tbuckley/cabot-search huggingface dataset:
Prognostic impact of discordance of ER and PR between primary and recurrent breast cancer.
Authors: LI Nani, Cao Wenming, Wang Xiao Jia
Journal: Journal of Clinical Oncology (2018)

e24295 Background: Many researches suggest that discordance of Estrogen (ER) and progesterone (PR) exists between primary and metastatic lesions.This study investigated receptor status of primary tumors and metastases, and explore its impact on the clinical prognosis. Methods: Recurrent or metastatic breast cancer patients were enrolled in Zhejiang Cancer Hospital from January 1st, 2012 to December 31st, 2015. All patients received biopsy for recurrence or metastasis. Estrogen (ER) and progesterone (PR) status were assessed by IHC with a threshold 1% were classified as receptor positive. The difference of clinical prognosis between receptor cordance and discordance groups was analyzed. Results: A total of 270 cases with intact primary and metastatic foci were obtained. There were 22.7% patients whose primary focals were ER positive converted to ER negative in metastasises, 16.5% patients with ER negative primary ones converted to positive in metastasises. There were 45.3% females lost PR, and 42.3% gained PR. The rate of change of ER or PR positive in primary focals to both ER and PR negative in metastasises was 18.8%, and the rate of change of both ER and PR negative in primary ones to positive in metastasises was 33.3%. 23.1% patients altered management on the basis of results of the biopsy.Patients with persistent positive ER or PR showed the best overall survival (OS)(P = 0.007), disease-free survival (DFS)(P = 0.000) and post-recurrence survival (PRS) (P = 0.016), while ER or PR persistent negative showed the worst survival (P < 0 .001). Lost ER or PR suggested worse DFS and PRS while gained both ER and PR suggested better DFS (P = 0.001) and PRS (P = 0.009). Conclusions: Discordance of ER and PR exists between primary focals and metastasises of breast cancer and effects patients’ survivals. Patients gained ER seemed to have better survivals while ER or PR lost with worse prognosis.
Phase 1, multicenter, open-label, dose-escalation, study of marizomib (MRZ) and bevacizumab (BEV) in WHO grade IV malignant glioma (G4 MG).
Authors: Daniela Annenelie Bota, Annick Desjardins, Warren P. Mason, Howard Alan Fine, Steven D. Reich, Mohit Trikha
Journal: Journal of Clinical Oncology (2016)

2037 Background: MRZ is an irreversible, brain-penetrant, pan-proteasome inhibitor (PI). It inhibits glioma cell proliferation and invasion in vitro, prolongs survival in in vivo mg tumor models, with little effect on normal neuronal stem cells, suggesting minimal neurotoxicity (Neuro Oncol 2015 Dec 17. pii: nov299). Intravenous (IV) MRZ has been administered to ~300 patients (pts) with solid tumors and hematologic cancers. This trial is evaluating the safety, pharmacodynamics, and efficacy of MRZ and BEV in BEV-naïve pts with G4 mg who are in first or second relapse with no prior anti-angiogenic or PI therapy. Methods: Phase 1, dose-escalation (3+3 design) followed by dose-expansion at recommended Phase 2 Dose (RP2D); three dose cohorts - MRZ 0.55 (n = 6 pts), 0.7 (n = 3 pts), and 0.8 mg/m2 (n = 3 pts). MRZ infused IV (10 min) on Days 1, 8, & 15; BEV IV 10 mg/kg on Days 1 & 15 (over 28-Day Cycles). Tumor response is assessed every other Cycle by RANO criteria; blood proteasome inhibition assessed every Cycle. Results: In dose-escalation, 12 pts enrolled: median age 53 yrs (44-61); 83% male; 83% Caucasian; Karnofsky Score > 80. As of 6 Jan 2016, duration of dosing is 5-33 weeks with treatment ongoing in 7 pts. MRZ/BEV was well tolerated; most common adverse events (AEs): headache (9), fatigue (7), hypertension (5), infusion site pain (5), and nausea (5). Grade 3 AEs related to MRZ or BEV: hypertension (2), confusional state (1), fatigue (1), hallucinations (1), and headache (1). One pt (cohort 1) had fatigue as DLT, but no DLTs at higher doses. MRZ caused > 70% inhibition of chymotrypsin-like activity on Cycle 1 Day 1 with 100% by Day 28. Transient hyperactivation of trypsin-like (T-L) and caspase-like (C-L) activities after the first 1-2 MRZ doses, followed by 40-60% inhibition of T-L and 10-30% inhibition of C-L activities in Cycle 3. RANO responses in the 3 cohorts: 4/12 partial response, 6/12 stable disease and 2/12 progressive disease. Conclusions: The MRZ/BEV combination was well tolerated with only one DLT at MRZ 0.5 mg/m2. To date, rapid and pronounced pan-proteasome inhibition has been observed with 4/12 pts achieving confirmed PRs. MRZ 0.8 mg/m2 is the RP2D in the ongoing dose-expansion stage. Clinical trial information: NCT02330562.
Utility and prognostic value of <sup>18</sup>F‐FDG positron emission tomography‐computed tomography scans in patients with newly diagnosed multiple myeloma
Authors: Mohammed A. Aljama, M. Hasib Sidiqi, Francis K. Buadi, Martha Q. Lacy, Morie A. Gertz, Angela Dispenzieri, David Dingli, Eli Muchtar, Amie L. Fonder, Suzanne R. Hayman, Miriam A. Hobbs, Wilson I. Gonsalves, Rahma M. Warsame, Taxiarchis Kourelis, Yi Lisa Hwa, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2018)

