tbuckley/cabot-search huggingface dataset:
Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation
Authors: Liheng Yin, Alexandra Zahradnikova, Riccardo Rizzetto, Simona Boncompagni, Camille Rabesahala de Meritens, Yadan Zhang, Pierre Joanne, Elena Marqués-Sulé, Yuriana Aguilar-Sánchez, Miguel Fernández-Tenorio, Olivier Villejoubert, Linwei Li, Yue Yi Wang, Philippe Mateo, Valérie Nicolas, Pascale Gerbaud, F. Anthony Lai, Romain Perrier, Julio L. Álvarez, Ernst Niggli, Héctor H. Valdivia, Carmen R. Valdivia, Josefina Ramos-Franco, Esther Zorio, Spyros Zissimopoulos, Feliciano Protasi, Jean-Pierre Benitah, Ana M. Gómez
Journal: Circulation Research (2021)

Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca 2+ release channel/RyR2 (type 2 ryanodine receptor) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal domain, RyR2 R420Q . Objective: To determine the arrhythmogenic mechanisms of this mutation. Methods and Results: Ventricular tachycardias under stress conditions were observed in both patients with catecholaminergic polymorphic ventricular tachycardia and knock-in mice. During action potential recording (by patch-clamp in knock-in mouse cardiomyocytes and by microelectrodes in mutant human induced pluripotent stem cell-derived cardiomyocytes), we observed an increased occurrence of delayed afterdepolarizations under isoproterenol stimulation, associated with increased Ca 2+ waves during confocal Ca 2+ recording in both mouse and human RyR2 R420Q cardiomyocytes. In addition, Ca 2+ -induced Ca 2+ -release, as well as a rough indicator of fractional Ca 2+ release, were higher and Ca 2+ sparks longer in the RyR2 R420Q -expressing cells. At the ultrastructural nanodomain level, we observed smaller RyR2 clusters and widened junctional sarcoplasmic reticulum measured by gated stimulated emission depletion super-resolution and electron microscopy, respectively. The increase in junctional sarcoplasmic reticulum width might be due to the impairment of RyR2 R420Q binding to JPH2 (junctophilin-2), as there were less junctophilin-2 coimmunoprecipitated with RyR2 R420Q . At the single current level, the RyR2 R420Q channel dwells longer in the open state at low intracellular Ca 2+ ([Ca 2+ ] i ), but there is predominance of a subconductance state. The latter might be correlated with an enhanced interaction between the N terminus and the core solenoid, a RyR2 interdomain association that has not been previously implicated in the pathogenesis of arrhythmias and sudden cardiac death. Conclusions: The RyR2 R420Q catecholaminergic polymorphic ventricular tachycardia mutation modifies the interdomain interaction of the channel and weakens its association with JPH2. These defects may underlie both nanoscale disarrangement of the dyad and channel dysfunction.
Updated results of a phase 1b study of regorafenib (REG) 80 mg/day or 120 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).
Authors: Anthony B. El-Khoueiry, Richard D. Kim, William Proctor Harris, Max W. Sung, Dirk Waldschmidt, Roniel Cabrera, Vittorio Luigi Garosi, Hong Zebger-Gong, Barbara J. Brennan, Ying A. Wang, Udo Mueller, Tatiane Cristine Ishida, Peter R. Galle
Journal: Journal of Clinical Oncology (2021)

4078 Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]
Comparative study on iron content detection by energy spectral CT and MRI in MDS patients.
Authors: Yao Zhang, Chao Xiao, Jing Li, Lu-Xi Song, You-Shan Zhao, Shuang Han, Zhao-Wei Li, Cha Guo, Jun-Gong Zhao, Chun-Kang Chang
Journal: Journal of Clinical Oncology (2021)

