tbuckley/cabot-search huggingface dataset:
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against unmutated or mutant Bcr-Abl-expressing human leukemia cells
Authors: W. Fiskus, M. Pranpat, M. Balasis, P. Atadja, P. Manley, F. Giles, K. Bhalla
Journal: Journal of Clinical Oncology (2006)

6592 Background: AMN107 has potent in vitro and in vivo activity against the un-mutated and most mutant forms of Bcr-Abl tyrosine kinase (TK). We have previously demonstrated that in CML cells the pan-histone deacetylase inhibitor LBH589 depletes both unmutated and mutated Bcr-Abl, as well as attenuates p-AKT and Raf-1 levels. In the present studies we determined the effects of AMN107 and/or LBH589 in unmutated or mutated Bcr-Abl-expressing mouse BaF3 cells, or human CML K562 and LAMA-84 cells, as well as in primary CML cells procured from patients with imatinib mesylate (IM)-refractory CML. Methods: Cultured and primary CML cells were exposed to 20 to 100 nM AMN107 and/or LBH589 for 24 to 48 hours. Following this, the % of apoptotic cells was determined, as well as immunoblot analyses were performed to determine Bcr-Abl, p-STAT5, p-AKT, p-CrkL, Bim, Bcl-x L and p27 levels. Synergy between the apoptotic effects was determined by the median dose-effect isobologram analysis. Results: AMN107 was 20-fold more potent than IM, and was more potent in inhibiting Bcr-Abl TK activity and attenuating p-STAT5, p-AKT, Bcl-x L , and c-Myc levels in K562 and LAMA-84 cells. Co-treatment with LBH589 and AMN107 exerted synergistic apoptotic effects against human CML (but not the normal bone marrow progenitor cells), with more attenuation of p-STAT5, p-ERK1/2, c-Myc and Bcl-x L and increased p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of unmutated Bcr-Abl or the IM-resistant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis in IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared to either agent alone, co-treatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Conclusions: These findings support in vivo testing of the combination of LBH589 and AMN107 against IM naïve or resistant CML, with the goal to eradicate IM sensitive or resistant CML. [Table: see text]
Pharmacodynamic study of the biologic effects of GW572016 (lapatinib) in cellular apoptosis and signaling pathways in HER2-positive ductal carcinoma in situ (DCIS) of the breast.
Authors: L. Garcia-Estevez, A. Suárez, I. Calvo, L. Ugidos, C. Miró, H. Duran, Y. Quijano, M. Herrero, F. López-Ríos, M. Hidalgo
Journal: Journal of Clinical Oncology (2010)

e11044 Background: DCIS is a heterogeneous disease, with increasing incidence, accounting for up to 25% of screen-detected cancers. Approximately 60% of cases of DCIS overexpress HER2. Lapatinib is a tyrosine kinase inhibitor that directly inhibits HER2 receptor signaling by blocking the receptor's kinase activity. We hypothesize that Lapatinib must have substantial activity against HER2 positive DCIS; such activity will be assessed by measurement of PI3K/AKT and RAS/ERK inhibition pathways, as well as apoptosis induction. Methods: The trial was conducted among patients (pts) with DCIS diagnosed by core needle biopsy with low risk of having a hidden invasive component. All of the DCIS had to have HER2 amplification (FISH rate > 2.2). Neoadjuvant lapatinib 1,500 mg daily was administered for 4 weeks prior to surgical resection. EGFR was analyzed by FISH in the biopsy specimen. Ki67, PTEN, AKT, pAKT and nuclear pERK were evaluated by IHQ. PI3KCA mutations were screened at the exons 9 and 20 by PCR. Apoptosis was analyzed by TUNEL assay. All biological markers were measured before and after lapatinib treatment. Results: So far, 11 pts with HER2-positive DCIS have been included. Pre-lapatinib treatment evaluation: none of the pts had EGFR amplification; six pts (54%) had a Ki67 > 25%; AKT was overexpressed in 3 pts (27%); positive nuclear pERK was observed in 4 pts (36%); loss of PTEN expression was detected in 3 pts (27%). PI3KCA mutations were detected in only 1 pt (9%). Post-lapatinib treatment evaluation: 9 pts were evaluable. No change in Ki67 index was found. Only one of the three patients with loss of PTEN had no residual DCIS. A trend for inactivation of the RAF/ERK signaling pathway was observed, whereas no change was observed in the pAKT signaling pathway. In addition, 3 pts (33%) showed an increase in the apoptotic index. Conclusions: High-grade DCIS usually overexpresses/amplifies HER2. In our study, four weeks of lapatinib against HER2- positive DCIS caused a trend for inactivation of nuclear pERK as well as apoptosis induction. We expect this trend to be confirmed with the inclusion of more pts. No significant financial relationships to disclose.
