tbuckley/cabot-search huggingface dataset:
Kathryn Ackerman #StraightShooter
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

Relax. Keep taking chances and work hard. It’s going to turn out great and nothing like you expect!

Depends on the day. Get up early with my husband at 04:30 so we can enjoy coffee together and have some quiet time. Check email. Workout. Help get the three kids up and ready, have breakfast fast with the family and get to work by 08:00 or 08:30. Or hit snooze multiple times, curse that I didn’t get it all done, kiss everyone goodbye and rush off to work!

Combining sports medicine and endocrinology and explaining it in a relatable way. I love studying issues related to sports endocrinology, but I really enjoy applying what I learn to patients to help them feel and perform better. I also try to be a knowledgeable and fun mentor to students and trainees, as I have had great mentors who truly inspired me.

I have a few.

Barbara Drinkwater, for her groundbreaking work on the Female Athlete Triad, her leadership, her sense of humour, her openness to ‘Relative Energy Deficiency in Sport (RED-S)’ as an expansion of the Triad concept in order to study more health and performance consequences and to help more athletes. Her guidance is practical, humble and humbling.

I am also a huge fan of my husband and many others who have not been afraid of honesty, trailblazing and standing up for the right thing.



Persistence.

I was working at the Boston Marathon in 2013. It was a tragic combination of sports and …
TCT-35 Impact of Cardiovascular Rehospitalizations Following PCI vs. CABG For Left Main Coronary Artery Disease: A Sex-Specific Analysis From the EXCEL Trial
Authors: Ioanna Kosmidou, Roxana Mehran, Patrick Serruys, Joseph Sabik, A. Pieter Kappetein, Ovidiu Dressler, Ori Ben-Yehuda, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Gemcitabine-cisplatin (GC) + necitumumab (N) versus GC as first-line treatment for stage IV squamous cell lung cancer (SqCLC): An open-label randomized multicenter phase Ib-II trial in Japan.
Authors: Hiroshige Yoshioka, Satoshi Watanabe, Hiroshi Sakai, Katsuyuki Hotta, Mitsuhiro Takenoyama, Kazuhiko Yamada, Shunichi Sugawara, Yuichi Takiguchi, Yukio Hosomi, Keisuke Tomii, Seiji Niho, Nobuyuki Yamamoto, Makoto Nishio, Yuichiro Ohe, Ami Kamada, Kazumi Suzukawa, Yukie Omori, Sotaro Enatsu, Kazuhiko Nakagawa, Tomohide Tamura
Journal: Journal of Clinical Oncology (2018)

9038 Background: A randomized global phase III trial (SQUIRE) demonstrated statistically significant improvement in OS and PFS for GC+N versus GC in patients (pts) with advanced SqCLC. Methods: Phase Ib part was a single arm (GC+N) study to determine the recommended dose for the phase II part. Phase II part was a randomized study and pts were assigned on a 1:1 basis to GC+N or GC (G, 1250 mg/m2 on Days 1 and 8 based on the result from the phase 1b part; C, 75 mg/m2 on Day 1 of maximum four 3-week cycles; N, 800 mg on Days 1 and 8 continued until PD). The primary endpoint of phase II part was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to treatment failure (TTF), health outcomes and safety. Results: Of 183 pts randomized, each 90 and 91 pts received GC+N or GC in the phase II part. Baseline patient characteristics were balanced between arms. The OS was prolonged in GC+N compared with GC (Hazard ratio (HR) = 0.656 [95% Confident Interval, CI = 0.465, 0.926]; p = 0.0161). The median OS was 14.9 months (mos) and 10.8 mos for GC+N and GC, respectively. The HR for PFS was 0.562 [0.406, 0.777]; p = 0.0004, and the median PFS was 4.2 mos and 4.0 mos for GC+N and GC, respectively. The ORR was 51.1% and 20.9%, respectively; the HR for TTF was 0.588 [0.433, 0.800]; p = 0.0006. The analysis of health outcomes assessed by the Lung Cancer Symptom Scale and the EuroQol-5D suggested that QOL was not negatively impacted by the addition of N. No deaths occurred on treatment. Grade ≥3 adverse events with GC+N that showed a > 5% increase over GC were neutrophil count decreased (42.2% vs. 35.2%), febrile neutropenia (12.2% vs. 3.3%), decreased appetite (11.1% vs. 4.4%) and dermatitis acneiform (5.6% vs. 0). The safety data obtained in the study were consistent with the safety profile expected for GC+N. Conclusions: The study demonstrates a clinically meaningful treatment benefit for GC+N in the first-line treatment of Japanese pts with stage IV SqCLC. GC+N was well tolerated. The totality of the efficacy data with the safety profile of N+GC demonstrates a favorable benefit-risk profile for this combination treatment. Clinical trial information: NCT01763788.
Ramucirumab (RAM) exposure-response (ER) relationship in RANGE, a randomized phase III trial of docetaxel (DOC) with or without RAM in advanced urothelial carcinoma (UC) patients (pts) who progressed on or after platinum therapy.
Authors: Ronald De Wit, Thomas Powles, Daniel E. Castellano, Andrea Necchi, Jae-Lyun Lee, Michiel Simon Van Der Heijden, Nobuaki Matsubara, Aristotelis Bamias, Aude Flechon, Cora N. Sternberg, Alexandra Drakaki, Evan Y. Yu, Oday Hamid, Annamaria Zimmermann, Ling Gao, Amanda Long, Richard A. Walgren, Katherine M. Bell-McGuinn, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2018)