e19032 Background: Myelodysplastic syndrome(MDS) patients may have iron overload due to long-term RBC transfusion or combined with abnormal iron metabolism.what are the differences of iron content detection by magnetic resonance imaging (MRI) and dual energy spectrum computed tomography (DECT)? What are the advantages and disadvantages of the two methods in the state of high and low iron deposition? Can the two methods complement each other? The purpose of this study was to compare the difference of liver/cardiac iron content detection in MDS patients by DECT and MRI under different adjust serum ferritin (ASF) levels. Methods: Liver and cardiac iron content were detected by DECT and MRI. Patients divided into different subgroups according to ASF. Compared the detection rate between DECT and MRI group, and correlation between liver/cardiac iron content detected by DECT/MRI and ASF in each subgroups. Results: The detection rate of iron overload(IO) in DECT group was lower than that of MRI group with ASF &lt; 1000ng/ml subgroup,DECT and MRI had similar detection rates of moderate to severe IO with 1000≤ ASF &lt; 5000ng/ml subgroup, detection rate of severe IO in MRI was lower than that of DECT with 5000ng/ml ≤ ASF subgroup. In patients underwent DECT and MRI examination at the same time, ASF was significantly correlated with hepatic VIC but not with liver iron concentration (LIC), and LIC correlated with ASF after removed these data of ASF &gt; 5000 mg/L. LIC expression are not significantly different among 1000≤ ASF &lt; 5000ng/ml and 5000 ng/ml ≤ASF subgroup. LIC and liver virtual iron content (VIC) were all significant correlation with ASF when ASF &lt; 2500ng/ml, liver VIC was still correlation with ASF but LIC was not when 2500ng/ml≤ ASF. Neither cardiac VIC nor myocardial iron content (MIC) correlation with ASF in these subgroups. Conclusions: This study showed that MRI and DECT can be used complementary to each other. In high iron content, such as ASF ≥5000ng/ml, DECT detection is more reliable. In patients with low iron content, such as SF &lt; 1000 ng/ml, MRI detection is more reliable. According to ASF, the appropriate detection method can be selected to evaluate the iron content more accurately.
Comparative efficacy of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).
Authors: Stephen J. Schuster, Jie Zhang, Hongbo Yang, Abhijit Agarwal, Wenxi Tang, Marcela Martinez-Prieto, Vamsi Bollu, Qiufei Ma, David Kuzan, Richard T. Maziarz, Marie José Kersten
Journal: Journal of Clinical Oncology (2021)

7535 Background: Chimeric antigen receptor T-cell therapies tisa-cel and liso-cel are effective treatments for r/r DLBCL (Schuster 2019, Abramson 2020). This study compared efficacy outcomes of tisa-cel and liso-cel in r/r DLBCL using matching-adjusted indirect comparison (MAIC). Methods: Individual patient-level data (IPD) from JULIET (tisa-cel; NCT02445248; 02/2020 datacut) were weighted to match the patient population in TRANSCEND (liso-cel; NCT02631044; 08/2019 datacut). Baseline prognostic factors available in both trials were adjusted for age, sex, histology, ECOG performance status [ECOG PS], left ventricular ejection fraction, radiologic sum of product diameters, lactate dehydrogenase, prior stem cell transplantation [SCT], use of bridging therapy, and number of and refractoriness to prior therapies, in the MAIC. Overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and overall response (OR) rate were compared. Primary analyses compared infused patients in JULIET (N=106, excluding 8 without lymphodepleting chemotherapy [LDC] and 1 large cell neuroendocrine carcinoma) with efficacy-evaluable set in TRANSCEND (N=256, infused patients). A scenario analysis compared JULIET infused to TRANSCEND primary analysis set (PAS) (N=133, dose level 2, excluding those with ECOG PS 2, prior allogeneic SCT, primary mediastinal B-cell lymphoma, follicular lymphoma [FL] 3B, or transformation from indolent lymphoma besides FL). Sensitivity analyses included JULIET patients with only fludarabine-based LDC or only adjusted significantly different baseline prognostic factors. Safety outcomes were not compared because adverse event management has evolved and differed between the two trials; MAIC is unable to adjust for such differences. Results: After adjusting for differences in baseline characteristics, OS, PFS, and CR were comparable between tisa-cel infused patients and the liso-cel efficacy-evaluable set (Table). The results were consistent across all scenario and sensitivity analyses. OR rate trended higher in the TRANSCEND efficacy-evaluable set (72.7% vs. 62.9%, p=0.07) and was higher in TRANSCEND PAS than in the respectively matched JULIET infused set (74.4% vs. 60.9%, p &lt; 0.05). Conclusions: The MAIC results indicate there is no evidence suggesting differences in OS, PFS and CR between tisa-cel and liso-cel in r/r DLBCL. Analyses using IPD from both trials and/or real-world evidence are warranted to confirm these findings.[Table: see text]
CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.
Authors: Catherine Thieblemont, Bettina Altmann, Olivier Casasnovas, Fabian Frontzek, Franck Morschhauser, Lucie Oberic, Viola Poeschel, Olivier Fitoussi, Loïc Renaud, Georg Lenz, Nicolas Mounier, Andreas Rosenwald, German Ott, Thierry Molina, Marie Parrens, Loic Chartier, Marita Ziepert, Herve Tilly, Norbert Schmitz
Journal: Journal of Clinical Oncology (2021)

