tbuckley/cabot-search huggingface dataset:
Potential Benefits of Inhaled Nitric Oxide in Pulmonary Hypertension With Hypoplasia in Premature Neonates—Reply
Authors: Kevin R. Ellsworth, Amy L. Weaver, William A. Carey
Journal: JAMA Pediatrics (2018)

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Prediction of unresectability and overall survival in patients with pancreatic cancer using preoperative plasma CA 19.9, IL-6 and YKL-40.
Authors: Camilla Palmquist, Christian Dehlendorff, Dan Calatayud, Jane Preuss Hasselby, Carsten Palnaes Hansen, Julia S. Johansen
Journal: Journal of Clinical Oncology (2016)

e15689 Background: Some patients admitted to surgery for pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AAC) are perioperatively diagnosed with advanced disease and thus unresectable pancreatic cancer (PC) (stage III or IV). These patients could instead benefit from neoadjuvant chemotherapy. The aims were to investigate 1) whether unresectable patients already preoperatively had higher plasma CA 19-9, IL-6 and YKL-40 than patients with resectable tumors; and 2) if high preoperative levels of these biomarkers predict short overall survival (OS) in patients going through surgery, thus indicating non-radical procedure. Methods: Preoperative blood samples were collected from 211 patients with PDAC (138 resectable, 73 unresectable (Stage III n = 15; Stage IV n = 58)) and 41 patients with AAC (28 resectable, 13 unresectable (Stage III n = 12; Stage IV n = 1)) included in the BIOPAC Study from December 2010 to December 2014. IL-6 and YKL-40 concentrations in plasma were determined by ELISAs (IL-6: R&D; YKL-40: Quidel). Results: Plasma IL-6 was significantly (p < 0.05) elevated in patients with unresectable tumors compared to patients with resectable tumors (9.5 vs. 7.4 ng/l), whereas CA 19.9 and YKL-40 were similar in the two groups (p > 0.40). IL-6 could predict resectability with AUC = 0.58 (95%CI: 0.50-0.65). Operated patients with high preoperative levels (above median) of the biomarkers had significantly (p < 0.02) shorter OS than operated patients with levels below median (CA 19-9: HR = 1.97, 95% CI 1.24-3.13; IL-6: HR = 1.79, 1.13-2.82; YKL-40: HR = 1.78, 1.11-2.84). Patients with two or three elevated biomarkers had significantly shorter OS than patients with no elevated biomarkers (p < 0.01) (HR = 3.34, 1.51-7.42; HR = 2.94, 1.26-6.91; for 2 and 3 elevated biomarkers, respectively). Conclusions: The combination of high preoperative plasma CA19-9, IL-6, and YKL-40 may be useful to identify a subgroup of patients with PDAC and AAC with poor prognosis. These patients operated for PC may benefit from either neoadjuvant chemotherapy or postoperative adjuvant chemotherapy with gemcitabine+nab-paclitaxel or FOLFIRINOX.
Symptom assessment in patients with JAK inhibitor naïve and JAK inhibitor failed myelofibrosis.
Authors: Yun Su, Adrian Woolfson, Josef T. Prchal, Kathleen Wyant Turnbull, Claire N. Harrison, Elias Jabbour, Robyn Marie Scherber, Alan Shields, Meaghan Krohe, Funke Ojo, Farrah Pompilus, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2016)

