bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidermal growth factor receptor expression in and targeted therapy for metastatic squamous cell carcinoma of the penis
Authors: Pagliaro L. C. , Osai W. , Tamboli P. , Vakar-Lopez F. , Pettaway C. A. 
Published: March 2020

14045 Background: Penile carcinoma is highly fatal when associated with bulky regional or distant metastases, despite chemotherapy and surgery. Epidermal growth factor receptor (EGFR) is a potential target for systemic therapy, but little is known about its expression or significance in penile carcinoma. Methods: The results of EGFR immunohistochemistry in cases of metastatic squamous cell carcinoma of the penis performed in our Department of Pathology over a 2-year period were reviewed retrospectively. The antibody used in the assay was Zymed clone 31G7. To assess the biological significance of EGFR expression, we reviewed the charts of these patients for EGFR-targeted therapies and outcomes. Results: Thirteen cases were assayed for EGFR expression. The tissue was from a lymph node metastasis in 5 patients, inguinal or scrotal skin metastasis in 2 patients, and the primary tumor in six patients. Tumor cells in all cases were positive for EGFR, and 9 were scored as 3+ or strongly positive. The percentage of cells positive for EGFR was >90% in six cases, 40–50% in one case, and not specified in six cases. All of the patients received one or more EGFR-targeted therapies including erlotinib (one patient), cetuximab (three patients), or cetuximab combined with one or more cytotoxic agents (nine patients). Six patients received a second or third EGFR-targeted therapy. Grade 3 or 4 adverse events were limited to cellulitis, thrombocytopenia, and tumor hemorrhage (one patient each). Two patients had disease progression during initial treatment with paclitaxel, ifosfamide, and cisplatin (TIP), then had partial responses to TIP plus cetuximab. Two patients had partial responses to cetuximab and cisplatin, also after having disease progression while receiving TIP. A patient with visceral metastases who had extensive prior chemotherapy received cetuximab and cisplatin as salvage treatment and experienced objective tumor regression lasting 3 months. Conclusions: High levels of EGFR expression are common in metastatic penile carcinoma. Five of 13 patients showed evidence of response to cetuximab in combination with cisplatin or TIP. These results indicate that EGFR plays a clinically important role in metastatic penile carcinoma and is a promising target for therapy. No significant financial relationships to disclose.
Preliminary results of a phase II study of continuous low dose metronomic (LDM) cyclophosphamide (CTX) and celecoxib (CEL) for asymptomatic hormone refractory prostate cancer (HRPC) with assessment of anti-angiogenic biomarkers
Authors: Berry S. R. , Ko Y. , Emmenegger U. , Shaked Y. , Choo R. , Klotz L. , Zhang L. , Lee C. , Kerbel R. 
Published: March 2020

14046 Background: LDM CTX is a minimally toxic anti-angiogenic therapy that has demonstrated activity in multiple tumour types including HRPC. Increased Cyclooxygenase 2 (COX 2, a prostaglandin synthase enzyme) expression appears to be a consistent feature of a variety of human tumours, including prostate cancer. COX 2 inhibitors like CEL exhibit anti-tumour activity in pre-clinical studies, at least in part due to their anti-angiogenic activity. Pre-clinical work supports the concept that the combination of selective angiogenesis inhibitors like CEL with metronomic chemotherapy can enhance the effects of these agents on tumour angiogenesis. Methods: Men with asymptomatic HRPC at a single Canadian centre received celecoxib 400 mg po BID and cyclophosphamide 50 mg po daily. The primary efficacy endpoint of this 2 stage phase II study is disease control rate (DCR): 50% PSA response, tumour response or prolonged (=6 mos) PSA or stable measurable disease. This study is also assessing the safety of LDM CTX and CEL as well as potential anti-angiogenic biomarkers in these patients including circulating endothelial cells and their precursors (CEC/P), plasma levels of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). Results: Enrollment for the first stage of this study (10 men) has been completed. There were 2 patients with disease control by the a priori criteria: one patient with a partial tumour response (PR) (PR duration 13 mos with PSA stabilization for 12 mos) and one patient that had both prolonged stable PSA (7 mos) and prolonged stable measurable disease (8 mos). In addition, another patient had an unconfirmed PR. The therapy was well tolerated. One patient had angina that responded well to medical therapy but there were no serious arterial-thromboembolic events. One patient developed grade 3 hypertension. All other toxicities were grade 1/2. Data on CEC/P, TSP-1 and VEGF levels will be presented at the meeting. Conclusions: LDM CTX + CEL is a well tolerated therapy in men with asymptomatic HRPC. 2/10 patients achieved disease control in the first stage of the trial, meeting the criteria to proceed to the second stage. [Table: see text]
Epigenetic regulation of IFN-α2b in multiple myeloma by a hydroxamic acid histone deacetylase (HDAC) inhibitor (SAHA) and a non-hydroxamic acid HDAC inhibitor (A-423378)
Authors: Cheriyath V. , Glaser K. B. , Healan-Greenberg C. , Waring J. F. , Kalaycio M. , Borden E. C. 
Published: March 2020

