tbuckley/cabot-search huggingface dataset:
Transcription factor NFkB a potential molecular marker for predicting and improving treatment efficacy in esophageal cancer
Authors: J. G. Izzo, T. Wu, U. Malhotra, J. Ensor, R. Luthra, C. K. Chao, S. G. Swisher, Z. Liao, B. B. Aggarwal, W. N. Hittelman, J. A. Ajani
Journal: Journal of Clinical Oncology (2006)

10065 Background: Esophageal/gastroesophageal junction adenocarcinoma (E/GEJAC) remains one of the most aggressive malignancies. Chemoradiotherapy (CTXRT) followed by surgery has been used for localized E/GEJAC. Patients (pts) achieving pathologic complete response (pathCR) have an improved survival, but ≈70% of pts exhibit at surgery resistant residual, highly aggressive tumors despite CTXRT. There is a need to identify this high-risk population and target molecular pathways associated with cancer resistance. We have shown that nuclear NFκB was associated with poor clinical outcome of E/GEJAC pts undergoing 5FU, Docetaxel and Cisplatinum therapy. To validate our findings, we examined the impact of nuclear NFκB on clinical outcome of pts undergoing diverse CTXRT regimens. Methods: Pre- treatment tumor biopsies and post-treatment resected residual tumors were analyzed from pts receiving neo-adjuvant CT or CTXRT. NFκB protein expression was assessed by immunochemistry and correlated to pathCR and clinical outcome. Tumors were considered NFκB positive (pos) when ≥5% of cells expressed nuclear NFκB. Results: 80 pts, clinically staged II, III and IVA, were studied. All pts received antifolates, and 80%, 65% &amp; 31% received taxanes, topo-1 inhibitors and/or platinum analogues, respectively. Radiation therapy was 50.4 Gy at 1.8 Gy once a day to all pts. 75/80 pts had available pre-treatment biopsies, all 58 pts with &lt;pathCR had available residual tumors. Pre-treatment NFκB was predictive for lack of response to CTXRT [NFκB pos: 2/22 pathCR vs 27/53 &lt;pathCR; P=.006]. In multivariate analysis, including clinical stage, tumor histology, pathCR and lymph nodes metastasis, pre-treatment NFκB was an independent prognostic factor of progression-free (P=.0029, HR=2.90, 95%CI:1.44–5.86) and overall (P=.0073,HR=2.70, 95%CI:1.30–5.60) survivals. NFκB was associated with recurrent disease [pre-treatment NFκB pos 14/29 (48%) vs NFκB negative11/46 (24%), P=.04; pre- or post- NFκB pos 22/47 (47%) vs NFκB neg 4/33 (12%), P=.003]. Conclusions: our data suggest that NFκB defines cancer biology and patterns to therapy response irrespective of the type of chemoradiation used. NFκB may serve as potential molecular target to improve treatment efficacy. No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and gemcitabine/cisplatin (GC) for the treatment of advanced solid malignancies
Authors: J. Crawford, H. A. Burris III, M. Stein, J. Stephenson, J. Gilbert, S. Underwood, Y. Sun, L. Yang, J. Wiezorek, L. S. Schwartzberg
Journal: Journal of Clinical Oncology (2006)

13005 Background: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Kit receptors. Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr) and has shown efficacy and tolerability in pts with solid tumors. The primary objectives of the first part of this multicenter, 2-part, dose-finding study were to establish the safety and tolerability of AMG 706 + panitumumab with GC. Secondary objectives included PK of all agents. Methods: Pts were sequentially enrolled in 1 of 5 AMG 706 dose cohorts: no AMG 706, 50 mg, 75 mg, 100 mg, and 125 mg QD; all pts received panitumumab (9 mg/kg i.v. on day 1), G (1250 mg/m 2 i.v. on days 1 and 8), and C (75 mg/m 2 i.v. on day 1) Q3W. Pts had advanced cancer for which GC is indicated, ECOG of 0 or 1, no symptomatic or untreated CNS metastases, no history of venous thrombosis, and no more than 1 prior chemotherapy regimen for advanced disease. Results: As of 8/05, 15 pts were enrolled (n = 7, no AMG 706; n = 8, AMG 706 50 mg QD). Baseline characteristics included 8M/7F, median (range) age of 61 (32, 72) years, 9 with ECOG 0 and 6 with ECOG 1. Tumor types included: non-small cell lung (8), pancreatic (3), esophageal (2), ovarian (1), and unknown (1). Safety for all 15 pts is presented (see table ). The PK of AMG 706 at 50 mg when coadministered with panitumumab/GC was similar to the PK for AMG 706 monotherapy at the same dose. Conclusions: These data suggest that AMG 706 can be safely combined with panitumumab and GC with no effect on the PK of AMG 706 at 50 mg QD. Updated safety and PK data will be presented. [Table: see text] [Table: see text]
Chemoembolization (CE) with carboplatin and doxorubicin for hepatocellular cancer (HCC): Introduction of a novel combination and preliminary results
Authors: P. Bhargava, D. C. Gammon, D. Kim, D. Phillips, S. Mehta, L. Shick, L. Cicalese
Journal: Journal of Clinical Oncology (2004)