e18559 Background: Myelofibrosis(MF) is characteristically symptomatic, and symptoms reduction is a key endpoint in clinical trials of MF agents. A symptom assessment patient-reported outcome (PRO) tool was previously approved for use in patients naïve to JAK inhibition. It remains unclear, however, whether the same tool is appropriate to patients resistant or intolerant to treatment with a JAK inhibitor (JAK failed). The current study aims to identify symptomatic differences between patients who are JAK naïve and those who have failed one or more prior JAK inhibitors. It also seeks to address new regulatory requirements in PRO claims. Methods: The Myeloproliferative Neoplasm Symptom Assessment Diary (MPN-SAD) was developed and qualitatively validated in MF patients through concept elicitation (open-ended symptom probes) and cognitive debriefing (interpretability) interviews. These were supplemented with literature reviews and clinical expert interviews. Results: A total of n=7 JAK naïve and n=16 JAK failed patients were interviewed. The mean patient age was 63 years (58.7 years for JAK naïve and 67.2 years for JAK failed). Concept saturation was demonstrated with 5 JAK naïve and 16 JAK failed patients. Dyspnea emerged as a key symptom reported in 11 of the 16 JAK failed patients. Other key symptoms reported by the patients are detailed in Table 1. The findings were confirmed by four clinical experts and literature reviews. Based on patient feedback, the MPN-SAD instructions were amended. The fatigue and the bone/muscle pain items were clarified, and items relating to dyspnea and appetite loss added. Conclusions: The MPN-SAD was qualitatively validated per regulatory guidance. Quantitative psychometric validation is needed to facilitate development, regulatory approval, and expedited availability of novel medicines to fulfill unmet needs of patients naïve to or failing a first-line JAK-inhibitor. Patient reported MF symptoms. JAK-naïve N=7 JAK-failed N=16 MF severity Mild 5 1 Moderate 1 11 Severe 1 4 Key Reported Symptoms Fatigue 4 16 Pain under left ribs 4 7 Enlarged spleen 4 9 Filling up quickly 4 6 Night sweats 4 6 Itching 4 5 Bone pain 1 6 Abdominal discomfort 1 5 Appetite loss 1 0 Dyspnea 0 11
Management of uni- or bilateral retinoblastoma with radiologic optic nerve invasion at diagnosis.
Authors: Marie-Louise Choucair, Herve Brisse, Paul Freneaux, Livia Lumbroso, Marion Chevrier, Francois P. Doz, Isabelle Aerts
Journal: Journal of Clinical Oncology (2017)

10551 Background: To evaluate treatment and outcome of patients with uni- or bilateral retinoblastoma (RB) with radiologic optic nerve invasion (RONI) at diagnosis. Methods: Retrospective clinical, radiological and histological review of patients with uni- or bilateral RB with RONI at diagnosis treated in the Institut Curie. Results: Between 1997 and 2014, 936 patients with RB were treated in the Institut Curie. Eleven patients had detectable RONI confirmed by Computed Tomography and/or Magnetic Resonance Imaging. RB was unilateral in 10/11 patients, bilateral in 1. Median age at diagnosis was 29 months (range 12-96). The patient with the bilateral RB had a unilateral RONI. Nine patients had ON enhancement and 3 had meningeal sheath enhancement. Nine received neoadjuvant chemotherapy (CT) and 2 had a primary enucleation. Partial response to neoadjuvant CT was obtained for all the patients. Enucleation was performed in 10/11 patients, by anterior approach in 3 patients, by anterior and subfrontal approach in 7 patients. Three patients had positive ON margin and among them, 2 were primary enucleated. All enucleated patients received adjuvant treatment (conventional CT: 10, High Dose CT: 7 and radiotherapy: 5). Three patients died of meningeal progression (2 during treatment and 1 during the first year after treatment). The patient with the bilateral RB was lost to follow up just after a meningeal progression during treatment. Seven are still alive (median follow up: 8 years, range : 1.5-17.5). Conclusions: Neoadjuvant CT has an important place in the management of unilateral RB with RONI at diagnosis. Pretreatment accurate staging by orbital and brain MRI is mandatory, as well as preoperative reassessment. Surgery should be performed by experienced ophthalmologists and if necessary neurosurgical team in order to obtain the best conditions for a tumor-free resection margin in patients with RONI.
Patient driven efforts for quality outcomes and research in head and neck cancer.
Authors: Ayaka J. Iwata, Heather A. Olden, Karen E. Kippen, Warren C. Swegal, Steven Chang
Journal: Journal of Clinical Oncology (2018)

