tbuckley/cabot-search huggingface dataset:
Phase I study of sorafenib, pemetrexed, and cisplatin for the treatment of advanced solid tumors.
Authors: N. Fujioka, A. Dudek, M. N. Kirstein, P. Kumar
Journal: Journal of Clinical Oncology (2010)

e13055 Background: Cisplatin and pemetrexed is the standard first-line therapy for unresectable malignant mesothelioma but has reached a therapeutic plateau. Mesothelioma has been shown to highly overexpress VEGF and PDGF. Sorafenib is an oral multikinase inhibitor with activity against VEGFR and PDGFR. This trial was designed to determine the safety and maximum tolerated dose (MTD) of sorafenib in combination with cisplatin and pemetrexed. Methods: Eligible adult patients had advanced nonhematologic malignancy except squamous cell carcinoma of the lung, and had failed standard therapy. Patients with mesothelioma were eligible without prior therapy. Subjects received cisplatin 75mg/m2 IV and pemetrexed 500 mg/m2 IV on day 1 every 21 days. Subjects at dose level 1 were given sorafenib 200 mg po bid in addition to chemotherapy. Subjects at dose level 2 were given sorafenib 400 mg bid. A standard phase I dose- escalation scheme was used. Toxicity was assessed during the first cycle. Results: 13 patients were enrolled; 9 males and 4 females with a median age of 63 (range 49-74). Primary tumor type included prostate (2), urothelial (1), pancreas (1), SCLC (5), colorectal (2), mucoepidermoid (1), and bronchoalveolar NSCLC (1). Median number of cycles was 5 (range 1-12). Dose-limiting toxicity (DLT) at dose level 1 included grade 3 somnolence (1), grade 3 fatigue (3), grade 3 weakness (2), grade 3 hyponatremia (3), and grade 3 hypoalbuminemia (1). DLT at dose level 2 included grade 3 hyponatremia (1), grade 3 hypophosphatemia (1), grade 3 hyperlipasemia (1), and grade 4 pulmonary embolism (1). Best response was a partial response in 2 (1 urothelial, 1 SCLC), and stable disease in 8 (3 SCLC, 2 prostate, 2 colorectal, 1 bronchoalveolar, 1 mucoepidermoid). One subject with SCLC progressed after 2 cycles. Two subjects with stable disease remain on therapy after 5 and 8 cycles, respectively; the others progressed after a median of 5 cycles (range 4-6). Response was not evaluable in 2 subjects. Conclusions: Sorafenib 400 mg bid in combination with cisplatin and pemetrexed is safe and well tolerated. Enrollment of 3 subjects into the second dose group is ongoing, as is pharmacokinetic analysis of total and unbound sorafenib. No significant financial relationships to disclose.
Novel Evidence That Neuroblastoma and Rhabdomyosarcoma, Two Types of Small Round Blue Cell Tumors, Frequently Infiltrate Bone Marrow and Express Functional Erythropoietin Receptor (EpoR)—therapeutic Implications
Authors: Agata Poniewierska-Baran, Gabriela Schneider, Janina Ratajczak, Magdalena Kucia, Mariusz Z Ratajczak
Journal: Blood (2014)
Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma.
Authors: James Kochenderfer, Robert Somerville, Tangying Lu, Victoria Shi, James C. Yang, Richard Sherry, Christopher Klebanoff, Udai S. Kammula, Stephanie L. Goff, Adrian Bot, John Rossi, Marika Sherman, Arianne Perez, Allen Xue, Tatyana A. Feldman, Jonathan W. Friedberg, Mark J. Roschewski, Steven Feldman, Lori McIntyre, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2016)