4526 Background: RAM+DOC improved PFS & had acceptable safety in UC (Petrylak, et al Lancet, 2017). RAM ER relationships are reported. Methods: Pts received RAM (10 mg/kg) + DOC (75 mg/m2) or placebo (P) + DOC (Day 1 of a 21 day cycle) until discontinuation criteria were met. Evaluable pts (n = 161) were classed into high v low groups at the median observed RAM Cmin-1 (minimum concentration after first dose) or Cmin-1 quartiles (Q1 = lowest). Matched case controls (MCC) were based on UC prognostic factors. Cox regression was performed. Exposure (E)-safety data are descriptive. Results: Subgrouping by baseline prognostic factors indicated pts with 2-4 Bellmunt risk factors, ≥3 metastatic sites, < 10g/dL hgb or < 3.5g/dL albumin often achieved low Cmin-1. PFS did not differ between low Cmin-1 & P+DOC pts. High Cmin-1 pts had ↑ PFS v P+DOC pts in 5 (Table) of the 10 subgroups. From Cmin-1 Q1-4, ORRs were 10.9%%, 38.3%, 34.8% & 37.5%. In a MCC analysis, pts achieving higher E had ↑ PFS & ↓ HR (Table). From Q1-4, grade ≥3 neutropenia increased, but no clear trends were seen for the other grade ≥3 events- fatigue, hypertension and febrile neutropenia. Conclusions: Q1 pts had lower mPFS & ORR v Q2-4. The potential association between baseline risk factors & E achieved may confound ER analysis & warrants further exploration. Safety appears manageable across RAM E levels. Clinical trial information: NCT02426125. P+DOC High ObsCmin-1 N / # events Median, mo N / # events Median, mo HR P-value Pure Transitional Cell Histology 174 / 146 2.8 66 / 44 5.5 0.472 0.0075 Hemoglobin ≥10 g/dL 190 / 156 2.8 71 / 48 5.5 0.519 0.014 Primary site is Bladder 138 / 120 2.8 52 / 36 5.5 0.480 0.0163 Albumin > 3.5 g/dL 204 / 168 2.8 77 / 54 5.5 0.552 0.023 Liver metastases absent 166 / 132 2.9 59 / 38 5.6 0.534 0.021 PFS MCC Analysis P+DOC RAM+DOC HR(95% CI) P-value(Wald’s) N / #events Median, mo (range) N / #events Median,mo (range) Q1 40 / 34 2.3 (1.4, 2.8) 40 / 33 4.1 (1.9, 4.3) 0.782 (0.484, 1.265) 0.3166 Q2 40 / 33 2.8 (1.4, 4.3) 40 / 35 5.1 (2.3, 6.0) 0.754 (0.467, 1.218) 0.2487 Q3 40 / 33 2.7 (1.4, 4.3) 40 / 29 4.3 (3.0, 5.8) 0.567 (0.343, 0.936) 0.0266 Q4 41 / 34 2.9 (2.6, 5.3) 41 / 28 5.6 (4.0, 8.1) 0.591 (0.358, 0.976) 0.0399
Method for definition of CIS-TRANS status in double CEBPA mutations.
Authors: Miguel Mitne-Neto, Caroline Mônaco Moreira, Ana Maria Fraga
Journal: Journal of Clinical Oncology (2017)

