tbuckley/cabot-search huggingface dataset:
A randomized phase II study of pemetrexed versus pemetrexed plus erlotinib in second-line treatment for locally advanced or metastatic, nonsquamous NSCLC.
Authors: J. Von Pawel, Z. Papai-Szekely, N. Vinolas, C. Sederholm, M. Klima, D. Desaiah, M. I. Leschinger, C. Dittrich
Journal: Journal of Clinical Oncology (2011)

7526 Background: PEM and ERL have been approved as second-line monotherapy for locally advanced or metastatic NSCLC. The combination of PEM + ERL showed synergistic activity in preclinical studies. This multicenter, randomized, open-label study assessed the efficacy and safety of PEM + ERL vs PEM. Methods: Patients (pts) with NSQ NSCLC who have failed one prior platinum-based chemotherapy regimen for advanced or metastatic disease, ≥1 measurable lesion by RECIST, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 were eligible. Pts received PEM 500 mg/m2 (with vitamin B12 and folic acid supplementation) q3w alone or combined with ERL 150 mg daily until progression. The primary endpoint of progression-free survival (PFS) was analyzed using the log-rank test with one-sided alpha of 0.20. Results: Of 165 pts with NSQ NSCLC who were randomized (PEM: 86; PEM + ERL: 79), 159 were treated (PEM: 83 and PEM + ERL: 76). The baseline characteristics for PEM/PEM + ERL were: median age of 61/64 yrs, stage IV disease in 84.3%/84.2%, and ECOG PS 2 in 13.3%/12.0% of pts. The median PFS (months) was 2.9 [95% CI: 1.9, 3.4] in PEM versus 3.2 [95% CI: 2.9, 4.7] in PEM + ERL (hazard ratio [HR] 0.63; 95% CI: 0.44, 0.90; log-rank P=0.005). The median overall survival (OS; months) was 7.8 [95% CI: 5.3, 10.4] in PEM versus 11.8 [95% CI: 8.2, 16.7] in PEM + ERL (HR 0.68; 95% CI: 0.47, 0.98; log-rank P=0.019). Response rates were 10.8% in PEM and 17.1% in PEM + ERL; disease-control rates were 51.8% in PEM and 55.3% in PEM + ERL. Two pts died in PEM + ERL due to drug-related lung abscess and febrile neutropenia. Study drug-related grade (G) 3 + 4 laboratory toxicities (in ≥10% of pts) in PEM/PEM + ERL were anemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). G 3 + 4 non-laboratory drug-related toxicities (in ≥5% of pts) in PEM/PEM + ERL were rash (1.2%/9.2%), diarrhea (1.2%/5.3%), and febrile neutropenia (2.4%/10.5%). Conclusions: PEM + ERL significantly improved PFS and OS compared with PEM, and was well tolerated. The benefit of this combination therapy should be confirmed in a phase III study.
Purinergic Stimulation of Human Bone Marrow-Derived Mesenchymal Stem Cells Modulate Their Function and Differentiation Potential.
Authors: Marilena Ciciarello, Valentina Salvestrini, Davide Ferrari, Sara Gulinelli, Roberta Zini, Rossella Manfredini, Luisa Caione, Wanda Piacibello, Giovanna Lucchetti, Lara Rossi, Sergio Ferrari, Francesco Di Virgilio, Roberto M. Lemoli
Journal: Blood (2010)
Approach to hypersensitivity reactions from intravenous iron preparations
Authors: C. A. Morales Mateluna, K. Scherer Hofmeier, A. J. Bircher
Journal: Allergy (2016)

Hypersensitivity reactions (HSRs) to intravenous iron preparations (IVIPs) are well known. With newer preparations, HSRs have become rarer; however, severe reactions may still occur. We retrospectively reviewed records of patients evaluated for HSRs to IVIPs, to determine the safety of controlled re-administration (CRA). Allergological work-up included a detailed history, skin prick tests (SPTs) with IVIP, and basophil activation tests (BATs) in some patients. CRA with an IVIP was carried out if indicated. Thirty-one patients with mild to severe reactions were evaluated. SPTs and BATs were negative in all patients tested. Eighteen CRAs in 15 patients were performed. Twelve patients tolerated the procedure, including three with a previous grade IV HSR. Two developed urticaria and one developed urticaria and dyspnea. The pathophysiology of HSRs to IVIPs remains currently unclear. SPTs and BATs provided no additional information. However, in appropriate situations, CRA under surveillance can be safely performed in most patients.
Repeat <i>Clostridium difficile</i> Testing
Authors: Arjun Gupta, Sahil Khanna
Journal: JAMA (2016)

