tbuckley/cabot-search huggingface dataset:
Drug points: Thrombolysis and low back pain
Authors: D Fishwick, A Prasan, P Adams
Journal: BMJ (1995)

<h3>Introduction</h3> Smoking increases the risk of asthma and reduces lung function among subjects with and without asthma. We assessed the effects of smoking on lung function reflecting both central and small airways among adults with newly onset asthma. <h3>Methods</h3> In a population-based study, 521 (response rate 86%) working-aged adults with clinically defined newly diagnosed asthma answered a questionnaire on personal smoking and other factors potentially influencing lung function, and performed spirometry. We applied multiple linear regression analysis to estimate the relations between smoking and lung function adjusting for confounding. <h3>Results</h3> Among asthmatics, FEV<sub>1</sub> level was reduced significantly, on average 208 mL, related to regular smoking (adjusted effect estimate −0.208, 95% CI −0.355 to −0.061) and 245 mL in relation to former smoking, that is, among those who quit less than a year ago (−0.245, 95% CI −0.485 to −0.004). In contrast, FEV<sub>1</sub> was not significantly related to occasional smoking or former smoking among those who quit over a year ago. Forced expiratory flow (FEF) levels (L/s) were also significantly reduced among regular smokers (FEF<sub>25–75%</sub>: −0.372, 95% CI −0.607 to −0.137; FEF<sub>50%</sub>: −0.476, 95% CI −0.750 to −0.202). An exposure–response pattern related to both daily smoking rate and lifetime cumulative smoking was seen both among men and women. <h3>Conclusions</h3> This study provides new evidence that among working-aged adults with new asthma, regular smoking and former smoking reduce lung function levels with a dose–response pattern. The lung function parameters applied as outcomes reflect both larger and smaller airways.
EFICACIA DEL PLASMA RICO EN PLAQUETAS EN DOS MODELOS EXPERIMENTALES (RATA Y CERDO) CON RESECCIÓN MUCOSA ENDOSCÓPICA
Authors: V Lorenzo-Zúñiga García, R Bartoli, V Moreno De Vega, J Boix
Journal: Endoscopy (2015)

Introducción: El plasma rico en plaquetas (PRP) es un concentrado autólogo con una concentración de plaquetas 3 – 5 veces superior al valor normal. Las plaquetas también juegan un papel muy importante en la reparación y regeneración de diferentes tejidos.
Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety.
Authors: Sagar Lonial, Sundar Jagannath, Philippe Moreau, Andrzej J. Jakubowiak, Marc S. Raab, Thierry Facon, Ravi Vij, Eric Bleickardt, Donna Ellen Reece, Lotfi Benboubker, Jeffrey A. Zonder, Wei Deng, Anil K. Singhal, Paul Gerard Guy Richardson
Journal: Journal of Clinical Oncology (2013)

8542 Background: Elotuzumab (Elo) is a humanized anti-CS1monoclonal antibody that enhances natural killer cell mediated antibody dependent cellular cytotoxicity of CS1 expressing myeloma cells. This study included a dose finding Ph I cohort (N=28) and a Ph II cohort (N=73). Here we update Ph II data and provide long term safety data from both cohorts. Methods: Patients (pts) treated with ≥1 (Ph I) or 1–3 (Ph II) prior therapies received Elo + Len/dex as described previously (Lonial JCO 2012; Richardson ASH 2012) until disease progression, unacceptable toxicity, or death. All pts received a premedication regimen including methylprednisolone, diphenhydramine or equivalent, ranitidine or equivalent, and acetaminophen to mitigate infusion reactions. Adverse events (AEs) in Ph I/II pts occurring ≤18 months (mo) (N=98) were compared to AEs with a &gt;18 mo onset in a subgroup of pts treated &gt;18 mo (n=49). This safety analysis excluded 3 Ph I pts treated with Elo 5 mg/kg. Results: In the Ph II cohort (median 63 yr), objective response rate (ORR) was 84%; 92% with 10 mg/kg (n=36) and 76% with 20 mg/kg (n=37). At a median follow-up of 20.8 mo, median progression free survival (PFS) was not reached (10 mg/kg) and 18.6 mo (20 mg/kg). Most common treatment emergent grade ≥3 AEs were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%) and anemia (14%). Most common grade 3/4 AEs emerging ≤18 vs &gt;18 mo in Ph I/II cohorts are shown (Table). 15 pts discontinued due to AEs; none after 18 mo of treatment. There were 4 second primary malignancies; none were reported after 18 mo. Conclusions: Elo 10 mg/kg + Len/dex was generally well tolerated and resulted in a high ORR and encouraging PFS in pts with RR MM. AEs emergent after 18 mo of therapy were consistent with AEs during the initial 18 mo. Updated Ph II safety/efficacy data and long term safety data from Ph I/II cohorts will be presented.
Clinical and histologic characterization of dermatologic adverse events from the pan-PI3K inhibitor buparlisib (BKM-120).
Authors: Katja Schindler, Ronnie Abraham, Payal Deepak Shah, Sarat Chandarlapaty, Paul K. Paik, Katherine Bell-McGuinn, Dean F. Bajorin, Ingo K. Mellinghoff, Anas Younes, Mrinal M. Gounder, Matthew G. Fury, Klaus J. Busam, Maura N. Dickler, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2014)

