tbuckley/cabot-search huggingface dataset:
Integrated analysis of somatic genetic alterations and immune microenvironment in malignant pleural mesothelioma.
Authors: Wickii T. Vigneswaran, Hiroyuki Inoue, Jae-Hyun Park, Kazuma Kiyotani, Sope Olugbile, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2016)

e20080 Background: Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor and rapidly fatal when untreated. Advanced high-throughput sequencing technologies allow comprehensive characterization of genetic alterations in tumors. Genomic landscape of MPM is not well understood. Knowledge of immune microenvironment of MPM is critical for developing effective targeted therapies. Methods: We examined biopsies from 12 MPM patients that were removed during maximal cyto-reductive surgery. Specimens from 3 sites (anterior, posterior and diaphragm, a total of 36 tissue samples) were studied through whole exome sequencing, T cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs), and expression levels of immune-related genes. We also performed in silicoprediction of potent neoantigens derived from non-synonymous somatic mutations in each specimen. Tumor tissues from 3 sites were compared using hierarchical clustering for tumor heterogeneity and differences in immune environment. Results: High mutation/neoantigen load correlated with higher clonal expansion of TILs (r = 0.46). High expression of immune-associated cytolytic factors, granzyme A and perforin 1 (r = 0.48), were observedin tumor tissues. In the clustering analysis, heterogeneous MPM cases revealed unique neoantigens and clonotypes of TILs that were restricted to each of tumor site, suggesting infiltration of the neoantigen-specific T cells. Further sub-analysis according to histologic types showed biphasic tumors had higher mutation/neoantigen load and stronger oligo-clonal T cell expansion than epithelioid tumors (p = 0.01). Conclusions: A significant correlation was noted between somatic mutation/neoantigen load, clonality of TILs, and the immune-related tumor microenvironment in MPM. Our findings suggest that high mutation/neoantigen load in tumor cells might promote effective expansion and infiltration of tumoricidal T cells into the tumor bed. Findings provide a rationale for selecting MPM patients who can benefit from immune checkpoint blockades. This may accelerate development of the neoantigen targeting TCR-engineered T cell therapy for MPM.
Development and validation of a new prognostic score on 4,646 patients with luminal-like breast cancer (BC) enrolled in 7 randomized prospective trials.
Authors: Caterina Fontanella, Bianca Lederer, Lucia Del Mastro, Carsten Denkert, Sabino De Placido, Claus Hanusch, Francesco Cognetti, Jens Bodo Huober, Michele De Laurentiis, Christian Jackisch, Giancarlo Bisagni, Sherko Kummel, Ornella Garrone, Andreas Schneeweiss, Filippo Montemurro, Michael Untch, Claudia Bighin, Gunter Von Minckwitz, Sibylle Loibl, Fabio Puglisi
Journal: Journal of Clinical Oncology (2016)

529 Background: At the 2014 ASCO meeting we presented the prognostic STAR score, designed in a dataset of 2,248 pts with low/intermediate grade Lum like BC (HER2-/estrogen receptor [ER]+/G1-2) combining tumor stage (AJCC Cancer Staging 7), progesterone receptor [PR] status, and age at baseline. In this study we included pts with high grade Lum like BC in the neoadjuvant dataset and validated the STAR score in the adjuvant GIM2 trial. Methods: EXPLORATORY COHORT (EC): 3,036 Lum like BC (HER2-/ER+/any grade) pts enrolled in 6 prospective randomized trials and treated with anthracycline-taxane based neoadjuvant therapy. VALIDATION COHORT (VC): 1,610 pts with Lum like BC from the 2x2 factorial randomized GIM2 trial (Del Mastro L, Lancet 2015) investigating dose-dense chemotherapy (CT) and the of addition of 5-FU to epirubicin-cyclophosphamide regimen. All patients received adjuvant endocrine treatment. We used uni/multivariate Cox regression analyses to explore the effect of the score on disease free (DFS) and overall survival (OS). Results: In the EC, multivariate analysis adjusted for CPS+EG score (Mittendorf EA, JCO 2011), CT density, and pCR (ypT0/is ypN0) demonstrated that the STAR score added significant independent information on DFS (p= .007) and OS (p= .002). In the VC, the STAR score added similar prognostic information after adjustment for tumor grade, Ki67 (cut off 20%), and CT density (DFS p< .001; OS p <.001). Multivariate analysis hazard ratios (HR) are shown in the table. Conclusions: The STAR score using stage at diagnosis, PR status and age discriminates Lum like BC with worse prognosis, receiving (neo)adjuvant CT and ET. EC VC DFS HR 95% CI p OS HR 95%CI p DFS HR 95%CI p OS HR 95%CI p A Stage I-IIA/PR+/age ≥ 40 1.0 1.0 1.0 1.0 B IIB/PR+/age ≥ 40 1.6 1.1-2.4 .043 1.5 0.8-2.6 .220 2.1 1.2-3.6 .011 3.4 1.5-7.7 .004 C I-IIA/PR-/age ≥ 40 I-IIA/PR+/age < 40 IIB/PR+/age < 40 IIIA-B/PR+/age ≥ 40 2.0 1.2-3.2 .006 2.1 1.1-4.0 .032 2.6 1.6-4.1 < .001 3.8 1.8-7.9 < .001 D I-IIA/PR-/age < 40 IIB/PR-/any age IIIA-B/PR+/age < 40 IIIA-B/PR-/any age 2.6 1.5-4.5 .001 3.0 1.4-6.4 .004 4.2 2.6-6.9 < .001 6.7 3.1-14.3 < .001 E IIIC 3.4 1.7-6.8 .001 5.5 2.3-13.0 < .001 9.2 8.5-14.3 < .001 13.0 6.4-26.6 < .001
Safety results of the Canadian Expanded Access Program (EAP) of palbociclib (PAL) plus letrozole (L) in postmenopausal patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) deemed appropriate candidates for first-line (1L) endocrine therapy (ET) with L.
Authors: Anil A. Joy, Shailendra Verma, Louise Provencher, Kathy Puyana Theall, Dongrui (Ray) Lu, Florence Dequen, Daniel Rayson
Journal: Journal of Clinical Oncology (2017)

e12534 Background: In the PALOMA-2 study, 1L PAL+L prolonged progression-free survival in women with estrogen receptor-positive/HER2- ABC vs placebo + L (hazard ratio 0.58; P&lt; 0.001). Here we assess a cohort of Canadian pts treated with 1L PAL+L for ABC in an EAP study (NCT02142868). Methods: This was an open-label, single-arm study of US and Canadian postmenopausal women (N = 337) with HR+/HER2- ABC for whom 1L ET with L was deemed appropriate. The primary objective was to allow pt access to PAL in combination with L. PAL (125 mg/d orally [3 wk on, 1 wk off]) was administered with L (2.5 mg orally QD) until PAL was commercially available. Secondary objectives included safety and patient-reported outcomes (PROs). Results: 96/97 (99%) treated/enrolled Canadian pts were assessed for safety and PROs (treated pt characteristics: median age 62.5 y, white/Asian [89%/7%], metastatic sites bone/lung/liver [71%/25%/17%], ECOG PS 0-1/2 [93%/7%], 89% with prior systemic anticancer treatment [tx]). Median exposure was 4 x 28 d cycles of tx, and the median average PAL dose was 125 mg/d. All-causality treatment-emergent adverse events (AEs) were reported in 100% pts; 68% had grade 3/4 events, the most common events were neutropenia (61%), infections (3%), and alanine aminotransferase increase (3%). Grade 4 neutropenia and grade 3 febrile neutropenia were reported in 2% and 1% of pts, respectively. Due to AEs, PAL was temporarily discontinued in 59% and 31% had ≥1 dose reduction. The main reasons pts permanently discontinued from the study were sponsor study termination, 77%; objective progression, 11%; and AE related/unrelated to study drug, 6%/2%. All EQ-5D questions were completed by 96% pts at baseline and 85% by end of tx (EOT). At EOT, the median EQ-5D index and the EQ visual analog scale scores were not significantly changed from baseline. Conclusions: A safe and tolerable profile was observed for PAL+L in 1L treatment of Canadian pts with HR+/HER2− ABC, consistent with other studies. Sponsor Pfizer Clinical trial information: NCT02142868.
Entering the Modern Era of Gene Therapy
Authors: Xavier M. Anguela, Katherine A. High
Journal: Annual Review of Medicine (2018)

Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients-not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.
Oncotype Dx analysis in early stage breast cancer (BC) in BRCA mutation carriers versus non-carriers.
Authors: Maryam Nemati Shafaee, Heather Y. Lin, Angelica Gutierrez Barrera, Banu Arun
Journal: Journal of Clinical Oncology (2016)

e12065 Background: While Oncotype-Dx testing has become the standard of care in early stage ER positive BC, its role in the management of BRCA associated breast cancer is not well defined. Inherited mutations in the BRCA gene are responsible for 5-10% of breast cancers. BRCA2 mutation predisposes to ER positive BC 50% of the time, while BRCA1 mutation is more commonly associated with ER negative tumors. In this report, we sought to evaluate the role of Oncotype Dx in a population of patients (pts) with known BRCA status. Methods: We performed an IRB approved single institution retrospective analysis of women with known BRCA status diagnosed with stage I-II BC (T0-T3, N0-N1). We included women diagnosed with ER and/or PR positive, Her2 neu normal BC between years 1974-2015. Tumor grade and Oncotype –Dx scores were retrieved. We evaluated the relationship between BRCA and Oncotype-Dx scores. Results: 691 pts were included in this study. 133 (19%) were BRCA1 or 2 positive and 558 (81%) were negative. 65 of the 691 pts underwent Oncotype-Dx testing, 13 in mutation carriers and 52 in non-carriers. Rate of Oncotype-Dx testing was significantly higher in women diagnosed in 2009 and after compared to earlier; 24/472 (5.1%) versus 41/219 (18.7%) (p < 0.0001). Oncotype-Dx mean scores were 25 and 17 in mutation carriers versus non-carriers respectively (p = 0.004). Higher nuclear grade, G3, was significantly associated with a higher Oncotype-DX score (p = 0.002). Conclusions: Our study reveal that patients with ER positive breast cancer and BRCA mutations have a higher Oncotype Dx score compared to ER positive, but BRCA negative patients. Studies evaluating the impact on outcome need to be evaluated.
Complementary and alternative medicine use and hormonal therapy initiation in women with hormone receptor-positive breast cancer: The BQUAL study.
Authors: Heather Greenlee, Alfred I. Neugut, Zaixing Shi, Grace Hillyer, Donna Buono, Jeanne S. Mandelblatt, Janise M. Roh, Isaac J. Ergas, Marilyn L. Kwan, Marion Lee, Wei-Yann Tsai, Lois E. Lamerato, Lawrence H. Kushi, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2017)

e13097 Background: Use of complementary and alternative medicine (CAM) has been associated with initiation of breast cancer chemotherapy.We examined the association of CAM use with initiation of hormonal therapy in women with hormone receptor-positive (HR+) breast cancer. Methods: In aprospective cohort study designed to examine predictors of breast cancer treatment initiation and adherence, 699 women with non-metastatic stage I-III breast cancer and aged &lt; 70 years were recruited from Kaiser Permanente Northern California during 2006-2010. Baseline interviews assessed current use of five CAM modalities (dietary supplements: vitamins/minerals, herbs/botanicals, other natural products; mind/body therapies: mind-body self-practice, mind-body practitioner-based). Based on electronic pharmacy records, hormonal therapy initiation was defined as ≥2 prescriptions of ≥30 pills of any hormonal therapy drug within 1 year after diagnosis. Multivariable logistic regression analysis examined a priori hypotheses testing whether current CAM use was associated with hormonal therapy initiation, adjusted for demographic, tumor characteristics, and cancer treatment. Results: Of the 699 participants,552 were diagnosed with HR+ breast cancer. Among the 552 women with HR+ breast cancer, 494 (89%) used at least 1 modality of CAM, 414 (76%) used dietary supplements, and 391 (71%) used mind/body therapies. Within 1 year after diagnosis, 481 (87%) participants initiated hormonal therapy. The rate of initiation was comparable between CAM users and non-users (87% vs. 86%). In multivariable analyses, baseline overall CAM use was not associated with initiation of hormonal therapy. However, vitamins/minerals users were more likely to initiate hormonal therapy compared to non-users (OR = 1.87, 95% CI: 1.04, 3.51). Conclusions: CAM use was high among early stage HR+ breast cancer patients. Overall, use of CAM was not associated with hormonal therapy initiation. Current use of vitamins/minerals was associated with higher initiation rate of hormonal chemotherapy.
Human germline hedgehog pathway mutations predispose to fatty liver
Authors: Maria J. Guillen-Sacoto, Ariel F. Martinez, Yu Abe, Paul Kruszka, Karin Weiss, Joshua L. Everson, Ramon Bataller, David E. Kleiner, Jerrold M. Ward, Kathleen K. Sulik, Robert J. Lipinski, Benjamin D. Solomon, Maximilian Muenke
Journal: Journal of Hepatology (2017)
Too sick to enroll? Comorbidities limiting recruitment in early phase trials, review of over 1,100 clinical trials.
Authors: Narjust Duma, Sejal Kothadia, Zhen Wang, Sarah Lee, Jesyree Veitia Campos, Bryant Van Leeuwen, Ramya Undamatla, Ricardo Parrondo, Komal Patel, Rima Panchal, Marshall McKenna, Veronica Mariotti, Jieqi Liu, Miguel Gonzalez Velez, Brittany Gladney, Larysa Jessica Sanchez, Shijia Zhang, Martin Gutierrez
Journal: Journal of Clinical Oncology (2016)

2529 Background: Early phase clinical trials (EPCT) evaluate the potential benefits of new regimens and help guide the care of oncology patients (pts).The inclusion/exclusion criteria in EPCT are usually rigorous and may exclude many pts commonly seen in clinical practice. Our objective was to study the most common comorbidities excluded in EPCT Methods: ClinicalTrials.gov was queried in December 1st of 2015. We reviewed the eligibility criteria of 1114 phase I/II trials including: age, organ function and comorbidities. Logistic regressions were completed and exclusion was studied as a binary variable based on the comorbidity Results: We reviewed 1114 trials, cancers included: 41% breast, 31% colorectal, 20% lung and 8% of trials included all solid tumors. 23% of the trials excluded pts > 70 years and 12% pts > 65 years. With regards to organ function, 423 (38%) trials required an albumin level > 3.0 g/dL, 355 (32%) creatinine levels < 1.5 mg/dL, and 333 (30%) liver function tests < 2.5 of the upper limit. Hematologic function was a significant exclusion factor: 434 (39%) trials required hemoglobin > 9 g/dL, 161 (14.5%) > 10 g/dL and 492 (44%) excluded pts with < 100,000 platelets. In terms of comorbidities, 570 (51%) excluded pts with myocardial infarction/angina within 12 months, 362 (33%) with atrial fibrillation, and 239 (22%) excluded pts on any anticoagulation therapy. Diabetes was not a significant factor of exclusion, only 10% of the trials excluded pts with “uncontrolled diabetes.” On univariable analysis, investigator initiated trials were less likely to exclude pts with cardiovascular disease (OR: 0.43, 95%CI: 0.25-0.74, p < 0.002) and mutation driven drugs were more likely to exclude pts with below normal hematologic values (OR: 2.39, 95%CI: 1.41-4.03, p < 0.001). No multivariable associations were significant. Conclusions: 23% of the trials excluded pts > 70 years or older, 33% pts with atrial fibrillation and 22% pts on any anticoagulation therapy, highlighting that a great percentage of EPCT are not designed to treat our aging oncology population. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols.
Do we need vasoconstrictors up to 5 days after successful hemostasis by ligation of bleeding varices?
Authors: Gin‐Ho Lo
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. To the Editor: I read with interest the article by Garcia‐Tsao et al. regarding the guidance statements on portal hypertensive bleeding in patients with cirrhosis.1 This comprehensive review is very helpful for clinicians in the management of gastroesophageal variceal bleeding. The authors suggested that patients who do not belong to the "high‐risk" categories should continue with vasoactive drugs up to 5 days depending on control of bleeding and severity of bleeding. This issue actually needs further clarification. Previous studies and a meta‐analysis showed enhanced efficacy by the combination of endoscopic therapy and vasoconstrictors. The reported efficacy of sclerotherapy alone with a median of 69% in these studies was lowest compared with other studies. Thus, the benefit of combined therapy has been regarded as an overestimation.2 The efficacy of banding ligation alone with a hemostatic rate >95% has proven superior to sclerotherapy alone in the control of acute esophageal variceal hemorrhage.3 A study from Pakistan found that after successful hemostasis by banding ligation, adjuvant therapy with terlipressin 1 mg every 6 hours for 24 hours was as effective as adjuvant therapy, with terlipressin 1 mg every 6 hours for 72 hours in 5‐day hemostasis, 100% versus 98%; 30‐day rebleeding, 1.5% versus 3.1%, respectively; and mortality.4 Our study demonstrated that once initial hemostasis was achieved by endoscopic variceal ligation, adjuvant therapy with either terlipressin or a proton pump inhibitor without vasoconstrictor could achieve similar 5‐day hemostasis, 96% and 98%, respectively.5 The combination of terlipressin was associated with adverse events in 55% of patients, though this was usually modest.5 Thus, it appears that once hemostasis of acute variceal bleeding is achieved by banding ligation, the necessity of adjuvant therapy with vasoactive drugs for 2‐5 days becomes controversial.
FRI0139 Prevalence of hyperparathyroidism is higher among rheumatoid arthritis patients compared to the general population: an observational, cohort study
Authors: A Emamifar, L Stilgren, R Hviid Larsen, R Asmussen Andreasen, IM Jensen Hansen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with Rheumatoid Arthritis (RA) are at increased risk of different comorbidities which may affect long-term prognosis.[1] Primary hyperparathyroidism (PHP) is a metabolic disorder of one or more of the parathyroid glands with a prevalence of 1–7 per 1000 adults.[2] <h3>Objectives</h3> To define the prevalence of PHP in patients with RA. <h3>Methods</h3> All RA patients who were registered in the local part of Danish Danbio registry were included in this study. Patients9demographic data and serology results (rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-ccp)) were extracted from Danbio. Patients9 electronic hospital records including laboratory results (Parathyroid hormone (PTH) and calcium levels) were reviewed to reveal if they had been diagnosed with PHP as well. <h3>Results</h3> 1035 RA patients were included in this study [table 1]. Prevalence of PHP was 2.8% (29/1035). RA Patients with PHP had significant longer disease duration compared to patients with isolated RA (p=0.003). There was no significant difference between RA patients with and without PHP with respect to age, gender, RF and anti-ccp positivity (Table 1). <h3>Conclusions</h3> Clinicians should pay special attention to higher prevalence of PHP among RA patients compared to the general population. Presence of PHP in RA patients may aggravate the effect of RA on bones and joints by means of interaction with cytokines and inflammatory markers involved in RA. Concurrent PHP can be diagnosed at early stage by testing PTH and calcium levels which minimize the future morbidities e.g. fracture due to osteoporosis. <h3>References</h3> Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis 2014;73:62–8. Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab 2013;98:1122–9. <h3>Acknowledgements</h3> We thank Mrs. Maryam Mousavi for her contribution to data collection. <h3>Disclosure of Interest</h3> None declared
Abstract P434: The Relationship Between Level of Glycemic Control and First Manifestation of Coronary Artery Disease (CAD) Differs by Sex in Type 1 Diabetes (T1D)
Authors: Rachel G Miller, Tina Costacou, Trevor J Orchard
Journal: Circulation (2013)

The nature of the association between glycemic control and CAD in T1D is unclear. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D has not demonstrated a consistent relationship between glycemic control and incidence of CAD, with neither baseline HbA1c nor average HbA1c over follow-up reliably predicting CAD. However, it is possible that glycemic control may influence the type of first CAD event observed. As CAD often manifests differently in men and women, our objective was to examine whether the manifestation of CAD differs by glycemic control up to the time of the CAD event separately by sex. Data are from 604 (304 men, 300 women) participants in the Pittsburgh EDC Study of childhood-onset (&lt;17 years old) type 1 diabetes without prevalent CAD at baseline and represent 20 years of follow-up for CAD incidence ascertainment. Participants were first assessed 1986-1989 (mean age, 28 and duration, 19 years), with 8 subsequent exams occurring approximately every 2 years thereafter. First CAD event was divided into 5 categories: fatal event/CAD death, nonfatal myocardial infarction (MI), revascularization/stenosis &gt;=50%, ischemia (Minnesota codes 1.3, 4.1, 4.3, 5.1, 5.3, 7.1), or angina. The average HbA1c from baseline until CAD event or last follow-up for noncases was calculated (median # HbA1c measures=4); the median average HbA1c was 8.7%. This value was used as a cut point to divide the cohort into 2 groups: persons with HbA1c≥8.7% at all study visits prior to CAD incidence (80 men, 60 women) versus all others (224 men, 240 women). In women, the 20-year incidence of CAD was 40% (n=24) and 24.6% (n=59) in the consistently high HbA1c group and all others, respectively (p=0.02). In men, CAD incidence was 38.8% (n=31) and 28.6% (n=64) in the high HbA1c group and all others, respectively (p=0.09). Of the CAD cases, nonfatal MI was a significantly more frequent first event in the consistently high HbA1c group compared to all others in both men (48.4% v 21.9%, p=0.009) and women (37.5% v 15.3%, p=0.04). Angina was a significantly less frequent first event in the consistently high HbA1c group in women (25% v 52.5% in all others, p=0.02), but no significant difference in angina incidence by HbA1c group was observed in men. Fatal CAD was a marginally more frequent first event in the high HbA1c group in women (16.7% v 3.4%, p=0.06), but did not differ by HbA1c in men. No differences for revascularization or ischemia as first events were seen by HbA1c group in either sex. These results suggest that, in T1D, glycemic control may influence the manner of CAD manifestation, in particular nonfatal MI and angina, and that this effect may differ by sex. Particularly, there may be a need for more aggressive monitoring and treatment of CAD risk factors in women with high HbA1c, as they may be at higher risk of fatal events.
cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells
Authors: Kazuki Miyano, Horacio Cabral, Yutaka Miura, Yu Matsumoto, Yuki Mochida, Hiroaki Kinoh, Caname Iwata, Osamu Nagano, Hideyuki Saya, Nobuhiro Nishiyama, Kazunori Kataoka, Tatsuya Yamasoba
Journal: Journal of Controlled Release (2017)