Oxaliplatin and docetaxel as first line chemotherapy for patients with non-small cell lung cancer (NSCLC)
Authors: E. S. Santos, L. E. Raez, C. Rocha-Lima, K. Tolba, L. Negret, N. Farfan, T. Decesare, G. Lopes, M. F. Rosado, J. Wu
Journal: Journal of Clinical Oncology (2005)

7268 Background: Combining Oxaliplatin and Docetaxel (DOCOX) is a biologically rational and feasible option. Oxaliplatin cross-links DNA strands and has shown more activity in vitro than cisplatin. Docetaxel is a mitotic spindle inhibitor, approved as first-line therapy for metastatic (or advanced) non-small cell lung cancer (NSCLC). Methods: We designed a phase II trial to evaluate the efficacy and safety of DOCOX for first-line treatment of patients (pts) with stage IIIB/IV NSCLC, ECOG PS 0–1. We have enrolled 24 pts out of 30 initially planned. Treatment included: docetaxel 70 mg/m2 followed by oxaliplatin 130 mg/m2 on day 1, and pegfilgastrim 6 mg subcutaneous on day 2, for a maximum of six cycles if there was evidence of response. Results: Median age is 59 years (range 39–70), 12 of the patients are female, 18 are white, 12 are Hispanic. Nineteen pts had an ECOG PS 1. The most common histology is adenocarcinoma (18 pts) and most of them are stage IV: 21/24 (88%). Seven of the 24 pts (29%) presented with brain metastasis and received palliative radiation before enrollment. Data for response is available in 16 patients. A partial response was seen in 6 pts (37%, 90% CI:18–61%), and stable disease in 7 (44%, 90% CI:23–67%). Three pts (19%, 90% CI:5–42%) had disease progression. Four pts are ineligible for response. Seventy-nine cycles of chemotherapy have been administered and we have documented 7 severe (grade 3 and 4) adverse events, 2 of which might be related to this combination: grade 3 diarrhea (docetaxel/oxaliplatin), and grade 3 hypersensitivity (docetaxel). Other grade 3 toxicity reported included dyspnea and edema. No grade 3 or 4 hematologic toxicity was seen. Conclusion: The DOCOX combination is safe and efficacious in the treatment of NSCLC. Final results will be presented in the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Sanofi Aventis, Sanofi Aventis, Sanofi
Antisense chemoradioimmunotherapy consisting of anti-IGF-I/HGF bs-scFv linked onto high-energy radioisotopes and TFO targeted to DNMT1 and conjugated to vinorelbine induce ADCC, apoptosis and anoikis in metastatic NSCLC characterised by radio and chemoresistance
Authors: G. N. John, E. Michailakis, E. Maragudakis, N. Alexandropoulos, J. Giannios
Journal: Journal of Clinical Oncology (2005)

7194 Introduction: Metastatic NSCLC is resistant to almost all cytotoxic drugs and radiation. Materials and Methods: We obtained surgically 132 metastatic NSCLC specimens from patients. MS-PCR ehibited hypermethylation of oncosuppressors VHL, p63, p53,IGFBP4,p16,RASSF1A,RAR-b2,PTEN, Smad4, DAPK,E-cadherin,15-PGDH,p14,IGFBP4,HNF3-beta, CHK2,DPPIV,(RB)2/p130,LLC,4E-BP1 and FUS1. Quantitative IHC,WB,SB and RT-PCR exhibited overexpression of DNMT1,HIF1,HGF,IGF-I,VEGF,MMP-2,MMP-9,Glut-1,COX-2,TGF-beta1, cyclinA,TGFa,cdk2,UPAR,c-Met,EGFR,bcl-2,HDGF,Raf-1 and cdc25c. We treated NSCLC with anti-IGF-I/HGF bs-scFv attached onto high energy- radioisotopes,triplex forming oligonucleotides targeted to DNMT1 and conjugated to vinorelbine. Results: Post-treatment,we detected re-expression of all oncosuppressor genes after inhibition of DNMT1mRNA.There was downregulation of IGF-I and HGF due to targeted bs-scFv and inactivation of bcl-2,Raf-1 and cdc25c