tbuckley/cabot-search huggingface dataset:
Targeting EGFR in glioblastoma: Preclinical testing of dacomitinib.
Authors: Juan Manuel Sepúlveda, Cristina Zahonero, Aurelio Hernandez-Lain, Angel Perez-NuÃƒÂ±ez, Maria Victoria Bolós, Pilar Sanhez
Journal: Journal of Clinical Oncology (2014)

e13015 Background: EGFR is amplified in nearly 50 % of glioblastoma (GBM), making it a promising therapeutic target. However first generation TK inhibitors have been tested in clinical trials with GBM patients with modest results. With this study we wanted to test the antitumoral activity of a second generation inhibitor, dacomitinib (D) (PF299804, Pfizer) that binds in an irreversible way to the receptor. D can also inhibit other member of the HER family. Simultaneously to our pre-clinical research, a phase II clinical trial with D is being performed in patients with recurrent GBM with amplification of the EGFR gene (EudraCT: 2011-004671-37; GEINO11). Our goal was to elucidate its mechanism of action and to determine the molecular features of the different GBM in which D treatment could be efficient. Methods: We have performed in vitro experiments in GBM primary cell lines in order to determine how D affects their viability, self-renewal capacity and proliferation. In parallel to the clinical trial we have used lines with EGFR amplification, with or without the presence of the EGFR-vIII, as well as non-amplified GBM lines. We have also carried out in vivo experiments with D to determine if it affects GBM tumor burden. With the heterotopic xenografts we have performed tumor growth curves and we have analyzed the tumor tissue looking for changes in the molecules acting downstream of EGFR (by western blot & IHC). Survival experiments have also been carried out with orthotopic models. Results: Our results confirm that D has an effect on cell viability, self-renewal and proliferation in EGFR amplified +/- EGFRvIII GBM cells. Moerover the in vivo tumor growth rate of these cell lines was also strongly impaired after intragastric administration of D, both in hetherotopic and orthotopic models. Tumors formed in animals treated with D were smaller and presented a reduced number of mitotic cells and an increase of apoptotic cells when compared with control-treated tumors. In contrast with other EGFR inhibitors, D treatment clearly impairs receptor signaling. Conclusions: The results of this research supports the idea that D is active in recurrent glioblastoma and could help to select molecular determinants of response in clinical trials ongoing.
Adolescent and young adults (AYA) with secondary thyroid cancers: Shorter latency as a predictor of death.
Authors: Melanie Goldfarb, Stephen Francis Sener
Journal: Journal of Clinical Oncology (2014)

e20582 Background: Cancer survival rates in adolescents and young adults (AYA: ages 15-39 years) have stagnated. Thyroid cancer (TC) is one of the top AYA cancers and one of the most frequent secondary neoplasms. This study explores the risk of death in AYAs who develop a secondary TC. Methods: SEER ‘Multiple Primary Standardized Incidence Ratios session’ was used to identify all AYA patients with a primary invasive cancer who developed a subsequent TC in the SEER 9 (1973-2010) and 13 (1992-2010) databases. Latency was categorized as < 1 year, 1-5 years, and in 5-year intervals thereafter. Kaplan-Meir and Cox-proportional regression analysis determined survival. Results: Of 660 AYA patients who developed a secondary TC, most were female (86.5%), white (85.5%), non-Hispanic (89.2%), and developed TC before age 45 (68.2%). The most common primary malignancies were lymphoma, melanoma, breast, germ cell, and cervical cancer. On multivariate cox regression, stage of primary AYA cancer [(compared to localized) regional – HR: 2.36, CI: 1.18-4.72; distant – HR: 3.47, CI: 1.58-7.61], having ≥3 tumors (HR: 3.66, CI: 1.89-7.09), a poor or undifferentiated primary malignancy (HR: 2.11, CI: 1.06-4.19), thyroid tumor size >4cm (HR: 2.99, CI: 1.24-7.23), and not undergoing a total thyroidectomy (HR: 2.44, CI: 1.33-4.46) all increased risk of death from any cause. However, the most significant risk of death was a decreased latency to developing TC [compared to >20 years) < 1yr – HR: 93.95, CI: 24.85-355.28; 1-5yrs – HR: 25.33, CI: 6.69-95.87; 5-10yrs – HR: 9.49, CI: 2.57-35.03; 10-15yrs – HR: 8.28, CI: 2.42-28.27). Hematologic vs. solid primary malignancy did not impact overall survival. Conclusions: AYA patients who develop a synchronous or early secondary TC have an increased risk of death compared to patients who develop a secondary TC many years later. Early development of secondary TC may be a marker of genetic instability or a biologically more aggressive primary AYA cancer, not a consequence of prior treatment.
Probability of detection of circulating tumor cells in colorectal cancer stage III-IV.
Authors: Elena Alekseevna Nikipelova, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Aleksey Yurievich Maksimov, Andrey Vladimirovich Bakhtin, Olesia Vladimirovna Nistratova, Elena Petrovna Ulianova, Valeria Anapalian
Journal: Journal of Clinical Oncology (2014)

