tbuckley/cabot-search huggingface dataset:
Exposure-efficacy and safety analysis of durvalumab in patients with urothelial carcinoma (UC) and other solid tumors.
Authors: Chaoyu Jin, Yanan Zheng, Xiaoping Jin, Pralay Mukhopadhyay, Ashok Kumar Gupta, Phillip A. Dennis, Yong Ben, Lorin Roskos, Rajesh Narwal
Journal: Journal of Clinical Oncology (2017)

2568 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD-80. The objective of this analysis was to evaluate the relationship between durvalumab PK exposure with efficacy and safety following 10 mg/kg Q2W durvalumab. Methods: Data from Study 1108 (Phase 1/2; all tumor types) and ATLANTIC (Phase 2; NSCLC) were used for exposure-safety analysis for Study 1108 UC cohort, Study 1108 all patients and ATLANTIC patients, respectively, whereas the exposure-efficacy analysis was performed using data from Study 1108 UC cohort. The observed PK exposure metrics included PK concentrations after the first, second or steady state doses. Efficacy endpoints used were objective response rate (ORR) and best percentage change in target lesion from baseline per BICR assessment. Safety endpoints included Grade 3+ AE (any AE, drug-related AE, AESI, and drug-related AESI) and AE leading to treatment discontinuation. Results: Overall, no association of PK exposure with efficacy or safety was observed. Distribution of PK metrics were similar between responders and non-responders. The probability of objective response was similar in all quartiles of exposure (p-value ranged from 0.37 to 0.67; n = 96) with no obvious trends between PK exposures and change in tumor size. For Grade 3+ AE (all types) and AE leading to treatment discontinuation, higher PK exposure was not associated with an increased risk of AE (p-value ranged from &lt; 0.00005 to 0.88; n = 158, 929 and 434 for 1108 UC cohort, 1108 all patients and ATLANTIC all patients, respectively). A few inverse trends were observed, likely due to confounding effect of ECOG or albumin since covariate analysis demonstrated that both variables correlated with PK and AEs. In addition, the association of ECOG and albumin versus PK exposure were also observed in the population PK modeling. Conclusions: The exposure-efficacy and exposure-safety analyses suggested that 10 mg/kg IV Q2W regimen was an appropriate dose for durvalumab as single agent in UC patients. Overall, no relationship of PK exposure with either the efficacy or safety was observed following 10 mg/kg IV Q2W regimen. Clinical trial information: NCT02087423 and NCT01693562.
High-dose versus standard-dose rituximab with BEAM in autologous stem cell transplantation (SCT) for relapsed aggressive b-cell non-Hodgkin’s lymphomas (NHL).
Authors: Samer Ali Srour, Issa F. Khouri, Yago Nieto, Uday R. Popat, Muzaffar H. Qazilbash, Paolo Anderlini, Partow Kebriaei, Elizabeth J. Shpall, Richard E. Champlin, Chitra Hosing
Journal: Journal of Clinical Oncology (2016)