LBA3010 Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with low-dose conditioning chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m 2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m 2 of cy on the same schedule. All patients received fludarabine 30 mg/m 2 daily for 3 days on the same days as cy. Patients received a single dose of CAR T cells 2 days after completion of chemotherapy. Blood CAR T cells and serum cytokines were analyzed in all patients. Results: Nineteen patients with various subtypes of diffuse large B-cell lymphoma (DLBCL) had the following responses: 8 CR, 5 PR, 2 SD, and 4 PD. One patient with mantle cell lymphoma obtained a CR. Two patients with follicular lymphoma both obtained CRs. Durations of response currently range from 1 to 20 months; 10 remissions are ongoing. All but 4 patients had either chemotherapy-refractory lymphoma or lymphoma that had relapsed after autologous stem cell transplant. The most prominent toxicities were various neurological toxicities. Other toxicities included fever and hypotension. The median peak blood CAR+ cell level was 47/μL (range 4-1217/μL). Patients obtaining CRs or PRs had higher peak blood CAR+ cell levels than patients experiencing SD or PD. The mean serum IL-15 level was 4 pg/mL before the conditioning chemotherapy and 32 pg/mL after chemotherapy (P &lt; 0.0001). Conclusions: Anti-CD19 CAR T cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemotherapy. In the near future, CAR T cells will likely be a standard therapy for lymphoma. Clinical trial information: NCT00924326.
Platelet-Activating Anti-Platelet Factor 4/Polyanion Antibodies without Preceding Heparin Therapy: A Transient Autoimmune Disorder Resembling Heparin-Induced Thrombocytopenia (“Spontaneous HIT”).
Authors: Theodore E. Warkentin, Richard M. Jay, Michael Makris, John G. Kelton
Journal: Blood (2006)
Characterization of Prostate Cancer in a Functional Eunuch
Authors: John J. Stocking, Michael V. Fiandalo, Elena A. Pop, John H. Wilton, Gissou Azabdaftari, James L. Mohler
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: Eunuchs rarely, if ever, develop prostate cancer (CaP). This article reports on a 62-year-old functional eunuch from prepubertal mumps orchitis who developed clinically localized CaP. Methods: Serum and CaP and benign prostate tissue androgen levels were measured using a validated liquid chromatography-tandem mass spectrometry assay. The assay measures testosterone; dihydrotestosterone (DHT); the adrenal androgens, androstenedione and dehydroepiandrosterone; and the androgen metabolites, androsterone and androstanedione. Gene and protein expression levels of androgen metabolism enzymes, and androgen receptor and androgen-regulated genes were measured using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry, respectively. Results: Intracrine androgen metabolism produced tissue DHT when serum and tissue testosterone levels were castrate and undetectable, respectively. Androgen receptor, androgen-regulated, and androgen metabolism enzyme genes were expressed but at lower levels in CaP than benign tissues. Conclusions: DHT was synthesized using the primary backdoor androgen metabolism pathway and not using androstenedione or dehydroepiandrosterone via the frontdoor or secondary backdoor pathways.
Asthma-COPD overlap syndrome (ACOS)<i>vs</i>‘pure’ COPD: a distinct phenotype?
Authors: D. Caillaud, P. Chanez, R. Escamilla, P-R. Burgel, I. Court-Fortune, P. Nesme-Meyer, G. Deslee, T. Perez, J-L. Paillasseur, C. Pinet, G. Jebrak, N. Roche
Journal: Allergy (2016)