14048 Background: Full clinical potential of IFN-a2b is yet to be achieved in multiple myeloma. Although IFN-a2b leads to the induction of pro-apoptotic interferon stimulated genes (ISGs) (>100 fold) in myeloma cells, <20% of cells underwent apoptosis. Thus, we hypothesized that epigenetic silencing of ISGs may be responsible for the sub-optimal cellular response of myeloma to IFNs. Re-expression of suppressed ISGs by inhibiting HDACs could enhance IFNs effects. Methods: Myeloma cell lines NCI H929, RPMI 8266 and U266 treated for 96 hr with increasing concentrations of SAHA (Suberoyl Anilide Hydroxamic Acid) or A-423378, were assessed with alamar blue to determine IC50, and synergy between IFN-a2b and HDAC inhibitors (HDACi). Microarray analysis was performed to determine the effects on gene expression. Results: Both SAHA and A-423378 inhibited myeloma cell growth (IC50 100–400 ?M). Combinations of IFN-a2b and sub-IC50 concentrations of A-423378 or SAHA synergistically reduced the viability of NCI H929 and RPMI 8266. Treatments at their IC50 did not increase the expression of p21, p27 or p16, known mediators of HDACi. To identify target genes mediating cellular effects, RNA from RPMI 8266 cells treated for 18 or 72 hr with IFN-a2b, A-423378, SAHA or their combinations were hybridized to Affymetrix human genome U133A array. A-423378 had a greater effect on global gene expression (3228 genes) than SAHA (2249 genes) at 18 hr. But, at 72 hr SAHA (1344 genes) had more persistent effect on gene modulation than A-423378 (1091 genes). IFN-a2b altered the expression of 2072 genes at 18 hr and 1374 genes at 72 hr. Combination of IFN-a2b with A-423378 further altered the gene expression (IFN-a2b plus A-423378 3589 genes, IFN-a2b plus SAHA 2017 genes at 18 hr). RARRES3, a tumor suppressor gene was synergistically induced (34 fold) by IFN-a2b and HDACi combinations. Conclusions: A-423378 had a greater effect on global gene expression at early time points whereas SAHA had a more persistent effect. HDACi of different classes enhanced anti-viability effects of IFN- a2b. RARRES3, a tumor suppressor gene, may mediate antiproliferative effects of HDACi and IFN-a2b. No significant financial relationships to disclose.
Evaluation of statistical designs of phase I/II clinical trials for cancer patients published in 2005
Authors: Houede N. , Kramar A. , Paoletti X. 
Published: March 2020

14077 Background: Phase I trials determine the maximal safe dose that could be used in phase II trials. Designs are based on the assumption that efficacy and toxicity increase with dose. Phase I/II trials determine the safety, dosage levels, and response rate. This review addresses statistical issues of phase I/II studies designs. Methods: We reviewed phase I/II clinical trials for cancer patients published in 2005. The main criteria were: type of treatment, statistical design, endpoints, expected efficacy and toxicity, one- or two-steps designs, dose levels, definition of Dose Limiting Toxicity and recommended dose, objective response, survival, patient selection and follow-up. Results: 41 phase I/II trials were found. All but one, targeted a specific type of tumor. 14 studies included combined cytotoxic therapies. 21 studies included a cytotoxic agent combined with a targeted therapy (12) or with radiations (9). Others used monochemotherapy, immunotherapy, vaccine or gene therapy. 23 studies were a two steps design, i.e. a phase I followed by a phase II trial, and used a classical Fibonacci escalation dose model. All others used a one-step design evaluating efficacy and toxicity concomitantly. Among them, 3 had a Fibonacci-like design with a desescalation model and 4 had a randomization to different dose levels. In 1 trial, dose escalation was performed in the same patient. In the 10 remaining studies, 1 evaluated only one dose level and was improperly presented as a phase I/II study, and 9 did not describe any statistical design. DLT was described in only 27 trials. Also, recommended doses for further trials were only provided in 30 studies. Efficacy was evaluated with clinical or radiological response for 34 studies, biological marker was evaluated in 5 cases and time to progression in 2 cases. Conclusion: Most of the phase I/II trials published in 2005 used a classical two steps design with an adapted Fibonacci dose escalation. None of them used new designs such as continual reassessment method (CRM), which have the advantage to incorporate data during the course of the trial, leading to optimization of the study in terms of cost and speed. Methodological progresses are necessary to address issues related to multiple endpoints and to help clinicians to feel comfortable with the CRM. No significant financial relationships to disclose.
Patterns of management of rash associated with epidermal growth factor receptor inhibitors (EGFRIs): A national practice survey
Authors: Lacouture M. E. , Lai S. , Rademaker A. W. , Liu D. , Pfeiffer C. , Mauro D. 
Published: March 2020

