tbuckley/cabot-search huggingface dataset:
LGG-10. AN UNUSUAL PRESENTATION OF BILATERAL OPTIC NERVE GLIOMA IN CROUZON SYNDROME
Authors: Brian Na, Anthony C Wang, Christopher Travis Watterson, Julian A Martinez-Agosto, Sulagna Saitta, Marina Dutra-Clarke, Franceska Hinkamp, Stacy L Pineles, Peter de Blank, Vivian Y Chang, Theodore Moore
Journal: Neuro-Oncology (2021)

Abstract Optic pathway gliomas (OPGs) are low grade gliomas intrinsic to the visual pathway, frequently associated with Neurofibromatosis Type 1 (NF-1). Bilateral OPGs without chiasmatic involvement are almost pathognomonic for NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month old male patient with craniosynostosis and Crouzon Syndrome, an autosomal dominant disorder caused by activating FGFR2 mutations associated with craniosynostosis and optic atrophy. The patient’s c.1032 G&amp;gt;A pathogenic variant in FGFR2 is a variant known to affect splicing and results in a protein that lacks part of an important domain involved in ligand binding. Although FGFR1 mutations have been implicated in low-grade glioma through MAPK activation, FGFR2 mutations have not yet been described in OPGs, although they have been described in epileptogenic low-grade gliomas and mixed neuronal-glial tumors. Our patient presented with worsening vision in the setting of known Crouzon Syndrome. An eye examination revealed bilateral primary optic atrophy. Brain and orbital MRIs demonstrated fusiform dilation and STIR hyperintensity of the intraorbital segments of the optic nerves bilaterally with normal pre-chiasmatic optic segments. There were no other radiographic or physical stigmata suggestive of NF-1. Next generation sequencing and copy number analysis from peripheral blood were negative for variants in NF1. RNA based studies for NF1 aberrations are pending. Although follow up MRI scans demonstrated stable size of his OPGs, the risk of further visual deficit was considered significant due to his pre-existing optic atrophy and poor baseline visual acuity. Therefore, he was started on vincristine and carboplatin chemotherapy according to A9952, and induction therapy has been well tolerated. To our knowledge, this is the first patient with Crouzon Syndrome who has developed bilateral optic pathway gliomas. Orbital MRIs should be considered for these patients with worsening visual acuity not explained by other causes.
Abstract 9538: A Novel Short Interfering Ribonucleic Acid Shows Potent and Sustained Reduction of Serum Lipoprotein (a) in Cynomolgus Monkeys
Authors: Manuela Aleku, Mona Eisermann, Kathrin Löffler, Sibylle Dames, Christian Frauendorf, Marie Wikstrom Lindholm, Steffen Schubert, David Rider
Journal: Circulation (2019)

Introduction: SLN360 is a liver targeted GalNAc-conjugated siRNA developed for the treatment of cardiovascular disorders associated with elevated Lp(a). Lp(a) is a key independent, genetically dete...
Comprehensive Anatomy of the Pericardial Space and the Cardiac Hilum
Authors: Shumpei Mori, Peter Hanna, Michael J. Dacey, Taro Temma, Joseph Hadaya, Ching Zhu, Grace Chang, Warwick J. Peacock, Michael C. Fishbein, Kalyanam Shivkumar
Journal: JACC. Cardiovascular imaging (2021)
Successful treatment of pulmonary lymphangitic carcinomatosis by anlotinib in 14 Chinese patients with advanced non-small cell lung cancer.
Authors: Shencun Fang, Wanwan Cheng, Yingming Zhang, Haitao Zhang, Si Li, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2021)

e21064 Background: Pulmonary lymphangitic carcinomatosis (PLC) occurs in 6%-8% of intrathoracic metastases among malignant tumor. The median survival was only 2.0 months from time of pulmonary symptoms to death in cases during 2000-2018, which is a poor prognosis. Effective interventions were needed besides standard chemotherapy and symptomatic support. Anlotinib showed a critical effect on lymphangiogenesis, and lymphatic metastasis in mouse models of lung adenocarcinoma, it might be a therapeutic option for tumor lymphatic metastasis. In this study, we retrospectively analyzed the efficacy and safety of anlotinib for PLC in patients with Non-small Cell Lung Cancer (NSCLC). Methods: We retrospectively investigated NSCLC patients with PLC at our hospital between May 2018 and November 2020, who received anlotinib monotherapy or combined therapy for PLC. Data were analyzed for progression-free survival (PFS), overall survival (OS), objective response rate(ORR), disease control rate(DCR) and adverse events (AE). The impact of clinical and genomic factors on PFS and OS were also assessed. Results: A total of 14 patients were enrolled with a median age of 64 years. 10(71.4%) were male, 4(28.6%) has smoking history, 10(71.4%) of patients had a performance status of 2-3. 9, 3, 2 patients had TP53 mutation, EGFR mutation, ALK fusion respectively. 9(64.3%) patients received anlotinib monotherapy. Of 14 patients, 8 achieved partial response (PR), 5 presented stable disease (SD), 1 had progressed disease. The ORR and DCR were 57.1% and 92.9% respectively. The median PFS was 3.1 months (95% CI: 2.0-4.2), the median OS for 1, 2, ≥3 line were 13 months, 7.2 months, 5.2 months, respectively. Median PFS and OS (≥3 line) were significantly longer for patients with TP53-mutant tumors compared with those with TP53–wild-type tumors (median PFS: 7 vs. 1.1 months, median OS (≥3 line): 6.8 vs. 1.9 months). No difference of PFS and OS (≥3 line) was found between EGFR or ALK alteration and the corresponding wild type patients. The most frequently reported AEs were high blood pressure (11, 78.6%), hand foot syndrome (6, 42.9%), diarrhea (5, 35.7%), fatigue (4, 28.6%), hoarseness (3, 21.4%), proteinuria (2, 14.3%) and stomatitis (2, 14.3%). Conclusions: Anlotinib presented favorable efficacy in patients with pulmonary lymphangitic carcinomatosis and conferred considerable survival benefit compared with previous studies, especially in patients harboring TP53 mutations. The AEs were manageable. These indicated that anlotinib can be a promising therapeutic treatment of PLC. More clinical data is needed to validate this finding.
Polatuzumab vedotin + obinutuzumab + venetoclax in patients with relapsed/refractory (R/R) follicular lymphoma (FL): Primary analysis of a phase 1b/2 trial.
Authors: Rajat Bannerji, Sam Yuen, Tycel Jovelle Phillips, Christopher Arthur, Iris Isufi, Paula Marlton, John Francis Seymour, Paolo Corradini, Annalia Molinari, Giuseppe Gritti, Robert Emmons, Jamie Hirata, Lisa Musick, Sourish Saha, Brandon Croft, Christopher Flowers
Journal: Journal of Clinical Oncology (2021)

7534 Background: Polatuzumab vedotin (Pola) + obinutuzumab (G) demonstrated activity and tolerability in a Phase 1b/2 trial of patients (pts) with R/R FL (Phillips, et al. Blood 2016). Preclinical studies with venetoclax (Ven) showed that concurrent treatment with Pola promotes MCL-1 degradation, a known mechanism of resistance to Ven, and enhances in vivo anti-tumor efficacy (Amin, et al. AACR 2020). Here, we report the primary safety/efficacy analysis with Pola-G-Ven in a Phase 1b/2 study of pts with R/R FL (GO29833; NCT02611323). Methods: Pts received induction treatment every 21 days (D) x six cycles (C) of: Pola 1.4–1.8mg/kg intravenously (IV) in dose escalation (DE) or recommended Phase 2 dose (RP2D) on D1; G 1000mg IV (C1: D1, D8, D15; C2–6: D1); and oral Ven 200–800mg (DE or RP2D; D1–21). Pts with complete response/partial response/stable disease (CR/PR/SD) at end of induction (EOI) received maintenance with G (1000mg on D1 every 2 months [mo] for 24 mo) and Ven (200–800mg daily) for 8 mo. Primary endpoints were safety/tolerability and positron emission tomography (PET)-CR rate at EOI by independent review committee (IRC) using modified Lugano criteria. Results: At the primary analysis (Oct 05, 2020), 74 pts were enrolled. Median pt age was 64 years (range 36–78); male (57%); Ann Arbor Stage III–IV (86%); FL International Prognostic Index high risk ≥3 (55%); bulky disease ≥7cm (16%); prior lines of therapy ≥2 (74%); refractory to: last prior therapy (51%), any prior anti-CD20 therapy (55%), both anti-CD20 therapy and an alkylating agent (double refractory; 55%). Grade 3–4 adverse events (AEs) were experienced by 73% of pts; most commonly, neutropenia (39%), thrombocytopenia (19%), and infections (16%; mainly pneumonia). AEs led to dose reduction in 38% and interruption in 68% of pts (mainly modifications to Ven). One fatal AE was reported (pneumonia). In total, 49 pts were treated at RP2D (Pola 1.8mg/kg + Ven 800mg) and were evaluable for efficacy. PET-CR rate at EOI by IRC was 57% (Table). With a median follow-up of 14.4 mo (range 8.2–28.4), the 12-mo progression-free survival (PFS) was 73% (95% confidence interval: 59.4–86.9). Median PFS was not reached. Conclusions: The safety profile of Pola-G-Ven is consistent with the known profiles of the individual drugs. Response rates at EOI with Pola-G-Ven are encouraging in this R/R FL patient population. Additional follow-up is needed to assess PFS benefit during maintenance treatment and beyond. Clinical trial information: NCT02611323. [Table: see text]
EMBR-22. RATIONAL DEVELOPMENT OF SYNERGISTIC THERAPIES ALONGSIDE BMI1 INHIBITION FOR GROUP 3 MEDULLOBLASTOMA
Authors: David Bakhshinyan, Ashley A Adile, Chitra Venugopal, Kevin Brown, Katherine Chan, Maleeha A Qazi, Chirayu Chokshi, William D Gwynne, David Tieu, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors targeting BMI1 have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscores the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of the tumors extracted from the brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways to be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. The combined treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and is currently being evaluated in preclinical studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.
REPLACEMENT trial in progress: Combination therapy with atezolizumab plus bevacizumab for TACE unsuitable patients with beyond up-to-seven criteria in intermediate stage hepatocellular carcinoma: A phase II study.
Authors: Kazuomi Ueshima, Masatoshi Kudo, Takeharu Yamanaka, Hiroshi Aikata, Tatsuya Yamashita, Masafumi Ikeda, Ryosuke Tateishi, Michihisa Moriguchi, Atsushi Hiraoka, Kaoru Tsuchiya, Sadahisa Ogasawara, Satoshi Mochida, Shiro Miyayama, Kiyoshi Hasegawa, Kenichi Yoshimura, Tetsuo Takehara
Journal: Journal of Clinical Oncology (2021)

