tbuckley/cabot-search huggingface dataset:
Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer
Authors: Roland Seiler, Ewan A. Gibb, Natalie Q. Wang, Htoo Zarni Oo, Hung-Ming Lam, Kim E. van Kessel, Charlotte S. Voskuilen, Brian Winters, Nicholas Erho, Mandeep M. Takhar, James Douglas, Funda Vakar-Lopez, Simon J. Crabb, Bas W.G. van Rhijn, Elisabeth E. Fransen van de Putte, Ellen C. Zwarthoff, George N. Thalmann, Elai Davicioni, Joost L. Boormans, Marc Dall'Era, Michiel S. van der Heijden, Jonathan L. Wright, Peter C. Black
Journal: Clinical Cancer Research (2018)

Abstract Purpose: After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. Experimental Design: Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin &amp; Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis. Results: Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis. Conclusions: This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.
CDK inhibitors in advanced HR+ Her 2- breast cancer: A systematic review and meta-analysis of randomized trials.
Authors: Carlo Messina, Marco Messina, Giulia Buzzatti, Carlo Cattrini, Luigi Cerbone, Maria Maddalena Latocca, Giacomo Vallome, Elisa Zanardi, Francesco Boccardo
Journal: Journal of Clinical Oncology (2018)

e13047 Background: Combining abemaciclib/palbociclib/ribociclib and aromatase inhibitors (AIs) or fulvestrant improved outcomes for the treatment of metastatic HR+ Her 2- breast cancers. We performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of abemaciclib/palbociclib/ribociclib plus AIs or fulvestrant and the impact of all CDK inhibitors plus endocrinal therapy (ET) in HR+ Her2- breast cancer. Methods: A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 January 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression free survival (PFS), as well as Odds Ratios (ORs) for objective response rates and ≥ G3-G4 adverse events (AEs) were calculated for each trial. A pooled analysis was carried out using the random effects model. Results: six RCTs were eligible including 1979 breast cancer patients. Adding abemaciclib/palbociclib/ribociclib to AI (HR: 0.55, 95% CI 0.48-0.64) or abemaciclib/palbociclib to fulvestrant (HR: 0.49, 95% CI 0.37-0.63) improved significantly the PFS of metastatic HR+ Her 2- breast cancers regardless menopausal status and site of metastasis. CDK inhibitors plus ET meaningfully improved PFS (HR: 0.53, 95% CI 0.47-0.59) and objective response rate (OR: 0.52, 95% CI 0.40-0.67) but the use of these drugs was characterised by a significant increase of G3-G4 AEs (OR: 7.61, 95% CI 5.54-10.45). Conclusions: Emerging data provide a new potential standard treatment for advanced HR+/Her2- breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities and costs.
Comparison of neoadjuvant systemic treatment (chemotherapy with or without trastuzumab) responses with dynamic contrast-enhanced breast magnetic resonance imaging and histopathology in locally advanced breast cancer.
Authors: Ozge Orbay, Hatice Mirac Binnaz Demirkan, Pinar Balci, Merih Durak, Serdar Saydam
Journal: Journal of Clinical Oncology (2012)

