tbuckley/cabot-search huggingface dataset:
Multiparametric MRI assessment during cisplatin and trastuzumab therapy in esophageal adenocarcinoma xenografts.
Authors: Connie Yip, Amanda Weeks, Karen Shaw, Gary J. R. Cook, David B. Landau, Muhammad Siddique, Vicky Goh
Journal: Journal of Clinical Oncology (2015)

e15108 Background: Standard CT imaging is limited for determining neoadjuvant treatment response in esophageal cancer but there is increasing interest in assessing multiparametric MRI (mpMRI) in this role.We evaluated changes in mpMRI during Trastuzumab and Cisplatin therapy in a gastroesophageal adenocarcinoma xenograft model (OE19) expressing human epidermal growth factor receptor 2 (HER2). Methods: 3 groups of female severe combined immunodeficient mice (n = 15) were injected subcutaneously with 5x106 OE19 cells. Animals were treated with intraperitoneal (IP) saline twice a week (Control), Cisplatin 4mg/kg once a week (Group C) or Trastuzumab 20mg/kg twice a week (Group T) for a total of 2 weeks. Animals were scanned on a 9.4T MR imaging system (Bruker, Germany) at 3 time points: before (t0), 24 hours after first IP treatment (t1) and on completion of treatment (t2). Contrast-enhanced T1-weighted (T1w), T2-weighted (T2w), diffusion weighted (DW) and T2*-weighted (T2*) sequences were acquired. Early (t1 - t0) and late (t2 - t0) parameter, tumour volume and image heterogeneity changes were compared between the groups using Kruskal-Wallis test. Results: A reduced growth rate was observed in Group T (Δvolume = 106%) compared to Control (680%) and Group C (305%) (p = 0.041) between t2-t0. Significant changes in DW and T2* (t2 - t0) were also observed. DW skewness increased in Group T (107%) but decreased in Group C (-28%) and Control (-89%) (p = 0.048). A greater reduction in T2* entropy (Group T -7.1% vs Group C -0.2% vs Control -2.2%, p = 0.032), T2* 50thpercentile (-18% vs 4% vs 15%, p = 0.034) and T2* 75th percentile (-13% vs 0.7% vs 21%, p = 0.024) were observed in Group T. A greater increase in T2* uniformity was found in Group T (48%) compared to Group C (3%) and Control (18%) (p = 0.032). There were no significant differences between groups at early t1-t0 assessment. Conclusions: Significant changes were found in DW and T2* parameters in animals treated with Trastuzumab, Cisplatin and Control, possibly reflecting the different drug mechanisms of action & tumour control, on completion of but not early in treatment. These findings offer potential new clinical imaging biomarkers for response assessment.
Major role of the effector to target ratio in rituximab mediated B cell depletion and interferon-Γ production by NK cells: Relevance in NHL and B-cell CLL
Authors: S. Dall’ozzo, C. Kantari, G. Cartron, C. Le Guellec, P. Bardos, H. Watier, G. Thibault
Journal: Journal of Clinical Oncology (2005)

2566 Background: It has proposed that ADCC is a major mechanism for the therapeutic effect of rituximab (RTX) in NHL and may be less important in CLL. A cytokine-release syndrome (CRS) has been observed in RTX-treated CLL patients and it has been assumed that FcγRIIIa engagement on NK cells may be responsible for the CRS. The fact that NK cells may be preferentially directed to ADCC in NHL and to cytokine production in CLL led us to compare the stimulating conditions inducing ADCC and IFN-γ production by human NK cells upon FcγRIIIa engagement by RTX. Methods: IFN-γ production by NK cells was analysed by flow cytometry (FCM). Standard 51Cr assay was used to compare the concentration-effect relationship and the PKC involvement of RTX-induced NK-cell cytotoxicity and IFN-γ production in response to CD20+ Daudi cells. B cell depletion in whole blood samples from healthy donors was analysed by measuring the decrease of CD19+ cells by FCM. IFN-γ production by NK cells was analysed in whole blood samples from h...