Abstract Positron emission tomography‐computed tomography (PET‐CT) can identify bony lesions, assess disease burden, and detect extramedullary disease (EMD) in patients with multiple myeloma. We retrospectively reviewed records of patients who underwent PET‐CT within 60 days of a new diagnosis (before therapy commenced) to identify the nature and prognostic impact of PET‐CT abnormalities. Patients ( N = 313) were seen from April 2005 through June 2017. Of the 234 patients (75%) with focal lesions (FLs), 182 (58%) had at least 3 FLs, 38 (12%) had EMD, and 204 (65%) had documented myelomatous lytic lesions. The median maximum standardized uptake value (SUV max ) for the entire cohort was 5.9 (range 1.5‐48.3). Presence of at least 3 FLs and EMD predicted inferior overall survival (OS); median OS was 57.8 months for patients with 3 or more FLs and 103.6 months for patients with fewer than 3 FLs ( P = .003). The median OS was 45.5 and 71.8 months for patients with and without EMD, respectively ( P = .004). No clear SUV max cutoff was predictive of progression‐free survival or OS. PET‐CT is a valuable tool for assessing disease burden and could provide prognostic information about a contemporary cohort of patients with newly diagnosed myeloma who received treatment with novel agents.
Mechanisms of Vascular Aging
Authors: Zoltan Ungvari, Stefano Tarantini, Anthony J. Donato, Veronica Galvan, Anna Csiszar
Journal: Circulation Research (2018)

Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.
Abstract 19284: Myocardial Perfusion Imaging Has a Higher Rate of False Positivity Compared to CT Angiography in Intermediate Risk Chest Pain Patients Undergoing Catheterization
Authors: Shey Mukundan, Jeffrey Levsky, Daniel Spevack, Mark Travin
Journal: Circulation (2015)

