tbuckley/cabot-search huggingface dataset:
Correlation of trastuzumab treatment benefit with quantitative HER2 expression levels in HER2 positive metastatic breast cancer.
Authors: Beatrice Bachmeier, Jeff Sperinde, Jodi Marie Weidler, Yolanda Lie, Ahmed Chenna, John Winslow, Jutta Engel, Gabriele Schubert-Fritschle, Christian Sommerhoff, Christos J. Petropoulos, Michael Patrick Bates, Weidong Huang, Andreas Nerlich
Journal: Journal of Clinical Oncology (2015)

593 Background: The HERmark Breast Cancer Assay (Monogram Biosciences) is used as an adjunct to HER2 immunohistochemistry (IHC) and HER2 fluorescence in-situ hybridization (FISH) to determine the HER2 status of breast cancer (BC). Based on the high degree of concordance of HERmark with centrally determined HER2 status by IHC/FISH, it is expected that HERmark positive BC patients would realize greater benefit from trastuzumab treatment than HERmark negative BC patients. In the current study, this hypothesis was confirmed using a cohort comprised of: (1) HER2 positive BC patients treated before the availability of trastuzumab, (2) trastuzumab-treated HER2 positive BC patients and (3) HER2 negative BC patients. Methods: HERmark was performed retrospectively on formalin-fixed, paraffin-embedded tumors derived from 305 metastatic breast cancer patients in the Munich Cancer Registry with a median follow up of 10 years. Cases were evenly divided between trastuzumab-untreated HER2 positive (n = 91), trastuzumab-treated HER2 positive (n = 115) and HER2 negative (n = 99) tumors. Cutoffs for HERmark positive and negative status were pre-specified (Huang, Am J Clin Pathol, 134:303 2010). Results: HER2 positive patients treated with trastuzumab had longer overall survival (OS) than those not treated with trastuzumab, as expected (HR = 0.35; p < 0.0001). As reassessed by HERmark, HER2 positive patients treated with trastuzumab experienced longer OS (HR = 0.33; p = 0.0005). In contrast, the benefit of trastuzumab treatment in HERmark negative patients was not statistically significant (HR = 0.55; p = 0.13). Additionally, there was a statistically significant interaction between the degree of trastuzumab benefit and quantitative levels of HER2 expression within the HERmark positive subset (interaction p = 0.032). Potential correlations between additional markers, including p95HER2 and HER3, and treatment outcome are currently being assessed. Conclusions: The HERmark assay identified breast cancer patients who benefited from trastuzumab treatment. Within this group, increased levels of quantitative HER2 expression correlated with increased degree of benefit from trastuzumab therapy.
Myeloma-Derived Exosomes and Soluble Factors Suppress Natural Killer Cell Function
Authors: Tarun K. Garg, Jessica I Gann, Priyangi A Malaviarachchi, Kate Stone, Veronica Macleod, Amy D Greenway, Nisreen S Akel, Ricky D Edmondson, Faith E Davies, Joshua Epstein, Gareth J Morgan, Frits van Rhee
Journal: Blood (2016)
Durable Control of Metastatic AKT1-Mutant WHO Grade 1 Meningothelial Meningioma by the AKT Inhibitor, AZD5363
Authors: Michael Weller, Patrick Roth, Felix Sahm, Isabel Burghardt, Bernhard Schuknecht, Elisabeth J. Rushing, Luca Regli, Justin P. Lindemann, Andreas von Deimling
Journal: JNCI Journal of the National Cancer Institute (2017)

High-throughput analyses have revealed the presence of activating mutations in the AKT1 gene in a subpopulation of meningiomas. We report a female patient with multiple intracranial tumor manifestations and histologically verified meningotheliomatous meningioma in the lung. The tumor was continuously growing at multiple sites despite six surgical resections, radiotherapy, and two lines of systemic therapy. Following detection of an AKT1E17K mutation in three independent tumor samples by sequencing, treatment with AZD5363, a selective AKT inhibitor, was initiated. Ex vivo cultured meningioma cells exhibited sensitivity to the drug as shown by pAKT accumulation on immunoblots. Treatment with AZD5363 resulted, for the first time, in stable disease and minor radiographic response. The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. This is the first report of an AKT1-mutant meningioma responding to AKT inhibition, suggesting that molecular screening may result in clinical benefit.
Low-dose interleukin-11 has activity in patients with bone marrow failure
Authors: R. Kurzrock, I. Khouri, C. Bueso-Ramos, F. Giles, S. Pilat, D. A. Thomas, J. Cortes, A. M. Tsimberidou
Journal: Journal of Clinical Oncology (2004)