Contributions of the kinase cross-reactivity profile of MK-0457 to clinical activity
Authors: C. A. Buser, B. Furey, R. Hoover, M. Harding, J. Pollard
Journal: Journal of Clinical Oncology (2007)

7050 Background: MK-0457 was designed as a small-molecule inhibitor of the Aurora kinases, AUR A, B, and C (Ki,app = 0.66–18 nM). Kinase screens indicate high selectivity of MK-0457 over other Ser/Thr kinases, but nM potency against a small set of wild type and mutant Tyr kinases, including BCR-ABL, JAK-2, and FLT-3. Consistent with this biochemical profile, MK-0457 has clinical activity in patients with chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) with the T315I BCR-ABL mutation and in patients with JAK-2 positive myeloproliferative diseases (MPD). This study compared the enzyme inhibitory profile of MK0457 with kinase inhibition profiles in cell models to further associate biological and clinical activity. Methods: MK-0457 was tested against a panel of ∼200 kinases (at Km for ATP). Viability of BaF3 cells transfected with wild type or mutant BCR-ABL or FLT3 (D845Y and FLT3-ITD mutants) was measured in MTS assays (72 hrs). Cell cycle profiles were determined by FACS analyses. Cellular inhibition of kinase activities was measured by Western Blots using phospho-substrate specific antibodies. Results: In enzyme profiling, MK-0457 (200 nM) shows = 50% inhibition of ABL, T315I ABL, ABL2, FLT-3, FLT-3 D835Y, BMX, JAK2, YES, LYN, and LCK kinases. Western blot analyses indicate nM IC50s for inhibition of phosphorylation of AUR B, Histone H3 (AUR B substrate), FLT-3, BCR-ABL, and STAT5 (substrate of BCR-ABL and FLT-3 mutants). In addition to AUR kinase inhibition, the Tyr kinases are expected to be inhibited at clinical doses of 24–32 mg/m 2 /hr (achieving plasma exposures of &gt;1 μM in patients). Depsite its multi-kinase profile, MK-0457 induces similar cytotoxicity (IC50 ∼300 nM) and shows an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. Conclusions: MK-0457 is a potent Aurora kinase inhibitor with cross-reactivity against a small set of Tyr kinases. Although MK-0457 displays an AUR inhibition phenotype in cells, inhibition of these Tyr kinases may contribute to its observed clinical activity in T315I mutant CML and ALL and in JAK-2 positive MPD. No significant financial relationships to disclose.
Development of phenotypic indexes for the description of morphological injury in breast cancer cell mitochondria
Authors: L. Putignani, S. Raffa, R. Pescosolido, F. Signore, D. Menichella, R. Boldrini, M. Torrisi, P. Grammatico
Journal: Journal of Clinical Oncology (2009)

e22055 Background: Mitochondriopathy has been recently rekindled as new cancer theory. We report on structural damage of breast-infiltrating ductal carcinoma (IDC) mitochondria characterised by reduced expression levels of the oxidative phosphorylation system (OXPHOS). Methods: Mitochondria from HMC-1 (human mammary carcinoma) and HMEC (human mammary epithelial cell) cultures, traced by Mitotracker, were assayed for OXPHOS expression levels using cryo-immunoelectron microscopy (CIEM) quantitative labelling and fluorescence immunolabelling on unfractionated HMC-1 and HEMC cells. Convolution degeneration was established by transmission electron microscopy (TEM). Twenty different cell sections for both HMC-1 and HEMC cells, including 65 and 72 mitochondria, respectively, were randomly recorded and quantitatively analyzed for the percentage of area occupied by intact cristae to provide a grading of mitochondrial damage (cristae loss index). Results: Depressed expression levels were detected for all HMC-1 OXPHOS complexes by CIEM. Normalized labelling density (HEMC/HMC-1), expressed