tbuckley/cabot-search huggingface dataset:
Clinical impact of pretransplant use of multiple tyrosine kinase inhibitors on the outcome of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia
Authors: Takeshi Kondo, Tokiko Nagamura‐Inoue, Arinobu Tojo, Fumitaka Nagamura, Naoyuki Uchida, Hirohisa Nakamae, Takahiro Fukuda, Takehiko Mori, Shingo Yano, Mineo Kurokawa, Hironori Ueno, Heiwa Kanamori, Hisako Hashimoto, Makoto Onizuka, Minoko Takanashi, Tatsuo Ichinohe, Yoshiko Atsuta, Kazuteru Ohashi
Journal: American Journal of Hematology (2017)

Abstract Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with chronic myelogenous leukemia in the chronic phase (CML‐CP), and outcomes of TKI treatment for patients with CML‐CP have been excellent. Since multiple TKIs are currently available, second‐line or third‐line TKI therapy is considered for patients who are intolerant of or resistant to the previous TKI treatment. Therefore, allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is considered only for patients with disease progression or for patients after treatment failure with multiple TKIs. To reflect the current clinical situation of patients with CML‐CP, we tried to clarify whether prior TKI treatment affects the outcome of allo‐HSCT. Data from 237 patients for whom the number of pretransplant TKIs varied from one to three were used for analysis. Before allo‐HSCT, 153 patients were treated with one TKI, 49 patients were treated with two TKIs and 35 patients were treated with three TKIs. In addition to conventional risk factors, i.e., disease status at transplantation and patient's age, the use of three TKIs before transplantation was identified as a significant adverse factor for prognosis. Nonrelapse mortality rate was higher in patients treated with three TKIs than in patients treated with one or two TKIs. Our results suggest that allo‐HSCT could be considered for young patients with CML‐CP who manifest resistance to second‐line TKI therapy and who have an appropriate donor.
Interventions to Improve Oral Chemotherapy Safety and Quality
Authors: Jessica A. Zerillo, Benjamin A. Goldenberg, Ritesh R. Kotecha, Alok K. Tewari, Joseph O. Jacobson, Monika K. Krzyzanowska
Journal: JAMA Oncology (2017)

With the growing use of oral chemotherapy, there is an urgent need to develop safe and effective systems to administer and manage these agents. A comprehensive synthesis of literature on oral chemotherapy care delivery programs to which clinicians can look for best practices is lacking.To summarize the peer-reviewed and gray literature on interventions to improve oral chemotherapy care delivery toward describing best practices and identifying current gaps.Using search terms pertaining to the concepts of oral chemotherapy, cancer, and interventions and outcomes, we performed a systematic review of PubMed, EMBASE, and CINAHL from January 1995 to May 24, 2016, to identify oral chemotherapy intervention programs. We searched the gray literature from January 1995 through February 2016 and contacted gray literature authors for further information. Four physician abstractors reviewed the titles, abstracts, and articles. Quality of the articles was assessed using SQUIRE2 guidelines. Interventions were evaluated in the categories of prescribing, preparation/dispensing, education, administration, monitoring, and storage/disposal. The population of interest included all ages and was limited to traditional cytotoxic and targeted anticancer oral agents.From 7984 abstracts identified in the peer-reviewed literature search, 16 full-text articles met inclusion criteria representing 3612 patients. Interventions focused on prescribing (n = 1), preparation/dispensing (n = 2), education (n = 11), administration (n = 5), monitoring (n = 14), and storage/disposal (n = 1). In the 10 articles with adherence as the primary outcome, 4 evaluation methods were used. Most improvements were seen in toxic effects/safety compared with adherence. Of the 7 interventions with statistically significant improvement in the primary outcome, 3 nursing phone calls to contact patients within the first few days after treatment initiation, 2 of them with standardized toxic effects management protocols. Interventions using technology to increase touch points between care teams and patients (including video directly observed therapy, automated voice response, and text messages) were not effective.A framework for the oral chemotherapy management process with standardized outcome definitions is needed to ensure constructive research. Existing data suggest that a monitoring program should include personal contact with patients within the first weeks of treatment. Whether such contact can be enhanced by technology is uncertain.
Association of a Policy Mandating Physician-Patient Communication With Racial/Ethnic Disparities in Postmastectomy Breast Reconstruction
Authors: Elham Mahmoudi, Yiwen Lu, Allan K. Metz, Adeyiza O. Momoh, Kevin C. Chung
Journal: JAMA Surgery (2017)