2538 Background: Interleukin-11 (IL-11) stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitors and induces megakaryocyte maturation. The objectives of this study were to assess the toxicity, safety and efficacy of low-dose recombinant IL-11 in patients with bone marrow failure (BMF). Methods: Eligibility criteria included chronic BMF-related thrombocytopenia due to myelodysplastic syndromes (MDS), graft failure, chemotherapy, or aplastic anemia (AA); no chemotherapy for >2 months; no progressive disease; performance status 0–2 (Zubrod scale); and no ATG treatment for >3 months (AA patients). IL-11 was administered daily at a dose of 10 μg/kg s.c. for 2 weeks followed by a 2-week rest period. Two induction courses were given, followed by maintenance daily or every other day therapy for as long as hematologic improvement without Grade 3–4 toxicities was seen. Results: Thirty-three patients were evaluable (MDS, n=14; AA, n=16; prolonged thrombocytopenia following stem cell transplantation or chemotherapy, n=3). The median age was 58 years (range, 5–85). The median platelet count was 17 x 109/L (range, 1–48 x 109/L). Three patients (9%) had poor risk cytogenetics. Nine patients (27%) responded to IL-11 (MDS=6, AA=3). Of these, 3 patients treated with IL-11 alone (n=1) or IL-11 plus other growth factors (n=2) showed multilineage recovery. The median time to response was 0.9 months (range, 0.3–11.0 months) and the median response duration was 3.0 months (range, 1.4–34.5+ months). Among responders, the median increment in platelet count was 111 x 109/L (range, 43–165 x 109/L) net increase above the baseline platelet counts. Factors associated with higher response rates in univariate analysis were age >50 years (p=0.008), diagnosis of MDS vs. AA (p=0.025), and creatinine level >1mg/dl (p=0.0004). The most common side effects were Grade 1–2 lower extremity edema, conjunctival injections and fatigue. Grade 3 toxicities, which may have been related to IL-11 included arrhythmia (n=1) and transient ischemic attack (n=1). Ten patients (30%) had no side effects. Conclusions: Low-dose IL-11 has activity in patients with BMF and is generally well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Inc.
Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in NSCLC: Implications for targeted combinations.
Authors: Emrullah Yilmaz, Lauren Averett Byers, Lixia Diao, Uma Giri, Jayanthi Gudikote, You Hong Fan, Jing Wang, Kevin R. Coombes, Luc Girard, John D. Minna, John Heymach
Journal: Journal of Clinical Oncology (2012)

10612 Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling. We investigated the signaling pathways modulated by LKB1 mutations and by mTOR inhibition in NSCLC. Methods: Protein expression in cell lines was measured by reverse phase protein array. Differences in protein expression at baseline in LKB1 wild-type versus mutant cell lines and the effects of protein modulation by treatment were assessed by ANOVA. Results: LKB1 mutant cell lines had lower expression of phosphorylated AMPK and TSC (p&lt;0.01 for both) consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the IGF1R pathway including IGFR1b (p&lt;0.0001); AIB1, which is known to upregulate IGF1 (p&lt;0.0001); and IGFBP2 (p=0.016). LKB1 mutant cell lines (n=11/25) were 1.5-fold more sensitive to the AMPK activator metformin, although this did not reach statistical significance (p=0.10). Expression levels of IGF1R pathway proteins increased significantly after 48h treatment with metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after metformin treatment (p=0.02 and 0.005, respectively); IRS1 and IGFR1 were elevated after temsirolimus or PI103 (p&lt;0.05 for both). Following treatment with metformin and temsirolimus, there was also increased pAkt, a downstream target of IGF1R and activator of mTOR (p&lt;0.01 for both). Modulation of the IGF1R pathway by these drugs was independent of LKB1 mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.
Results of PX-171-003-A1, An Open-Label, Single-Arm, Phase 2 (Ph 2) Study of Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory Multiple Myeloma (MM)
Authors: David Samuel diCapua Siegel, Thomas Martin, Michael Wang, Ravi Vij, Andrzej J Jakubowiak, Sundar Jagannath, Sagar Lonial, Vishal Kukreti, Nizar J Bahlis, Melissa Alsina, Asher A. Chanan-Khan, George Somlo, Francis Buadi, Frederic J. Reu, Jeffrey A. Zonder, Kevin Song, Edward Stadtmauer, Alvin F. Wong, Marcy Vallone, Yu-Lin Chang, Michael Kauffman, Robert Z. Orlowski, A. Keith Stewart, Seema B. Singhal
Journal: Blood (2010)
ASSESSMENT OF LEFT VENTRICULAR CONTRACTION PATTERNS USING GATED SPECT MPI TO IMPROVE CARDIAC RESYNCHRONIZATION THERAPY RESPONSE
Authors: Ningchao Tao, Haipeng Tang, Yuanhao Qiu, Weihua Zhou, Zhiyong Qian, Yao Wang, Xiaofeng Hou, Jiangang Zou
Journal: Journal of the American College of Cardiology (2017)
Staphylococcus aureus bacteremia in patients with rheumatoid arthritis – Data from the prospective INSTINCT cohort
Authors: Insa Joost, Achim Kaasch, Christine Pausch, Gabriele Peyerl-Hoffmann, Christian Schneider, Reinhard E. Voll, Harald Seifert, Winfried V. Kern, Siegbert Rieg
Journal: Journal of Infection (2017)
The International Congress on Peer Review in Biomedical Publication
Authors: Drummond Rennie
Journal: JAMA (1989)

"Peer review" has a variety of meanings for physicians. All physicians are accustomed to surveillance of their use of hospital beds or of the records they keep about the patients in those beds by utilization review and quality assurance committees made up of their peers. Physicians face yet more peer review when they double as investigators, put their proposals before institutional review boards, and have their grant applications assessed by expert panels of their peers. Finally, the product of all this—the manuscript that embodies their scientific brainchild and carries their hopes of fame and promotion—is subjected by journal editors to yet another round of peer review. Understandably, it is this last version that tends to interest journal editors the most. However, the workings of the editorial peer review system are of vital concern to every scientist and ultimately to all physicians and patients because all the important advances in science
Evaluation of KPT-SINE (Selective Inhibitors of CRM1-Mediated Nuclear Export) in AML and T-ALL.
Authors: Julia Etchin, Alex Kentsis, Takaomi Sanda, Andrew L. Kung, Richard M. Stone, Dilara McCauley, Michael Kauffman, Sharon Shacham, A. Thomas Look
Journal: Journal of Clinical Oncology (2012)

e13586 Background: CRM1 is the major nuclear exporter that mediates transport of a variety of molecules, including proteins involved in tumor suppressor and cellular proliferation pathways. The crystal structure of CRM1, in complex with its export cargo, Snurportin 1, has been recently resolved. The molecular understanding of the CRM1-cargo binding interface has led to the development of novel small molecule inhibitors of CRM1-cargo interaction, termed KPT-Selective Inhibitors of Nuclear Export (SINE). KPT-SINE are potent, drug-like CRM1 inhibitors that irreversibly inactivate the CRM1-directed protein export by covalent modification of the essential CRM1-cargo binding residue Cys528. The inhibition of the CRM1 nuclear export has been shown to lead to selective apoptosis in cancer cells when compared to normal cells. Here, we assess the efficacy of the KPT-SINE in human AML, T-ALL, and normal hematopoietic cells. Methods: The viability of a panel of human AML and T-ALL cell lines upon treatment by the KPT-SINE was assessed. Dose-response measurements were done using serial dilutions of KPT-SINE from 1 µM to 0.3 nM and luminescent cell viability assay. Apoptosis was measured using Annexin V staining and TUNEL assays. Results: KPT-SINE induces rapid apoptosis in 10 of 14 AML and 12 of 15 T-ALL cell lines with IC50s of 15-100 nM. In the KPT-SINE-sensitive cell lines, BCL2 overexpression suppresses KPT-SINE-induced apoptosis, indicating its intrinsic pathway mediation. Importantly, KPT-SINE compounds, either KPT-251 at 75 mg/kg or KPT-330 at 15 or 25 mg/kg, induced remarkable growth suppression in MV4-11 human AML cells engrafted into immunodeficient NSG mice with minimal toxicity to normal mouse hematopoietic cells after 35 days of treatment. Bone marrow biopsies of KPT-treated mice were remarkable in that they showed normal hematopoietic cell morphology and cellularity after 35 days of treatment. Xenograft studies to address the potency of the KPT-251 and KPT-330 on MOLT-4 human T-ALL cells in vivo are ongoing. Conclusions: These studies emphasize the clinical promise of the KPT-SINE as a novel and selective drug candidate for the treatment of AML and T-ALL.
Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction
Authors: Yvette L. Kasamon, Ephraim J. Fuchs, Marianna Zahurak, Gary L. Rosner, Heather J. Symons, Javier Bolaños-Meade, Richard J. Jones
Journal: Blood (2016)
Clinical Presentation and Outcomes of Patients with Light Chain Amyloidosis Who Have Non-Evaluable Free Light Chains at Diagnosis
Authors: Surbhi Sidana, Nidhi Tandon, Angela Dispenzieri, Morie A. Gertz, Francis K Buadi, Martha Q. Lacy, David Dingli, Amie Fonder, Suzanne R. Hayman, Miriam Hobbs, Wilson I Gonsalves, Yi L. Hwa, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A Lust, Stephen J. Russell, Steven R. Zeldenrust, S. Vincent Rajkumar, Shaji K. Kumar
Journal: Blood (2016)
Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury
Authors: Shinji Tanaka, Tetsuhiro Tanaka, Takahisa Kawakami, Hideki Takano, Mai Sugahara, Hisako Saito, Yoshiki Higashijima, Junna Yamaguchi, Reiko Inagi, Masaomi Nangaku
Journal: Kidney International (2017)
Mortality, Length of Stay, and Cost Implications of Procedural Bleeding After Percutaneous Interventions Using Large-Bore Catheters
Authors: Björn Redfors, Brendan M. Watson, Thomas McAndrew, Emilie Palisaitis, Dominic P. Francese, Mehdi Razavi, Jordan Safirstein, Roxana Mehran, Ajay J. Kirtane, Philippe Généreux
Journal: JAMA Cardiology (2017)

Bleeding complications after percutaneous transcatheter interventions that used large-bore catheters are frequent and associated with high mortality and morbidity.To describe the incidence of bleeding complications among patients undergoing contemporary endovascular interventions involving large-bore catheters and its association with in-hospital mortality, length of stay, and health care cost.This retrospective cohort study analyzed all 17 672 patients from the Healthcare Cost and Utilization Project's National Inpatient Sample database who were recorded as having undergone a transcatheter aortic valve replacement (n = 3223), an endovascular aneurysm repair (n = 12 633), or a percutaneous left ventricular assist device implant (n = 1816) between January 1, 2012, and December 31, 2013. Bleeding complication was defined as any transfusion, any hemorrhage or hematoma, or the need for percutaneous or surgical intervention to control the bleeding event. Health care costs were determined by multiplying the total charge for each visit by the cost to charge ratios reported for each hospital code in the database. Data were collected from the database on April 29, 2016.Adjusted association between bleeding complications and mortality was determined by multivariable logistic regression. Length of stay and total health care costs were compared using multivariable linear regression between patients who did and patients who did not have bleeding complications.Bleeding complications occurred in 3128 patients (17.7%) (1984 men and 1144 women, with a mean [SD] age of 75.6 [11.9] years). Bleeding was associated with higher mortality (adjusted odds ratio, 2.70; 95% CI, 2.27-3.22; P < .001) and longer hospital stay (adjusted multiplicative difference, 2.14; 95% CI, 2.06-2.16; P < .001). Median (interquartile range) total health care costs were $48 663 ($32 620-$71 547) for patients with bleeding complications compared with $29 968 ($21 924-$43 287) for patients without a bleeding complication (adjusted multiplicative difference, 1.55; 95% CI, 1.52-1.59; P < .001).Periprocedural bleeding was common among patients who underwent transcatheter intervention using large-bore catheters and was associated with a statistically significant increase in mortality, length of stay, and cost.
PROGNOSTIC VALUE OF RIGHT VENTRICLE-PULMONARY ARTERY COUPLING IN TAVR PATIENTS: TIME TO INTEGRATE THE RIGHT SIDE UNIT
Authors: Joao Cavalcante, Islam Abdelkarim, Michael Sharbaugh, Andrew Althouse, Jeffrey Xu, Wei Han, William Katz, Frederick Crock, Matthew Harinstein, Dustin Kliner, Forozan Navid, Joon Lee, John Schindler, Thomas Gleason
Journal: Journal of the American College of Cardiology (2017)
LEFT VENTRICULAR HYPERTROPHY AND SUBSEQUENT CARDIOVASCULAR RISK: DOES IT MATTER HOW IT IS DIAGNOSED?
Authors: Manan Pareek, Evan Fletcher, Muthiah Vaduganathan, Deepak L. Bhatt, Søren S. Petersen, Line R. Pedersen, Margrét Leósdóttir, Michael H. Olsen
Journal: Journal of the American College of Cardiology (2017)
Understanding patient expectations in early-phase clinical trials
Authors: K. P. Weinfurt, D. M. Seils, J. P. Tzeng, K. L. Compton, D. P. Sulmasy, A. B. Astrow, K. A. Schulman, N. J. Meropol
Journal: Journal of Clinical Oncology (2007)

