tbuckley/cabot-search huggingface dataset:
Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial
Authors: Hyun-Ah Kim, Jong Won Lee, Seok Jin Nam, Byeong-Woo Park, Seock-Ah Im, Eun Sook Lee, Yong Sik Jung, Jung Han Yoon, Sung Soo Kang, Soo-Jung Lee, Kyong Hwa Park, Joon Jeong, Se-Heon Cho, Sung Yong Kim, Lee Su Kim, Byung-In Moon, Min Hyuk Lee, Tae Hyun Kim, Chanheun Park, Sung Hoo Jung, Geumhee Gwak, Jeryong Kim, Sun Hee Kang, Young Woo Jin, Hee Jeong Kim, Se-Hwan Han, Wonshik Han, Min Hee Hur, Woo Chul Noh
Journal: Journal of Clinical Oncology (2019)

PURPOSE The addition of ovarian function suppression (OFS) for 5 years to tamoxifen (TAM) for treatment of premenopausal patients with breast cancer after completion of chemotherapy has beneficial effects on disease-free survival (DFS). This study evaluated the efficacy of adding 2 years of OFS to TAM in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. PATIENTS AND METHODS We enrolled 1,483 premenopausal women (age ≤ 45 years) with estrogen receptor–positive breast cancer treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years that involved monthly goserelin administration (TAM + OFS) group. DFS was defined from the time of enrollment to the time of the first event. RESULTS A total of 1,293 patients were randomly assigned, and 1,282 patients were eligible for analysis. The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (hazard ratio, 0.69; 95% CI, 0.48 to 0.97; P = .033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM-only group (hazard ratio, 0.31; 95% CI, 0.10 to 0.94; P = .029). CONCLUSION The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.
A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory <i>BRAF</i> V600 Mutation–Positive Solid Tumors
Authors: Mark W. Kieran, Birgit Geoerger, Ira J. Dunkel, Alberto Broniscer, Darren Hargrave, Pooja Hingorani, Isabelle Aerts, Anne-Isabelle Bertozzi, Kenneth J. Cohen, Trent R. Hummel, Violet Shen, Eric Bouffet, Christine A. Pratilas, Andrew D.J. Pearson, Lillian Tseng, Noelia Nebot, Steven Green, Mark W. Russo, James A. Whitlock
Journal: Clinical Cancer Research (2019)

The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced
Successful endoscopic retrieval of a toothpick stuck in the small intestine using double-balloon enteroscopy
Authors: Takashi Abe, Kouki Kusatsu, Takayuki Nagai, Kazunari Murakami
Journal: Endoscopy (2019)

A 59-year-old man was admitted to our hospital with nausea and vomiting. Laboratory test results demonstrated an elevated white blood cell count of 10 540/µL (normal range 3200 – 8000/µL) and his C-reactive protein (CRP) level was 2.82 mg/dL (normal < 0.30 mg/dL). He had a history of appendectomy for appendicitis and ventriculoperitoneal shunting for subarachnoid hemorrhage. Abdominal computed tomography (CT) showed a small-bowel obstruction (SBO) with dilatation, fluid collection, and caliber change in the proximal part of the small intestine ([Fig. 1 a]). Ascites, abscesses, and free air were not observed; however, a high-density needle-shaped structure was noted incidentally inside the proximal part of the small intestine with minimal surrounding inflammation ([Fig. 1 b]).
A Meta-analysis of Passive Immunization Studies Shows that Serum-Neutralizing Antibody Titer Associates with Protection against SHIV Challenge
Authors: Amarendra Pegu, Bhavesh Borate, Yunda Huang, Matthias G. Pauthner, Ann J. Hessell, Boris Julg, Nicole A. Doria-Rose, Stephen D. Schmidt, Lindsay N. Carpp, Michelle D. Cully, Xuejun Chen, George M. Shaw, Dan H. Barouch, Nancy L. Haigwood, Lawrence Corey, Dennis R. Burton, Mario Roederer, Peter B. Gilbert, John R. Mascola, Ying Huang
Journal: Cell Host & Microbe (2019)
Quantitative MNase-seq accurately maps nucleosome occupancy levels
Authors: Răzvan V. Chereji, Terri D. Bryson, Steven Henikoff
Journal: Genome biology (2019)