e18511 Background: Acute myeloid leukemia (AML) is characterized by infiltration of blood and bone marrow by proliferative, clonal and abnormally differentiated hematopoietic cells, affecting 3 in 100.000 adults. CEBPA is a transcription factor and a biomarker for cytogenetically normal (CN) patients. Somatic CEBPA mutations occur in 10% of CN patients and recent studies have shown that a favorable outcome may only be obtained in those carrying CEBPA mutations in different alleles ( trans). The evaluation of double mutations and the definition of bi-allelic ( trans) versus mono-allelic ( cis) status applies long protocols, involving gene cloning and sequencing, which are challenging for the diagnostic routine and negatively impacts the turnaround time (TAT). The present study aimed the development of an alternate method for the identification of double mutations in CEBPA and its CIS- TRANScondition. Methods: A previously screened sample carrying double CEBPA mutations was selected and its DNA was extracted. This sample and a DNA control were quantified and diluted in order to obtain ½ DNA molecule per well for amplification, using digital PCR rationale. Samples were distributed in 40 wells of a 96 well plate. A pair of primers was used to amplify the entire CEBPA coding region in a Real-Time PCR using SYBR green-based detection in QuantStudio System. A subset of primers was used to amplify and to sequence the regions of interest. The entire process was repeated three times, in order to prove its reproducibility. Results: The above described dilution allowed an estimation that half of the wells had no DNA and half contained a single DNA molecule. An average of 18 wells presented amplification. Five of the positive wells were used as templates for a nested PCR followed by Sanger sequencing analysis. Since each mutation was identified as the result of distinct well amplification, we concluded that the mutations were in trans. Conclusions: Our results show that it is possible to determine the CIS- TRANS allelic configuration of CEBPA dual-mutation in a cost-effective process and with a short TAT, avoiding gene cloning systems. Additionally, the process is reproducible, can be easily implemented as a routine analysis and has a great impact for AML patients’ diagnosis.
Genomic profiling of early-onset metastatic Chinese colorectal cancer (mCRC) patients: The development of a PFS prediction model for first line treatments.
Authors: Xicheng Wang, Lin Shen, Jing Zhang, Lu Zhang, Xinru Mao, Ting Hou, Hao Liu, Han Han-Zhang, Jian Li, Jing Gao, Yanyan Li
Journal: Journal of Clinical Oncology (2018)

e15657 Background: The incidence of CRC is rising in early-onset patients despite a decline in overall incidence. In this study we interrogated the mutation spectrum of mCRC patients diagnosed before age 55 and established a model for predicting progression-free survival (PFS) for 1st line treatments, integrating both clinical and molecular features. Methods: Variables with p-values < 0.05 were entered into multivariate analyses using Cox stepwise regression model to select independent predictors as input. A final model was selected using a backward step-down process. Results: We performed targeted sequencing on 187 resected or biopsied tumor tissue samples and matched white blood cells of early onset mCRC patients using a panel consisting of 520 cancer-related genes. We identified 13.9% patients (26/187) with pathogenic germline mutations in cancer susceptibility genes. Comparing to TCGA data set, our cohort revealed a distinct mutation profile, reflected by significantly higher mutation frequencies in TP53, BRAF, RET, EP300 and a lower frequency in APC in patients with left-sided primaries. In patients with right-sided primaries, our cohort showed significantly higher frequencies in TP53, DOTIL and lower frequencies in APC, EP300, CREBBP and FBXW7. To predict the probability of 12-month and 18-month PFS of patients undergoing 1st line chemotherapy± biologic agents, we constructed a nomogram incorporating both clinical and molecular features, including T stage, tumor location, BRAF V600E, ARID1A, PIK3CG, the presence of germline pathogenic mutations and mutations affecting the proofreading domains of POLE /POLD1, achieving a C-index of 0.683. The predictive power drops to 0.62 if only stage and location, the two most commonly used predictors, are used as input. We confirmed the performance of our model by grouping patients into 3 subgroups based on total points obtained, and demonstrated significant difference in PFS (p < 0.01) independent of treatments. Conclusions: We revealed a distinctive genomic landscape for early onset Chinese mCRC patients and developed a PFS prediction model for patients undergoing 1st line treatments.
P05.56 Treatment algorithm of patients with primary CNS germinoma: the experience of N.N. Burdenko Neurosurgery Institute
Authors: G L Kobiakov, A A Poddubskiy, D I Pitskhelauri, N A Mazerkina, L I Ataf’eva, O V Absalyamova, Y Y Trunin, N K Serova, N N Grigoryeva, M V Ryzhova, L V Shishkina, P L Kalinin, I V Chernov, K S Lodygina
Journal: Neuro-Oncology (2018)

