bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a novel MUC1 biomarker/target antigen for pancreatic cancer
Authors: Gold D. V. , Modrak D. E. , Newsome G. , Karacay H. , Sharkey R. M. , Goldenberg D. M. 
Published: March 2020

4096 Background: Pancreatic cancer provides a major challenge in terms of diagnosis and treatment. We have developed an anti-MUC1 MAb, PAM4, which identifies an epitope that is more restricted to MUC1-expressed by pancreatic cancer than MUC1 from other forms of cancer. PAM4 has been studied for in vitro and in vivo detection and therapy of pancreatic cancer. Methods: The in vitro immunoassay consists of PAM4 as the capture reagent and an IgG fraction derived from a polyclonal, anti-MUC1 antiserum as the probe. For in vivo detection and therapy, PAM4 is either directly radiolabeled or used in a 2-step pretargeting protocol. Results: The PAM4-based immunoassay provided high sensitivity (77%) and specificity (95%), with a value ≥ 10.2 units/ml indicating a high likelihood of pancreatic cancer, as compared to normal and benign disease groups and non-pancreatic cancers. A direct pairwise comparison of the PAM4 and CA19–9 immunoassays for discrimination of pancreatic cancer and pancreatitis demonstrated a superior performance of the PAM4-immunoassay (P<0.003). Initial clinical studies with directly labeled 131I-PAM4 provided positive imaging in 8/10 patients, with one negative patient having only pancreatitis, and the other negative patient having a tumor that was MUC1-negative. A Phase I, dose-escalation study of 90Y-humanized PAM4 administered as a single dose to patients with advanced pancreatic cancer is in progress (Immunomedics, Inc), and has already achieved doses of 20 mCi/m2. Finally, pretargeting involving a bispecific MAb with one arm being PAM4 targeting MUC1 and the other arm capturing a hapten peptide carrying a radionuclide is under preclinical evaluation. This second generation targeting system has shown higher tumor/nontumor ratios and improved imaging (111In) as compared to directly radiolabeled PAM4. Conclusions: These results suggest that the PAM4-reactive MUC1 epitope may prove useful as a selective biomarker/target antigen for diagnosis, detection, imaging, and therapy of pancreatic cancer. (Supported in part by grants CA96924and CA98488 from the NIH). [Table: see text]
Long-term results of concurrent gemcitabine (G) and radiotherapy (GRT) for locally advanced (LA) or high-risk resected (R) pancreatic cancer
Authors: Townsley C. , Brade A. M. , Brezden-Masley C. , Hedley D. , Gallinger S. , Pond G. R. , Oza A. M. , Brierley J. , Moore M. J. 
Published: March 2020

4101 Background: G is active against pancreatic carcinoma and is a potent radiosensitizer. We present extended follow up data from a phase I/II study of patients treated with combination GRT. Methods: Eligible patients had either LA or high-risk resected [R] pancreatic cancer [positive nodes or positive margin]. 28 were enrolled in a Phase I study of increasing doses of radiotherapy (35 Gy [n = 7]/43.75 Gy [n = 11]/52.5 Gy [n = 10] given over 4, 5 or 6 weeks, respectively in 1.75 Gy fractions) concurrently with 40 mg/m2 gemcitabine biweekly. Subsequently 35 were treated with induction gemcitabine (G) 1000 mg/m2 7/8 weeks followed by concurrent bi-weekly gemcitabine (40 mg/m2) with 52.5 Gy (30 fractions of 1.75 Gy over 6 weeks). In total there were 63 patients (31 LA and 32 R) treated between March 1999–July 2001. Results: In the LA population the best response observed was CR - 1, PR - 2, SD - 10, PD - 10. GRT was not delivered to 8 patients due to progression on G alone (n = 5) or patient request (n = 3). By intent to treat analysis, the median survival in LA disease was 15.1 months and the 2 year survival was 19%. In the resected population the median time to progression was 14.3 months, the median survival was 17.9 months and the 5 year survival was 19%. The treatment was generally well tolerated during both the induction G and the GRT ( Table ). Conclusion: Survival for both LA and HR patients with this concurrent gemcitabine radiotherapy regimen is promising and warrants further investigation. [Table: see text] No significant financial relationships to disclose.
Impact of surgery and chemotherapy on survival in patients with advanced cholangiocarcinoma: A multivariate analysis in a cohort of 242 consecutive patients
Authors: Dreyer C. , Le Tourneau C. , Faivre S. , Paradis V. , Zhan Q. , Degos F. , Farges O. , Hammel P. , Ruszniewski P. , Belghiti J. , Raymond E. 
Published: March 2020