e20639 Background: Agents that block specific or all isoforms of phosphatidylinositol 3-kinase (PI3K) are being investigated in a variety of solid and hematologic tumors. A class effect appears to be the development of dermatologic (derm) events, most notably rash. To date, the incidence and clinical characteristics of rash with PI3K inhibitors (PI3Ki) have not been characterized. Methods: We analyzed a total of 103 patients (pts) treated with buparlisib as single agent or in combination with cytotoxic or targeted therapy, between 2011 and 2013 in 7 phase I/II trials. Data for incidence, grade (CTCAE v4.0), clinical type, histology, and outcome from treatment for rash was included. Results: Of 91 pts in trials investigating buparlisib as single agent or in combination with paclitaxel, 29 (32%) developed derm AEs, 23 (79%) were maculopapular rash and 6 (21%) were acneiform rash, the latter only occurring in pts receiving either paclitaxel and/or steroids. None of the treated lymphoma pts developed rash. Derm AEs were mostly grade 1 (52%) and 2 (34%). Only 4/29 events (14%) were grade 3. In 12 pts treated with BKM-120 plus a MEKi, 10 (83%) developed a rash, which was acneiform (n= 8, 62%) and/or maculopapular (n= 5, 38%). Of these, 23% were grade 1, 69% grade 2 and 8% grade 3 (n=1). Of all 39 pts with a rash, 29 (74%) were treated with topical steroids, 8 (21%) with short-term systemic steroids and 14 (36%) with oral antihistamines. Self-reported allergies were not associated with a higher incidence of rash. Of pts with grade 3 rash, dose reduction was needed in 3, discontinuation in 2 pts (8% and 5% of all pts with rash, respectively). Skin biopsies were obtained from 10 pts with rash. All samples showed a non-specific pattern, with perivascular infiltrate and/or eosinophils and interface dermatitis. Conclusions: This analysis reveals that a subset of pts treated with buparlisib develop a maculopapular rash, mostly grade 1/2 in severity. The clinical presentation of rash to buparlisib differs from that previously reported for EGFR, mTOR, and RAF inhibitors. Management with topical and/or oral corticosteroids and antihistamines allowed for continued dosing in the majority of pts.
Prospective clinical phase-II trial on docetaxel and estramustine with or without epoeitin-α in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Axel Heidenreich, Kurt Miller, Ursula Steiner, Martin Schostak
Journal: Journal of Clinical Oncology (2015)