Introduction: Although noninvasive testing continues to hold an important role in the assessment of chest pain, imprecise categorization of coronary artery disease (CAD) severity may lead to unnecessary invasive procedures. We compared the frequency with which noninvasive tests were falsely positive for severe coronary stenosis in patients hospitalized for intermediate risk chest pain who underwent cardiac catheterization. Methods: We identified 400 subjects hospitalized with chest pain, who had been randomized to either myocardial perfusion imaging (MPI) [n=200] or coronary CT angiography (CTA) [n=200] as part of a clinical trial. Invasive angiography, performed at the discretion of the treating physicians within one year following noninvasive testing, occurred in 30 subjects assigned to CTA and in 32 assigned to MPI. MPI, CTA and invasive angiogram exams were each interpreted for the presence or absence of severe coronary stenosis (&gt;70% diameter) by the study investigators. Results: Subjects catheterized were 60 ± 10 years, 52% female, 55% obese, 42% diabetic, 76% hypertensive and 48% smokers. On presentation, chest pain occurred for greater than 15 minutes in 66%, while 78% had an abnormal ECG. Amongst those catheterized, false positivity was common in the MPI group (n=11, 34%) and was rare in the CTA group (n=2, 7%), p&lt; 0.01. The odds for false positivity were increased in those undergoing MPI, odds ratio 6.9 [95% confidence interval: 1.1, 72.1, p = 0.02]. On multivariate analysis, after considering multiple clinical and electrocardiographic potential contributors to false positivity, the presence of slight ST segment depression (&lt; 1mm) on presenting ECG was the only independent predictor of having a false positive MPI exam. Conclusion: In patients having catheterization for intermediate risk chest pain, the rate of falsely positive noninvasive test was substantially higher in those having MPI compared to those undergoing CTA.
TCT-567 Cangrelor in Cardiogenic Shock: A Global, Multicenter, Matched Analysis with Oral P2Y12 Inhibition from the IABP-SHOCK II Trial
Authors: Michal Droppa, Muthiah Vaduganathan, Ramkumar Venkateswaran, Steffen Schneider, Russel Roberts, Arman Qamar, Uwe Zeymer, Georg Fuernau, Steffen Desch, Holger Thiele, Gawaz Meinrad, Deepak Bhatt, Tobias Geisler
Journal: Journal of the American College of Cardiology (2018)
Smoking cessation counseling in advanced non-small cell lung cancer (aNSCLC).
Authors: Janna Radtchenko, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2017)

e20551 Background: Lung cancer is the leading cause of cancer mortality, with smoking the major risk factor 1 . Advances in treatment (tx) are lengthening survivorship increasing the importance in smoking cessation among diagnosed pts. Barriers to counseling include: time, skill, patient motivation, prognosis and short survival 2 . This study analyzed smoking status and cessation counseling in better prognosis aNSCLC patients (pts) defined as those who completed at least two lines of systemic therapy (2L). Methods: Using Inovalon’s MORE 2 Registry ® claims data for July 2013–2014, pts with aNSCLC identified by ICD-9 codes and treated with chemotherapy (chemo) or targeted therapy (TT; erlotinib, ceritinib, afatinib, or crizotinib) were selected. Pts &gt;18 years of age and treated with 1L therapy within 6 months of diagnosis and who completed 2L were eligible. Pts with small cell lung cancer or secondary malignancies, or pts enrolled in a trial, were ineligible. Smoking history was assessed based on ICD-9 codes (305.1, 649.0, 989.84, V15.82), cessation drug use (bupropion, varenicline, nicotine gum or patches), counseling procedure codes (99406, 99407, G0436, S9453). Results: Of 5,319 pts, 2,198 completed 2L; of those 241 (11%) received 1L TT and 1,957 (89%) 1L chemo. 1L TT had a higher proportion of females (66% vs. 52%, p&lt;0.0001) and a lower smoking rate (33% vs. 58%, p&lt;0.0001) compared to chemo. Cessation rates (counseling or drug) were 9% for 1L TT and 13% for 1L chemo. Conclusions: RWE assessment of smoking incidence and cessation counseling is feasible. Despite methodological limitations one third pts on 1L TT had smoking documentation. Evidence of smoking cessation was present in 12% of pts irrespective of 1L tx choice. Our findings warrant increased focus on smoking cessation in aNSCLC. [Table: see text]
Enhancing chemotherapy capabilities in rural hospitals: Implementation of a tele-chemotherapy model (QReCS) in North Queensland, Australia.
Authors: Sabe S. Sabesan, Amy Brown, Abhishek Jagdish Joshi
Journal: Journal of Clinical Oncology (2018)