7524 Background: High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide, and melphalan (BEAM) and SCT was effective and tolerable in a single-arm study for relapsed/refractory (R/R) aggressive B-cell NHL. This is the first prospective, randomized phase 2 study comparing efficacy and safety of HD-R vs. standard-dose rituximab (SD-R) combined with BEAM in R/R-NHL. Methods: Patients with R/R-NHL (44 DLBCL, 49 others) were randomized to HD-R or SD-R using Bayesian adaptive algorithm. HD-R (1000 mg/m2) or SD-R (375 m2) were administered on days +1 and +8 after stem cell infusion. Primary endpoint: disease-free survival (DFS), defined as time from SCT to disease progression or death. Overall survival (OS) and safety analysis were secondary endpoints. Based on an intention-to-treat analysis, Kaplan-Meier estimator (DFS & OS) and Cox proportional hazards regression (multivariate analysis) were used. Results: A total of 93 patients (29% females) with a median age of 63 years (6-75) were randomized to HD-R (n = 42) or SD-R (n = 51). No significant differences in patient demographic and clinical characteristics. With a median follow-up of 4.12 years (7.92 for alive patients), the 5-year DFS and OS were 42% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (37% vs 47%; p = 0.208) and OS (42% vs 52%; P = 0.395). In multivariate analyses, only disease status before SCT [complete remission (CR) vs no CR] (HR 0.57, 95% CI: 0.35-0.95) and prior treatments received ( ≤ 2 vs > 2 lines of treatment) (HR 0.53, 95% CI: 0.32-0.89) were associated with worse DFS. Similarly, these were significant poor prognostic factors for OS. Patients who had SCT while in CR or who received ≤ 2 lines of treatment prior to SCT had better 5-year OS (57% vs 35%; P = 0.02 and 54% vs 30%, P = 0.001, respectively). No differences in G3-4 toxicities, infection rates or engraftment between both arms. Conclusions: SD-R is not significantly different from HD-R when combined with BEAM in B-Cell aggressive R/R-NHL in terms of DFS and OS. Patients in CR and those with ≤ 2 prior treatments at time of SCT have a better prognosis in both study arms Clinical trial information: NCT00472056.
Advances in the delivery of RNA therapeutics: from concept to clinical reality
Authors: James C. Kaczmarek, Piotr S. Kowalski, Daniel G. Anderson
Journal: Genome Medicine (2017)

The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic.
MRI for depicting DCIS components of invasive breast cancers prior to surgery.
Authors: Christiane K. Kuhl, Kevin Strobel, Simone Schrading
Journal: Journal of Clinical Oncology (2016)

1061 Background: DCIS-components of invasive breast cancers are a major cause of positive margins and reoperations in women undergoing breast conserving surgery. We compared the diagnostic accuracy of breast MRI vs. that of conventional imaging for depiction of DCIS-components, and investigated the surgical outcome (positive margin rates, mastectomy rates) associated with preoperative breast MRI in women with vs. without DCIS-components. Methods: Prospective two center study on consecutive patients with biopsy proven invasive breast cancer who underwent breast MRI in addition to conventional imaging (CI, digital-mammography and breast ultrasound). MR-guided biopsy and/or preoperative MR guided lesion bracketing was done for DCIS-components visible by MRI alone. We compared the accuracy of breast MRI for diagnosing DCIS-components with that of CI, with surgical histology serving as the SOR. Surgical outcomes (positive margin and mastectomy rates) of women with DCIS-components were compared with those of women without DCIS-component Results: 593 women were included. Surgical pathology documented DCIS-components in 139/593 (23.4%) women. Sensitivity of MRI (84.9%; 118/139) for demonstrating DCIS-components was significantly higher than that of CI (36.7%; 51/139) (p < 0.0001); over half (51.1%; 71/139) of DCIS-components were only MRI-detected. The sensitivity advantage of MRI over CI increased with increasing relative size and nuclear grade of DCIS-components (sensitivity for marginal DCIS-components: 56.8% vs. 29.7%; for extensive: 91.7% vs. 41.7%; for predominant: 100.0% vs. 35.7%), and with increasing nuclear-grading (low grade: 74.0% vs. 40.7%; intermediate-grade: 84.1% vs. 34.9%; high-grade: 91.8% vs. 36.7%). Positive margin rates were low overall (3.7%) and did not differ significantly between the 139 women with DCIS-components (5.0%) compared to those observed in the 454 without such components (3.3%). The same was true for mastectomy-rates (10.8% vs. 8.1%). Conclusions: Breast MRI significantly improves depiction of DCIS-components of invasive breast cancers prior to surgery, and translates into low positive margin and mastectomy rates that are independent of the presence or absence of DCIS-components.
Head injuries in professional male football (soccer) over 13 years: 29% lower incidence rates after a rule change (red card)
Authors: Florian Beaudouin, Karen aus der Fünten, Tobias Tröß, Claus Reinsberger, Tim Meyer
Journal: British Journal of Sports Medicine (2017)