e16064 Background: Docetaxel (DOC) and estramustine phosphate (EMP) have shown to exert a survival benefit in mCRPC. Anemia is one of the significant side effects associated the DOC with negative effect on progression and survival. We evaluated the effect of epoeitin-a on overall survival, quality of life and hematoxicity ≥ grade 3. Methods: 139 pts with mCRPC were randomized to DOC at 35 mg/m2 on days 2, 9, 16 of a 4-week cycle repeated 3 times. EMP was given at 140 mg TID on days 1,2,3, 8,9,10 and 15,16 17. In group A EPO was administered at a dose of 40.000 IE/week at a hemoglobin level < 10.5 g/dl and it was continued until an upper level of 13.0 g/dl; in group B anemia was treated with best supportive care. Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival, anemia ≥ 3, quality of life and treatment-associated toxicity according to NCI-CTC. Results: 75 and 64 pts were enrolled in group A and B, resp. Median age was 64.3 and 64.9 years in group A and B, resp. Mean follow-up was 30.9 and 47.3 months in group A and B, resp. Mean treatment duration was 25.5 vs 41.3 weeks in group A and B (p = 0.004), mean number of treatment sequences was 1.57 vs 2.19 (p = 0.01); mean total dose of DOC was significantly higher in group A vs B (p = 0.005). We identified significant differences in HB-levels < 10 g/dl at the end of DOC between group A and B (9.1% vs 24.6%, p = 0.024), frequency of red blood cell transfusions (p = 0.026), development of grade 3/4 toxicities (2.1% vs 3.7%, p = 0.009) which comprised leukopenia (p = 0.036) and thrombocytopenia (p = 0.030) to a similar extent. PFS after sequence1 and 2 was significantly different in group A vs B (p = 0.012 and p = 0.06, resp). Median OS was longer in group A with a trend to significance (13.7 vs 10.8 months, p = 0.06), whereas overall survival rate was significantly higher (62.5% vs 29.3%, p < 0.001). Conclusions: Supportive treatment with EPO results in significantly reduced frequencies of TAE, significant improvement of OS and PFS which was a true effect of elevated HB-levels during treatment. Supportive treatment with EPO seems reasonable in pts experiencing significant anemia during DOC-therapy. Clinical trial information: AUO-AP/33/02.
Activity of RX-3117, an oral antimetabolite nucleoside, in patients with pancreatic cancer: Preliminary results of stage 1 of the phase 1a/2b.
Authors: Drew W. Rasco, Christine Peterson, Ely Benaim, Jaime R. Merchan
Journal: Journal of Clinical Oncology (2017)

445 Background: RX-3117 is an oral smallmolecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 1 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 1 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage Simon design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% (2 out of 10 subjects) rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% (1 of 10 subjects) with a partial response rate or better. Results: As of Sep 2016, 8 out of 10 subjects have been enrolled (4 females, 4 males), the mean age was 70 years, ECOG performance status was 1 and 5 subjects had received more than 4 prior therapies. Two subjects met the primary endpoint of stable disease with a duration of 140-168 days at the time of this submission. The most frequent adverse events were moderate to severe anemia, mild to moderate fatigue, abdominal pain and diarrhea. Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. As the primary endpoint has been achieved, the study will now move to stage 2 where an additional 40 subjects with advanced pancreatic cancer will be enrolled. Clinical trial information: NCT02030067.
A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic (P) and colorectal (CR) cancers.
Authors: Michael Morse, Sandip Pravin Patel, Melony A. Beatson, Philip M. Arlen
Journal: Journal of Clinical Oncology (2013)

3070 Background: NPC-1C is a chimeric mab developed to treat P and CR cancers. This mab was selected from a panel of hybridomas derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC expressed specifically by human P and CR tumors with minimal cross-reactivity to normal GI mucosa. Methods: A phase IIa study with NPC-1C is enrolling patients (pts) with advanced P and CR cancer refractory to standard therapy. Primary objectives are to measure efficacy by analysis of CT scans pre- and post-therapy, clinical lab tests, and physical examinations. Secondary objectives are to determine safety, pharmacokinetics (PK), and select immune responses to the mab. Analyses of pts peripheral blood mononuclear cells (PBMCs) for antibody-dependent cell-mediated cytotoxicity (ADCC) and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome and correlation with clinical benefit. Results: Pts received 1.5 mg/kg IV of NPC-1C every two weeks. 10 subjects (8 colorectal, 2 pancreatic) have enrolled on study (2/10 non-evaluable). Treatment was well tolerated with grade 1 and 2 constitutional symptoms noted. Coombs positivity was reported in 4/8 pts shortly after the infusions, but only grade 1 hemolysis was reported (in 2/8 patients). There was 1 episode of each of the following grade 3 AE’s: weakness, increased bilirubin, and abdominal pain, possibly related to NPC-1C. 5 of 19 pts treated in this and the phase Ia study demonstrated stable disease (SD) on scans after completing the first course of treatment (4 doses). Conclusions: Preliminary results with NPC-1C show signs of clinical activity based on SD in heavily pretreated pts with P and CR cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy. Clinical trial information: NCT01040000.
Mesothelin as a marker of response in malignant pleural mesothelioma
Authors: P. Wheatley-Price, B. Yang, D. Patel, C. Ma, W. Xu, N. Leighl, R. Feld, B. Cho, M. De Perrot, G. Liu
Journal: Journal of Clinical Oncology (2009)