e11507 Background: It is reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may have the potential of predicting response to neoadjuvant chemotherapy (NAC) for patients with breast cancer and it is more accurate than the other radiologic methods. We aimed to compare the responses to NAC ± trastuzumab with DCE-MRI and histopathologic findings in locally advanced breast cancer. Methods: Between January 2007 and October 2011, 38 female patients patients with locally advanced breast cancer who recieved NAC ± trastuzumab and had whole breast DCE-MRI before / after treatment and who also had surgery after treatment were included in our study. Patients received 4 cycles of antracyclin based and 4 cycles of taxane based chemotherapy protocols sequentially. 9 patients with HER-2 (+) breast cancer also received trastuzumab with taxane based chemotherapy. Before and after NAC ± trastuzumab, tumor measurements were evaluated by mammography (MG), ultrasound (US), DCE-MRI and compared with postoperative histopathologic findings. Response rates were assessed with RECIST (Response Evolution Criteria in Solid Tumors) 1,1 criteria. MRI were done with 1,5 Tesla MR ( Gyroscan Achieva Intera, Philips ). SPSS 15.0 and Kappa test were used for statistical analysis. Results: After NAC ± trastuzumab, breast DCE-MRI revealed 13.2% complete response (CR), 73.7% partial response (PR), 10.5% stabile disease (SD), and 2.6% progressive disease (PD) and 15.8% CR, 73.7% PR, 7.9% SD and 2.6% PD were shown with histopathology. After neoadjuvant systemic treatment, histopathologic and DCE-MRI responses revealed high positive correlation with kappa test (kappa: 0,63), but there were low correlation between not only histopathologic and MG responses but also US responses with kappa test (kappa: 0,2). Conclusions: DCE-MRI is more effective method than other radiologic methods for the evaluation of response to NAC ± trastuzumab when compared with the histopathologic findings.
Impact of t(11;14) on outcomes in African American (AA) and non-AA (NAA) patients (Pts) with newly diagnosed multiple myeloma (NDMM): Connect MM registry.
Authors: Cristina Gasparetto, Rafat Abonour, Sundar Jagannath, Brian G. Durie, Jatin J. Shah, Mohit Narang, Howard R. Terebelo, Kathleen Toomey, James Hardin, Lynne I. Wagner, Shankar Srinivasan, Amani Kitali, E. Dawn Flick, Faiza Zafar, Amit Agarwal, Robert M. Rifkin
Journal: Journal of Clinical Oncology (2017)

8023 Background: t(11;14) is a common cytogenetic abnormality historically associated with standard-risk and generally favorable MM outcomes, but has shown poor prognosis in some retrospective analyses. Connect MM is a prospective, US, observational, multicenter registry that collects data on management and natural history of NDMM pts in clinical practice. The impact of t(11;14) on survival outcomes was assessed in AA and NAA pts. Methods: Adult NDMM pts who completed induction and were tested for t(11;14) by FISH/cytogenetics were grouped by race (AA vs NAA). Endpoints were PFS and OS. Kaplan-Meier analyses were adjusted for differences in cohort, age, ISS stage, transplant intent, t(4;14), hemoglobin, platelets, calcium, creatinine, and diabetes history. Data cutoff was Jul 7, 2016. Results: 3011 pts were enrolled in 2 cohorts (Cohort 1: n = 1493, Sep 2009–Dec 2011, median follow-up = 39.3 mos; Cohort 2: n = 1518, Dec 2012–Apr 2016, median follow-up = 16.4 mos). Of 1539 (52%) pts tested for t(11;14), 363 (24%) were t(11;14)-positive, including 53 (26%) of 205 AA and 310 (23%) of 1334 NAA pts. First-line bortezomib exposure was similar across groups. A trend of shorter PFS was observed in AA pts with t(11;14) vs AA without t(11;14) (Table). AA pts with t(11;14) had significantly higher risk of death compared to those without t(11;14) and higher rate of early mortality than NAA pts. No differences in PFS or OS were noted in NAA pts with or without t(11;14). For OS, the interaction between race and t(11;14) status was statistically significant ( P= 0.004). Conclusions: In Connect MM, the effect of t(11;14) on OS was significantly different between AA and NAA pts. t(11;14) was associated with poorer survival outcomes in AA pts, and thus, may be a risk factor for poor prognosis. Additional analyses will be conducted to elucidate the role of induction treatment, transplant and maintenance in AA and non-AA pts with t(11;14). Clinical trial information: NCT01081028. [Table: see text]
VANCE: First-in-human phase I study of a novel ChAdOx1-MVA 5T4 vaccine in low and intermediate risk prostate cancer.
Authors: Irina Redchenko, Federica Cappuccini, Emily Pollock, Richard John Bryant, Lucy Carter, Clare Verrill, Julianne Hollidge, Louise Goodwin, Richard Harrop, Pedro Julio Romero, Selena Vigano, Tom Evans, James Catto, Freddie Hamdy, Adrian V.S. Hill
Journal: Journal of Clinical Oncology (2018)