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]
Proliferation index and survival in men with prostate cancer starting long-term androgen deprivation therapy in the STAMPEDE clinical trial.
Authors: Larissa Mendes, Christopher D. Brawley, Emily Grist, Adnan Ali, Sara Santos Vidal, Marina Parry, Sharanpreet Lall, Nafisah B. Atako, Sofeya Ishaq, Malissa Richmond, Aine Haran, Alex Hoyle, Leila Zakka, Christopher Sweeney, Noel W. Clarke, Mahesh K. B. Parmar, Nicholas D. James, Louise C. Brown, Daniel Berney, Gerhardt Attard
Journal: Journal of Clinical Oncology (2021)

5076 Background: Treatment intensification with docetaxel or abiraterone improved survival for advanced prostate cancer starting androgen deprivation therapy (ADT) in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE, NCT00268476) trial. However, survival and time-to-progression is highly variable on ADT, introducing the risk of unnecessary toxicity from additional treatments for some patients. Here we test the prognostic association of proliferation index using Ki67 scores in the control arm of the STAMPEDE population of high-risk localised (M0) and metastatic (M1) prostate cancer. Methods: Pre-ADT diagnostic needle biopsies were obtained from 517 men randomized in STAMPEDE arm A between 2006 and 2015. These were assessed for proliferation using an analytically optimised Ki67 immunohistochemistry assay. Ki67 was tested for associations with baseline clinico-pathological variables (Grade group, pre-ADT serum PSA and imaging metastatic burden) in univariable linear-regression models, and for associations with survival outcomes in multivariable Cox-regression models adjusted for these and additional confounding variables. Primary outcome measure was overall survival, secondary outcomes were prostate cancer-specific, failure-free, progression-free and metastatic progression-free survival. Results: Ki67 was available for 475 patients who received ADT only for at least 2 years ± radiotherapy. Of 202 M0, 74 were node positive. Of 273 M1, 116, 127 and 30 were respectively low, high and unknown radiological M1 volume. Ki67 score associated with higher Gleason (p=7.15x10 -11 ) and presence of extra-pelvic metastases (p=1.41x10 -8 ). Increasing Ki67 scores showed a strong linear association with poorer overall survival, with an estimated 2% increase in the hazard of death per percentage increase in the score (adjusted HR=1.02, 95% CI 1.01-1.02; p=1.04x10 -5 ). There was also strong evidence that Ki67 associated positively with all secondary outcomes, including prostate cancer-specific survival (adjusted p=5.50x10 -6 ) and metastatic progression-free survival (adjusted p=3.50x10 -9 ). Conclusions: Ki67 immuno-score is strongly prognostic in clinically advanced prostate cancer independent of Gleason score and the other clinicopathological variables tested in this study. Ki67 is a clinically scalable assay that could improve selection for treatment intensification and provide a tool for screening patients most likely to benefit from further molecular investigation.
EPEN-06. CELL ECOSYSTEM AND SIGNALING PATHWAYS OF PRIMARY AND METASTATIC PEDIATRIC POSTERIOR FOSSA EPENDYMOMA
Authors: Rachael Aubin, Emma Troisi, Adam Alghalith, MacLean Nasrallah, Mariarita Santi, Pablo Camara
Journal: Neuro-Oncology (2021)

