tbuckley/cabot-search huggingface dataset:
A Social Justice Framework for Lead Policy
Authors: Jessica Wolpaw Reyes
Journal: JAMA Pediatrics (2018)

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Enrollment of Hispanics in cancer clinical trials: An FDA analysis.
Authors: Lola A. Fashoyin-Aje, Laura L. Fernandes, Patricia Keegan, Rajeshwari Sridhara, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

e18670 Background: New Drug- and Biologics License Applications are required to include demographic data, including data on race/ethnicity, according to categories set forth in the Office of Management &Budget (OMB) Directive 15, which defines 5 race categories: American Indian/Alaska Native, Asian, Black/ African American, Native Hawaiian/ Other Pacific Islander, or White, and 2 ethnicity categories (Hispanic/Latino or Not Hispanic/Latino). The Directive was intended to identify potential lack of representation of demographic subgroups to enable redress early in CT conduct. We assessed the proportion of patients identified as ‘Hispanic/Latino’ (Hispanic) in clinical trials (CTs) supporting the approval of new drugs for the treatment of solid tumor malignancies. Methods: We reviewed the marketing applications of approved new cancer drugs between 2011- 17, to identify CTs that provided the primary safety and efficacy data. Demographic data were pooled across trials and analyzed in aggregate. Results: Hispanic patients represented 2.5% (n = 906) of the total population; 35% were enrolled in the US and 77% reported ‘White’ race. The majority of Hispanic patients enrolled outside the US were enrolled in sites in Spain (23%), Brazil (18%), Italy (11%) and France and Mexico (7% each). Patients who reported Hispanic ‘race’ represented 0.21% of all patients. Conclusions: Census estimates indicate that Hispanics comprise 11% of the US population. This analysis suggests that patients who report Hispanic ‘ethnicity’ or ‘race’, may be underrepresented in CTs. This finding is limited by inconsistencies in the reporting of race/ethnicity data in the applications we reviewed. For many patients, ‘ethnicity’ was not collected or, reporting did not meet FDA requirements. Measures are needed to ensure that the data submitted to the FDA meet the requirements of OMB Directive 15. Most patients reporting ‘Hispanic’ ethnicity were enrolled in European sites. This subgroup may not be representative of the Hispanic population in the US which predominantly reflects emigration from Mexico and Central America. Ethnicity EX-US n = 26275 % US n = 9342 % Hispanic 2 3 Not Hispanic 32 51 Not collected 40 22 Not reported 25 22 Other* 1 2 *Ethnicity not reported in accordance with OMB.
TCT-275 Percutaneous Transapical Left Ventricular Access to Treat Paravalvular Leak and Ventricular Septal Defect is Clinically Effective and Associated with Infrequent Adverse Events
Authors: Joseph Venturini, Isla McClelland, Akhil Narang, Rohan Kalathiya, Jonathan Rosenberg, Taishi Hirai, Roberto Lang, Karima Addetia, John Blair, Jonathan Paul, Sandeep Nathan, Valluvan Jeevanandam, Atman Shah
Journal: Journal of the American College of Cardiology (2018)
P04.56 Brain tumor patients with impaired cognitive flexibility do not efficiently update functional connectivity within the fronto-parietal network
Authors: W de Baene, J M Jansma, G Rutten, M M Sitskoorn
Journal: Neuro-Oncology (2018)