With the stabilization of breast cancer incidence and substantial improvement in survival, more attention has focused on postmastectomy breast reconstruction (PBR). Despite its demonstrated benefits, wide disparities in the use of PBR remain. Physician-patient communication has an important role in disparities in health care, especially for elective surgical procedures. Recognizing this, the State of New York enacted Public Health Law (NY PBH Law) 2803-o in 2011 mandating that physicians communicate about reconstructive surgery with patients undergoing mastectomy.To evaluate whether mandated physician-patient communication is associated with reduced racial/ethnic disparities in immediate PBR (IPBR).This retrospective study used state inpatient data from January 1, 2008, through December 31, 2011, in New York and California to evaluate a final sample of 42 346 women aged 20 to 70 years, including 19 364 from New York (treatment group) and 22 982 from California (comparison group). The primary hypothesis tested the effect of the New York law on racial/ethnic disparities, using California as a comparator. The National Academy of Medicine's (formerly Institute of Medicine) definition of a disparity was applied, and a difference-in-differences method (before-and-after comparison design) was used to evaluate the association of NY PBH Law 2803-o mandating physician-patient communication with disparities in IPBR. Data were analyzed from July 1, 2016, to February 24, 2017.New York PBH Law 2803-o was implemented on January 1, 2011. The preexposure period included January 1, 2008, through December 31, 2010 (3 years); the postexposure period, January 1 through December 31, 2011 (1 year).The primary outcome was use of IPBR among white, African American, Hispanic, and other minority groups before and after the implementation of NY PBH Law 2803-o.Among the 42 346 women (mean [SD] age, 53 [10] years), 65.3% (27 654) were white, 12.7% (5365) were Hispanic, 9.4% (3976) were African American, and 12.6% (5351) were other minorities. The new legislation was not associated with the overall IPBR rate or disparity in IPBR between whites and African Americans (reduction of 1 percentage point; 95% CI, -0.02 to 0.04), but it was associated with a reduction in disparities in IPBR between Hispanic and white patients by 9 (95% CI, 0.06-0.11) percentage points and between other minorities and white patients by 13 (95% CI, 0.11-0.16) percentage points.Physician-patient communication may help to address inequity in the use of elective surgical procedures, such as IPBR. However, lack of patient trust and/or effective physician-patient communication may reduce the potential effect of mandatory communication for some subpopulations, including African American individuals.
MEDU-26. DISTINCT EXPRESSION OF THE CD166/ACTIVATED LEUKOCYTE CELL ADHESION MOLECULE (ALCAM) IN MEDULLOBLASTOMA SUBGROUPS
Authors: Takamune Achiha, Noriyuki Kijima, Naoki Kagawa, Chisato Yokota, Yasunori Fujimoto, Toshiki Yoshimine
Journal: Neuro-Oncology (2017)

CD166/activated leukocyte cell adhesion molecule (ALCAM) is a member of the immunoglobulin superfamily, widely expressed in various tissues, and involved in several functions such as neurogenesis, angiogenesis, hematopoesis. ALCAM is also reported to be a cell surface marker for mesenchymal stem cells, cancer stem cells in several kinds of cancer, including glioblastoma. However, ALCAM expression in medulloblastoma (MB) is not extensively studied. In this study, we investigated the expression of ALCAM in MB by immunohistochemistry. Formalin-fixed and paraffin-embedded tumor tissues from 22 MB patients were stained and analyzed for the expression of ALCAM based on the molecular subgroups of MB (WNT, SHH, Group3, and Group4). Nine of 22 MB samples (9/22: 41%) were ALCAM positive, which were diffuse and/or insular patterns. Interestingly, only 1/9 Group4 MB expressed ALCAM while other subgroups variably expressed ALCAM. (WNT 1/1, SHH 2/3, Group3 3/3: 86%) Our result showed distinct expression of ALCAM in MB subgroups and also suggested that ALCAM could be a marker to distinguish Group4 MB from other subgroups of MB.
Long-lasting tuberculous pleurisy
Authors: Elisa Petruccioli, Thomas J. Scriba, Linda Petrone, Mark Hatherill, Daniela M. Cirillo, Simone A. Joosten, Luigi R. Codecasa, Tom H. Ottenhoff, Claudia M. Denkinger, Delia Goletti
Journal: European Respiratory Journal (2017)

