tbuckley/cabot-search huggingface dataset:
Clonal T-cells and monocytosis in cancer patients and relationship to prognosis, and incidence of autoimmunity, fatigue, and second primary malignancies.
Authors: Michael Snyderman, Judy Mikovits
Journal: Journal of Clinical Oncology (2013)

e22038 Background: Clonal T-cell expansion and monocytosis could explain inflammation, fatigue and autoimmunity seen with cancer if both cell types release excess amounts of cytokines and disregulate the immune system. Cytokines can also have a paracrine effect and increase malignant cell proliferation. Methods: 48 patients with various neoplasms from an oncology practice were studied. Myeloid dyscrasias were excluded to allow interpretation of monocytosis. Clonal TCR rearrangements were done in a reference lab. Cancer-Related Fatigue (CRF) data as defined by the NCCN was available in 34 patients. The study was done 2010–2013. Results: See Table. Conclusions: Presence of a clonal T-cell expansion was associated with the greatest likelihood of high stage disease, second malignancy, autoimmunity and CRF. Monocytosis had a similar effect but less than clonal T-cell positivity. The patients with the least likelihood of high stage disease and CRF had no detectable clonal T-cell expansion and no monocytosis. Of the 25 originally negative or undetectable clonal T-cell expansions, 4 became positive 1-2 years later. The clonal T-cell and monocyte proliferation are unlikely to be reactive because a true tumor-specific antigen is rare and because there appeared to be a negative rather than a neutral or positive impact on multiple parameters. Further investigation to determine the subsets of T-cells and monocytes that are expanded and their production of proinflammatory cytokines, etiology of their proliferation and their role in the progression of neoplasia could lead to new treatments to improve the course and prognosis of cancer patients. [Table: see text]
QOLP-38. PATIENT REPORTED OUTCOMES IN GLIOMA: THE ROLE OF IDH MUTATION ON QUALITY OF LIFE AND MOOD
Authors: Michael Parsons, Adomas Bunevicius, Jorg Dietrich
Journal: Neuro-Oncology (2019)

Abstract Isocitrate dehydrogenase 1 (IDH) mutation has important clinical prognostic value in glioma patients conferring improved survival and better neurocognitive function (NCF) compared to IDH wild type (IDH-WT) patients. It is not known whether IDH mutation status has an impact on patient reported outcomes (PRO). The goal of this single institution retrospective study was to examine the impact of IDH-mutation status on PRO’s in patients who also completed neuropsychological evaluation. METHODS Out of 101 glioma patients referred for neuropsychological evaluation between 2018–2019, 73 completed the Functional Assessment of Cancer Therapy-Brain (FACT-Br; non-completion due to severe cognitive impairment, poor English). In addition to the total score, the FACT-Br includes 5 subscales of wellbeing (Physical, Social, Emotional, Functional, and Brain specific symptoms). 69 patients completed the Beck Depression Inventory (BDI) and 61 completed the Beck Anxiety Inventory (BAI). Self-reported symptoms were compared between those with IDH-Mut vs IDH-WT by ANOVA. RESULTS Diagnoses included glioblastoma (20), diffuse astrocytoma grade II/III (29) and oligodendroglioma grade II/III (24). 29/73 (40%) patients were IDH-mut. FACT-Br total scores did not differ between IDH-WT and IDH-Mut glioma patients (F=2.685; p=ns). Separate analyses of the 5 FACT-Br subscales showed that only the emotional functioning subscale differed significantly, with IDH-Mut patients reporting better emotional functioning than IDH-WT patients (F=7.4; p&amp;lt; 0.05). BDI and BAI scores did not differ by group (F= 2.2 and 1.9, respectively; p=NS). CONCLUSIONS IDH mutation was related to patient reported emotional status on the FACT-Br in this mixed clinical sample of glioma patients. Analysis is complicated by the heterogeneity of the sample and retrospective nature of the study. Routine inclusion of PRO’s as standard of care may allow a more comprehensive understanding of the impact of IDH throughout the natural history of glioma.
The efficacy of secukinumab with continued use in the treatment of psoriasis
Authors: M. Augustin, D. Thaci, K. Eyerich, A. Pinter, M. Radtke, F. Lauffer, U. Mrowietz, S. Gerdes, D. Pariser, M. Lebwohl, C. Sieder, N. Melzer, K. Reich
Journal: British Journal of Dermatology (2020)

Affecting at least 100 million people worldwide, psoriasis is a disease causing red, scaly patches of skin that may cover a large area of the body and may also affect the nails, scalp, palms and soles. This can lead to a severe impairment in quality of life. For patients with moderate to severe disease, the use of drugs called biologic therapies can result in clear or almost clear skin. Since psoriasis is a long‐term condition, it is important for patients to experience long‐lasting effects from biologic therapies. However, some patients can eventually stop responding to biologic treatments, meaning the drugs no longer work. The extent to which patients stop responding, and rates of subsequent regain of response with continued treatment (meaning it starts working again), have not been studied at the level of individual patients. A study of a drug's continued ability to treat the disease (its efficacy) is known as a study of its stability. Secukinumab, a licensed biologic therapy for psoriasis, has shown long lasting efficacy and safety in large clinical trials. Treatment with secukinumab can achieve a 90% reduction of psoriasis within 16 weeks of treatment and long term efficacy has been demonstrated up to 5 years. In this study, investigators from Germany and the U.S.A. studied the stability of response to secukinumab in people who took part in two large clinical trials. They found that efficacy with secukinumab was stable over one year of treatment in most patients, and continued treatment with secukinumab resulted in a regain of efficacy after loss in some patients. Persistent loss of response was uncommon. Patient factors including body weight, previous biologic treatment failure and levels of the drug in the blood plasma could influence the stability of response. This summary relates to the study: Continued treatment with secukinumab is associated with high retention or regain of response
Mapping and targeting of the leukemic microenvironment
Authors: Matthew T. Witkowski, Stavroula Kousteni, Iannis Aifantis
Journal: The Journal of Experimental Medicine (2019)

Numerous studies support a role of the microenvironment in maintenance of the leukemic clone, as well as in treatment resistance. It is clear that disruption of the normal bone marrow microenvironment is sufficient to promote leukemic transformation and survival in both a cell autonomous and non–cell autonomous manner. In this review, we provide a snapshot of the various cell types shown to contribute to the leukemic microenvironment as well as treatment resistance. Several of these studies suggest that leukemic blasts occupy specific cellular and biochemical “niches.” Effective dissection of critical leukemic niche components using single-cell approaches has allowed a more precise and extensive characterization of complexity that underpins both the healthy and malignant bone marrow microenvironment. Knowledge gained from these observations can have an important impact in the development of microenvironment-directed targeted approaches aimed at mitigating disease relapse.
Terminal Erythroid Maturation Is Associated with Dynamic Changes in the Abundance of Histone Marks Associated with Active Transcription Elongation and RNA Polymerase II Pausing
Authors: Zachary C. Murphy, Tyler A Couch, Jacquelyn Lillis, Michael Getman, Kimberly Lezon-Geyda, Vincent P Schulz, Mohandas Narla, Patrick G. Gallagher, Laurie A. Steiner
Journal: Blood (2019)
Looking at the COPD spectrum through “PRISm”
Authors: Amin Adibi, Mohsen Sadatsafavi
Journal: European Respiratory Journal (2020)

COPD is a major burden globally. According to the Global Burden of Disease study, COPD caused 3.2 million deaths in 2015, accounting for 5% of all deaths worldwide, making it the third leading cause of death in the world [1]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines spirometrically confirmed COPD based on a forced expiratory volume during the first second (FEV1) to a forced vital capacity (FVC) ratio smaller than 0.7 [2]. The severity of airflow obstruction is further defined through GOLD severity grades based on the ratio of FEV1 to its predicted value, with GOLD 1, 2, 3 and 4 defined around cut-off points of 80%, 50%, and 30% [2]. Preserved ratio impaired spirometry (PRISm) is a prevalent, neglected condition whose prognosis is close to that of COPD <http://bit.ly/2Oydvq1>
Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis
Authors: Vince B C Biemans, Frank Hoentjen, Marieke J Pierik
Journal: New England Journal of Medicine (2020)

Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative ColitisTo the Editor: In the randomized, head-to-head VARSITY trial comparing two biologic therapies that have different mechanisms of action (vedolizumab and adalimumab) in patients with ulcerative colitis, Sands et al. (Sept.26 issue) 1 aim to fill a crucial knowledge gap: the comparative efficacy of treatments in ulcerative colitis.We have concerns about the generalizability of the results.First, regarding the suggested lower efficacy of adalimumab, patients who had not had a response to a tumor necrosis factor (TNF) inhibitor were eligible for inclusion, although guidelines recommend a shift out of class given the reduced efficacy of a second TNF inhibitor. 2Second, no dose intensification was permitted, but real-world data show that dosages are increased more often within the first year in patients who receive adalimumab (in 55 to 65% of patients) 3,4 than in patients who receive vedolizumab (in 21%) 5 ; thus, the dose of adalimumab might have been too low.Third, a treatment goal in ulcerative colitis is corticosteroid-free clinical remission, and this outcome was not achieved more often with vedolizumab than with adalimumab.Besides efficacy, cost utility should be taken into account when selecting treatment, and this was not assessed.The aim of this trial was to assess the comparative efficacy of vedolizumab and adalimumab for the treatment of ulcerative colitis, but because of the trial design and outcomes, the implications for clinical practice are limited.
A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.
Authors: Andrea S. Teague, Manik A. Amin, Kian-Huat Lim, Albert C. Lockhart, Ashiq Masood, Joel Picus, Preet Paul Singh, Rama Suresh, Benjamin R. Tan, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2016)

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m 2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.
Complete Metabolic Response Assessed by FDG PET/CT to Paclitaxel-Ramucirumab in Patients With Metastatic Gastroesophageal Junction Cancer
Authors: Karim Amrane, Solène Querellou, Ulrike Schick, Ronan Abgral, Jean-Philippe Metges
Journal: Clinical Nuclear Medicine (2019)

Abstract Paclitaxel-ramucirumab chemotherapy is indicated in second line of metastatic gastroesophageal junction cancer (mGEJC) after progression under platinum–5-FU chemotherapy. Nevertheless, the reported common response after treatment is only partial within series. To date, only 1 case report of negative posttreatment FDG PET/CT was published without baseline examination from RAINBOW trial. We illustrated the interest of FDG PET/CT to evaluate treatment especially paclitaxel-ramucirumab with 2 examples of complete metabolic responses in 2 patients having different HER2 biomarker profiles of mGEJC. As illustrated, FDG PET/CT emerges as a useful approach for therapeutic assessment of targeted drugs in mGEJC.
The Relationships between Target Gene Transduction, Engraftment of HSCs and RBC Physiology in Sickle Cell Disease Gene Therapy
Authors: Melissa Bonner, Julie Kanter, Elizabeth Macari, Ricky Lane, Gretchen Lewis, Paige Coles, Sarah Kassenaar, Sai Mynampati, Robert Schulze, Madison Hebert, Mark C. Walters, Alexis A. Thompson, Mohammed Asmal, John F. Tisdale, Francis J. Pierciey
Journal: Blood (2019)
Association Between Maternal Fluoride Exposure and Child IQ
Authors: Queen N. Aghaji, Chike C. Nwabuo
Journal: JAMA Pediatrics (2019)

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Great diversity of oncogenic human papillomaviruses is revealed in an outbreak of multifocal epithelial hyperplasia
Authors: Sandra Margarita Jiménez Aguilar, Daniel Lizárraga Rodríguez, Víctor Fernando Muñoz Estrada, Silvestre Guadalupe Cázarez Salazar, Jesús Salvador Velarde Félix, Rocío Susana Méndez Martínez
Journal: Journal of the American Academy of Dermatology (2019)
Pharmacological Inhibition of Nemo-like Kinase Rescues mTOR-Mediated Translation and Primes Progenitors for Leucine-Stimulated Erythroid Expansion in Pre-Clinical Models of Diamond Blackfan Anemia
Authors: Mark C Wilkes, Jacqueline D Mercado, Mallika Saxena, Jun Chen, Kavitha Siva, Hee-Don Chae, Minyoung Youn, Ethan Patrick Wentworth, Kevin Jung, Ryan Sathianathen, Hiral Patel, Bertil Glader, Anupama Narla, Claire E Repellin, Hanna T Gazda, Manuel Serrano, Johan Flygare, Kathleen M. Sakamoto
Journal: Blood (2019)
Цитомегаловирусная и смешанные вирусные инфекции у пациентов с воспалительными заболеваниями кишечника
Authors: G.H. Babayeva
Journal: GASTROENTEROLOGY (2019)

Актуальность. Вопрос распространенности оппортунистических инфекций у лиц с воспалительными заболеваниями кишечника (ВЗК) остается актуальным. Особое внимание среди оппортунистических инфекций уделяется цитомегаловирусной (ЦМВ) инфекции. Клиническая активность ЦМВ-ассоциированного ВЗК, его длительность и степень тяжести, а также использование стероидов и анти-ФНО-α-агентов были идентифицированы как факторы риска неблагоприятных исходов. В диагностике ЦМВ важно не просто выявить наличие вируса в организме пациента, но и уточнить его этиологическую роль в развитии заболевания. В настоящее время рекомендуется проведение скрининга на ЦМВ у всех пациентов с ВЗК при гормональной резистентности, потере эффекта от поддерживающей терапии и при тяжелых эпизодах заболевания. Цель исследования: оценка частоты выявления изолированной цитомегаловирусной инфекции и смешанных (герпес и парвовирус В19) вирусных инфекций у пациентов с ВЗК и их влияние на активность заболевания. Материалы и методы. Обследовано 189 пациентов с ВЗК, 102 с язвенным колитом и 87 с болезнью Крона, среди них 98 женщин и 91 мужчина. Возраст пациентов составлял от 16 до 63 лет, в среднем (41,4 ± 4,8) года. Кроме стандартного клинико-эндоскопического обследования в соответствии с положениями Европейской организации по изучению болезни Крона и язвенного колита (ЕССО), активность заболевания оценивалась по показателям высокочувствительного С-реактивного белка, гомоцистеина, витамина D в сыворотке крови, альбумина в моче, кальпротектина и лактоферрина в кале. Всем пациентам проведено серологическое исследование крови методом иммуноферментного анализа на специфические антитела к герпесвирусам и IgG-/IgM-антитела к парвовирусу В19, а также определение ДНК вирусов простого герпеса 1, 2, 6-го типов, вируса Эпштейна — Барр, цитомегаловируса, герпеса зостер методом полимеразной цепной реакции. У всех пациентов также определяли уровни цитокинов в крови (фактор некроза опухоли α, интерлейкины 1β, -2, -4, -6, -8, -10, -18). Результаты. У пациентов с ВЗК частота выявления изолированной цитомегаловирусной инфекции составляет, по нашим данным, 19,5 %, а с учетом смешанных поражений — 29,6 %. Клинико-эндоскопическая картина (рефрактерность к базисной терапии, несоответствие между эндоскопической картиной и патоморфологическим заключением), а также данные лабораторных исследований указывают на более тяжелое течение заболевания при наличии цитомегаловирусной инфекции. Выводы. Полученные данные позволяют нам рекомендовать в дополнение к протоколам ЕССО определение наличия оппортунистических инфекций у пациентов с впервые выявленным ВЗК до начала базисной терапии, не дожидаясь развития рефрактерных к лечению форм заболевания.
Moving Molecular Profiling to Routine Clinical Practice: A Way Forward?
Authors: Boris Freidlin, Carmen J Allegra, Edward L Korn
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Molecular profiling of a patient’s tumor to guide targeted treatment selection offers the potential to advance patient care by improving outcomes and minimizing toxicity (by avoiding ineffective treatments). However, current development of molecular profile (MP) panels is often based on applying institution-specific or subjective algorithms to nonrandomized patient cohorts. Consequently, obtaining reliable evidence that molecular profiling is offering clinical benefit and is ready for routine clinical practice is challenging. In particular, we discuss here the problems with interpreting for clinical utility nonrandomized studies that compare outcomes in patients treated based on their MP vs those treated with standard of care, studies that compare the progression-free survival (PFS) seen on a MP-directed treatment to the PFS seen for the same patient on a previous standard treatment (PFS ratio), and multibasket trials that evaluate the response rates of targeted therapies in specific molecularly defined subpopulations (regardless of histology). We also consider some limitations of randomized trial designs. A two-step strategy is proposed in which multiple mutation-agent pairs are tested for activity in one or more multibasket trials in the first step. The results of the first step are then used to identify promising mutation-agent pairs that are combined in a molecular panel that is then tested in the step-two strategy-design randomized clinical trial (the molecular panel–guided treatment for the selected mutations vs standard of care). This two-step strategy should allow rigorous evidence-driven identification of mutation-agent pairs that can be moved into routine clinical practice.