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Charles A Enke

Publications and source records attributed to Charles A Enke.

18 recordsLinked to original sources
PubMed2007

Emerging role of platelet-derived growth factor receptor-beta inhibition in radioimmunotherapy of experimental pancreatic cancer.

PURPOSE: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. EXPERIMENTAL DESIGN: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on (131)ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-beta. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of (131)ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. RESULTS: Biodistribution studies revealed a 50% improvement in the tumor uptake of (131)ICC49 in mice treated with imatinib. Tumor development was practically arrested for approximately 3 weeks in response to the treatment composed of (131)ICC49 and imatinib with tumor quadrupling time (T(Q)) of 40.8 days. (131)ICC49 alone and imatinib alone also delayed the tumor growth to T(Q) of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d. for 3 days. Xenografts in control mice receiving injection of PBS had T(Q) of 23 days. CONCLUSIONS: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodality treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-beta inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.

Animals↗
PubMed2006

Ultrasound-based guidance of intensity-modulated radiation therapy.

In ultrasound-guided intensity-modulated radiation therapy (IMRT) of prostate cancer, ultrasound imaging ascertains the anatomical position of patients during x-ray therapy delivery. The ultrasound transducers are made of piezoelectric ceramics. The same crystal is used for both ultrasound production and reception. Three-dimensional (3D) ultrasound devices capture and correlate series of 2-dimensional (2D) B-mode images. The transducers are often arranged in a convex array for focusing. Lower frequency reaches greater depth, but results in low resolution. For clear image, some gel is usually applied between the probe and the skin contact surface. For prostate positioning, axial and sagittal scans are performed, and the volume contours from computed tomography (CT) planning are superimposed on the ultrasound images obtained before radiation delivery at the linear accelerator. The planning volumes are then overlaid on the ultrasound images and adjusted until they match. The computer automatically deduces the offset necessary to move the patient so that the treatment area is in the correct location. The couch is translated as needed. The currently available commercial equipment can attain a positional accuracy of 1-2 mm. Commercial manufacturer designs differ in the detection of probe coordinates relative to the isocenter. Some use a position-sensing robotic arm, while others have infrared light-emitting diodes or pattern-recognition software with charge-couple-device cameras. Commissioning includes testing of image quality and positional accuracy. Ultrasound is mainly used in prostate positioning. Data for 7825 daily fractions of 234 prostate patients indicated average 3D inter-fractional displacement of about 7.8 mm. There was no perceivable trend of shift over time. Scatter plots showed slight prevalence toward superior-posterior directions. Uncertainties of ultrasound guidance included tissue inhomogeneities, speckle noise, probe pressure, and inter-observer variation. Some published studies detected improvement in treatment based on gastrointestinal toxicity and the reduction of prostate movement.

Humans↗
PubMed2006

Comparison of Kodak EDR2 and Gafchromic EBT film for intensity-modulated radiation therapy dose distribution verification.

The quantitative dose validation of intensity-modulated radiation therapy (IMRT) plans require 2-dimensional (2D) high-resolution dosimetry systems with uniform response over its sensitive region. The present work deals with clinical use of commercially available self-developing Radio Chromic Film, Gafchromic EBT film, for IMRT dose verification. Dose response curves were generated for the films using a VXR-16 film scanner. The results obtained with EBT films were compared with the results of Kodak extended dose range 2 (EDR2) films. The EBT film had a linear response between the dose range of 0 to 600 cGy. The dose-related characteristics of the EBT film, such as post irradiation color growth with time, film uniformity, and effect of scanning orientation, were studied. There was up to 8.6% increase in the color density between 2 to 40 hours after irradiation. There was a considerable variation, up to 8.5%, in the film uniformity over its sensitive region. The quantitative differences between calculated and measured dose distributions were analyzed using DTA and Gamma index with the tolerance of 3% dose difference and 3-mm distance agreement. The EDR2 films showed consistent results with the calculated dose distributions, whereas the results obtained using EBT were inconsistent. The variation in the film uniformity limits the use of EBT film for conventional large-field IMRT verification. For IMRT of smaller field sizes (4.5 x 4.5 cm), the results obtained with EBT were comparable with results of EDR2 films.

Dose-Response Relationship, Radiation↗
PubMed2005

Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy.

Whereas radioimmunotherapy of hematologic malignancies has evolved into a viable treatment option, the responses of solid tumors to radioimmunotherapy are discouraging. The likely cause of this problem is the interstitial hypertension inherent to all solid tumors. Remarkable improvements in tumor responses to radioimmunotherapy were discovered after the inclusion of STI571 in the therapy regimen. A combination of the tumor stroma-reactive STI571, a potent platelet-derived growth factor receptor-beta (PDGFr-beta) antagonist, and the tumor-seeking radiolabeled antibody B72.3 yielded long-lasting growth arrest of the human colorectal adenocarcinoma LS174T grown as s.c. xenografts in athymic mice. The interaction of STI571 with the stromal PDGFr-beta reduced tumor interstitial fluid pressure (P(IF)) by >50% and in so doing improved the uptake of B72.3. The attenuation of P(IF) also had a positive effect on the homogeneity of antibody distribution. These effects were dose-dependent and under optimized dosing conditions allowed for a 2.45 times increase in the tumor uptake of B72.3 as determined in the biodistribution studies. Single-photon emission computed tomography imaging studies substantiated these results and indicated that the homogeneity of the radioisotope distribution was also much improved when compared with the control mice. The increased uptake of radioimmunotherapy into the tumor resulted in >400% increase in the tumor absorbed radiation doses in STI571 + radioimmunotherapy-treated mice compared with PBS + radioimmunotherapy-treated mice. The improved antibody uptake in response to the attenuation of tumor P(IF) was identified as the primary reason for the growth arrest of the STI571 + radioimmunotherapy-treated tumors. Two related causes were also identified: (a) the improved homogeneity of monoclonal antibody distribution in tumor and (b) the increased tumor radiosensitivity resulting from the improved tumor oxygenation.

