tbuckley/cabot-search huggingface dataset:
Phase 0 (Ph0) and Window-of-Opportunity (WoO) trial quality and reporting.
Authors: Omar Farooq Khan, Sunil Parimi, Hatim Karachiwala, Yongtao Lin, Jose Gerard Monzon, Vincent C. Tam, Eric Chen, Janet Dancey, Patricia A. Tang
Journal: Journal of Clinical Oncology (2018)

e14518 Background: This study evaluated the quality of reporting for Ph0 and WoO trials and impact as measured by citations. Methods: Trials from 1974-2017 were identified using MEDLINE, EMBASE and PubMed. Data were extracted regarding quality of reporting and concordance with definitions previously established in a survey of 113 North American experts. 50% of the data was assessed by a second reviewer for data integrity; discrepancies were resolved via discussion and consensus with a third reviewer. Web of Science citations (for trials reported up to 2014) were assessed as a surrogate measure of Ph0 and WoO impact on drug development. Results: One hundred (28 Ph0 and 72 WoO) trials were identified, with most trials (78.0%) reported after 2010. Ph0 and WoO trials most commonly studied breast (38.0%) and head/neck (11.0%) malignancies, with limited representation of gastrointestinal (3.0%) and genitourinary (6.0%) malignancies. Nearly half of trials reported as Ph0 (42.9%) did not meet expert consensus definitions, while nearly all WoO trials (97.2%) met these definitions. WoO trials were most often Phase II studies (58.3%), while most Ph0 trials were combined with pre-clinical or Phase I studies (64.3%). 39.3% of Ph0 trials did not clearly delineate dose escalations. 67.9% of Ph0 and 55.6% of WoO trials did not specify if primary treatment was delayed due to trial participation. Ph0 trials were most likely to assess pharmacokinetic outcomes (82.1%; 64.3% as a primary outcome), while WoO trials were more likely to assess pharmacodynamic outcomes (75.0%; 68.1% as a primary outcome). Few Ph0 (17.9%) and WoO (31.9%) trials assessed clinical efficacy outcomes. Toxicities were inconsistently reported (Ph0 50.0% and WoO 65.3%). More than half of WoO trials (68.9%), but few Ph0 trials (22.2%) were cited in Web of Science by subsequent clinical trials. Conclusions: While utilization of Ph0 and WoO trials is increasing, the number of trials remains low, and many tumour sites are under-represented. Trials inconsistently report methods, outcomes and toxicities. The impact of WoO and Ph0 trials on drug development is unclear. Clear consensus definitions to guide Ph0 and WoO trials are needed to improve the quality of trial reporting.
The (Emotive) worm at the core: The role of emotional problems in the process from physical suffering to psychological distress—A multiple step mediation analysis.
Authors: Alessandro Rossi, Maria Marconi, Giuseppe Di Lucca, Raffaella Morena, Chiara Rossini, Luciano Banfi, Claudio Verusio
Journal: Journal of Clinical Oncology (2016)

10063 Background: Anxiety, depression and fear are all among oppressive emotions that oncological patients have to face almost every day. On one hand, these emotional problems seem to be triggered by physical, relational and practical problems; and on the other hand, these emotive troubles seem to lead to psychological distress – one of the most important indexes of mental health suffering in oncological patients (NCCN, 2002). The aim of the study was to test a multiple step mediation model (Hayes, 2013) in which emotional problems have a central role in the process leading to psychological distress. Methods: An observational research design was used. Patients (N = 211, mean age: 64.84, SD = 11.35) were consecutively enrolled at the Department of Medical Oncology at Presidio Ospedaliero of Saronno, ASST Valle Olona, Italy. Patients were tested with Distress Thermometer and Problem List (DT&PL; NCCN, 2003), assessing: (A) distress; (B) practical problems (α = .62); (C) social relations (α = .64); (D) emotional (α = .82) and (E) physical problems (α = .72). Results: First, a CFA was performed in order to test the structure of the proposed Problem List. The original five factor solution was supported by adequate fit indices: RMSEA = .055 (.048–.062), p(RMSEA < .05) = .118. Afterward, multiple step mediation analysis (5000 bootstrap resampling) showed model’s statistical significance [F = 57.52, p < .001; R2 = .54; η2 = .288]. The relationship between physical problems and distress was fully mediated (path c’: β = .089; p = .306; 95%CI: -.083, .262), first by practical problems (path a1: β = .057, p < .001; 95%CI: .031, .084), hence by relationships problems (path d1: β = .207, p < .001; 95%CI: .097, .316), and finally by emotional problems (path d2: β = .962, p < .001; 95%CI: .544, 1.37; and path b3: β = .808, p < .001; 95%CI: .612, 1.01). Conclusions: These results highlight the role of emotions, practical and relational problems in the process that lead to distress. These findings point out a new way in which psycho-oncologists should structure psychological interventions, in order to both reduce psychological suffering and improve a better quality of life in oncological settings.
Daratumumab-based therapies in patients with AL amyloidosis.
Authors: Jithma P. Abeykoon, Saurabh Zanwar, Shaji Kumar, Angela Dispenzieri, S. Vincent Rajkumar, Martha Lacy, David Dingli, Nelson Leung, Eli Muchtar, Wilson I. Gonsalves, Taxiarchis Kourelis, Francis Buadi, Robert A. Kyle, Morie A. Gertz, Prashant Kapoor
Journal: Journal of Clinical Oncology (2018)

8053 Background: Treatment options for patients (pts) with relapsed/refractory (RR) AL amyloidosis are limited. Daratumumab (dara) has been approved as monotherapy (DMT) or combination therapy (DCT) for multiple myeloma (MM). Data for dara-based therapy (DBT) in AL are sparse. Methods: We studied pts with RR AL without coexisting MM seen at Mayo Clinic from 11/2015 to 02/2018 & treated with DBT. Hematologic response (HR) & organ response (OR) were defined per Consensus criteria. All time to event analyses were done from the time of DBT initiation. Pts with dFLC < 4 mg/dL at the time of start of DBT were considered non evaluable (NE) for HR other than disease progression. DCT included dara, pomalidomide & dexamethasone (dex) (35%), dara, lenalidomide & dex (26%), dara, bortezomib & dex (22%) & other DBT regimens (17%). Results: 45 pts (DMT, n = 22; DCT, n = 23) received DBT; median age at DBT initiation was 64 years (range: 46-82). Data for HR assessment were available in 44 pts & 31 were evaluable for HR. HR & end points are outlined in Table 1. Among 13 NE pts, response improved to CR in 5 (38%) while remaining 8 continued to be NE. Of these 13 pts, 77% reached dFLC < 1 mg/dL at last follow up (FU). Cardiac, renal & liver involvement was observed in 59%, 43% & 7% of pts. Cardiac, renal and liver OR was 46%, 32%, 0%, respectively. At last FU, 31 pts were on DBT. Three (7%) pts had disease progression. Hematologic toxicity (HT) from DBT included anemia ≤2 grade (Gr = ) 69%, 3 Gr 3%; thrombocytopenia 1 Gr 38%; neutropenia ≤2 Gr21% & > 2 Gr 7%. Non-HTs included fatigue (23%), infusion reactions (21%), & treatment-emergent neuropathy (14%). Conclusions: DBT is safe & effective in heavily pretreated pts with AL. HR is achieved rapidly with DBT, particularly with DCT. Entire cohort, N = 45 DMT, N = 22a DCT, N = 23b Median prior lines of therapy, n (range) 3 (1-8) 3 (1-5) 3 (1-8) ORR /CR/ VGPR/ PR, (%) 84 / 19 / 61 / 3 77/14/ 64/ 0 88/ 22 / 59 / 6 Time to 1st/ best response, m (CI) 2 (2-5) / 6 (5-8) 4 (2-6) / 6 (2-9) 2 (1-3) / 6 (2-12) Median FU, m (CI) 10 (8.5-13) 8.5 (5.7-10.4) 13.1 (9.1-19.1) PFS, m (CI) NR (NR- NR) NR (13-NR) 16 (NR-NR) Duration of response, m (CI) NR (13-NR) NR (NR-NR) NR (13-NR) OS, m (CI) NR (17-NR) NR (13-NR) NR (15.5-NR) a14 evaluable for HR, b17 evaluable for HR, CI: 95% Confidence Interval, NR: Not Reached, m: months
LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial
Authors: Frances Game, William Jeffcoate, Lise Tarnow, Judith L Jacobsen, Diane J Whitham, Eleanor F Harrison, Sharon J Ellender, Deborah Fitzsimmons, Magnus Löndahl, Ketan Dhatariya, Harvey Chant, Gill Spyer, Mollie Donohoe, Elizabeth Uchegbu, Donald Whitelaw, Rahul Nayar, Peter Rossing, Hans Gottlieb, Morton Michelsen, Anna Marie Nielsen, Kim Houlind, Jan Sørensen, Eskild Henneberg, Bo Jørgensen, Kilimangalam Narayanan, Marie-France Kong, Ammar Tarik, Rajiv Gandhi, Christian Hariman, Victor Oguntolu, Gerry Rayman, Haroon Siddique, Ryan D'Costa, Deidre Maguire, Theingi Aung, Helene Holmer, Sergiu-Bogdan Catrina, Arthur Ogunko, Satyan Rajbhandari, David Russell
Journal: The Lancet Diabetes & Endocrinology (2018)
Robotic procedure versus open surgery for simultaneous resection of colorectal cancer with liver metastases: Short-term outcomes of a randomized controlled study.
Authors: Jianmin Xu, Ye Wei, Qinghai Ye, Xiaoying Wang, Wenju Chang, Mi Jian, Li Ren, Dexiang Zhu, Qingyang Feng, Xinyu Qin, Jia Fan
Journal: Journal of Clinical Oncology (2017)

3575 Background: The simultaneous resecting both colorectal cancer and liver metastases is a safety and efficacy surgical procedure for treating colorectal cancer patients with liver metastases (CRCLM).The safety and efficacy of robot-assisted simultaneous resection of CRCLM is unclear. Furthermore, what kind of selective CRCLM patients would obtain benefits from robotic procedure need identify. The aim of this study was designed to compare robotic procedure with open surgery, and establish robotic surgery indications to identify benefit population of CRCLM. Methods: CRCLM patients were evaluated and confirmed with surgical indication by multidisciplinary team (MDT), and randomized to two groups, robotic arm (n = 58) and open arm (n = 57). The primary endpoint is 3-year DFS, the second endpoints include short-term surgical outcomes, complications and safety. Results: A total of 115 patients were randomized between September 2013 and September 2016. Despite longer operating time, patients assigned to robot-assisted surgery had less blood loss (100ml vs. 150ml, P &lt; 0.001), a shorter time to pass first flatus (3 d vs. 4 d, P &lt; 0.001) and return to diet (3 d vs. 5 d, P = 0.002), shorter hospital stay with improved sexual function. Furthermore, followed benefits were observed in robotic arm versus open arm: lower serum C reactive protein (CRP) level on postoperative day 1 (POD1) (16 mg/L vs. 37 mg/L,P &lt; 0.001), and POD3 (112 mg/L vs. 160 mg/L, P &lt; 0.001), lower level of liver transaminase on POD5, and lower liver-related complication morbidity(10.3% vs 28.1%, p = 0.016). In addition, we identified and recommended selective CRCLM patients with the number of liver metastases &lt; 3, maximal tumor size &lt; 5cm, tumor not located in segment I to accept robotic procedure. Conclusions: We identified and recommended selective CRCLM patients to accept robotic surgery for treating liver metastases. Robotic surgery result in similar safety as open procedure, with shorter recovery time, decreased morbidity, and improved sexual function. Clinical trial information: NCT02642978.
Phase I/II study of durvalumab (anti–PD-L1 antibody) as monotherapy and in combination in patients with lymphoma or chronic lymphocytic leukemia.
Authors: Thomas E. Witzig, Carla Casulo, Guillaume Cartron, Jia Ruan, Simon Rule, Kiyoshi Ando, Cathy Burton, Antonio Pinto, Steven Le Gouill, Nathan Hale Fowler, Pier Luigi Zinzani, Sabine De Bedout, Nurgul Kilavuz, Nils Rettby, Myron Stefan Czuczman, Armando Santoro
Journal: Journal of Clinical Oncology (2017)

