tbuckley/cabot-search huggingface dataset:
Outcomes for non-syndromic extra-cranial peripheral nerve sheath tumors.
Authors: Alireza Mansouri, Shivani Ahlawat, Jaishri O'Neill Blakeley, Allan Joel Belzberg
Journal: Journal of Clinical Oncology (2018)

e13584 Background: Symptomatic peripheral nerve sheath tumors (PNSTs) or those with features concerning for malignancy may require surgical intervention. However, the rate of symptomatic progression or malignant conversion is not known. Methods: An institutional review of the radiology database was conducted for terms relevant to the differential of PNSTs (Jan 1 2000 - Jan 1 2017). Syndromic cases and cranial lesions were excluded. The proportion and rate of tumor growth in the observation cohort was calculated. Predictors of successful long-term observation were identified using multivariate logistic regression. Chi-squared test was used to compare intraoperative blood loss, neurological deficit, and length of stay between upfront and delayed surgery cohorts to determine whether the latter was associated with additional risk to patients. Results: 265 patients were identified: 117 (44%) were resected upfront. Pain was the indication for surgery in the majority (76/117, 65%).148/265 (56%) were initially assigned to observation with 24 (16%) ultimately requiring surgery. Peripheral location and symptomatic presentation were independent predictors for upfront surgery (P < 0.01). Only 41/124 (33%) tumors in the observation cohort had progression at mean follow-up 32 months. Those with growth grew 2.2mm/year. In the observation cohort, incidental presentation (85/124, 68%) and location within spinal canal (84/124, 68%) were most common. In the 24 tumors requiring surgery after initial observation, symptom progression (11/24, 46%) and peripheral nerve location (9/24, 38%) were most common. Among 167 histopathological specimens (141 surgical and 26 biopsy samples), 146 (87%) were schwannomas. Only one malignant tumor was identified, which was resected upfront. There was no malignant conversion in the observation cohort. There were no differences in adverse events between upfront and delayed surgical intervention. Conclusions: Among non-syndromic PNSTs, asymptomatic lesions can often be managed with surveillance as there was no malignant conversion in lesions recommended for observation and many lesions did not grow. A preliminary decision algorithm for isolated PNST is proposed.
Abstract 12423: Rapid And Robust Reprogramming Of Fibroblasts Into Integration-free Functional Cardiomyocytes With Sendai Viral Vectors
Authors: Kazutaka Miyamoto, Hiroyuki Y amakawa, Naoto Muraoka, Taketaro Sadahiro, Hidenori Kojima, Sho Haginiwa, Mari Isomi, Yuki Kuishi, Shintaro Ninomiya, Keiichi Fukuda, Masaki Ieda
Journal: Circulation (2015)

Rationale: Direct reprogramming of fibroblasts into functional cardiomyocytes (iCMs) holds great potentials for disease modeling and regenerative purposes, but the technique thus far has been slow and inefficient. Moreover, integration of viral transgenes into host genome may hinder clinical applications of this strategy. Objective: The aim of this study is to develop new Sendai viral vectors (SeVs) which overexpress reprogramming factors without genomic integration, and to determine the efficiency and safety of cardiac reprograming with SeVs. Methods and Results: We generated separate Gata4 (G), Mef2c (M), and Tbx5 (T) SeVs, and a polycistronic SeV containing GMT in a single transgene (SeV-GMT). Transduction of separate G, M, T SeVs did not induce cardiac reprogramming in mouse fibroblasts. In contrast, the polycistronic SeV-GMT greatly promoted cardiac reprogramming and induced spontaneously beating iCMs up to 40% of the starting fibroblasts, which was 100-fold greater than the retroviral-mediated reprogramming. Moreover, SeV-GMT shortened the duration to induce beating cells from 30 to 10 days, compared to retrovirus-GMT, demonstrating rapid and robust cardiac induction with SeV-GMT. FACS analyses demonstrated that the number of cardiac troponin T (cTnT) + cells and the intensity of cTnT expression were strongly increased with SeV-GMT compared with retrovirus-GMT. EdU incorporation assays and sequential gene expression profiles revealed that the increase in beating iCMs with SeV-GMT was not due to cell proliferation or conversion to multipotent cardiac progenitor cells. SeV-GMT transduction resulted in lower expression of Tbx5 compared to separate G, M, T SeV transduction or retroviral-GMT transduction. Supplementation of Tbx5 in SeV-GMT-transduced cells greatly reduced cardiac reprogramming, suggesting stoichiometry of transcription factors might be optimal in SeV-GMT. Genomic DNA analyses revealed that the SeV transgenes were not integrated into the host genome, and no tumors were detected in culture after 2 months of SeV-GMT transduction. Conclusions: We developed a highly efficient and safe direct cardiac reprogramming platform with SeV-GMT.
Prevalence of residual tumor in the prostate after contemporary systemic therapy.
Authors: Yao Zhu, Beihe Wang, Jun Luo, Stephen J. Freedland, Dingwei Ye
Journal: Journal of Clinical Oncology (2018)

e17001 Background: Systemic treatment can have significant survival benefits when used early for metastatic hormone-sensitive prostate cancer. Whether local therapy in this setting adds benefit is unclear. Effectiveness of aggressive systemic therapies in local control is a relevant topic. We tested the hypothesis that tumors in the prostate may not be eradicated by aggressive systemic treatment. Methods: We conducted a systematic review of neoadjuvant trials of chemo- and hormonal- therapies in prostate cancer focusing on evaluation of pathological outcome measured by pT0 rates. Results: Docetaxel and hormonal therapies resulted in pT0 rates of 2.0% and 3.6%, respectively. In spite of a substantially decreased intra-prostatic androgen after new androgen targeted therapies (abiraterone), pT0 rate remained low at 5.5%. High Gleason score was an independent predictor for poor pathological response to systemic treatment (adjusted p = 0.01). Conclusions: Given the high prevalence of residual tumor in the prostate after aggressive systemic treatment (docetaxel or new androgen targeted therapy), it seems reasonable to test whether definitive control of the primary tumor may contribute to delayed progression when combined with contemporary systemic treatment for men with metastatic hormone-sensitive prostate cancer.
Patients treated with bladder preserving trimodality chemoradiation therapy (BPTMCRT) off-trial compared to those on trials.
Authors: Anesa Waheda Ahamad, Alvaro Martinez, Sharon Salenius, Rudi Ross, Eduardo Fernandez
Journal: Journal of Clinical Oncology (2017)

e16014 Background: We assessed characteristics and outcome of patients treated with radiotherapy for muscle-invasive bladder cancer off-trial at forty-four community-based radiotherapy centers in the United States compared to those on clinical trials. Methods: We retrospectively reviewed 155 patients who had been treated from August 2010 to June 2014. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Results were compared to a pooled analysis of six RTOG protocols. Results: Characteristics were significantly inferior versus those on RTOG studies: lower rate of complete transurethral resection of bladder tumor: 36.8% versus 70.7% (p&lt;0.0001), poorer performance status (PS): 36.8% were 0 to 1 versus 100% (p&lt;0.0001), higher median age: 79 years versus 66 (p&lt;0.0001), more medically inoperable: (51.0%) versus 0% in RTOG (p&lt;0.001). Forty-seven percent had refused surgery. Fewer patients underwent concurrent chemotherapy: 56.1% versus 100% (p&lt;0.0001). Median radiotherapy dose was similar: 64.8 Gy. At median follow-up of 12.6 months (range, 3.1-49.2), 36-month OS was 51.3% for those who refused surgery versus 24.5% for medically inoperable (p=0.009); 36-month OS was 58.1% post complete TURBT versus 29.8% if incomplete (p=0.07); 18-month PFS was 74.9% for PS 0-1 versus 36.3% for &gt;1 (p=0.04). PS &gt;1 patients were deceased or censored by 24 months. The 36-month OS was 54.3% with chemoradiation therapy (CRT) versus 17.2% without chemotherapy (p=0.03). Among CRT patients, the 36-month OS was 38.9% for medically inoperable versus 66.3% for those who refused surgery (p=0.04), similar to the pooled analysis of prospective RTOG protocols. Conclusions: The 66.3% 36-month OS for patients who refused surgery and received CRT suggests that it is appropriate to offer BPTMCRT to these patients in free standing centers. However, we may not be able to translate clinical trial protocols to many patients in this setting due to their poor functional reserve. More treatment options are needed for these patients given the aging population.
TCT-713 Impact of Statins Preloading before PCI on Periprocedural Myocardial Infarction Among Stable Angina Pectoris Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials
Authors: Mohamad Soud, Gavin Ho, Rayyan Hemetsberger, Kayode Kuku, Alexandre Hideo-Kajita, Ron Waksman, Hector Garcia-Garcia
Journal: Journal of the American College of Cardiology (2018)
Development of biomarkers to guide the clinical development of tarloxotinib bromide, a hypoxia-activated irreversible EGFR/HER2 inhibitor.
Authors: Adam V Patterson, Randall J. Kimple, Victoria J Jackson, Adam D Swick, Chris P Guise, Maria R Abbattista, Matthew R Bull, Prashanth Jyothi Prabakaran, Shevan Silva, Jessica D Sun, Charles P Hart, Tillman E. Pearce, Jeff B Smaill
Journal: Journal of Clinical Oncology (2016)

e17521 Background: Tarloxotinib is a hypoxia-activated prodrug that releases an irreversible inhibitor of EGFR/HER2. A Phase 2 clinical study (NCT02449681) is ongoing in squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Molecular taxonomy studies in SCCHN patient samples identify the HPV-negative basal-like subtype as positive for both the HIF/hypoxia gene signature and HER pathway activation, suggesting a causal relationship. In the present work we seek to identify predictive biomarkers of sensitivity to tarloxotinib with biopsy samples collected from the clinical trial. Methods: Therapeutic response to tarloxotinib was assessed in patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of SCCHN and SCCS. Tarloxotinib was dosed at the human MTD equivalent (150 mg/m2) following matching of plasma drug exposure in mice. Tumor samples were collected and assessed for biomarkers of response, including hypoxic volume, inhibition of signal transduction, cell cycle modulation and induction of apoptosis. In clinical studies hypoxic tumor volume is being assessed by [18F]HX4 PET imaging and tissue biopsies collected for biomarker assessment. Results: Tarloxotinib was efficacious in PDX models of SCCHN as well as CDX models of SCCHN and SCCS, and accompanied by marked shutdown of tumor phospho-EGFR. Consistent with this observation, a relationship was observed between inhibition of p-AKT and anti-proliferation across a series of SCCHN and SCCS cell lines. Hypoxia induction of activated EGFR was observed in vitro and administration of tarloxotinib was associated with suppression of tumor hypoxic volume, including suppression of the HIF biomarker carbonic anhydrase 9 (CA9). Conclusions: Tarloxotinib is active in PDX and CDX models of human SCCHN. Loss of CA9 expression and shutdown of p-EGFR and p-AKT appear to be predictive of response to tarloxotinib. Assessment of these biomarkers is warranted in the context of clinical response data. These data support the weekly dose of 150 mg/m2 of tarloxotinib in the ongoing phase 2 clinical trial. Recruitment is ongoing with encouraging signs of activity.
Characterization of the immunogenomic landscape of follicular lymphoma.
Authors: Paola Dama, Kazuma Kiyotani, Girish Venkataraman, Sonali M. Smith, Yusuke Nakamura, Justin Paul Kline
Journal: Journal of Clinical Oncology (2018)

e19531 Background: Follicular Lymphoma (FL) is an indolent, but incurable form of non-Hodgkin lymphoma (NHL), with variable clinical behavior. The immune environment plays a major role in dictating the biology of FL. Emerging data has revealed a critical relationship between the genetic landscape and the immunogenicity of select solid tumors, but in FL, this relationship has not been studied. We hypothesized that neoantigens in FL are the targets of T cell recognition, and aimed to identify somatic mutations in FL Bcells that could serve as neoantigens for targeting by T cells. Methods: Whole exome sequencing (WES) was performed on FACS-purified FL B cells (CD10+CD19+ cells) and matched T cells from 11 FL biopsy samples using SureSelectXT Human All Exon V5 kit (Agilent Technologies, Santa Clara, CA). HLA A, B and C haplotypes were predicted using PolySolver, OptiType, Phlat and Seq2hla software with > 90% concordance. HLA binding affinity was predicted for all possible 8-11-mer peptides generated from each somatic mutation and corresponding wild-type peptides using NetMHCpan v2.8. These tiled peptides were analyzed for their predicted binding affinities (IC50 nM) to HLA class I molecules. Results: A median number of 72 somatic mutations were identified in each sample (range: 5-94 ). Non-synonymous single nucleotide variants (SNV) were cataloged, and in silico analysis was utilized to predict potential high-affinity epitopes capable of binding patient-specific HLA molecules. Consistent with published reports, recurrent somatic mutations were identified in EZH2, CREBBP, IGLL5, MUC21, PCLO, and PIM1. We also identified recurrent mutations in BCL2 and MLL2 (frameshift insertions) known to dominate the mutational landscape of FL. Mutations in HLA class II alleles were common. In silico analysis was employed to identify putative neo-antigens. Functional validation of lead candidate neo-antigen peptides is ongoing. Conclusions: Putative neo-antigens were identified in all patient samples analyzed. Our findings suggest that immune therapies incorporating neo-antigen-specific approaches, such as personalized vaccines, should be explored in FL patients.
Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma
Authors: Anna Bianchi-Smiraglia, Archis Bagati, Emily E. Fink, Hayley C. Affronti, Brittany C. Lipchick, Sudha Moparthy, Mark D. Long, Spencer R. Rosario, Shivana M. Lightman, Kalyana Moparthy, David W. Wolff, Dong Hyun Yun, Zhannan Han, Anthony Polechetti, Matthew V. Roll, Ilya I. Gitlin, Katerina I. Leonova, Aryn M. Rowsam, Eugene S. Kandel, Andrei V. Gudkov, P. Leif Bergsagel, Kelvin P. Lee, Dominic J. Smiraglia, Mikhail A. Nikiforov
Journal: Journal of Clinical Investigation (2018)

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.
Outcome of patients with solid tumors admitted to intensive care units.
Authors: Melissa Phillips, Sukaina Rashid, Miriam Hopkins, Anasofia Pericao, Sarah Louise Stewart, Maise Al-Bakir, Rowan Miller
Journal: Journal of Clinical Oncology (2018)

e18701 Background: Intensive care units (ICU) are increasingly managing cancer patients (pts) with life-threatening disease and treatment-related complications. 5% of cancer pts require ICU admission in the early phase of their disease. We sought to determine the outcome of solid tumor (ST) pts admitted to ICU in two UK cancer centres and investigate factors associated with outcome. Methods: Medical records of ST pts admitted to ICU over a 2-year period, with a minimum of 6 months follow-up, were reviewed. Information on cancer treatment, reason for ICU admission, co-morbidities and outcome, was collected. Elective ICU admissions post-surgery were excluded. Results: 137 pts, median age 56 years (range 16-88) were identified. Common tumor types included GU (28%), sarcoma (19%), lung (18%), colorectal (15%) and breast (12%). The majority of pts (71%) had AJCC stage 4 disease. At the time of ICU admission, 74% of pts were on active treatment (9% radical, 18% adjuvant and 46% palliative), 11% were treatment naïve and 15% were on surveillance or receiving best supportive care. Respiratory failure (20%), sepsis (18%) and renal failure (14%) were the most common reasons for ICU admission. The majority of pts had one (56%) or two (31%) organ failure. Median duration of ICU admission was 3 days (0 to 64 days) and total hospital admission was 19 days (0 to 374 days). 29% of pts died on ICU. Overall, 49% survived to hospital discharge. Median overall survival (OS) from ICU admission was 34 days (0 to 989 days) with 47%, 37% and 21% of pts alive at 30 days, 60 days and 6 months, respectively. OS was influenced by ECOG performance status (PS), treatment intent, tumor type and admission reason, but only PS (p = 0.0003) remained associated with OS on multivariate analysis, with median OS not reached for PS 0, 174 days, 32 days and 19 days for PS 1,2 and ≥3 respectively. Conclusions: The outcome of pts with ST requiring ICU admission is poor with only 49% surviving to hospital discharge. Pre-admission PS has a significant impact on outcome and should be considered by oncologists and intensivists as a selection criterion for ICU admission. Prospective studies are required to validate these findings and investigate additional factors associated with OS, disease-free survival and quality of life.
Computer-extracted stromal features of African-Americans versus Caucasians from H&amp;E slides and impact on prognosis of biochemical recurrence.
Authors: Hersh Kumar Bhargava, Patrick Leo, Robin Elliott, Andrew Janowczyk, Jon Whitney, Sanjay Gupta, Kosj Yamoah, Timothy Rebbeck, Michael D Feldman, Priti Lal, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

12075 Background: There has been recent interest in investigating differences in the prostate cancer (PCa) phenotype between African-Americans (AA) and Caucasian-Americans (CA). Separately, there is evidence that stromal morphology may be predictive of cancer aggressiveness. The objective of this work was to evaluate whether computer extracted measurements of stromal nuclei in PCa histology (1) were significantly different between AA and CA populations and (2) could be used to create more accurate, population-specific prognostic models for biochemical recurrence (BCR) following surgery. Methods: Radical prostatectomy specimens from 200 patients (93 AA, 93 CA, 73 BCR, 113 non-BCR) were reviewed (ethnicity self-declared). Patients were randomly partitioned into training (n = 124) and validation sets (n = 62). Image features from stromal nuclei were computed from scanned H&E slides and used with 3 machine learning (ML) models (random forest, top 4 features by t-test) to predict BCR in each population subset. We validated these models against the independent validation cohort and compared them with extant clinical recurrence risk prediction nomograms (KATTAN, CAPRA-S). Results: 23 stromal features had significantly differing distributions between the BCR and non-BCR cohorts (p < 0.05). These included descriptors of nuclear shape and arrangement. 31 features were significant in the AA cohort while only 4 were in the CA cohort. Our ML models based on these features significantly (log-rank p < .005) outperformed existing nomograms for AA patients and had an AUC of 0.82. Conclusions: Stromal nuclear features were predictive of PCa BCR in AA patients. Taking into account population-specific information significantly improves accuracy of computational pathology based prognostic models for AA PCa patients. Comparison of our model with nomograms for AA validation cohort. Classifier Features Statistics Random Forest 4 descriptors of nuclear shape. AUC: 0.82 Logf-rank p = 0.0046 Hazard ratio: 19.95 CAPRA-S Clinical variables (PSA, grade, stage, age, etc.). AUC: 0.61 Log-rank p = 0.4265 Hazard ratio = 0.5514 KATTAN AUC: 0.64 Log-rank p = 0.3385 Hazard ratio = 0.54
Investigating strategies to improve clinical trial opportunities in oncology in New Zealand (INSIGHT).
Authors: Yeojeong So, Malcolm Cameron Anderson, Michael P. N. Findlay, Kate Gregory, Chris Jackson, Michael B. Jameson, Mark Jeffery, Vincent Newton, Richard T. North, Anne O'Donnell, Katrina J. Sharples, Michelle K. Wilson
Journal: Journal of Clinical Oncology (2018)

e18851 Background: Despite the importance of clinical trials, fewer than 5% of adult cancer patients are enrolled in them. Multiple patient (pt), clinician and institutional barriers have been identified. This study aimed to explore what factors impact access to cancer trials in NZ. Methods: After ethics approval, a 28-point survey was circulated via 9 DHBs and 4 cancer foundations to pts with a cancer diagnosis. Questions covered demographics and potential factors that might impact participation in trials e.g. travel. A 23-point survey was sent to research staff across the 9 DHBs. Results: Between July 2016 and June 2017, 691 pts responded; 63% were female, 77% were over the age of 50. Most pts (89%) knew of clinical trials and 86% would consider participating in a trial. The proportion did not differ by age, location, income, tumor type or gender. 44% would consider treatment at a different hospital, and 11% would consider relocating for a trial. 130 pts (19%) had been on a trial of whom only 3 pts (2%) would not consider a trial in the future. Only 10% thought trials should be a last resort. Participation factors seen as advantages included: benefiting others (such as doctors’ research) (93%), better treatment (70%), more scans and longer follow-up (51%). Disincentives for participation included fear of randomization (78%), treatment toxicities (72%), time and cost of more visits (40%) and unspecified future use of tissue (33%). Of 111 responses from research staff, 54% had experience as either a principal investigator (PI) or sub-PI. The 3 most commonly reported barriers by research staff were time (73%), money (70%) and infrastructure (49%). Researchers felt additional tests, language issues and pt awareness of trials were key barriers to pt participation. Conclusions: The identified barriers to trial participation appear similar in NZ to other developed countries. In this motivated cohort, many pts did not mind extra travel or tests, in contrast to perceptions of the research team. There is a strong interest from pts with cancer to consider participation in trials at any stage of their treatment. This suggests that addressing the areas of clinician and infrastructure barriers may help improve access to clinical trials in NZ.