Background Some studies suggest that asthma–COPD overlap syndrome (ACOS) is associated with worse outcomes than chronic obstructive pulmonary disease (COPD). The goal of this study was to further explore the clinical characteristics and survival of patients with ACOS identified in a real-life cohort of patients with COPD. Methods Data from the French COPD cohort 'INITIATIVES BronchoPneumopathie Chronique Obstructive' (n = 998 patients) were analyzed to assess the frequency of ACOS defined as a physician diagnosis of asthma before the age of 40 years and to analyze its impact. Univariate analyses were performed to assess the relationship between ACOS and sociodemographic characteristics, risk factors (smoking, occupational exposure, atopic diseases), symptoms (chronic bronchitis, dyspnea-modified Medical Research Council scale and baseline dyspnea index), quality of life (QoL), mood disorders, exacerbations, comorbidities, lung function, prescribed treatment, and survival. Results ACOS was diagnosed in 129 patients (13%). In multivariate analyses, ACOS was associated negatively with cumulative smoking (odds ratio [OR]: 0.992; 95% CI 0.984–1.000 per pack-year) and positively with obesity: OR: 1.97 [1.22–3.16], history of atopic disease (hay fever: OR: 5.50 [3.42–9.00] and atopic dermatitis: OR 3.76 [2.14–6.61]), and drug use (LABA + ICS: 1.86 [1.27–2.74], antileukotrienes 4.83 [1.63–14.34], theophylline: 2.46 [1.23–4.91], and oral corticosteroids: [2.99;.1.26–7.08]). No independent association was found with dyspnea, QoL, exacerbations, and mortality. Conclusions Compared to 'pure' COPD patients, patients with ACOS exhibit lower cumulative smoking, suffer more from obesity and atopic diseases, and use more asthma treatments. Disease severity (dyspnea, QoL, exacerbations, comorbidities) and prognosis (mortality) are not different from 'pure' COPD patients.
5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) as postoperative adjuvant chemotherapy (CT) for node-positive rectal cancer after radiochemotherapy (R-CT) and surgery.
Authors: H. Reinel, K. Schäßburger, D. Meyer, K. Pfändner, S. Kanzler
Journal: Journal of Clinical Oncology (2010)

e14125 Background: To evaluate the activity and safety of postoperative adjuvant CT of 8 cycles FOLFOX4 in patients with node-positive rectal cancer after neoadjuvant R-CT and surgery. Methods: We included 41 pts with preoperative node positive adenocarcinoma of the rectum (inferior margin within 12 cm from the anal verge) and no evidence of distant metastases (cT1-4 N+ M0) into this prospective single center study. The preoperative R-CT treatment consisted of 50.4 Gy (1.8 Gy per day, five days per week) and 5-fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg/m2 per day during the first and fifth week. Surgery (total mesorectal excision) was scheduled 4 to 6 weeks after the completion of R-CT. 4 to 6 weeks after surgery 8 cycles of FOLFOX4 were administered (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 per day 1 + 2 followed by 5-fluorouracil bolus of 400 mg/m2 and then 22 h infusion of 600 mg/m2 on day 1 + 2; repeated day 15). The main end points were feasibility and activity of postoperative CT with FOLFOX4. Results: From 5/2006 to 11/2008 a total of 41 pts with cT1-4 N+ M0 rectal cancer were included. Median age was 66 yrs (range 38-80). 7 of 41 pts (17%) did not receive postoperative FOLFOX4 therapy because of patient refusal (n = 3), contraindication to oxaliplatin (n = 1) or complications prior to start of FOLFOX4 (n = 3). 34 of 41 pts (83 %) received postoperative CT with FOLFOX4. Of these 34 pts 15 (44%) completed all 8 cycles FOLFOX4 with 100 % dose intensity. 15 pts (44%) received less than 100 % but more than 50 % of FOLFOX4 dose intensity. No grade 3 or 4 toxicities were observed. Grade 1 or 2 leucopenia occurred in 6 of 34 pts (18%), but no infection or febrile episode was observed. 1 of 34 pts (3%) experienced grade 2 and 15 of 34 pts (44%) grade 1 sensory neuropathy. Sensory neuropathy was the main cause of dose modification of oxaliplatin. After a median follow up of 26 months 3 of 34 pts (9%) had a cancer recurrence (local n = 1, local/distant n = 1, distant n = 1). Conclusions: Postoperative adjuvant CT with 8 cycles FOLFOX4 is a well tolerated and effective treatment for patients with node-positive rectal cancer after R-CT and surgery. No significant financial relationships to disclose.
Droplet Digital PCR for DNMT3A and IDH1/2 Mutations to Improve Early Diagnosis of Acute Myeloid Leukemia Relapse after Allogeneic HSCT
Authors: Chiara Brambati, Cristina Toffalori, Elisabetta Xue, Lara Crucitti, Raffaella Greco, Alessandra Crippa, Benedetta Mazzi, Cristina Tresoldi, Silvia Galbiati, Chiara Bonini, Jacopo Peccatori, Matteo G Carrabba, Massimo Bernardi, Maurizio Ferrari, Vito Lampasona, Fabio Ciceri, Luca Vago
Journal: Blood (2014)
Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study
Authors: Charles D. Resor, Ashwin Nathan, Dean J. Kereiakes, Robert W. Yeh, Joseph M. Massaro, Donald E. Cutlip, P. Gabriel Steg, Wen-Hua Hsieh, Laura Mauri
Journal: Circulation (2016)