Abstract Childhood ependymoma is a cancer of the central nervous system with a chronic relapsing pattern. In children, 90% of ependymal tumors occur intracranially where prognosis is grim. Standard care for this disease includes surgical resection followed by radiation. Despite several clinical trials, adjuvant chemotherapies have yet to extend patient survival, highlighting a need for more effective treatment options. Ependymal tumors have been stratified into nine molecular subgroups based on their DNA methylation profile. The most prevalent and aggressive pediatric subgroup is known as posterior fossa ependymoma type A (PFA) which represents approximately 60% of pediatric cases and has a 5-year progression free survival rate of 30%. Whole genome sequencing studies have revealed that PFA tumors rarely harbor recurrent mutations. To inform the potential development of new treatment options for this disease, we sought to decipher the specific mechanisms leading to the tumorigenesis, progression, and metastasis of PFA tumors. By means of single-nuclei RNA-seq and an array of computational methods, we show that the expression profile of PFA tumor cells recapitulate the developmental lineages of radial glia in neurogenic niches, and is consistent with an origin in LGR+ stem cells and a pro-inflammatory environment. In addition, our analysis reveals the abundance of a mesenchymal cell population expressing TGF-β signaling, reactive gliosis, and hypoxia-related genes in distal metastases from PFA tumors. Taken together, our results uncover the cell ecosystem of pediatric posterior fossa ependymoma and identify WNT/β-catenin and TGF-β signaling as candidate drivers of tumorigenesis for this cancer.
Adjuvant toripalimab or combined with S-1 in recurrent, previously irradiated head and neck squamous cell carcinoma treated with salvage surgery: A phase II clinical trial (The RePASS study).
Authors: Shengjin Dou, Rongrong Li, Lin Zhang, Wen Jiang, Lulu Ye, Guopei Zhu
Journal: Journal of Clinical Oncology (2021)

6039 Background: The predominant pattern of failure for Head and Neck Squamous Cell Carcinoma (HNSCC) is locoregional disease. Salvage surgery remains the standard of care for operable disease. Re-irradiation after previous full course radiotherapy generally has been considered contraindicated. Since anti-PD-1 antibodies were efficacious and safety in recurrent/metastatic HNSCC, this study aimed to evaluate the efficacy and safety of adjuvant toripalimab (anti-PD-1 antibody) in recurrent, previously irradiated HNSCC treated with salvage surgery. Methods: This study was a single-arm, phase II study. Patients with HNSCC occurring in an area of previously irradiated and with at least one high risk factors after salvage surgery (1- positive margin; 2- extranodal extension; 3- rStaging T3-4/N2-3/T2N1) were enrolled. In the Stage I of 12 patients, patients received toripalimab 240mg once every 3 weeks until confirmed disease progression or unacceptable toxicity, for 12 months. In the stage II of 8 patients with PD-L1 CPS≥1, patients received toripalimab combined with S-1, which was given orally at 25 mg/m 2 , twice daily, on day 1 to 14, repeated every 21 days for 4-6 cycles. The primary endpoint was 1-year progression-free survival (PFS). We hypothesized a 1-year PFS of at least 56% and assumed a null hypothesis of 34%. A retrospective cohort of 16 patients was compared. Results: Between May 2019 and December 2020, 20 patients were enrolled. High-risk factors included ENE (35%), positive margin (25%), T3-4(30%) and T2N+(10%). Seventeen patients have PD-L1 CPS≥1 and 3 patients have CPS＜1. With a median follow-up of 11.2 months, estimated 1-year PFS and overall survival was 57.0% (95% confidence interval, 32%– 77%) and 79.2% (51%–91%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. When compared to the retrospective cohort, the PFS was significantly better(p=0.001)，even for Stage I patients(Median PFS: 5.1 vs 3.7 months, p=0.03 ). Stage II patients resulted a better PFS and OS compare to stage I (p=0.02 and p=0.002). For patients with CPS≥1, 1-year PFS and OS was 79.1% (95% confidence interval, 51%–91%) and 91.7%(68%–99%), which were significantly better than patients with CPS＜1 (p=0.001 and p=0.05). Adjuvant Toripalimab or combine with S-1 was well-tolerated with no grade 3-4 toxicity and dose interruption as a result of treatment-related adverse event only occurred in 2 patients. Flow cytometry revealed that patients with short PFS had fewer baseline overall count of B cells(p=0.09). Conclusions: Adjuvant Toripalimab or combined with S-1 after salvage surgery is efficacious and safety in recurrent, previously irradiated HNSCC, and a better PFS was observed in patients treated with combined therapy and with CPS≥1. Further randomized trials are warranted. Clinical trial information: NCT04126460.