tbuckley/cabot-search huggingface dataset:
P04.18 Unravelling the tumour microenvironment of glioma
Authors: K McKelvey, A Hudson, H Wheeler, C Diakos, V Howell
Journal: Neuro-Oncology (2018)

With the incidence and mortality of brain cancer almost equivocal there is a vital need to understand the intricacies of the glioma microenvironment. This study details the temporal and spatial localisation of immune cell populations and mediators during glioma development using the murine orthotopic Gl261 glioma model. Male C57Bl/6 mice were stereo-tactically inoculated with 1x106 Gl261 cells at AP0.1mm, ML1.0mm, DV2.4mm Bregma. Immune cell populations were assessed at D0, D1, D3, D7, D14, D21 post-inoculation by veterinary haematological analyser (Coulter Ac·Tdiff™) and 16-parameter flow cytometry (Fortessa™). Significant temporal changes were observed in all immune cell populations among the splenic, bone marrow and peripheral blood systemic compartments: WBCs, RBCs, platelets, CD3+ T cell, CD3+CD4+ Th, CD3+CD4+CD25+ Treg, CD3+CD8+ Tc, NK1.1+ NK, NK1.1+CD3+ NK/T, CD115+CD11b+ monocyte, CD115+CD11b+CD80+ M1, CD115+CD11b+CD206+ M2, CD115-CD11b+ DC, CD115-CD11b+Ly6ChighLy6G- M-MDSC, CD115-CD11b+Ly6C+Ly6G+ PMN-MDSC, CD117+ HSC and CD19+ B cell (Kruskal-Wallis with Dunn’s multiple comparison test; p=0.02- p<0.0001). Analysis of plasma coagulation and inflammatory mediators, and histopathology of the tumour microenvironment is to be completed. The data derived provides baseline characteristics to study the changes associated with radiation, chemotherapy and immunotherapy treatment and to sequence therapies to maintain immune modulation. This information will contribute to identifying those immunotherapies which will have maximal benefit among the glioma patient population, where currently anti-CTLA-4 and anti-PDL-1 immunotherapies have had little impact. KM is supported by a Matt Callander Beanie for Brain Cancer HMRI Fellowship funded by the Mark Hughes Foundation, and grants from The Brain Cancer Group and Sydney Vital Translational Cancer Centre; AH is supported by a The Brain Cancer Group Fellowship.
Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study.
Authors: Eytan M. Stein, Courtney Denton Dinardo, Daniel Aaron Pollyea, Amir Tahmasb Fathi, Gail J. Roboz, Jessica K. Altman, Richard M. Stone, Ian Flinn, Hagop M. Kantarjian, Robert Collins, Manish R. Patel, Anthony Selwyn Stein, Mikkael A. Sekeres, Ronan T. Swords, Bruno C. Medeiros, Robert D. Knight, Samuel V. Agresta, Stéphane de Botton, Martin S. Tallman
Journal: Journal of Clinical Oncology (2017)

7004 Background: Recurrent mutations in isocitrate dehydrogenase 2 (m IDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 protein. Methods: This phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in pts with m IDH2 myeloid malignancies. Safety for all pts and efficacy outcomes for R/R AML pts from the phase 1 dose-escalation and expansion phases are reported. Results: In all, 239 pts received enasidenib. In the dose-escalation (n=113), the MTD was not reached at doses up to 650 mg daily. Median 2HG reductions from baseline were 92%, 90%, and 93% for pts receiving &lt;100 mg, 100 mg, and &gt;100 mg daily, respectively. Enasidenib 100 mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1–25). Grade 3-4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (ie, retinoic acid syndrome; 7%). For R/R AML pts, overall response rate (ORR) was 40.3%, including 34 (19.3%) complete remissions (CR; Table). Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) for R/R AML pts was 9.3 months (mos). For pts who attained CR, OS was 19.7 mos. Pts who had received ≥2 prior AML regimens (n=94; 53%) had median OS of 8.0 mos. Conclusions: Enasidenib was well tolerated, induced CRs, and was associated with OS of &gt;9 mos in pts who had failed prior AML therapies. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. Clinical trial information: NCT01915498. [Table: see text]
A public health perspective on personalized periodontics
Authors: Ellie T. Knight, W. Murray Thomson
Journal: Periodontology 2000 (2018)

