tbuckley/cabot-search huggingface dataset:
Skp2: A molecular prognostic marker in breast cancer
Authors: J. Goulart, T. O. Nielson, D. Voduc
Journal: Journal of Clinical Oncology (2008)

22024 Background: Skp2 is a protein involved in cell cycle control. Previous studies in immunohistochemistry and gene expression profiling have suggested that Skp2 positivity in breast cancer is associated with a poorer prognosis. Skp2 may also be implicated in antiestrogen resistance. Objective: The purpose of this study was to evaluate the prognostic power ofSkp2 in a large case series of primary breast cancer patients. Methods: The case series consists of 2,222 breast cancer patients treated in BC with a median follow up of 11 years. Paraffin blocks were available on all cases. These were used to construct a tissue microarray that was then stained for Skp2 with a commercially available mouse monoclonal antibody. Skp2 expression was considered positive if > 10% of breast cancer nuclei stained positive. A split- sample validation technique was used, whereby the cohort was randomized into equal training and validation sets. Hypothesis were generated from the training set and tested in the validation set. Results: Skp2 expression was positive in 183 cases. Skp2 was significantly associated with younger age, higher grade, larger size, positive lymph node status, and Her2 negative status. Skp2 was strongly associated with ER negative status (Pearson Chi-Square, p = 1.45 E -45). In univariate survival analysis of breast cancer specific survival (BCSS), Skp2 was a significant marker of poor prognosis (log rank test, p = 0.004, BCSS 10 yrs 64% vs. 76%). However, in multivariate survival analysis, Skp2 was not independently prognostic. In the subgroup of ER positive patients who received hormone therapy alone, Skp2 was prognostic (p = 0.03). In the subgroup of ER positive patients who did not receive adjuvant hormonal therapy, Skp2 was no longer prognostic (p = 0.122). Conclusions: Skp2 positive status is associated with poor clinicopathologic features. On univariate anaylsis, Skp2 expression predicts for poor survival in breast cancer. In this study, Skp2 expression was prognostic in the hormone treated ER positive subpopulation but this was lost in the subgroup without adjuvant hormones. This finding suggests that Skp2 may be predictive of antiestrogen response. No significant financial relationships to disclose.
CXCR4 in melanoma: A prognostic biomarker and a target of therapy
Authors: S. Scala, M. Napolitano, F. Fulciniti, P. Giuliano, F. Mauro, C. Ieranò, E. Simeone, A. Ottaiano, G. Botti, P. Ascierto, G. Castello
Journal: Journal of Clinical Oncology (2006)

8051 Background: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. In melanoma metastases CXCR4 is also expressed and functional suggesting that CXCR4 has a role in the melanoma biology. Differential chemokine receptors expression by activated tumor specific CD8+ T cells can be associated with divergent clinical outcomes. Expression of CXCR3 by CD8+ T cells was reported to be associated with survival in melanoma patients with stage III disease. To further characterize the role of CXCR4 in the melanoma metastatization we analyzed Fine Needle Ago Biopsy (FNAB) from disease involved lymph nodes. Moreover, we are currently evaluating CD8+ subpopulation for the expression of CXCR4 during the follow up Methods: FNAB of suspicious disease involved lymphnodes. was performed and the cell suspension was analyzed by flow cytometry and .immunocytochemistry. Peripheral blood lymphocytes (PBL) was analyzed by flow cytometry Results: FNAB were performed on 25. suspicious lymphnodes. Out of 25 FNAB 19 were positive per melanoma cells (HMB45 positive). Concomitant expression of HMB45 and CXCR4 was detected in 15 out of 19 samples.with the percentage of cells CXCR4 positive being the large majority ( 40–100%) of the detected melanoma cells. Ongoing studies are further characterizing the biology of the CXCR4/HMB45 cells. The inhibition of this cells migrating through the lymphnode may interfere with the metastatization. In relation to the CD8+ subpopulation for the expression of CXCR4 during the follow up preliminary data at the time of diagnosis showed a correlation between the activated CD8 + lymphocytes (HLA-DR+) /CXCR4 + and the level of invasion of the lesion. Conclusion: Altoghether these evidences confirm a role of CXCR4 in melanoma biology and as therapeuthic target . No significant financial relationships to disclose.
The use of pharmacokinetic and pharmacodynamic endpoints to determine dose of AQ4N given with radiotherapy (RT)
Authors: A. Benghiat, W. P. Steward, M. Middleton, D. Talbot, L. H. Patterson, S. J. Ford, C. Hayward, P. M. Loadman
Journal: Journal of Clinical Oncology (2005)