14081 Background: Dermatological toxicities are frequent in patients receiving epidermal growth factor inhibitors (EGFRIs), which significantly affect health and quality of life. No current consensus or guidelines exist for the management of these manifestations. In order to gain insight on actual management approaches, a retrospective survey was conducted across oncology practices in the US. Methods: A survey in person was carried out that included 51 questions to 110 practitioners administering EGFRIs in the US, during which time erlotinib, cetuximab and gefitinib were FDA-approved. Open- and closed-ended questions relating to frequency and CTC-graded (G) severity of rash observed, management patterns, and impact on continued EGFRI therapy were evaluated. Statistical testing for correlations was done using Fisher’s exact test. Results: Respondents (resp) included MDs (72%), nurses (23%), NPs (4%), and pharmacists (1%). Majority (>50%) of rash events observed were mild/moderate (G1 in 39% + G2 in 34%). Interventions against rash by resp was based on severity, with G1 treated by 47%, G2 (71%), G3 (87%), G4 (80%). Treatments for G1/2 included only topical agents (TA) by 30% of providers, and combined TA + systemic agents (SA) for G3 (G4) by 48% (30%) of providers. Interestingly, 84% of resp indicated G2 rash improved with TA+SA therapy and only 44% with SA only. Although severe events were reported infrequently (4% and 3% of resp see >50% of G3 and 4 events, respectively), EGFRIs were frequently dose modified (76%) or discontinued (32%) due to rash. Conclusions: Rash is frequent and its management heterogeneous across the US, which increases with rash G. These findings suggest that combined therapy (TA + SA) is more effective than single-agent. Therefore, the high frequency of dose EGFRI modification/discontinuations reported may be minimized by proactive interventions. Trials evaluating proactive and reactive combined TA + SA against rash are currently underway. No significant financial relationships to disclose.
A novel zinc-chelating small molecule exhibits cancer cell growth inhibition in vitro and in vivo by induction of tumor suppressors early growth response 1 (Egr-1) and Krüppel-Like Factor 4 (KLF4)
Authors: Lock L. , Khine A. , Huesca M. , Lawson V. , Peralta R. , Cammisa E. , Wang M. , Jin H. , Lee Y. , Wright J. , Young A. 
Published: March 2020

14084 Background: Lead compound LT-253 was selected from a group of 2-indolyl imidazol [4,5-d] phenanthroline derivatives with anticancer activity. It shows potent and selective anti-proliferative activity against several human cancer types in vitro, and in vivo in xenograft mouse models of human colon carcinoma (HT-29) and non-small cell lung carcinoma (H460). Methods: The mechanism of cell growth inhibition of LT-253 was investigated in HT-29 colon cancer cells using the XTT cell proliferation assay, flow cytometry and apoptosis assays. In vitro and in vivo zinc chelation was determined by competition assays using fluorescent and chromophoric chelators. Gene expression studies were performed by human genome microarray analysis and confirmed by quantitative real- time PCR. The transcription factor activity profile of LT-253-treated cells was determined by a multiplex transcription factor array and electrophoretic mobility shift assays. The functional role of specific genes was evaluated by siRNA gene knock-down. Results: LT-253 functions as chelator of zinc in vitro, and of intracellular labile zinc in HT-29 cells. Moreover, LT-253-mediated HT-29 cell growth inhibition was reversed by zinc supplementation. Gene expression profiling confirmed sustained changes in zinc-sensitive genes such as metallothionine and several zinc transporters, but not copper-sensitive or iron-sensitive genes. LT-253 induces cancer cell growth inhibition primarily through G1/S phase cell cycle arrest. Gene expression and transcription factor activities of both Egr-1 and KLF4 are induced within 4 hr post LT-253 treatment. Moreover, increased expression of both Egr-1 and KLF4 is observed in LT-253-sensitive cancer cell lines of various origins. Importantly, Egr-1 and KLF4 gene knock-down by siRNA reversed the LT-253-mediated cell growth inhibition of HT-29 cells. Conclusion: Selective chelation of intracellular labile zinc pool by LT-253 triggers immediate induction of stress-responsive tumor suppressor Egr-1 and sustained induction of zinc-responsive tumor suppressor KLF4, leading to G1/S phase cell cycle arrest and inhibition of tumor growth. No significant financial relationships to disclose.
A phase 1 dynamic accelerated titration dose escalation study of the vascular disrupting agent NPI-2358
Authors: Spear M. A. , LoRusso P. , Tolcher A. W. , Lin C. , Wang D. , Heath E. , Lloyd G. K. , Cropp G. , Papadopoulos K. P. 
Published: March 2020

