tbuckley/cabot-search huggingface dataset:
Effects of ipilimumab on expanded tumor-infiltrating lymphocytes in patients with stage IV malignant melanoma.
Authors: Jon Bjoern, Marco Donia, Rikke Andersen, Sine Reker Hadrup, Rikke Lyngaa, Inge Marie Svane
Journal: Journal of Clinical Oncology (2014)

3020 Background: Adoptive cell therapy (ACT) is currently one of the most effective treatments for stage IV malignant melanoma. Clinical studies have indicated a link between prior anti-CTLA-4 treatment (e.g. Ipilimumab), and a favorable response to subsequent ACT. Methods: We compared phenotype and functionality of T cells generated from melanoma biopsies harvested from Ipilimumab naïve patients with patients that had received treatment with Ipilimumab within six month prior to tumor removal. Tumor biopsies were obtained from 32 stage IV melanoma patients (16 treated with Ipilimumab and 16 ipilimumab naive). T cells were cultured and expanded according to the rapid expansion protocol. Cells were stained for intra- and extracellular markers and subjected to flow cytometric analysis. Additionally, combinatorial coding with MHC-I multimers and co-culture assays with autologous tumor cells were performed in order to assess tumor-specific responses. Results: Analysis for phenotypic markers revealed several significant differences related to prior treatment. Importantly, cultured cells from Ipilimumab treated patients showed a median ten-fold higher expression of CD27 in CD8+ T cells, compatible with a more naïve phenotype, and two-fold higher expression of intracellular CTLA-4 in both CD4+ and CD8+ positive T cells. Furthermore, both TIM-3 and LAG-3 were more abundantly expressed in CD8+ T cells from Ipilimumab treated patients. We detected no difference in reactivity towards autologous tumor cells. Combinatorial coding revealed frequent responses toward common tumor associated antigens in both groups of patients. Conclusions: Despite several weeks of culture, Ipilimumab appeared to have lasting impact on the phenotype of expanded tumor infiltrating T cells. We observed higher expression of CD27, which previously has been linked to a favorable outcome of ACT, and up regulation of markers associated with immune suppression, possibly due to homeostatic regulation of the T cells. Over all, results indicate that influx of T cells with a less exhausted phenotype may underlie the favorable effect of pre-treatment with Ipilimumab and ACT in the setting of metastatic malignant melanoma.
Abstract 17419: Chemogenetic Generation of Hydrogen Peroxide in the Heart: A New Model for ROS-Dependent Heart Failure
Authors: Andrea Sorrentino, Benjamin Steinhorn, Vsevolod Belousov, Thomas Michel
Journal: Circulation (2017)

The stable reactive oxygen species (ROS) hydrogen peroxide (H2O2) modulates physiological pathways in cardiac myocytes, but higher levels of ROS can cause pathological oxidative stress. We develope...
Intracellular expression of FLT3 in Purkinje cells: implications for adoptive T-cell therapies
Authors: Neşe Çakmak-Görür, Josefine Radke, Simone Rhein, Elisa Schumann, Gerald Willimsky, Frank L. Heppner, Thomas Blankenstein, Antonio Pezzutto
Journal: Leukemia (2019)
Hydrogel particles sequester and preserve low molecular weight, low abundance cancer biomarkers in blood
Authors: Alessandra Luchini, David Geho, Barney Bishop, Duy Tran, Cassandra Xia, Robert Dufour, Clinton Jones, Virginia Espina, Alexis Patanarut, Weidong Zhou, Alessandra Tessitore, Emanuel Petricoin, Lance Liotta
Journal: Cancer Research (2008)