We read with interest the correspondence from L. Ampollini and colleagues, in which they report the case of an immunocompetent patient who originally presented with pulmonary and extra-pulmonary tuberculosis (TB) at 33 years of age and which was thought to have persisted over many years. However, based on the clinical story described, we doubt that the patient had reactivation of TB at 65 years of age, when he presented with chest pain and dyspnoea and a computerised tomography (CT)-scan showed a calcifying pleurisy leading to a contralateral mediastinal shift and lung atelectasis. Mycobacterium tuberculosis was not isolated from the pleural effusion. Rather, a positive culture of Streptococcus was obtained and the patient was treated successfully with an anti-streptococcal therapy that was not TB-specific (amoxicillin/clavulanic acid for 3 weeks), with no sign of a TB relapse at follow up 2 years later. Therefore, it seems likely that L. Ampollini and colleagues are describing a case of bacterial pleuritis occurring in a patient with previous TB and calcified sequaele. It is necessary to find better tools to predict and monitor TB treatment outcomes and potential for reactivation <http://ow.ly/CBxr30aLdCE>
A diagnostic protocol designed for determining allergic causes in patients with blood eosinophilia
Authors: Jean-François Magnaval, Guy Laurent, Noémie Gaudré, Judith Fillaux, Antoine Berry
Journal: Military Medical Research (2017)

Blood eosinophilia is a common laboratory abnormality, and its characterization frequently represents a quandary for primary care physicians. Consequently, in France, specialists and particularly hematologists, often must investigate patients who present with blood eosinophilia that often, but not always, occurs because of allergic causes. Both the Departments of Hematology and Parasitology at Toulouse University Hospitals established a collaboration to rule out allergic causes of eosinophilia, particularly helminthiases, prior to initiating more sophisticated investigations. Since 2004, the authors employed the same protocol to investigate eosinophilic outpatients who attended the clinic of Parasitology at Toulouse University Hospitals, and they reported the performance of this diagnostic procedure that was designed to be rapid (no hospitalization required) and only moderately expensive. A total of 406 patients who presented with blood eosinophilia greater than 0.5 (×109, giga cells per litter, G/L) had an allergic etiology in 350 (86.2%) cases. Among the remaining 56 subjects, 17 did not undergo a follow-up and 39 were referred to another specialized department, mostly Hematology. However, only 21 patients attended then were subsequently investigated. Non-allergic causes of eosinophilia, including 3 cases of the lymphoid variant of hypereosinophilic syndrome and 2 cases of myeloproliferative disorder, were identified in 14 patients, whereas 7 remained diagnosed as having idiopathic eosinophilia. This study underlines the need to investigate patients presenting with even moderate blood eosinophilia. The work-up that was employed appears to be efficient and versatile and may be used by any medical specialist, such as in hematology, infectious disease, or internal medicine departments, who needs to investigate eosinophilic patients and should initially rule out any etiology of allergic eosinophilia.
Specific antidotes for bleeding associated with direct oral anticoagulants
Authors: Allison Burnett, Deborah Siegal, Mark Crowther
Journal: BMJ (2017)

#### What you need to know

An 83 year old woman is brought to the emergency department by her care giver who noticed her altered mental status following two episodes of passing black faeces. The woman has a history of ischaemic stroke associated with atrial fibrillation and hypertension and is on dabigatran for stroke prevention. She took her last dose a few hours ago. Computed tomography of the head shows no acute intracranial abnormalities. Abdominal and rectal exams are normal. Her blood pressure is 82/56 mm Hg. The multidisciplinary team in charge of her care arrives to talk with her and her family about antidotes for reversing her anticoagulation.

Direct oral anticoagulants (DOACs) are a relatively new class of oral anticoagulants developed as alternatives to vitamin K antagonists such as warfarin, and are indicated in non-valvular atrial fibrillation and venous thromboembolism (Box 1).