To evaluate the efficacy and outcomes of the complex treatment of primary CNS germinoma in patients in non-child population, evaluate the dynamic of the ophthalmological and endocrine functions. The retrospective analysis of 91 patients aged above 16 years with histologically verified primary CNS germinoma was performed. All patients underwent biopsy or surgery with subsequent shunting operation, if indicated. From 2 to 6 cycles (mainly 4 cycles, in 81 cases) of cisplatin and etoposide regimens combination was applied. After chemotherapy all patients underwent either whole ventricular (70 cases) or whole brain (19 cases) or craniospinal irradiation (2 cases) with 24 Gy in 12 fractions. The endocrine status of patients before and after treatment was evaluated in 44 cases. The dynamic of ophthalmological deficit was followed in 31 cases. Endocrine status at different stages of treatment was followed in 74 cases. All patients, who underwent combined treatment with chemotherapy and irradiation achieved a complete remission. Median follow-up time was 48 months (1–196 months). 5-year overall survival and progression-free survival rates were 96 and 92 % respectively. 7 patents out of 91 had a relapse within first 5 years of follow-up. The visual disturbances improved in 35%, oculomotor function improved in 5% of patients. Endocrine status improved in 20% of patients with initial deficit. Complex treatment of primary CNS germinoma, utilizing 4 cycles of cisplatin + etoposide regimen with subsequent 24 Gy whole ventricular or whole brain irradiation prove to be a good option, alternating craniospinal irradiation alone. Use of this regimen may preserve and improve the endocrine and ophthalmological deficit.
Abstract 12066: TIMP3 and CHADL Mutations Are Common in Turner Syndrome Aortopathy
Authors: Michael Silberbach, Holly Corbitt, Diedre Krupp, Brian O’Roak, Cheryl Maslen
Journal: Circulation (2016)

Introduction: Turner syndrome (TS) is caused by the loss of the second sex chromosome, which occurs in approximately 1 in 2,000 female births. TS alone is an independent risk factor for aortic enlargement. 25 to 50% of those with TS also have a bicuspid aortic valve (BAV) which is present in most who have aortic dissection and rupture. Methods: We used whole exome sequencing to study the genes of 188 TS subjects with BAV (88 cases) or normal aortic valves (100 controls). Aorta diameters as markers of aortopathy severity converted into Z-scores were utilized as covariates with BAV status, and as a sole predictor of genetic variation. Enlarged aorta was defined as an ascending aorta Z-score &gt; 2. Statistical analyses employed a kernel gene-based method, SKAT-O. Results: TS girls and women with BAV had significantly higher ascending aortic Z-scores than those without BAV (1.95 ± 1.97 vs 0.55 ± 1.01, t-test p= 1.6 x 10 -5 ).Mutations in TIMP3 and CHADL achieved exome-wide significance for association with BAV/aortic dilatation (p=1.6x10 -6 and 1.1x10 -6 , respectively). TIMP3 significance increased when aortic root Z-scores were included as a continuous covariant with BAV status (p=2.3x10 -7 ). Overall, 30.7% of those with aortic dilatation had mutations predicted by CADD scores to be deleterious in TIMP3 (8 individuals), CHADL (4 individuals), or both (4 individuals). Those with mutations in both genes were more likely to have enlarged aortas than those with 1 or none (chi-squared p=2.8x10 -3 ). Discussion and conclusions: BAV is known to be associated with aortopathy in TS. We found that TIMP3 and CHADL mutations occur commonly with those findings . TIMP3 is an inhibitor of several aortic matrix metalloproteinases, a group of peptidases that degrade extracellular matrix (ECM). CHADL is a collagen binding protein that regulates collagen fiber formation. Collagens are necessary for aortic structural integrity. We hypothesize that mutations in TIMP3 and CHADL disrupt the critical balance between ECM creation and degradation, thereby compromising aortic strength. There appears to be a synergy between TIMP3 and CHADL functions that may be involved in both BAV development and aortopathy. Both TIMP3 and CHADL may serve as biomarkers and pharmacologic targets for aortic disease in TS.
Facilitating rapid precision oncology in anaplastic thyroid cancer: Clinical implications of next generation sequencing (NGS) mutation testing and impact on survival.
Authors: Jennifer Rui Wang, Gilbert J Cote, Mark Zafereo, Priyanka C. Iyer, Ramona Dadu, Naifa Lamki Busaidy, Neil D. Gross, Erich M. Sturgis, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Jeffrey Myers, Stephen Yenzen Lai, Michelle D. Williams, Maria E. Cabanillas
Journal: Journal of Clinical Oncology (2018)