2434  There is an urgent need to discover novel biomarkers that provide sensitive and specific cancer detection. One of the major problems associated with biomarker discovery has been degradation of biomarkers. Degradation can occur immediately following the collection of blood or body fluid as a result of endogenous or exogenous proteinases and can greatly bias subsequent analysis. The goal of this study was to incorporate a bait in “smart” nano-particles in order to sequester and concentrate selected classes of proteins and peptides from complex mixtures of biomolecules such as serum, and protect them from degradation during subsequent sample handling.  N-isopropylacrylamide/acrylic acid (NIPAm/AAc) particles were synthesized by precipitation polymerization and characterized by means of light scattering and atomic force microscopy. The AAc component acted as bait for cationic proteins. Two different technologies were used to detect the particles’ ability to isolate low molecular weight, low abundance polypeptides, namely SDS PAGE and flow cytometry. Bait particles incubated with a solution containing platelet derived growth factor (PDGF, 14,000 Da) and bovine serum albumin (BSA, 66,000 Da) completely sequestered PDGF and totally excluded BSA, with PDGF being a representative model for low abundance low molecular weight protein biomarker in blood. By using a solution of protein molecular weight markers, the molecular weight cut off (MWCO) of the proteins sequestered by the particles was found to be around 20,000 Da, which is significant since the vast majority of possible biomarkers are thought to reside in the MW range from 0 to 20,000 Da.  Flow cytometry studies demonstrated that particles captured low molecular weight protein (i.e. FITC labeled insulin) spiked in human serum. Uptake was very rapid since it occurred in less than five minutes, as was quantified by reverse phase protein arrays.  Particles were incubated with human serum, and the captured proteins were electroeluted from particles. Analysis of the electroeluted proteins with mass spectrometry indicated that the particles had sequestered rare and small-sized serum proteins and peptide fragments with total exclusion of albumin and other large and high abundant proteins.  By means of two different proteases (trypsin and chymotrypsin) with different incubation times (1 hour, 3 hours and overnight) it was demonstrate that NIPAm/AAc particle completely blocked protease degradation of captured proteins even at 37 oC.  Taken together, these results provide evidence that such particles are a very promising tool that could help the discovery of novel biomarkers for early stage diseases such as cancer.
Adjustment of carboplatin dose in patients on peritoneal dialysis.
Authors: Achuta Kumar Guddati, Parijat Saurav Joy, Creticus Petrov Marak
Journal: Journal of Clinical Oncology (2014)

e22188 Background: The Calvert formula is often used to determine carboplatin dosage for chemotherapy. In anuric patients on dialysis, the GFR is often set to zero and the dose is calculated by directly multiplying the goal AUC with 25. However, in patients on peritoneal dialysis (PD), carboplatin remains in circulation for a longer period of time and may potentially increase the AUC leading to excessive toxicity. There have been no scientific formulas to predict the required dose of carboplatin for a given AUC in patients on PD. Methods: The formula for predicting the correction factor for carboplatin dose for a given AUC in hemodialysis patients was previously described in published work by us. Here, we have derived a modified formula for predicting the correction factor for carboplatin dosage in patients on PD: Correction Factor = (X/24) + Y*(((1-Z^n)/(1-Z))-1) Where: X is the number of hours between carboplatin infusion and the first PD session. Y is the number of days between PD sessions. Z is the amount of carboplatin retained after every PD session. n is the number of PD sessions. Results: Calvert formula predicts a dose of 125 mg for patients with GFR of 0 and an AUC of 5 mg/ml/min. By using the above formula, we show that for patients on intermittent PD for at least 40 sessions and with a clearance of 20% per session, the adjusted dosage of carboplatin is (see Table). For patients on PD 4 times/day, the carboplatin dose does not have to be adjusted if the PD is commenced immediately after carboplatin infusion. For patients on PD 3 times/day, the carboplatin dose needs to be adjusted to 76% if the PD is commenced immediately after carboplatin infusion. However, the dose has to be decreases to 64% and 43% if the PD is done 6 and 24 hours respectively after infusion. Conclusions: The AUC of carboplatin has been used to predict therapeutic efficiency and toxicity. Patients on PD comprise a unique set of patients whose carboplatin dosage needs to be modified based on the frequency of the PD. The formula derived here provides a framework to estimate the dosage of carboplatin in patients on PD. % of 125 mg dose Serial No PD started X hours after infusion For 2 PD sessions per day For 3 PD sessions per day For 4 PD sessions per day 1 0 50 76 100 2 6 44 64 80 3 12 40 55 67 4 18 36 48 57 5 24 33 43 50
From Mild Cytopenia to Overt MDS and AML, the Mutational Profile Predicts Progression, but Not Survival
Authors: Jakob Werner Hansen, Morten Munk Johansen, Maj Karoline Westman, Leonie Saft, Lene Dissing Sjö, Claus Werenberg Marcher, Mette Skov Holm, Marios Dimitriou, Mohsen Karimi, Klas Raaschou-Jensen, Andreas Birkedal Glenthøj, Marianne Tang Severinsen, Eva Hellström-Lindberg, Mette Klarskov Andersen, Kirsten Grønbæk
Journal: Blood (2018)
Relapsed or refractory extranodal DLBCL treated with lenalidomide: A single center study.
Authors: Giuseppe Altavilla, Carmela Arrigo, Cristian Di Mirto, Lorenza Garufi, Patrizia Mondello, Claudia Garipoli, Vincenzo Pitini
Journal: Journal of Clinical Oncology (2014)