e22065 Background: Patient-driven research is emerging as a new paradigm that increases the relevance of research efforts, identifies gaps in clinical knowledge, enhances design of studies, and accelerates the implementation of clinical research enterprises. We describe our experience, focusing on the major benefits and the lessons learned from establishing and sustaining partnerships with patients and caregivers. Methods: Patient Engagement Research Center (PERC) was developed in 2013 at Henry Ford Health Systems as an infrastructure for patient-centered outcomes research endeavors. It created the Patient / Family Advisory Councils (PFAC), which recruits and trains head and neck cancer patients and caregivers to reflect on their survivorship experiences. PFAC, which meets monthly, includes a multidisciplinary team of surgeons, speech language pathologists, dieticians, and psychologists. Advisors reviewed the clinical flow of care, from the initial cancer visits to the post-treatment visits. Gaps in clinical care were identified, and implementation of changes were discussed. The advisors also learned about patient-centered outcomes research, literature searches, and the research methodology. They shared their personal stories and experiences, and developed topics of interest. They identified research outcomes that were of relevance to their experience, and discussed research design. Results: Forty-five local advisors were recruited. Four virtual advisors, who skyped in other cities, were included as well. Oropharyngeal cancer had the highest representation, followed by oral cavity cancer, then laryngeal cancer. They improved the clinical flow including that of the pre-treatment clinic. They also identified the need for a dental oncology clinic and a post-treatment survivorship clinic. The PFAC experience led to the attainment of research grants, philanthropy donations, public awareness efforts, and patient participation in head and neck cancer symposiums. Conclusions: This methodology illustrates the feasibility of patient engagement in all phases of research, and offers a concrete description of its impact. Further research is needed to define and quantify the strength and results of patient engagement.
P02.10 Aggressiveness of meningiomas is predicted by cell immortalization in vitro and dependent on TERT promoter mutations
Authors: S Spiegl-Kreinecker, D Lötsch, K Neumayer, L Kastler, J Gojo, C Pirker, J Pichler, S Weis, R Kumar, G Webersinke, A Gruber, W Berger
Journal: Neuro-Oncology (2018)

TERT promoter mutations in meningiomas were recently found to be strongly prognostic and associated with malignant progression and risk of recurrence. However, the cellular factors underlying meningioma aggressiveness are comparably unexplored. Due to the limited meningioma cell lines available worldwide, it was aim of our study to analyse an extended cohort of WHO grade I-III meningiomas regarding the impact of TERT promoter mutations, telomerase activity and TERT mRNA expression on cell propagation in vitro. Tumor tissue from 128 meningiomas was analysed for TERT promoter mutations by direct sequencing. Telomerase activity (TA), TERT mRNA expression and telomere lengths were investigated by TRAP assay, RT-PCR, and qPCR, respectively. Correspondingly, tumor-derived primo-cell cultures (121/128) were established. The impact of the ETS-transcription factor inhibitor YK-4–279 on cell viability was analysed in selected primo-cell cultures by MTT assays. To elucidate whether ETS- transcription factor inhibition affects TERT promoter activity, luciferase-based reporter assays were performed. TERT promoter mutations were found in 6 % of all samples analysed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (p<0.0001 both). Meningioma derived primo-cell cultures were able to be propagated with comparable success rates from TA positive and- negative (55% versus 53%) tumors. In contrast, within the meningioma cohort harbouring TERT promoter mutations, 75% (6/8) viable primo-cell cultures could be established. Out of these, 2 primo-cell cultures (2/6; 33%) developed into stable immortalized cell lines. This strongly indicates that TERT promoter mutations but not telomerase activity or TERT mRNA expression were predicting indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4–279 inducing a significant downregulation of TERT mRNA expression. Accordingly, as shown by the luciferase-reporter assay, the enhanced activity of the mutated TERT promoter was completely blocked by presence of YK-4–279. Patients with TERT promoter mutated meningiomas exhibited a significantly shorter overall survival (p=0.0006; 53.8 vs 115.6 months). Aggressiveness of meningiomas reflected by cell immortalization in vitro is dependent on TERT promoter mutations. This fits well with the data of worse prognosis for meningioma patients harbouring a TERT promoter-mutated tumor. Additionally, TERT promoter mutations might open a promising novel therapeutic opportunity in progressive meningiomas.
A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer
Authors: Kelly E. Henry, Megan M. Dacek, Thomas R. Dilling, Jonathan D. Caen, Ian L. Fox, Michael J. Evans, Jason S. Lewis
Journal: Clinical Cancer Research (2018)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, with a 5-year survival rate of less than 10%. Physicians often rely on biopsy or CT to guide treatment decisions, but these techniques fail to reliably measure the actions of therapeutic agents in PDAC. KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC. A key downstream event of MYC is transferrin receptor (TfR), which has been identified as a biomarker for cancer therapeutics and imaging.In this study, we aimed to test whether zirconium-89 transferrin ([89Zr]Zr-Tf) could measure changes in MYC depending on KRAS status of PDAC, and assess target engagement of anti-MYC and anti-ERK-targeted therapies.Mice bearing iKras*p53* tumors showed significantly higher (P < 0.05) uptake of [89Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease (P < 0.05) of [89Zr]Zr-Tf uptake in drug versus vehicle-treated mice bearing Capan-2 and Suit-2 xenografts. IHC analysis of resected PDAC tumors reflects the data observed via PET imaging and radiotracer biodistribution.Our study demonstrates that [89Zr]Zr-Tf is a valuable tool to noninvasively assess oncogene status and target engagement of small-molecule inhibitors downstream of oncogenic KRAS, allowing a quantitative assessment of drug delivery.
Coffee consumption and gout: a Mendelian randomisation study
Authors: Young Ho Lee
Journal: Annals of the Rheumatic Diseases (2018)

