tbuckley/cabot-search huggingface dataset:
EPCT-10. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS
Authors: Sameer Farouk Sait, Stephen Gilheeney, Tejus Bale, Marc Rosenblum, Sofia Haque, Katarzyna Ibanez, Marc Dinkin, Stephanie Vitolano, Ira Dunkel, Matthias Karajannis
Journal: Neuro-Oncology (2021)

Abstract Background Oncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study. Methods Five children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior therapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks. RESULTS All AEs were grade 1–2. Most common treatment-related adverse events were hyperphosphatemia, ALT increased and hypoalbuminemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687E) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Molecular characterization of recurrent tumor from this patient demonstrated an NF1 deletion as a novel molecular mechanism of acquired resistance to FGFR inhibition. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (24 months and ongoing). Conclusions Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Specific attention to growth velocity and clinical symptoms with incorporation of imaging assessment of bone growth is warranted. Candidate biomarkers (FGFR1 V592M and K687E SNVs, FGFR-TACC fusions) may guide patient selection. Further studies in this population are warranted.
Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury
Authors: Min Xie, Geoffrey W. Cho, Yongli Kong, Dan L. Li, Francisco Altamirano, Xiang Luo, Cyndi R. Morales, Nan Jiang, Gabriele G. Schiattarella, Herman I. May, Jessica Medina, John M. Shelton, Anwarul Ferdous, Thomas G. Gillette, Joseph A. Hill
Journal: Circulation Research (2021)

Rationale: Reperfusion injury accounts for up to half of myocardial infarct size, and meaningful clinical therapies targeting it do not exist. We have reported previously that autophagy is reduced during reperfusion and that HDAC (histone deacetylase) inhibition enhances cardiomyocyte autophagy and blunts ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, whether inducing autophagy per se, as opposed to other effects triggered by HDAC inhibition, is sufficient to protect against reperfusion injury is not clear. Objective: We set out to test whether augmentation of autophagy using a specific autophagy-inducing peptide, TB (Tat-Beclin), protects the myocardium through reduction of reactive oxygen species (ROS) during reperfusion injury. Methods and Results: Eight- to 12-week-old, WT (wild type) C57BL6 mice and tamoxifen-inducible cardiomyocyte-specific ATG7 KO (ATG7 knockout) mice (to test the dependency on autophagy) were randomized into 2 groups: exposed to a control TS (Tat-scrambled) peptide or a TB peptide. Each group was subjected to I/R surgery (45-minute coronary ligation, 24-hour reperfusion). Infarct size, systolic function, autophagic flux, and ROS were assayed. Cultured neonatal rat ventricular myocytes were exposed to TB during simulated I/R injury. ATG7 knockdown by small interfering RNA in neonatal rat ventricular myocytes was used to evaluate the role of autophagy. TB treatment at reperfusion reduced infarct size by 20% (absolute reduction; 50% relative reduction) and improved contractile function. Improvement correlated with increased autophagic flux in the border zone with less oxidative stress. ATG7 KO mice did not manifest TB-promoted cardioprotection during I/R. In neonatal rat ventricular myocytes subjected to I/R, TB reduced cell death by 41% and reduced I/R-induced ROS generation. Conversely, ATG7 knockdown in neonatal rat ventricular myocytes abolished these beneficial effects of TB on cell death and ROS reduction. Conclusions: Induction of autophagy at the time of reperfusion is sufficient to mitigate myocardial reperfusion injury by reducing ROS and cell death. Maintenance of appropriate autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in acute myocardial infarction.
A national study of allogeneic stem cell transplantation for adults with acute myeloid leukemia: Do gender and age above 70 years matter?
Authors: Josephine Emole, Leyla Shune, Oleksandra Lupak, Ajoy Lawrence Dias
Journal: Journal of Clinical Oncology (2021)

