tbuckley/cabot-search huggingface dataset:
Expression profiles associated with disease progression in non-small cell lung cancer.
Authors: C. Frankenberger, S. Basu, N. Bild, A. Potti, M. Raponi, Y. Wang, D. G. Beer, J. Coon, P. Bonomi, J. A. Borgia
Journal: Journal of Clinical Oncology (2010)

e21103 Background: Lung cancer is the leading cause of cancer death in the developed world and non-small cell lung cancer (NSCLC) is the most common form of this disease. Patients with early-stage tumors have favorable prognosis when treated with surgical resection and lymph node sampling, however, disease recurrence occurs in 40% of these patients. Reposited cancer-focused microarray data has increased in size and quality. Bioinformatics tools to analyze large data sets have also become available in open source applications running on standard computing platforms. Here we performed an extensive evaluation of published expression array data to define a signature for metastatic progression in NSCLC. Methods: Combining multiple large studies of the same array platform (Affymetrix U133A) annotated with tumor stage and clinical follow-up, lymph node negative patient lung tumors with no recurrence in 24 months (n = 228) were compared to node positive patient lung tumors (n = 161). CEL files were processed using Bioconductor xps, arrayqualitymetrics and SAMR packages. The genes with the most significant variation across groups (p < 0.001) were analyzed using randomforest and rpart packages to determine robust and predictive biomarkers. Results: Analysis yielded a panel of twelve probes that correspond to eleven genes: KIAA1609 (matched two probes), lysosomal-associated membrane protein 3 (LAMP3), glycyl-tRNA synthetase (GARS), fibroblast growth factor 1 (acidic) transcript-variant 3 (FGF1), Transcribed locus chr 15 (probe ID 213700_s_at), cold inducible RNA binding protein transcript variant 1v(CIRBP), chromosome 2 open reading frame 37 (C2orf37), MAP/microtubule affinity-regulating kinase 4 (MARK4), neural precursor cell expressed developmentally down-regulated 9 transcript-variant 1 (NEDD9), HLA complex group 4 non-coding RNA(HCG4) and promyelocytic leukemia transcript-variant 8 (PML). Conclusions: This study establishes a robust panel of biomarkers which is being validated against other cohorts of reposited NSCLC microarray data performed on the Affymetrix U133plus2 platform. The wide range of biological functionality of some of the markers complemented by the genomic co-localization of others is promising. No significant financial relationships to disclose.
Discharge in less than 30 hours after an open radical retropubic prostatectomy. A prospective study
Authors: E. Café, M. Tannus, E. Nepomuceno, F. Quintiliano, P. Boente
Journal: Journal of Clinical Oncology (2009)

e16156 Background: Radical Retropubic Prostatectomy (RRP) is one of the most frequent surgery performed by urologists and it has been accompanied by an improvement in surgical results such as duration of hospitalization. In this study we prospectively analyzed the viability of an early discharge from hospital after an open RRP. Methods: There were 37 consecutive RRP performed by the same surgeon from March 1 st to August 30 th of 2007. All of the patients were informed about the possibility of discharge from hospital in less than 30 hours after the surgery. The procedures were performed using a modified Walsh technique under combined anesthesia (general anesthesia and epidural anesthesia p analgesia with morphine) through midline incision initiated approximately 5,0 centimeters below of umbilicus. Obturatory lymphadenectomy was performed in only three patients and Exclusion criteria included patients with an Body Mass Index above 30, patients who refused to participate in the study and those with prior indication to go to the intensive care unit postoperatively. Respiratory and motor physiotherapy were initiated soon after return from the surgical block. Criteria to discharge from hospital included: good acceptance of oral diet, no need for parenteral analgesics; urinary volume &gt; 75 ml/hour; no Foley catheter obstruction; absence of gross hematuria; urine drainage &lt; 150 ml/24 hours. Results: 32 patients (86%) had discharged from hospital in less than 30 hours after the surgery: there were 25 patients (68%) discharged in the first 24 hours after surgery and 07 patients discharged between 24 and 30 hours after surgery. There wasn't any readmission in a period of 15 days after discharge from hospital. There were only three complications (8%)on days 07, 10 and 13 and 01 patient need to wash an obstructed Foley catheter with blood clot at postoperative day four. Conclusions: By means of simple criteria it is possible to early discharge patients after an open RRP in selected patients and it may represent a significant reduction in costs. No significant financial relationships to disclose.
LAG-3 (CD223) molecule is preferentially expressed in human CD4+CD25+ T cells displaying suppressor activity
Authors: Chiara Castelli, Francesca Rini, Chiara Casati, Chiara Camisaschi, Arabella Mazzocchi, Frederic Triebel, Giorgio Parmiani
Journal: Cancer Research (2007)

