tbuckley/cabot-search huggingface dataset:
The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5
Authors: Meng Zhang, Weiwei Weng, Qiongyan Zhang, Yong Wu, Shujuan Ni, Cong Tan, Midie Xu, Hui Sun, Chenchen Liu, Ping Wei, Xiang Du
Journal: Journal of Hematology & Oncology (2018)

The long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been reported to be overexpressed in colorectal cancer (CRC). However, its underlying mechanisms in the progression of CRC have not been well studied. To investigate the clinical significance of NEAT1, we analyzed its expression levels in a publicly available dataset and in 71 CRC samples from Fudan University Shanghai Cancer Center. Functional assays, including the CCK8, EdU, colony formation, wound healing, and Transwell assays, were used to determine the oncogenic role of NEAT1 in human CRC progression. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and Dual-Luciferase Reporter Assays were used to determine the mechanism of NEAT1 in CRC progression. Animal experiments were used to determine the role of NEAT1 in CRC tumorigenicity and metastasis in vivo. NEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues. Altered NEAT1 expression led to marked changes in proliferation, migration, and invasion of CRC cells both in vitro and in vivo. Mechanistically, we found that NEAT1 directly bound to the DDX5 protein, regulated its stability, and sequentially activated Wnt signaling. Our study showed that NEAT1 indirectly activated the Wnt/β-catenin signaling pathway via DDX5 and fulfilled its oncogenic functions in a DDX5-mediated manner. Clinically, concomitant NEAT1 and DDX5 protein levels negatively correlated with the overall survival and disease-free survival of CRC patients. Our findings indicated that NEAT1 activated Wnt signaling to promote colorectal cancer progression and metastasis. The NEAT1/DDX5/Wnt/β-catenin axis could be a potential therapeutic target of pharmacological strategies.
Abstract 19063: Characterizing the Lay Public’s Perception of Cardiopulmonary Resuscitation Education Through Twitter
Authors: Shaun K McGovern, Audrey L Blewer, Andrew Murray, Marion Leary, Benjamin S Abella, Raina M Merchant
Journal: Circulation (2016)

Background: Understanding the lay public’s perception of CPR education could help address the problem of low training rates. Twitter, a popular microblogging social media platform, holds great pote...
Long-term outcome of penile squamous carcinoma: Single Argentinian institutional study.
Authors: Gaston Martin Reinas, Ernesto Gil Deza, Dario Niewiadomski, Monica Montiel, Leonardo Smolje, Mariana Abal, Sandra L. Ares, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2018)

e16593 Background: Squamous penile cancer is a rare malignancy affecting about 1 in 100,000 men worldwide per year. This retrospective study aims to evaluate treatments and outcome in penile cancer patients (Pt) followed at IOHM. Methods: Between 1/1/2003 and 12/31/2017 clinical records of penile cancer Pt were analyzed from the IOHM database. Pt characteristics considered: age, disease stage, histopathology, treatment modalities and outcome. Results: A total of 75 Pt (0.2%) out of 35,226 Pt were identified. Median age: 61 years (r = 31 - 87). Stage distribution: Stage 0:11 Pt (15%), Stage I: 27 Pt (36%) ; Stage II: 13 Pt (17%); Stage III: 12 Pt (16%), Stage IV: 12 Pt (16 %); Tumor (T) histopathology squamous : 75 T (100%), Tumor Infiltrating Lymphocytes (TIL) : 44 T ( 59%), Neural invasion: 11 T (15%) and Lymphovascular invasion: 6 T (8%) Surgical treatment: all stage 0 Pt were treated with excision biopsy. All Pt with stages I,II and III were initially treated with partial penectomy: 43 Pt (83%) or total penectomy: 9 pts (17%). Radiotherapy was administered in three stage III Pt. All stage IV Pt were treated with first line platinum-based chemotherapy and second line taxanes. At a median follow-up of 18 months, 51 Pt are alive and 24 Pt have died. Median overall survival (OS) by Stage was: 0 = 33m; I = 27m; II = 24m; III = 13m and IV = 8m (KM p = 0.0001). At stages I, II and III the only predictive factor for survival was TIL. Median OS was 27m with TIL vs 17m without TIL (KM p = 0.005). Conclusions: 1) Stages 0 and I Pt are curable with surgical treatment. 2) Stages II and III Pt have poor prognosis despite total penectomy treatment. 3) Stage IV Pt have poor response to Chemotherapy. 4) Future trials should address the benefits of immunotherapy modulation in squamous penile cancer with TIL.
Sequence variants in patients with primary and acquired resistance to ibrutinib in the phase 3 MCL3001 (RAY) trial.
Authors: Georg Lenz, Sriram Balasubramanian, Jenna Goldberg, Aleksandra Rizo, Michael Schaffer, Charles Phelps, Simon Rule, Martin H. Dreyling
Journal: Journal of Clinical Oncology (2016)