e19020 Background: Allogeneic stem cell transplantation (alloSCT) is increasingly being offered to older patients with acute myeloid leukemia (AML) due to availability of reduced-intensity conditioning regimens and better supportive care. Though studies have shown improving alloSCT survival outcomes in older age groups, it is still not known if older age confers higher mortality and morbidity during transplant hospitalization. We queried a national inpatient database to evaluate in-hospital mortality and resource utilization during alloSCT for AML in patients &gt;70 years compared to a younger age group. Methods: We conducted a retrospective study of alloSCT for AML patients ≥ 18 years using the 2018 National Inpatient Sample database. Hospitalizations were selected using International Classification of Disease, tenth revision (ICD-10) codes. Demographics, comorbidities, transplant, and outcome variables were compared between a reference age group (18-70 years) and a comparator group (&gt; 70 years). Study outcomes were in-hospital mortality, length of stay (LOS) and transplant complications. Regression models were fit to assess the association between predictors and outcomes. Results: During the study period, 2610 alloSCT met the inclusion criteria. This cohort consisted of 50% males and 77% Caucasians. Only 7% of these alloSCT were performed for patients &gt; 70 years. Patients &gt;70 yrs had a lower proportion of females compared to the reference age group (32% versus 52%, p&lt;0.01). There were no significant differences in racial distribution, Charlson comorbidity index or median income between the 2 age groups. In-hospital mortality rates for the reference age group versus &gt;70 years were 3% and 5% respectively (p=0.35). In a multivariable model, we found no association between age &gt;70 years and in-hospital transplant mortality. Acute graft versus host disease was more frequent among the reference age group (14% versus 2%, p=0.04), but there were no differences in LOS or rates of graft failure, respiratory failure, sepsis, and acute renal failure between the 2 groups. Conclusions: Despite similar in-hospital transplant outcomes as their younger counterparts, patients &gt;70 years comprised only a small proportion of alloSCT performed for AML in our study. Females were more disproportionately affected by this age disparity. More studies are necessary to identify barriers to alloSCT for older AML patients, more so for older females.
A phase II randomized controlled trial of exercise on biochemical progression in men with prostate cancer on active surveillance.
Authors: Dong-Woo Kang, Adrian S. Fairey, Normand G. Boulé, Catherine J. Field, Stephanie A. Wharton, Kerry S. Courneya
Journal: Journal of Clinical Oncology (2021)

5080 Background: Men with prostate cancer (PCa) undergoing active surveillance (AS) are at increased risks of cardiovascular death and disease progression. Any intervention that can address these issues during AS would be highly beneficial. Clinical and preclinical studies have demonstrated the benefits of exercise to improve cardiovascular health in cancer patients and suggested the potential role of exercise in suppressing PCa progression in men with PCa undergoing AS. Therefore, the purpose of this study was to investigate the effects of exercise on cardiorespiratory fitness and biochemical progress of PCa in men with PCa on AS. Methods: The Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial was a single-centre, two-armed, randomized controlled trial in Edmonton, Canada. 52 men with localized PCa who were undergoing AS were randomized to high-intensity interval training (HIIT; n = 26) or usual care (UC; n = 26). The HIIT group performed thrice-weekly, supervised, aerobic HIIT on a treadmill at 85-95% of peak cardiorespiratory fitness (VO 2peak ) for 12 weeks. The primary outcome was VO 2peak , and the secondary and exploratory outcomes included biochemical progression of PCa (prostate-specific antigen [PSA]), PSA kinetics, and growth of prostate cancer cell line LNCaP. Results: 46/52 participants (88%) completed the postintervention VO 2peak assessment and adherence to HIIT was 96%. Compared to UC, HIIT significantly improved VO 2peak (adjusted between-group mean difference, 1.6 ml·kg -1 ·min -1 ; 95% confidence interval [CI], 0.3 to 2.9; p= 0.014). HIIT also significantly reduced PSA level (adjusted between-group mean difference, -1.1 ug/L; 95% CI, -2.1 to 0.0; p= 0.043) and PSA velocity ( p= 0.040), and suppressed LNCaP cell growth ( p =0.024). No significant differences were found in PSA doubling time ( p= 0.10) and testosterone ( p= 0.24). Conclusions: The ERASE Trial is the first randomized controlled trial to demonstrate the impact of HIIT exercise for improving physical fitness and inhibiting biochemical progression of PCa in men with localized PCa on AS. Our findings suggest that supervised aerobic HIIT may be a promising intervention in this clinical setting. Larger-scale randomized controlled trials are warranted to determine if improvements in physical fitness and PCa-related markers translate into improved long-term clinical outcomes in these men such as disease progression, receipt of radical treatments, posttreatment complications, and survival. Clinical trial information: NCT03203460.
Molecular magnetic resonance imaging of Alpha-v-Beta-3 integrin expression in tumors with ultrasound microbubbles
Authors: Vertika Pathak, Teresa Nolte, Elena Rama, Anne Rix, Seyed Mohammadali Dadfar, Vera Paefgen, Srinivas Banala, Eva Miriam Buhl, Marek Weiler, Volkmar Schulz, Twan Lammers, Fabian Kiessling
Journal: Biomaterials (2021)
Association of alterations in DNA damage repair and Notch pathways with high tumor mutational burden in patients with cervical cancer.
Authors: Dongling Zou, Zirong Li, Jing Liu, Yunong Gao, Hong Zheng, Mingming Yuan, Haixia Wang, Li Yuan, Dong Wang, Jingshu Liu, Rongrong Chen, Xuefeng Xia, Qi Zhou
Journal: Journal of Clinical Oncology (2021)