221   LAG-3 (CD233) molecule is expressed on activated NK cells and CD4 +  and CD8 +  T lymphocytes and binds MHC class II molecules with a higher affinity than CD4. Studies in mice have indicated that this molecule has a complex role in controlling T cell functions and that it is directly involved in mediating the activity of murine Treg cells. We studied the expression of CD233 in different human T cell subsets of healthy donors: We found that, although expressed also by CD25-CD4+ T cells, CD233 is strongly up-regulated in naturally occurring CD4+CD25+ T cells and its level of expression is further enhanced in  in vitro  stimulated CD4+CD25+ T cells. In freshly isolated CD4+CD25+ T cells CD233 is often associated to the expression of CD45RO, HLA-DR, CD71, CD122, CD62L and to the high level of CD25. Moreover, inside the naturally CD4+CD25+ T cells or in  in vitro  allo-activated CD4+CD25+ T cells, CD233 defined a subset of cells showing high amount of Foxp3 expression. Functional studies using CD4+CD25+CD233+ T cells sorted from in vitro activated CD4+CD25+ showed that this T cell subset displayed potent suppressor activity if compared to the CD233 negative counterpart or to the unsorted population. Stage III-IV metastatic melanoma and colorectal cancer patients did show an increased frequency of CD4+CD25+CD233+ T cells in their PBMC as compared to healthy individuals. Moreover tumor invaded lymph nodes included CD4+ CD25 brigh  T cells expressing Foxp3 and CD233. Altogether, our data strongly suggest that, when used in combination with CD25, CD233 could be considered a good marker to define regulatory T cells with enhanced suppressor activity.
The prognosis of HER2/neu expression in axillary lymph node-negative breast cancer patients
Authors: G.-H. Di, H.-C. Li, Y.-F. Hou, J.-S. Lu, J. Wu, G.-Y. Liu, Z.-Z. Shen, Z.-M. Shao
Journal: Journal of Clinical Oncology (2004)

9653 Background:To evaluate the prognostic value of HER2/neu over-expression in node-negative patients. Methods:Specimens from the primary tumors of 137 axillary lymph node negative patients who underwent surgery between 1990–1998 were obtained from the files of the Department of Pathology at Cancer Hospital,Fudan University following an approved institutional review board protocol. Immunohistochemical analysis of HER2/neu protein expression in breast carcinoma samples was performed. We analyze the association of HER2/neu over-expression with other clinic-pathological factors by chi-square test. Univariate and multivariate analysis were performed to evaluate the prognostic significance of HER2/neu over-expression in relapse free survival and overall survival. Results:We found HER2/neu over-expression had no correlation with other clinic-pathological factors such as menopausal status, tumor size, tumor grade, p53, ER and histotype. We also found over-expression of HER2/neu is a significantly unfavorable prognostic factor for RFS in steroid receptor positive patients(log-rank test, p=0.0011), but not ER and PR negative patients. Multivariate analysis showed that HER2/neu together with tumor size and p53 was independently prognostic factor for RFS in node-negative patients (p<0.05). Conclusions:We concluded that for lymph node-negative patients, HER2/neu over-expression combined with steroid receptor status can be meaningful to patients'prognosis. No significant financial relationships to disclose.
Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL).
Authors: Lia Gore, Gerhard Zugmaier, Rupert Handgretinger, Franco Locatelli, Tanya M. Trippett, Susan R. Rheingold, Peter Bader, Arndt Borkhardt, Todd Michael Cooper, Maureen Megan O'Brien, Christian M. Zwaan, Anja Fischer, James Whitlock, Arend von Stackelberg
Journal: Journal of Clinical Oncology (2013)