e22035 Background: The purpose of the study was to conduct a quantitative assessment of CTCs in the peripheral blood of patients with colorectal cancer stage III-IV. Methods: 20 patients with locally advanced colorectal cancer (stage III) and 25 patients with diagnosed liver metastases (stage IV) were studied. Histological type of the tumors in all patients was adenocarcinoma G2-G3. For detection of CTCs the Veridex CellSearch system by Johnson and Johnson was used. Material was scanned by CellTracks Analyzer II. CTCs were separated and differentiated taking into account the morphological characteristics of scanned cells, expression of epithelial cell adhesion marker EpCAM, CD45 and cytokeratins 8,18,19. A blood sample with presence of 3 or more tumor cells was considered to be positive. Results: The analysis of the presence of CTCs in the blood of patients with colorectal cancer III stage reveals the presence of tumor cells in 15% of the cases (3 out of 20 patients), where they were noted from 1 to 3 with 100% frequency. This indicator did not exceed the threshold of positivity – 3 cells in 7.5 ml of peripheral blood. In the IV stage CTCs were found in 14 of 25 patients (56%): in 6 patients (42.9%) CTCs were detected in number from 1 to 3, in 3 patients (21.4%) CTCs were detected in number from 3 to 10, and in 5 patients (35.7%) CTCs were detected in number over 10. Conclusions: The minimum number of CTCs was found in patients after chemoradiation treatment, that can be one of the criteria for evaluating the efficiency of the performed therapy, in contrast all patients with CTCs number over 10 showed the progression of tumor process.
Exploring variations in multiple myeloma management through in-practice research.
Authors: Thomas William LeBlanc, Cristina Gasparetto, Sascha Alexander Tuchman, Peter Sheldon, Alexandra Howson, Wendy Turell, Zeba M. Khan, Satyin Kaura, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2014)

e19534 Background: The growing availability of novel therapeutic options for managing multiple myeloma has increased the complexity of clinical decision-making. Studies indicate variations in practice patterns (e.g. in risk-adapted therapy and referral for stem cell transplant) and in adherence to standards of care in myeloma management. However, the root causes of such variability remain under-explored. Methods: We are conducting 20-25 in-depth, audio-recorded interviews with a cohort of clinicians in 5 regional academic and 5 community-based oncology practices that together provide care for approximately 250 patients with myeloma per week, to explore factors that influence the selection of therapy and management strategies across the myeloma spectrum. Audio files have been de-identified, transcribed, and analyzed inductively and iteratively using a constant comparison method, aided by NVivo 10 software. Results: Initial analysis points to the following areas of contrast between clinicians who consider themselves specialist myeloma providers and generalist oncologists working in the community: Where specialists emphasize the importance of formal risk stratification and International Myeloma Working Group criteria to guide front line therapy, heuristic ‘rules of thumb’ may underlie decision-making of generalist oncologists; Specialists view themselves as earlier adopters of newly approved agents and as resources for educating general oncologists; Generalist oncologists characterize combination therapy at relapse as ‘hard to use’ whereas specialist physicians feel that combination therapy is ‘not used properly’ in the community. Conclusions: Emerging themes point to the variable role of ‘tacit knowledge’—knowledge that is acquired through experience and cannot be explicitly articulated—in informing patient management, which may have implications for the practice of evidence-based medicine and optimal myeloma management. General oncologists may rely more on ‘tacit knowledge’ instead of formal guidelines for risk-stratification and monitoring of treatment response, signaling a need for improved education and evidence implementation programs.
Fostamatinib, a Spleen Tyrosine Kinase Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia: Initial Results of the Multicenter, Open-Label Extension Period of the Soar Phase 2 Study
Authors: David J. Kuter, Richy Agajanian, Donald M. Arnold, Michael Boxer, Catherine Broome, Joshua J. Field, Irina Murakhovskaya, Kerry A. Rogers, Ann M Lowe, Sandra Tong, Hany Zayed, Anne-Marie Duliege
Journal: Blood (2018)
Randomized phase II study of personalized peptide vaccination in patients with advanced bladder cancer progressing after chemotherapy.
Authors: Masanori Noguchi, Kazumasa Matsumoto, Hirotsugu Uemura, Gaku Arai, Masatoshi Eto, Seiji Naito, Chikara Ohyama, Yasutomo Nasu, Masatoshi Tanaka, Fukuko Moriya, Shigetaka Suekane, Satoko Matsueda, Nobukazu Komatsu, Tetsuro Sasada, Akira Yamada, Kyogo Itoh
Journal: Journal of Clinical Oncology (2014)