due to phosphorylation by vinorelbine. Inhibition of HGF inactivated PEA3/EIAF(EIAF), Rho/ROCK,c-Met,ERK/MAPK,Akt while inhibition of IGF-I blocked IGF-I/IGF-IR/tPA. Re-expression of 4E-BP1 blocked the eIF-4F complex leading to inhibition of HDGF. We detected upregulation of p21waf1, Bid and Bak. Upregulation of Bad inactivated MAPKs,ERK1/2 and PI3K/AKT. Upregulation of p27 downregulated cyclinA,cdk2 and cdc25c. Re-expression of 15-PGDH downregulated COX-2 and bcl-2. Re-expression of IGFBP4 inhibited IGF1 and VEGF. Re-expression of Smad4 downregulated TGF-beta1. The radioisotopes induced DNA double strand breaks in NSCLC cells. Re-expression of VHL and p53 promoted ubiquitination and proteasomal degradation of HIF-1a which inhibited transcription of downstream genes Glut-1,ORPs,VEGF,MMP-2,MMP-9,IGF1R,TGFa,UPAR,c-Met and EGFR after the re-expression of PTEN. FUS1 re-expression induced Apaf-1 mediated mitochondria apoptosis. We observed induction of ADCC and anoikis. Conclusion: We have achieved to eradicate NSCLC cells with ACRIT. No significant financial relationships to disclose.
The number of lymph node metastases as a prognostic indicator of disease-specific survival in the era of sentinel lymph node mapping in colon cancer
Authors: S. Saha, S. Sirop, A. Korant, B. Chakravarty, N. Krishnaiah, D. Wiese, M. Soni, M. Arora, S. Nagpal, T. Singh
Journal: Journal of Clinical Oncology (2009)

e15000 Introduction: Sentinel Lymph Node Mapping (SLNM) in colon cancer (CCa) is shown to be successful, sensitive and accurate. We aimed to evaluate the survival of patients (pts) undergoing SLNM in addition to the standard colon resection, compare it to pts without SLNM and correlate it to the number of LN metastasis. Methods: Staging and survival analysis from our prospective database (gpA, 195 pts) were compared to the Surveillance, Epidemiology, and End Results (SEER) database (gpB, 126,484 pts) between 1996–2003. All pts had invasive CCa. GpA pts underwent SLNM plus complete resection. The minimum follow up (F/U) was 5 years. The primary outcome was cancer-specific survival. Exclusion criteria were stage IV disease, 2nd malignancy, or lost to F/U. Cancer specific survival of gpA was then analyzed according to the number of positive LNs. Results: In gpA (195 pts), SLNM was successful in 99.7%, of pts with a sensitivity, negative (-ve) predictive value, and false -ve rates of 86.3%, 91.7% and 14.6% respectively. In 15.1% of node +ve pts, the disease was upstaged because of micrometastasis (0.2–2mm). In gpA, 128 pts were included, of which 17(13.3%) lost to F/U as compared to 89,483 pts included in gpB, of which 47,168 (52.7%) lost to F/U. The average number of LNs examined per pt was 15 in gpA as compared to 12.4 in gpB (p=&lt;0.0001). The 5 year-cancer specific survival of pts in gpA vs gpB was 100% vs 94.9% in stage I, 91.2% vs 83.5% in stage II and 81.8% vs 63% in stage III disease. For gpA pts, the 5 year cancer-specific survival decreased from 95.0% in node -ve disease to 92.8% when 1 LN was +ve, 83.3% when 2 LNs were +ve and 71.4% when 3 or more LNs were +ve (Table). Conclusions: A significant number of pts with CCa are being upstaged and the true node -ve disease is being identified when SLNM is performed at the time of surgery leading to improved survival as compared to conventional surgery. Our study showed that the number of LN metastasis is a predictor of cancer specific survival even after SLNM in CCa. [Table: see text] No significant financial relationships to disclose.