10007 Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ≤1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be &lt;18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 µg/m²/d) and two DLTs at dose level 3 (30 µg/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 µg/m 2 /d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR &lt;10 -4 . Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782. [Table: see text]
Correlation between pre-existing MEK1<sup>P124</sup> mutations and clinical and in vitro response to BRAF inhibitors in metastatic melanoma.
Authors: Matteo S. Carlino, Carina Fung, Hamideh Shahheydari., Jason R Todd, Richard A Scolyer, Richard Kefford, Georgina V. Long, Helen Rizos
Journal: Journal of Clinical Oncology (2014)

9004 Background: MEK1 mutations can confer resistance to BRAF inhibitors although pre-existing MEK1P124 mutations do not preclude clinical responses to BRAF inhibitor therapy. We sought to determine if pre-existing MEK1P124 mutations affected clinical outcome in BRAF inhibitor treated melanoma. Methods: Data from three published data sets, and from patients treated at our institutions, were analyzed to determine if pre-existing MEKP124 mutations affect radiological response or progression-free survival (PFS) in BRAFV600 mutant metastatic melanoma patients treated with vemurafenib or dabrafenib. The effects of MEK1P124 mutations on MAPK pathway activity and response to dabrafenib were also investigated in a series of cell models. Results: 123 patients with pre-treatment tumors tested for MEK1 mutations were included. Those with a pretreatment MEKP124 mutation (n=12) had a poorer RECIST response (33% vs 71% CR or PR in MEK1P124 vs MEK1 wild-type, p=0.008), this was associated with a shorter median PFS in those with a MEK1P124 mutation (Median 3.1 vs 4.8 months, p=0.004). Introduction of MEK1 P124Q or P124S variants into BRAF-mutant SKMel28 melanoma cells resulted in diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival compared to cells ectopically expressing wild-type MEK1. The impact of MEK1P124-variants was significantly less than the effect of MEK1K57E, a known mechanism of acquired BRAF inhibitor resistance. Consistent with these data, two BRAF mutant cell lines with endogenous MEK1P124 mutations, including a short term culture generated pre-treatment from a patient who responded poorly to combined dabrafenib and trametinib, showed weak sensitivity to dabrafenib (IC50s 21 and 26nM) compared to a panel of MEK1 wild type/BRAF mutant cell lines (median IC50 7nM; range 4-14nM). In contrast, melanoma cell lines showed equivalent sensitivity to ERK inhibition, irrespective of the MEK1 genotype. Conclusions: Pre-existing MEKP124 mutations are associated with a reduced response to BRAF inhibitor therapy but are unlikely to affect response to ERK inhibitors.
Meta-analysis of the impact of human papillomavirus on cancer risk and overall survival in head and neck squamous cell carcinoma
Authors: F. Dayyani, C. Etzel, M. Liu, C. Ho, S. M. Lippman, A. S. Tsao
Journal: Journal of Clinical Oncology (2009)

6080 Background: Human papillomavirus (HPV) is an important etiologic factor in HNSCC and its prevalence has been reported in several independent studies. We conducted a meta-analysis to determine the prevalence of HPV, its impact on risk of developing HNSCC and overall survival (OS). Methods: Pubmed search terms “HPV” and “HNSCC” were used to identify 40 clinical and translational studies between the years 1980–2008 that reported the prevalence of HPV in HNSCC. Statistical software STATA 10.0 was used in the meta-analyses to identify the association of HPV and HNSCC risk and OS. Pooled adjusted odds ratio (OR) or hazard ratio (HR) were obtained using a random-effects model. The amount of heterogeneity between studies was estimated with both the Chi-squared based Q test and the I 2 statistic model. Potential sources of publication bias were detected using funnel plots. OS between the trials was compared in forest plot. Results: A total of 6,794 patients (pts) were included. The prevalence of HPV among HNSCC pts was 24.2%; and 86.8% of all HPV(+) tumors were HPV16. Thirteen studies (n = 1933 pts) determined HPV status by serology and the remainder detected HPV DNA in tumor tissue by PCR. Overall, HPV positivity conferred an increased risk for HNSCC (OR = 1.43; 95% CI 1.04–1.82). Risk for HNSCC among HPV16(+) pts was 4.47 times that of HPV16(-) pts. The OS was improved in HPV(+) pts compared to HPV(-) pts (HR = 0.40; 0.27–0.53). In HPV16(+) pts the HR for OS was 0.41 and the survival benefit was even more pronounced in the subgroup of HPV16(+) oropharyngeal cancers (HR = 0.38;0.17–0.58). Conclusions: This meta-analysis provides further evidence supporting the role of HPV as an important causative agent in HNSCC and supports HPV(+) HNSCC as a separate biologic entity which likely should be treated differently than HPV(-) HNSCC. Additional analysis on treatment outcomes to systemic and local therapy is ongoing. No significant financial relationships to disclose.
Outcomes of special histotypes of breast cancer after adjuvant endocrine therapy with letrozole or tamoxifen in the monotherapy cohort of the BIG 1-98 trial
Authors: E. Munzone, A. Giobbie-Hurder, B.A. Gusterson, E. Mallon, G. Viale, B. Thürlimann, B. Ejlertsen, G. MacGrogan, F. Bibeau, G. Lelkaitis, K.N. Price, R.D. Gelber, A.S. Coates, A. Goldhirsch, M. Colleoni
Journal: Annals of Oncology (2015)
Vascular endothelial growth factor (VEGF) is a survival factor for neuropilin-1-expressing lung tumour cells
Authors: M. P. Barr, G. P. Pidgeon Dr, K. J. O’Byrne Dr
Journal: Journal of Clinical Oncology (2006)