I have read with great interest the article by Larsson and Carlstrom1 regarding coffee consumption and gout. This Mendelian randomisation (MR) analysis demonstrates that coffee consumption may lower the risk of gout. When a randomised controlled trial is lacking because of an unethical or infeasible issue, MR studies may help address the causal relationship. However, it has some methodological issues. The primary concern relates to whether the MR study has adequate statistical power to detect an association. An increase in the variance in the trait of interest …
Association of <sup>18</sup>F-FDG uptake on PET with PD-L1 expression in patients with non-small cell lung cancer.
Authors: Kyoichi Kaira, Kimihiro Shimizu, Tetsuya Higuchi, Norimitsu Kasahara, Shinsuke Kitahara, Tetsunari Oyama, Takayuki Asao, Akira Mogi
Journal: Journal of Clinical Oncology (2018)

e24138 Background: 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography (PET) is a useful modality for the assessment of tumor glucose metabolism by up-regulation by hypoxia. Little is known whether the uptake of 18F-FDG within cancer cells is linked to the expression of programmed death ligand-1 (PD-L1), a predictor of anti-PD-1 antibody. We conducted a clinicopathological study to assess the expression of PD-L1 and tumor-infiltrating lymphocytes (TILs) in patients with surgically resected pulmonary adenocarcinoma (AC) and squamous cell carcinoma (SQC) who received preoperative 18F-FDG-PET. Methods: A total of 315 patients with lung AC and 167 patients with SQC who received 18F-FDG PET were enrolled in the study. Tumor specimens were stained by immunohistochemistry for glucose transporter 1 (Glut1), hypoxia-inducible factor-1α (HIF-1α), PD-L1, CD4, and CD8. We assessed whether the uptake of 18F-FDG was correlated with clinicopathological variables. Results: PD-L1 was highly expressed in 60% of patients with AC and 79% of those with SQC, and the expression level was significantly correlated with 18F-FDG uptake, glucose metabolism, and hypoxia. PD-L1 and the maximum standardized uptake value (SUVmax) were identified as independent prognostic predictors by multivariate analysis. In particular, PD-L1 could be a significant marker for predicting worse outcome in both AC and SQC patients with high 18F-FDG uptake, but not in those with low 18F-FDG uptake. According to the epidermal growth factor receptor (EGFR) mutation status, the expression of PD-L1 was significantly correlated with SUVmax in AC patients with EGFR mutation, whereas, PD-L1 was a significant prognostic predictor in those with wild-type EGFR. Conclusions: 18F-FDG uptake was significantly correlated with PD-L1 expression, and the latter was closely linked to the presence of glucose metabolism and hypoxia in patients with both histological types of non-small cell lung cancer.
Novel mechanisms-guided treatments for betel-nuts related head and neck squamous cell carcinoma in Taiwan.
Authors: Jo-Pai Chen, Jui-Ying Chang, Sung Hsin Kuo
Journal: Journal of Clinical Oncology (2017)