e18682 Background: Queensland Remote Chemotherapy Supervision (QReCS) model enables rural nurses to administer chemotherapy in smaller rural towns under supervision by health professionals from larger centres using telehealth. Its implementation began in North Queensland (NQ), Australia (population of 650,000) in 2014 between two regional cancer centres (Townsville and Cairns as primary sites) and six rural sites (125-1000km from primary sites). Our study reports on implementation processes, feasibility and safety of this model. Methods: Details of implementation and patients’ clinical details for the period of 2014-2016 for descriptive analysis were extracted from Tele-chemotherapy project notes and Oncology information systems of NQ respectively. Results: Following a successful pilot in Townsville Cancer centre, state-wide rural and cancer networks of Queensland health (QH) in collaboration with clinicians and managers across the state of Queensland developed the QReCS model and a guide for operationalizing it. QReCS was implemented in six sites during 2014-16. Main enablers across NQ included: collaboration among clinicians and managers, availability of common electronic medical records, funding from QH, and installation of telehealth infrastructure by state-wide telehealth services. Main barriers included turn-over of senior management and nursing staff at two rural towns. 62 patients received 327 cycles of low to medium risk chemotherapy agents. Rates of treatment delays, adverse events and hospital admissions were similar to that in face-to-face care. Conclusions: Implementation of QReCS model across a large geographical region is feasible with acceptable safety profiles. Leadership by and collaboration among clinicians and managers, adequacy of resources and common governance are key enablers.
Stress, allostatic load, and periodontal diseases
Authors: Wael Sabbah, Noha Gomaa, Aswathikutty Gireesh
Journal: Periodontology 2000 (2018)

Abstract Psychosocial stress plays an important role in periodontal disease through biological and behavioral pathways. In this paper we review studies that examine the relationship between stress and periodontal diseases, and discuss the different measures used to assess stress. Self‐reported measures, such as the Perceived Stress Scale and the Stress Appraisal Measure, have traditionally been used to assess stress. Frequent and repeated exposure to stressor(s) leads to wear and tear of the body's systems, resulting in what is known as allostatic load. In recent years, few studies examining the relationship between stress and periodontal diseases have used an aggregate variable, including primary and secondary markers of allostatic load, as a biological marker of stress. While research on the relationship between allostatic load and periodontal disease is still developing, as most of the studies used cross‐sectional data, this line of research presents a good opportunity for establishing a composite biological indicator as a risk factor for periodontal disease. Such an indicator is also potentially beneficial for personalized periodontics as it will help to target intervention to specific levels of risk and will help in integrating oral and general health promotion policies.
Molecular characterization of immune-related severe adverse events (irSAE).
Authors: Justin M. Balko, Rami N Al-Rohil, Daniel Ying Wang, Yan Liang, Giang Ong, Kristi Barker, Margaret Compton, Yu Wang, Joseph M Beechem, Yaomin Xu, Jeffrey Alan Sosman, Bret Mobley, Chanjuan Shi, Javid J. Moslehi, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2017)

3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; &gt; 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to several hundred (0.4%, 2.7%, and 3% of rearrangements, respectively), including high-frequency clones. Shared TCRβ sequences were also identified among and between colon-irSAE and Crohn’s specimens. Gene expression patterns of inflammation in colon-irSAE resembled that of Crohn’s disease in principle components and clustering analysis, highlighting likeness between these diseases/SAEs. NanoString digital spatial profiling of regions of inflammation across samples showed higher CD68 and PD-L1 positivity in colon-irSAE specimens versus normal colon or Crohn’s specimens and reduced beta-catenin levels in both Crohn’s and colon-irSAE specimens relative to normal controls. Finally, we detected a high degree of TCR clonality in the encephalitic brain, including a single sequence present in ~20% of &gt; 12,000 T cells, suggesting a distinct antigen-specific response. Conclusions: We report the molecular characteristics of irSAE in colon and brain specimens from patients receiving ICIs. Highly clonal TCRβ sequences were frequently detected, particularly in a unique case of encephalitis-irSAE. Furthermore, we identify molecular distinctions and similarities between autoimmune and colon-irSAEs at the gene expression and proteomic levels.
Phase I study of alternate-day administration of S-1, oral leucovorin, and bevacizumab for refractory metastatic colorectal cancer.
Authors: Toshiki Masuishi, Hiroya Taniguchi, Azusa Komori, Seiichiro Mitani, Hiroko Hasegawa, Yukiya Narita, Shigenori Kadowaki, Takashi Ura, Masashi Ando, Kei Muro
Journal: Journal of Clinical Oncology (2016)

e14021 Background: S-1 with oral leucovorin (LV) has promising efficacy in gastrointestinal cancer patients (pts) but is linked to high risk of mucositis and diarrhea. Compared with daily administration, alternate-day administration of S-1 was expected to decrease toxicity without decreasing efficacy. Methods: This was a phase Ib, 3+3, dose-escalation trial for metastatic colorectal cancer (mCRC) pts who were refractory or intolerant to standard therapies. Pts received escalating doses per week of S-1 (40 mg/m2, twice daily, level 1: administration on even-numbered days, level 2: administration on Mon, Wed, Fri, and Sun) and LV (25 mg, twice daily) orally on the same schedule as for S-1 and intravenous bevacizumab (5 mg/kg) every 2 weeks. Enrollment continued at the recommended dose level in the expansion cohort. Results: We enrolled 14 pts (level 1/2: 3/11 pts). Baseline characteristics: median age, 60 (range, 39–74); ECOG PS0, 8; and prior regorafenib/TAS-102, 8/11. Dose-limiting toxicity was not observed; level 2 was confirmed as the recommended dose. Common adverse events (any Grade, Grade 3–4) at level 2 were fatigue (73%, 0%), anorexia (64%, 9%), proteinuria (64%, 9%), nausea (64%, 0%), anemia (55%, 18%), diarrhea (55%, 9%), and mucositis (55%, 0%). There were no treatment-related deaths. Efficacies in all pts were as follows: response rate, 7%; disease control rate, 71%; and median progression-free survival, 5.3 months. The reason for discontinuation in all pts was disease progression. Conclusions: The recommended dose of S-1 was 40 mg/m2, twice daily on Mon, Wed, Fri, and Sun, with oral leucovorin and bevacizumab. Compared with daily administration, alternate-day administration of S-1 may decrease mucositis and diarrhea with promising antitumor activity for refractory metastatic colorectal cancer. We are now evaluating alternate-day administration of S-1, oral leucovorin, oxaliplatin, and bevacizumab as a first-line treatment for metastatic colorectal cancer. Clinical trial information: UMIN 000016094.
Abstract 336: Reactive Ion Surface Modification of Vascular Graft Materials Enhances Endothelialization Without Promoting Thrombosis
Authors: Deirdre E Anderson, Patrick L Jurney, Marie F Cutiongco, Grace Pohan, Pascale Chevallier, Diego Mantovani, Evelyn K Yim, Monica T Hinds
Journal: Circulation Research (2017)

Previous work demonstrated that poly(vinyl alcohol) (PVA) holds great potential as a cardiovascular biomaterial. PVA prevents thrombosis at least as well as expanded polytetrafluoroethylene (ePTFE) clinical vascular grafts in whole blood studies. However, long term in vivo success of this material will likely depend on its ability to support an endothelial cell (EC) monolayer. To promote EC attachment and growth we are treating the PVA surface with high energy reactive ions. We hypothesize that increasing the concentration of reactive groups on the surface of the PVA will increase endothelial outgrowth cell (EOC, a type of endothelial progenitor cell isolated from whole blood) attachment without increasing thrombosis. To test this hypothesis we exposed PVA films to reactive ion modifications using O 2 , N 2 , and Ar gases at a variety of powers and durations. Treated samples were then characterized with X-ray photoelectron spectroscopy to quantify surface chemistries. Samples were seeded with EOCs to quantify attachment and proliferation using immunohistochemistry. Platelet and fibrin accumulation was measured dynamically in PVA tubes using a baboon arteriovenous shunt with radiolabeled platelets for 1hr. Flow rate was controlled and no anticoagulants were given. O 2 and N 2 treatments encouraged cell adhesion on the PVA films in an energy dependent manner, which correlated to an increase in surface nitrogen. Initial shunt data (n=3) indicate that treated samples did not have increased platelet attachment compared to untreated PVA or ePTFE. In conclusion, reactive ion modified-PVA demonstrates a promising biomaterial by supporting EC growth without increasing thrombosis.