2062 Background: AQ4N is activated in hypoxic cells to AQ4, a topoisomerase II inhibitor with radiosensitizing properties. This phase 1 study evaluated AQ4N and RT in patients (pts) with advanced esophageal cancer. Methods: 22 pts (14 adenocarcinoma, 8 squamous carcinoma) suitable for palliative RT were studied (ages 55–88 years, M 16, F 6). AQ4N was given as a 30min iv infusion on days 1 and 14, with RT starting 6 hours after the second dose (20Gy in 5 daily fractions). The AQ4N dose was escalated from 22.5 to 447 mg /m2 in sequential pt cohorts. In 3 pts (all receiving 447mg/m2), biopsies of tumour and normal esophageal tissue were taken 24 - 48 hours after the first dose and tissue concentrations of AQ4N and AQ4 measured using a sensitive LC/MS/MS technique. Results: AQ4N was well tolerated, although pts developed transient generalised blue skin and urine discolouration. There were no drug related deaths. 1 pt was not evaluable. There were 16 episodes in 10 pts of grade 3 or 4 toxicity (probably drug related): lymphopenia (n=9), hyponatremia (n=3), fatigue (n=3) and hyperuricemia (n=1). None was clinically significant. PK studies showed a predictable dose related increase in AUC to a mean of 271+/- 127ug h ml−1 at 447mg/m2. This AUC is in excess of those seen in mice at therapeutic doses. A mean clearance of 2.54 l h m−2 (range 1.59 - 5.2) and a t 1/2 of 4.3h (range 2.1 -10.6) were calculated. 57+/-23.8% of dose was excreted unchanged in the urine within 24 hrs. Calculated concentrations (ng ml−1) of AQ4 in tumour and normal tissue were 1744 and 295, 316 and <101, 585 and 265 respectively for three individual patients. In each case tumour tissue concentrations were greater than those in normal tissue with a mean ratio of >3.7 fold. Tumour concentrations of the active AQ4 are well above the IC50 values needed in vitro. Conclusion: AQ4N is well tolerated without serious toxicity. The DLT and MTD were not reached in this study, but a dose for future development was chosen before toxicity occurred using PK targeting and from a demonstration of the preferential conversion to AQ4 in tumour tissue. No excess normal tissue radiation related morbidity was observed. (Supported by BTG International, UK) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kudos, Novacea
Metabolic control of brain cancer: role of glucose and ketone bodies
Authors: Thomas N. Seyfried, Purna Mukherjee, Elizabeth Adams, Tiernan Mulrooney, Laura E. Abate
Journal: Cancer Research (2005)

1147  Metabolic control theory applies principles of bioenergetics for the control or management of complex diseases. Since metabolism is a universal process underlying all phenotypes, modification of metabolism can modify phenotype. The theory is based on findings that compensatory genetic and biochemical pathways regulate the bioenergetic potential of cells. Glucose is the primary fuel for brain cells under normal physiological conditions, but both neurons and glia can transition to ketone bodies for energy when glucose levels become limiting. This is a conserved physiological adaptation that evolved to enhance survival during periods of prolonged food restriction. The transition from glucose to ketone bodies (β-hydroxybutyrate, β-OHB) as a major fuel source involves an increase in TCA cycle activity, a down regulation of glycolytic flux, and a general increase in the delta G’ of ATP hydrolysis. Ketone body metabolism can also reduce tissue inflammation that contributes to brain tumor angiogenesis. While normal brain cells possess metabolic flexibility in their use of energy metabolites, gliomas lack flexibility and are largely dependent on glycolytic energy. Nuclear mutations and mitochondrial defects are thought to underlie the metabolic inflexibility of glioma cells. Therapies that exploit the genetic and metabolic weaknesses of brain tumor cells should therefore be effective in controlling brain cancer. Our recent in vivo studies show that reduced caloric intake, which reduces glucose and elevates ketones, has powerful proapoptotic and antiangiogenic effects in experimental brain cancer. An in vitro system is presented to evaluate the role of glucose and β-OHB in brain tumor control using malignant mouse astrocytoma (CT-2A) cells and normal syngeneic mouse astrocytes grown in the presence or absence of glucose, glutamine, and β-OHB. The results show that caspase 3-mediated apoptosis is greater in the CT-2A astrocytoma cells than in the normal astrocytes under reduced glucose/glutamine conditions and that β-OHB can rescue normal astrocytes, but not the CT-2A astrocytoma cells. These findings support the hypothesis that brain tumors are potentially manageable through metabolic intervention. Supported by NCI grant (CA102135).
Risk of metastases in axillary lymph nodes of breast cancer patients with positive sentinel lymph node in relation to the cytokeratin 19 mRNA copy numbers detected by one-step nucleic acid amplification (OSNA).
Authors: S. Buglioni, B. Casini, C. A. Amoreo, E. Bria, M. Marino, P. Perri, F. Di Filippo, F. Marandino
Journal: Journal of Clinical Oncology (2010)