3092 Background: A personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anti-cancer immunity in the majority of patients along with the potential of survival benefits. The purpose of this study was to assess the efficacy and toxicity of personalized peptide vaccination (PPV) as second-line therapy in patients with advanced metastatic bladder cancer. Methods: We conducted a multicenter, randomized phase II study to compare PPV plus best supportive care (BSC) with BSC alone in patients with advanced metastatic bladder cancer who failed or progressed after first-line platinum-containing regimens. PPV treatment was using maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen (HLA) types and peptide-reactive immunoglobulin (IgG) titers, for 12 times of subcutaneously injections (8 injections, weekly; 4 injections, by-weekly). Primary outcome was progression free survival (PFS). Secondary outcomes were overall survival (OS), immune response and toxicity. Results: From 2010 to 2013, 80 patients were randomly assigned; 38 patients were assigned to PPV plus BSC, and 42 patients were assigned to BSC alone. After median follow-up of 4.5 months, the median OS was 8.3 months on PPV plus BSC versus 4.2 months on BSC alone (hazard ratio [HR], 0.533; log-rank p = 0.0423). PFS was not significantly longer on PPV plus BSC (HR, 0.622; log-rank p = 0.0621). Both treatments were well tolerated, without serious adverse drug reactions. Peptide-specific IgG or cytotoxic T-lymphocyte responses were observed in 20 of 26 patients (77%), or 8 of 19 patients (42%) on PPV plus BSC, respectively. Conclusions: PPV as second-line therapy in patients with advanced bladder cancer is active and well tolerated improving survival with immune responses. Further large scale, randomized trials are needed to confirm our preliminary results. Clinical trial information: UMIN000003157.
Amilorides: Familiar antihypertensive medications with a novel potential against breast cancer.
Authors: Jean Paul Atallah, Abhirami Vivekanandarajah, Muhammad Jawad Popalzai, Kavitha Paramanathan, Homam Alkaied, Nelly Antoine Aoun, Mario Castellanos, Frank J. Forte, Jimmie Fata
Journal: Journal of Clinical Oncology (2014)