4133 Background: Cholangiocarcinoma remains an orphan disease for which prospective studies are missing to evaluate the impact of systemic chemotherapy on survival. Methods: Univariate and multivariate analysis of parameters that might impact survival were analyzed in a cohort of 242 consecutive patients with cholangiocarcinoma treated in a single institution between 2000 and 2004. Variables were WHO performance status (PS), age, symptoms, tumor size, extent of the disease, lymph node involvement, site of metastasis, tumor markers, pathology, and type of treatment including surgery, chemotherapy and radiotherapy. Results: Statistically significant prognostic factors of survival in univariate analysis are displayed in the table : In multivariate analysis, PS, tumor size and surgery were independent prognostic factors. Subgroup analysis demonstrated that in patients with advanced diseases (lymph node involvement, peritoneal carcinomatosis and/or distant metastasis), patients who had no surgery benefited of chemotherapy (median survival 13.1 versus 7.4 months in patients with/without chemotherapy, p = 0.006). Moreover, survival was further improved when patients could benefit of chemotherapy following total and/or partial resection (median survival 22.9 versus 13.0 months in patients with/without chemotherapy, p = 0.03). Conclusions: This study strongly suggests the positive impact on survival of multimodality approaches including surgery and chemotherapy in patients with advanced cholangiocarcinoma. [Table: see text] No significant financial relationships to disclose.
Feasibility of a multi-institutional liver cancer registry
Authors: Sun W. , Schwartz J. , Zhu A. , Philip P. A. , Metz J. , Thomas M. B. 
Published: March 2020

4146 Background: Hepatocellular carcinoma (HCC) is one of major causes of cancer-related death globally, with increasing incidence in the United States. There is still a lack of effective therapy for the disease. Many small phase II studies of systemic therapies for advanced HCC have been performed in the US. Most studies are too small to make definitive conclusions. This registry was developed to pool phase II studies from member institutions of the Liver Cancer Research Group (LCRG) to evaluate the characteristics and outcomes of patients receiving systemic treatments in an attempt to validate known and to identify potentially new prognostic factors in HCC. Methods: An Internet based registry was initiated on the OncoLink website ( https://www.oncolink.org ) and directed by the LCRG. This registry has undergone IRB approval. All data is password protected and maintained on physical and electronically secure servers. The registry contains 37 fields for each patient, which details demographics, tumor parameters, underlying liver disease, and detailed treatment information of chemotherapy and/or biological therapies. Results: As of 1/10/2006, 101 patients have been entered in the database from 5 institutions. The median age of patients in these studies is 59 years old (range 26–82) with 22 female (22%) patients. The racial distribution was: 67% of Caucasian, 15% African American, 11% Asian, and 6% Hispanic. The median performance status of patients included in these phase II studies was ECOG 1 (PS 0/1/2: 41/56/4). A variety of cytotoxic and biological agents (either as a single agent or as combination) were included in the analysis including doxorubicin, epirubicin, gemcitabine, oxaliplatin, capecitabine, thalidomide, erlotinib, and bevacizumab. All patients had extensive disease, most of them with multiple lesions (51% ≥ 5 lesions) and bilobar involvement (69%). The mean size of lesions was 8.3 cm (range 1–20 cm). Within the population, 25% patents have hepatitis B and 44% have hepatitis C as their background diseases. Conclusions: This multi-institutional database for HCC treated on phase II clinical trials in the US is feasible. This database continues to expand through the support of the LCRG. As the data matures, future studies on outcomes related to biological and chemotherapeutic regimens will be presented. No significant financial relationships to disclose.
Two novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 are active against biliary tract cancer and potentiate the efficacy of gemcitabine
Authors: Wiedmann M. , Bluethner T. , Niederhagen M. , Schoppmeyer K. , Moessner J. , Caca K. 
Published: March 2020

