideline for diagnosis, treatment and follow‐up
Authors: Andrés J. M. Ferreri, Gerald Illerhaus, Jeanette K. Doorduijn, Dorothee P. Auer, Jacoline E. C. Bromberg, Teresa Calimeri, Kate Cwynarski, Christopher P. Fox, Khê Hoang‐Xuan, Denis Malaise, Maurilio Ponzoni, Elisabeth Schorb, Carole Soussain, Lena Specht, Emanuele Zucca, Christian Buske, Mats Jerkeman, Martin Dreyling
Journal: HemaSphere (2024)

Highlights This EHA‐ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS. The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow‐up. Algorithms for first‐line and salvage treatments are provided. The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe. Recommendations are based on available scientific data and the authors' collective expert opinion.
Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.
Authors: Hongye Wang, Haigang Geng, Zhaorong Wu, Yiqing Zhong, Zhenyu Song, Linke Bian, Dan Cui, Bo Zhai
Journal: Journal of Clinical Oncology (2024)

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.