14097 Background: NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models and also potentiates the effects of chemotherapeutic agents. Preclinical data indicate NPI-2358 may have advantages in terms of safety profile and activity (tumor blood flow remains markedly reduced after 24 hours). Methods: A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion for 3 weeks in 4-week cycles. Eight subjects have been enrolled. The dose of NPI-2358 was escalated in cohorts of 1–3 patients dependent on observed adverse events (any cohort may consist of 1 patient provided no =Grade 2 AE is reported in the prior cohort). A cohort is expanded to 6 patients if a DLT is reported. Escalation was conducted in 100% intervals, and decreased to 50% intervals once a Grade 2 adverse event was reported. In addition to weekly safety monitoring (including ECGs, Troponin I, and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 & D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. Results: The dose has been escalated from 2 mg/m2 to 9 mg/m2 (predicted minimum efficacious dose = 7.5 mg/m2) without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. Intrapatient values for Ktrans from DCE-MRIs appear highly reproducible. No responses have been reported, however, one patient with pancreatic adenocarcinoma has had stable disease (SD) for 3 cycles and continues to receive NPI-2358. Average Cmax and AUClast have increased from 16.2 ng/ml to 147 ng/ml, and from 101 to 360 ng/ml*hr respectively. No drug accumulation was observed; T1/2 was 4.2 ±1.9 h, clearance was 45 ±12 L/h and distributive volume was 251±57 L. Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. PK data show increasing Cmax and AUC with dose escalation and no drug accumulation on a weekly schedule. No significant financial relationships to disclose.
Long-term administration of oblimersen (OBL) plus chemotherapy: An analysis of safety in patients with solid tumors and hematologic cancers
Authors: Baron N. A. , Gilles E. , Novick S. , Ehlert J. , Wu J. 
Published: March 2020

14098 Background: Oblimersen (OBL; Genasense®) is designed to increase the efficacy of cancer therapy by reducing Bcl-2 protein. The agent has been studied in several randomized clinical trials, which prompted an evaluation of safety after extended administration in combination with various anticancer agents. Methods: We evaluated safety data from more than 900 patients (pts) with solid tumors or hematologic cancers who received OBL alone or in combination with chemotherapy in phase I-III studies. A total of 84 pts (65 with solid tumors, 19 multiple myeloma) who received OBL for = 6 months of on-cycle and between-cycle days were identified. We then compared the incidence of adverse events (AEs) in the Day (D) 1 to D180-period with the > D180 day period. Pts with solid tumors received OBL (0.6 to 12 mg/kg/d) in combination with dacarbazine, docetaxel, or mitoxantrone; pts with myeloma received OBL (7 mg/kg/d) combined with high-dose dexamethasone. Results: Among pts with solid tumors, the mean (± SD) number of 21 to 28-day cycles initiated was 12.3 (± 3.7; range, 7–25); the mean number of OBL treatment days was 65.6 (± 24.0; range, 45–156). In pts with myeloma, the mean number of 21 to 28-day cycles initiated was 13.3 (± 3.3; range, 9–20); the mean number of OBL treatment days was 105.3 (± 23.2; range, 77–148). Across both data sets, the incidence of AEs was lower or comparable in most system-organ classes (SOCs) in the > 180-day period compared with the D1 to D180-period. Events were consistent with those reported with short-term administration in multiple studies, and common AEs (including fatigue, fever, nausea, and vomiting) were similar in both periods. Conclusions: Oblimersen can be safely combined with multiple types of anticancer therapy. Prolonged treatment with these combinations for > 180 days has not been associated with the emergence of AEs qualitatively different from those reported with treatment for shorter periods. No significant financial relationships to disclose.
Phase I dose escalation study of E7080, a novel anti-angiogenic multikinase inhibitor, in Japanese patients with advanced solid tumors
Authors: Yamada K. , Fujiwara Y. , Yamamoto N. , Yamada Y. , Suzuki S. , Kobayashi N. , Koizumi F. , Nishio K. , Tamura T. 
Published: March 2020

14099 Background: E7080 selectively inhibits receptor phosphorylation of vascular endothelial growth factor (VEGF), platelet- derived growth factor (PDGF), fibroblast growth factor (FGF) and suppresses tumor angiogenesis and growth in preclinical studies. Methods: E7080 was orally administered to Japanese patients with advanced solid tumors twice daily by a 2 week-on 1 week-off schedule. The primary objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and the recommended dose for further study. The secondary objectives were to evaluate pharmacokinetics (PK), pharmacogenomics, and efficacy. Results: Twelve patients have been enrolled into cohorts of 1, 2, 4 or 8 mg/day. Major toxicities were hypertension and hyperlipidemia. Thus far, no DLTs or severe toxicities were reported. PK analysis in cohorts of 1, 2 and 4 mg/day showed the dose-proportional increase of Cmax and AUC. Three patients in cohorts of 1 and 2 mg/day experienced long stable disease (SD) for 18 weeks or longer. One patient with colorectal cancer in 4 mg/day cohort showed significant tumor shrinkage of multiple pulmonary metastasis. Biomarkers such as plasma angiogenic proteins and cytokines, circulating endothelial cells and circulating endothelial progenitor cells are exploratively evaluated. Conclusions: E7080 is well tolerated at doses up to 8 mg/day by a 2 week-on 1 week-off schedule. Some patients experienced clinical benefit without severe toxicity. MTD has not been reached and enrollment is ongoing. No significant financial relationships to disclose.
Non-oncogenic deletion mutants of adenoviral E1A enhance paclitaxel induced apoptosis of ovarian cancer cells
Authors: Kurzeder C. , Hanselmann C. , DeGregorio N. , Sauer G. , Opalka B. , Kreienberg R. , Deissler H. 
Published: March 2020

14102 Background: The phenotypical characteristics and spread of ovarian cancer cells, suggest intraperitoneal gene therapy of this disease. Phase I trials have been conducted to investigate the potential clinical benefits of adenoviral E1A-based gene therapy. Further gene therapeutic approaches which aim to enhance the efficacy of E1A-induced apoptosis in a multimodal approach including conventional chemotherapy are planned. However, besides tumor-suppressive effects, E1A is also known to transform rodent cells in conjunction with other factors, e.g. an activated ras oncogene. In an effort to eliminate elements favouring malignant conversion, the potential therapeutic effect of the E1AdelCR2 deletion mutant on ovarian cancer cells was studied. Methods: To avoid any selection bias, a doxycyclin-regulated system was used to express E1A wildtype protein and the mutant E1AdelCR2 lacking the p105RB-binding motif. The effects of the E1A proteins on proliferation and induction of apoptosis in ovarian carcinoma cell lines was studied with a WST-1 assay and fluorcytometric analysis of FITC labelled AnnexinV. Results: As confirmed by Western blot analyses, expression of the mutant proteins was almost completely suppressed in the presence of doxycyclin. Substantial reduction in proliferation was achieved by expression of both wildtype E1A and E1AdelCR2. Expression of E1AdelCR2 was sufficient by itself to induce apoptosis in 8,7% of ovarian carcinoma cells as shown by an increase of the fraction of Annexin binding OVMZ-8 cells. A strong synergistic effect with an increase of the fraction of apoptotoc cells by 16.7% was found when the cells were treated with paclitaxel. Conclusion: Deletion of the CR2 sequence should increase the safety of therapeutic applications of E1A without affecting tumor suppression. A doxycyclin-regulated expression system was established allowing the elucidation of the mechanisms underlying the therapeutic effects of E1A in ovarian cancer cells in the future by means of expression profiling and quantification of activated components of signal transduction pathways. No significant financial relationships to disclose.