Abstract In this paper, we consider personalized periodontics from a public health perspective. Periodontitis is an under‐acknowledged and important public health problem, and there has long been interest in identifying and treating those who are at high risk of developing this disease. Although susceptibility/risk‐assessment tools in periodontology are currently in their early stages of development, personalized periodontics is increasingly becoming a realistic approach. At the population level, however, personalized periodontics is not an effective way of improving periodontal health because it would target only those who seek help or are able to access care. The occurrence of periodontitis in populations is socially patterned, with those of lower socio‐economic position having poorer periodontal health and being far less likely to seek care. There is the potential for social inequalities actually to worsen as a result of personalized periodontics. In most health systems, personalized periodontics is likely to be accessible only to the social strata for whom it is affordable, and those with the greatest need for such an intervention will remain the least likely to be able to get it. Thus, personalized periodontics is likely to be a niche service for a small proportion of the adult population. This is at odds with the public health approach.
Risk of health-related quality of life and metabolic events and pulmonary toxicities in patients with advanced renal cell carcinoma treated with everolimus: A meta-analysis of phase 3 randomized controlled trials.
Authors: Rachana Yendala, Kyaw Zin Thein, Sriman Swarup, Anita Sultan, Nicholas C. D'Cunha, Sanjay Awasthi, Lukman Tijani
Journal: Journal of Clinical Oncology (2018)

e16551 Background: The mTOR inhibitor Everolimus (E) has shown to have clinical benefit and is a standard second-line treatment in advanced Renal cell carcinoma (RCC). Yet, there are notable toxicities. We undertook a meta-analysis of phase 3 randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL), metabolic and pulmonary toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention HRQOL and metabolic events and pulmonary toxicities as adverse effects were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: A total of 1860 patients were eligible. Studies compared E vs cabozantinib or placebo or nivolumab. The RR of all-grade side effects were as follows: fatigue, 0.91 (95% CI: 0.72-1.16, p = 0.46); asthenia, 1.29 (95% CI: 0.49-3.40, p = 0.60); decreased appetite, 1.41 (95% CI: 0.63-3.11, p = 0.39); pruritus, 1.08 (95% CI: 0.41-2.79, p = 0.87); rash, 2.25 (95% CI: 1.38-3.65, p = 0.001); hyperglycemia, 3.08 (95% CI: 1.93-4.91, p < 0.001); hypertriglyceridemia, 3.40 (95% CI: 1.52-7.63, p = 0.003); cough, 1.87 (95% CI: 1.38-2.54, p < 0.001); dyspnea, 1.58 (95% CI: 1.17-2.12, p = 0.002); peripheral edema, 2.38 (95% CI: 1.42-3.99, p = 0.001); and pneumonitis, 5.63 (95% CI: 1.05-30.22, p = 0.04). The RR of high-grade side effects were as follows: fatigue, 0.92 (95% CI: 0.46-1.85, p = 0.83); asthenia, 0.69 (95% CI: 0.23-2.06, p = 0.50); decreased appetite, 0.75 (95% CI: 0.18-3.04, p = 0.69); rash, 1.36 (95% CI: 0.40-4.57, p = 0.61); hyperglycemia, 4.38 (95% CI: 2.22-8.65, p < 0.001); hypertriglyceridemia, 5.17 (95% CI: 0.73-36.50, p = 0.09); dyspnea, 1.30 (95% CI: 0.64-2.63, p = 0.46); peripheral edema, 8.07 (95% CI: 1.003-64.95, p = 0.05); and pneumonitis, 3.26 (95% CI: 0.90-11.85, p = 0.07). Conclusions: Patients on Everolimus noted a significant increase in all grades of peripheral edema and hyperglycemia as well as all-grade pulmonary toxicities, rash and hypertriglyceridemia.
Incidence of thyroid function test abnormalities in patients receiving immune checkpoint inhibitor therapy for cancer: A single institution retrospective review.
Authors: Nisha Subhash Patel, Anais Oury, Lyudmila Bazhenova, Gregory A. Daniels, Sandip Pravin Patel
Journal: Journal of Clinical Oncology (2017)

e14569 Background: With the advent of immune-checkpoint inhibitor (ICI) therapy, thyroid function test abnormalities (TFTA) are common with reported incidence range of 2-15%. Our aim was to describe the incidence of TFTAs retrospectively in patients (pts) on ICI therapy. Methods: 285 pts reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had thyroidectomy (excluded). Pts received at least one dose of ipilimumab (I) and/or nivolumab (N) or pembrolizumab (P). Post-treatment TFTA was classified according to definitions of thyroid abnormalities when possible. Results: A total of 35% (76/218) pts had new onset TFTAs on ICI. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI. Median time to new onset or exacerbated baseline TFTA were 46 &amp; 33 days respectively. Of note, 65% (20/31) of pts on both I+N had new onset TFTA, compared to 31.3% (15/48) with I, 31.5% (28/89) N, 26% (13/50) P. Conclusions: Incidence of TFTAs with ICI was higher than expected in our pts. Pts with baseline TFTA and/or I+N combination therapy had higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more frequent evaluation of TFT in the first two months, especially in those with baseline TFTA. [Table: see text]
Validity and reliability of four value frameworks for cancer drugs.
Authors: Tanya GK Bentley, Joshua T. Cohen, Elena B. Elkin, Julie Huynh, Arnab Mukherjea, Thanh H. Neville, Matthew Genyeh Mei, Ronda Copher, Russell L. Knoth, Ioana Popescu, Jackie Lee, Jenelle Zambrano, Michael Broder
Journal: Journal of Clinical Oncology (2017)

6603 Background: Little is known about the validity and reliability of value assessment frameworks. Methods: Eight panelists used the ASCO, ESMO, ICER, and NCCN frameworks to conduct value assessments of 15 drugs for advanced lung and breast cancers and castration refractory prostate cancer. Panelists received instructions and published clinical data to complete the assessments, assigning each drug a numeric or letter score. We used Kendall’s W coefficient to measure convergent validity by cancer type among frameworks and intraclass correlation coefficients (ICC) to measure framework inter-rater reliability across cancers. Panelists were surveyed on their experiences. Results: Kendall’s W for breast, lung, and prostate cancer drugs were 0.560 ( p= 0.010), 0.562 ( p= 0.010), and 0.920 ( p&lt; 0.001), respectively. Pairwise and subdomain W are shown in the table. ICC (95% CI) for ASCO, ESMO, ICER, and NCCN were 0.800 (0.660-0.913), 0.818 (0.686-0.921), 0.652 (0.466-0.834), and 0.153 (0.045-0.371), respectively. Panelists generally agreed the frameworks were logically organized and easy to use. Conclusions: Convergent validity among the frameworks was fair to excellent, increasing with clinical benefit subdomain concordance and simplicity of drug trial data. Inter-rater reliability, highest for ASCO and ESMO, improved with clarity of instructions and specificity of score definitions. Continued use, analyses, and refinements of the frameworks will bring us closer to using value-based treatment decisions to improve patient care and outcomes. [Table: see text]
Phase II trial of apatinib in patients with recurrent and/or metastatic adenoid cystic carcinoma of the head and neck: Updated analysis.
Authors: Guopei Zhu, Lin Zhang, Rongrong Li, Shengjin Dou, Wenjun Yang, Chenping Zhang
Journal: Journal of Clinical Oncology (2018)

6026 Background: There is no specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic adenoid cystic carcinoma of the head and neck (ACCHN). Recently, anti-angiogenic targeted therapy represents a potential effective strategy. We conducted a single-arm, phase II trial to evaluate apatinib, a small-molecule inhibitor of VEGFR-2, in ACCHN, and promising response was observed (2018 Multidisciplinary Head and Neck Cancers Symposium Abstract: 20160). Here we report the updated efficacy and safety data. Methods: Pathologically confirmed recurrent and/or metastatic ACCHN patients (pts) who had evidence of disease progression within 3 months or had failed at least 1 line of systemic chemotherapy were eligible. All pts received continuous apatinib 500 mg qd until disease progression, death, or intolerable toxicity. Results: Between Apr 2016 and Dec 2017, 59 pts were recruited, including 22 (37.3%) males and 37 (62.7%) females. The median age was 47.5 years. 61.0% cases had metastases, and the main metastatic site was lung. All pts were evaluable for efficacy and safety analyses. At the cutoff date of 12/31/2017, 9 progression-free survival (PFS) events and 2 deaths after progression occurred. The median PFS and overall survival (OS) had not been reached; however, the median time of apatinib treatment was already 6.4 (IQR, 3.8–9.9) months. The 6-month PFS rate was 87.9% (95%CI, 76.6%–99.1%), and the 12-month PFS rate was 50.7% (95%CI 21.8%–79.7%). The 12-month OS rate was 96.3% (95%CI, 91.3%–101.3%). Moreover, the objective response rate and disease control rate was 47.1% and 98.1%, respectively. 34 (57.6%) pts experienced dose reduction. The incidence of drug-related adverse events (AEs) was 88.1% (52/59). 22.0% (13/59) pts developed AEs of Grade ≥3. Main AEs were hypertension (54.2%), hand-foot syndrome (33.9%), and proteinuria (23.7%). Conclusions: This updated analysis further confirmed that apatinib appears to be effective and safe for recurrent/metastatic ACCHN. It did achieve the best reported response rate and long duration of disease control with a good safety profile. Further investigation is warranted. Clinical trial information: NCT02775370.
An antibody derived from a cured AML patient to identify a unique epitope on CD43 (CD43s) as a novel target for acute myeloid leukemia and myelodysplastic syndrome.
Authors: Mette D. Hazenberg, Marijn Gillissen, Greta De Jong, Etsuko Yasuda, Sophie Levie, Koen Wagner, Arjen Bakker, Martijn Kedde, Paul Hensbergen, Julien Villaudy, Pauline Van Helden, Hergen Spits
Journal: Journal of Clinical Oncology (2017)

7009 Background: Immunotherapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hampered by the lack of tumor-specific targets. Methods: We took advantage of the tumor-immunotherapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) and searched the B cell repertoire of a patient with a lasting and potent graft versus AML response for AML-specific antibodies. Results: We identified a donor-derived B cell clone that produced an IgG1 antibody, AT1413, that specifically interacted with AML cell lines, with the patient’s autologous AML blasts, but not with lymphocytes or with cells from liver, colon, skin and other tissues. AT1413 recognized a unique, not previously described, sialylated epitope on CD43 (CD43s). CD43s is overexpressed on all types of AML and MDS, as illustrated by its reactivity with freshly isolated blasts of each of more than 60 randomly selected AML and MDS patients in our clinic, representing all WHO 2008 AML and MDS classes. AT1413 induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) of target cells in vitro. To investigate the effect of AT1413 in vivowe first generated mice populated with human effector cells (NK cells, CTL and myeloid cells) by injecting human hematopoietic stem cells into new born immunodeficient mice. After establishment of a human immune system in these mice we inoculated luciferase labeled AML cells via tail vein injection. Following engraftment of the tumor we dosed the mice biweekly with AT1413 or a control antibody. We observed strongly reduced numbers of AML cells in AT1413- but not in control antibody treated mice. Importantly, AT1413 treatment was tolerated well and did not affect numbers of non-malignant human myeloid cell in these mice. Conclusions: We have obtained an antibody from a cured AML patient which recognizes a unique sialylated epitope on CD43 (CD43s) that is selectively over-expressed on all WHO 2008 types of AML and MDS. This antibody was able to eliminate AML cells in vivo and therefore has high therapeutic potential.
A phase 0 pharmacodynamic study of dasatinib in women with newly diagnosed endometrial cancer.
Authors: Linda R. Duska, Heather Lothamer, William Faust, Gina R. Petroni, Paula M. Fracasso, Sarah Parsons
Journal: Journal of Clinical Oncology (2016)

e23207 Background: Dasatinib is a potent, oral inhibitor of Src family kinases, which are implicated in etiology and malignant behavior of various cancers. Direct measurement of dasatinib biologic effect in solid tumor has not been reported. We designed a Phase 0 trial of dasatinib in women with endometrial cancer to demonstrate inhibition of Src activity in tissue and blood and to correlate inhibition with blood and tissue levels. We hypothesized that activity in blood might serve as a surrogate for tissue. Methods: Patients were treated with dasatinib at 32 and 8 hours preoperatively at one of two dose levels (100 or 200 mg). Tissue and blood were collected prior to treatment and at surgery. Active Src (pY419) and total Src protein were analyzed from tissue and white blood cells by Western blot. For PK analysis, blood was drawn at 2, 4 and 8 hours following the second dose. Results: 11 patients were treated and 10 patients (5 at each dose level) received both doses of dasatinib. There were no serious adverse events. The most frequent related AE was headache (4 G1,1 G2). 5 patients had non-significant QTc prolongation (4 G1,1 G2). No surgeries were delayed. There was a protocol-defined decrease in phosphoSrc (pSrc) activity in tumor in 4 patients, 2 at each dose. This decrease was associated with a decrease in blood pSrc activity only at the lower dose. Tissue and blood pSrc were more reduced at the lower dose. Analysis was limited by intra- and inter- patient and assay variability. PK levels were demonstrated in blood and tumor. Dasatinib PK was significantly higher in the tumor compared to the normal endometrium (ratio 1.83, p = 0.014 by Wilcoxon sign rank). Conclusions: In this Phase 0 study in endometrial cancer, we demonstrated inhibition of Src activity in the tumor of 40% of patients. We demonstrated dasatinib levels in tumor tissue 9 hours after the second dose, with a significantly higher level in tumor tissue compared to normal. This study demonstrates that pre and post-treatment tumor biopsies in patients with endometrial cancer are feasible and can also provide invaluable information related to mechanism of action of anticancer agents. Clinical trial information: NCT01482728.Dasatinib plasma levels (ng/ml) 8 hrs. N median mean st dev Dose level 1 5 20.8 27.6 22.0 Dose level 2 5 67.3 93.3 65.9
Preliminary results from CECILIA, an open-label global safety study of bevacizumab (BEV), carboplatin (C) and paclitaxel (P) therapy for metastatic, recurrent or persistent cervical cancer (CC).
Authors: Andres Redondo, Nicoletta Colombo, Lydia Mary Dreosti, Mary McCormack, Angelica Nogueira Rodrigues, Margarita Donica, Leilani Morales, Antonio González-Martín
Journal: Journal of Clinical Oncology (2018)

5528 Background: Adding BEV to chemotherapy (cisplatin + P or topotecan + P) for advanced (a)CC significantly improved overall and progression-free survival (PFS) in the overall population in GOG240. The CECILIA study (NCT02467907) is evaluating BEV with more widely used CP. Methods: The primary objective is to determine the safety of BEV + CP for aCC, defined by the frequency and severity of gastrointestinal (GI) perforation/fistula, GI-vaginal fistula and genitourinary (GU) fistula. Eligible patients (pts) have metastatic/recurrent/persistent CC not amenable to curative surgery and/or radiotherapy (RT). Pts with ongoing bladder/rectal involvement, prior cobalt RT, history of fistula/GI perforation, or bowel resection ≤6 weeks or chemoRT ≤3 mo before the first dose are excluded. Pts receive BEV 15 mg/kg, P 175 mg/m2 and C AUC 5 q3w until progression, unacceptable toxicity or consent withdrawal. If BEV, C or P are stopped for adverse events (AEs), the remaining drug(s) can be continued alone. We report preliminary findings after ≥6 mo follow-up in all pts. Results: Between Jul 2015 and Dec 2016, 150 pts in Europe, South/Central America and South Africa began treatment. At study entry, 20% had persistent disease, 54% recurrent disease and 26% stage IV at diagnosis; 73% had squamous cell carcinoma, 71% had received prior RT (as part of chemoRT in 58%) and 59% prior platinum. At the data cutoff (12 Jun 2017), median follow-up was 11.2 mo. Median BEV duration was 9 cycles (range 1–28; 42 pts still on therapy). Grade 3/4 AEs occurred in 67% of pts, most often hematologic AEs and hypertension; 5 AEs (3%) were fatal. GI perforation/fistula occurred in 4.0% of pts (95% CI 1.5–8.5%), GI-vaginal fistula in 4.0% (1.5–8.5%) and GU fistula in 4.0% (1.5–8.5%), giving an overall rate of 18 fistula/GI perforations in 15 pts (10.0% [95% CI 5.7–16.0%]). All but 1 pt with fistula/GI perforation had received prior RT. PFS results are immature. Conclusions: These preliminary results suggest that BEV can be combined with CP in carefully selected pts. The fistula/GI perforation incidence was in line with GOG240. Final results are expected in 2019. Clinical trial information: NCT02467907.