A 28-year-old man develops abdominal discomfort and frequent bowel movements with a positive PCR test for Clostridium difficile toxin 6 weeks after treatment with metronidazole for C difficile infection. What would you do next?
Preventing Syphilis in the 20th Century—The Metchnikoff Pomade
Authors: Marianna Karamanou, Stylianos Chatzipanagiotou, Chrysoula Nikolaou
Journal: JAMA Dermatology (2016)

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P135 Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review
Authors: RG Edgar, M Patel, S Bayliss, E Sapey, AM Turner
Journal: Thorax (2016)

<h3>Introduction</h3> Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition predisposing individuals to COPD. The majority of treatment for AATD is similar to non-AATD related COPD; intravenous augmentation of Alpha-1 Antitrypsin is a specific treatment but is inequitably used across Europe and not used in the UK. There is a pressing need to systematically investigate efficacy since the publication of a new placebo controlled RCT and to identify patient centred, clinically meaningful outcomes.<sup>1</sup> <h3>Methods</h3> A systematic review was conducted using standard review methodology with meta-analysis and narrative synthesis (registered with PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. RCT’s were the primary focus however case series and uncontrolled studies (n &gt; 10 patients receiving treatment or usual care, with baseline and follow-up data &gt;3 months), were eligible for inclusion to ensure natural history of disease outside RCT’s could be determined. <h3>Results</h3> 7296 unique records were reviewed with 51 trials analysed on 5632 participants: 26 AAT-augmentation (3 for meta-analysis); 17 surgical intervention (5 Lung volume reduction (LVR) surgery, 1 Bronchoscopic valve LVR and 11 Lung transplantation); 3 medical interventions and 3 trials completed but not published. Meta-analysis of AAT-Augmentation demonstrated slower lung CT density decline, difference 0.79 g/l/year (95% CI: 0.29–1.29; p = 0.002), and a small increase in annual exacerbations 0.29/year (95% CI: 0.04–0.54; p = 0.02) compared to placebo (Figure 1). Survival benefit of transplant was observed in one study (p = 0.006) but not in a second with more stringent matching for groups; however significant improvements in health status, total SGRQ and all domain scores, at one year (p &lt; 0.01) were observed. Mortality post lung transplant was comparable between AATD and non-AATD related COPD cohorts. Surgical lung volume reduction demonstrated inferior outcomes when compared to non-AATD related emphysema. <h3>Conclusion</h3> CT density, FEV1, DLCO, health status and exacerbation rates were frequently used as outcomes in AATD related treatment trials. AAT-Augmentation is able to slow the progression of severity of emphysema when measured by CT density change compared to placebo. This systematic review will help assist in the improved monitoring and management of patients with AATD. <h3>Reference</h3> 1 Chapman KR, <i>et al</i>. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. <i>The Lancet</i> 2015;<b>386</b>(9991):360–368.
Selective Depletion of Alloreactive Donor T Cells with Adenosine: An Efficient, Scaleable, GMP-Compliant, Low-Cost Method to Prevent Gvhd While Preserving Antiviral and Antileukemic Activity in Haploidentical Stem Cell Transplant
Authors: Greg Whitehill, Shoba Amarnath, Keyvan Keyvanfar, Pawel Muranski, Minoo Battiwalla, Austin John Barrett, Dhana Chinnasamy
Journal: Blood (2015)
Response by Link et al to Letter Regarding Article, “Ablation of Atrial Fibrillation: Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation”
Authors: Mark S. Link, Michel Haïssaguerre, Andrea Natale
Journal: Circulation (2016)