6023 Background: Anaplastic thyroid cancer (ATC) is a rare malignancy characterized by rapid progression and median overall survival (OS) of less than 6 months. With the goal of improving ATC outcomes, a multi-disciplinary program (“FAST”) was developed at our institution, which provides rapid access to care, mutation testing, and personalized treatment. The objective of this study was to examine whether results of mutation testing are associated with OS in ATC patients. Methods: ATC patients seen between 2012-2017 at our institution who had adequate tumor samples for NGS testing were included. DNA was extracted from pre-treatment core biopsies or surgical specimens of primary ATC. Targeted mutation testing was performed using NGS platforms for 46-158 genes. Cox proportional hazards models were used to assess the associations between mutation status and OS. Results: A total of 101 pts were included (median age: 65.7 years, 55.5% male). 84% presented with T4b disease. 50% were M1 at presentation. Median OS at 1 and 2 years was 52% and 29%. The most common mutations detected were p53 (54%), BRAFV600E (50%), RAS (21%), PIK3CA (23%), and CDKN2A (7%). RAS and BRAFV600E mutations were mutually exclusive. In univariate analysis, BRAFV600E was associated with better OS (HR 0.59, 95% CI 0.35-0.98, p = 0.043) while RAS mutation was associated with worse OS (HR 3.41, 95% CI 1.94-5.99, p < 0.001). P53 mutation was not significantly associated with OS. After adjustment for additional clinical variables, RAS mutation was most significantly associated with OS (adjusted HR 3.03, 95% CI 1.45-6.33, p = 0.03). Twenty-four of 51 (47%) BRAFV600E+ pts were treated with a BRAF inhibitor. In BRAFV600E+ patients, BRAF inhibitor treatment was significantly associated with improved OS at 1 year (HR 0.25, 95% CI 0.08-0.78, p = 0.018). Conclusions: This is the largest study of mutation status and survival outcome in ATC to date. BRAFV600E and RAS are mutually exclusive drivers that impact prognosis in ATC. Mutation analysis at diagnosis offer prognostic evaluation and may lead to improvement in outcome by facilitating treatment with targeted therapies and enrollment in clinical trials.
MORPHEUS: A phase Ib/II multi-trial platform evaluating the safety and efficacy of cancer immunotherapy (CIT)-based combinations in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Melissa Lynne Johnson, Benjamin J. Solomon, Mark M. Awad, Byoung Chul Cho, Justin F. Gainor, Sarah B. Goldberg, Bhumsuk Keam, Dae Ho Lee, Chen Huang, Hans-Joachim Helms, Hila Barak, Marcella Fasso, Conrad Bleul, Edward Cha, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2018)

TPS9105 Background: CIT has demonstrated a significant survival benefit in multiple cancers. Despite this, only subsets of pts experience durable response with CIT monotherapy. Thus, CIT combinations may be needed to address the mechanisms that allow cancers to escape anti-tumor immunity. However, a large number of potential combinations would have to be tested in order to identify an effective CIT combination. The MORPHEUS platform consists of multiple, global, open-label, randomized, Phase Ib/II trials designed to assess the impact of CIT combinations in pts with different tumor types. The randomized trial designs allow comparison of a single control arm vs multiple CIT combination arms. These trials will aid development of CIT combinations by identifying early signals and will have the flexibility to open new treatment (Tx) arms with novel CIT combinations and to close arms that show minimal clinical activity or unacceptable toxicity. Various CIT combinations that simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells for elimination will be evaluated. Here we describe a MORPHEUS Phase Ib/II trial in pts with metastatic NSCLC, a population likely to benefit from CIT-based combinations. Methods: MORPHEUS-Lung (NCT03337698) will enroll 2 cohorts (C): C1 will enroll pts who are Tx naive for metastatic NSCLC and have high tumor PD-L1 expression (TPS ≥ 50% per Dako 22C3 or VENTANA SP263); C2 will enroll pts who have progressed on prior platinum and anti–PD-L1/PD-1 Tx given concurrently or sequentially, regardless of tumor PD-L1 expression levels. Pts with non-squamous and squamous NSCLC will be included; those with an EGFR mutation or ALK gene rearrangement will be excluded. Pts will be randomized to the control arm or one of several experimental arms (2 for C1; 5 for C2). Pts experiencing loss of clinical benefit or unacceptable toxicity may be eligible to switch to a different CIT combination arm. Safety measures and investigator-assessed ORR (RECIST v1.1) are primary endpoints. PFS, OS, DCR and DOR are among the secondary endpoints. Exploratory biomarkers will also be examined. Clinical trial information: NCT03337698.