Background: Continued dual antiplatelet therapy and optimal medical therapy (OMT) improve outcomes in selected patient populations with established coronary heart disease, but whether OMT modifies the treatment effect of dual antiplatelet therapy is unknown. Methods: The DAPT (Dual Antiplatelet Therapy) Study, a double-blind trial, randomly assigned 11 648 patients who had undergone coronary stenting and completed 1 year of dual antiplatelet therapy without major bleeding or ischemic events to an additional 18 months of continued thienopyridine or placebo. OMT was defined as a combination of statin, β-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in patients with an American College of Cardiology/American Heart Association class I indication for each medication. Per protocol, all patients were treated with 75 to 325 mg aspirin daily. End points included myocardial infarction, major adverse cardiovascular and cerebrovascular events, and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries moderate or severe bleeding events. Results: Of 11 643 randomly assigned patients with complete medication data, 63% were on OMT. Between 12 and 30 months, continued thienopyridine reduced myocardial infarction in comparison with placebo in both groups (on OMT 2.1% versus 3.3%, hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.48–0.86; P =0.003; off OMT 2.2% versus 5.2%, HR, 0.41; CI, 0.29–0.58; P &lt;0.001; interaction P =0.103). Comparing continued thienopyridine versus placebo, rates of major adverse cardiovascular and cerebrovascular events were 4.2% versus 5.0% among patients on OMT (HR, 0.82; CI, 0.66–1.02; P =0.077) and 4.5% versus 7.0% among those off OMT (HR, 0.63; CI, 0.49–0.82; P &lt;0.001; interaction P =0.250); rates of bleeding for thienopyridine versus placebo in patients on OMT were 2.2% versus 1.0% (HR, 2.13; CI, 1.43–3.17; P &lt;0.001), and in patients off OMT were 2.8% versus 2.2% (HR, 1.30; CI, 0.88–1.92; P =0.189; interaction P =0.073). Overall, patients on OMT had lower rates of myocardial infarction (2.7% versus 3.7%, P =0.003), major adverse cardiovascular and cerebrovascular events (4.6% versus 5.7%, P =0.007), and bleeding (1.6% versus 2.5%, P &lt;0.001) in comparison with patients off OMT. Rates of stent thrombosis (0.8% versus 1.0%, P =0.171) and death (1.6% versus 1.9%, P =0.155) did not differ. Conclusions: Continued thienopyridine therapy reduced the rate of myocardial infarction regardless of OMT status and had consistent effects on reduction in major adverse cardiovascular and cerebrovascular events and increased bleeding. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT00977938.
Use of intravenous tigecycline in patients with severe Clostridium difficile infection: a retrospective observational cohort study
Authors: B. Gergely Szabo, B. Kadar, K. Szidonia Lenart, B. Dezsenyi, P. Kunovszki, K. Fried, K. Kamotsay, R. Nikolova, G. Prinz
Journal: Clinical Microbiology and Infection (2016)
Cathepsin B Mediated Lysosomal Degradation in Macrophages Controls the Pharmacokinetics of the Therapeutic Protein Asparaginase
Authors: Laurens T Van Der Meer, Samantha YA Terry, Dorette van Ingen Schenau, Kiki Andree, Gerben M Franssen, Debbie Roeleveld, Bart Metselaar, Thomas Reinheckel, Peter M Hoogerbrugge, Otto C Boerman, Frank N van Leeuwen
Journal: Blood (2015)
An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis
Authors: Amy S. Paller, Yael Renert-Yuval, Maria Suprun, Hitokazu Esaki, Margeaux Oliva, Thy Nhat Huynh, Benjamin Ungar, Norma Kunjravia, Rivka Friedland, Xiangyu Peng, Xiuzhong Zheng, Yeriel D. Estrada, James G. Krueger, Keith A. Choate, Mayte Suárez-Fariñas, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2016)
A Korean patient with Guillain-Barré syndrome following acute hepatitis E whose cholestasis resolved with steroid therapy
Authors: Sung Bok Ji, Sang Soo Lee, Hee cheul Jung, Hong Jun Kim, Hyun Jin Kim, Tae Hyo Kim, Woon Tae Jung, Ok Jae Lee, Dae Hyun Song
Journal: Clinical and Molecular Hepatology (2016)