TPS4162 Background: Transarterial chemoembolization (TACE) had been developed as a standard of care in patients with intermediate-stage HCC at a time when systemic therapy was not available. This stage includes a certain TACE-unsuitable subpopulation, such as beyond up-to-seven criteria. Recently, the American Association for the Study of Liver Diseases and Asia-Pacific Primary Liver Cancer Expert Meeting have recommended systemic therapy for those patients to achieve overall survival (OS) beyond 2 years without impaired liver function in their consensus guideline. However, there is not enough data on systemic therapy for this population. Atezolizumab (Atezo), anti-PD-L1 antibody, plus Bevacizumab (Bev), anti-VEGF antibody, combination therapy has been shown to significantly improve OS, progression-free survival (PFS), and overall response rate (ORR) against sorafenib, which is a standard of care in unresectable HCC according to a phase III randomized controlled trial, IMbrave150. Therefore, we investigate the efficacy and safety of Atezo+Bev combination therapy in patients with HCC beyond up-to-seven criteria in this trial. Methods: REPLACEMENT trial is a multicenter, single-arm phase II study of Atezo+Bev combination therapy. Key eligibility criteria are age ≥20 years, ECOG performance status 0-1, Child-Pugh A, no vascular invasion, no extrahepatic metastasis, beyond up-to-seven criteria, and patients who have received neither systemic therapy nor TACE. Patients will be administrated Atezo 1200 mg/body + Bev 15 mg/kg once every 3 weeks. The primary endpoint is PFS per modified RECIST (mRECIST). The secondary endpoints include PFS, ORR, duration of response (DOR) per mRECIST; PFS, ORR, DOR per RECIST ver.1.1; OS and safety including change of liver function based on albumin-bilirubin (ALBI) score until disease progression. A total of 60 events are necessary to investigate the hypothesis that a target point estimation of PFS rate at 6 months (null population: 55%, alternative population: 73%). The estimated sample size is, therefore, 70 patients. In addition, the results of the Atezo+Bev therapy in this arm will be compared with those in approximately 600 TACE treated consecutive patients with intermediate-stage HCC, using the propensity score matching method, as an exploratory analysis of a possible replacement of TACE by the Atezo+Bev therapy. Patients’ enrollment had already started in December 2020, and 12 patients were enrolled as of 16th February ’21. Clinical trial information: jRCTs071200051.
Warm up: Breaking Down Barriers
Authors: Paul Hunter, Carolyn A Emery, Christopher Napier
Journal: British Journal of Sports Medicine (2021)

Since the beginning of the COVID-19 pandemic, there have been a lot of words and phrases that have become part of the daily news such as ‘unprecedented’, ‘cohort’ and ‘the new normal’. We also hear people speaking about how they or their families are adapting to the change. Adaptation can be defined as a process of change or evolution that allows the individual or group to cope with a situation. In sports, we see athletes do this on a continual basis. The demands of training impose physical and mental stress on the body and mind so that there are adaptations, which make the athlete stronger and more resilient. This also happens at an organisational level. Every company, government, sporting organisation, athlete and individual has had to adapt to the new reality. The year 2020 was supposed to be a full year of in-person planning, sport conferences and credentialling exams—not to mention an Olympic Summer Games. Instead, as the world abruptly shut down, Sport Physiotherapy Canada (SPC) had to pivot rapidly. We did what …
Improved Disease Course Associated With Early Initiation of Biologics in Polyarticular Juvenile Idiopathic Arthritis: Trajectory Analysis of a Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans Study
Authors: Mei Sing Ong, Sarah Ringold, Yukiko Kimura, Laura E. Schanberg, George A. Tomlinson, Marc D. Natter
Journal: Arthritis & Rheumatology (2021)

To investigate the effects of early introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) on the disease course in untreated polyarticular juvenile idiopathic arthritis (JIA).
Overall and cardiac-specific mortality following serious cardiovascular events in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Wendy Bottinor, Cindy Im, Saro Armenian, Borah Hong, Rebecca M. Howell, Kirsten K. Ness, Kevin C. Oeffinger, Gregory T. Armstrong, Yutaka Yasui, Eric Jessen Chow
Journal: Journal of Clinical Oncology (2021)

