tbuckley/cabot-search huggingface dataset:
Deleterious effect of baseline steroids on efficacy of PD-(L)1 blockade in patients with NSCLC.
Authors: Kathryn Cecilia Arbour, Laura Mezquita, Niamh Long, Hira Rizvi, Edouard Auclin, Ai Ni, Gala Martinez Bernal, Jamie E. Chaft, Roberto Ferrara, Wei-Chu Victoria Lai, Lizza Hendriks, Joshua K. Sabari, Caroline Caramella, Andrew J. Plodkowski, Darragh Halpenny, David Planchard, Gregory J. Riely, Benjamin Besse, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2018)

9003 Background: Treatment with PD-(L)1 inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of steroids may reduce efficacy of PD-(L)1 blockade. On-treatment steroids for treatment of irAEs do not appear to affect efficacy, but the potential impact of baseline steroids at time of treatment initiation is unknown. Clinical trials typically excluded patients receiving baseline corticosteroids leading us to use real-world data to examine the effect of steroids at treatment initiation. Methods: We identified 640 PD-(L)1 naïve patients with advanced NSCLC from two institutions (Memorial Sloan Kettering Cancer Center [MSKCC] and Gustave Roussy Cancer Center [GRCC]) treated with single agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify IV or PO steroid use at the time of beginning PD-(L)1 and stratified into two groups: ≥10mg qd prednisone equivalents vs < 10mg/no steroids on Day 1 of PD-(L)1 therapy. Response was evaluated according to RECIST 1.1. Progression free survival (PFS) and overall survival (OS) comparisons were made using log-rank test. Multivariate analyses were performed using Cox proportional hazards model and logistic regression. Results: 14% (90/640) received ≥10mg/qd steroids at the start of PD-(L)1 blockade. Common indications for steroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts (MSKCC and GRCC), baseline steroids were associated with decreased ORR, PFS, and OS with PD-(L)1 blockade (Table). In the pooled population, after adjusting for smoking history, performance status, and history of brain metastases, baseline steroids remained significantly associated with decreased ORR (p = 0.05), PFS (p = 0.03), and OS (p < 0.001). Conclusions: Baseline steroid use of ≥10mg of prednisone was associated with poorer outcome in NSCLC patients treated with PD-(L)1 blockade. Prudent use of steroids at the time of initiating PD-(L)1 blockade is recommended. Institution Progression Free Survival Overall Survival Best Overall Response HR p-value HR p-value +steroids No/low steroids p-value MSKCC 1.9 < 0.01 2.7 < 0.01 6% 19% 0.02 GRCC 1.6 0.04 2.5 < 0.01 8% 18% 0.2
Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of 47 patients.
Authors: Donato Callegaro Filho, Alpa Manchandia Nick, Mark F. Munsell, Pedro T Ramirez, David Marc Gershenson, Andrea S. Dickens, Dina Patel, Patricia J. Eifel, Elizabeth D. Euscher, Kathleen M. Schmeler
Journal: Journal of Clinical Oncology (2015)

e16541 Background: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare disease with fewer than 300 reported cases. Recent studies have shown association with a mutation in the SMARCA4 gene. However, management of this disease remains a challenge and prognosis is poor. Methods: We conducted a retrospective analysis of 47 patients with SCCOHT evaluated at a tertiary cancer care center between January 1990 and August 2014. Medical records were reviewed for demographic information, pathologic findings, treatment regimens and outcomes. Results: Median age at diagnosis was 30 years (range 5-46). A unilateral salpingo-oophorectomy (USO) was performed in 26 patients (55%) and hysterectomy with bilateral salpingo-oophorectomy (BSO) in 21 patients (45%). Staging procedures were performed in 40 patients (85%). All tumors were unilateral and median tumor size was 16 cm (range, 4-30). Sixteen patients (34%) had stage I disease, six (13%) stage II, 23 (49%) stage III, and two (4%) stage IV disease. Serum calcium levels were elevated at diagnosis in 91% of the 11 patients with results available. Information on adjuvant treatment was available for 43 patients: 33 (77%) received adjuvant treatment with chemotherapy alone, 6 (14%) chemotherapy followed by radiotherapy, one (2%) chemotherapy and radiotherapy, and three (7%) did not receive any treatment. The adjuvant chemotherapy regimens administered included platinum doublet (n = 23) and multi-agent regimen with three (n = 4) or more (n = 12) drugs. Median follow-up was 13 months (range, 0.1 to 210). Median survival was 14.9 months, and 29 patients died, all of disease. Five-year survival for the entire cohort was 29% (95% CI 16% to 44%). Patients with stage III/IV disease had significantly poorer five-year survival (10%, 95% CI 2% to 27%) compared with patients with stage I/II disease (52%, 95% CI 26% to 73%), p < 0.001. Conclusions: SCCOHT is a rare and aggressive disease. Further study is needed to improve outcomes in these patients including the development of new systemic therapies such as novel agents targeting specific mutations.
Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury
Authors: Chengjun Hu, Yihao Tian, Hongxin Xu, Bo Pan, Erin M. Terpstra, Penglong Wu, Hongmin Wang, Faqian Li, Jinbao Liu, Xuejun Wang
Journal: Journal of Clinical Investigation (2018)

The ubiquitin-proteasome system (UPS) degrades a protein molecule via 2 main steps: ubiquitination and proteasomal degradation. Extraproteasomal ubiquitin receptors are thought to couple the 2 steps, but this proposition has not been tested in vivo with vertebrates. More importantly, impaired UPS performance plays a major role in cardiac pathogenesis, including myocardial ischemia-reperfusion injury (IRI), but the molecular basis of UPS impairment remains poorly understood. Ubiquilin1 is a bona fide extraproteasomal ubiquitin receptor. Here, we report that mice with a cardiomyocyte-restricted knockout of Ubiquilin1 (Ubqln1-CKO mice) accumulated a surrogate UPS substrate (GFPdgn) and increased myocardial ubiquitinated proteins without altering proteasome activities, resulting in late-onset cardiomyopathy and a markedly shortened life span. When subject to regional myocardial ischemia-reperfusion, young Ubqln1-CKO mice showed substantially exacerbated cardiac malfunction and enlarged infarct size, and conversely, mice with transgenic Ubqln1 overexpression displayed attenuated IRI. Furthermore, Ubqln1 overexpression facilitated proteasomal degradation of oxidized proteins and the degradation of a UPS surrogate substrate in cultured cardiomyocytes without increasing autophagic flux. These findings demonstrate that Ubiquilin1 is essential to cardiac ubiquitination-proteasome coupling and that an inadequacy in the coupling represents a major pathogenic factor for myocardial IRI; therefore, strategies to strengthen coupling have the potential to reduce IRI.
In Situ Synchrotron X‐Ray Diffraction Characterization of Corrosion Products of a Ti‐Based Metallic Glass for Implant Applications
Authors: Petre Flaviu Gostin, Owen Addison, Alexander P. Morrell, Yue Zhang, Angus J. M. C. Cook, Alethea Liens, Mihai Stoica, Konstantin Ignatyev, Steven R. Street, Jing Wu, Yu‐Lung Chiu, Alison J. Davenport
Journal: Advanced Healthcare Materials (2018)

Abstract Ti‐based bulk metallic glasses are under consideration for implants due to their high yield strength and biocompatibility. In this work, in situ synchrotron X‐ray diffraction (XRD) is used to investigate the corrosion products formed from corrosion of Ti 40 Zr 10 Cu 34 Pd 14 Sn 2 bulk metallic glass in artificial corrosion pits in physiological saline (NaCl). It is found that Pd nanoparticles form in the interior of the pits during electrochemical dissolution. At a low pit growth potential, the change in lattice parameter of the Pd nanoparticles is consistent with the formation of palladium hydride. In addition, a salt layer very close to the dissolving interface is found to contain CuCl, PdCl 2 , ZrOCl 2 ∙8H 2 O, Cu, Cu 2 O, and several unidentified phases. The formation of Pd nanoparticles (16 ± 10 nm at 0.7 V vs Ag/AgCl) containing small amounts of the other alloying elements is confirmed by transmission electron microscopy. The addition of albumin and/or H 2 O 2 does not significantly influence the nature of the corrosion products. When considering the biological compatibility of the alloy, the biological reactivity of the corrosion products identified should be explored.
Correlation between the TTF-1 expression and immune-related thyroid dysfunction and efficacy of anti-PD1 treatment in non-small cell lung cancer.
Authors: Junji Koyama, Atsushi Horiike, Takahiro Yoshizawa, Yosuke Dotsu, Ryo Ariyasu, Masafumi Saiki, Tomoaki Sonoda, Ken Uchibori, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Hironori Ninomiya, Yuichi Ishikawa, Makoto Nishio
Journal: Journal of Clinical Oncology (2018)

e21100 Background: Recent studies have suggested a correlation between immune-related adverse events, particularly thyroid dysfunction (irTD), and the better efficacy of anti-PD1 treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. This study aims to validate our hypothesis that the TTF-1 expression in NSCLC might correlate with the incidence of irTD and efficacy of anti-PD1 treatment. Methods: We identified 132 patients with advanced NSCLC (non-squamous [Nsq], 99; squamous [Sq], 33) treated with the anti-PD-1 antibody (nivolumab, 121; pembrolizumab, 11) at our hospital between December 2015 and June 2017. We evaluated the TTF-1 expression in tumors using immunohistochemistry. Then, we retrospectively assessed the incidence of irTD and efficacy of anti-PD-1 treatment in patients with TTF-1 positive (+) or negative (−). We defined two or more successive abnormal levels of thyroid-stimulating hormone during anti-PD1 treatment as irTD. Results: Of 132 patients, 67 (51%) and 65 (49%) were TTF-1 (+) and TTF-1 (−) NSCLC, respectively. In addition, TTF-1 (+) Nsq were 66, TTF-1 (−) Nsq were 33, TTF-1 (+) Sq was 1, and TTF-1 (−) Sq were 32. We observed irTD in 19 patients, of whom 6 were TTF-1 (+), whereas 13 were TTF-1 (−). Remarkably, the incidence of irTD was 9% (6/67) and 20% (13/65) in TTF-1 (+) and TTF-1 (−) NSCLC patients, respectively (P = 0.086). Particularly, the incidence of irTD in TTF-1 (−) Nsq patients (30%; 10/33) was significantly higher than TTF-1 (+) Nsq (9%; 6/66; P = 0.010). Furthermore, the longer median progression-free survival (10.3 months) was observed in TTF-1 (−) irTD (+) NSCLC patients compared to TTF-1 (+) irTD (+), TTF-1 (+) irTD (−), and TTF-1 (−) irTD (−) NSCLC patients (4.2, 1.4, and 2.4 months, respectively). Conclusions: This study suggests that the TTF-1 expression in NSCLC, especially Nsq-NSCLC, might correlate with irTD and efficacy of anti-PD1 treatment.
Establishment of a medical student elective on the oncology consult service using the seven principles of teaching.
Authors: Hari Anant Deshpande, Stacey Stein
Journal: Journal of Clinical Oncology (2018)

TPS11021 Background: A busy academic oncology consult service has challenges for effective student teaching. The aim of this research is to establish an academic oncology elective through signature pedagogies - learning in the practice setting. Methods: The Seven Principles of teaching and learning will be used to develop an effective teaching model for the Inpatient Oncology Consult service. 1 Prior knowledge is the key to learning 2 Prior knowledge must be activated 3 Learners must be actively involved in constructing personal meaning (ie: understanding) – the links are more improtant than the elements 4 Making more and stronger links requires time 5 Context provides important cues for storing and retrieving information 6 - A Intrinsic motivation is associated with deep approaches to learning; B Extrinsic motivation and anxiety are associated with surface approaches to learning 7 - Teaching should be geared toward making the teacher increasingly unnecessary; that means the development of learner autonomy as well as intellect To address these principles: 1 - A short 10 question quiz to ascertain prior knowledge of general oncology 2 - Activate prior knowledge by asking about experiences or planting concepts at the beginning of the discussion. This should reflect the students’ interests: e.g.. focusing on the disease, the social aspects, financial aspects, symptom management or end of life care. 3 - Encourage teachers to be guides, coaches or co-inquirers more than a source of knowledge during rounds to encourage deep and holistic rather than surface discussions. 4 - Allow students time to elaborate their knowledge base – make links between subjects as well as between theory and practice to focus on intrinsic motivation. Limit the size of the teaching service. 5 - Teach in the context from which they eventually use their knowledge. Observe patient encounters and critique their presentations. 6 - A flipped curriculum where the student studies an aspect that then can be discussed in more detail; this becomes the basis for constructing a management plan. 7- A feedback session to stay within the students’ zone of proximal development and maintain in the course. Development of a smartphone app for assessment.
TCT-536 Impact of Aortic Valve Gradient and Left Ventricular Ejection Fraction Upon Outcomes Following Transcatheter Aortic Valve Implantation
Authors: John Schindler, Suresh Mulukutla, Dustin Kliner, Forozan Navid, Michael Sharbaugh, Matthew Berezo, Andrew Althouse, Joao Cavalcante, Ibrahim Sultan, Thomas Gleason, Joon Lee, John Schindler
Journal: Journal of the American College of Cardiology (2018)
BRAF V600 and non-V600 mutations across distinct tumor types.
Authors: Qichao Xie, Jiaojiao Huan, Jun Zhao, Yu Chen, Jie Gao, Naixin Liang, Yu Zeng, Lianke Liu, Chunwei Xu, Chen Chen, Yan-Fang Guan, Ling Yang, Xuefeng Xia, Xin Yi
Journal: Journal of Clinical Oncology (2018)

e24297 Background: BRAF gene mutation, especially V600E, was frequently mutated in melanoma, vemurafenib and dabrafenib has already been approved in melanoma and NSCLC. But the landscape of BRAF non-V600 mutation across solid tumor was rarely descripted. Methods: 8819 normal-paired samples from multiple-solid cancer patients were analyzed using hybridization capture-based next generation sequencing and alterations including single nucleotide variants (SNVs), short insertions/deletions (indels), copy number variations (CNVs) and structural variations (SV) were analyzed. Results: BRAF V600 (gain of function, GOF) and non-V600 mutations (GOF: K601N/E, G469V/R/A, N486_P490del, L597V, and loss of function/LOF: G469E, D594N/G, N581S/I, G466V/A, K483E, G596R), has previously been reported to increase MEK/ERK activation, were detected in 59.6% (96/161) and 36.6% (59/161) of BRAF functional mutation patients. CNVs and SVs were founded in 2.5% (4/161) and 1.3% (2/161) respectively. No patient has two or more GOF/LOF mutations. These mutations were extensively detected in melanoma, thyroid, colorectal, lung, pancreatic and other 17 cancer types. In lung cancer cohort, BRAF non-V600-mutated patients amounted to almost half (50% vs 47.6%), but it was infrequently in colorectal (94% vs 6%). V600E was detected in almost all of the melanoma (7/8) and thyroid (7/7). We also found that 81.4% of the BRAF mutation carriers also owned the other actionable or driver mutation, the most frequent one was TP53 (74.8%), then was PIK3CA (15.3%), EGFR (13.7%), APC (13.7%) as well as KRAS (10.7%). It was similarly distributed in lung cancer (70/84). However, this phenomenon was not popular in melanoma (2/7) and thyroid (1/7). Conclusions: BRAF gene was extensively mutated in distinct solid tumor with different frequency. Non-V600 mutation was surprising frequently detected in some cancer type especially for lung. It’s necessary to recruit non-V600 mutated patients into the clinical trials focused on RAF Inhibitors therapeutic effect besides V600E-mutated patients.