6543 Background: Participants in early-phase clinical trials have reported high expectations of benefit from their participation. There is concern that participants misunderstand the trials to which they have consented. Such concerns are based on assumptions about what patients mean when they respond to questions about likelihood of benefit. In this study, we explored some of these assumptions. Methods: Participants were 27 women and 18 men in phase 1 or 2 oncology trials and randomized to 1 of 3 interview protocols corresponding to 3 target questions about likelihood of benefit: frequency-type (‘Out of 100 patients who participate in this study, how many do you expect will have their cancer controlled as a result of the experimental therapy?‘); belief-type (‘How confident are you that the experimental therapy will control your cancer?‘); and vague (‘What is the chance that the experimental therapy will control cancer?‘). In semistructured interviews, we queried participants about how they understood and answered the target question. Each participant then answered and discussed one of the other target questions. Results: Participants tended to provide higher expectations in response to the belief-type question (median, 80) than in response to the frequency-type or vague questions (medians, 50) (P=.02). Only 7 (16%) participants said their answers were based on what they were told during the consent process. The most common justifications for responses involved positive attitude (n=27 [60%]) and references to physical health (n=23 [51%]). References to positive attitude were most common among participants with high (&gt;70%) expectations of benefit (n=11 [85%]) and least common among those with low (&lt;50%) expectations of benefit (n=3 [27%]) (P=.04). Conclusions: We identified two factors that should be considered when determining whether high expectations of benefit are signs of misunderstanding. First, participants report different expectations of benefit depending on how the question is asked. Second, the justifications participants give for their answers suggest that many participants use their responses to express hope rather than to describe their understanding of the clinical trial. These findings should inform methods for evaluating the quality of informed consent in early-phase trials. No significant financial relationships to disclose.
Role of perfusion computed tomography (CTp) for pretherapy assessment and induction chemotherapy monitoring (IC) in patients with squamous cell carcinoma (SCC) of the head and neck
Authors: G. Petralia, L. Preda, F. Chiesa, F. Nolè, G. d'Andrea, G. Giugliano, E. Verri, M. Cossu Rocca, M. Bellomi
Journal: Journal of Clinical Oncology (2009)

e17015 Background: Reliable assessment of the response to IC is required to stratify further treatments, as responders are considered the best candidates for organ preservation strategies. We evaluated the role of CTp for pre-therapy assessment and IC monitoring in patients with SCC of the head and neck. Methods: From November 2004, 28 consecutive patients with locally advanced SCC of the head and neck were enrolled, undergoing CTp and volumetric CT before and after IC with cisplatin, administered at a dose of 100 mg/m 2 iv, on day 1, and 5-fluorouracil, administered at a dose of 1,000 mg/m 2 ci from day 1 to day 5, q3wks for 2 or 3 cycles. Perfusion parameters were calculated for tumor: blood flow (BF), blood volume (BV), mean transit time (MTT) and capillary permeability-surface (PS). The Wilcoxon rank sum test was used to test for differences in the pre-therapy perfusion parameters between the different tumor grades, as well as between responders and nonresponders to IC. The post-therapy perfusion parameters were compared with the pre-therapy ones by the Wilcoxon signed rank test and percent changes in perfusion parameters were correlated with percent changes in tumor volume calculated by volumetric CT after IC by the Spearman correlation coefficient. Results: Pre-therapy BF was significantly higher in G3 tumors, compared to G1 and G2 (p = 0.01) and G2 tumors (p = 0.03), and pre-therapy BV significantly higher in responders than in nonresponders (p = 0.01). Of the 20 patients who underwent post-therapy CTp, the 17 responders had significant reduction of BF (p = 0.003) and BV (p = 0.014) and increase of MTT (p = 0.04) in the post-therapy CTp, whereas the 3 non responders no significant changes in perfusion parameters. In the 17 responders, percent reduction in BF and BV showed correlation (Spearman R = 0.71, p = 0.0013 and R = 0.82, p = 0.00005, respectively) with percent reduction in tumor volume after IC. Conclusions: In our cohort of patients with SCC of the head and neck, CTp showed potential for pre-therapy assessment, as well as for IC monitoring; further studies are required to confirm our preliminary results. No significant financial relationships to disclose.