1085 Background: When compared to normal breast epithelial cells, breast cancer cells exhibit increased metabolic activity, which produces excessive intracellular hydrogen ions (H+). This increase in intracellular acidity (decrease in pH) is ameliorated by increasing the activity of the hydrogen pump, NHE1, which exchanges one intracellular H+ with an extracellular Na+. Therefore, breast cancer cells require the constant activity of NHE1, whereas normal cells do not. Methods: The objective of this project is to:1) Test the anti-cancer effects of two different NHE1 inhibitors (5-methyl-N-isobutyl Amiloride (MIA) and the well know antihypertensive Amiloride Hydrochloric Acid (A-HCl) ) on three human breast cancer cell lines (MCF-7, SKBR3, and MDAMB468); 2) Determine whether MIA can potentiate the effects of Cyclophosphamide (CPA) or Doxorubicin (Dox); 3) Assess the relationship between MIA treatment and the pro-survival transcription factor NF-kappa-B. Results: Treatment of all of three breast cancer cell lines with either MIA or A-HCl induced a dose-dependent cytotoxic response, with MIA being ~10-times more effective than A-HCl. The cancer cells MDAMB468, which models triple negative breast cancer, were the most sensitive to amiloride treatment. MIA when delivered in combination with CPA, increased the latter’s cytotoxic effect, however, this was not seen when breast cancer cells were exposed to a combination of MIA and DOX. In response to MIA treatment alone, breast cancer cells exhibit an immediate increase in nuclear localization of NF-kappaB. Conclusions: Our results suggest that amilorides can be used alone or in combination with existing chemotherapies to effectively kill breast cancer cells. Cyclophosphamide with MIA combination demonstrated enhanced antitumor activity. The molecular response of amiloride treatment, involves at least in part, nuclear localization of the transcription factor NF-kappaB. Amilorides as antihypertensives have a very good safety profile. We show that inhibiting NHE1 activity with amilorides offers a novel approach to treating breast cancer.
Adding Hydroxyurea in Combination with Ruxolitinib Improves Clinical Responses in Hyperproliferative Forms of Myelofibrosis
Authors: Novella Pugliese, Claudia Giordano, Davide Nappi, Luigia Luciano, Claudio Cerchione, Mario Annunziata, Beniamino Casale, Elena Crisà, Maria Rosaria Villa, Luca Pezzullo, Mariolina Iovine, Marco Picardi, Francesco Grimaldi, Maria Monteverde, Fabrizio Pane
Journal: Blood (2018)
Abstract 17402: Young Women Have More Impaired Left Ventricular Diastolic Function than Young Men in Patients with Never Treated Primary Arterial Hypertension
Authors: Seong-Mi Park, Sua Kim, Mi-Na Kim, Wan-Joo Shim
Journal: Circulation (2014)

Introduction & Purposes: Although the prevalence of arterial hypertension (HT) is higher in men than women in young adults, the gender difference of the anatomic and functional cardiac remodeling b...
Neoadjuvant chemotherapy with nonpegylated liposome-encapsulated doxorubicin (NPLD) plus cyclophosphamide followed by trastuzumab plus nabpaclitaxel for HER2-positive breast cancer (BC).
Authors: Silvana Saracchini, Luisa Foltran, Anna Bassini, Sandro Sulfaro, Michele Lorenzon, Elvia Micheli, Alessandro Favero, Wally Marus, Alessandro Del Conte, Giuseppina Gusso, Stefania Manente, Salvatore Tumolo
Journal: Journal of Clinical Oncology (2014)

648 Background: Using a liposomal delivery system NPLD has shown similar efficacy and less cardiac toxicity compared to conventional anthracyclines. Similarly albumin-bound paclitaxel (nabpaclitaxel) has demonstrated higher response rates and improved tolerability compared to conventional taxanes. This study aimed to evaluate the activity and safety of neoadjuvant chemotherapy with NPLD, nabpaclitaxel and trastuzumab for early or locally advanced HER2 positive BC. Methods: Preoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by nabpaclitaxel (260 mg/mq iv) plus trastuzumab (8 mg/mq loading dose iv, then 6 mg/mq iv) every 3 weeks for 4 cycles. All patients received granulocyte colony-stimulating factor as prophylaxis of febrile neutropenia. Primary objective of the study was pathologic complete response (pCR) defined as the absence of residual invasive cancer both in the breast and regional nodes. Also, breast MRI, Contrast-Enhanced-Spectral-Mammography (CESM) and Ki-67 after 1 cycle of chemotherapy were exploratory investigated to assess the ability to predict pCR. Results: 15 pts were treated from September 2011 to November 2013. 14 pts were evaluable for response and completed the planned treatment. Median age was 52 years (range: 28-70), the majority of pts had T2 stage (64%), clinical nodes involvement N+ (71%), ER positive (64%). 6 out of 14 pts had clinical stage III BC. All tumours were grade 3 and 93% had Ki-67 ≥20%. pCR was reported in 64% (9 of 14). The most frequent grade 3 adverse event was myalgia (21%). Breast MRI after 1 cycle showed a significant difference on “signal-intensity/time” (SIT) curve between pCR pts and no-pCR pts, with an increase (type-II to type-III) in 50% of pCR pts and 0% of no-pCR pts. Conclusions: The nanoparticle formulations, nabpaclitaxel and NPLD, combined with trastuzumab seem to be an active and manageable regimen. It may represent an attractive and promising option in neoadjuvant treatment for HER2 positive BC. The role of Breast MRI, CESM and Ki-67 needs further exploration to predict pathologic response.
Abstract 41: Initial Hyperoxia Is Associated with Survival in Postarrest Patients Enrolled in the PATH Database
Authors: David F Gaieski, Anne V Grossestreuer, Sarah M Perman, Robert W Neumar, Marion Leary, Anthony M Napoli, Lance B Becker, Benjamin S Abella
Journal: Circulation (2012)

Introduction: During and after resuscitation from cardiac arrest, patients often receive supplemental oxygen with high FiO 2 . Recent human data suggest that arterial hyperoxia within hours after resuscitation is associated with worse outcomes. We hypothesized that neurologically intact survivors would more likely be normoxic rather than hyperoxic or hypoxic. Methods: Retrospective chart review of post-arrest patients treated with therapeutic hypothermia (TH) in the Penn Alliance for Therapeutic Hypothermia (PATH) database from 11 institutions. Demographic variables were analyzed using chi-square tests. Data were collected at first arterial blood gas (ABG), and 12 hrs, 24 hrs, 36 hrs, and 48 hrs post arrest. Logistic regression was performed to assess the relationship between initial hypoxia (PaO 2 300 mmHg), mortality, and neurologic outcome. Results: We enrolled 179 patients with mean age 59.6 ± 16.4 yrs, 54% male, and 31% of initial rhythms were VF/VT. Sixty-six (37%) survived to discharge; and 50/66 (76%) had good neurologic outcome (cerebral performance category 1 or 2). An increasing percentage of PaO 2 values were in the optimal range at consecutive times (51% 0 hr; 82% 12 hrs; 90% 24 hrs; 93% 36 hrs; 92% 48 hrs). Survivors had significantly higher initial PaO 2 values than non-survivors (242 vs. 187 mmHg; p=0.03). When controlling for initial rhythm and gender, initial hyperoxia (&gt; 300 mmHg) was associated with improved survival relative to normoxia (OR 2.07, 95% CI 0.98-4.36, p=0.055) while initial hypoxia did not affect outcomes (OR 0.63, 95% CI 0.23-1.70, p=ns). Thirty percent (54/179) were hyperoxic at time 0 and 39% (21/54) of them survived with good neurologic outcome. No significant association was found between oxygen status and neurologic outcomes (hyperoxia (OR 1.89, 95% CI 0.83-4.32, p=ns); hypoxia (OR 0.91, 95% CI 0.30-2.77, p=ns). Conclusions: Increasing percentages of patients had arterial oxygen levels optimized after ROSC. Increased survival was shown in patients with hyperoxic initial PaO 2 values when compared to normoxic values. There was no relationship between the arterial oxygen values and neurologic outcomes post-arrest.
Evaluation of retinal microvascular perfusion in systemic sclerosis: a case–control study
Authors: Matthias Rothe, Felix Rommel, Sebastian Klapa, Jens Y Humrich, Relana Nieberding, Tanja Lange, Jan A M Sochurek, Pauline Plöttner, Salvatore Grisanti, Gabriela Riemekasten, Mahdy Ranjbar
Journal: Annals of the Rheumatic Diseases (2019)

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised by obliterative vasculopathy that is not limited to the peripheral microcirculation of the skin, but is also observed in other organs.1 Retinal vascular disease in SSc indicating endothelial cell damage has a prevalence of 34%–55% and might be apparent long before patients become symptomatic.2 3 The gold standard to evaluate retinal microvascular alterations has been fluorescence angiography (FA) for the last 60 years.4 However, the use of FA is quite laborious because it is an invasive procedure that takes time and needs an experienced ophthalmologist to review the resulting images carefully. Recently, optical coherence tomography angiography (OCTA) has been introduced, which generates angiographic images based on motion contrast imaging to high-resolution volumetric blood flow information in a few seconds.5 OCTA is a non-invasive technique, which allows the quantification of perfused and non-perfused areas of the retina in primarily ocular pathologies, but it also mirrors vascular involvement in systemic diseases as most recently shown for systemic lupus erythematosus.6 The aim of this study was to evaluate …