The majority of brain tumor patients suffers from cognitive deficits. These deficits can be very disruptive for a person’s daily functioning, quality of life and treatment compliance. Examining functional connectivity patterns during the performance of a cognitive task may enhance our understanding of the relationship between functional brain networks and cognitive performance. Despite the similarity in network topology across rest and task states, there are also meaningful differences in functional connectivity that are likely to be linked to cognitive performance. Currently, it is largely unknown how differences between rest and task functional connectivity patterns are related to cognitive functioning in brain tumor patients. The goal of this study was therefore to explore this relationship, whereby we focussed on cognitive flexibility. We expected less intense task-evoked network reconfiguration in patients with worse cognitive flexibility abilities. Resting state and functional MRI data (while performing several working memory tasks) were acquired in 50 brain tumor patients (23 meningioma, 13 low grade and 14 high grade glioma patients) before tumor resection. Performance on the “Shifting Attention Test” (SAT; part of CNS-VS) was used as an independent measure of a patient’s cognitive flexibility. Task-evoked network reconfiguration was investigated at the whole-brain and at the network level (fronto-parietal (FPN), cingulo-opercular (CON), and default mode (DMN) network). Whole-brain and network-specific connectivity matrices were created for each patient. We used the Pearson correlation value as a measure of similarity between rest and task functional connectivity patterns. For each network and for the whole brain, a linear regression (4 in total) using demographic and clinical factors, tumor characteristics and the reconfiguration measure was performed to test the relationship between the reconfiguration measure and cognitive flexibility performance while correcting for the other variables. We found that, across patients, SAT performance was negatively associated with the similarity of the FPN connectivity pattern between task and rest (β= -75.84, t(42)=-3.63, p<0.001). No association was found between SAT scores and degree of reconfiguration at the whole brain level or for the CON or DMN. Our results show that cognitive flexibility problems in brain tumor patients are associated with a higher rest-task similarity in the fronto-parietal network topology. Possibly, the problems with cognitive flexibility are related to reduced capacity to update the fronto-parietal connections to changing cognitive demands. Our findings provide an important step towards individually-tailored treatment of cognitive deficits.
An evaluation of c-myc aberrations in patients with newly diagnosed multiple myeloma (NDMM).
Authors: Amy Guzdar, Caitlin Costello
Journal: Journal of Clinical Oncology (2018)

e20006 Background: Multiple myeloma (MM) is a plasma cell dyscrasia marked by clonal evolution and preceded by a premalignant stage, which progresses via pathway deregulation, including MYC activation. Activation of MYC, an oncogenic protein that is part of the MAP kinase growth and proliferation pathway, has been implicated in the progression to active multiple myeloma. Methods: We performed a retrospective review of clinical features of patients with NDMM and myc aberrations between Oct 2015 and Nov 2017. c-myc abnormalities were found on diagnostic bone marrow evaluations in 19 patients by conventional karyotype and/or fluorescent in situ hybridization assays. Results: 10 (53%) of these patients had a myc 8;14 translocation, 5 (26%) had an overexpression of myc, and 4 (21%) had an underexpression of myc, with a laboratory cutoff for expression at 4% for each of these mutations. 14 (76%) of patients were under 65 years, whereas 5 (24%) of patients were 65 years or older. Evaluation of CRAB features in these myc-mutated newly diagnosed MM patients were as follows: 5 (26%) presented with renal disease (Cr > 2mg/dL); 5 (26%) with hypercalcemia (Ca > 11mg/dL); 16 (84%) with osteolytic lesions found on radiography; 11 (58%) with anemia (Hgb < 10g/dL). This is consistent with previous data of presenting symptoms in NDMM. R-ISS staging for c-myc mutated NDMM patients included: 3 (16%) Stage I; 9 (47%) Stage II, 4 (21%) Stage III, and 3 (16%) with missing staging data. Conclusions: These data suggest that the presence of a myc mutation is not explicitly associated with features thought to otherwise confer a poor prognosis including high-risk cytogenetics, high beta 2 microglobulin, high LDH, and decreased albumin. Further evaluation is necessary to confirm these findings in a larger group of patients and to evaluate the apparent age discrepancy noted in this small retrospective study. Characteristics No. of Patients (N = 19) Percent of Patients (%) Male 10 53% Female 9 47% Age < 65 14 74% Age ≥ 65 5 26% White 8 42% Black 3 16% Asian 1 5% Other 7 37% R-ISS Stage I 3 16% R-ISS Stage II 9 47% R-ISS Stage III 4 21% R-ISS Missing 3 16% Hypercalcemia (Ca > 11mg/dL) 5 26% Renal Disease (Cr > 2mg/dL) 5 26% Anemia (Hgb < 10g/dL) 11 58% Radiographic Osteolytic Lesions 16 84%
Prospective assessment of patient perception and quality of life in gynecologic patients after pelvic exenteration.
Authors: Shannon Dawn Armbruster, Charlotte C. Sun, Pamela T. Soliman, Shannon Neville Westin, Diane C. Bodurka, Lois M. Ramondetta, Andrea Michele Bradford, Karen Basen-Engquist
Journal: Journal of Clinical Oncology (2016)