4149 Background: Chromatin remodelling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. NVP-LAQ824 and NVP-LBH589 are two novel chemical entities belonging to a cinnamic hydroxamic acid class of compounds. Little is known about their efficacy for the treatment of biliary tract cancer. Methods: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for p21WAF-1, acH3Lys9 and acH4, cell cycle analysis, PARP assay, TUNEL assay, and immunhistochemistry for MIB-1. Results: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines (mean IC50 (3d) 0.08 and 0.04 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H3 and H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and induction of apoptosis (PARP cleavage). After 28 d, NVP-LBH589 reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis (TUNEL) and reduced cell proliferation (MIB-1). Conclusions: Our findings suggest that NVP-LBH589 > NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended. No significant financial relationships to disclose.
Reduced thromboembolic events with DN-101 (high-dose calcitriol) treatment of androgen-independent prostate cancer: Hypothesis for a new class of anticoagulants
Authors: Venner P. M. , Ryan C. , Petrylak D. P. , Chatta G. S. , Ruether J. , Chi K. N. , Curd J. , Beer T. M. 
Published: March 2020

4505 Background: Thromboembolic events (TEs) occur at an increased rate in patients with advanced malignancies including androgen-independent prostate cancer (AIPC). DN-101, a new high-dose oral formulation of calcitriol (1,25-dihydroxycholecalciferol), is the active form of Vitamin D and the natural ligand for the nuclear receptor VDR. Calcitriol upregulates thrombomodulin, a natural anticoagulant, and downregulates tissue factor, a procoagulant both in vitro and in vivo. Further, VDR knockout mice demonstrate increased susceptibility to thrombosis. ASCENT is a double-blind, placebo-controlled study in 250 men with metastatic AIPC. Efficacy results have been previously reported (ASCO, 2005). Methods: 250 patients were randomized 1:1 to docetaxel 36 mg/m2 plus 45 μg DN-101 weekly or to the same docetaxel regimen plus placebo. In this exploratory analysis the incidence of TE (defined as deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA) and arterial thrombosis (AT)) in the two study groups was compared using the Fisher’s exact test. Results: There were fewer patients with serious adverse events (SAEs) in the DN-101 group than in the placebo group (27 % vs. 41%). As shown in the table , DN-101 treated patients experienced fewer TEs including fewer TE SAEs, Grade 3 or 4 TEs and all grade TEs. No imbalance in baseline use of anticoagulants was observed. Conclusions: The well-described effects of calcitriol on protein components of the coagulation cascade provide a biologic basis for the observed reduction in thromboembolic events in the DN-101 treated patients. This hypothesis should be tested prospectively in future studies of DN-101. [Table: see text] [Table: see text]
Increased late toxicity in 12–20 year survivors of germ cell tumors (GCT)
Authors: Raghavan D. , Davis M. S. , Tsao-Wei D. , Ross R. , Groshen S. 
Published: March 2020

4509 Background: There is extensive literature on occurrence of late effects of cisplatin-based chemotherapy, but it comes from centers of excellence and may reflect case selection or ascertainment biases. Funded by the NIH SEER Program and the Lance Armstrong Foundation, we studied community-based late outcomes via identification of cases from the Los Angeles SEER Tumor Registry and comparison with a control group. Methods: We identified 951 patients treated in Los Angeles County through the records of the L.A. SEER Cancer Registry/Cancer Surveillance Program (CSP) for 1983–1987, giving a minimum follow-up of 12 years. Consent was obtained from physician of record and forms sent to the patients, requesting information about a broad range of demographic, treatment-related and psycho-social issues. In addition, patients were asked to provide a “control”, a friend of approximately the same age at time of diagnosis, known to the patient before diagnosis and known not to have a history of testis cancer. Questionnaires were also sent to controls, to allow data comparison with patients. Anticipated initial difficulties included mobility of young males and invalid addresses. This occurred in > 50% of cases, and we used a planned strategy for acquisition through State agencies, Department of Motor Vehicles, etc. Results: Surveys were returned by 298 cases and 67 control subjects, and 35 patients refused. In 1983–87, success rates were lower, and 142 patients had died. An unexpected problem was reluctance or inability of subjects to identify friends of comparable age to provide a control population. Differences in groups are summarized in the Table. Conclusions: Long term survivors with GCT have an excess of late toxicity, including cardiovascular, neurological, hematologic, musculoskeletal and neoplastic problems, which increase with time. These data should assist in design of surveillance protocols. [Table: see text] No significant financial relationships to disclose.
A prospective study of 18FDG PET in the prediction of relapse in patients with high risk clinical stage I (CS1) non-seminomatous germ cell cancer (NSGCT): MRC study TE22
Authors: Huddart R. , O’Doherty M. , Padhani A. , Rustin G. , Mead G. , Joffe J. K. , Vasey P. , Hain S. , Kirk S. J. , Stenning S. P. 
Published: March 2020