TPS7574 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.
Radiomics-based assessment of radiation-induced lung injury after stereotactic ablative radiotherapy.
Authors: Angel Moran, Megan Eileen Daly, Stephen S. F. Yip, Tokihiro Yamamoto
Journal: Journal of Clinical Oncology (2016)

e23156 Background: Assessment of radiation-induced lung injury, which is common after stereotactic ablative radiotherapy (SABR), is often qualitative and subjective. We aimed to perform higher-order characterization of post-SABR lung injury using computed tomography (CT)-based radiomics. Methods: 45 CT scans (acquired before SABR and at 3, 6 and 9 months post-SABR) from 13 patients were retrospectively analyzed. Lung injury was manually delineated and scored by a radiation oncologist. Texture features of delineated regions of interest were quantified: seven gray level co-occurrence matrix (GLCM) features (entropy, energy, contrast, dissimilarity, homogeneity, inverse difference moment, and correlation) and two first-order features as reference (mean and standard deviation [SD] of density). The ability of texture features to distinguish radiation oncologist-defined moderate/severe lung injury from none/mild lung injury was assessed using logistic regression and area under the receiver operating characteristic curve (AUC). Time dependency of texture changes was also assessed. Results: Significant correlations with radiation oncologist-scored lung injury were found for several GLCM features: correlation (p= 0.01), dissimilarity (p= 0.03) and contrast (p= 0.04), whereas no significant correlations were found for first-order features: mean (p= 0.99) and SD (p= 0.10). AUCs were greater for GLCM features (range: 0.689-0.750) than for first-order features (range: 0.543-0.661). Time dependency of changes in GLCM features differed from first-order features, e.g., dissimilarity significantly decreased at 3 months post-SABR and increased after 6 months. However, first-order features significantly increased at 3 months and remained constant after 6 months. Conclusions: Texture features were significantly correlated with radiation oncologist-scored post-SABR lung injury, suggesting the potential for radiomics to provide a quantitative, objective measurement of post-SABR lung injury. Time dependency of changes in texture features may indicate progression, persistence or regression of lung injury, which requires further studies to be validated.
P21 ACCELERATED ATHEROSCLEROSIS AND MYOCARDIAL INJURY IN PEOPLE LIVING WITH HIV
Authors: Dr G Manmathan, Mr A Hunter, Prof M Johnson, Dr R Rakhit
Journal: Cardiovascular Research (2018)

Vascular endothelial dysfunction promotes intimal retention and oxidation of low density lipoproteins (oxLDL)).This incites a pro-inflammatory response.Monocytes are recruited and upon diapedesis, use scavenger receptor mediated pathways to internalise the OxLDL, thus forming arterial foam cells, a lineage widely assumed to be pro-inflammatory.Reversing this process may dampen the chronic pro-inflammatory state in atherosclerosis, propagated by foam cells.Here, we investigate the role of eicosapentaenoic acid (EPA) in targeting this process.Classical monocytes were separated from the blood of healthy donors and cultured in 10% autologous serum for 7 days under 3 conditions; 1) untreated or 2) treated with fluorescently labelled OxLDL (Dil-OxLDL) or 3) treated with Dil-OxLDL with EPA.Uptake of oxLDL was analysed using fluorescent confocal microscopy.Culture supernatants at day 7 from each condition were stored and the secretory profile for cytokines and chemokines was analysed using cytokine membrane arrays.Co-localisation analysis showed a significant reduction in Dil-OxLDL uptake, and hence foam cell formation, with EPA treatment.Semi-quantitative analysis of cytokine arrays demonstrated an overall pro-inflammatory profile in foam cells compared to macrophages.Interestingly, EPA treatment was able to reverse this effect in foam cells.Thus, EPA has an inhibitory role in foam cell formation.In addition, EPA can affect the secretory profile of foam cells, promoting an anti-inflammatory environment.This study shows that further investigations into how EPA might be involved in the regression of atherosclerosis are warranted.
Potential relevant targets in synovial sarcoma.
Authors: Jorge Martinez Tlahuel, Mark Verburg, Tania E Gandara-Marti, Erik Ramos, Jose Antonio Matute-Briseno, Fernando ALFONSO Durazo-Bustamante, Pedro ALEJANDRO Lucero-Diaz, Mario ALBERTO Perez-Astorga, Juan Pablo Marquez-Manriquez
Journal: Journal of Clinical Oncology (2016)

e22527 Background: The potential clinical important targets for synovial sarcoma (SS) are mainly unknown. We performed a systematic review and we found eight potential proteins to be targeted in this deadly malignancy and immunohistochemistry was performed. Additionally there is limited information about the immune infiltration in synovial sarcoma. With that in mind we also analyze by regular hematoxylin and eosin staining and by immunohistochemistry (IHC) the adaptive immune cells specifically CD8 T cells and FOXP3 in primary surgical removed tumors. Methods: We performed a systematic review using terms “ synovial sarcoma and protein overexpression and multivariate analysis”. We found 8 proteins were overexpressed in this neoplasia. By using IHC we evaluated in SS (N = 20) all of them and simultaneously we performed IHC for tumors with immune infiltration staining CD8 cells and FOXP3 T cells. Additionally we evaluated PD-1 and PDL-1. Results: Four proteins showed significant overexpression. Fascin-1 (50%), Survivin (90%), Ape-1 (90%) and VCP (35%). Only 3% of the tumors were positive for CD8 T cells, 1% for FOXP3. Proteins such as EGFR (0%), Sox2 (5%), EBAG9 (5%), Thymidine phosphorylase (15 %), PD-1 (0%) and PD-L1 (0%) had null or low expression. Conclusions: SS is a complex neoplasia with very limited treatment options. It is important to explore potential clinical targets and or prognosis biomarkers in order to improve prognosis. Immunologically speaking little is known how the immune based therapies may benefit objectively in SS. Further we will prepare clinical correlations with this preliminary data to expand the cohort and focus on the proteins with more overexpression and also which is the role of the CD8 infiltration in terms of prognosis in SS.
Second-line drug regimens in metastatic melanoma patients based on BRAF mutation status: A Canadian real-world retrospective study.
Authors: Samantha Bremner, Marc Lapierre, Arushi Fraelic, Dave Stewart
Journal: Journal of Clinical Oncology (2016)

e21054 Background: Overall survival for metastatic melanoma patients has improved with targeted- and immuno-therapies. This study describes the second-line drug regimens in these patients based on their BRAF mutation status. Methods: This retrospective observational study utilized IMS Health Real-World Oncology Data, an anonymised patient database which includes patient and treatment metrics. This database is populated via an electronic questionnaire completed by physicians who treat metastatic melanoma patients. Second-line regimens, BRAF mutation status, co-morbidities and sites of metastasis were identified in a subset (N=383) of stage IV patients treated in Canada between October 2014 and September 2015. The second-line drug regimens were classified as immuno-, targeted-, combined immuno- and targeted- and chemo-therapies. The proportions of patients receiving each treatment modality were compared across the BRAF mutation status populations, with statistical testing of the differences at a 5% level of significance. Results: Of the 383 study patients receiving second-line treatment, 204 (53%) were BRAF+, 126 (33%) were BRAF- and 53 (14%) had unknown BRAF status. A statistically higher proportion of patients diagnosed as BRAF+ received targeted therapy compared to patients diagnosed as BRAF- (p=<0.05). Whereas, a statistically higher proportion of the patients diagnosed as BRAF- were treated with immunotherapy compared to BRAF+ patients (p=<0.05). Within our data, a subset of patients (N=28) received combined immuno- and targeted-therapies, predominantly in the BRAF+ patient group. Conclusions: The second-line landscape in metastatic melanoma is now dominated by immuno- and targeted-therapies in Canada. The synergistic effects of combining these two modalities are currently an area of research and this practice has been captured in our dataset. This study provides real-world evidence of the use of immuno- and targeted-therapies in patients with metastatic melanoma. Therapeutic Base BRAF+ (%) BRAF- (%) Unknown BRAF Status (%) Immunotherapies 21% 70% 36% Targeted Therapies 45% 7% 21% Combined Immuno- and Targeted- therapies 13% 1% 0% Chemotherapies 22% 22% 43%