4275 Background: CE results in tumor shrinkage and may improve survival in pts with HCC. CE using doxorubicin (Dox), cisplatin and mitomycin has shown good results. The mixture of these agents with lipiodol results in an unstable emulsion that rapidly precipitates into droplets and must be mixed vigorously before injection into the hepatic artery. Cisplatin is no longer available in powder form in the United States, and the reconstituted solution is available only at a concentration of 1mg/ml. Therefore, the use of cisplatin at doses reported in the literature results in large volumes of the emulsion that are difficult to administer in patients with underlying liver disease. Carboplatin (Carbo) is available in powder form, and its use for CE is supported by one study in the literature. Methods: We developed an emulsion using Carbo powder (300mg), Dox (30mg/m2 mixed in 10ml renograffin) and lipiodol (10ml). The emulsion showed minimal precipitation. The procedure involved superselective catheterization of the branches of hepatic artery supplying the tumor and injection of the chemotherapy emulsion followed by embolization of the blood vessels using gelfoam particles. Results: 15 pts have undergone CE using this procedure: 12M/3F, median age 58 (46–73), ECOG PS 1 (13) or 2 (2), Child-Pugh class A (3) or B (12). Nine pts had hepatitis B/C, 10 had history of alcohol abuse, and all had underlying cirrhosis. Three pts underwent CE twice. Toxicities consisted of nausea, abdominal pain, fever, confusion, increased ascites and hair loss (all grade 1–2). Elevation of liver enzymes (grade 2–3) was seen in all pts that returned to baseline in 14–28 days. Tumor response was assessed by CT scans 2–3 months following CE. Of 14 evaluable pts, PR (≥50% decrease) was seen in 3, MR (16–40%) in 6, and SD in 5 pts. Four pts underwent orthoptic liver transplantation between 3–12 months following CE; Extensive tumor necrosis was seen in all pts. Conclusion: The combination of carboplatin and doxorubicin is safe and active, and offers a new alternative for use in CE of HCC. Larger studies are planned to assess the efficacy of this combination. No significant financial relationships to disclose.
Detection of first recurrences in cutaneous melanoma patients: A prospective study
Authors: A. B. Francken, H. M. Shaw, W. H. McCarthy, S. J. Soong, N. A. Accortt, J. F. Thompson
Journal: Journal of Clinical Oncology (2004)