12073 Background: The direct impact of a major cardiovascular (CV) event on mortality among childhood cancer survivors is not well described. We hypothesized that mortality following a major CV event would be higher among survivors compared with siblings and that mortality would be influenced by primary cancer treatment. Methods: The CCSS cohort has conducted longitudinal follow-up of 25,658 survivors of childhood cancer and 5,051 siblings. All-cause and CV-cause specific mortality after a first event of heart failure (HF), coronary artery disease (CAD), or stroke occurring at least 5 years after cancer diagnosis, was estimated using the Kaplan-Meier method. The relative hazards (HR) and 95% confidence intervals (CI) between survivors and siblings as well as the influence of demographic (sex, age, race/ethnicity) and cancer treatment factors were estimated via Cox regression. Results: In total, 1780 survivors and 91 siblings experienced a serious CV event. Total deaths included 706 survivors (271 cardiac causes, 381 non-cardiac causes, 54 unknown causes) and 14 siblings. Survivors were a median age of 31.5 years (range 6.5-61.5) and 20.0 years (range 5.0-44.6) since cancer diagnosis at time of CV event. After a CV event, estimated 10- and 20-y all-cause mortality was significantly higher among survivors than siblings (Table). The HR for all-cause mortality was significantly higher among survivors than siblings after HF (HR 5.2, CI 2.1-13.0), CAD (HR 4.2, CI 2.0-9.0), and stroke (HR 4.6, CI 1.5-14.6). HF and stroke-specific mortality were not significantly increased among survivors versus siblings, in contrast to CAD-specific mortality (HR 3.5, CI 1.1-11.0). Among survivors, heart dose from radiotherapy (per 10 Gy) was associated with increased all-cause and cause-specific mortality after HF (HR 1.2, CI 1.0-1.3; HR 1.3, CI 1.0-1.7), all-cause mortality after CAD (HR 1.2, CI 1.0-1.3), and cause-specific mortality after stroke (HR 2.5, CI 1.2-4.9). Brain dose from radiotherapy was associated with increased all-cause mortality (HR 1.1, CI, 1.0-1.2, per 10 Gy) after stroke. Anthracycline dose was not associated with increased overall or cause-specific mortality risk after a CV event. Conclusions: After a CV event, mortality is higher among survivors than siblings. In survivors, mortality is primarily driven by non-cardiac causes. CAD and prior radiotherapy exposure to the heart and brain also influenced mortality.[Table: see text]
A noninvasive gastric cancer Her2 test using surrogate methylation markers.
Authors: Xin Liu, Gengtai Ye, Chunhui Cui, Hui Li, Ting Yang, Xuetao Lei, Guofan Zhang, Boyang Zheng, Lang Xie, Xiaotian Lei, Chaorui Wu, Xinjian Song, Jiang Yu, Zhiwei Chen, Jianbing Fan
Journal: Journal of Clinical Oncology (2021)

e16084 Background: There are 10-20% of gastric cancer (GC) with overexpressed Her2. Her2 status remains an essential biomarker for guiding the trastuzumab (Herceptin) therapy, a monoclonal antibody approved for the first-line treatment of late-stage Her2-positive GC. Although IHC, together with FISH, is comprehensively applied to verify Her2 status on tissue samples, an accurate blood test is highly desirable due to the inaccessibility of tissue samples, especially in very late stage GC patients as well as tumor heterogeneity of tissue biopsy. Detecting copy number aberration of Her2 gene in cell-free DNA (cfDNA) gains a lot of interest for its non-invasive approach. However, the limited signal-to-noise ratio poses a great challenge for the accuracy and robustness of the tests (either targeted sequencing or ddPCR). Here, we report a non-invasive test for Her2 status verification based on novel surrogate DNA methylation markers. Methods: Genome-wide DNA methylation sequencing was performed in 30 Her2-negative (IHC 0/1+) and 44 Her2-positive (IHC 3+) tissue samples to identify Her2-overexpression-specific methylation markers. Then we analyzed the performance of these candidate markers using methylation-specific quantitative PCR (qMSP) in plasma samples collected from 102 GC patients before surgical treatment. A Her2-status diagnostic model was built and further validated in a multi-center, prospective cohort (n = 150). The concordance of Her2 status between GC plasma and matching tissue samples (IHC/FISH) was determined. Results: We first discovered 102 statistically significant methylation markers of Her2 status in tissue. Out of these candidate markers, a 3-marker diagnostic model was built and validated on plasma samples, which could discriminate Her2-positive from Her2-negative GC patients with high sensitivity (86.7%) and specificity (96.8%). The overall plasma-tissue concordance of this liquid biopsy test was 95.3%. Furthermore, the Her2-status test was able to classify Her2 2+ status (IHC) into either Her2-negative or Her2-positive status, which was confirmed by conventional FISH test. Conclusions: Overall, the cfDNA-based test is a novel, accurate and noninvasive approach for determining Her2 status in GC patients. The high concordance with IHC/FISH results of this blood test holds great promise as an auxiliary method for guiding Her2-targeted therapy in GC patients. A clinical trial is undergoing to validate this test in the phase-2 clinical trial of a Her2-targeted drug (for GC) in China.