Absolute numbers of head injuries in football (soccer) are considerable because of its high popularity and the large number of players. In 2006 a rule was changed to reduce head injuries. Players were given a red card (sent off) for intentional elbow-head contact.To describe the head injury mechanism and examine the effect of the rule change.Based on continuously recorded data from the German football magazine "kicker", a database of all head injuries in the 1st German Male Bundesliga was generated comprising seasons 2000/01-2012/13. Injury mechanisms were analysed from video recordings. Injury incidence rates (IR) and 95% confidence intervals (95% CI) as well as incidence rate ratios (IRR) to assess differences before and after the rule change were calculated.356 head injuries were recorded (IR 2.22, 95% CI 2.00 to 2.46 per 1000 match hours). Contact with another player caused most head injuries, more specifically because of head-head (34%) or elbow-head (17%) contacts. After the rule change, head injuries were reduced by 29% (IRR 0.71, 95% CI 0.57 to 0.86, p=0.002). Lacerations/abrasions declined by 42% (95% CI 0.39 to 0.85), concussions by 29% (95% CI 0.46 to 1.09), contusions by 18% (95% CI 0.43 to 1.55) and facial fractures by 16% (95% CI 0.55 to 1.28).This rule change appeared to reduce the risk of head injuries in men's professional football.
A single-blind, randomized, placebo-controlled phase II study to evaluate the impact of oral bisphosphonate treatment on bone mineral density in osteopenic women receiving adjuvant aromatase inhibitors: Interim analysis of “BONADIUV” trial.
Authors: Vieri Scotti, Icro Meattini, Sara Cecchini, Maria Laura De Feo, Calogero Saieva, Carla De Luca Cardillo, Lorenzo Livi
Journal: Journal of Clinical Oncology (2014)

TPS658 Background: Aromatase inhibitors (AIs) are a highly effective well-tolerated treatment for post-menopausal endocrine-responsive breast cancer (BC). However, their use is associated with accelerated bone loss and increased risk of fractures. The ARIBON trial published by Lester et al in 2008 showed that monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole. BONADIUV trial is a single-blind, randomized, placebo-controlled phase II study designed to evaluate the impact of oral ibandronate (150 mg monthly) on bone mineral density (BMD) in osteopenic women on AIs in adjuvant setting. Methods: All patients underwent histological proven diagnosis of BC. Patients received breast surgery and adjuvant treatment according to clinical and pathological status at Our Institute. Enrolled patients were candidate to 5 years of adjuvant AIs. Major exclusion criteria were: previous diagnosis of solid tumors, psychiatric disorders, premenopausal status, smokers patients, chronic use of steroids, ipertyroidism, iperparathyroidism, rheumatoid arthritis, severe thinness (body mass index <16), age less than 18 years or more than 70. All patients were treated with vitamin D supplementation for an overall treatment of 24 months. The primary endpoint was the change in BMD at lumbar spine or hip after 12 and 24 months of treatment in ibandronate-treated patients (Arm A) compared with those receiving placebo (Arm B). Patients were also stratified by menopausal age, body mass index and age. Secondary end points included adverse events monitoring. Common Terminology Criteria for Adverse Events (CTCAE) 4.0 were utilized to record toxicity related events. Recruiting is ongoing: 105 of planned 196 patients have been enrolled. Fifty-three patients were allocated in arm A and 52 patients were allocated in arm B. At 12 months' follow up visit, complete data were assessable in 86 cases. At 24 months' follow up visit, complete data were assessable in 40 patients.
Dysregulated expression of long noncoding RNAs in gynecologic cancers
Authors: Elahe Seyed Hosseini, Matthieu Meryet-Figuiere, Hamed Sabzalipoor, Hamed Haddad Kashani, Hossein Nikzad, Zatollah Asemi
Journal: Molecular Cancer (2017)