Autochthonous hepatitis E virus (HEV) is an emerging pathogen in developed countries, and several cases of acute HEV infection have been reported in South Korea. However, there have been no reports on HEV-associated Guillain-Barré syndrome (GBS) in Korea. We recently experienced the case of a 58-year-old Korean male with acute HEV infection after ingesting raw deer meat. Persistent cholestasis was resolved by the administration of prednisolone. At 2.5 months after the clinical presentation of HEV infection, the patient developed weakness of the lower limbs, and was diagnosed with GBS associated with acute hepatitis E. To our knowledge, this is the second report on supportive steroid therapy for persistent cholestasis due to hepatitis E, and the first report of GBS in a Korean patient with acute HEV infection.
Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip
Authors: Yu Shrike Zhang, Andrea Arneri, Simone Bersini, Su-Ryon Shin, Kai Zhu, Zahra Goli-Malekabadi, Julio Aleman, Cristina Colosi, Fabio Busignani, Valeria Dell'Erba, Colin Bishop, Thomas Shupe, Danilo Demarchi, Matteo Moretti, Marco Rasponi, Mehmet Remzi Dokmeci, Anthony Atala, Ali Khademhosseini
Journal: Biomaterials (2016)
The Need for Postdischarge, Patient-Centered Data in Trauma
Authors: Arturo J. Rios-Diaz, Jimmy Lam, Cheryl K. Zogg
Journal: JAMA Surgery (2016)

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SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents
Authors: Warren Fiskus, Veena Coothankandaswamy, Jianguang Chen, Hongwei Ma, Kyungsoo Ha, Dyana T. Saenz, Stephanie S. Krieger, Christopher P. Mill, Baohua Sun, Peng Huang, Jeffrey S. Mumm, Ari M. Melnick, Kapil N. Bhalla
Journal: Cancer Research (2016)

SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone. Elevated levels of SIRT2 sensitized breast cancer cells to intracellular DNA damage and cell death induced by oxidative stress, as associated with increased levels of nuclear FOXO3A and the proapoptotic BIM protein. In addition, elevated levels of SIRT2 sensitized breast cancer cells to arsenic trioxide, an approved therapeutic agent, along with other intracellular ROS-inducing agents. Conversely, antisense RNA-mediated attenuation of SIRT2 reversed ROS-induced toxicity as demonstrated in a zebrafish embryo model system. Collectively, our findings suggest that the tumor suppressor activity of SIRT2 requires its ability to restrict the antioxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity. Cancer Res; 76(18); 5467-78. ©2016 AACR.
G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling
Authors: Besnik Bajrami, Haiyan Zhu, Hyun-Jeong Kwak, Subhanjan Mondal, Qingming Hou, Guangfeng Geng, Kutay Karatepe, Yu C. Zhang, César Nombela-Arrieta, Shin-Young Park, Fabien Loison, Jiro Sakai, Yuanfu Xu, Leslie E. Silberstein, Hongbo R. Luo
Journal: The Journal of Experimental Medicine (2016)

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.
Case 12-1967
Authors: Perry J. Culver, Benjamin Castleman
Journal: New England Journal of Medicine (1967)

Presentation of CaseA seventy-seven-year-old woman was admitted to the hospital because of pain in the abdomen.Five months previously she had the onset of pain in the right upper quadrant of the abdomen that radiated to the back, accompanied by anorexia and episodes of belching and nausea. There was a loss of 25 pounds in weight. She complained of a sensation of fullness in the stomach and early satiety. There was no history of fever or chills, vomiting, alteration in bowel habits or change in the color of the urine or stools.For twenty-two years she had had diabetes . . .