A retrospective validation of a circulating microvesicle–based assay for the detection of prostate cancer.
Authors: C. D. Kuslich, A. S. Kibel, R. Vessella, D. B. Spetzer, S. P. Stratton
Journal: Journal of Clinical Oncology (2011)

e15172 Background: Circulating microvesicles (cMV) are small membrane bound particles ranging from 30 to 1000 nm in diameter secreted by many cell types, including tumor cells. The quantity and biomarker composition of cMV can be used to detect and monitor the presence of disease. A cMV biosignature composed of 6 surface biomarkers, the tetraspanins CD9, CD81, and CD63, the prostate-associated proteins PSMA and PCSA, and the tumor-associated protein B7H3, was developed for a novel plasma-derived cMV-based assay. Validation studies for the assay, Carisome Prostate cMV 1.0, are reported. Methods: A multiplexed immunoassay for characterizing cMV from plasma was used to develop a cMV-derived biosignature consisting of the 6 biomarkers, CD9, CD81, CD63, PSMA, PCSA, and B7H3. The suitability of the biosignature for detecting prostate cancer (PCa) was validated using a cohort of 943 retrospective plasma samples from PCa patients and age-range matched controls of which 899 produced valid results. The sample cohort included four sub-cohorts: a training set (42 PCa, 42 controls), a blinded validation set (41 PCa, 37 controls), a Clinical Laboratory Improvement Amendment (CLIA) validation set (84 PCa, 59 controls), and an academic and commercial validation set (594 samples). Sensitivity and specificity were determined, and a receiver operating characteristic curve was constructed. Results: The assay had the following performance characteristics in each validation set (sensitivity/specificity): 98%/90% (training set), 81%/95% (blinded validation set), 83%/88% (academic validation set), and 92%/81% (CLIA validation set). In total, 899 retrospective samples were analyzed, with an overall sensitivity of 86%, specificity of 87%, and an area under the curve of 0.94. Conclusions: This study demonstrates that the cMV-based assay Carisome Prostate cMV 1.0 is able to distinguish PCa plasma samples from controls with high sensitivity and specificity. Analytic validation demonstrates that the assay has the potential to be a robust and informative blood-based detection assay for PCa. Profiling cMV from patient plasma offers a powerful new tool that can aid in identifying individuals who may be candidates for prostate biopsy.
Experience with the implant of vascular access devices by medical oncologist and in non-surgical scenery
Authors: E. Esteban, J. Vieitez, N. Villanueva, J. Fra, B. Mareque, E. Uña, A. J. Lacave
Journal: Journal of Clinical Oncology (2004)

8188 Background: The use of central venous catheters to facilitate drug delivery and supportive treatment in cancer patients (pts) is increasing continuously. Methods: Staff of our department specially trained routinely implant central venous accesses in the office or in the hospitalization yard, under strict aseptic measures without fluoroscopic control or sedation. Results: From Sep 94 to Sep 97, 683 devices (613 port systems [PS] and 70 external catheters [EC]) were implanted in 642 pts, with age 46 yr (14–78) and K.I. 70% (50–100) (mean, range), female 365/male 277. Venous access: right interior jugular 377, left subclavian 205, right subclavian 68, left interior jugular 30, right femoral 3. A thorax X-ray was performed after each procedure and in the first 72 pts prophylactic antibiotics were given. The venous access remained in situ a median of 265 days (1- 2210 +), 120 d (1- 450+) for EC and 327 d (1- 2210+) for PS. Complications occurred in 102 placements (15%): Infections 48 (7%): [30 in EC and 18 in PS]; deep venous thrombosis 27 (4%) [Left placements 23, right placements 2, femoral 2]; obstruction 4 (0,6%); malposition 8 (1.2%); PS fractures/migration 9 (1.5); pneumothorax 2 (0.3); local skin necrosis 4 (0.6%). A hundred and seventy devices have been removed, 102 (25%) after completing planned therapy and 68 (10%) due to complications [Infections (36), migration (9), malposition (5), venous thrombosis (10), obstruction (4) and skin necrosis (4)]. Conclusions: The best access route in order to avoid complications seems to be the right internal jugular vein. External catheters have been associated with a greater incidence of infections and a shorter longevity. Our results are comparable with those obtained when the venous access is placed in the operating room, under fluoroscopic control and a prophylactic antibiotic is administered. This procedure is more comfortable and less expensive for patients. No significant financial relationships to disclose.
Abstract 18909: Impact of Coronary Plaque Morphology Assessed by Optical Coherence Tomography on Periprocedural Cardiac Troponin Elevation in Patients With Non-ST Segment Elevation Acute Coronary Syndrome
Authors: Tetsumin Lee, Tadashi Murai, Asami Suzuki, Yoshihisa Kanaji, Junji Matsuda, Makoto Araki, Takashi Niida, Mitsuaki Isobe, Tsunekazu Kakuta
Journal: Circulation (2014)

Backgrounds and Aims:  We used optical coherence tomography (OCT) to study the relationship between pre-PCI plaque morphology and PCI-related cTn elevations in patients with non-ST-segment elevation acute coronary syndrome (NATE-ACS). We further assessed the association between PCI-related cTn elevations and adverse cardiac event during follow-up in these patients.   Methods and Results:  We studied 165 patients with NSTE-ACS who had identifiable native de novo culprit lesions suitable for PCI and OCT examination. All patients underwent OCT imaging before stent implantation. Cardiac troponin I (cTnI) was analyzed on admission, before PCI, and after PCI, and periprocedural myocardial injury (PMI) was defined as a patient showing stable pre-PCI cTnI values or fall, followed by post-PCI cTnI rise >20%. Forty patients (24.2%) with increasing cTnI values before PCI were excluded from subsequent analyses. We finally evaluated 126 patients with stable or falling cTnI values after admission. Clinical and OCT findings were compared between patients with (n=58, 46%) or without (n=68, 54%) PMI. After PCI, long-term follow-up data were collected. Thin-cap fibroatheroma (TCFA) was defined as lipid-rich plaque (one or more quadrants) with fibrous cap thickness    Conclusions:  OCT analysis showed that PCI-related myocardial injury occurs more frequently in lesions with TCFA in NSTE-ACS patients. OCT may allow identification of NSTE-ACS patients who are likely to have PCI-related myocardial injury, who may have higher risk of adverse cardiac events during follow-up despite otherwise successful PCI.
Vitamin D (VD) deficiency and skeletal abnormalities are very common findings in adult acute lymphocytic leukemia (ALL) and lymphoblastic lymphoma (LL)
Authors: M. E. Cabanillas, D. Thomas, A. Hoff, G. Mattiuzzi, M. Foudray, H. Kantarjian, C. Escalante, R. Gagel
Journal: Journal of Clinical Oncology (2005)

6608 Background: At diagnosis, children with ALL have been found to have osteopenia, various skeletal abnormalities (SA), evidence of suppressed bone turnover, but normal 25-hydroxyvitamin D (25OHD3) levels. These findings have not been investigated in adult ALL. VD inhibits clonogenic growth of leukemic B-cells in vitro and is a differentiating agent in leukemic myeloid cell lines. Methods: Patients (pts) with newly diagnosed ALL or LL treated with hyperCVAD were evaluated. Each pt had baseline bone mineral densities (BMD), serum 25OHD3, and serum corrected calcium (Ca) performed. Pts with a low 25OHD3, had intact PTH (iPTH) and ionized Ca performed. Results: Nine men and 6 women were evaluated. Median age was 41 (r: 21–71). Ten pts had ALL, 5 had LL. Low 25OHD3 levels (<20pg/ml) were found in 10/15 (67%), while 3/15 pts (20%) had low normal levels (20–25pg/ml). Evidence of secondary hyperparathyroidism (high iPTH, low 25OHD3) was seen in 5/15 of pts (33%). Two of these pts had iPTH levels above 100 with low ionized Ca, indicating a more severe VD deficiency. Baseline SA were seen in 13/14 (93%) (osteopenia: 8/14, osteoporosis: 1/14, vertebral fracture: 1/14, lytic bone lesions: 1/14, and osteosclerosis: 2/14). Mean SD lumbar spine BMD T and Z scores were -0.9 (range -2.9–2.2) and -0.5 (range -2.7–3.1), respectively. There was no correlation between elevated WBC count and any of these abnormalities. Although these abnormalities occured in both diseases, the pts with the most striking abnormalities had B-ALL. Conclusions: 1) Abnormalities of VD deficiency and secondary hyperparathyroidism are common in pts with ALL and LL. 2) These data suggest that unlike pediatric ALL pts, who have adequate stores of VD, adult ALL pts have evidence of VD deficiency. 3) There are significant baseline SA in this pt group. 4) These abnormalities may be caused by the leukemic process since they are seen at baseline. 5) The frequency of VD deficiency in this population and the known role of this compound in hematopoietic differentiation suggests that further studies are needed to define a pathophysiologic relationship. No significant financial relationships to disclose.
Phase I study to determine the safety and pharmacokinetics of 4-hour intravenous infusion of TAS-106 on a once per week for 3 consecutive weeks every 28-day schedule in patients with solid tumors
Authors: R. Chadha, A. Mita, M. Iwasaki, Y. M. Lassere, K. R. Bogaard, S. A. Waldrum, J. L. Abbruzzese, M. B. Thomas
Journal: Journal of Clinical Oncology (2007)

2556 Background: Most solid tumors are slow growing so the S-phase-specific anti-tumor drugs have limited efficacy. The antitumor nucleoside 3’-C-ethynylcytidine (ECyd, TAS-106) inhibits RNA synthesis by blocking RNA polymerases. In vitro, TAS-106 has demonstrated cytotoxicity 300 times greater than that of 5-FU against human lung, colorectal, gastric, pancreas and breast cancer cells. This trial was based on a previous clinical trial, in which study drug was administered as a bolus injection wkly for 3 consecutive weeks every 28- days and TAS-106 caused reversible dose-limiting peripheral neuropathy, and the safety dose was 1.32 mg/m 2 /dose. Methods: Objectives of this study were to determine the recommended phase II dose (RP2D) and the dose-limiting toxicity of TAS-106 administered by 4-hour IV infusion wkly for 3 consecutive weeks every 28-days; to investigate the clinical pharmacokinetics and pharmacodynamics of TAS-106, and document any antitumor activity observed. Results: A total of 18 patients (pts) were treated in the study; 16 pts were evaluable. The med age was 59; 11 female. A total of 44 courses of therapy were initiated by pts during the study; 39 courses (88.6%) were completed. Six pts had best tumor responses of stable disease (SD) and 9 pts had best tumor responses of progressive disease (PD); no pts had a complete or partial response. The mean duration of SD was 103.7 days. Median time to treatment failure was 57.0 days. At the RP2D (2.04 mg/m 2 /dose), 2 of 8 pts had best tumor response of SD with a mean duration of 132.0 days and three of the 8 pts had PD. For 12 pts (66.7%), adverse events (AEs) were considered to be related to TAS-106; the most commonly reported drug-related AEs were tremor (8 pts, 44.4%), neuropathy (4 pts, 22.2%), and peripheral neuropathy and fatigue (3 pts, 16.7% each) . No Grade 4 drug-related AEs were reported. Plasma concentrations increased with increasing dose, and at 2.04 mg/m 2 , the Cmax was 47.6±1.3 ng/mL. Conclusions: The safety profile of TAS-106 administered via wkly 4-hour IV infusion appears to be similar to the toxicity profile of TAS-106 when administered as a wkly bolus. In wkly 4-hour IV infusion, peripheral neuropathy was acceptable at the RP2D. No significant financial relationships to disclose.