7581 Background: Malignant pleural mesothelioma (MPM) is a rare malignancy related to asbestos exposure. Radiological assessment of disease status and treatment response using RECIST criteria is often difficult, therefore blood markers of disease burden may be useful adjunctively. Soluble mesothelin related peptide (sMRP) can distinguish between MPM and benign pleural disease. We performed an exploratory analysis to determine whether sMRP correlates with MPM disease course. Methods: From December 2006 to August 2008 blood samples were collected from MPM patients during clinic visits. Plasma sMRP levels were measured using the MESOMARK assay (Fujirebio diagnostics). Changes in sMRP levels were compared with corresponding radiological tests, scored as progression, stable or disease shrinkage. Results: From 41 patients, 165 samples were collected (median 4/patient; range 2–10). At study entry 34/37 (92%) patients with measurable disease had elevated sMRP (&gt;9ng/ml, range 14–60). In 22 patients receiving chemotherapy or biologic therapy, relative (Fisher's exact test, p=3.2x10–6) and absolute (p=2.6x10–5) changes in sMRP correlated with radiological assessment (Table). All 4 post-surgery surveillance patients, with no evidence of recurrence, had normal sMRP levels (1.8–4.9). Of 8 patients who underwent surgical resection, 7 had elevated pre-operative sMRP that fell to normal post-operatively (Wilcoxon rank (WR) p=0.02). Absolute sMRP rose in all patients with radiological progression (systemic therapy, n=9, WR p=0.004; supportive care, n=10, WR p=0.02). Conclusions: sMRP levels not only correlate with surgical debulking but we report, for the first time, that they also correlate with treatment response and radiological progression in MPM patients undergoing systemic therapy or supportive care. sMRP may be a clinically useful biomarker in MPM clinical trials and in patient management. These findings should be validated prospectively. [Table: see text] [Table: see text]
CD96 antibody TH-111 for detection of AML leukemic stem cells, and purging of autografts for stem cell transplantation.
Authors: Matthias Staudinger, Christian Kellner, Matthias Peipp, Natalie Schub, Andreas Humpe, Martin Gramatzki
Journal: Journal of Clinical Oncology (2014)