e17511 Background: The outstanding efficacy of pembrolizumab reported in study KEYNOTE-158 led to FDA approval of pembrolizumab in the treatment of patients (pts) with positive PD-L1 expression (CPS ≥1) cervical cancer (CC) and tumor mutational burden-high [TMB-H, ≥10 mutations/megabase (mut/Mb)] solid tumors including CC. This study aims to investigate the immunotherapy-related molecular characteristics in pts with CC. Methods: The study recruited pts with CC whose tissues were send to perform parallel hybridization-based next-generation sequencing and/or immunohistochemistry of PD-L1 with 22C3 assay. KEGG pathway enrichment analysis was conducted to explore whether the differentiated mutated genes (DMGs) that were more frequently mutated in the TMB-H cohort were enriched in certain pathways. In addition, pair-wise comparison of TMB and PD-L1 was analyzed to identify the proportion of pts who might benefit from immunotherapy. Results: Among 249 pts with TMB evaluated, median TMB was 5 muts/Mb (range: 0 - 58.56 muts/Mb). The prevalence of microsatellite instability was 1.2% (3/255). The threshold of TMB was defined as 10 muts/Mb according to KEYNOTE-158. Consequently, 47 pts were considered as TMB-H and 202 pts were TMB-L. Regardless that TERC amplification was only found in the TMB-L group (9.5%, 19/202), Fisher’s exact test identified 98 genes with significantly higher alteration frequency in the TMB-H group compared with TMB-L group, including MLL2/3, TERT, PIK3CA, LRP1B, EP300 and ARID1A. Pathway enrichment analysis suggested that these DMGs were mainly enriched in mismatch repair, Notch, homologous recombination and Fanconi anemia pathways. There was no evident correlation between TMB and MSI (spearman r=0.2401, p=0.0101). The positivity rate of TMB or PD-L1 was 71.9%. Conclusions: Mutations in DNA damage repair and Notch pathways may explain TMB-H in pts with CC who might may serve as surrogate markers for TMB in CC.
SARS-CoV-2 antigen testing: weighing the false positives against the costs of failing to control transmission
Authors: Elizabeth Fearon, Iain E Buchan, Rajenki Das, Emma L Davis, Martyn Fyles, Ian Hall, T Deirdre Hollingsworth, Thomas House, Caroline Jay, Graham F Medley, Lorenzo Pellis, Billy J Quilty, Miguel E P Silva, Helena B Stage, Tom Wingfield
Journal: The Lancet Respiratory Medicine (2021)
GERM-02. MANAGEMENT STRATEGY FOR CHEMO-REFRACTORY, PROGRESSIVE PEDIATRIC IMMATURE TERATOMA
Authors: Sarah McNutt, Nidhi Shah, Elias Rizk
Journal: Neuro-Oncology (2021)