7546 Background: The value of follow-up in cutaneous melanoma patients is controversial, and no consensus exists regarding the appropriate frequency of follow-up visits. The aim of this study was to investigate the detection of melanoma recurrences, by patient or doctor, with the ultimate goal of formulating evidence-based guidelines for follow-up. Methods: Patients who presented to the Sydney Melanoma Unit (SMU) with a first recurrence between Jul 2002 and Feb 2003 were prospectively selected and interviewed by telephone regarding the detection of their recurrence (Group A). Information for patients who could not be interviewed was retrieved from their medical records (Group B). Patient demographics and pathologic features of their primary melanoma, as well as factors relating to their last follow-up visit and the recurrence, were obtained from the SMU database. Univariate analysis and multivariate logistic regression were performed to examine factors related to the person who detected the recurrence. Results: 227 patients (85 women), median age 63 (8–94) years, were included (Group A 177, Group B 50). AJCC stage distribution was Stage I - 62 (28.4%), Stage II - 103 (47.2%), Stage III - 46 (21.1%) and Stage IV - 7 (3.2%) (9 missing values). The distribution of recurrence types was local - 24 (10.6%), intransit - 36 (15.9%), regional node - 103 (45.4%) and distant - 64 (28.2%). 74.5% of all recurrences were detected by the patient (164). No statistical difference was found between Group A and B. The median time between last follow-up visit and recurrence detection was 4 (3–64) months. Symptomatology (specific or non-specific) related to the recurrence was the only independent predictor of detection by the patient (p=0.0001). No other clinical, primary melanoma pathology or recurrence related factors were found as predictors of the person detecting the recurrence. Conclusions: Three-quarters of first recurrences were detected by the patient, despite frequent follow-up visits. Patient-detected recurrences could not be predicted on the basis of clinical, demographic or pathologic variables. These findings should be considered when planning follow-up for individual patients. No significant financial relationships to disclose.
Are Advanced Radiation Therapy Technologies Required for Treating Patients With Hodgkin Lymphoma?
Authors: Richard T. Hoppe
Journal: Journal of the National Comprehensive Cancer Network (2016)

In the past 2 decades, remarkable advances have occurred in radiation therapy technology, including development of inverse treatment planning, improved patient immobilization techniques and organ motion adaptations, precision treatment delivery systems, and treatment verification. These advances have been facilitated by improvements in diagnostic imaging, including MRI and PET/CT. At first, these innovations were used for the treatment of solid tumors, wherein it became possible to further escalate tumor dose in an effort to improve local control, or to lower doses to organs at risk (OARs), decreasing the likelihood of acute or subacute effects.
Abstract 11183: Three-Dimensional Finite Element Analysis of Atherosclerotic Plaque Rupture Based on ex vivo Cryo Imaging
Authors: Ahmad Abdul-Aziz, Ross Cotton, Simon Richards, Ali Faramarzalian, David L Wilson, Hiram G Bezerra, Marco A Costa
Journal: Circulation (2012)

Introduction: Cryo-imaging is an ex vivo vascular imaging modality that acquires serial 2D fluorescence and bright-field images at 5µm increments without sacrifice to tissue morphology. These featu...
Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression or gene amplification.
Authors: D E Merkel, S A Fuqua, A K Tandon, S M Hill, A U Buzdar, W L McGuire
Journal: Journal of Clinical Oncology (1989)

Multiple drug resistance (MDR), consisting of acquired cross resistance to anthracyclines, vinca alkyloids, and other antineoplastic antibiotics, has been described in a variety of cell lines. This MDR phenotype is associated with overexpression and sometimes amplification of a gene coding for a 170 kDa glycoprotein, termed P-glycoprotein. To understand the role of this mechanism in clinical breast cancer, 248 breast cancer specimens representing both untreated primary and refractory relapsing disease were probed for evidence of P-glycoprotein gene amplification or overexpression using Southern, Northern, or Western blot techniques. In no case was an increase in P-glycoprotein gene copy number or expression detected. Though these findings do not necessarily rule out a role for P-glycoprotein in mediating drug resistance in breast cancer, electrophoretic analysis of clinical specimens is unlikely to provide useful predictive information. More sensitive assays must be developed to overcome the difficulties inherent in analyzing heterogenous tissue samples.
Authors’ reply to Minisola and colleagues, Kausar, and Sharvill
Authors: Kurt A Kennel, Spyridoula Maraka
Journal: BMJ (2015)

We appreciate Minisola and colleagues’ comments and confirm that bisphosphonates may be considered in patients with monoclonal gammopathy of undetermined significance, which affects bone health.1 2

An oral solution of alendronate sodium is available in the US in a 70 mg/75 mL formulation. We were unaware of the alendronic acid solution 70 mg/100 mL available in the UK. We could find no comparisons of the tolerability of these products with other oral bisphosphonate formulations but note the high prevalence of baseline gastrointestinal problems in those who might be prescribed bisphosphonates.3

We wrote “Before starting bisphosphonates it is necessary to assess for and correct hypocalcemia and vitamin D deficiency” with Bertoldo and colleagues’ data in mind but appreciate the additional attention Minisola and colleagues bring to this matter.4