17084 Background: Lung cancer is the leading cause of cancer mortality in Ireland. The formation of new blood vessels, angiogenesis, is essential for tumour growth and metastasis and is induced by several angiogenic factors, including vascular endothelial growth factor (VEGF). Several studies have suggested a role of VEGF as a survival factor for endothelial and some tumour cells. We investigated the effect of VEGF on lung tumour cell survival and examined the VEGF receptor profile of these cells. Methods: A panel of lung cancer cell lines, H460, H647, A549 and SKMES1 were treated with recombinant VEGF (100 ng/ml). Tumour cell survival was assessed using the BrdU proliferation assay. Apoptosis was examined by flow cytometry using Annexin-V and PI staining. VEGF receptor profiles for Flt-1 (VEGFR-1), KDR (VEGFR-2), Neuropilin-1 (NP1) and Neuropilin-2 (NP2) were examined at the mRNA and protein level by RT-PCR and Western blotting, respectively. Tumour cell expression of the Plexin family of signalling receptors was investigated, in addition to the class III Semaphorins which have been shown to bind the Neuropilin receptors. Results: All lung cancer cells expressed NP1 with the exception of the H460 cell line. Using endothelial cells as a positive control, neither VEGFR-1 or VEGFR-2 were identified on the panel of lung cancer cell lines examined at the mRNA and protein level. A dose-response in tumour cell proliferation was observed with the addition of VEGF at 10ng and 100ng/ml. This increase in tumour cell proliferation was significant in all NP1-positive cells, with no effect on NP1-negative H460 cells. VEGF decreased apoptosis in cells expressing NP1, with no effect observed in H460 cells. Our preliminary data show that in addition to NP1, lung cancer cells also express NP2, Plexin-A1, Sema-3A and Sema-3C mRNA which are potential mediators of the NP1 signalling cascade. Conclusions: These results demonstrate that VEGF promotes survival of lung cancer cells, potentially through NP1 signalling. We are currently examining VEGF/VEGFR signalling and the downstream anti- and pro-apoptotic pathways activated in response to VEGF on lung cancer cells. Blockade/inhibition of VEGF and its receptors may offer potential as a therapeutic biological strategy in lung cancer. No significant financial relationships to disclose.
Randomized phase II study of dacarbazine with or without sorafenib in patients with advanced melanoma
Authors: D. F. McDermott, J. A. Sosman, F. S. Hodi, R. Gonzalez, G. Linette, J. Richards, J. K. Jakub, M. Beeram, K. Patel, L. Cranmer
Journal: Journal of Clinical Oncology (2007)

8511 Background: Sorafenib (SOR), a potent and selective multi-kinase inhibitor, exerts its anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1, -2, -3, PDGFR-a, -β, and Raf. Dacarbazine (DTIC) is an FDA-approved cytotoxic agent for advanced melanoma. Phase I/II results of SOR + DTIC were encouraging and prompted this randomized phase II study. Methods: This was a multi- center, double-blinded, placebo-controlled study; eligibility criteria included measurable disease by RECIST, no prior cytotoxic chemotherapy, and no active brain metastases. Advanced melanoma patients (pts) stratified by stage (unresectable III vs IVM1a/M1b vs M1c) and ECOG PS (0 vs 1) were randomized to receive DTIC 1,000 mg/m 2 q 21 days + oral placebo (PL) or oral SOR 400 mg bid continuously until the occurrence of progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS) of DTIC+SOR vs DTIC+PL. Using a two-sided test with a = 0.05, 77 PFS events were needed to detect a hazard ratio (HR) of 0.5 (SOR/PL) with 86 % power. The secondary endpoint was overall survival and tertiary endpoints were objective response rate (ORR), time to progression, and duration of response. Results: 101 pts were enrolled over 12 months (51 DTIC+SOR, 50 DTIC+PL). Treatment arms were balanced for age (median 58 yrs), gender (male 70%), PS (ECOG 1 39%), stage (Stage IV M1c 52%) and baseline LDH (&gt;ULN 29%). At the time of analysis by independent assessment, the median PFS of DTIC+PL vs DTIC+SOR was 11.7 wks (95% CI 6.1, 17.9) vs 21.1 wks (95% CI: 16, 28); HR 0.67 [p=0.07]; PFS rate at Day 180 was 18% vs 41%; and ORR was 12% vs 24%. Survival data are immature. Toxicities of Grade 3 or higher (DTIC+PL vs DTIC+SOR) included neutropenia (12% vs 33%), leukopenia (6% vs 14%), thrombocytopenia (18% vs 35%), thrombosis/embolism (0% vs 6%), hypertension (0 vs 8%), hand-foot skin reaction (0 vs 4%), and CNS hemorrhage (0% vs 8%). 3 of the 4 pts with CNS hemorrhage had new brain metastases. No treatment-related deaths occurred in either arm. Conclusions: DTIC+SOR was well tolerated and showed a strong efficacy trend compared with DTIC+PL in median PFS, PFS rate at 6 months and ORR in chemotherapy-naïve pts with advanced melanoma. This regimen warrants further evaluation in larger clinical trial settings. No significant financial relationships to disclose.
Prognostic value of tumor markers CA 15–3 and CEA during fulvestrant treatment
Authors: R. Bartsch, G. Steger, C. Wenzel, U. Pluschnig, D. Hussian, U. Sevelda, R. Mader, C. C. Zielinski
Journal: Journal of Clinical Oncology (2005)

730 Background: Tumor markers are often used to monitor response to therapy in patients with metastatic breast cancer (MBC) and a surge in tumor markers after 3 months of treatment may be a sign of de novo disease progression (PD). Here we evaluated the prognostic value of tumor markers at predicting response and secondary progression during fulvestrant (‘Faslodex’) therapy. Methods: Patients with MBC were treated with fulvestrant 250 mg/month as part of a Compassionate Use Program. Changes in cancer antigen 15–3 (CA 15–3) and carcinoembryonal antigen (CEA) were prospectively monitored on a monthly basis in patients experiencing a partial response (PR), stable disease (SD) ≥6 months and de novo PD. Levels of these markers were also retrospectively evaluated for the 3 months preceding secondary progression in patients who had previously experienced clinical benefit (CB) with fulvestrant. Results: Tumor markers were monitored in 67 patients; seven patients (10.4%) had a PR, 28 patients (41.8%) had SD ≥6 months and 32 patients (47.8%) had de novo PD. In patients with a PR, a non-significant trend towards increased CA 15–3 levels was noted during the first 4 months of treatment; similar results were seen at 6 months. A trend towards reduced CEA levels was seen in these patients after 3 months, which reached significance (p=0.0406) after 6 months of treatment. In patients with SD ≥6 months, CA 15–3 levels increased significantly (p=0.0023) between baseline and 4 months; no clear trends were noted in CEA levels. In those experiencing de novo PD, CA 15–3 levels increased significantly (p=0.0214) after 4 months of treatment; CEA levels also increased, but not significantly. A significant surge (p=0.0016) in CA 15–3 levels was also noted in the final 3 months preceding secondary progression; CEA levels showed a small non-significant increase during this time. Conclusions: Patients experiencing de novo PD or secondary progression with fulvestrant show significantly increasing CA 15–3 levels. However, those experiencing SD ≥6 months and even those with a PR may also show an initial surge in CA 15–3 levels; this should not be taken as a sign as PD without radiological verification. CEA was a poor prognostic marker for response in patients receiving fulvestrant. No significant financial relationships to disclose.