tbuckley/cabot-search huggingface dataset:
PD1 inhibition in soft-tissue sarcomas with tertiary lymphoid structures: A multicenter phase II trial.
Authors: Antoine Italiano, Alban Bessede, Emmanuelle Bompas, Sophie Piperno-Neumann, Christine Chevreau, Nicolas Penel, Francois Bertucci, Maud Toulmonde, Carine A. Bellera, Jean-Philippe Guegan, Catherine Sautes-Fridman, Antoine Bougoüin, Coralie Cantarel, Francois Le Loarer, Jean-Yves Blay, Wolf-Herman Fridman
Journal: Journal of Clinical Oncology (2021)

11507 Background: PD1 inhibition has shown limited activity in all comers clinical trials including patients with advanced soft-tissue sarcomas (STS). In the PEMBROSARC study, objective response rate, progression-free (PFS) and overall survival (OS) were respectively 2.1%, 1.4 and 7.1 months respectively (Toulmonde et al. Jama Oncol 2017). We have recently shown that the presence of tertiary lymphoid structures (TLS) may represent a biomarker to select patients who are more likely to benefit from immunotherapy (PetitPrez et al., Nature 2020). We report here the first clinical trial investigating the efficacy of PD1 inhibition in TLS-positive STS. Methods: PEMBROSARC is an open-label multicenter phase II study of pembrolizumab in combination with low-dose cyclophosphamide in pts with STS selected based on the presence of TLS. TLS status has been assessed centrally has previously described (PetitPrez et al., Nature 2020). Eligible patients received pembrolizumab 200mg IV q21 days and cyclophosphamide 50 mg BID 1week on, 1 week off. All patients had confirmed progressive disease at inclusion based on central review of two imaging performed at less than 6 months interval. The primary efficacy endpoint was 6-month non-progression (as per RECIST evaluation criteria v1.1). Based on the following hypotheses: 15% 6-month non-progression rate (H0), 40% acceptable 6-month non-progression rate (H1), 5% type I error rate, 90% power, a total of 29 assessable patients were necessary and 8 patients or more had to be progression-free at 6 months to reach the first endpoint. Results: 240 patients were screened for TLS status between September 2018 and January 2020 in 7 centers of the French Sarcoma Group. Among them, 48 were found to be TLS+ as per central review and 35 were included in the study. The three most frequent histological subtypes were: well-differentiated/dedifferentiated liposarcoma (n = 13); UPS (n = 6), and leiomyosarcoma (n = 4). 30 patients were eligible for efficacy. Of those, as per central imaging review, 13 patients (43.3%) had tumor shrinkage resulting in partial response in 8 patients (26.7%) and stable disease in 5 cases (16.7%). 10 patients had progressive disease. Twelve patients were progression-free at 6 months (40.0% 95%CI = [22.7 – 59.4]).Median PFS and OS were 4.1 months (95%CI, 1.4-9.6) and 14.5 months (95%CI, 8.5- 18.3 months), respectively. Conclusions: With an objective response and a 6-month non-progression rates of 26.7% and 40% respectively versus 2.1% and 4.2% in all comers, the PEMBROSARC study confirms that selection based on TLS status is an efficient approach to tailor immunotherapy in STS patients. Clinical trial information: NCT02406781.
The predictive value of neutrophil-to-lymphocyte ratio on overall survival and pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Wenjie Tang, Linlin Wang, Jinming Yu, Yishan Yu
Journal: Journal of Clinical Oncology (2021)