These respondents allude to “treatment failure” and …
Sensitization of B-NHL resistant tumor cells overexpressing Bcl-xL to TRAIL-induced apoptosis by the novel proteasome inhibitor Salinosporamide A (NPI-0052)
Authors: Eriko Suzuki, Michael Palladino, Genhong Cheng, Benjamin Bonavida
Journal: Cancer Research (2007)

1445   Tumor cells develop resistance to various cytotoxic chemotherapeutics and, therefore, immunotherapy is currently being evaluated as a novel therapeutic intervention to overcome drug resistance. TRAIL, a member of the TNF superfamily, has been shown to be minimally toxic on normal tissues while cytotoxic to sensitive tumor cells. However, many tumors are resistant to TRAIL and require sensitizing agents to be used in combination with TRAIL/anti-DR4, DR5 monoclonal antibodies to reverse TRAIL-resistance. The sensitizing agent must therefore target gene products involved in the regulation of resistance. Tumor cells invariably exhibit constitutive activation of NF-κB resulting in the expression of many anti-apoptotic gene products such as members of the Bcl-2 and IAP families. We and others have demonstrated that inhibition of NF-κB sensitizes tumor cells to TRAIL-induced apoptosis. Various NF-κB inhibitors were effective such as DHMEQ, Bay11-7085, bortezomib and NPI-0052. However, many tumor cells, in particularly lymphomas, have been shown to overexpress Bcl-xL that was accompanied by resistance and high risk. We have then examined whether NPI-0052 can sensitize the human B-NHL cell line Ramos stably overexpressing Bcl-xL to TRAIL-induced apoptosis. We demonstrate that treatment with NPI-0052 (0.1-5.0 nM) synergistically sensitized Ramos that overexpress Bcl-xL to TRAIL-induced apoptosis. The mechanism underlying sensitization was examined and we demonstrate that NPI-0052 inhibited the constitutive expression of Bcl-xL with no effect on the plasmid-induced Bcl-xL. In addition, we demonstrate that NPI-0052 inhibited NF-κB activity and downstream inhibited the transcription repressor YY1, which we have shown to negatively regulate the transcription of the TRAIL-receptor DR5. We also demonstrate that NPI-0052 resulted in significant upregulation of DR5 expression and inhibition of YY1 activity. Overall, the findings demonstrate that NPI-0052 is a significant sensitizing agent for tumor cells overexpressing Bcl-xL when used in combination with TRAIL and DR4/DR5 mAbs. Further, the studies suggest that NPI-0052 may be of therapeutic value when used in combination with TRAIL, agonistic antibodies to TRAIL receptors or immunomodulating agents that activate host effector cells expressing TRAIL in vivo.
Phase II study of continuous infusion fluorouracil with epirubicin and cisplatin in patients with metastatic and locally advanced breast cancer: an active new regimen.
Authors: A L Jones, I E Smith, M E O'Brien, D Talbot, G Walsh, F Ramage, H Robertshaw, S Ashley
Journal: Journal of Clinical Oncology (1994)

PURPOSE To investigate the efficacy and toxicity of continuous infusion fluorouracil (5-FU) with every-3-weeks epirubicin and cisplatin (ECF) in advanced breast cancer in a phase II study. PATIENTS AND METHODS Forty-three patients with metastatic (n = 29) or locally advanced/inflammatory (n = 14) breast cancer were treated with 5-FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks, for eight courses. RESULTS The overall response rate (complete plus partial) was 84% (95% confidence interval [Cl], 76% to 96%), with a complete response rate of 24% (95% Cl, 9% to 40%) in patients with metastatic disease and 36% (95% Cl, 11% to 61%) in patients with locally advanced disease. The main World Health Organization [WHO] grade 3 or 4 toxicities included leukopenia, emesis, and alopecia. CONCLUSION Infusional ECF is a highly active regimen in advanced breast cancer and warrants evaluation in high-risk early breast cancer.
Phase I study of GW572016 (lapatinib), a dual kinase inhibitor, in combination with irinotecan (IR), 5-fluorouracil (FU) and leucovorin (LV)
Authors: R. Midgley, K. T. Flaherty, D. G. Haller, M. J. Versola, D. A. Smith, K. M. Koch, L. Pandite, D. J. Kerr, P. J. O’Dwyer, M. R. Middleton
Journal: Journal of Clinical Oncology (2005)