Micrococcal nuclease (MNase) is widely used to map nucleosomes. However, its aggressive endo-/exo-nuclease activities make MNase-seq unreliable for determining nucleosome occupancies, because cleavages within linker regions produce oligo- and mono-nucleosomes, whereas cleavages within nucleosomes destroy them. Here, we introduce a theoretical framework for predicting nucleosome occupancies and an experimental protocol with appropriate spike-in normalization that confirms our theory and provides accurate occupancy levels over an MNase digestion time course. As with human cells, we observe no overall differences in nucleosome occupancies between Drosophila euchromatin and heterochromatin, which implies that heterochromatic compaction does not reduce MNase accessibility of linker DNA.
Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development
Authors: Peng Tan, Lian He, Changsheng Xing, Jingrong Mao, Xiao Yu, Motao Zhu, Lixia Diao, Leng Han, Yubin Zhou, James M. You, Helen Y. Wang, Rong-Fu Wang
Journal: Journal of Clinical Investigation (2019)

Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil–B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil–B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.
Prognostic Significance of <i>MYC</i> Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium
Authors: Andreas Rosenwald, Susanne Bens, Ranjana Advani, Sharon Barrans, Christiane Copie-Bergman, Mad-Helenie Elsensohn, Yaso Natkunam, Maria Calaminici, Birgitta Sander, Maryse Baia, Alexandra Smith, Daniel Painter, Luu Pham, Shuchun Zhao, Marita Ziepert, Ekaterina S. Jordanova, Thierry J. Molina, Marie José Kersten, Eva Kimby, Wolfram Klapper, John Raemaekers, Norbert Schmitz, Fabrice Jardin, Wendy B.C. Stevens, Eva Hoster, Anton Hagenbeek, John G. Gribben, Reiner Siebert, Randy D. Gascoyne, David W. Scott, Philippe Gaulard, Gilles Salles, Catherine Burton, Daphne de Jong, Laurie H. Sehn, Delphine Maucort-Boulch
Journal: Journal of Clinical Oncology (2019)

MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene.The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes.A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001).The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.
Utilization of Hepatitis C Virus (HCV)‐Viremic Organs for HCV Negative Recipients: Is Practice Speeding Past the Evidence?
Authors: Elizabeth C. Verna, Demetra Tsapepas, Jean C. Emond, Robert S. Brown, Sumit Mohan
Journal: Hepatology (2019)

Verna, Elizabeth C. M.D., M.S.; Tsapepas, Demetra Pharm.D.; Emond, Jean C. M.D.; Brown, Robert S. Jr. M.D., M.P.H.; Mohan, Sumit M.D., M.P.H. Author Information
Mutated RAS: Targeting the “Untargetable” with T Cells
Authors: Praveen D. Chatani, James C. Yang
Journal: Clinical Cancer Research (2019)

The RAS family of proteins is at the apex of several pathways implicated in a multitude of epithelial cancers but has remained stubbornly resistant to the wave of targeted small molecules and antibodies that have revolutionized clinical oncology. KRAS, the most commonly mutated of the isoforms, represents an attractive target for treatment, given its ubiquity, central role as a driver mutation, and association with poor prognosis. This review is a comprehensive summary of the existing approaches to targeting KRAS spanning small-molecule inhibitors, cancer vaccines, and with a focus on trials in adoptive cell therapy. Here we explain how the limitations of existing drugs and nonspecific immune-based therapies are circumvented with techniques in modern immunotherapy. The successes outlined represent the most promising path to finally targeting the prototypical "undruggable" RAS oncogene family.
Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model
Authors: Nathan McDannold, Yongzhi Zhang, Jeffrey G. Supko, Chanikarn Power, Tao Sun, Chengueng Peng, Natalia Vykhodtseva, Alexandra J Golby, David A. Reardon
Journal: Theranostics (2019)