Abstract Background Localized NGGCT, a heterogeneous entity, treated with chemo-radiotherapy harbors an overall survival of around 93% based. Here, we present a case of a child whose immature teratoma progressed on chemotherapy, while tumor markers remain within normal range. Salvage therapy for progressive immature teratoma is variable, and can include surgery, chemotherapy and/or craniospinal radiation. Case: 10 year old boy with precocious puberty presented to the local Emergency room with tonic-clonic seizures. Imaging showed a localized pineal mass, with mixed cystic and solid components. Biopsy results were diagnostic for mixed germ cell tumor with components of immature teratoma. Prior to the start of chemotherapy, serum and cerebrospinal fluid (CSF) tumor markers showed slight elevation of both alpha feto- protein (AFP) and beta-human chorionic gonadotropin hormone (β-HCG). The patient underwent two cycles of chemotherapy per ACNS1123, stratum 1, with normalization of tumor markers. Unfortunately, near the end of Cycle 2 of chemotherapy, patient presented with clinical signs of herniation, and was noted to have significant progression of pineal mass on imaging. Tumor was gross totally resected, with pathology conclusive for only immature teratoma. Pre- and post-operative tumor markers remained normal. Proton-beam craniospinal radiation was then administered. Patient is now almost 6 months off therapy, with unremarkable serum and CSF tumor markers, as well as serial imaging that remains negative for disease, with neurological development appropriate for age. Conclusion This case highlights the unusual nature of progression of an immature teratoma with no elevation of tumor markers while on chemotherapy. While salvage chemotherapy, in the form of a metronomic regimen or high-dose consolidative regimen, can be considered, these do present quite a bit of short-term and long-term toxicity to the growing child. Craniospinal irradiation followed by close monitoring is a reasonable alternative, with less short-term toxicity, for an entity that is radio-sensitive.
Troubleshooting CardioMEMS After Implant—Failure to Read
Authors: Ersilia M. DeFilippis, Ajay J. Kirtane, Kelly Axsom
Journal: JAMA Cardiology (2021)

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LGG-08. TREATMENT OUTCOMES AND TOLERABILITY OF TRAMETINIB IN PROGRESSIVE CIRCUMSCRIBED LOW-GRADE GLIOMAS
Authors: Emily Hanzlik, Bridget Archambault, Mays Dairi, Kristin Schroeder, Mallika Patel, Eric S Lipp, Song Boucree, Katherine Peters, David Ashley, Daniel Landi
Journal: Neuro-Oncology (2021)

Abstract Circumscribed low-grade gliomas comprise roughly one-third of pediatric CNS tumors. Most of these tumors are caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Drugs targeting the MAPK pathway are effective in other cancers and are being utilized in low-grade gliomas. We describe treatment outcomes and toxicities in a series of thirteen low-grade glioma patients treated with trametinib. We performed a retrospective chart review to evaluate response on T2/FLAIR MRI images per updated RANO criteria, visual outcomes, tolerability, and durability of response in progressive low-grade glioma patients treated with trametinib. Thirteen patients age 22 months to 34 years were included. Best radiographic response on therapy included 2/13 partial response, 3/13 minimal response, 5/13 stable disease, and 3/13 progressive disease. Diagnoses included pilocytic astrocytoma (n=6), desmoplastic infantile ganglioglioma (DIG; n=1), and low-grade glial neoplasms (n=2). Molecular drivers included BRAF:KIAA1549 fusion (n=3), V600E mutation (n=1), and somatic NF1 mutation (n=1). Three patients had germline NF1. In patients with partial or minimal response, best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 12 months on therapy. Five patients completed prescribed therapy. Three patients remain stable off therapy at 6, 12, and 21 months; two patients recurred at 1 and 10 months off therapy. Skin manifestations were the predominant form of toxicity. This was more severe in older males, and symptoms improved with intermittent dosing. All patients with optic pathway tumors showed at least stable vision throughout treatment, with some patients having dramatic improvement. Trametinib is effective and well-tolerated in patients with low-grade glioma. Dermatologic toxicity can be mitigated by intermittent dosing. Best responses tended to occur later in therapy, sometimes after relatively stable MRIs. Patients with optic pathway lesions showed stable to improved vision even in the absence of significant radiographic response.
心臓再同期療法に対する応答者の予測における心エコー検査の役割 日本心臓再同期療法レジストリ試験(J-CRT)の結果
Authors: Seo Yoshihiro, Ito Hiroshi, Nakatani Satoshi, Takami Mitsuaki, Naito Shigeto, Shiga Tsuyoshi, Ando Kenji, Wakayama Yuji, Aonuma Kazutaka
Journal: Circulation (2011)
Association of increased intensity of prostate-specific antigen screening in younger African American men with improved prostate cancer outcomes.
Authors: Edmund Qiao, Nikhil V. Kotha, Vinit Nalawade, Alexander Qian, Rohith S. Voora, Tyler J. Nelson, Tyler F. Stewart, John Kellogg Parsons, Brent S. Rose
Journal: Journal of Clinical Oncology (2021)