7570 Background: In the phase 3 RAY study in patients with relapsed/refractory mantle cell lymphoma (MCL) comparing ibrutinib (Ibr) with temsirolimus (T), Ibr significantly prolonged PFS (14.6 vs 6.2 mo; p < 0.0001) and increased ORR (72 vs 40%; p< 0.0001). To understand underlying molecular mechanisms of response and resistance to ibrutinib, we performed next-generation sequencing. Methods: Clinical results of RAY are reported elsewhere (Dreyling 2015). Patients were grouped by best ORR + PFS (Durable Response: CR/PR + PFS ≥ 4 mo; Moderate Clinical Benefit: PR + PFS < 4 mo or SD; and Primary Resistant). For primary resistance, baseline variant differences between groups were analyzed. For acquired resistance, baseline and samples obtained at progression after response were compared. Deep sequencing was performed on DNA from tumor cells using a custom gene panel. Sequences were aligned to hg19 reference genome, variants described using SAMtools, and filters applied to identify possible somatic mutations. Results: Mutations associated with primary resistance to Ibr were identified in NF-kB signaling pathways, both canonical (e.g., A20) and noncanonical (e.g., BIRC2); in epigenetic modifiers; and in the EGFR family. 34 paired samples (11 Ibr; 23 T) were analyzed to explore acquired resistance. Two PLCg2 mutations were found in patients with durable PRs (18.5 and 8.5 mo); a CARD11 mutation after PR was found in 1 patient (after 12 mo). Mutations in epigenetic modifiers and alternate NF-kB or PI3K/mTOR pathways were found after a short treatment duration ( < 4 mo). No primary or acquired BTK C481S mutations were detected. Conclusions: Mutations in the NF-kB pathway bypassing BTK appear to be a common mechanism of resistance in this MCL population. The similarity between primary and acquired mutations, as well as the lack of BTK C481S mutations to date, may possibly be explained by the short follow-up and shorter response duration compared with CLL. Some mutations seen in the acquired setting (eg, CARD11, PLCg2) have been associated with Ibr resistance. Understanding both primary and acquired resistance patterns is key in order to improve outcomes and define the populations that benefit from Ibr treatment. Clinical trial information: NCT01646021.
Optimizing the timing of eribulin monotherapy for patients with metastatic breast cancer.
Authors: Sumito Shingaki, Takahiro Kogawa, Mototsugu Shimokawa, Yumi Fujimoto, Kenichi Harano, Yoichi Naito, Nobuaki Matsubara, Reiko Matsui, Ako Hosono, Hirofumi Mukai, Toru Mukohara
Journal: Journal of Clinical Oncology (2018)