e12625 Background: Neutrophil-to-lymphocyte ratio (NLR) has been found to offer clear predictive utility for the overall survival (OS) and pathologic complete response (pCR) in breast cancer (BC) patients receiving neoadjuvant chemotherapy(NAC). However, previous studies mainly focused on pre-NLR. The aim of this study was to explore the role of pre-/post-NLR towards OS and longitudinal NLR kineticsonpCR for BC patients undergoing NAC. And we also tried to build a nomogram for OS prediction based on these parameters. Methods: In this study, we retrospectively collected 501 female patients with locally advanced BC receiving 4-8 cycles of NAC from 2009 to 2018. Clinicopathological characteristics, NLR at pre-, mid-(every two cycles of NAC) and post-treatment were collected. The primary endpoint was OS. Among the patients, 421 patients with available pre- and post-NLR were included in the survival analysis. These patients were randomly divided into a training cohort (n = 224) and a validation cohort (n = 197). Multivariate survival model was built by including all the significant prognostic factors from the univariate analysis in the training cohort, and a nomogram model was established by “R” version 3.4.3. The performance of the model was further tested in the validation cohort by the concordance index. The second endpoint was pCR. Longitudinal analysis of NLR was performed using a mixed-effects regression model to predict pCR among 176 patients who finished 8 cycles of NAC. Results: The median follow-up time was 43.2 months for 421 patients. In the training cohort, multivariate analysis revealed that ER status, clinical node stage , pCR , pre-NLR, and post-NLR (all Ps＜0.05) were independent predictors of OS. Nomogram for OS prediction was established by combining all these significant factors. The C-indexes of the nomogram were 0.764 and 0.693, respectively in the training and validation cohort. In the longitudinal analysis, patients achieved pCR experienced a reduction of NLR every 2 cycles (Coef = -0.032, std error = 0.014, P = 0.024). Conclusions: This study demonstrated the prognostic value of pre-NLR and post-NLR towards BC patients received NAC. Based on that , a novel nomogram was established to predict the 3- and 5- year OS for BC patients. And we also found patients who experienced a decline of NLR during NAC seems to be more likely to achieve pCR from chemotherapy. Routine assessment of NLR may be an easy and affordable tool for defining prognosis.
Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial
Authors: Brian G Feagan, Silvio Danese, Edward V Loftus, Séverine Vermeire, Stefan Schreiber, Timothy Ritter, Ronald Fogel, Rajiv Mehta, Sandeep Nijhawan, Radosław Kempiński, Rafał Filip, Ihor Hospodarskyy, Ursula Seidler, Frank Seibold, Ian L P Beales, Hyo Jong Kim, John McNally, Chohee Yun, Sally Zhao, Xiaopeng Liu, Chia-Hsiang Hsueh, Chantal Tasset, Robin Besuyen, Mamoru Watanabe, William J Sandborn, Gerhard Rogler, Toshifumi Hibi, Laurent Peyrin-Biroulet
Journal: The Lancet (2021)
Non-Transferrin-Bound Iron Serves As Iron Source for Aspergillus Fumigatus Growth
Authors: Verena Petzer, Piotr Tymoszuk, Markus Seifert, Dorothea Orth-Höller, Martin Wermke, Uwe Platzbecker, Günter Weiss, Hubertus Haas, Igor Theurl
Journal: Blood (2017)
Heterogeneity in <i>NECTIN4</i> Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin
Authors: Carissa E. Chu, Martin Sjöström, Emily A. Egusa, Ewan A. Gibb, Michelle L. Badura, Jun Zhu, Vadim S. Koshkin, Bradley A. Stohr, Maxwell V. Meng, Raj S. Pruthi, Terence W. Friedlander, Yair Lotan, Peter C. Black, Sima P. Porten, Felix Y. Feng, Jonathan Chou
Journal: Clinical Cancer Research (2021)

Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance.Molecular subtyping and NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1,915 total specimens) were used to assess NECTIN4 expression across molecular subtypes. The outcome of the transcriptomic analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays.NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes. NECTIN4 expression is positively correlated with luminal markers GATA3, FOXA1, and PPARG across all cohorts. NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 leads to EV resistance.Sensitivity to EV is mediated by expression of NECTIN4, which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials.See related commentary by Teo and Rosenberg, p. 4950.
Abstract 11897: Significant Delayed Activation at Right Ventricular Outflow Tract Represents Upward Electrical Axis of the Right Ventricle and Complete Right Bundle Branch Block in Brugada Syndrome
Authors: Yoshimasa Morimoto, Hiroshi Morita, Saori Tsukuda, Masakazu Miyamoto, Satoshi Kawada, Koji Nakagawa, Nobuhiro Nishii, Atsuyuki Watanabe, Kazufumi Nakamura, Hiroshi Ito
Journal: Circulation (2018)

Introduction: Appearance of complete right bundle branch block (CRBBB) in Brugada syndrome (BrS) is associated with severe clinical phenotype, such as frequent ventricular fibrillation (VF). Epicar...
Impact of <i>KRAS</i> mutational variant on response to immunotherapy in metastatic NSCLC.
Authors: Shelley Kuang, Sally C. M. Lau, Kieran Sharma, Juehea Lee, Malcolm Isaiah Ryan, Sabine Schmid, Penelope Ann Bradbury, Geoffrey Liu, Frances A. Shepherd, Ming Sound Tsao, Natasha B. Leighl, Adrian G. Sacher
Journal: Journal of Clinical Oncology (2021)

e21127 Background: KRAS alterations constitute the most common driver mutations in metastatic non-small cell lung cancers (mNSCLC) and occur in approximately 30% of patients. KRAS mutational subtype as well as the presence of co-mutations has been associated with altered activation of downstream signaling pathways in preclinical models. We hypothesize that different KRAS G12C mutational subsets will be associated with variable clinical outcome and response to therapy. To this end, we have performed a retrospective analysis of survival and treatment outcomes by KRAS mutation subtype (G12C vs non-G12C). Methods: A review of KRAS-mutated mNSCLC patients treated with immunotherapy between 2013 and 2020 was conducted. Patient demographics, smoking status, KRAS mutational subtype, co-mutations and PD-L1 status were collected. Overall response rate (ORR) and progression-free survival (PFS) were analyzed in each subgroup. Results: 98 KRAS mutant mNSCLC patients were treated with immune checkpoint inhibitors (ICI): 37% with a KRAS G12C mutation, 62% with a non-G12C mutation. Patients with a G12C mutation were more likely to be of Caucasian ancestry (86% vs 56%; p = 0.01) whereas all other characteristics were similar between the groups including smoking history, PD-L1 expression ≥50% (61% vs 40%) and the presence of a TP53 co-mutation (48% vs. 54%); all p &gt; 0.05. Treatment patterns were similar between the groups, with PD-1 inhibitor monotherapy given in 86% vs 79% of KRAS G12C and non-G12C patients. Overall response rate was 51% vs 27% in G12C vs non-G12C (p = 0.03). PFS was superior in G12C mutants (19.6 months vs 4.0 months), even after adjusting for smoking history, TP53 co-mutation status and PD-L1 expression (adjusted HR 0.51; p = 0.02). In subgroup analyses, the superiority in PFS was driven by the G12C mutants with high PD-L1 expression (n = 19): 26.8 months in G12C, PD-L1 high vs 4.7 months in G12C, PD-L1 low vs. 4.7 months in KRAS transversion mutations, PD-L1 high vs 4.0 months in transversion mutations, PD-L1 low vs. 3.0 months in transition mutations; p &lt; 0.001. Conclusions: The presence of a KRAS G12C mutation is associated with improved ORR and PFS after treatment with ICI compared to non-G12C mutations in mNSCLC. The greatest benefit in PFS was observed in the subgroup with G12C mutation and high PD-L1 expression. Differential activation of downstream signaling associated with specific KRAS codon 12 mutation variants may modulate the composition of the tumor immune microenvironment thereby contributing to the variable response to immunotherapy. Further understanding on these molecular mechanisms may direct the development of new treatment strategies in KRAS mutant lung cancers.
18F-THK5351 PET Can Identify Core Lesions in Different Amyotrophic Lateral Sclerosis Phenotypes
Authors: Mana Higashihara, Kenji Ishibashi, Aya M. Tokumaru, Atsushi Iwata, Kenji Ishii
Journal: Clinical Nuclear Medicine (2021)

Two patients with different amyotrophic lateral sclerosis (ALS) phenotypes underwent 18F-THK5351 PET to visualize lesions undergoing astrogliosis by measuring monoamine oxidase B activity. Patient 1 was a 57-year-old man with flail leg syndrome. Elevated uptake was observed inside the motor cortex, corresponding to the leg area in a cortical homunculus. Patient 2 was a 64-year-old man with ALS-frontotemporal dementia semantic variant. Elevated uptake was observed around the left anterior temporal lobe. Both core lesions were consistent with their respective neurological features. Hence, 18F-THK5351 PET is a useful technique to assess ALS pathophysiology by visualizing the core lesions.
A trial-level correlation analysis of progression-free survival as a surrogate for overall survival in the immunotherapy era.
Authors: Emre Yekeduz, Elif Berna Koksoy, Hakan Akbulut, Gungor Utkan, Yuksel Urun
Journal: Journal of Clinical Oncology (2021)

e18580 Background: Progression-free survival (PFS) is accepted as a surrogate endpoint for cancer drugs approval by the Food and Drug Association. In the expanding immunotherapy era, there is no convincing data for reliable surrogacy of PFS. Methods: We systematically searched PubMed and included all phase III trials of ICIs. Besides, we manually included phase III trials of ICIs presented in congresses. Trials including non-metastatic patients and hematologic malignancies were excluded. The primary endpoint was the relationship between treatment effects (i.e., hazard ratio (HR) of PFS and overall survival (OS)). The secondary endpoint was the relationship between the median PFS (mPFS) and median OS (mOS). We also performed subgroup analyses by ICIs subtypes (i.e., anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1)), treatment lines (i.e., the first-line and subsequent treatments), ICI plus CT combination, and ICI monotherapy. To ensure parametric assumptions, we addressed logarithmic conversion to HRs by using log 10 . We used Pearson’s correlationand weighted linear regression for parametric variables and Spearman’s rank-order correlation for non-parametric variables. We assessed the relationship between variables by using correlation coefficient (r) and coefficient of determination (R 2 ). Results: We included 57 phase III clinical trials with 39,525 patients. A total of 67 outcomes were compared. There was a good correlation between the logarithmic HR of PFS (log HR PFS ) and OS (log HR OS ) (r=0.71, R 2 =0.50 p&lt;0.001). In subgroup analyses, there was a weak or moderate correlation between the log HR PFS and log HR OS in anti-PD-L1, ICI plus CT, and the first-line treatment subgroups (r=0.61, R 2 =0.38 p=0.004 for anti-PD-L1; r=0.65, R 2 =0.43 p=0.008 for ICI plus CT; r=0.70, R 2 =0.49 p&lt;0.001 for the first-line treatment). Conversely, there was a good correlation between the log HR PFS and log HR OS in the anti-PD-1, ICI monotherapy, and subsequent treatment line subgroups (r=0.81, R 2 =0.66 p&lt;0.001 for anti-PD-1; r=0.71, R 2 =0.51 p&lt;0.001 for ICI monotherapy; r=0.78, R 2 =0.62 p&lt;0.001 for subsequent treatment line). Correlations between the mPFS and mOS were good or strong in all subgroups. (Table). Conclusions: PFS might be considered a reliable surrogate endpoint for OS, particularly in anti-PD-1 ICIs, ICI monotherapy, and subsequent metastatic cancer treatment lines.[Table: see text]
OncotypeDx scores according to race/ethnicity and age in a diverse cohort of breast cancer patients.
Authors: Eileen Chen, Corinne Jones, Ian Pagano, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2021)

e12512 Background: Breast cancer incidence and mortality rate differ across racial/ethnic populations in the US, but little is known about the relationship between Oncotype DX scores and race/ethnicity. Oncotype DX scores are used in early stage, hormone positive breast cancers to estimate the likelihood of breast cancer recurrence and benefit from receiving chemotherapy. Most available literature assesses disparities between race and receipt of an Oncotype DX score, with only some assessing distribution of scores by race. Populations previously studied mainly focus on Black compared to White women, with very few including Asian and Native Hawaiian/Pacific Islander subpopulations. When included, they are often grouped together as Asian/Pacific Islander. Current studies suggest there is a similar distribution of scores among Black and White women, but some studies report that Black women may be more likely to have high-risk scores. Methods: We examined 476 unique breast cancer cases in the Hawaii Pacific Health system diagnosed in 2018-2020. We used univariable and multivariable analyses on all of those cases that received an Oncotype DX score to determine correlation to age and race. Results: In 328 breast cancer cases that received an Oncotype DX score, age of diagnosis ranged from 29 to 84 with race/ethnicity including Japanese (n = 90, 27%), White (n = 78, 24%), Filipino (n = 54, 17%), Native Hawaiian (n = 52, 16%), Chinese (n = 24, 7%), and other (n = 30, 9%) populations. Cases with age at diagnosis between 60-69 (n = 118, 36%) were found to have a mean Oncotype DX score of 13.91 (CI 12.19-15.62, p = 0.04) which was statistically lower than other ages groups on both univariable and multivariable analysis. We found no other significant relationships between Oncotype DX score and race or age at diagnosis on our analyses. Conclusions: These findings contribute more information about Oncotype DX scores within Asian and Native Hawaiian populations to the available literature.
A phase 3, randomized, double-blind, adaptive, placebo/paclitaxel-controlled study of AVB-S6-500 in combination with paclitaxel in patients with platinum-resistant recurrent ovarian cancer (GOG-3059/ENGOT OV-66/AVB500-OC-004).
Authors: Katherine Cynthia Fuh, Thomas J. Herzog, Kathleen N. Moore, Tashanna K. N. Myers, BJ Rimel, Joyce F. Liu, Angeles Alvarez Secord, Erika P. Hamilton, Thomas J. Reid, Sharyn Nan Lewin, Mary M Mullen, Kathryn A. Mills, Randy Anderson, Reshma A. Rangwala
Journal: Journal of Clinical Oncology (2021)