P01.045 Adherence to Tumor Treating Fields in patients with high-grade glioma - a single center experience
Authors: A Kessler, J Weiland, M Breun, T Linsenmann, R Ernestus, C Hagemann, M Löhr
Journal: Neuro-Oncology (2018)

The addition of alternating electric fields with low intensity (1–3 V/cm) and intermediate frequency (100–300 kHz), known as Tumor Treating Fields (TTFields), to adjuvant temozolomide after surgical resection and radiochemotherapy in patients with newly diagnosed glioblastoma (GBM) demonstrated a significant increase in progression free (PFS), overall (OS) and long-term survival in a phase III multi-center trial (EF-14 trial). Post-hoc analysis of this trial revealed a strong correlation of adherence to TTFields therapy with prolonged OS, underlining the importance of a high compliance rate. However, the visibility of the transducer arrays poses a potential social exposure of TTFields patients and their relatives, especially in female patients, and may impact therapy compliance. Here, we report on TTFields therapy adherence of thirty-four patients with high-grade glioma (HGG) who were treated with TTFields. Thirty-four patients diagnosed with GBM (28 patients) and astrocytoma WHO°III (6 patients), respectively, were treated with TTFields at our institution. Patients were introduced to the therapy during our neurooncologic consultation hours. We evaluated the compliance reports that were generated at the monthly technical check of the device. The median age of HGG patients at therapy start was 53.5 years (range 32–67 years). 21 of the 28 GBM patients were newly diagnosed and the remainder had recurrences. These patients showed gender distribution female to male of 1:1.15, demonstrating a higher ratio of female patients compared to the typical GBM population with 1:1.7. Patients with newly diagnosed GBM were on TTFields therapy for a median of 6.5 months with median treatment compliance of 86.4%. No significant difference regarding compliance was observed between female (87.1%) and male (81.7%). Comparison between patients with newly diagnosed GBM and recurrent GBM showed no significant difference in therapy adherence with a median compliance of 80.0%. Astrocytoma WHO°III patients showed a compliance rate of 86.2%. The patients treated with TTFields at our institution showed a high median compliance to TTFields therapy irrespective of sex and diagnosis. In all groups, the compliance was substantially above the recommended 75% threshold. TTFields therapy was well accepted by high grade glioma patients, in particular by female GBM patients, at a high compliance rate.
Validation of tumor infiltrating lymphocytes (TIL) and tumor budding as predictors of prognosis in patients with stage III colon cancers treated in a FOLFOX-based adjuvant trial: NCCTG N0147 (Alliance).
Authors: Frank A. Sinicrope, Qian Shi, Hee Eun Lee, Nathan R. Foster, Steven R. Alberts, Thomas C. Smyrk
Journal: Journal of Clinical Oncology (2018)

3583 Background: TIL density reflects the anti-tumor immune response; tumor budding indicates an epithelial to mesenchymal transition (EMT). We determined if these features are prognostic in a single colon cancer (CC) stage with known DNA mismatch repair (MMR) status. Methods: TIL densities (per HPF) and tumor buds (per .785 mm2 field) were quantified at light microscopy in 1,532 CC. Tumor budding at invasive margin was defined as single or cluster of ≤ 4 tumor cells. We divided the cohort into training and validation sets. Optimal cutpoints were identified; associations with 3-year disease-free survival (DFS) were evaluated by multivariable Cox regression. Results: TIL and tumor budding cutpoints identified in training set were confirmed in validation set for prognosis. Patients whose tumors had low (≤ 3) vs high TILs were significantly more likely to have higher T, N stage, low histologic grade, left sidedness, worse performance status, non mutated BRAF, and proficient (p) MMR. Tumors with high budding ( > 3) had higher T, N stage; most had pMMR. Overall, significantly shorter DFS was found for tumors with low TILs [HRadj= 1.74 (95% CI 1.35, 2.24), p < .0001], or with high budding [HRadj= 1.37 (1.13, 1.67), p = .0011]. When combined, low TILs plus high budding showed poor DFS [HRadj= 2.07 (1.50, 2.88), p < .0001]. Similar results were found for pMMR tumors (Table). Within dMMR, patients whose tumors had low (≤ 3) vs high TILs had significantly shorter DFS (HRadj= 2.14; p = .0173); budding was not prognostic (Table). Conclusions: Low TILs and high budding were each validated as markers of poor prognosis in FOLFOX-treated stage III CC, indicating that reduced anti-tumor immunity and an EMT phenotype increase tumor aggressiveness. Whereas TILs and budding each stratified pMMR tumors by DFS, only TILs were prognostic in dMMR tumors and identified the subset with poorest survival. pMMR (n = 1357) dMMR (n = 153) HRadj 3-year DFS Padj HRadj 3-year DFS Padj TILs High Ref 81% P = .0002 Ref 78% P = .0173 Low 1.65 (1.25, 2.16) 71% 2.14 (1.14, 4.01) 53% Tumor Budding Ref P = .0009 Ref P = .8577 High 1.41 (1.15, 1.73) 69% 1.06 (0.56, 2.02) 67% Low Ref 79% Ref 71%
Algorithmic prediction of response to checkpoint inhibitors: Hyperprogressors versus responders.
Authors: Shipra Gandhi, Sarabjot Pabla, Mary Nesline, Manu Pandey, Marc S. Ernstoff, Grace K. Dy, Jeffery M. Conroy, Sean Glenn, Blake Burgher, Maochun Qin, Jonathan Andreas, Vincent Giamo, Antonios Papanicolau-Sengos, Lorenzo Galluzzi, Ji He, Mark Gardner, Carl Morrison
Journal: Journal of Clinical Oncology (2017)

11565 Background: Predicting response to checkpoint inhibitors (CPIs) using biological knowledge-based decision processes with machine learning (ML) has a great potential to predict rapid progression in patients treated with checkpoint inhibitors (CPIs) (hyperprogressive disease (HPD)) as well as responders. ML models risk overfitting data and do not always evaluate the underlying biology, thus performing well in the initial training cohort but lack generalizability when extended to other cohorts. Biology-based decision may not perform as well initially due to limited understanding and a simplified rule set, but often perform equally well when extended to larger similar cohorts of patients. Methods: A custom NGS cancer immune gene expression assay compared 87 patients treated with CPIs classified as CR, PR, or SD versus 12 HPD. A ML-based polynomial regression model based on 54 immune-related genes combined with mutational burden was optimized for prediction of response. A biological 4-gene decision tree model was constructed independently based on ML. A second biological decision tree incorporated the weighted average relative rank of the expression of multiple genes in 4 different immune functions including immune cell infiltration, regulation, activation, and cytokine signaling. Bayesian model average (BMA) incorporated all three models’ results into the final prediction. Results: For87 patients classified as CR, PR, or SD the PPV &gt;96% for responders and a NPV &gt;90% for non-responders was achieved with the regression model, however with response indeterminate for 24% of the population. While the two biological decision tree models’ PPV were in the 70% range, they accurately revealed the critical genes’ roles in immune response with strong literature support. BMA process integrated these three models resulted in a PPV &gt;96% and a NPV &gt;90% and eliminated the indeterminate group. For HPD a unique biology related to priming of short term memory T-cells was identified. Conclusion: Prediction of response to CPIs is best attained by combining ML with biological knowledge. Decision tree models using a large panel of immune related genes in the context of archival samples from patients treated with CPIs can be used to better understand the biology of responders versus non-responders and provides new insights into HPD.