3086 Background: Lapatinib is an orally active reversible inhibitor of ErbB1/ErbB2 tyrosine kinases. This study evaluated the safety, tolerability and pharmacokinetics (PK) of daily lapatinib in combination with IR/FU/LV (FOLFIRI) q14d. Methods: Cohorts of 3 patients (pts) each (25 total) with solid tumours received lapatinib (1000 or 1250mg daily) and FOLFIRI (80% or 60% of the standard doses) to determine the optimally tolerated regimen (OTR). Additional pts were enrolled at the OTR to evaluate the PK of lapatinib and FOLFIRI alone and in combination. Results: The standard FOLFIRI doses were reduced to 80% and 60% due to DLTs of diarrhea and/or myelosuppression at the starting doses. Toxicity required the lapatinib dose to be interrupted or reduced at these doses. The OTR was defined as lapatinib 1250mg with IR 120mg/m2, FU 240mg/m2 bolus and 360mg/m2 infusion, plus LV 200mg/m2on days 1 and 2, every 14 days. At the OTR, common non-hematological adverse events were grade 1 or 2 diarrhea, nausea/vomiting, fatigue, alopecia, anorexia, mucositis, constipation, weight loss, and headache. Co-administration resulted in 50% higher AUC for the SN-38 metabolite of IR, 30% higher Cmax and 14% higher AUC for lapatinib. Four pts achieved PRs (2 CRC, 1 pancreatic, 1 hepatoma), duration 1–6 months, and 10 pts achieved SD, duration 1–4 months. Conclusions: The combination of lapatinib /FOLFIRI is tolerable but required dose reductions of both FOLFIRI and lapatinib that were consistent with the altered PK and common toxicity. Promising activity was seen, particularly in pancreatic and hepatic tumours. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Phase II study of combined external beam radiation therapy (EBRT), brachytherapy (PB), total androgen suppression (TAS), and adjuvant docetaxel (AD) in poor-risk, localized prostate cancer (PCa)
Authors: S. J. Dibiase, N. Dawson, M. Naslund, A. Hussain, R. Kataria, M. Bangalore, A. Dhople, C. Guo, P. Amin
Journal: Journal of Clinical Oncology (2004)

4764 Background: Encouraging responses rates to Docetaxel in advanced PCa have been shown. However, our understanding of Docetaxel with radiation in localized PCa is limited. This prospective, phase II study evaluates the efficacy and safety of AD when combined with EBRT, PB, and TAS in high-risk, localized PCa. Methods: Inclusion criteria: T3/T4, or Gleason score (GS) 7 and PSA >10 or GS 8–10 and PSA >7 without extrapelvic disease, no prior chemotherapy or EBRT, no prior androgen deprivation, KPS ≥ 70%, and adequate hepatic, renal, cardiac, and bone marrow reserve. Patients received pelvic EBRT (45.0Gy) followed by a permanent PB implant 4 weeks after EBRT. AD was started 1 month after PB at 35 mg/m2 weekly x 3 q 4wks x 3 mos. TAS (anti-androgen x 4 wks and LHRH x 2 yrs) started day 1 of EBRT. Results: 36 patients have been enrolled from 6/00–11/03. One pt discontinued after EBRT and another pt refused chemotherapy resulting in 34 evaluable for this report. Median age was 63 years (51–78), median baseline PSA 17.8 (1.2–84.6) and a GS of 8–10 in 50%. PSA relapse-free survival (PRFS) time was calculated from the date of EBRT initiation to the date of last PSA in 2003. The median follow-up time of PRFS was 20 months (range: 1–32 months). Since there have been no biochemical or clinical failures to date in the 34 evaluable patients, all PRFS times are censored (100% survival to date). Most toxicity was Grade 1–2 GU. Grade 3 GU toxicities: nocturia (3), and urinary frequency (3). No Grade 3 or higher GI toxicity occurred. Two patients experienced DVT's (one GR3 and one GR4). While receiving chemotherapy, Grade 3 toxicities included anemia (2) and leukopenia (2). Conclusions: Multi-modality therapy as described in this study was well tolerated for high-risk Pca. Although the follow-up interval is short, tumor control rates are very encouraging. Additional follow-up and patient accrual will be needed to validate these findings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals