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1.  The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients 
Glioblastoma multiforme (GBM) remains one of the most devastating tumors, and patients have a median survival of 15 months despite aggressive local and systemic therapy, including maximal surgical resection, radiation therapy, and concomitant and adjuvant temozolomide. The purpose of antineoplastic treatment is therefore to prolong life, with a maintenance or improvement of quality of life. GBM is a highly vascular tumor and overexpresses the vascular endothelial growth factor A, which promotes angiogenesis. Preclinical data have suggested that anti-angiogenic treatment efficiently inhibits tumor growth. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A, and treatment has shown impressive response rates in recurrent GBM. In addition, it has been shown that response is correlated to prolonged survival and improved quality of life. Several investigations in newly diagnosed GBM patients have been performed during recent years to test the hypothesis that newly diagnosed GBM patients should be treated with standard multimodality treatment, in combination with bevacizumab, in order to prolong life and maintain or improve quality of life. The results of these studies along with relevant preclinical data will be described, and pitfalls in clinical and paraclinical endpoints will be discussed.
PMCID: PMC4186574  PMID: 25298738
primary treatment; VEGF; quality of life; monoclonal antibody; patient survival; vascular tumor
2.  The Use of Longitudinal 18F-FET MicroPET Imaging to Evaluate Response to Irinotecan in Orthotopic Human Glioblastoma Multiforme Xenografts 
PLoS ONE  2014;9(6):e100009.
Brain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.
Human GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.
The relative tumor-to-brain (T/B) ratio of SUVmax was significantly lower after one week (123±6%, n = 7 vs. 147±6%, n = 7; p = 0.018) and after two weeks (142±8%, n = 5 vs. 204±27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = −0.62, p = 0.04) and LAT2 (r = −0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.
18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.
PMCID: PMC4053391  PMID: 24918622
3.  Sorafenib in Advanced Hepatocellular Carcinoma: A Nationwide Retrospective Study of Efficacy and Tolerability 
The Scientific World Journal  2013;2013:931972.
Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP) as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS) of 6.2 months, compared to 1.8 months in patients with poorer PS (P = 0.005). Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P = 0.0001). Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.
PMCID: PMC3569916  PMID: 23431262
4.  Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial 
Neuro-Oncology  2010;12(5):508-516.
The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide). Bevacizumab and irinotecan were administered IV every 2 weeks. The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis. Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not: 340 and 125 mg/m2, respectively. Cetuximab 400 mg/m2 as loading dose followed by 250 mg/m2 weekly was administered IV. Forty-three patients were enrolled in the trial, of which 32 were available for response. Radiographic responses were noted in 34%, of which 2 patients had complete responses and 9 patients had partial responses. The 6-month progression-free survival probability was 30% and median overall survival was 29 weeks (95% CI: 23–37 weeks). One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery. One patient was excluded due to suspicion of interstitial lung disease. Three patients had deep-vein thrombosis; all continued on study after adequate treatment. Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity, with an encouraging response rate. However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.
PMCID: PMC2940618  PMID: 20406901
bevacizumab; cetuximab; EGFR; glioblastoma multiforme; irinotecan
5.  Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2009;27(25):4116-4123.
Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4.
Patients and Methods
Patients with non–small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti–SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study).
Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 μg/kg (NSCLC and PC) and 15 μg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 μg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56.
ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
PMCID: PMC2734423  PMID: 19636016
6.  Active Transport of D-Xylose in the Isolated Small Intestine of the Bullfrog 
The Journal of General Physiology  1966;49(5):1029-1041.
Fluxes of D-xylose-1-C14 (xylose) across the wall of the isolated intestine of the bullfrog were studied. When sodium was the principal cation in the mucosal bathing fluid, the transport rate of xylose from the mucosa to the serosa was about 5 times greater than the transport rate from the serosa to the mucosa, indicating an active intestinal transport for this sugar. With potassium as the principal cation on the mucosal side, the transport rate of xylose from the mucosal to the serosal compartment is reduced about 5 to 6 times without appreciable change in the serosal to mucosal transport. The asymmetry was also considerably reduced when ouabain was added to the mucosal and serosal compartments. The data confirm the in vitro and in vivo observations indicating active transport of xylose and are also in accord with the earlier findings that active transport of sugars in the intestine is dependent upon the presence of sodium ions in the mucosal compartment and is inhibited by cardioactive steroids. Since the chemical constitution of xylose does not meet the requirements which were hitherto considered necessary for active transport of sugars in the intestine, this structural requirement has to be revised.
PMCID: PMC2195526  PMID: 5961352

Results 1-6 (6)