as colloidal gold particles/mitochondrial area (ρ) provided the following values: 1.77 for the NADH-ubiquinone oxidoreductase complex I NDUFS3; 1.86 for the succinate- dehydrogenase complex II SDH-B protein; 1.63 for the ubiquinol cytochrome c reductase complex III UQCRC2; 4.88 and 1.58 for the cytochrome-oxidase complex IV (CO) subunit I and IV, respectively; 2.70 for the ATP-synthase complex V F1β protein. Fluorescence immunolabelling confirmed CIEM quantitative data. MitoTracker's co-staining showed altered membrane potential and permeability. Injury grading was categorised assigning three levels of morphological damage: i) severe, ii) moderate, iii) slight, corresponding to 0 % (6.2 % and 1.4 % for HMC-1 and HMEC, respectively), 1–50 % (21.5 % and 2.8 % for HMC-1 and HMEC, respectively) and 51–75 % (44.6 % and 15.3 % for HMC-1 and HMEC, respectively) of area occupied by intact cristae (p&lt;0.0001, χ 2 Test). The entire HMC-1 mitochondrial damage resulted 3.7 times higher than that observed for HMEC cells (72.3 HMC-1 %/19.5 HMEC %). Conclusions: New phenotypic harm indexes for IDC cell mitochondria might provide new hallmarks in breast cancer cell biology. No significant financial relationships to disclose.
Detection of combinations of cytogenetic abnormalities in chronic lymphocytic leukemia (CLL) by fluorescent in situ hybridization (FISH) probes.
Authors: M. T. Schweizer, Y. Zhang, R. Kunnavakkam, T. Karrison, M. M. Le Beau, R. A. Larson
Journal: Journal of Clinical Oncology (2010)

6591 Background: Recurring chromosomal aberrations are detectable in ∼70% of patients (pts) with CLL using interphase FISH. Four common abnormalities associate with time to treatment, clinical response, and survival. The frequency of multiple abnormalities and the significance of these combinations on outcomes has not been well described. Methods: We studied CLL cells from 171 consecutive pts using a standard protocol in our Cancer Cytogenetics Lab for del(13q), +12, del(11q), and del(17p). We measured survival from first FISH analysis. Median follow up was 15.5 months (range, 0-82.1). Results: 47 (28%) pts have died with a median survival of 58.8 mos. 17 pts were studied twice; 8 pts had unchanged FISH results; 3 acquired an additional abnormality [del(17p) in 2]; 6 lost an abnormality, most often reverting to normal. 5 of 6 pts who lost an abnormality and 2 of 3 who acquired an abnormality had received treatment during the interval. 39 (23%) pts had multiple abnormalities. By overlapping percentages of positive cells, at least 14 (8%) pts had 32 co-existing abnormalities in the same cells. Multivariate analysis based on a hierarchical model (Dohner, NEJM 2000;343:1910) revealed a hazard ratio for death for all pts with a del(17p) to be 4.4 (p<0.001). Other subgroups did not reach statistical significance. Conclusions: Pts with sole del(13q) and +12 tended to have longer survivals. The combination of del(13q) with other less favorable abnormalities did not confer a longer survival, however. Larger numbers in each small subgroup must be studied to provide adequate power to detect significant differences. FISH abnormality No. of pts (%) Median survival (mos) None 45 (26) 60.4 del(13q) sole 40 (23) >53.7 del(11q) sole 3 (1.8) * +12 sole 34 (20) 58.8 del(17p) sole 10 (5.9) 11.7 del(13q), del(11q) 10 (5.9) >18.5 del(13q), +12 5 (2.9) * del(13q), del(17p) 8 (4.7) 12.1 del(11q), +12 3 (1.8) * del(17q), +12 8 (4.7) >1.1 del(13q), del(11q), del(17p) 1 (<1) * del(13q), del(11q), +12 1 (<1) * del(13q), +12, del(17p) 2 (1.2) * del(11q), +12, del(17p) 1 (<1) * * Too few pts to estimate median survival. No significant financial relationships to disclose.