e13063 Background: We hypothesized that eribulin as the former-line chemotherapy is more beneficial than as the latter-line, given preclinical data on its potential effect in alleviating distant metastasis by suppressing epithelial–mesenchymal transition. The aim of this retrospective study was to explore the optimal line of administering eribulin for patients with metastatic breast cancer (MBC). Methods: We identified all consecutive female patients with breast cancer who received eribulin monotherapy for metastatic disease in our institution, excluding patients with HER2-positive disease. Patients who received eribulin as the primary or secondary chemotherapeutic treatment for MBC were classified as the earlier-line eribulin cohort (EE), otherwise classified as the later-line eribulin cohort (LE). We conducted survival comparisons between both cohorts using the inverse probability of treatment weighted method, balancing the following characteristics: age, hormone receptor (HR) status, presence of visceral disease at initiation of the first-line chemotherapy for MBC, and primary metastatic disease or relapsed disease. Results: We identified 127 patients between July 2012 and December 2017 with a median age of 58 years (range, 34–81), of which 104 (81.9%) had HR-positive disease, 30 (23.6%) had primary metastatic disease and 97 (76.4%) had relapsed disease, and 107 (79.5%) had visceral disease. Progression-free survival (PFS) after eribulin therapy was 0.2 years (95% CI, 0.2–0.3): after adjusting for the patient’s characteristics, 0.3 years (95% CI, 0.2–0.5) in the EE and 0.3 years (95% CI, 0.2–0.6) in the LE (p = 0.6947). Overall survival (OS) after the first-line chemotherapy for MBC was 2.6 years (95% CI, 2.2–3.2): after adjusting for the patient’s characteristics, 1.3 years (95% CI, 0.7–2.3) in the EE and 2.1 years (95% CI, 1.7–2.4) in the LE (p = 0.3694). Conclusions: To our knowledge, this is the first report to address the real-world data on eribulin monotherapy for patients with MBC, comparing EE and LE. In contrast to our hypothesis, the EE failed to demonstrate significant survival benefit in the current study.
A curative intent trimodality approach for advanced isolated abdominal nodal metastasis in metastatic colorectal cancer: Update of a single-institutional experience.
Authors: Benny Johnson, Zhaohui Jin, Michael G. Haddock, Christopher Leigh Hallemeier, James A. Martenson, Rory L. Smoot, David W. Larson, Eric J. Dozois, David M. Nagorney, Axel Grothey
Journal: Journal of Clinical Oncology (2017)

3556 Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy &amp; the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.
SARC016: Phase II study of everolimus in combination with bevacizumab in sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors (MPNST).
Authors: Brigitte C. Widemann, Christian Frederick Meyer, Gregory Michael Cote, Rashmi Chugh, Mohammed M. Milhem, Brian Andrew Van Tine, AeRang Kim, Brian Turpin, Eva Dombi, Nalini Jayaprakash, Scott H. Okuno, Lee J. Helman, Ndidi Onwudiwe, Seth M. Steinberg, Denise K. Reinke, Karen Cichowski, John Peter Perentesis
Journal: Journal of Clinical Oncology (2016)

11053 Background: There are no effective medical treatments for MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR signaling and angiogenesis contributes to disease progression. In a genetically engineered mouse model of NF1 MPNST sirolimus prolonged progression free survival and sunitinib extended these effects. Methods: We conducted a phase II study of everolimus (10 mg PO once daily, 1 cycle = 28 days) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) [complete response, partial response (PR), or stable disease (SD) ≥ 4 months]. Tumor response was assessed after every 2 cycles (WHO criteria). Patients (pts) ≥ 18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. A two-stage design targeting a 25% CBR was used: If ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results: Twenty-five pts (15F:10M), 17 NF1 MPNST (median age 29 years, range 19-63) and 8 sporadic MPNST (median age 62 years, range 19-72) were enrolled. Twenty-one pts had metastatic disease at enrollment. One of 15 pts in stage 1 had clinical benefit (sporadic MPNST, SD for 6 cycles). Of 10 additional pts enrolled in the second stage, 2 had clinical benefit (1 NF1 MPNST SD for 6 cycles, 1 NF1 MPNST SD 7+ cycles, still on treatment). The best response was SD except in 1 pt with a PR after cycle 2, but PD after cycle 4. The median number of completed cycles was 3 (range 1-7+). Everolimus dose was reduced/discontinued for grades 1-3 oral mucositis (n = 3), grade 2 ear pain (n = 1), and grade 3 fatigue (n = 1). Bevacizumab and everolimus were permanently discontinued in 4 patients for drug related adverse events: grade 1-2 proteinuria (n = 2) per investigator decision, grade 5 intra-abdominal intra-tumor hemorrhage (n = 1), and grade 3 ALT elevation (n = 1). Conclusions: With a CBR of 12% (3/25) the combination of everolimus and bevacizumab did not reach the study’s target response rate and is not considered active in refractory MPNST. Adverse events were similar to those known for this combination. Clinical trial information: NCT01661283.
Characteristics and outcomes of Latino patients with EGFR-mutant NSCLC.
Authors: Matthen Mathew, Galina G. Lagos, Nisha Rao, Ramsey Nicholas Asmar, Xinhua Liu, Naiyer A. Rizvi, Manuela A. Orjuela, Catherine A. Shu
Journal: Journal of Clinical Oncology (2018)

e13578 Background: There is limited information on the spectrum of epidermal growth factor receptor (EGFR) mutations in Latino patients with non-small cell lung cancer (NSCLC) and their response to therapy with tyrosine kinase inhibitors (TKIs). We compared differences between Latinos and non-Latinos with EGFR-mutant NSCLC at an academic center serving a multiethnic population. Methods: EGFR-mutant NSCLC patients (n = 277) were identified from 2010-2016. For patients with self-identified ethnicity data (n = 270), demographic and clinical data were compared between Latinos and non-Latinos. Comparisons were performed with regards to age, gender, smoking status, stage at diagnosis, and spectrum of mutations. For patients who received treatment with a TKI for advanced disease (n = 119), progression free survival (PFS) and overall survival (OS) were examined. Results: Median age was 69.5 years, 16.3% were Latinos, 47.8 % were never-smokers, and 74.8% were female. Compared with non-Latinos, Latinos were more likely to present with Stage 4 disease (OR 4.2; p < 0.001) and were more likely to harbor tumors with common, sensitizing EGFR mutations (exon 21 L858R and exon 19 deletions), compared with other mutations (e.g. exon 18 and exon 20), (OR 3.0; p = 0.03). Latinos were significantly more likely to present with stage 4 disease after adjusting for age at diagnosis, gender, and type of EGFR mutation (OR 3.7; p < 0.001). A total of 30 (25.2%) Latinos and 89 (74.8%) non-Latino patients received treatment with a TKI. Median PFS was 1.09 years and median OS was 3.63 years. Risk of progression between Latinos and non-Latinos did not differ. However, after accounting for other factors including stage at diagnosis and type of EGFR mutation, Latinos had significantly worse OS compared to non-Latino patients (HR 2.23, 95% CI 1.23-4.05, p < 0.01). Conclusions: Latino NSCLC patients with EGFR mutations are more likely to present with advanced stage disease and have worse OS than non-Latinos. Further work is needed to clarify the poor long-term outcomes seen in Latino patients, especially since these patients have a favorable mutation profile and similar responses to initial TKI therapy compared to non-Latinos.
Risk stratification by detection of clonal circulating plasma cells (CPCs) by multi-parametric flow cytometry (MFC) in light chain amyloidosis (AL).
Authors: Surbhi Sidana, Nidhi Tandon, Angela Dispenzieri, Morie A. Gertz, Francis Buadi, Martha Lacy, David Dingli, Amie L. Fonder, Suzanne R. Hayman, Miriam A. Hobbs, Yi Lisa Hwa, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John Anthony Lust, Stephen J. Russell, S. Vincent Rajkumar, Shaji Kumar, Wilson I. Gonsalves
Journal: Journal of Clinical Oncology (2017)

8047 Background: Presence of CPCs by six color MFC is associated with worse outcomes in multiple myeloma (MM). Using a slide based immunofluorescence assay, CPCs are associated with worse prognosis in AL, but outcomes with MFC are not known. Methods: We retrospectively analyzed 154 patients (pts) from Jan 2008 – Dec 2015 with AL who had CPCs analyzed by MFC at diagnosis. Results: CPCs were present in 42% pts (n = 64, median = 88 per 150,000 events, range 6-17844). Table 1 lists baseline characteristics, treatment and response. In univariate analysis, bone marrow (BM) plasma cells &gt; 15% (p&lt;0.0001), dFLC &gt; 60 mg/dL (p=0.02) and presence of active MM (p=0.0004) were associated with detectable CPCs. In multivariate (MV) model, only BM plasma cells &gt; 15% predicted for presence of CPCs (p=0.02). There was no difference in hematologic or organ response in the 2 groups. Median follow up was 43 months (m). Pts with detectable CPCs had worse survival than those without detectable CPCs (90 m vs. 98 m, p=0.0004). In MV analysis model with Mayo Stage and detectable CPCs, presence of CPCs at diagnosis was independently associated with poor survival (CPCs p= 0.02, Mayo Stage p &lt; 0.0001). Conclusions: Presence of detectable CPCs is an independent adverse prognostic factor for survival in AL. Comparatively fewer pts with detectable CPCs underwent early ASCT, which may reflect a more aggressive disease presentation. [Table: see text]
Impact of comorbidity on immune checkpoint blockade tolerance across tumor types.
Authors: Sean Clark-Garvey, Thomas Holden, Daniel S. Altman, Sheel A. Patel, Sharon Li, Reetu Mukherji, Philip Margiotta, Mario Caldararo, Marlana M. Orloff, Jennifer Maria Johnson, Ryan Michael Weight
Journal: Journal of Clinical Oncology (2018)

e15068 Background: Immune Checkpoint Blockade (ICB) has demonstrated efficacy across a variety of tumor types. However, treatment is often complicated by immune related adverse events (irAEs), leading to discontinuation of therapy. Patients with poor performance status are excluded from most clinical trials. Therefore, the effect of comorbid conditions on the development irAEs is unknown. We analyzed a large single institution registry to determine the correlation of comorbidity and discontinuation of ICB across tumor types. Methods: A single institution registry of 113 patients who received and discontinued ICB, (ipilimumab [n = 18], nivolumab [n = 33], pembrolizumab [n = 18], atezolizumab [n = 4]) was reviewed. Reasons for discontinuing ICB were analyzed by tumor type and immunotherapy agent. Tumor subtypes included: Melanoma (43), NSCLC (40), Bladder (9), and other (21). ECOG PS and Charleston Comorbidity Index (CCI) were independently analyzed and correlated with development of irAEs. Results: The most common cause for discontinuation across all tumors was POD (64.6%); while 18.6% discontinued due to irAEs. Interestingly, there was no statistically significant difference between the rate of treatment-limiting irAEs and ECOG PS (p = 0.12) or CCI (p = 0.99). Only 1 of 18 patients with an ECOG PS of 2-3 discontinued therapy due to an irAE. See Table 1 Conclusions: Pre-treatment comorbidity did not influence the discontinuation rate of immune checkpoint blockage due to irAEs. The low rate of therapy discontinuation in patients with poor performance status and high comorbidity index provides insight into the application of immune checkpoint blockage outside of a clinical trial. Table 1. Treatment Discontinuation Rates by Immunotherapy Type, ECOG PS, and CCI Reasons for Discontinuation Progression of Disease (POD) irAEs Comorbidity/ Other Toxicity/ Death Number of patients, n (%) 73 (64.6) 21 (18.6) 19 (16.8) ECOG PS, n (%) 0 13 (46.4) 9 (32.1) 6 (21.5) 1 34 (64.2) 9 (17) 10 (18.8) 2-3 14 (77.8) 1 (5.6) 3 (16.6) CCI (Mean)* 8.1 7.71 7.67 Treatment, n (%) Nivolumab 33 (68.8) 5 (10.4) 10 (20.8) Pembolizumab 18 (75) 2 (8.3) 4 (16.7) Ipilumumab 18 (52.9) 14 (41.2) 2 (5.9) Atezolizumab 4 (57.1) 0 (0) 3 (42.9) *Reported as the average value for all patients.
Bakare Ummukulthoum #United4PlayerCare #TeamEffort
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

I believe my career still has a long way to go and I am looking forward to every bit of it. So far it would have to be seeing sports medicine acknowledged as a profession in my home country. It has not been easy, but I believe that when passion drives you, you really can change the culture and make a difference.

A Few Good Men (1992). I think Lieutenant Daniel Kaffee (Tom Cruise) hits home as the attorney who was left to defend the two marines fighting for their very lives because they followed orders. At the initial stages, he too was convinced that the marines were guilty and was only banking on a plea bargain until his co-counsel Lieutenant Commander JoAnne Galloway (Demi Moore) made him realise he needed to look more closely and make a case. It is a lot like sports medicine; we cannot afford to be in a rush to decide what is wrong, although the urgency may be required. We need to be patient to identify the problem and make an adequate care plan.





The real world is as competitive as high school. Be prepared and always stay on top of your game! Be the hardest worker in the room and stay humble. Knowledge is a continuum and there is no end to continuous self and professional development. Always work as a team because together everyone achieves more! 



I will describe my top two. First, when all the eight gold medals won by my athletes at the 2016 Paralympic Games in Rio for Team Nigeria set new world records. We finished 11th on the table …