The blood-brain barrier (BBB) restricts delivery of most chemotherapy agents to brain tumors.Here, we investigated a clinical focused ultrasound (FUS) device to disrupt the BBB in rats and enhance carboplatin delivery to the brain using the F98 glioma model.Methods: In each rat, 2-3 volumetric sonications (5 ms bursts at 1.1 Hz for 75s) targeted 18-27 locations in one hemisphere.Sonication was combined with Definity microbubbles (10 µl/kg) and followed by intravenous carboplatin (50 mg/kg).Closed-loop feedback control was performed based on acoustic emissions analysis.Results: Safety and reliability were established in healthy rats after three sessions with carboplatin; BBB disruption was induced in every target without significant damage evident in MRI or histology.In tumor-bearing rats, concentrations of MRI contrast agent (Gadavist) were 1.7 and 3.3 times higher in the tumor center and margin, respectively, than non-sonicated tumors (P<0.001).Tissue-to-plasma ratios of intact carboplatin concentrations were increased by 7.3 and 2.9 times in brain and tumor respectively, at one hour after FUS and 4.2 and 2.4 times at four hours.Tumor volume doubling time in rats receiving FUS and carboplatin increased by 96% and 126% compared to rats that received carboplatin alone and non-sonicated controls, respectively (P<0.05); corresponding increases in median survival were 48% and 66% (P<0.01).Conclusion: Overall, this work demonstrates that actively-controlled BBB disruption with a clinical device can enhance carboplatin delivery without neurotoxicity at level that reduces tumor growth and improves survival in an aggressive and infiltrative rat glioma model.
Recombinant type VII collagen significantly increases transwell migration in squamous cell carcinoma keratinocytes isolated from patients with recessive dystrophic epidermolysis bullosa
Authors: C. Pourreyron, C. Hogan, C. L. Cole, L. Bruckner-Tuderman, J. A. McGrath, I. M. Leigh, A. P. South
Journal: British Journal of Dermatology (2009)
Absence of Iodine Staining Associates With Progression of Esophageal Lesions in a Prospective Endoscopic Surveillance Study in China
Authors: Mengfei Liu, Zhen Liu, Fangfang Liu, Chuanhai Guo, Ruiping Xu, Fenglei Li, Anxiang Liu, Haijun Yang, Sanshen Zhang, Lin Shen, Liping Duan, Qi Wu, Changqi Cao, Yaqi Pan, Ying Liu, Jingjing Li, Hong Cai, Zhonghu He, Yang Ke
Journal: Clinical Gastroenterology and Hepatology (2019)
Abstract 13956: Cystatin C Based Estimated Glomerular Filtration Rate is a Feasible Parameter for Incident Stroke in Patients With Atrial Fibrillation
Authors: Naoto Hashimoto, Satoshi Nishiyama, Tetsu Watanabe, Masahiro Wanezaki, Gensai Yamaura, Takanori Arimoto, Hiroki Takahashi, Tetsuro Shishido, Takuya Miyamoto, Isao Kubota
Journal: Circulation (2015)

Introduction: Chronic kidney disease (CKD) is an important risk factor of stroke in patients with atrial fibrillation (AF). Since AF patients with high CHADS2 score are likely to be old and have history of TIA or stroke, there could be patients who have sarcopenia. Cystatin C based estimated glomerular filtrarion rate (eGFRcys) is less affected by age, gender and muscle mass compared to creatine based eGFR (eGFRcr). We investigated whether eGFRcys is more closely associated with incident stroke in AF patients compared to eGFRcr. Methods: We performed transthoracic and transesophageal echocardiography and measured eGFRcys and eGFRcr in 349 patients with paroxysmal AF and chronic AF (256 males, 64.4 ± 11.7 years). We excluded those who had severe valvular heart disease and end stage renal desease. There were 42 patients with stroke history. Results: eGFRcys showed better correlation with left atrial volume index, levels of brain natriuretic peptide, von Willebrand factor, and left atrial appendage emptying flow velocity, than eGFRcr. eGFRcys was decreased with increading CHADS2 and CHA2DS2VASc score. Patients with left atrial appendage and/or spontaneous echo contrast had a significantly lower eGFRcys compared to those without. The proportion of patients with stroke was increased with advancing CKD stage in eGFRcys. Although eGFRcys and eGFRcr were associated with stroke in logistic regression analysis, eGFRcys but not eGFRcr was an independent predictor for stroke after adjustment for CHADS2 score. Conclusion: eGFRcys is a feasible parameter for incident stroke in AF patients.
Alveolar soft PART sarcomas (ASPS): A tertiary care center experience from India.
Authors: Vijai Simha, Sujith Kumar Mullapally, Sonal Dandekar, Siddharth Turkar, Bharat Rekhi, Jyoti Bajpai
Journal: Journal of Clinical Oncology (2019)