3018 Background: Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings. However, neither of the two clinically most advanced PCa vaccines, Sipuleucel-T and ProstVac, induced strong T cell immunity. In our study, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus and MVA, targeting an oncofetal self-antigen 5T4 in early stage PCa. Methods: 40 patients, either newly diagnosed with early stage PCa and scheduled for radical prostatectomy or patients with stable disease on active surveillance protocol, were randomised to a "standard" immunisation regimen to receive 3 vaccinations four weeks apart, or to an "accelerated" immunisation protocol to receive 2 vaccinations at one week interval. Study primary endpoints were vaccine safety and immunogenicity. Secondary endpoints included immune infiltration into the prostate and PSA level change secondary to treatment. As exploratory endpoints, phenotype and functionality of antigen-specific T cells and breadth of induced T cell responses were assessed. Results: 39 patients completed the study and were eligible for analysis. The vaccine had an excellent safety profile, with the majority of vaccine-related AEs graded as mild. Vaccination-induced 5T4-specific T cell responses were measured in blood by ex vivo IFNγ ELISPOT and were detected in the majority of patients. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive TILs were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA level increase 2-8 weeks following vaccination possibly indicating an inflammatory response in the target organ. Quantitative immunohistochemical analysis of paired pre- and post-treatment prostate tissue samples will be reported. Conclusions: We report for the first time, that ex vivo T cell responses to a tumour self-antigen can be elicited in the majority of PCa patients. A Phase II study is starting to test this vaccine in combination with PD1 blockade in early stage and metastatic PCa. Clinical trial information: NCT02390063.
PD.1.03 Ensartinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients: Updated Data
Authors: T. Leal, H. Wakelee, K. Reckamp, S. Waqar, S. Patel, G. Blumenschein, J. Neal, K. Harrow, A. Holzhausen, C. Liang, G. Dukart, L. Horn
Journal: Journal of Thoracic Oncology (2018)
Cannabis use in hematopoietic transplantation survivors.
Authors: Elizabeth Trice Loggers, Barry Storer, Steven Pergam, Renata Urban, Heather Greenlee, Jesse R Fann, Stephanie Lee
Journal: Journal of Clinical Oncology (2018)

10084 Background: Approximately 20% of cancer patients report cannabis use (CU) within the last month despite limited data regarding its risks/benefits. CU among hematopoietic transplantation survivors (HTS) is of interest given the high symptom burden, infectious risk and research regarding cannabidiol in graft versus host disease prevention. Methods: From January 1 to June 1, 2017, a 15-question module addressing CU was included in a self-administered, annual survey of all adult HTS at Fred Hutchinson Cancer Research Center (Seattle, WA). Analysis included descriptive statistics and logistic regression. Results: Responders (n = 697, 32%) were more likely to be older, white and female than non-responders (all p < 0.001). Among responders, 329 (47%) considered CU and 124 (18%) reported CU. Reasons for considering CU included: physical symptoms (86%), emotional concerns (50%), recreation (45%) and to treat cancer (22%). While HTS aged 18-39 were 4-fold more likely to consider CU than those > 65 years (odds ratio 4.04, 95% confidence interval 2.25-7.27, p < 0.0001), age was not associated with CU. Instead, white race, perception of benefits of CU, CU for cancer treatment, and communication/receipt of information from clinicians, naturopaths or cannabis dispensers or peers was associated with CU (see Table 1). CU was not associated with the legal status of cannabis in the HTS’s state/province. Conclusions: While most HTS use cannabis to address physical and emotional concerns, nearly a quarter use it with the hope of improving their cancer outcomes. Whereas the perceived benefits of, and communication regarding, cannabis may play a significant role in use, age and legality likely do not. Factors associated with cannabis use (n = 329). OR (95% CI) p-value Race White 1.0 Other 0.35 (0.12-0.96) 0.04 Transplant relapse* Yes 0.27 (0.06-1.12) 0.07 Believe cannabis has benefit* Yes 2.18 (1.21-3.95) 0.01 Considered use to treat cancer* Yes 2.74 (1.31-5.72) 0.008 Discussed with/received information from: Doctor, nurse, or nutritionist* Yes 2.92 (1.69-5.05) 0.0001 Naturopath or medicinal/recreational staff person* Yes 2.62 (1.35-5.10) 0.005 Family, friend, or other cancer patient* Yes 2.54 (1.37-4.72) 0.003 * No = referent (OR = 1.0)
Abstract 15199: Cysteine Oxidation of Cu Importer CTR1 Promotes VEGF Signaling and Angiogenesis
Authors: Archita Das, Young-Mee Kim, Seock-Won Youn, Sudhahar Varadarajan, Jack Kaplan, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2016)

Background: Reactive oxygen species (ROS) and copper (Cu), an essential micronutrient, play an important role in angiogenesis with unknown mechanisms. Cysteine sulfenic acid (Cys-OH) formation is i...
Abstract 10909: LDL and HDL Particle vs. Cholesterol Concentration in Metabolic Syndrome and Diabetes for the Prediction of Coronary Heart Disease: The Multiethnic Study of Atherosclerosis
Authors: David M Tehrani, Yanglu Zhao, Michael Blaha, Samia Mora, Rachel Mackey, Erin Michos, Matthew Budoff, William Cromwell, James Otvos, Paul Rosenblit, Nathan Wong
Journal: Circulation (2015)

Background: A more important role of both low and density lipoprotein (LDL-P and HDL-P) than cholesterol (LDL-C and HDL-C) concentration in predicting coronary heart disease (CHD) has been noted. However, the role of these factors and extent of particle-cholesterol discordance in metabolic syndrome (MetS) and diabetes (DM) for event prediction is unknown. Methods: In adults aged 45-84 from the Multi-Ethnic Study of Atherosclerosis, a prospective study of subjects without baseline cardiovascular disease, we defined percent discordance of LDL and HDL based on a subject’s difference between baseline particle and cholesterol percentiles. Separate Cox regressions adjusted for standard risk factors were performed to assess the relationship of the continuous lipoprotein discordance variables, as well as LDL-C, LDL-P, HDL-C, and HDL-P, to incident CHD events in those with DM, MetS (without DM), or neither condition. Results: Among 6,417 subjects (52.5% male, mean age 62.1) with 10 year follow-up, those with DM and MetS had significantly greater LDL and HDL discordance compared to those without these conditions (Figure). In discordance models, only LDL discordance [per standard deviation (SD)] within the MetS group was positively associated with CHD events [Hazard Ratio (HR) =1.25, p&lt;0.01]. In models with individual particle/cholesterol variables (per SD), within the DM group, HDL-P was negatively (HR=0.71, p&lt;0.05) and LDL-C positively (HR=1.47, p&lt;0.05) associated with CHD. In those with MetS, only LDL-P was positively associated with CHD (HR=1.34, p&lt;0.05). In those with neither disease, only LDL-C was positively associated with CHD (HR=1.27, p&lt;0.05). Conclusion: LDL discordance (mainly through higher LDL-P) in those with MetS and higher LDL-C with lower HDL-P in those with DM predicts CHD risk. These results support a potential role for examining lipoprotein particles and discordances in persons with MetS and DM to better assess CHD risk.
A single-Institution retrospective analysis of metastatic bronchial carcinoids with a focus on recurrence pattern.
Authors: Marta Peri, Francesca Spada, Chiara Maria Grana, Edoardo Botteri, Nicole Rotmensz, Giuseppe Badalamenti, Antonio Russo, Nicola Fazio
Journal: Journal of Clinical Oncology (2016)

e20586 Background: Bronchial carcinoids (BCs) are rare, usually slow-growing malignancies that develop from diffuse neuroendocrine cells in the lungs and airways. Their prognosis is good when they are radically resected, although recurrences are possible even after many years. Furthermore rarely they can present with distant metastases at diagnosis. We present a large series of patients with metastatic BCs managed in a single Institution, describing more in details the pattern of recurrence. Methods: Clinical records of patients with cytological or histological diagnosis of BC, evaluated at the European Institute of Oncology (IEO) between 1997 and 2014, were retrospectively analyzed. P-value descriptive data, uni- and multi-variable survival analysis were generated for all variables. Results: A total of 111 patients with metastatic BC were included in the study. Sixty-three had metachronous and 48 synchronous disease. With a median follow-up of 52 months, 5-year OS was 67% and median survival 79 months for the whole population. Median (IQR) time to relapse was 5 (range 3-9) years, particularly it was 6 years after non-radical surgery and 4 years after radical surgery (p-value = 0.14). Liver (67%), lymph node (25%), bone (22%) and lung (16%) were the most common sites of relapse, along with subcutis (6%). The most common methods of first recurrence detection were CT scan (59%), liver ultrasound (13%), somatostatin receptor scintigraphy (4%) and CgA levels (4.8%). In 62%, Ki-67 values of first relapse were missing; the median of Ki-67 expression level was 14.5% (range: 0–60%). Bone (HR of 2.78), liver (HR of 3.52) or contralateral lung metastases and Ki-67 > 10% (HR of 6.16) significantly correlated with survival. Moreover there was a significant positive correlation between time to relapse and 5-year OS. Conclusions: This study has raised important questions about the nature of these tumours and generated hypotheses for future prospective studies. We confirm that a long-lasting clinical/radiological follow-up is recommended in BCs, since metastases may develop several years after primary tumor surgery.
Adverse events (AEs) in early phase cancer clinical trials.
Authors: Grace Mishkin, Andrea Denicoff, S. Percy Ivy, Richard Piekarz, Shanda Finnigan, Jared C. Foster, Lori M. Minasian
Journal: Journal of Clinical Oncology (2018)

2542 Background: AE reporting is required in the conduct of clinical trials for patient safety and to understand the toxicities from treatment interventions. This analysis used a uniquely comprehensive dataset of AEs from early-phase NCI trials to describe overall clinician-reported AE frequency and prevalence, as well as changes in frequency and prevalence over time. Methods: Data were used from early phase trials using NCI-sponsored agents with complete AE reporting. Patients ages 25+ with at least one AE were included. These AEs were collected for treatment courses started 2000-2016 and standardized to CTCAE v4.0. R was used for analysis. Results: Over this 17-year period complete AE reporting was available for 1,594 early phase clinical trials representing a wide range of disease areas and agents. There were 1,417,529 total AEs reported for 59,023 patients. There are 790 CTCAE terms, but the 15 most frequently reported AEs represented 48% of all AEs reported (Table 1). Grade 3 AEs represented 13.1% of the AEs for 2000-2003, but decreased to 9.9% for 2012-2016. Conclusions: These initial results from an extensive AE database show a small number of AE terms represent most AEs reported. The proportion of AEs which were grade 3 decreased over time, potentially due to changes in agents and improvements in supportive care. As more trials which include patient reporting of AEs are completed, joint analysis could lead to more comprehensive understanding of the tolerability of lower grade AEs. Analysis by agent class, patient age, and disease is ongoing. 15 most commonly reported ctcae terms. CTCAE Term # AEs % AEs (n = 1433896) # Patients % Patients (n = 59802) Fatigue 105012 7.4% 36645 62.1% Anemia 78350 5.5% 27746 47.0% White blood cell decreased 58984 4.2% 21114 35.8% Nausea 56993 4.0% 27456 46.5% Platelet count decreased 56157 4.0% 21497 36.4% Diarrhea 52412 3.7% 22696 38.5% Neutrophil count decreased 50901 3.6% 20145 34.1% Hyperglycemia 32542 2.3% 13650 23.1% Anorexia 32510 2.3% 17360 29.4% Peripheral sensory neuropathy 30533 2.2% 10166 17.2% Lymphocyte count decreased 27904 2.0% 11724 19.9% Aspartate aminotransferase increased 27057 1.9% 13564 23.0% Alopecia 25679 1.8% 8379 14.2% Rash maculo-papular 25547 1.8% 12303 20.8% Vomiting 24186 1.7% 15576 26.4%