In Response: Dr Maesen and fellow authors comment that our article on atrial fibrillation (AF) focuses mainly on catheter ablation of AF. 1 Our article on AF ablation did not cover solely ablative techniques but rather the comprehensive care of patients around the time of AF ablation, including patient selection, anticoagulation, techniques, and preventive measures after ablation.Our target audience was cardiologists, not electrophysiologists.The authors are correct in their observation of our discussion of ablative techniques.Far more data exist on catheter ablation than on surgical ablation.In addition, there are more surgical ablation data on concomitant ablation than on standalone surgical ablation.The data on concomitant surgical ablation are compelling.Most if not all randomized, controlled trials have shown higher long-term sinus rates in those with concomitant AF ablation.Thus, surgical AF ablation when the patient is undergoing another cardiac surgery is a Class IIa indication in both the European and US guidelines. 2,3he data for stand-alone surgical AF ablation are limited.In the FAST trial [Ablation or Surgery for Atrial Fibrillation (AF) Treatment], referenced in our article, of 124 patients with drug-refractory AF, left atrial dilation, and hypertension (n=42) or failed catheter ablation (n=82), extensive catheter ablation was compared with a video-assisted thoroscopy with pulmonary vein isolation and various other additional ablation lines, along with left atrial appendage removal.Surgical patients had an improved 12-month end point of freedom of AF. 4 Subgroup analysis showed that patients with paroxysmal AF and prior failed ablation were most likely to benefit from surgery.However, serious complications were more common in the surgical group.In the meta-analysis of Phan et al 5 that included 2 additional randomized, controlled trials and 5 retrospective observational studies, patients undergoing videoassisted surgery had lower rates of recurrent AF compared with patients undergoing catheter ablation but with a significantly higher risk of major complications.With these and other data, stand-alone surgical ablation of AF is a Class IIb recommendation in both the US and European guidelines. 2,3e agree that ablation science is emerging for both catheter and surgical ablation.In particular, improvements in surgical outcomes and combined endocardial and epicardial approaches may play an increasing role, especially for those patients with persistent AF or those with failed catheter ablation.AF ablation has evolved tremendously since 1998 but still is in its adolescence.We await and are excited for the continued evolution of the field.
Telomere Length of Hematopoietic Cells in Long-Term Post-Autograft Survivors: No Evidence of Accelerated Replicative Cell Senescence Despite the Persistent Reduction of Both Committed and Immature Progenitor Cell Compartments.
Authors: Alberto Rocci, Irene Ricca, Chiara Della Casa, Paolo Longoni, Mara Compagno, Maurizio Battistelli, Roberto Francese, Federica De Marco, Daniele Caracciolo, Mario Boccadoro, Dario Ferrero, Marco Ladetto, Carmelo Carlo-Stella, Corrado Tarella
Journal: Blood (2004)
Serum Soluble LR11 As a Novel Biomarker for B Cell Lymphoma
Authors: Takeharu Kawaguchi, Chikako Ohwada, Morihiro Higashi, Masahiro Takeuchi, Shio Sakai, Yusuke Takeda, Naomi Shimizu, Emiko Sakaida, Kohei Takubo, Hiroyuki Ebinuma, Isamu Fukamachi, Jun-Ichi Tamaru, Koutaro Yokote, Hideaki Bujo, Chiaki Nakaseko
Journal: Blood (2011)
Optimization of Ex Vivo Gamma Delta T (GDT) Cell Expansion from Patients with Solid Tumor.
Authors: Jacqueline S. Morley, Qiao Wang, Hang-Fai So, Stephen R. Mattarollo, Tomomi Hagi, Hirotake Tokuyama, Vy Truong, Mie Nieda, Kiyoshi Yokokawa, Andrew Nicol
Journal: Blood (2006)
Replacement Therapy with Imiglucerase Improves Magnetic Resonance Imaging (MRI) Abnormalities in Almost Half Patients with Non-Neuronopathic Form of Gaucher Disease After Twelve Months of Therapy: Results of a Semi-Quantitative MRI Method.
Authors: Veroniki Komninaka, Dionysia Kolomodi, Theodore Marinakis, Konstantina Repa, Dimitrios Christoulas, Ersi Voskaridou, Meletios A Dimopoulos, Evangelos Terpos
Journal: Blood (2012)
Lenalidomide and dexamethasone (LEN plus DEX) treatment in relapsed/refractory multiple myeloma (RRMM) patients (pts) and risk of second primary malignancies (SPM): Analysis of MM-009/010.
Authors: M. A. Dimopoulos, R. Z. Orlowski, R. Niesvizky, S. Lonial, N. A. Brandenburg, D. M. Weber
Journal: Journal of Clinical Oncology (2011)

8009
Abstract 1094: Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets
Authors: Amit Mandal, Maria Romina Girotti, Amaya Viros, Gabriela Gremel, Elena Galvani, Rebecca Lee, Kok Haw Jonathan Lim, Simon J. Furney, Paul Lorigan, Richard Marais
Journal: Cancer Research (2015)

Abstract In cutaneous melanoma, the most lethal form of skin cancer, BRAF is mutated in ∼45% of cases and NRAS in a further ∼20% of cases. The lack of known drivers in the remaining proportion of samples represents a challenge for personalized medicine. We hypothesize that the BRAF/NRAS double wild-type (WT) samples are a heterogeneous group driven by multiple events that arise independently. We performed whole exome sequencing (WES) and complimentary RNA-seq of 23 tumor tissue samples from 21 patients. Six of these tumors were WT for BRAF and NRAS, so we studied these cases further. The SNV load in the WT samples is more variable than the BRAF or NRAS driven melanomas. The median number of SNVs/Mb (± SD) for BRAF mutant (n = 9), NRAS mutant (n = 7) and BRAF WT/ NRAS WT (n = 6) samples were: 12.2 ± 8.0, 42.2 ± 82.7 and 12.6 ± 90.2 respectively. Next we analyzed the TCGA cutaneous melanoma cohort where there are 154 BRAF and 92 NRAS mutated and 76 BRAF WT/NRAS WT samples. The median numbers of SNVs (± SD) were 374 ± 638.3, 577 ± 518.3 and 146.5 ± 1221.6 respectively. The p-value for the comparisons BRAF vs. WT and NRAS vs. WT were 0.087 and 0.002 respectively (two-tailed Mann-Whitney test). We identified the somatic mutations that are specifically enriched for double wild-type samples and observed that the top two hits, NF1 (30.2% in double WT vs. 5.7% otherwise) and KIT (15.8% in double WT vs. 0.8% otherwise) are known driver gene candidates for wild-type melanomas, but we also find other novel candidate driver genes. Thus, we present a framework for identification of driver mutations and therapeutic targets in double wild-type melanomas and integration of these types of data with other large datasets such as those derived from RNA-seq and RPPA will assist in the development of approaches to stratify double wild-type patients for targeted or immune-therapies. Citation Format: Amit Mandal, Maria Romina Girotti, Amaya Viros, Gabriela Gremel, Elena Galvani, Rebecca Lee, Kok Haw Jonathan Lim, Simon J. Furney, Paul Lorigan, Richard Marais. Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2015-1094
Abstract 3924: A homogenous bioluminescent system for measuring GTPase, GAP and GEF activities
Authors: Subhanjan Mondal, Kevin Hsiao, Said A. Goueli
Journal: Cancer Research (2015)

Abstract GTPases play a major role in various cellular functions such as cell signaling, cell proliferation, cell differentiation, cytoskeleton modulation and cell motility. Deregulation or mutation of these proteins has considerable consequences resulting in multiple pathological conditions. Targeting GTPases and its regulators have been challenging due to lack of convenient assays. To overcome the challenges in analyzing activities of GTPases and their regulatory proteins GTPase Activating Proteins (GAP) and Guanine Nucleotide Exchange Factors (GEF) we have developed a homogenous bioluminescent assay (GTPase/GAP/GEF-Glo) system to analyze these proteins in a simple, convenient “add-mix-read” format. Mg2+ plays a critical role in influencing affinity of GTPases with GTP/GDP and the process of nucleotide exchange. Manipulating Mg2+ concentrations in the GTPase reaction buffer allows continuous progression of the GTPase cycle and faster hydrolysis of GTP. The assay relies on enzymatic conversion of GTP remaining after the GTPase reaction to ATP and detection of the ATP using luciferin/luciferase combination. We show that the assay is sensitive, and robust when analyzing for analyzing intrinsic GTPase- activity, GAP-stimulated GTPase- activity, GAP-activity and GEF- activity. The system can also be used to analyze these proteins expressed in cells as a fusion protein performing the assay in a pulldown -format. Furthermore, there was minimal false hits when tested for compound interference using the library of pharmacologically active compounds (LOPAC) and its robustness as indicated by high Z’-factor of 0.93 and CV of 2.2%. Citation Format: Subhanjan Mondal, Kevin Hsiao, Said A. Goueli. A homogenous bioluminescent system for measuring GTPase, GAP and GEF activities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3924. doi:10.1158/1538-7445.AM2015-3924
Abstract 1079: Transcriptional profiling reveals uterine leiomyoma subtypes with distinct pathways and biomarkers of tumorigenesis
Authors: Miika Mehine, Eevi Kaasinen, Esa Pitkänen, Nanna Sarvilinna, Hanna-Riikka Heinonen, Netta Mäkinen, Jari Sjöberg, Lauri A. Aaltonen
Journal: Cancer Research (2015)

Abstract Uterine leiomyomas, also known as fibroids, are benign smooth muscle tumors with an estimated prevalence of 77% among women of reproductive age. Although benign, they frequently cause a variety of health complications and are the leading cause of hysterectomy worldwide. Recent studies utilizing high-throughput sequencing have revealed recurrent and mutually exclusive mutations in a variety of genes, suggesting that distinct molecular pathways are involved in the initiation of leiomyoma tumorigenesis. The consequences of these mutations are poorly understood and expression signatures associated with these driver mutations may provide further insights. The aim of this study was to explore transcriptional differences between genetic subgroups of leiomyomas utilizing Affymetrix exon arrays and RNA-sequencing. We performed transcriptional profiling of ∼100 leiomyomas harboring different genetic drivers; these included leiomyomas harboring MED12 mutations, HMGA2/HMGA1 rearrangements, biallelic inactivation of FH and COL4A5-COL4A6 deletions. We identified a long non-coding transcript of RAD51B to be specifically upregulated in MED12 mutant leiomyomas. Genes involved in key metabolic pathways, including pentose phosphate pathway and glutathione biosynthesis, were specifically upregulated in FH-deficient leiomyomas. AKR1B10 was the most significantly upregulated gene in leiomyomas of the FH type. This gene was not expressed in other leiomyomas and may serve as a robust biomarker for FH-deficient leiomyomas. Overexpression of the proto-oncogene PLAG1 was specifically seen in leiomyomas harboring HMGA2 or HMGA1 aberrations, suggesting that these tumors exert their tumorigenic effect through dysregulation of PLAG1. This was supported by identification of one uterine leiomyoma harboring a translocation of PLAG1 resulting in a similar overexpression. While this study highlights the importance of stratifying each leiomyoma into a specific subgroup, it also shows that several genes are commonly dysregulated among all leiomyomas. Targeting these genes would be ideal in developing treatments for this disease. Citation Format: Miika Mehine, Eevi Kaasinen, Esa Pitkänen, Nanna Sarvilinna, Hanna-Riikka Heinonen, Netta Mäkinen, Jari Sjöberg, Lauri A. Aaltonen. Transcriptional profiling reveals uterine leiomyoma subtypes with distinct pathways and biomarkers of tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1079. doi:10.1158/1538-7445.AM2015-1079
Abstract 685: Mechanisms of intrinsic and acquired resistance to third generation inhibitors in EGFR mutant NSCLC
Authors: Matt J. Niederst
Journal: Cancer Research (2015)

Abstract Acquired resistance is a fundamental problem limiting the efficacy of tyrosine kinase inhibitors (TKIs) in EGFR mutant NSCLC. In over half of the cases of acquired resistance to the first generation inhibitors gefitinib and erlotinib, a secondary mutation to EGFR, T790M, promotes resistance by preventing these drugs from fully suppressing the receptor. The recent development of next generation EGFR TKIs has proven to be a major breakthrough in the treatment of these patients. In clinical trials testing the third generation EGFR inhibitors CO-1686 and AZD9291, response rates of greater than 50% in T790M+ patients have been reported. While these drugs hold a great deal of promise, they too will be limited, initially by intrinsic resistance, and eventually by acquired resistance. To study intrinsic resistance in this setting, we have developed a panel of cell lines derived from biopsies of T790M+ erlotinib-resistant patients, tested their sensitivity to third generation inhibitors and identified biomarkers that predict a lack of response. To study acquired resistance, we have generated resistance in these cells lines in vitro and derived additional models directly from patient biopsies following progression on the clinical trial. Using a combination of functional, sequencing, and drug screening approaches we have begun to identify resistance mechanisms to third generation inhibitors. Citation Format: Matt J. Niederst. Mechanisms of intrinsic and acquired resistance to third generation inhibitors in EGFR mutant NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 685. doi:10.1158/1538-7445.AM2015-685