5004 Background: African-American (AA) men are substantially more likely to present with lethal prostate cancer (PCa) at younger ages than non-Hispanic White men. Despite this disparity, AA men are poorly represented in the prostate-specific antigen (PSA) screening studies on which evidence-based PCa screening guidelines are based. This limits proper PSA screening guidance for AA men, especially for those younger than 55. We examined associations of PSA screening intensity with disease severity at diagnosis and prostate cancer-specific mortality (PCSM) in AA men &lt; 55 years of age. Methods: The earliest recommended age to begin discussion of PSA screening is 40 years. We identified AA men aged 40-55 years, diagnosed with PCa from 2004 to 2017 within the Veterans Health Administration. PSA screening was identified using procedural codes. Screening intensity was defined as percentage of years screened within the pre-diagnostic observation period. This included up to 5 years prior to diagnosis. Multivariable logistic regression assessed the influence of PSA screening intensity on metastatic disease at diagnosis. Lead-time correction using published screening-dependent lead times was performed. PCSM was evaluated using Fine-Gray regression and non-cancer death as a competing event. Additional analysis was performed stratifying PSA screening into ‘High’ and ‘Low’ groups centered on the mean. Results: The cohort included 4,654 AA men at a mean age of 51.8 years with mean PSA screening rate of 53.2%. The pre-diagnostic observation period ranged from 1 to 5 years (median = 5 years). Median follow-up was 7 years. At diagnosis, there was a higher prevalence of Gleason sum ≥ 8 (Grade Group ≥ 4) and metastatic disease in the ‘Low’ group compared with the ‘High’ group ([Gleason sum ≥ 8 (Grade Group ≥ 4)]: 18.6% vs. 14.4%, p &lt; 0.01; Metastatic disease at diagnosis: 3.7% vs. 1.4%, p &lt; 0.01). Increased PSA screening intensity was associated with significantly reduced odds of metastatic disease at diagnosis (odds ratio: 0.61, 95% confidence interval (CI) = [0.47-0.81], p &lt; 0.01) and decreased risk of PCSM (sub-distribution hazard ratio: 0.75, 95% CI = [0.59-0.95], p = 0.02). Conclusions: In this large national cohort of AA men aged 40 to 55 years, PSA screening increased intensity was associated with decreased risk of lethal disease and metastases at time of diagnosis and decreased PCSM. These data support the hypothesis that PSA screening and early prostate cancer detection may improve outcomes in younger AA men.
Smoking History as a Potential Predictor of Immune Checkpoint Inhibitor Efficacy in Metastatic Non-Small Cell Lung Cancer
Authors: Xinan Wang, Biagio Ricciuti, Joao V Alessi, Tom Nguyen, Mark M Awad, Xihong Lin, Bruce E Johnson, David C Christiani
Journal: JNCI Journal of the National Cancer Institute (2021)

Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive.