tbuckley/cabot-search huggingface dataset:
Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review
Authors: Alison M Pease, Harlan M Krumholz, Nicholas S Downing, Jenerius A Aminawung, Nilay D Shah, Joseph S Ross
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence. <b>Design</b>&nbsp;Systematic review. <b>Data sources</b>&nbsp;Drugs@FDA database and PubMed. <b>Study inclusion</b>&nbsp;All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. <b>Results</b>&nbsp;Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively. <b>Conclusions</b>&nbsp;The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.
B-Cell Markers Predict Response to Venetoclax in Multiple Myeloma
Authors: Vikas A. Gupta, Scott Newman, Nizar J. Bahlis, Jonathan J Keats, Shannon Matulis, Michael R. Rossi, Daniel Auclair, Mmrf CoMMpass Network, Ajay K Nooka, Jonathan L. Kaufman, Sagar Lonial, Lawrence H. Boise
Journal: Blood (2016)
An Early Thymic Precursor Phenotype Predicts Outcome Exclusively in HOXA-Overexpressing Adult T-ALL: A GRAALL Study
Authors: Jonathan Bond, Tony Marchand, Aurore Touzart, Agata Cieslak, Amélie Trinquand, Laurent Sutton, Isabelle Radford-Weiss, Salvatore Spicuglia, Hervé Dombret, Elizabeth Macintyre, Norbert Ifrah, Jean-François Hamel, Vahid Asnafi
Journal: Blood (2015)
CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma
Authors: Constantin Lapa, Ken Herrmann, Andreas Schirbel, Heribert Hänscheid, Katharina Lückerath, Margret Schottelius, Malte Kircher, Rudolf A. Werner, Martin Schreder, Samuel Samnick, Saskia Kropf, Stefan Knop, Andreas K. Buck, Hermann Einsele, Hans-Juergen Wester, K. Martin Kortüm
Journal: Theranostics (2017)

C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer.We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM).Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles).ERT was administered in combination with chemotherapy and autologous stem cell support.End points were occurrence and timing of adverse events, progression-free and overall survival.ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs.With absorbed tumor doses >30-70 Gy in intra-or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission.Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome.Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313).During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive.CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease.Further assessment of this novel treatment option is highly warranted.
In Reply:
Authors: Laurence H. Baker
Journal: Journal of Clinical Oncology (2006)

of children with the same disease, whereas angiomatoid fibrous histiocytoma is proportionally 24.1 times greater in children as in adults.Also proportionally more common in children are embryonal sarcoma (72.2 times), clear cell sarcoma of the kidney (25.3 times), mesenchymal chondrosarcoma (8.9 times), desmoplastic small round cell tumor (7.2 times), alveolar soft part sarcoma (7 times), and clear cell sarcoma arising outside of the kidney (6 times).In addition, certain entities, such as infantile fibrosarcoma, are unique to pediatric populations.Recently published data on STS in adults and children also support a different distribution of STS in pediatric and adult populations.In the largest published series of pediatric patients with NRSTS, synovial sarcoma and malignant peripheral nerve sheath tumor were consistently among the top three diagnoses. 1,[3]4][5][6][7] It is more difficult to find series of unselected adults with STS, but liposarcoma, malignant fibrous histiocytoma, and leiomyosarcoma are routinely among the top five, in large series of adults with extremity and retroperitoneal primary tumors. [8][[10] Some may question the importance of the precise terminology used to describe childhood soft tissue sarcomas other than rhabdomyosarcoma.We argue, however, that the terminology should accurately reflect the epidemiologic characteristics of these neoplasms, rather than categorizing them as adult-type tumors in children.Although considerable similarities likely exist, prospective data about prognostic factors, therapeutic responsiveness, and outcomes in pediatric patients are presently limited.Certain relatively chemosensitive subtypes (eg, synovial sarcoma) account for a significantly higher proportion of STS in pediatric populations, and such differences must be taken into account in defining a therapeutic strategy.Data about the biology of these tumors in childhood are also lacking; therefore, it is unclear whether they are biologically identical in pediatric and adult populations.Because growth and development are important factors in children, treatment considerations in childhood differ from those in adults.For these reasons, although Baker reports that medical oncologists "giggle snidely at the phrase," we believe that the term NRSTS is the most accurate and appropriate descriptor for this group of diseases in childhood, and we suggest that most thoughtful medical oncologists would agree.It is hoped that someday STS will no longer be considered a single disease entity, and that such awkward terminology will no longer be necessary.The forthcoming pediatric NRSTS clinical trials of the Children's Oncology Group and the European Pediatric Soft Tissue Sarcoma Study Group are an encouraging sign.These studies will certainly provide valuable new information about childhood NRSTS and will hopefully give rise to future histology-specific trials.
Inferring the physical properties of yeast chromatin through Bayesian analysis of whole nucleus simulations
Authors: Jean-Michel Arbona, Sébastien Herbert, Emmanuelle Fabre, Christophe Zimmer
Journal: Genome biology (2017)

The structure and mechanical properties of chromatin impact DNA functions and nuclear architecture but remain poorly understood. In budding yeast, a simple polymer model with minimal sequence-specific constraints and a small number of structural parameters can explain diverse experimental data on nuclear architecture. However, how assumed chromatin properties affect model predictions was not previously systematically investigated. We used hundreds of dynamic chromosome simulations and Bayesian inference to determine chromatin properties consistent with an extensive dataset that includes hundreds of measurements from imaging in fixed and live cells and two Hi-C studies. We place new constraints on average chromatin fiber properties, narrowing down the chromatin compaction to ~53–65 bp/nm and persistence length to ~52–85 nm. These constraints argue against a 20–30 nm fiber as the exclusive chromatin structure in the genome. Our best model provides a much better match to experimental measurements of nuclear architecture and also recapitulates chromatin dynamics measured on multiple loci over long timescales. This work substantially improves our understanding of yeast chromatin mechanics and chromosome architecture and provides a new analytic framework to infer chromosome properties in other organisms.
Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update
Authors: Thomas Lehrnbecher, Paula Robinson, Brian Fisher, Sarah Alexander, Roland A. Ammann, Melissa Beauchemin, Fabianne Carlesse, Andreas H. Groll, Gabrielle M. Haeusler, Maria Santolaya, William J. Steinbach, Elio Castagnola, Bonnie L. Davis, L. Lee Dupuis, Aditya H. Gaur, Wim J.E. Tissing, Theo Zaoutis, Robert Phillips, Lillian Sung
Journal: Journal of Clinical Oncology (2017)

Purpose To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients. Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low. Results Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN. Conclusion Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.
Association Between Maternal Smoking During Pregnancy and Severe Mental Illness in Offspring
Authors: Patrick D. Quinn, Martin E. Rickert, Caroline E. Weibull, Anna L. V. Johansson, Paul Lichtenstein, Catarina Almqvist, Henrik Larsson, Anastasia N. Iliadou, Brian M. D’Onofrio
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness. <h3>Objective</h3> To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs. <h3>Design, Setting, and Participants</h3> This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design. <h3>Exposures</h3> Maternal self-reported smoking during pregnancy, obtained from antenatal visits. <h3>Main Outcomes and Measures</h3> Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using<i>International Classification of Diseases</i>codes for bipolar disorder and schizophrenia spectrum disorders. <h3>Results</h3> Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses. <h3>Conclusions and Relevance</h3> This population- and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.
Nociceptive brain activity as a measure of analgesic efficacy in infants
Authors: Caroline Hartley, Eugene P. Duff, Gabrielle Green, Gabriela Schmidt Mellado, Alan Worley, Richard Rogers, Rebeccah Slater
Journal: Science Translational Medicine (2017)

A measure of nociceptive brain activity that can be used to assess analgesic efficacy in infants is derived and validated.
Bright Polymer Dots Tracking Stem Cell Engraftment and Migration to Injured Mouse Liver
Authors: Dandan Chen, Qiong Li, Zihui Meng, Lei Guo, Ying Tang, Zhihe Liu, Shengyan Yin, Weiping Qin, Zhen Yuan, Xuanjun Zhang, Changfeng Wu
Journal: Theranostics (2017)

Stem cell therapy holds promise for treatment of intractable diseases and injured organs. For clinical translation, it is pivotal to understand the homing, engraftment, and differentiation processes of stem cells in a living body. Here we report near-infrared (NIR) fluorescent semiconductor polymer dots (Pdots) for bright labeling and tracking of human mesenchymal stem cells (MSCs). The Pdots exhibit narrow-band emission at 775 nm with a quantum yield of 22%, among the highest value for various NIR probes. The Pdots together with a cell penetrating peptide are able to track stem cells over two weeks without disturbing their multipotent properties, as confirmed by the analyses on cell proliferation, differentiation, stem-cell markers, and immunophenotyping. The in vivo cell tracking was demonstrated in a liver-resection mouse model, which indicated that the Pdot-labeled MSCs after tail-vein transplantation were initially trapped in lung, gradually migrated to the injured liver, and then proliferated into cell clusters. Liver-function analysis and histological examination revealed that the inflammation induced by liver resection was apparently decreased after stem cell transplantation. With the bright labeling, superior biocompatibility, and long-term tracking performance, the Pdot probes are promising for stem cell research and regenerative medicine.
Clinical distuingishing characteristics and management of phyllodes tumors of the breast.
Authors: Mustafa Tukenmez, Cemil Burak Kulle, Mehmet Velidedeoglu, Orhan Agcaoglu, Gunes Parlakgul, Fatih Aydogan, Semen Onder, Atilla Bozdogan, Enver Ozkurt, Mahmut Muslumanoglu, Abdullah Igci, Ahmet Dinccag, Vahit Ozmen, Varol Celik, Hasan Karanlik, Emre Merdan Fayda, Fatma Sen, Adnan Aydiner, Neslihan Cabioglu
Journal: Journal of Clinical Oncology (2015)

e12060 Background: Phyllodes tumor of the breast is a rare fibroepithelial lesion. Appropriate surgical and oncological management remains a subject of debate. The aim of this study was to determine patient and tumor and outcome characteristics associated with borderline/malignant phylloides . Methods: Between January 1994 and October 2014, 102 patients diagnosed with phyllodes tumor, were retrospectively analyzed in terms of demographic and clinicopathologic features and outcome and treatment modalities. Results: The median age was 39 (range, 15-84). The histopathological analyses identified 54 benign (53%), 19 borderline (19%), and 29 malignant filloides tumors (28%). Of 102 patients, 86 (84%) underwent wide local excision whereas 16 patients (16%) had mastectomy. After definitive final surgery, 21 (23%) patients diagnosed with benign filloides had positive margins ( < 1mm), whereas the remaining 32 patients (35%) had close margins (1 mm-10 mm), whereas 38 patients (42%) had wide negative margins ( ≥ 10 mm). Among those with malignant phyllodes, 6 patients received both chemotherapy and chest wall irradiation followed by mastectomy (n = 4) or lumpectomy (n = 2) whereas one patient only had chemotherapy. Median follow-up time was 35 months (4-215). Of patients with benign phylloides, 2 patients with positive or close margins had local recurrences as malignant phylloides at 7th and 10th month, respectively. Patients with borderline/malignant phylloides were more likely to present with local recurrences (borderline/malignant:n = 8, 16.7% vs n = 2 3.7%; p = 0.043). Two patients with malignant phylloides presented with liver (at 12th month) or lung metastases (15th month). The 5-year disease free survival (DFS) of all patients was 82%. As expected, patients with borderline/malignant phylloides have shown significantly worse prognosis than patients with benign phylloides (5-year DFS: 67% vs 94.5%, p = 0.02). Conclusions: Margin negative surgery plays a major role in the management of patients diagnosed with phyllodes tumors including benign subtype. However, the survival benefit of adjuvant chemotherapy or radiation treatment warrants further investigation for patients presenting with malignant phylloides.
RIRS in the elderly: Is it feasible and safe?
Authors: F. Berardinelli, P. De Francesco, M. Marchioni, N. Cera, S. Proietti, D. Hennessey, O. Dalpiaz, C. Cracco, C. Scoffone, G. Giusti, L. Cindolo, L. Schips
Journal: International Journal of Surgery (2017)
Observational Study of Magnetic Resonance Imaging Monitoring in Patients with Aplastic Anemia (AA) and Low or Int-1 Risk of Myelodysplastic Syndromes(MDS) Complicated with Iron Overload
Authors: Yali Du, Bing Han, Zhangbiao Long, Miao Chen, Bo Hou, Feng Feng, Zhao Wang
Journal: Blood (2016)
Are Subpleural Consolidations on Lung Ultrasound Early Findings of Acute Chest Syndrome?
Authors: Stephanie G. Cohen, Zayir M Malik, Robert Hagbom, Samuel H Friedman, Stephen T Russell, Kenneth J Buchanan, Adina L Alazraki, Courtney E. McCracken, Olufolake Adisa, April G. Zmitrovich, Claudia R. Morris
Journal: Blood (2016)
The microbiota: an underestimated actor in radiation-induced lesions?
Authors: Harry Sokol, Timon Erik Adolph
Journal: Gut (2017)

The co-evolution of humans and microbes that colonise the GI tract is shaped by environmental factors and evolved to promote health.1 Microbial derangements (termed dysbiosis) have been observed for a variety of intestinal and extraintestinal diseases.1 Metabolic, autoimmune, liver and intestinal disorders have been linked to microbial dysbiosis which promotes susceptibility to inflammatory disease in some cases as largely assessed in animal models.2 Intestinal dysbiosis has also been implicated in colorectal cancer3 and microbes may determine treatment response for non-intestinal malignancies.4 

For more than 10 years, intestinal microbial alterations have been associated with localised radiation in humans and mouse models.5–8 Importantly, mice that lack colonisation of microbes (ie, raised germ free) were resistant to lethal radiation enteritis, indicating that the microbiota controls intestinal disease processes consequent to radiation-induced damage.9 In this context, however, the …
Tumor infiltrating lymphocytes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: A meta-analysis of published randomized clinical trials
Authors: C. Solinas, M. Ceppi, M. Lambertini, M. Scartozzi, S. Garaud, D. Fumagalli, E. De Azambuja, R. Salgado, K. Willard-Gallo, M. Ignatiadis
Journal: Annals of Oncology (2017)