#### Box 1: Direct oral anticoagulants (DOACs)

##### Commercially available DOACs include

Randomised controlled trials and meta-analyses among patients with non-valvular atrial fibrillation or acute venous thromboembolism have shown DOACs to be at least as effective as vitamin K antagonists in preventing or treating thromboembolic events.3 4 …
LOX-1 in Atherosclerosis and Myocardial Ischemia
Authors: Naga Venkata K. Pothineni, Sotirios K. Karathanasis, Zufeng Ding, Arockiasamy Arulandu, Kottayil I. Varughese, Jawahar L. Mehta
Journal: Journal of the American College of Cardiology (2017)
Survival in Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis - Correlation of Clinical Phenotype with Histomorphological Diagnosis
Authors: Georg Jeryczynski, Albert Woelfler, Bettina Gisslinger, Martin Schalling, Sonja Burgstaller, Veronika Buxhofer-Ausch, Maria Theresa Krauth, Klaus Geissler, Ernst Schlögl, Thamer Sliwa, Ana-Iris Schiefer, Leonhard Muellauer, Ingrid Simonitsch-Klupp, Christine Beham-Schmid, Jürgen Thiele, Heinz Gisslinger
Journal: Blood (2016)
Non-invasive imaging of barriers to drug delivery in tumors: monitoring changes in interstitial fluid pressure
Authors: Yaron Hassid, Erez Eyal, Raanan Margalit, Edna Furman-Haran, Hadassa Degani
Journal: Clinical Cancer Research (2007)

PR-6  Drugs are transferred to tissues according to concentration gradients and pressure gradients. Solid tumors often develop high interstitial fluid pressure due to increased water leakage from the capillaries and impaired lymphatic drainage, which leads to water accumulation, as well as due to increased collagen production and interaction with the fibroblasts surrounding the tumors9 cells, which posses pressure on the tissue. The high interstitial fluid pressure modulates the physiological positive pressure gradients from the capillaries outwards and forms a barrier to drug delivery. We have developed a novel, non invasive method based on MRI, which maps throughout the entire tumor the transfer rates determined by pressure gradients and concentration gradients, and hence enables to predict barriers to drug delivery. This method was applied in order to monitor the results of treatment with collagenase, an enzyme that degradates the collagen fibers and reduces interstitial hypertension. The method and its application to monitor collagenase effects were tested in H460 ectopic human non-small-cell lung cancer xenografts in immunodeficient mice. Sequential images were recorded during slow infusion of a Gd-based contrast agent and were analyzed using an extended mathematical model of tumor perfusion. The final output provided physiological parameters such as concentration dependent and pressure dependent transfer constants, intravascular and extracellular volume fractions. The tumors exhibited positive pressure dependent transfer constants at the boundaries and negative pressure dependent transfer constants in internal region. These negative transfer constants reflected increased interstitial fluid pressure as was confirmed by using the wick in needle method. After treatment with collagenase the tumors9 central regions demonstrated a significant increase in the pressure dependent transfer constant, from negative to positive values, while the concentration gradients dependent transfer rates, as well as the other physiological parameters did not change significantly. It is therefore possible to map non invasively, for the first time, the in vivo physiological parameters which could be used to evaluate the barriers to successful drug delivery to tumors, and provide a quantitative measure for testing new drugs that eliminate these barriers.
Abstract 284: Disruption of Nrf2 Promotes Atrial Remodeling and Fibrillation on Aging
Authors: Naser Abu-Rmaileh, Sankaranarayanan Kannan, Kensuke Tsushima, Kevin Whitehead, E Dale Abel, Nassir F Marrouche, Rajasekaran Namakkal Soorappan
Journal: Circulation Research (2013)