10082 Background: Pelvic exenteration (PE) is surgical procedure associated with significant morbidity offered to select women with centrally recurrent gynecologic cancers. This ongoing study aims to examine multifaceted quality of life (QOL) domains and patient satisfaction with PE. Methods: Since January 2009, prospectively enrolled participants completed questionnaires evaluating body image (BIS), depression (CESD), social support (DUFSS), symptoms (MDASI), sexual function (SAQ), QOL (SF-12, Stoma-QOL), bladder QOL (FACT-BL), satisfaction with decision (SWD) and an investigator-designed survey at baseline, 4-6 weeks, 6 and 12 months after PE. Mann-Whitney and Wilcoxon signed-rank tests were used to evaluate the data. Results: 52 women enrolled; 22 completed surveys at baseline and 1 year. Median age was 60 years (range 37, 76). Median BMI was 31.5 kg/m2. 75% were white. Cancer diagnoses included 40% cervix, 21% uterine, 19% vaginal, 17% vulvar and 2% ovarian. 78% underwent a total PE. As measured by SF-12, physical (PCS) and mental component scores (MCS) decreased at 6 months (p = 0.01; p = 0.03) but returned to baseline at 1 year (PCS p = 0.10; MCS p = 0.29). Bladder-related QOL declined at 4-6 weeks (p = 0.003), returned to baseline at 6 months (p = 0.36) and remained stable at 1 year (p = 0.11). Body image declined at 1 year (p = 0.03). At baseline, 38% of women reported sexual activity. At 1 year, sexually active women (22%) had reduced sexual pleasure (p = 0.02); sexual discomfort remained stable (p = 0.58). Physical problems (44%) and lack of interest (35%) accounted for sexual inactivity at 1 year. Women remained satisfied with their decision for PE between 6 and 12 months (p = 0.44). At 6 months, 82% of women reported that they would have a PE again; the remainder were unsure. Depression levels, social support, symptom assessment and stoma-QOL remained stable over the study period. Conclusions: Despite a transient decrease in QOL, persistent low body image and sexual dysfunction, most women were satisfied with their decision and would undergo a PE again. This finding supports the use of PE in properly selected women, while identifying QOL domains that should be supported during survivorship care.
Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström's macroglobulinemia.
Authors: Meletios A. Dimopoulos, Alessandra Tedeschi, Judith Trotman, Ramón Garcia-Sanz, David MacDonald, Veronique Leblond, Beatrice Mahe, Charles Herbaux, Constantine Tam, Maria Lia Palomba, Jeffrey Matous, Chaim Shustik, Efstathios Kastritis, Steven P. Treon, Jianling Li, Zeena Salman, Thorsten Graef, Christian Buske
Journal: Journal of Clinical Oncology (2018)

8003 Background: Single-agent ibrutinib (ibr) is highly active in relapsed Waldenström’s Macroglobulinemia (WM) and is approved in the US and EU for WM. We report the results of a multinational, prospective, randomized trial of ibr/rituximab (IR) vs placebo/rituximab (R) in WM at a preplanned interim analysis. Methods: Pts with confirmed symptomatic WM were randomized to daily ibr (420 mg) or placebo, both with R (375 mg/m2/wk IV for infusions at wks 1-4 and 17-20). Pts treated with a prior R-based regimen required a response (≥MR) to the last R therapy. The primary endpoint was PFS by IRC. We also report response rates, Hb improvement, TTnT, OS, and safety. Results: For 150 randomized pts, median age was 69 y; 38% had a high IPSSWM; 45% were treatment-naïve. MYD88L265P and CXCR4WHIM mutations were found in 85% and 36% of 136 pts with available data. At median follow-up of 26.5 mo, IR prolonged PFS compared with R (median PFS, not reached [NR] vs 20 mo; HR, 0.20; CI: 0.11-0.38, P < 0.0001); 30-mo PFS rates were 82% vs 28%. PFS improved in all relevant subgroups, including treatment-naïve (HR, 0.34; CI: 0.12-0.95), relapsed (HR, 0.17; CI: 0.08-0.36), MYD88L265P/CXCR4WT (HR, 0.17; CI: 0.06-0.49), MYD88L265P/CXCR4WHIM (HR, 0.24; CI: 0.09-0.66), and MYD88WT/CXCR4WT (HR, 0.21; CI: 0.04-1.1). Overall (≥MR) and major (≥PR) response rates by IRC were higher for IR vs R, 92% vs 47% and 72% vs 32% (both P < 0.0001). Improvements in Hb were seen in 73% vs 41% of IR and R patients (P < 0.0001). 75% of IR pts continued on treatment. Median TTnT was NR for IR and 18 mo for R (HR, 0.096; P < 0.0001). The 30-mo OS rates were 94% vs 92% in the 2 arms. With median time on treatment of 25.8 mo for IR, grade ≥3 treatment-emergent AEs occurred in 60% vs 61% of pts on each arm. Serious AEs occurred in 43% vs 33% of pts on IR vs R, whereas no fatal AEs occurred with IR and 3 with R. Meaningful reductions in any grade IgM flare (8% vs 47%) and grade ≥3 infusion reactions were observed (1% vs 16%) with IR. Conclusions: The IR combination demonstrated superior efficacy to R, producing significant improvements in PFS for all WM patients regardless of prognostic or genotypic factors with a predictable toxicity profile. IR should be considered a standard therapeutic option for patients with WM. Clinical trial information: NCT02165397.
Integrative clinical genomics of early-onset breast cancer.
Authors: Lixi Li, Zongbi Yi, Chunxiao Li, Xiuwen Guan, Binghe Xu, Fei Ma
Journal: Journal of Clinical Oncology (2018)