e22553 Background: Alveolar soft part sarcomas (ASPS) are rare, vascular, soft tissue sarcomas and response to conventional chemotherapy is disappointing. There is sparse data from India and other lower and middle-income countries (LMICs) and merits exploration. Methods: This is a retrospective analysis of patients of ASPS treated at Tata Memorial Center, patterns of care and outcomes were analyzed. Results: Fifty four patients of ASPS were treated between January 2002 to July 2018. The median age was 30 years and most common primary site 45 (80%) was extremities. Distant metastasis were seen in 36 (67%) patients; 20 upfront and 16 on recurrence. In the period from 2002-2014, 18/34 (54%) patients were declared “best supportive care” for want of effective systemic therapies. Only 16 (47%) patients with metastatic disease received systemic chemotherapy. 8 (11%) patients received conventional chemotherapy. Most commonly used regimen was combination of Ifosfamide and Adriamycin, however, 5/8 ( 62.5%) had progressive disease on chemotherapy and 37.5% had grade ≥3 toxicity mainly in form of neutropenias . Since the year 2015, the pattern of care evolved and 6 patients with metastatic disease were treated with antiangiogenic therapies (Sunitinib and Pazopanib). Responses were seen in 4/6 (66.6%) including 2 partial and 2 complete responses. The median progression free survival of these patients was 23 months (95% CI 14.3- 27.3 months) and was significantly better than that of conventional therapies - 7 months (95% CI 5.1-9.8 months) p = 0.03. Conclusions: ASPS is a systemic disease with high metastatic potential and poor chemosensitivity. Our institute practice has evolved from a policy of therapeutic nihilism to that of effective and feasible treatment in form of antiangiogenic therapy with meaningful responses.
Clinical validation of a self-organizing map (SOM)-based quantitative prediction algorithm to determine the site of origin of cancers of unknown primary (CUP)
Authors: S. J. Potts, R. Chen, K. Z. Qu, B. Crossley, R. A. Bender
Journal: Journal of Clinical Oncology (2007)

21064 Background: As many as 100,000 new cases of CUP are diagnosed each year in the United States. Identifying the site of origin of the CUP is critical for effective cancer management, and several genomic assays have been developed to facilitate this process. The genomic profile generated does not always fit into a discrete classification, however, and communicating results in a simple, easily understood format is important to clinical practice. Methods: We created a novel algorithm that combines SOMs for qualitative visualization with a quantitative clustering algorithm to predict the site of origin of metastatic cancers. We trained the algorithm on a dataset of 231 tumor-bank samples from 9 primary sites. After fixing all thresholds and algorithm settings, we evaluated the algorithm's performance in making a correct first or second prediction on a second blinded and independent dataset of 63 samples. Results: The algorithm correctly predicted the primary site in 82% of cases with the first prediction, and 89% with either the first or second prediction. The map visualization component helped to reduce the biological and mathematical complexity of the test into an easy to understand format for practicing physicians. The map- based approach allowed a fuzzy prediction that complements a class-based prediction and provides substantial additional information on the relationship between an unknown specimen and other related specimens of known provenance. Conclusion: CUP is a formidable clinical problem; correctly identifying the primary site and rendering specific treatment translates into improved patient outcomes. The use of an SOM to depict the genomic profile of the tumor specimen makes it easier for the clinician or pathologist to understand what tumor type the CUP most closely resembles and facilitates further diagnostic or therapeutic decisions. No significant financial relationships to disclose.
ICON PART-T 2019–International Scientific Tendinopathy Symposium Consensus: recommended standards for reporting participant characteristics in tendinopathy research (PART-T)
Authors: Ebonie Kendra Rio, Sean Mc Auliffe, Irene Kuipers, Michael Girdwood, Hakan Alfredson, Roald Bahr, Jill L Cook, Brooke Coombes, Siu Ngor Fu, Alison Grimaldi, Robert-Jan de Vos, Jeremy S Lewis, Nicola Maffulli, Peter Malliaras, S P Magnusson, Edwin H G Oei, Craig Robert Purdam, Jonathan D Rees, Alex Scott, Karin Gravare Silbernagel, Cathy Speed, Inge van den Akker-Scheek, Bill T Vicenzino, Adam Weir, Jennifer Moriatis Wolf, Johannes Zwerver
Journal: British Journal of Sports Medicine (2019)

We aimed to establish consensus for reporting recommendations relating to participant characteristics in tendon research. A scoping literature review of tendinopathy studies (Achilles, patellar, hamstring, gluteal and elbow) was followed by an online survey and face-to-face consensus meeting with expert healthcare professionals (HCPs) at the International Scientific Tendon Symposium, Groningen 2018. We reviewed 263 papers to form statements for consensus and invited 30 HCPs from different disciplines and geographical locations; 28 completed the survey and 15 attended the meeting. There was consensus that the following data should be reported for cases and controls: sex, age, standing height, body mass, history of tendinopathy, whether imaging was used to confirm pathology, loading tests, pain location, symptom duration and severity, level of disability, comorbidities, physical activity level, recruitment source and strategies, and medication use history. Standardised reporting of participant characteristics aims to benefit patients and clinicians by guiding researchers in the conduct of their studies. We provide free resources to facilitate researchers adopting our recommendations.
Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations
Authors: Anqi Lin, Ting Wei, Hui Meng, Peng Luo, Jian Zhang
Journal: Molecular Cancer (2019)

Abstract Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.