Cancers of the female reproductive system include ovarian, uterine, vaginal, cervical and vulvar cancers, which are termed gynecologic cancer. The emergence of long noncoding RNAs (lncRNAs), which are believed to play a crucial role in several different biological processes, has made the regulation of gene expression more complex. Although the function of lncRNAs is still rather elusive, their broad involvement in the initiation and progression of various cancers is clear. They are also involved in the pathogenesis of cancers of the female reproductive system. LncRNAs play a critical physiological role in apoptosis, metastasis, invasion, migration and cell proliferation in these cancers. Different expression profiles of lncRNAs have been observed in various types of tumors compared with normal tissues and between malignant and benign tumors. These differential expression patterns may lead to the promotion or suppression of cancer development and tumorigenesis. In the current review, we present the lncRNAs that show a differential expression between cancerous and normal tissues in ovarian, cervical and endometrial cancers, and highlight the associations between lncRNAs and some of the molecular pathways involved in these cancers.
Increased risk of liver toxicity secondary to nivolumab therapy in the treatment of cancer.
Authors: Kevin Zarrabi, Shenhong Wu
Journal: Journal of Clinical Oncology (2017)

e14559 Background: Nivolumab, a humanized immunotherapy targeting PD-1, is approved for the treatment of a number of solid and liquid cancers and is associated with liver toxicity. This meta-analysis was conducted to determine the overall risk of hepatotoxicity with nivolumab therapy in cancer patients. Methods: An analysis from all phase I, II, and II clinical trials up to December 2016 examining the role of nivolumab in a variety of cancers was conducted. Eligible trials included those in which patients received nivolumab. Data on all-grade and high-grade (grade 3 and 4) elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random - or fixed - effect models with 95% confidence intervals. Results: The data from 27 eligible trials were included for analysis. A total of 5,287 patients were evaluated (Nivolumab: n = 3515, Control: n = 1772). The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI: 3.2% - 9.1%) and 1.60% (95% CI: 0.9% - 3.0%), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI: 2.9% - 8.2%) and 1.5% (95% CI: 0.9% - 3.1%), respectively. Elevations of both laboratory markers were significantly increased when compared to control (P &lt; 0.001). Nivolumab increased the RR of AST/ALT elevations; RR of all-grade AST elevations was 1.58 (95% CI: 1.1 - 2.2), all-grade ALT elevations was 1.62 (95% CI: 1.2 - 2.3). Subgroup analysis of all-grade AST elevations revealed melanoma patients exhibited a significantly higher rate compared to other solid tumors with an incidence of 8.7% (95% CI: 4.3 - 18.2%). All-grade ALT elevations in melanoma patients revealed the same incidence rate. Of note, renal cell carcinoma patients exhibited a particularly low incidence of all-grade transaminitis with AST 1.6% (95% CI: 0.6 - 11.1%) and ALT 1.8% (95% CI: 0.6 - 14.6%). Conclusions: Nivolumab is associated with significantly increased risk of all-grade and high-grade elevations in AST and ALT. Therapy should include careful monitoring of hepatotoxicity.
CHAPTER XIII: Associated Clinical and Laboratory Findings
Journal: Circulation (1973)