1541 Background: The peak onset age of breast cancer in China is about 10 years ahead of Europe and the United States. Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The spectrum of germline mutation among unselected patients with early-onset breast cancer is largely uncertain, and it has never been studied among women under 25 years old. Exploring the mutation spectrum of early-onset breast cancer can help identify molecular markers and provide therapeutic targets for clinical treatment. Methods: About 20,000 women with breast cancer visited National Cancer Center between 2000 and 2015, and nearly 5% of those patients were 35 years old or younger, of whom 242 women were included in this study. Peripheral blood samples were collected and germline DNA was sequenced with a 139-gene panel using next generation sequencing. Clinicopathological characteristics were assessed by age at diagnosis and mutation status. Results: In this study, 58 of the 242 (24.0%) women with early-onset breast cancer had at least one pathogenic germline mutation. The cumulative frequency of pathogenic germline mutations increased with decreasing age at diagnosis (P < 0.001). In addition to most of genes previously implicated in breast cancer (BRCA1, BRCA2, CHEK2, TP53, PALB2, MSH2, MSH6, MLH1, RAD51D, RAD51B, ATM), a number of novel mutated genes were identified, including APC, SLX4, TSC2, TGFBR2, RET, SBDS and FANCE. Germline mutation differed according to clinicopathological characteristics. Similar to the association between BRCA1 and TNBC, BRCA2 germline mutation was enriched in luminal B subtype and predicted worse prognosis, and CHEK2 p.H371Y mutation predicted HER2 negativity. Conclusions: The cumulative frequency of germline mutations increased with decreasing age at diagnosis. Hereditary susceptibility could account for 50% of breast cancer in ultra-young patients (≤25 years). Germline mutation could predict clinical characteristics and prognosis in early-onset breast cancer. Because of the high frequency and wide spectrum of pathogenic mutations, early-onset breast cancer should be offered genetic testing with a multigene panel.
Tumour-infiltrating CD8<sup>+</sup> lymphocytes as a prognostic marker in colorectal cancer: A retrospective, pooled analysis of the QUASAR2 and VICTOR trials.
Authors: Mark Glaire, Enric Domingo, George Nicholson, Marco Novelli, Kay Lawson, Dahmane Oukrif, Wanja Kidal, Havard Emil Danielsen, Rachel Kerr, David J. Kerr, Ian Tomlinson, David N. Church
Journal: Journal of Clinical Oncology (2018)

3515 Background: The intensity of the T cell anti-tumour response influences colorectal cancer (CRC) outcome, and may predict benefit from immunomodulatory therapies. However, previous studies have been limited by their modest size, heterogeneous non-experimental populations, and failure to adjust for confounders such as mismatch repair deficiency (MMR-D), POLE mutation, and chromosomal instability (CIN). Methods: We performed a prospective-retrospective, pooled biomarker study of 1804 CRCs from the QUASAR2 and VICTOR trials. The densities of CD8+ and CD3+ tumour infiltrate were quantified, and their association with clinical outcome analysed by univariable and multivariable Cox proportional hazards regression. Results: CD8+ cell density was strongly correlated with CD3+ infiltrate (Spearman rho = 0·65; P= 2·2x10-16), and was significantly associated with stage II disease (P= 1·5x10-4), right-sided primary tumour (P= 4·1x10-6), MMR-D/POLE mutation (P= 4·9x10-12), absence of chromosomal instability (CIN) (P= 1·2x10-3) and BRAF mutation (P= 3·2x10-3). In the QUASAR2 trial, CD8+ density was a stronger predictor of CRC recurrence than CD3+ alone, and showed similar discriminative ability to both markers in combination. In a pooled analysis of both studies, increasing CD8+ density was associated with significantly reduced risk of tumour relapse and death. Unadjusted estimates of recurrence-free probabilities at 3 years were 76·3% (95%CI = 73·4 – 79·4) vs. 83·8% (95%CI = 81·4 – 86·3) for CRCs with CD8+ cell density at the 10th and 90th centiles respectively. In multivariable analysis, CD8+ density was a stronger predictor of CRC recurrence (HR for each two-fold increase = 0·92, 95%CI = 0·87–0·97, P= 3·2 x10-3) and overall survival (HR = 0·93; 95% CI = 0·87–0·99, P= 0·02), than MMR-D/POLE mutation or CIN, which were not significantly associated with either endpoint after adjustment for CD8+ infiltrate. Conclusions: Quantification of CD8+ cell density holds promise to refine prognostication in CRC beyond current clinicopathological and molecular factors.
Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial
Authors: Sören Verstraete, Sascha C Verbruggen, José A Hordijk, Ilse Vanhorebeek, Karolijn Dulfer, Fabian Güiza, Esther van Puffelen, An Jacobs, Sandra Leys, Astrid Durt, Hanna Van Cleemput, Renate D Eveleens, Gonzalo Garcia Guerra, Pieter J Wouters, Koen F Joosten, Greet Van den Berghe
Journal: The Lancet Respiratory Medicine (2018)
A phase II trial of Q3 week or weekly paclitaxel in combination with bevacizumab for metastatic or unresectable angiosarcoma.
Authors: Nam Bui, Nikhil Kamat, Vinod Ravi, Kristen N. Ganjoo
Journal: Journal of Clinical Oncology (2017)

e22513 Background: Paclitaxel (P) and bevacizumab (B) are both agents that provide clinical benefit in advanced angiosarcoma. The objective of this study was to assess the efficacy and safety of P-B in two regimens: Q3 week or weekly P with B for patients with advanced AS. Methods: We conducted a multicenter phase II trial. Patients were to receive P 200mg/m2 IV with B 15mg/kg IV every 21 days (Regimen A) or P 90mg/m2 IV weekly D1, 8, 15 with B 15mg/kg IV D1 of a 28 day cycle (Regimen B) x6 cycles. Maintenance B followed at a dose of 15 mg/kg intravenously once every 21 days. The primary end point was 4 month non-progression rate (NPR, RECIST 1.1). Results: A total of 16 patients were entered in the study between June 2010 through September 2013. Sites of disease included soft tissue (n = 5), skin/scalp (n = 5), breast (n = 4), and viscera (n = 2). All four breast patients were radiation induced after treatment for breast adenocarcinoma. 11 were chemotherapy naïve while 5 had received prior systemic chemotherapy. Results are reported as both an aggregate as well as per regimen (Table 1). 4 month NPR was 62.5% with median overall survival 16 months and median progression free survival 5.06 months. Of the 16 patients, 11 made it to cycle 3 and thus were evaluable for response. There were 1 CR, 4 PR, 2 SD, and 6 PD. There were no grade 5 toxicities, ten grade 3 toxicities and four grade 4 toxicities. The most common grade 3 toxicity was neutropenia (3/10) with other notable toxicities including peripheral neuropathy, hypertension, and heart failure. Grade 4 toxicities included neutropenia, bowel perforation, atrial flutter, and acute coronary syndrome. The breakdown between the two regimens revealed comparable efficacy and safety with similar ORR, 4mNPR, mOS, mPFS, and G3/4 toxicities. Conclusions: P and B followed by maintenance B is active and has a tolerable safety profile. Q3 week and weekly paclitaxel appear similar in efficacy and safety. Clinical trial information: NCT01055028. [Table: see text]