e19517 Background: Approximately one third of Diffuse Large B-cell Lymphoma (DLBCL) arise in tissue different from the lymph node and they are usually termed as extranodal DLBCL. Patients (pts.) with relapsed or refractory disease not eligible to high dose chemotherapy and transplantation had a dismal prognosis. The immunomodulatory agent Lenalidomide shows consistent activity with tolerable safety in multiple phase II studies or relapsed/refractory aggressive NHL. On this basis we conducted a single center study to investigate efficacy and safety of Lenalidomide alone in relapsed pts. with heaviling pre-treated extranodal DLBCL. Methods: 31 extranodal stage 3-4 DLBCL pts. (GI tract 13, liver 2, soft tissue 2, bone 6, breast 6, lung 2 cases) 16 male, 15 female, median age 63 years, received a standard dose of oral Lenalidomide , 25 mg/day for 21 days every 28 days as single agent between March 2011 and August 2013 until disease progression or unacceptable toxicities. Results: All pts. were analyzed. Bone marrow was involved in 16 pts. and 8 case presented a bulky disease. All pts. undervent more than 3 previously lines of therapy, and median time from last previous therapy and Lenalidomide treatment was 3 months. Overall response rate was 32% (10 pts.: with 3 CR, 4 PR, 3 SD) with a median time to response of 2.2 months and median duration of response of 16.8 months, not yet reached in pts. with CR. Toxicity was globally mild: although 15 pts. (48.4%) required at least one dose reduction or interruption, most common grade 3-4 adverse events were neutropenia 7 pts.-22.6%, anemia 7 pts.-22.6% and thrombocytopenia 6 pts.-19.4%. Six pts. had grade 3-4 infectious and 4 pts. had thromboembolic events. Conclusions: Lenalidomide as single agent is effective and safe and produced rapid and durable responses in pts. with extranodal DLBCL also in pts. with heavily pre-treated disease.
Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial
Authors: Tero Varimo, Hanna Huopio, Laura Kariola, Sirpa Tenhola, Raimo Voutilainen, Jorma Toppari, Sanna Toiviainen-Salo, Esa Hämäläinen, Mari-Anne Pulkkinen, Mitja Lääperi, Annika Tarkkanen, Kirsi Vaaralahti, Päivi J Miettinen, Matti Hero, Taneli Raivio
Journal: The Lancet Child & Adolescent Health (2019)
Updated overall survival and time to progression results in NETs treated with everolimus combination with octreotide LAR as first-line treatment.
Authors: Emilio Bajetta, Laura Catena, Sara Pusceddu, Francesca Spada, Nicola Fazio, Giusi Blanco, Sergio Ricci, Michele Aieta, Francesca Pucci, Monica Valente, Nadia Bianco, Italo Sarno, Giandomenico Di Menna
Journal: Journal of Clinical Oncology (2014)

e15160 Background: We previously presented data about this phase II study showing that the combination of Everolimus and octreotide LAR in the first line setting for advanced NETs, is an active and a safe treatment. At a medium follow-up of 277 days, the median time to progression (TTP) and the overall survival (OS) have not been reached (ASCO 2013 Abs. 4136). Methods: We performed a phase 2, multicenter trial using a Simon two-stage minmax design. Patients with advanced well differentiated, previously untreated NETs of a gastroenteropancreatic (GEP) tract and of a lung, received ocreotide LAR 30mg every 28 days in combination with everolimus 10mg per day continuously. The primary end point was objective response rate (ORR). Currently we perform a further analysis of OS and TTP at a median follow-up of 17.8 months. Results: A total of 50 patients (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%), jejunum in 1 and duodenum in 1 of patients. One patient add a complete response, 16% a partial response and 72% achieved stable disease. At a median follow-up of 17.8 months of a median TTP is 33.2 months (95% CI 19-41.7). The median overall survival has not been reached. Currently 13 patients are still benefiting from the treatment (11 NETs of the GEP tract and 2 typical carcinoid of the lung). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs. The current analysis showed a futher prolungation of TTP suggesting a possible long term benefit of this combination in NETs. Aknowledgments:Italian Trials in Medical Oncology (I.T.M.O.) Group, Giacinto Facchetti Foundation and Novartis.
HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib
Authors: Y. Wang, T. Jiang, Z. Qin, J. Jiang, Q. Wang, S. Yang, C. Rivard, G. Gao, T.L. Ng, M.M. Tu, H. Yu, H. Ji, C. Zhou, S. Ren, J. Zhang, P. Bunn, R.C. Doebele, D.R. Camidge, F.R. Hirsch
Journal: Annals of Oncology (2018)

BackgroundEffective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib.Patients and methodsUsing patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented.ResultsPyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months.ConclusionPyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy.Clinical trial registrationNCT02535507.
Evaluation of CNS and peripheral antitumor activity of ANG1005 in patients with brain metastases from breast tumors and other advanced solid tumors.
Authors: Nancy U. Lin, Nashat Y. Gabrail, John Sarantopoulos, Lee Steven Schwartzberg, Santosh Kesari, Susan Elaine Bates, Carey K. Anders, Anthony D. Elias, Jean-Paul Castaigne, Vihra Iordanova, Betty Lawrence, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2014)

2523 Background: ANG1005 consists of 3 paclitaxel molecules covalently linked to a proprietary 19 AA peptide that targets the LRP1 receptor. This receptor is highly expressed on endothelial cells of the blood-brain barrier, where it mediates transcytosis, and on multiple tumor cells, where it mediates endocytosis. Thus, ANG1005 is both brain-penetrant and tumor-penetrant due to the LRP1-targeting peptide moiety. Methods: Ph I: Patients with advanced solid tumors and brain metastases received ANG1005 by IV infusion q3w at escalating doses of 30-700 mg/m2 (n=56), including 20 patients at 650 mg/m2 (MTD). Study objectives included safety/tolerability and overall tumor response (CNS and peripheral). Ph II: Patients with breast cancer brain metastases received ANG1005 by IV infusion q3w at a starting dose of 650 mg/m2 (n=13) or 550 mg/m2 (n=67). Study objectives included independent CNS and peripheral tumor response evaluations as per RECIST 1.1. Results: Safety and tolerability of ANG1005 were consistent with a taxane profile. In the Ph I study, 5/27 (18.5%) patients were observed with an overall PR and 11/27 (41%) with SD at doses ≥420 mg/m2. Eighteen of these patients were evaluated for CNS response and 16 for peripheral response, based on unidimensional measurements. In the Ph II study, 80 patients were dosed, with 61 and 33 patients evaluable for CNS and peripheral tumor response, respectively (Table). Peripheral tumor reductions were observed in various metastatic tumor locations, such as liver, lung, bone and lymph nodes. In the Ph I study, 3 patients showed complete lesion disappearance in some of these organs. Conclusions: ANG1005 has shown antitumor activity in both CNS and peripheral metastases. Clinical trial information: NCT00539383. Study Ph I: solid tumors (ANG1005-CLN-02) Ph II: breast cancer (CP1005B016) Dose level ≥420 mg/m2 550 mg/m2 650 mg/m2 Best response CNS Peripheral CNS Peripheral CNS Peripheral Sample size n=18 n=16 n=51 n=29 n=10 n=4 CR 0 0 0 1 (3%) 0 0 PR 4 (22%) 4 (25%) 10 (20%) 7 (24%) 4 (40%) 1 (25%) SD 10 (56%) 7 (44%) 31 (61%) 16 (55%) 4 (40%) 2 (50%) PD 4 (22%) 5 (31%) 10 (20%) 5 (17%) 2 (20%) 1 (25%)
pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin
Authors: Pin Dong, Fitsum Feleke Sahle, Silke B. Lohan, Siavash Saeidpour, Stephanie Albrecht, Christian Teutloff, Roland Bodmeier, Michael Unbehauen, Christopher Wolff, Rainer Haag, Jürgen Lademann, Alexa Patzelt, Monika Schäfer-Korting, Martina C. Meinke
Journal: Journal of Controlled Release (2018)
Markers of sensitivity or resistance to tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring wild type EGFR.
Authors: Paola Ulivi, Elisa Chiadini, Alessandra Dubini, Maurizio Puccetti, Marco Angelo Burgio, Angelo Delmonte, Alberto Verlicchi, Alessandro Gamboni, Maximilian Papi, Giovenzio Genestreti, Wainer Zoli, Lucio Crino, Claudio Dazzi
Journal: Journal of Clinical Oncology (2014)

e19086 Background: Tyrosine kinase inhibitors (TKIs) are the first choice of treatment in a subset of patients with non- small cell lung cancer (NSCLC) harboring specific epidermal growth factor receptor (EGFR) mutations. However, about 10% of patients carrying wild type (wt) EGFR also respond to TKIs, and the reason for this sensitivity is unclear. Methods: We considered a total of 42 patients with advanced NSCLC and wt EGFR who received erlotinib after one or more chemotherapy lines. Eighteen patients were defined as responsive (stable disease or partial response for at least 6 months), while 24 were non-responsive. All patients had progressive disease at the start of treatment with erlotinib. Data were analyzed by MassArray (Sequenom) using the LungCarta panel kit which is capable of concomitantly assessing the mutation status of 26 genes. Results: Sequenom analysis revealed that, among responsive patients previously identified as EGFR wt by pyrosequencing analysis, 2 had an EGFR mutation that was probably present in cell subclones and only detectable with more sensitive methods, while 4 had showed a mutation in genes involved in the control of proliferation (PIK3CA, AKT, NTRK2, STK11). Moreover, 3 of the responding patients had a KRAS mutation (G12V, G12D, G13D). Of the 24 non responsive patients, 2 showed a resistance mutation in EGFR (P753S and L747S), 3 a KRAS mutation (G12D, G12C, G12V), and 4 a p53 mutation (R273L, G245C, R158C, R273C). Conclusions: Response to TKIs in patients with EGFR wt status would seem to be attributable to under-represented EGFR mutations, detectable only with high-sensitive methods, and to the presence of mutations in genes involved in the proliferation pathway. Conversely, EGFR resistance mutations and p53 alterations were found in non-responsive patients. KRAS mutations would not seem to play a role in predicting response to TKIs.
The Landscape of Structural Variant Signatures in Multiple Myeloma Identifies Distinct Disease Subgroups with Implications for Pathogenesis
Authors: Francesco Maura, Daniel Leongamornlert, Nicos Angelopoulos, Kevin J Dawson, Mehmet Kemal Samur, Raphael Szalat, Yu-Tzu Tai, Stephane Minvielle, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth C. Anderson, Hervé Avet-Loiseau, Peter J. Campbell, Nikhil Munshi, Niccolò Bolli
Journal: Blood (2018)
Utilizing nomogram-predicted outcomes as the control group in randomized clinical trials.
Authors: Arielle C. Lutterman, Jeffrey M. Switchenko, Tony Pan, William L. Read
Journal: Journal of Clinical Oncology (2014)

6592 Background: Phase III randomized clinical trials require a large study population to demonstrate improved outcomes. Validated nomograms exist that predict survival outcomes for cancer patients. Nomogram-predicted outcomes for a study population could be used as a virtual control group, obviating the need for a live control group. To test this hypothesis, we used data from CLB 9344, a randomized study demonstrating a benefit of adjuvant paclitaxel in breast cancer. Methods: The nomogram developed by Michaelson (http://cancer.lifemath.net) was used to create a virtual control group matching the 1570 paclitaxel treated participants from 9,344. This virtual control group was compared to observed data to determine whether paclitaxel improved survival over that predicted for AC alone. Cumulative deaths were compared with the cumulative hazard (expected deaths) using a one-sample log-rank test. Sample size estimates were calculated for deaths and total study population needed for 80% power, with a type I error of 0.05. Results: See Table. A statistically significant mortality benefit favoring the experimental group emerged by year 7. By year 15, cumulative hazard is significantly higher than the observed number of deaths, indicating paclitaxel improves survival over standard of care. Conclusions: These results validate the use of existing nomograms as a virtual control group in clinical trials, allowing for smaller, faster, statistically valid Phase III studies. The lack of a live control group together with tighter prediction of expected outcomes for the participants suggest sample sizes could be reduced by 50-80%. Nomogram-predicted survival with AC and observed survival with AC + T. Year P value #Deaths/1,570 Cumulative hazard Nomogram-predicted survival rate (AC) 9,344 observed KM survival rate (AC + T) 1 0.09 21 30.27 0.98 0.99 2 0.90 94 95.28 0.94 0.94 3 0.31 187 173.73 0.89 0.88 4 0.71 256 250.03 0.84 0.84 5 0.67 312 319.52 0.80 0.80 6 0.14 357 385.77 0.75 0.77 7 0.02 398 447.99 0.72 0.74 8 0.001 429 506.39 0.68 0.72 9 <0.001 461 563.03 0.64 0.70 10 <0.001 491 614.04 0.61 0.68 11 <0.001 515 666.13 0.58 0.66 12 <0.001 548 715.83 0.54 0.63 13 <0.001 579 762.72 0.51 0.61 14 <0.001 610 807.66 0.49 0.58 15 <0.001 623 849.14 0.46 0.57