Background: Heart failure is a leading health problem with over 500,000 new cases and 275,000 deaths annually in the United States. Recent reports indicate that atrial fibrillation (AF) is linked to various forms of ventricular dysfunction (VD). Over 2 million Americans have AF, which is more prevalent in people over 65 years of age. However, the molecular “cause and effect” relationship between AF and VD has not been elucidated. We hypothesize that abrogation of nuclear erythroid-2 like factor-2 (Nrf2), a master antioxidant transcriptional regulator, induces atrial remodeling and fibrillation on aging. Methods: Age and sex matched WT and Nrf2-/- mice were used in this study. Atrial mass, remodeling, antioxidants and molecular redox signaling were studied at 2 and &gt;20 months of age. Echocardiography, immunoblotting, quantitative real-time PCR and immunofluorescence (fibrosis) analyses were performed in the atrial tissue. Results: At 2 months of age, WT and Nrf2-/- mice had comparable levels of ROS in the atrium. On aging, the ROS levels were significantly increased in atria of Nrf2- null when compared to wild-type (WT) mice at 20 months of age. While decreased Nrf2-antioxidant signaling in response to increased ROS generation in atria of Nrf2- null mice was observed, ventricular function appeared to be normal at 20 months of age. However, upon endurance exercise stress (EES), hypertrophy markers including ANF, BNF, PLN and SERCA2A were significantly (p&lt;0.05) altered in Nrf2- null when compared to age-matched WT mice. Further, activation of fibrotic process was evident in the Nrf2- null mouse atrium as indicated by significantly (p&lt;0.05) increased markers of tissue remodeling (i.e. MMP2/9) on aging. These results indicating an early onset of atrial hypertrophy/remodeling due to age-induced oxidative stress, which cause AF in Nrf2- null mice. Age-dependent decline in Nrf2 and sustained progression of AF could lead to ventricular dysfunction and heart failure. Conclusion: Our findings indicate that atria are primary targets to age-associated oxidative stress and exhibit fibrosis, which promotes atrial fibrillation and remodeling. Thus, activation of Nrf2 signaling to prevent oxidative stress could be a potential therapeutic target for AF.
Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives
Authors: Kan Yue, Xiuyu Li, Karsten Schrobback, Amir Sheikhi, Nasim Annabi, Jeroen Leijten, Weijia Zhang, Yu Shrike Zhang, Dietmar W. Hutmacher, Travis J. Klein, Ali Khademhosseini
Journal: Biomaterials (2017)
EPND-12. TYROSINE KINASE INHIBITORS AXITINIB, IMATINIB AND PAZOPANIB ARE SELECTIVELY POTENT IN EPENDYMOMA
Authors: Andrew Donson, Elliot Werner, Vladimir Amani, Andrea Griesinger, Davis Witt, Anandani Nellan, Rajeev Vibhakar, Todd Hankinson, Michael Handler, Kathleen Dorris, Nicholas Foreman
Journal: Neuro-Oncology (2017)

Reproducibly effective chemotherapy has yet to be identified for ependymoma (EPN), partly due to a lack of models for preclinical drug screening. Treatment of EPN has therefore changed little over the last 40 years and is essentially limited to surgery and radiation. Recurrence risk is high, particularly in those EPN harboring chromosome 1q gain. To address this, we have established 2 posterior fossa 1q+ EPN cell lines and we have utilized these in a high-throughput drug screen of FDA-approved oncology drugs. Treatment effect was measured using a tritiated-thymidine incorporation proliferation assay and EPN-selective sensitivity was determined by comparison to a panel of other pediatric brain tumor types (medulloblastoma, glioblastoma, DIPG and AT/RT). Using this approach, we identified a group of 3 small molecule tyrosine kinase inhibitors (TKIs) that showed greater potency in EPN than control cell lines. These TKIs – namely axitinib, imatinib and pazopanib – commonly target VEGFR, PDGFR and c-kit. Of note, axitinib has been proposed for an upcoming phase 1 trial for recurrent pediatric brain tumors including EPN. Studies of axitinib in other tumors demonstrated a beneficial immunomodulatory effect, of particular relevance in EPN given the key role of immunity in this tumor. Axitinib may therefore have a dual mechanism of tumor control in EPN. We selected this drug for further evaluation in our preclinical model of EPN. Dose curve analysis confirmed that axitinib more is potent in EPN than other cell types. Transcriptomic analysis of axitinib treated EPN revealed a decrease in mitosis-related gene expression and in increase in type-I interferon-associated gene expression. Further screening studies identified treatments that showed synergistic effects in EPN, most notably cisplatin. Collectively these data support clinical evaluation of axitinib for treatment EPN and provide information of potentially synergistic treatment combinations that might overcome single agent resistance.