Clinical, electrocardiographic, biochemical, and roentgenographic abnormalities commonly used as a basis for diagnosing acute pulmonary embolism were often absent in 160 patients with angiographically proven pulmonary embolism. Pulmonary embolism should be suspected in any predisposed patient who experiences sudden, unexplained dyspnea or pleuritic pain; the patient should then be screened with perfusion lung scanning and, if necessary, pulmonary angiography to confirm the diagnosis. Whereas a clinical history proved relatively insensitive in screening for the presence of pulmonary embolism, physical findings such as ↑S 2 P, S 3 or S 4 gallop, and cyanosis often indicated right atrial and pulmonary arterial hypertension; these signs occurred more frequently in patients with massive embolism. Conversely, pleuritic pain and hemoptysis were more common in patients with submassive pulmonary embolism. Age, sex, and a history of prior pulmonary embolism bore no relation to angiographic massiveness, but venous disease was more common in patients with massive than in those with submassive pulmonary embolism. Women taking oral contraceptives tended to have more submassive embolism. Except for LDH, preinfusion enzyme and bilirubin concentrations appeared to have no relation to angiographic massiveness.
First-line ribociclib plus letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-2 safety results.
Authors: Wolfgang Janni, Howard A. Burris, Kimberly L. Blackwell, Lowell L. Hart, Arlene Chan, Arnd Nusch, Olga Nikolaevna Burdaeva, Emilio Alba, Denise A. Yardley, Thomas Denis Bachelot, Miguel J. Gil Gil, Donald A. Richards, Joseph A. Sparano, Joseph Gergi Kattan, Hugues Pierre Bourgeois, Fadi Rafic El Karak, Bhuvaneswari Ramaswamy, Santosh C. Sutradhar, Michelle Kristine Miller, Pier Franco Conte
Journal: Journal of Clinical Oncology (2017)

1047 Background: In the randomized, phase III MONALEESA-2 study (NCT01958021), first-line therapy with ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor; 600 mg/day; 3-weeks-on/1-week-off) + letrozole (LET; 2.5 mg/day) in postmenopausal women with HR+, HER2– ABC significantly prolonged progression-free survival vs placebo (PBO) + LET (hazard ratio: 0.556; p = 0.00000329; Hortobagyi GN et al. N Engl J Med 2016;375:1738–48). Here we present further safety analyses from MONALEESA-2. Methods: Adverse events (AEs) were characterized per CTCAE v4.03. Analyses of key AEs included time to first event, duration (time to AE resolution), and the rate of associated dose interruptions or reductions. Results: Safety analysis included 664 patients (pts; RIB + LET: 334; PBO + LET: 330). Neutropenia was the most common all-grade (G) and G3/4 AE in the RIB + LET arm (Table); febrile neutropenia rates were low (RIB + LET arm: 1.5%) with no associated deaths. Median time to first event for G ≥2 neutropenia in the RIB + LET arm (based on neutrophil counts) was 16 days. Other common G3/4 AEs (increased by ≥5% in the RIB + LET vs PBO + LET arm) were leukopenia (21% vs 1%), elevated alanine aminotransferase (ALT; 9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (AST; 6% vs 1%). Neutropenia was the most common AE leading to dose interruptions/reductions; G3/4 neutropenia led to dose interruptions in 48% vs &lt; 1% and reductions in 30% vs 0% of pts in the RIB + LET vs PBO + LET arm. 7.5% vs 2.1% of pts (RIB + LET vs PBO + LET) discontinued due to AEs; common AEs leading to discontinuation ( &gt; 1% pts) were elevated ALT (5% vs &lt; 1%), elevated AST (3% vs 1%), and vomiting (2% vs 0%). Conclusions: First-line RIB + LET had a manageable safety profile in postmenopausal women with HR+, HER2– ABC. Neutropenia was the most common AE in the RIB arm, and was transient and reversible with dose modifications. Additional AE analyses will be presented. Clinical trial information: NCT01958021. [Table: see text]
Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction
Authors: Ricardo Sanz-Ruiz, Ana Casado Plasencia, Luis R. Borlado, María Eugenia Fernández-Santos, Reem Al-Daccak, Piet Claus, Itziar Palacios, Rafael Sádaba, Dominique Charron, Jan Bogaert, Miguel Mulet, Raquel Yotti, Immaculada Gilaberte, Antonio Bernad, Javier Bermejo, Stefan Janssens, Franciso Fernández-Avilés
Journal: Circulation Research (2017)

Rationale: Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. Objective: In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. Methods and Results: With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. Conclusions: This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging–based efficacy end points. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.