7090 Background: High relapse rates observed in AML patients after autologous stem cell transplantation may be due to residual leukemic stem cells (LSC) in the graft. Therefore, elimination of LSC by targeted therapy represents a promising therapeutic option. Here, strategies are described addressing CD96 - a marker antigen recently identified on AML LSC - for engineering autologous stem cell grafts by magnetic cell sorting (MACS). Moreover, attempts to improve antibody-dependent killing (ADCC) of LSC may allow therapeutic use in other situations. Methods: Biotinylated CD96 antibody TH111 raised in our laboratory was used for MACS separation of AML-LSC. Healthy hematopoietic progenitor cells (HPC) viability, their differentiation properties and the efficiency of depletion were analyzed by colony forming assays and flow cytometry. Chimeric ADCC-optimized CD96 antibodies were analyzed for purity by SDS page and specific binding by flow cytometry. Antibody-mediated effector functions were measured in 51Cr-release assays. Results: To determine the efficiency of antibody mediated LSC purging, stem cell containing grafts were spiked with AML cells. Using biotinylated CD96 antibody up to a 1000-fold depletion of targeted cells was achieved. Viability of healthy HPC as well as their potential to proliferate and differentiate were not affected. To recruit NK cells for lysis of CD96+ AML-LSC by ADCC, chimeric antibodies containing wild type or affinity maturated variable regions in combination with an ADCC optimized human IgG1Fc were generated. Due to a higher antigen binding affinity of the maturated antibody (EC50 of 0.6 µg/ml vs. 2 µg/ml), the NK cell mediated lytic properties against CD96-positive target cells were elevated (EC50: 0.02 µg/ml vs. 0.15 µg/ml; E:T ratio 2.5:1). Conclusions: The efficient elimination of AML-LSC by MACS may be beneficial for the development of graft-engineering strategies to avoid transplantation of AML-LSC and revitalize autologous stem cell transplantation in this indication. The in vivo application may possibly open additional therapeutic avenues in eliminating residual disease in autologous as well as allogeneic situations.
Letter to the Editor, Re: Cadier et al. (2017)
Authors: Chibuzo Iloabuchi, Amanda Stover, Pragya Rai, Yifan Zhang, Khalid M. Kamal
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Kamal received grants from Novartis and Johnson & Johnson. TO THE EDITOR: 1 The article by Cadier et al.1 used Markov modeling to establish cost‐effectiveness of gold‐standard testing in hepatocellular carcinoma (HCC) compared to the standard of care in the French and U.S. health care systems. However, we noted some inconsistencies in the presented data. First, the authors stated that the base year for the cost was 2015, but the costs were reported as 2013 U.S. dollars with a 4% discount rate. Also, because the French data were taken from a 2012 claims database and the U.S. data from 2010‐2016 costs, it is not clear how the costs were adjusted or what the adjustment year is. Second, the authors matched unit costs for surveillance and procedures from the Medicare prospective payment system (PPS). The starting age of patients in the model was 55 years, which is not eligible for Medicare enrollment (≥65 years) in the United States, indicating that the cost data did not adequately reflect the modeled population. There was also no mention of the year of the Medicare hospital outpatient PPS data. The Centers for Medicare & Medicaid Services publishes corrected PPS rates annually; hence, more detailed information about time frame and discounting/inflation methods would have provided more clarity. Third, regarding data input, a search of Medicare part B coverage for diagnostic tests revealed that Medicare does not cover regular screening tests for HCC, raising questions on the justification of such costs for screening tests associated with HCC detection.3 Furthermore, the transplant costs reported for the United States ($137,000) conflict with the referenced data ($278,765).4 Fourth, the authors conducted two analyses—one for the French and the other for the U.S. health care system—stating that the clinical practice guidelines in France was in line with guidelines from the United States. However, we found that the guidelines differ from country to country.(4) Hence, the analysis should have been presented separately for the two countries. Finally, the article stated that the hypothetical model cohort was demographically (age and sex) representative of the target population; however, the authors did not clarify whether the target populations in both countries were equivalent. This is important because the transition probabilities in the simulation model were based on French cohorts alone. Thus, it is questionable to directly apply them to the U.S. population given a totally different health care system, different treatment guidelines, and standard of care. Whereas the study model was well thought out overall, it seems this article would have been better served focusing on either French or a U.S. cohort, not both.
Integrative Genetic and Clinical Analysis through Whole Exome Sequencing in 1001 Diffuse Large B Cell Lymphoma (DLBCL) Patients Reveals Novel Disease Drivers and Risk Groups
Authors: Jenny Zhang, Anupama Reddy, Cassandra Love, Andrea B. Moffitt, Deepthi Rajagopalan, Sirpa Leppä, Annika Pasanen, Leo Meriranta, Marja-Liisa Karjalainen-Lindsberg, Peter H Norgaard, Mette Pederson, Anne Ortved Gang, Estrid Hogdall, Kristy L. Richards, Yuri D. Fedoriw, Leon Bernal-Mizrachi, Jean L. Koff, Ashley D. Staton, Christopher Flowers, Ora Paltiel-Clarfield, Neta Goldschmidt, Maria Calaminici, Andrew James Clear, John Gribben, Evelyn Nguyen, Magdalena Czader, Sarah Lynn Ondrejka, Angela Collie, Eric D Hsi, Rex au-Yeung, Kwong Yok-Lam, Wai Lap Choi, Gopesh Srivastava, Andrew M Evens, Monika Pilichowska, Manju Sengar, Nishitha Reddy, Shaoying Li, Elaine S. Jaffe, Tiffany Tzeng, Jyotishka Datta, David Dunson, Sandeep Dave
Journal: Blood (2016)