tbuckley/cabot-search huggingface dataset:
Comparison of different phase II studies using sequential combinations of targeted agents for treating chronic lymphocytic leukemia.
Authors: Von Tresckow Julia, Paula Cramer, Jasmin Bahlo, Sandra Robrecht, Othman Al-Sawaf, Petra Langerbeins, Moritz FÃ¼rstenau, Anja Engelke, Anna-Maria Fink, Kirsten Fischer, Karl A Kreuzer, Matthias Ritgen, Sebastian Boettcher, Clemens Martin Wendtner, Stephan Stilgenbauer, Barbara Eichhorst, Michael J. Hallek
Journal: Journal of Clinical Oncology (2018)

7513 Background: The German CLL study group (GCLLSG) performed three similar phase-II-trials combining a CD20-antibody, ofatumumab (O) or obinutuzumab (G, for GA-101), with ibrutinib (I) or venetoclax (A) in an all-comer population of treatment-naïve or relapsed/refractory CLL patients (pts). Methods: In all 3 trials, pts with high tumor burden received optional bendamustine debulking (BD). Subsequent induction therapy consisted of 6 cycles of I plus O (BIO trial), or I plus G (BIG) or A plus G (BAG). Induction therapy was followed by a maintenance phase using the same drugs until achieving a minimal residual disease (MRD) negative complete remission or up to 24 months. The primary endpoint was the overall response rate (ORR) at the end of induction; secondary endpoints were MRD and safety. Results: 66 pts each were enrolled in the 3 trials. Pts with < 2 induction cycles were excluded from the analysis as per protocol, resulting in 65, 61 and 63 evaluable pts in BIO, BIG and BAG, respectively. The primary endpoint was met in all trials. BD achieved an ORR of 61 % across all trials. During combination therapy one fatal adverse event occurred in each trial; during induction 46 SAEs occurred in BIO, 29 in BIG and 59 in BAG. Patients’ characteristics and major results are shown in the Table. Conclusions: The sequential combination concept shows very good efficacy and tolerability. BD reduced the number of IRR. Combination therapies with G seemed more efficient when compared to O. Additionally, combining A plus G seemed to evoke deeper responses than I plus G. Clinical trial information: NCT02689141, NCT02401503 and NCT02345863. BIO BIG BAG Patients (N) 65 61 63 Median age (years) 61 66 59 Prior therapies (median) 1.5 1.0 2.0 TP53 mutations or del(17p) 21 (32%) 13 (21%) 17 (28%) CLL-IPI high or very high risk 42 (67%) 41 (67%) 38 (63%) Response ORR 60 (92%) 61 (100%) 60 (95%) Complete remission (CR) 0 0 5 (8%) Clinical CR or CR with incomplete recovery of the marrow 20 (31%) 28 (46%) 20 (32%) MRD negative ( < 10-4) after induction 9 (14%) 29 (48%) 55 (87%) Infusion related reactions during induction (CTC gr. 1 4) with BD 17 (33%) 13 (29%) 13 (28%) without BD 8 (57%) 10 (59%) 7 (37%) Tumor lysis syndrome during induction (CTC gr. 1 4) with BD 0 1 (2%) 1 (2%) without BD 0 0 1 (5%)
Embedding palliative care in an outpatient oncology specialty clinic.
Authors: Judith Salmon Kaur
Journal: Journal of Clinical Oncology (2018)

e18560 Background: Access to palliative care is now considered a measure of quality comprehensive cancer programs. Our academic medical center has had inpatient palliative care consultations for over ten years but limited out patient services for patients. Data suggests that many patients benefit with improved symptom control and quality of life and potentially even increased survival with the addition of palliative care earlier in the disease process. Our Medical Oncology group opted to embed a Medical Oncologist who is double boarded in Palliative Care into a half day five day a week out patient Medical Oncology Supportive Care Clinic. The oncologist met with each disease oriented group to determine which patients should be considered for referral to this new clinic with concomitant treatment by their primary oncologist. Other members of our interdisciplinary team also were helpful in patient support through social workers, a dedicated palliative care pharmacist and chaplaincy. Where appropriate, patients were transitioned to a community hospice program for terminal care. Methods: Analysis of the first 6 months of this out patient Oncology Supportive Care Clinic Results: There were 241 referrals in the first six months with demographic data provided in the table below. Nearly all patients, except those selecting imminent hospice admission, had one or more return visits to the Oncology Supportive Care Clinic. The service was overwhelmingly approved by patients and providers. Conclusions: A dedicated Oncology Supportive Care Clinic embedded in the Medical Oncology specialty practices is a model that can meet both patient and provider needs to improve access to palliative care for oncology. Our pilot project showed a diverse patient population was referred and served through this model. ONCOLOGY SUPPORTIVE CARE CLINIC REFERRALS INITIAL 6 MONTH REVIEW GENDER M = 55% F = 45% RACE/ETHNICITY NHW = 85% AA = 10% other = 5% AGE RANGE 22 to 95 TUMOR TYPE LUNG = 20% GI = 40% GU = 10% HEME = 20% OTHER = 10% DEATHS 20%
Early assessment by FDG PET/CT to predict short-term outcome in clear cell renal carcinoma treated with nivolumab.
Authors: Noboru Nakaigawa, Tadashi Tabei, Keiichi Kondo, Tomohiro Kaneta, Kazuki Kobayashi, Ichiro Ikeda, Tomio Inoue, Masahiro Yao
Journal: Journal of Clinical Oncology (2018)

e16548 Background: We reported previously the usefulness of the early assessment by 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) to predict prognosis of renal cell carcinoma (RCC) treated with molecular targeted agents. Herein we evaluated the potency of FDG PET/CT at early time as an imaging biomarker predicting the response of RCC to nivolumab. Methods: Patients with metastatic or recurrent clear-cell RCC for which they had received previous treatment and started nivolumab treatment at Yokohama City University hospital from October 2016 to March 2017 were enrolled in this study. All patients were evaluated by pre-therapy FDG PET/CT and 4 weeks later as a first response assessment and by computed tomography (CT) as second response assessment another 12 weeks later. We measured diameters and maximum standardized uptake values (SUVmax) of all lesions at each time point and investigated the relationship among them. Results: There were 9 patients and 30 lesions. Median days of first assessment with FDG PET/CT and second assessment by CT scan from initiation of treatment are 47 (33–82) and 127 (116–167), respectively. Lesions whose diameter decreased > 20% at second assessment were defined as responding, and lesions whose diameter did not decrease > 20% were defined as non-responding. We compared change in diameter and SUVmax at first assessment with FDG PET/CT, respectively. All lesions with decreased diameter and elevated SUVmax at first assessment with FDG PET/CT showed responding at second assessment by CT scan, while most lesions with increased diameter and declined SUVmax at first assessment showed non-responding at second assessment. Conclusions: Our findings suggest that the early assessment using FDG PET/CT can predict the response of RCC to nivolumab. However, larger prospective studies are needed to confirm these preliminary results. Clinical trial information: 000008141.
Meta-analysis of the cardiac events in the adjuvant trastuzumab trials.
Authors: Evandro De Azambuja, Noam Falbel Ponde, Marion Jennifer Procter, Priya Rastogi, Reena S. Cecchini, Karla V. Ballman, Alvaro Moreno-Aspitia, Dimitrios Zardavas, Lise Roca, Richard D. Gelber, Martine Piccart, Thomas M. Suter
Journal: Journal of Clinical Oncology (2018)

10066 Background: Cardiac dysfunction may occur in patients (pts) receiving adjuvant trastuzumab-based chemotherapy and long follow-up is required to better understand it. This meta-analysis of 3 adjuvant trials investigated the incidence, timing and risk factors for trastuzumab-associated cardiac events. Methods: We have conducted an individual patient level data meta-analysis of 3 phase III trials investigating the role of 1 year of trastuzumab (T): HERA, NSBAP B-31, and NCCTG 9831 (Alliance). Definitions of severe CHF (NYHA III or IV) and asymptomatic or mildly symptomatic (NYHA II) cardiac events were considered as per each study, as the precise definitions varied between studies. Results: A total of 7445 pts were included in the analysis with a median follow-up in excess of 10 years (119.2-137.2 months): 4017 were in the T arm and 3428 were in the control arm (observation). Nearly all pts (97.5%) in the T arms received anthracycline-based chemotherapy. Table 1 summarizes the incidence of cardiac events in pts treated with 1 year adjuvant T. In total, 452 pts experienced a cardiac event (11.3%). Most of the cardiac events occurred during T use (78.1%). Adjuvant T was completed by 76.2% of pts and 10.0% of pts discontinued T due to a cardiac event. Significant baseline risk factors for cardiac events were LVEF normal but ≤60%, hypertension, high BMI ( > 25), and age ≥60. Conclusions: 1-year of T increases the risk of cardiac events, though most are asymptomatic or mildly symptomatic LVEF drops. As cardiac events may lead to interruption in treatment, careful risk-factorr based patient selection, close follow-up and medical intervention (if necessary), are needed. Support: U10CA180868, -180822, UG1-189867, U24-196067; Genentech Incidence of cardiac events in T treated patients CHF: cardiac heart failure. Trastuzumab Combined N = 4017 HERA N = 1682 NSABP B-31 N = 1055 N9831 N = 1280 Any cardiac event 452(11.3%) 92(5.5%) 205(19.4%) 155(12.1%) Cardiac death 7(0.2%) 3(0.2%) 2(0.2%) 2(0.2%) Severe CHF (NYHA class III/IV) 94(2.3%) 15(0.9%) 41(3.9%) 38(3.0%) Asymptomatic or mildly symptomatic (NYHA class II) 351(8.7%) 74(4.4%) 162(15.4%) 115(9.0%) Note: NSABP B-31 dataset considers an ITT population
Differential association of 5-hydroxymethylcytosine levels with clinical and histopathological characteristics in breast cancer tumors.
Authors: Omar Peña-Curiel, Diddiera Prada, Miguel Otero, José Díaz-Chávez, Cynthia Villarreal-Garza, Montserrat Justo, Nancy Reynoso, Clementina Castro Hernandez, Paula Cabrera-Galeana, Enrique Bargallo-Rocha, Yolanda Villaseñor-Navarro, Claudia Caro-Sánchez, Jaime G. De La Garza, Luis Alonso Herrera Montalvo
Journal: Journal of Clinical Oncology (2017)

e23173 Background: Breast cancer is one of the top causes of cancer death worldwide. In Mexico, locally advanced breast cancer (LABC) comprises the majority of the breast cancer stages at diagnosis. Recent studies have suggested that 5-hydroxymethylcytosine (5hmC), could be a prognostic marker in breast cancer. However, the role of 5hmC on clinical and histopathologic characteristics in LABC has not been explored. Methods: From a cohort of locally advanced and advanced breast cancer patients treated at the National Cancer Institute in Mexico City with a 3-year follow-up, we measured 5hmC levels by immunodetection from fresh frozen tissue samples taken from the initial biopsy (N = 193). We determined the association between 5hmC levels and the most relevant clinical and histopathological characteristics. Results: From the full cohort analyzed; 42% were luminal A (n = 82), 33% were luminal B (N = 63), 9% were HER2-positive (N = 18), and 15% were triple-negative tumors. We found higher levels of global 5hmC in HER2 positive tumors vs. all other subtypes (p = 0.028, Kruskal-Wallis test). In luminal B tumors, 5hmC levels were associated with Ki67 (β = -0.04, 95%CI: -0.08, -0.01, p = 0.01 from multivariable model) but not in luminal A. Furthermore, we found that low 5hmC levels were associated with higher histological grade in HER2-positive tumors (p = 0.03, Kruskal-Wallis test). In subgroup analysis of LABC patients, we found higher 5hmC levels in non-ductal vs. ductal invasive tumors (β = 1.38, 95%CI: 0.049, 2.911, p = 0.043 from multivariable model). Also, lower 5hmC levels were associated with Ki67 (β = -2.53, 95%CI: -4.32, -0.74; p = 0.009 from multivariable model) and with histological type (p = 0.028, Kruskal-Wallis test) in LABC luminal B tumors. A borderline association with OS (p = 0.07, log-rank test) and RFS (p = 0.071, log-rank test) was observed in luminal A tumors in the LABC group. Conclusions: Our findings suggest that 5hmC levels are differentially associated with distinct clinical and histopathological characteristics in breast cancer, especially those linked to aggressiveness, including Ki67, histological type, and grade.
Prognostic role of peripheral blood scores in lymphoepithelioma of the nasopharynx (LN).
Authors: Beatriz Cirauqui, Vanesa Quiroga, Clara Lezcano, Laia VilÃ Martinez, Maria de los Llanos Gil, Max Hardy, Iris Teruel, Eudald Felip, Juan Jose Garcia, Mireia Margeli
Journal: Journal of Clinical Oncology (2016)

e17564 Background: Neutrophil/lymphocyte (NLR) and lymphocyte/monocyte ratio (LMR) have been described as prognostic factors in cancer. Lymphoepithelioma is a type of poorly differentiated nasopharyngeal carcinoma characterized by prominent infiltration of lymphocytes in the area involved by tumor. The purpose of this study was to investigate the prognostic value of pretreatment scores in patients with LN. Methods: A retrospective analysis of 41 patients with LN treated between 2004 and 2015 in our institution was carried out. Patient records were evaluated and neutrophil, lymphocyte and monocyte counts in peripheral blood were documented before treatment and at the time of relapse, together with sex, age, toxic habits, disease staging, second primary tumors, relapse and survival data. Results: A high NLR ( > 3) was significantly associated with poor overall survival (OS) (p 0,02) and a trend to higher relapse rate (RR)( p 0,07), with the greatest significance seen in patients with the highest NLR (57 months in the highest quartile vs 204 months in the lowest quartile). Patients with LMR > 4 before treatment had shorter OS (24 months vs 74 months, p 0,001). Absolute lymphocyte count > 1400 before treatment was also significantly related to worse OS (p 0,002). In patients who relapsed, no significant differences compared to baseline values were found. No significant differences according to patient and tumor characteristics were present. Conclusions: Pretreatment peripheral blood scores may have a prognostic role in LN, but more numerous prospective trials are needed.
Global burden of multiple myeloma: A systematic analysis for the Global Burden of Disease study 2016.
Authors: Andrew Cowan, Edward N. Libby, Christina Fitzmaurice
Journal: Journal of Clinical Oncology (2018)

e20023 Background: Multiple myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality. A comprehensive description of the global burden of multiple myeloma is needed to help direct health policy, resource allocation, research, and patient care. In this study we describe the burden of multiple myeloma, and the availability of effective therapies for 21 world regions, and 195 countries and territories from 1990 to 2016. Methods: We report incidence, mortality, and disability-adjusted life-years (DALYs) estimates from the Global Burden of Disease 2016 study. Data sources include vital registration system, cancer registry, drug availability, and survey data for stem cell transplant rates. We analyzed the contribution of aging, population growth, and changes in incidence rates to the overall change in incident cases between 1990 and 2016 globally, by Sociodemographic Index (SDI), and by region. We calculated the stem cell transplant to myeloma incidence ratio as an indicator of transplant availability. Results: Worldwide in 2016 there were 138 509 (95% uncertainty interval (UI), 119 064–158 268) incident cases of MM with an age-standardized incidence rate (ASIR) of 2.1 (95% UI, 1.8–2.4). Incident cases between 1990 and 2016 increased by 126% globally and between 106% and 192% for all SDI quintiles. The three world regions with the highest ASIR of MM were Australasia (5.8; 95% UI, 4.4–6.5), North America (5.2; 95% UI, 4.7–6.5), and Western Europe (4.6; 95% UI, 3.7–5.5). MM caused 2.1 million (95% UI, 1.9 to 2.3 million) DALYs globally. The highest stem cell transplant to MM rates were found in Jordan (2.5 transplants per myeloma case), followed by Israel (2.3), Saudi Arabia (2.0), and Singapore (1.6). In 2016 lenalidomide and bortezomib have been approved in 73 and 103 countries, respectively. Conclusions: The burden of multiple myeloma is very heterogeneous by location. However, incident cases increased in all locations. Effective therapy for MM exists and could be delivered in low and middle income (LMIC) countries if availability of these agents was expanded. There is potential to develop fundamental myeloma care programs in LMIC countries.
Results obtained from the association of boron neutron capture therapy with bevacizumab.
Authors: Laurentia Minea Gales, Anghel Rodica Maricela, Oana Trifanescu, Xenia Bacinschi, Iuliana Gruia
Journal: Journal of Clinical Oncology (2016)

e23001 Background: It is our presumption that oxygen reactive species initiate angiogenesis signalling. Put into a certain scenario oxidative stress may activate signalling metabolic pathways, modulating the activity of various enzymes and critical transcription factors. With our experiment we aimed to explore the oxidative stress route as enabler of angiogenesis inducing signal pathways. Methods: We used experimentally induced RS-1 hepatoma cells carrier animals that we treated with an angiogenesis inhibitor Bevacizumab and, in a later phase, with BNCT irradiation. RS-1 alveolar hepatoma type used in our experiments is a chemically induced tumour obtained by mixing 2- acetylaminofluorene in the rats’ food. Thus we obtained a hepatocellular cholangiocarcinoma. The Wistar rats were treated with bevacizumab 5 mg/kg weekly for a month after which BNCT protocol was applied. They received i.v. BPA in 5% fructose solution at a 300 mg/kg dosage. The irradiation time was set at 120 minutes. The serum was processed by centrifugation in view of determining the oxidative stress parameters, while cells from the tumour tissue were collected with the purpose to establish apoptosis through flow-cytometry. Results: Results obtained from flow cytometry measurements indicate the occurrence of apoptosis after a second course of Bevacizumab. After a first round of Bevacizumab, apoptosis increased from 9.12% to 20.14% but dropped to 12.05% following BNCT administration. These results highlight an expansion in the oxidative metabolism, at the level of the tumour tissue, compared to values registered after serum determination. The administration of an anti-angiogenic compound triggers lower oxygen and nutrients flow thus determining a slower lipid peroxidation reaction. Conclusions: The obtained values lead to several conclusions: oxygen reactive species are secondary signalling messengers; when produced in small quantities they will have an active participation in the signalling cascade but when they come in large concentrations they become destructive effectors and thus can be used in the monitoring of radiation therapy results.
3D spheroid invasion drug screen platform for pancreatic ductal adenocarcinoma.
Authors: Claire Wells, Hoyin Lam, Victoria Sanz-Moreno, Verity Sabin, Debashis Sarker
Journal: Journal of Clinical Oncology (2018)

e24212 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by early cancer cell dissemination and poor response to current available treatments, highlighting the need for novel therapeutics. Desmoplastic stroma in the tumor microenvironment of PDAC contributes towards tumor growth, metastasis and resistance to therapy. However, the majority of current screening assays do not include components of the stroma and are based mainly on cell viability. Here we present the development of a 3D co-culture spheroid screening platform to assess the ability of compounds to inhibit PDAC growth and invasion in the presence of pancreatic stellate cells. Methods: The human PDAC cell line PaTu8902 was chosen as the screening cell line based on its robust ability to form spheroids and invasive potential. PS-1 human stellate cells were used in conjunction to form the co-culture spheroid. Invasion of spheroids were conducted in collagen I matrix. Fluorescent tagging of both cell compartments allows semi-automated analysis of the invasion, supported by manual invasive scoring. Cells were screened against an FDA approved drug library of 99 compounds together with 10 compounds targeting pathways of interest. DMSO was used as negative control, and gemcitabine and dasatinib were used as positive control of growth and invasion inhibition. Results: Treatment with gemcitabine or dasatinib inhibited the invasion and growth of the PDAC co-culture spheroids. Our semi-automated analysis of the invasion with demonstrated robustness across the screen with a Z score of > 0.5. Furthermore, these results correlated with the manual scoring. Five potential hits emerged from the drug repurposing screen, including CRT0276621[1], a pan-p21-activated kinase inhibitor and nebivolol. Both these drugs elicited a similar/stronger inhibition of tumor cell dissemination and invasive growth compared to gemcitabine. Conclusions: The spheroid invasion assay is a suitable platform to assess promising drug treatments simultaneously against PDAC growth and invasion. Future work will validate top hits. [1] CRT0276621 is a novel pan-PAK inhibitor identified by Cancer Research UK Therapeutic Discovery Laboratories and licensed to Pangaea Oncology.
A novel genomic rearrangement signature to predict poor survival among women with high grade serous ovarian cancer.
Authors: Robert Tyler Hillman, Karen H. Lu, Phillip Andrew Futreal
Journal: Journal of Clinical Oncology (2017)

5509 Background: Resistance to platinum-based chemotherapy is a major cause of disease progression and mortality among women with high grade serous ovarian cancer (HGSOC). It is not known whether patterns of genomic rearrangement are predictive of clinical outcome in HGSOC. Methods: This was a retrospective cohort analysis of whole genome sequences from 80 HGSOC tumors. Genomic rearrangements were identified and categorized by size and type (inversion, duplication, deletion, or translocation). Non-negative matrix factorization was then used to extract rearrangement signatures. Wilcoxon rank-sum test was used for comparison of continuous variables. Univariate and multivariate analyses were performed using Cox proportional hazards models. Results: A rearrangement signature characterized by 10 kilobase to 10 megabase duplications and deletions was identified. The median overall survival (OS) was 22.5 months (95% CI, 20.1 to 33.5 months) in the Sig-High group versus 46.0 months (95% CI, 27.7 to 80.6 months) in the Sig-Low group (hazard ratio, 2.13; 95% CI, 1.27 to 3.55; P=0.004). Exploration of clinical variables showed a significantly higher median signature contribution in platinum-resistant disease than platinum-sensitive disease (20.0% vs 9.1%, p=0.007). Multivariate analysis showed a hazard ratio for death of 2.1 associated with the Sig-High group (Table). Validation of this signature was performed using HGSOC copy number data from the Cancer Genome Atlas. In this cohort, the median OS was 38.8 months (95% CI, 36.7 to 44.5 months) in the Sig-High group versus 49.5 months (95% CI, 45.2 to 56.3 months) in the Sig-Low group (hazard ratio, 1.44; 95% CI, 1.14 to 1.82; P=0.024). Conclusions: A genomic rearrangement signature is associated with chemoresistance and poor prognosis in HGSOC. Prediction of poor survival outcomes could allow early identification of women who may be candidates for clinical trials. [Table: see text]