TPS5605 Background: The AXL receptor and its activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention, but the strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with ̃200-fold higher affinity than wild-type (WT) AXL. AVB-S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. A Phase 1b study in platinum resistant ovarian cancer showed no dose limiting toxicities and established a recommended Phase 2 dose of 15mg/kg administered every 2 weeks. Longer progression free survival (PFS) and overall survival (OS) times were observed in patients who had not been previously treated with bevacizumab. Furthermore, retrospective analyses demonstrated that serum soluble AXL to GAS6 ratio may identify patients more likely to respond to this therapy. Methods: Patients with high grade serous, platinum resistant ovarian cancer, who have received no more than 4 prior therapy regimens will be randomized 1:1 to AVB-500 + PAC or PAC + placebo. Patients will be stratified by recurrence after last platinum regimen (&lt;3, 3-6 months), prior lines (1-2, 3-4), and prior bevacizumab (yes, no). The primary endpoint is PFS by RECIST v 1.1 as assessed by the investigator, with OS a key secondary endpoint. The study design is adaptive; with two interim analyses addressing conditional power in the bevacizumab treated subset, and in a serum soluble AXL, GAS6 biomarker subset, respectively, with interim results used to define the final target population. Simulations confirm a nominal one-sided type 1 error below 0.025, and show &gt;90% statistical power for PFS under the following assumptions of PFS medians. Study recruitment began in Q1. Clinical trial information: NCT04729608.
Post radical prostatectomy prostate-specific antigen doubling-time kinetics: Observations of increasing versus decreasing doubling times.
Authors: Linda My Huynh, Erica Huang, Douglas Skarecky, Tom Edward Ahlering
Journal: Journal of Clinical Oncology (2021)

e17002 Background: Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of distant metastatic progression or prostate cancer (PC) death, consequently resulting in overtreatment. Further, little has been published about active surveillance (AS) specific management recommendations. Herein, we validate the practicality of using the kinetics (change) of PSA doubling time (PSADT) to direct continued observation versus intervention. Methods: In a retrospective cohort analysis of 406 men with BCR (defined as adjuvant therapy or PSA &gt; 0.2 ng/dl, x2), 284 men were monitored post RP with PSADT graphs for all patients, and the PSADT was characterized as increasing vs decreasing. Receiver-operator characteristic (ROC) curves were generated to assess the sensitivity/specificity/positive predictive value/negative predictive value of PSADT progression on treatment and prostate cancer specific mortality at 10 years post-RARP, respectively. Results: The median follow-up was 7.6 (IQR: 4.6-10.6) years. Of 284 men, 109 (38%) and 175 (62%) were in the no treatment versus treatment groups, respectively. 87% of men receiving treatment had a decreasing PSADT and 100% men with PCSM had a decreasing PSADT. ROC analysis showed 0.870 sensitivity and 1.0 specificity when predicting secondary treatment (AUC = 0.935) and 0.857 sensitivity and 0.50 specificity when predicting PCSM (AUC = 0.679). Conclusions: A decreasing PSADT is a sensitive and specific metric for predicting the need for secondary intervention. We also found all men who died of PC had a decreasing PSADT. Lastly an increasing DT predicts a benign course without need for treatment. The current findings suggest that the kinetics of PSADT, increasing versus decreasing, is an accurate metric for the need of treatment. A direct comparison between PSADT kinetics and PSADT is needed.