e23217 Background: Betel-nuts related HNSCCs in Taiwan will cause (1)strong inflammation, invasion, and angiogenesis; (2)poor response to chemotherapy, radiation, and epidermal growth factor receptor inhibitors. Methods: HNSCC cell lines(SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6, betel-nuts related) were used to evaluate (1)the in vitro drug sensitivity; (2)synergistic effects of different treatment combinations with MTT assay, colony formation, flow cytometry, and western blotting; (3)invasion capacity by wound healing. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2. Results: TW2.6 was resistant to chemotherapies, radiation, &amp; EGFR inhibition; but sensitive to PI3K/mTOR dual inhibition(BEZ235), CDK4/6 inhibitor(palbociclib), Bcl2 inhibitor(ABT-199), WEE1 inhibitor(AZD1775), FGFR inhibitor(BGJ398), ALK/IGF-1R inhibitor(ceritinib), &amp; eribulin. Polo-like kinase inhibitor(volasertib) with radiation, resulting in G2/M arrest in flow-cytometry and increased cyclin B levels in western blotting, caused TW2.6 apoptosis. Nintedanib &amp; regorafenib(VEGFR/PDGFR/FGFR inhibitor) and foretinib (VEGFR/c-MET/Axl inhibitor) would suppress HUVEC, block invasion capacity of TW2.6, inhibit TW2.6 growth, and resensitize TW2.6 to docetaxel, afatinib, and volasertib. Western blotting showed (1)mesenchymal markers(Slug, Snail, Axl, Twist, Vimentin, Claudin-1), PI3K/Akt/mTOR signaling(p-Akt &amp; p70S6K), and BMI-1 dropped after nintedanib, regorafenib, and foretinib; (2)PDL1 drop after foretinib use. BYL719, ABT-199, and ceritinib also sensitize TW2,6 to docetaxel. Astragalus polysaccharides, minimally cytotoxic on TW2.6, could inhibit tumor migration, suppress epithelial-mesenchymal transformation &amp; PI3K/AKT/mTOR pathway, and induce PDL1 drop. APS re-sensitizes TW2.6 to afatinib &amp; volasertib. Olaparib(PARP inhibitor) also had poor effect on TW2.6; but volasertib, AZD1775, and foretinib could reverse olaparib resistance. Conclusions: TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. Several novel-mechanisms-guided treatment combinations could be developed in the future.
Long-term outcomes after irradiation (RT) for pediatric low-grade glioma.
Authors: Derek S. Tsang, Erin Sennett Murphy, Thomas E. Merchant
Journal: Journal of Clinical Oncology (2017)

10549 Background: Treatment for pediatric low-grade glioma (LGG) is variable, depending on age and tumor location. Systemic therapy (ST) is often used to delay RT, but ST does not result in durable local control. The goal of this study was to evaluate event-free survival (EFS) and toxicities for pediatric LGG treated with RT over a 30-year period. Methods: All patients age ≤21 with intracranial pediatric LGG (WHO grade I-II) treated with RT at a single institution since May 1986 were included in this retrospective review. Patients with metastatic disease (M+) received craniospinal irradiation (CSI); otherwise, RT was conformal. EFS and overall survival (OS) were measured from the first day of RT. Events included death, progression, or secondary high-grade glioma. Results: 221 patients were eligible. Median follow-up was 11.3 yrs (range, 0.1-30.5). Median RT dose was 54 Gy. 10-yr EFS and OS were 67.9% (95% CI 60.4-74.3) and 91.1% (95% CI 85.8-94.5) for non-metastatic patients, respectively. For 12 M+ patients treated with CSI, 10-yr EFS and OS were 58.9% (95% CI 23.4-82.5) and 70.0% (32.9-89.2), respectively. 28.6% developed pseudoprogression (PP) with median time to onset and resolution of 6.1 months (IQR 3.6-14.6) and 6.4 months (IQR 3.5-11.7), respectively. Patients with PP had improved 10-yr EFS (83.4% vs. 61.0%, HR 0.40, p = .006). Patients with grade II tumors and who received pre-RT ST had lower EFS (Table). Sex, NF-1, tumor location, extent of surgery and CSI were not independently associated with EFS. 10-yr cumulative incidence of grade ≥2 vasculopathy was 7.5% (95% CI 4.9-11.4). There were 12 cases of secondary high-grade glioma, with a 20-yr cumulative incidence of 5.5% (95% CI 2.6-11.4). Conclusions: Irradiation provides long-term control of pediatric LGG in a majority of patients. Receipt of pre-RT systemic therapy was associated with reduced EFS; this association requires further investigation. [Table: see text]