e11012 Background: The accuracy of the OSNA assay for metastases detection in sentinel lymph nodes (SLNs) has recently been validated in our Institute and adopted as an intra-operative test for breast cancer (BC) patient management. The aims of this study in a series of early BC patients, were: 1) to correlate the copy numbers of cytokeratin 19 (CK19) mRNA with the size of nodal metastases and with the risk of additional disease in non-sentinel lymph nodes (NSLNs); 2) to investigate the relationship between SLN status with OSNA method, and conventional bio-pathological factors taking into account the molecular BC classification: luminal A, luminal B, HER2 subtype, and triple- negative; 3) to identify a subgroup of patients with positive SLN with higher risk of NSLNs metastatic involvement. Methods: 525 SLNs from 417 patients were clinically processed using both OSNA assay and post-operative histology. The results of these two methods were then compared. The correlation between the size of metastases and the copy numbers of CK19 mRNA was calculated using the Spearman correlation coefficient. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of OSNA assay positivity and the probability of having a positive lymph node axillary dissection was calculated by the unconditional logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification based on the immunohistochemistry phenotypic patterns. Results: OSNA positivity was reported in 24.4% of the patients for a sensitivity of 94%. Considering the 102 patients with SLN positivity the size of metastatic foci was significantly correlated to the copy numbers of CK19 mRNA. The complex relationships among the bio-pathological variables analyzed by multiple correspondence analysis (MCA) showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers of CK19 mRNA and HER2 subtype tumors. Conclusions: OSNA specificity (95%) and negative predictive value (98.5%) clearly demonstrated its reliability to guide ALND decision. No significant financial relationships to disclose.
Transarterial chemoembolization (TACE) with doxorubicin eluting beads (DEB) for the treatment of hepatocellular carcinoma (HCC)
Authors: A. Vit, F. De Pauli, M. Sponza, M. Mazzer, L. Foltran, M. Montanari, G. Piccoli, G. Fasola, D. Gasparini, G. Aprile
Journal: Journal of Clinical Oncology (2008)

4598 Background: Level 1A of evidence proves that TACE may prolong survival in HCC patients, for whom potentially curative treatment is no longer possible. DEB-TACE is a drug delivery system comprised of micrometer-sized polyvinyl alcohol hydrogel particles preloaded with doxorubicin, combining vascular embolization with intratumoral drug release. Methods: Among other major inclusion criteria, pathological diagnosis of HCC, uneligibility from curative options, age >18 yrs, and adequate liver/hematological function were all required. DEB were selectively infused into the hepatic artery, or superselectively instilled into a few of its minor branches to block the blood flow while slowly discharging the drug. Patients were treated with doxorubicin dose adjustment for bilirubin values and BSA. Responses were evaluated accordingly to modified EASL criteria. Toxicities were registered using NCI-CTC criteria. Results: Over 28 months, we treated 158 liver lesions in 71 consecutive Child A/B, ECOG PS 0–1 HCC patients, who had previously failed other local procedures. Median age at the time of treatment was 69 years. Median diameter of the predominant lesion and median tumor load were 30 and 43 mm, respectively. Median dose of delivered doxorubicin was 60 mg (range 50–100). Radiological confirmed response rate was 94.2%. Among complete responders (74%), 77% and 67% had no further evidence of disease after a median follow-up of 6 and 12 months, respectively. The persistence of arterial enhancement (vascularization) in the treated area predicted hepatic recurrence (p=0.03). Postprocedural mild nausea, fever and local pain were frequently reported, but no myelotoxicity was registered. Although 30-days mortality rate was limited to 4%, prolonged hospitalization was needed in 5 cases: 1 severe abdominal pain, 2 hemorrhagic duodenitis, and 2 progressive hepatic failures. After complete response, two patients were reconsidered for curative procedures and finally underwent orthotopic liver transplantation. Conclusions: DEB-TACE is highly active, reasonably safe, and represents a feasible opportunity to achieve prolonged disease control in pretreated HCC patients. Occasionally, it may be considered as a bridge to liver transplantation. No significant financial relationships to disclose.
Expanded phase I combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHPRC)
Authors: W. Gerritsen, A. J. van den Eertwegh, T. de Gruijl, H. P. van den Berg, R. J. Scheper, N. Sacks, I. Lowy, E. Stankevich, K. Hege
Journal: Journal of Clinical Oncology (2008)

5146 Background: A Phase 1 trial is underway to study GVAX immunotherapy for prostate cancer [GVAX immunotherapy (GVAX IT)] and ipilimumab (Ipi) in chemonaïve mHRPC patients (pts). Methods: Twelve pts were treated in a dose-escalation phase for 24 weeks (wks) with bi-weekly intradermal injections of GVAX IT and monthly Ipi. Pts were enrolled in cohorts of 3; each cohort received an escalating dose of Ipi: 0.3, 1, 3 or 5 mg/kg. Sixteen pts were then enrolled in an expansion cohort to be treated with GVAX IT and 3 mg/kg Ipi. Results: Escalation Cohort: Median follow-up of 12 pts is 21.2 months (m). Five of six pts at the higher Ipi doses (3 and 5 mg/kg) developed Grade 2 or 3 immune-related adverse events (irAEs), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. Late onset PSA responses (declines > 50%) were seen in these 5 pts with response durations of 6.7, 8.6, 9.5, 13.8 (on-going), and 23.1 m. Four of these pts had stable disease on bone scan for at least 12 m, and up to 21 m. Multiple tumor-reactive antibodies (abs) induced by treatment were identified by serologic analysis (SEREX), including abs to filamin B, PSMA and NY-ESO-1. Biopsies of injection sites showed T cell infiltration and Granzyme B expression; these T cells are being tested for antigen-specific lytic activity. Expansion Cohort: Sixteen pts were enrolled, 6 have completed treatment, 10 are on-going. Three pts have experienced irAEs of Grade 1 diarrhea, Grade 3 adrenal insufficiency, and a Grade 3 hepatitis that resolved with steroids. With median follow-up of 6.5 months in the 6 pts who have completed treatment, 1 pt had a PSA response (> 50% decline) and 3 obtained stable PSA, accompanied in one pt by pain relief and decrease in alkaline phosphatase. Conclusions: The GVAX IT and ipilimumab combination is active in mHRPC in this trial. IrAEs appear manageable and may correlate with anti-tumor activity. The maximum tolerated dose of the combination is not established. Follow-up on the 16 expansion cohort pts will provide data on safety, clinical activity and immunologic correlates. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cell Genesys, Medarex Cell Genesys, Medarex Cell Genesys
Efficacy of sorafenib in patients with oligometastatic hepatoceulluar carcinoma (HCC).
Authors: Kiruthikah Thillai, Dimitrios Ziogas, Ippokratis Korantzis, MH Ruhe Chowdhury, Dionysios Papadatos-Pastos, Abid Suddle, John O'Grady, Nigel Heaton, Paul J. Ross, Debashis Sarker
Journal: Journal of Clinical Oncology (2015)

389 Background: HCC is the second leading cause of cancer related mortality worldwide. Standard treatment for advanced disease is sorafenib, which is associated with a modest improvement in overall survival. We hypothesized that patients with oligometastatic disease treated with sorafenib have improved outcomes over those with extensive metastases. Methods: A retrospective analysis of all patients with advanced HCC treated with sorafenib at a large HCC centre. 190 patients were identified (177 patients with sorafenib alone, 13 patients treated with a combination of sorafenib and erlotinib/placebo as part of the SEARCH trial). Disease distribution was defined as intra-hepatic, oligometastatic (3 or fewer extra-hepatic metastases) and extensive (more than 3 metastases) at the time of starting sorafenib. Overall survival (OS), progression free survival (PFS) and toxicities were recorded. Results: The median age for all patients was 66 years (26-87), 157 male and 33 female. Underlying liver disease included hepatitis B (N=39, 20.4%,) hepatitis C (N=38, 19.9%), alcoholic liver disease (N=38, 19.9%), non-alcoholic fatty liver disease (N=27, 14.1%), unknown aetiology (N=42, 21.9%) and other (N=7, 3.6%). 157 patients had Child-Pugh A status, 33 patients Child-Pugh B. 113 patients had intra-hepatic disease, 45 patients had extensive disease and 32 patients had oligometastatic disease. Median OS for all patients treated with sorafenib was 7.6months(m) and PFS was 4.3m. For patients with oligometastatic disease, OS was significantly longer than those with extensive disease (10.4m vs. 6.3m p=0.034). PFS was also increased at 5.9m vs. 2.8m p=0.028). 50 patients (26%) developed grade 3 or greater toxicity, including diarrhea (N=10, 5.2%), fatigue (N=15, 7.8%) and skin (N=12, 6.3%). There were no statistically significant differences in toxicities amongst patients with oligometastatic disease compared with those with extensive disease. Conclusions: This study suggests that patients with oligometastatic disease have improved survival outcomes compared with patients with extensive disease. Further prospective research is needed to confirm these findings.
Addressing BCR/Abl resistance: Evolving dasatinib to a novel inhibitor of the T315I BCR/Abl mutation
Authors: H. Zhu
Journal: Journal of Clinical Oncology (2007)

13004 We have previously shown that inhibition of the BCR/Abl.T315I mutation can be achieved by using a benzotriazine small molecule in both enzymatic and cell proliferation assays. We have further evolved the benzotriazenes into a class of structurally simplified BCR/Abl inhibitors with enhanced pharmaceutical properties. A representative of this new class, TG101114, inhibits Abl and Abl.T315I enzyme as well as proliferation of cells expressing either BCR/Abl or BCR/Abl.T315I. It displays desirable pharmaceutical properties (e.g. oral bioavailability&gt;20% and T 1/2 &gt;5 h). Consistent with its potency and PK, orally administered TG101114 inhibits the growth of BCR/Abl-driven tumors in a SCID mouse xenograft model and BCR/Abl.T315I-induced STAT5 phosphorylation in the spleens of mice implanted with BCR/Abl.T315I cells. In an ex vivo assay, TG101114 normalized colony formation of stem cells isolated from a BCR/Abl.T315I + CML patients. To further expand upon the themes of these structurally simplified scaffolds, we have transformed dasatanib into a potent and selective T315I inhibitor, thus inhibiting both abl and T315I.abl with equal nM potency in enzymatic and cellular assays. TG101477, an exemplary compound from this class, has shown potency in both enzyme and cell proliferation assays as well as appealing PK properties in mice (e.g. oral bioavailability&gt;20% and T 1/2 &gt;5 h). Furthermore, TG101477 has exceptional selectivity as was demonstrated in a commercial kinase assay in which TG101477 potently inhibited only 6 of 76 kinases in a panel of phylogenetically diverse kinases. We conclude that these classes of BCR-abl inhibitors present new themes for circumventing gatekeeper mutations and represent new prototypes for the treatment of drug resistant forms of CML. No significant financial relationships to disclose.
P-025 Long non-coding RNA AOC4P suppressed hepatocellular carcinoma metastasis by inhibiting epithelial-mesenchymal transition
Authors: T.-H. Wang, Y.-S. Lin, C.-T. Yeh, T.-C. Chen
Journal: Annals of Oncology (2015)

Introduction: Recently, increasing evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the regulation of diverse cellular processes such as cell growth, differentiation, cell cycle progression, and apoptosis. Additionally, several lncRNAs are frequently aberrantly expressed in various human cancers, with both oncogenic and tumor suppressive potential roles. Nevertheless, just a few reports addressed the role of lncRNAs in hepatocellular carcinoma (HCC) progression. In this study, we tried to identify and characterize the role of lncRNA-AOC4P in the regulation of hepatocarcinogenesis. Methods: The expression level of AOC4P was examined in 121 paired HCC and para-tumoral liver tissues using quantitative real-time RT-PCR. The correlation between AOC4P levels, clinical parameters, and survival outcomes were analyzed to elucidate the clinical significance of AOC4P in HCC. In vitro and in vivo functional assays were also performed to dissect the underlying mechanisms. Results: The expression of AOC4P was significantly downregulated in HCC tissues and low expression of AOC4P correlated with poor prognostic outcomes. Furthermore, in vitro functional assays indicated that AOC4P significantly reduced cell proliferation, migration and invasion ability through inhibiting epithelial-mesenchymal transition. The in vivo animal model also demonstrated the tumor suppressor role of AOC4P via reducing tumor growth and metastasis. Conclusion: AOC4P may act as a tumor suppressor in HCC by reduced cell proliferation, migration and invasion ability through suppressing epithelial-mesenchymal transition. The findings could help us to further understand the mechanism of HCC progression and to develop new therapeutic strategies for HCC.