4520 Background: High risk stage I NSGCT is characterised by vascular or lymphatic invasion within the primary tumour. This group comprises ∼50% of stage I pts with, (untreated) a relapse rate of 35–40%. Options for the management of such pts include adjuvant chemotherapy, retroperitoneal lymph node dissection (± adjuvant chemotherapy) and surveillance, each achieving similarly high cure rates. An FDG PET scan may be able to aid discrimination between pts without occult metastatic disease, for whom surveillance is an attractive option, and those requiring immediate therapy. Methods: High risk (vascular invasion +ve) CS1 NSGCT pts underwent FDG PET scanning within ∼8 weeks of orchidectomy. PET+ve pts went off study, PET -ve pts were followed on surveillance. The primary outcome measure was the -ve predictive value of PET, defined as the 2-year relapse-free rate (RFR) in pts with a negative PET scan. Assuming a RFR of ∼90%, to exclude a RFR < 80% with 80% power (5% significance), ∼100 PET negative pts were required from ∼135 scanned pts. All baseline CT scans were subject to central review blinded to PET result and relapse status and, in relapsed pts, a retrospective comparison of the CT and PET scan results. Results: Pts were registered between 5/02 and 1/05, when the trial was stopped early by the independent Data Monitoring Committee due to an unacceptably high relapse rate in the PET-ve pts. 116 pts were registered of whom 111 underwent PET scans. 88 pts (79%) were PET-ve; 87 proceeded to surveillance and one requested adjuvant chemotherapy. With median follow-up of 11 months, 33 of the 87 pts on surveillance relapsed for a one-year relapse-free rate of 63% 90% CI (54%, 72%). The PET +ve/relapse rate was 69% in patients with normal markers pre-orchidectomy (n = 36) and 41% in those with raised markers (n = 66). There has been one death (suicide) amongst the PET -ve pts. The radiology and PET scan review will be completed by May 2006. Conclusions: Though PET identified a proportion of pts with disease not detected by CT scan the relapse rate amongst PET -ve pts remains high. The study results therefore suggest that 18FDG PET scanning is not able to identify pts at sufficiently low risk of relapse to replace other treatment options in this setting. No significant financial relationships to disclose.
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Authors: Amato R. J. , Misellati A. , Khan M. , Chiang S. 
Published: March 2020

4530 Background: RAD001 an oral serine-threonine kinase inhibitor of mTOR, blocks progression from the GI to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. Mechanistically, it is thought that RAD001 may play a role in VEGF inhibition. Main endpoints were to evaluate: time to progression (TTP), response rate, toxicity and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included: progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤ 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into the study. Results: 25 pts have been enrolled as of this review. 19 male/6 female, range 43–80 (median 60) years. All pts had predominant clear cell elements with progressive MRCC. 17 pts received prior immunotherapy, targeted agents, or chemotherapy. 22 pts had a ZPS of 0, 2/1 and 1/2. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 10 pts/2 metastatic sites and 8 pts/3 or more metastatic sites. 22 pts continue to receive RAD001 therapy. 7 pts had partial responses, 11 pts were stable for 3+ months, (5 pts/6+ months). 4 pts too early. Median duration of therapy is 7+ months (range 1+ to 9+). Treatment related adverse events to date include: mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia and elevated LFTs. Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC as demonstrated by a 33% partial response rate. Anti-tumor activity was further suggested by prolonged TTP ≥ 3 months for 86% of pts. The tumor effect was also demonstrated as a second line therapy. Independent radiology review is planned. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. [Table: see text]
Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: Houk B. E. , Amantea M. , Motzer R. J. , Michaelson M. D. , Rini B. I. , George D. J. , Redman B. G. , Hudes G. R. , Poland B. , Bello C. L. 
Published: March 2020

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]