IgE recognition of multiple novel Api m 10 isoforms evaluated by protein array technology
Authors: Matthias Van Vaerenbergh, Lina De Smet, S Blank, E Spillner, D Ebo, T Jakob, Bart Devreese, Dirk de Graaf
Journal: Allergy (2013)

Background: Until now, two splice variants of the honeybee venom allergen Api m 10 have been described. Variant 2 exhibits IgE reactivity with approximately 50% of honeybee venom sensitized patients. Our proteomic analysis of honeybee venom gave an indication for the existence of additional Api m 10 isoforms. As such, further research was needed to identify these isoforms and investigate the impact of protein heterogeneity on IgE recognition.
Method: Novel isoforms were searched by sequence analysis of cloned RT-PCR amplicons. All isoforms were produced as synthetic peptides or aglycosylated recombinant proteins and were spotted on nitrocellulose-coated glass slides. The colorimetric protein array technology was used to test IgE reactivity of the complete panel of isoforms using sera of 22 Api m 10 sensitized patients. 
Results: Nine additional Api m 10 isoforms were found, which derive from the same genomic locus by a complicated alternative splicing. Some truncated isoforms are produced by frameshifts which introduce an alternative stop codon. All 11 variants were obtained as synthetic peptides or purified bacterial recombinants. The colorimetric protein array showed differential IgE reactivity of different Api m 10 isoforms and allowed to predict an IgE epitope.
Conclusion: Differential IgE reactivity of eleven Api m 10 isoforms was investigated using the colorimetric protein array technology. This approach shows some major benefits for testing IgE reactivity of a broad antigen panel. First, compared to many other technologies, only very low amounts of serum (25 µl) are needed. Second, in contrast to fluorescent arrays, the colorimetric signal detection allows the use of much cheaper scanners.
AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study
Authors: R. Dummer, C. Robert, P. B. Chapman, J. A. Sosman, M. Middleton, L. Bastholt, K. Kemsley, M. V. Cantarini, C. Morris, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2008)

9033 Background: AZD6244 is an orally available, potent, selective, ATP uncompetitive inhibitor of MEK1/2, with preclinical and phase I data suggesting it has the potential for anti-tumor activity in pts with melanoma. Here we evaluate the efficacy and safety of AZD6244 vs TMZ in an overall population of advanced melanoma pts and in mutated BRAF (BRAF+) or mutated NRAS (NRAS+) subgroups. Methods: Eligibility included AJCC stage 3/4 malignant melanoma, RECIST measurable disease, and no prior chemotherapy for advanced melanoma. Pts were randomized 1:1 to AZD6244 (100mg BD continuously) or TMZ (200 mg/m2 for 5 days, q28d). Pts randomized to TMZ could receive AZD6244 after disease progression. The primary outcome variable was progression-free survival (PFS), which was then adjusted for source of primary tumor (uveal vs non-uveal), mutation status, LDH (> or ≤2 x ULN), and WHO PS (0–2). Mutation status was assessed in archival or fresh tumor samples by DNA sequencing. Results: A total of 104 and 96 pts were randomized to AZD6244 and TMZ, respectively. To date, 146 pts have their mutation status confirmed, 67 were BRAF+, and 24 NRAS+. Of the non-uveal pts, 50% were BRAF+ and 68% were either BRAF+ or NRAS+. For PFS, there was no difference between the two treatment arms in the overall population (151 events; HR 1.07; 80% CI 0.86, 1.34) or in the BRAF+ subgroup (HR 0.85; 80% CI 0.58, 1.24). Overall survival (OS) data are immature (67 deaths) but the interim analysis showed no difference between the two arms in the overall population (HR 1.23; 80% CI 0.88, 1.71). In BRAF+ pts (25 deaths) the HR estimate for OS favored AZD6244 (HR 0.68; 80% CI 0.38, 1.21). Six pts receiving AZD6244 had a confirmed PR, of which 5 were BRAF+ (12% of BRAF+ pts). Nine pts receiving TMZ had a confirmed PR, 3 of which were BRAF+ (12% of BRAF+ pts). Commonly reported adverse events with AZD6244 were acneiform dermatitis (60%), diarrhea (56%), nausea (50%), peripheral edema (38%), fatigue (27%), and vomiting (26%). Updated trial data will be presented. Conclusions: Anti-tumor activity with AZD6244 has been seen but there was no significant difference in PFS between the treatment arms. The trial is being followed for mature OS data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Bayer, Genentech, Wyeth AstraZeneca AstraZeneca, Bayer, Genentech, Wyeth AstraZeneca
AB0648 Disease Mapping in Anca Associated Vasculitis (AAV). Yield of FDG-PET/CT Imaging Versus a Conventional Clinico-Pathological Approach,:
Authors: H. Laustrup, M.J. Velander, P. Junker, S. Hess
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> AAVs are systemic autoimmune diseases which mainly involve small to medium sized vessels in a diversified and often unpredictable manner leading to disease patterns which can be difficult to diagnose upon first encounter. Moreover, early or clinically quiescent lesions may go unrecognized leading to missed therapeutic opportunities. While there is emerging evidence for a diagnostic role of FDG-PET/CT in large vessel vasculitis, there is still uncertainty concerning the utility of this technique in small vessel vasculitis. <h3>Objectives</h3> To compare the number and distribution of inflammatory lesions in incident AAV as assessed by conventional diagnostics versus FDG-PET/CT. <h3>Methods</h3> In 2009-2012, FDG-PET/CT was done in 17 patients who subsequently turned out to have AAV according to current criteria. Medical files were searched for vasculitis associated disease manifestations, laboratory/imaging findings and indications for FDG-PET/CT scans. The Birmingham Vasculitis Activity Score (BVAS) was calculated. All scans were re-evaluated visually and maximum standardized uptake values (SUVmax) were recorded. <h3>Results</h3> Median age was 62 years (range 48-81), Female/Male ratio 5/12. Fourteen had granulomatosis with polyangiitis and 3 had eosinophilic granulomatosis with polyangiitis or microscopic polyangiitis. 6/17 had received intermediate or high dose glucocorticoid treatment for median 5 days (range 1-27) before scanning. Indications for FDG-PET/CT were suspected cancer 9/17 (53%), infection 3/17 (29%), vasculitis 2/17 (12%) and unspecified 1/17 (6%). A total of 15/17 (88%) had increased FDG uptake at one or more sites. The only 2 patients with a negative FDG-PET/CT scan had received glucocorticoids before the procedure. The distribution of organ involvement assessed clinically or by FDG-PET/CT is presented in the table. Clinically silent sites with increased FDG uptake were recorded in 4 patients including the aorta, pericardium, lung and shoulder. Three additional patients had increased renal FDG uptake without corresponding laboratory findings indicating kidney disease. There was no correlation between SUV max and BVAS. <h3>Conclusions</h3> A classical clinical approach was superior to FDG-PET/CT alone to detect small vessel vasculitis related disease manifestations in all organs. There was no correlation between SUV max and disease activity expressed as BVAS. Increased kidney FDG uptake should be interpreted with caution because it may reflect normal renal excretion. The significance of increased FDG uptake in clinically silent areas is uncertain. <h3>Disclosure of Interest</h3> None declared
Expression of the adhesion molecule ICAM-1 in non-Hodgkin's lymphoma: relationship with tumor dissemination and prognostic importance.
Authors: M J Terol, A López-Guillermo, F Bosch, N Villamor, M C Cid, C Rozman, E Campo, E Montserrat
Journal: Journal of Clinical Oncology (1998)

PURPOSE To study the expression of intercellular adhesion molecule-1 (ICAM-1) by non-Hodgkin's lymphomas and to assess its correlation with disease extension and prognosis. PATIENTS AND METHODS ICAM-1 (CD54-IOL54) expression was studied in 70 patients (35 male/35 female; median age, 56 years) with non-Hodgkin's lymphoma from a single institution. Immunostaining was performed using a streptavidine-biotin alkaline phosphatase method and ICAM-1 expression was evaluated in a semiquantitative manner. The histologic distribution of the cases was the following: small lymphocytic, five cases; follicular, 14; mantle cell, five; diffuse large cell, 41; and T lymphoblastic, five. Forty patients (57%) were in stage IV, bulky disease was observed in 25 patients (36%), and extranodal involvement in 48 patients (69%). RESULTS ICAM-1 expression was negative (-) in 14 patients (20%), weak (+) in 21 (30%), positive (++) in 30 (43%), and strongly positive ( ) in five (7%). No significant relationship was found between ICAM-1 expression and the lymphoma histologic subtype. Patients with negative or weak ICAM-1 expression had more frequently disseminated (stage IV) disease (74% v 40%; P = .007), extranodal involvement (86% v 51%; P = .004), and bone marrow infiltration (57% v 26%; P = .015) than the remainders. Positive ICAM-1 patients had survival rates significantly better than those in whom ICAM-1 was negative or weakly expressed [2-year overall survival: 77% v 50%, respectively; P &lt; .025]. In a multivariate study, ICAM-1 (P = .005) maintained, along with histologic subtype (P = .001) and the international prognostic index (IPI) (P = .056), its importance for predicting survival. Finally, when the group of aggressive non-Hodgkin's lymphoma patients was analyzed, ICAM-1 expression inversely correlated with advanced stage (P = .025), extranodal involvement (P = .01), and bone marrow infiltration (P = .01), complete response (CR) achievement (65% v 32%; P = .025), and overall survival (70% v 26% at 2 years; P &lt; .005). CONCLUSION In lymphoma patients, ICAM-1 expression correlates with lymphoma dissemination and is useful to assess prognosis.
Tumor reduction in pancreatic versus metastatic sites in a randomized phase III study (MPACT) of weekly <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) versus Gem alone.
Authors: Volker Kunzmann, Ramesh K. Ramanathan, David Goldstein, Darryl Neil Penenberg, Stefano Ferrara, Brian Lu, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2015)

382 Background: nab-P + Gem was superior to Gem alone in MPACT, a phase III metastatic pancreatic cancer (PC) trial, for all endpoints examined. An updated analysis verified the superior overall survival of nab-P + Gem vs Gem alone (median 8.7 vs 6.6 months; hazard ratio 0.72; P &lt; 0.001). Whether antitumor agents may have differential activity on pancreatic vs metastatic lesions in PC has not been definitively addressed. This prespecified analysis examined the activity of nab-P + Gem vs Gem alone in reducing tumor size in pancreatic and metastatic lesions. Methods: Previously untreated metastatic PC pts (N = 861) were randomized 1:1 to receive nab-P 125 mg/m 2 + Gem 1000 mg/m 2 days 1, 8, and 15 every 4 weeks or Gem alone 1000 mg/m 2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycles ≥ 2). Most pts (99%) underwent spiral CT imaging, allowing precise tumor measurement. Changes in the sum of target tumor diameter from baseline to postbaseline nadir were evaluated separately for pancreatic and metastatic lesions by independent radiological review. Results: Baseline sizes of pancreatic and metastatic tumors were comparable between treatment arms (Table). nab-P + Gem elicited an approximately 3-fold greater median percentage decrease vs Gem alone in pancreatic (−22.15% vs −7.02%) and metastatic (−24.27% vs −8.74%) tumor size, agreeing with the 3-fold higher overall response rate of target lesions by RECIST. Tumor shrinkage was similar between pancreatic and metastatic lesions. Conclusions: nab-P + Gem was associated with a greater reduction in tumor size of both primary and metastatic lesions compared with Gem alone. Clinical trial information: NCT00844649. [Table: see text]