Adenocarcinoma↗
PubMed2005

Effects of field parameters on IMRT plan quality for gynecological cancer: a case study.

Traditional external beam radiotherapy of gynecological cancer consists of a 3D, four-field-box technique. The radiation treatment area is a large region of normal tissue, with greater inhomogeneity over the treatment volume, which could benefit more with intensity-modulated radiation therapy (IMRT). This is a case report of IMRT planning for a patient with endometrial cancer. The planning target volume (PTV) spanned the intrapelvic and periaortic lymph nodes to a 33-cm length. Planning and treatment were accomplished using double isocenters. The IMRT plan was compared with a 3D plan, and the effects of field parameters were studied. Delineated anatomical contours included the intrapelvic nodes (PTV), bone marrow, small bowel, bladder, rectum, sigmoid colon, periaortic nodes (PTV), spinal cord, left kidney, right kidney, large bowel, liver, and tissue (excluding the PTVs). Comparisons were made between IMRT and 3D plans, 23-MV and 6-MV energies, zero and rotated collimator angles, different numbers of segments, and opposite gantry angle configurations. The plans were evaluated based on dosevolume histograms (DVHs). Compared with the 3D plan, the IMRT plan had superior dose conformity and spared the bladder and sigmoid colon embedded in the intrapelvic nodes. The higher energy (23 MV) reduced the dose to most critical organs and delivered less integral dose. Zero collimator angles resulted in a better plan than "optimized" collimator angles, with lower dose to most of the normal structures. The number of segments did not have much effect on isodose distribution, but a reasonable number of segments was necessary to keep treatment time from being prohibitively long. Gantry angles, when evenly spaced, had no noticeable effect on the plan. The patient tolerated the treatment well, and the initial complete blood count was favorable. Our results indicated that large-volume tumor sites may also benefit from precise conformal delivery of IMRT.

Adenocarcinoma↗
PubMed2005

Cell-phone interference with pocket dosimeters.

Accurate reporting of personal dose is required by regulation for hospital personnel that work with radioactive material. Pocket dosimeters are commonly used for monitoring this personal dose. We show that operating a cell phone in the vicinity of a pocket dosimeter can introduce large and erroneous readings of the dosimeter. This note reports a systematic study of this electromagnetic interference. We found that simple practical measures are enough to mitigate this problem, such as increasing the distance between the cell phone and the dosimeter or shielding the dosimeter, while maintaining its sensitivity to ionizing radiation, by placing it inside a common anti-static bag.

Artifacts↗
PubMed2005

Prostate motion and isocenter adjustment from ultrasound-based localization during delivery of radiation therapy.

PURPOSE: To study prostate motion from 4,154 ultrasound alignment fractions on 130 prostate patients treated with conformal radiotherapy or intensity-modulated radiation therapy at the University of Nebraska Medical Center. METHODS AND MATERIALS: Each prostate patient was immobilized in a vacuum cradle. Daily treatment was verified by ultrasound scan after laser setup with skin marks and before radiation delivery by the same physician responsible for anatomic delineation during planning. Directional statistics were employed to test the significance of shift directions. RESULTS: Polar histograms showed the prevalence of prostate motion in superior-posterior directions. The average direction was about 27 degrees from the superior axis. The average changes of prostate position in superior to inferior (SI), anterior-posterior (AP), and left to right (LR) directions and in radial distance were 0.25, -0.13, 0.03, and 0.92, cm respectively. Our data indicated that prostate motion was not patient specific, and its average magnitude remained virtually unchanged over time. Recommended planning target volume (PTV) margins for use without ultrasound localization were 0.90 cm in SI, 1.02 cm in AP, and 0.80 cm in LR directions. CONCLUSION: Ultrasound localization revealed a predominance of prostate shift from planning position in the superior-posterior direction, with an average closer to the superior axis. The motion data provides recommended margins for PTV.

Algorithms↗
PubMed2005

Follicular lymphoma: expanding therapeutic options.

The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin's lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.

Antibodies, Monoclonal↗
PubMed2004

Role of polymorphonuclear leukocytes, nitric oxide synthase, and cyclooxygenase in vascular permeability changes induced by C5a agonist peptides.

Tumor responses to radioimmunotherapy combined with peptide agonists of human C5a anaphylatoxin such as GCGYSFKPMPLaR (C5aAP) are two- to four-fold better, depending on the dose of C5aAP, than responses to radioimmunotherapy alone. The enhanced tumor vascular permeability (VP) is the key factor responsible for this improvement. These studies were designed to identify the sequence of events leading to the improved extravasation of immunoglobulin in response to C5aAP. The VP changes were measured in mice after administration of C5aAP alongside of various mediators. The depletion of circulating polymorphonuclear neutrophils (PMN) in mice abolished the C5aAP-induced VP increase. Blocking of P-selectin also returned VP to its basal levels after the C5aAP treatment, indicating that C5aAP-induced VP changes are initiated by interactions of C5aAP with PMNs. Aminoguanidine, an inducible nitric oxide synthase (NOS) inhibitor, given before C5aAP returned VP to control levels. N(omega)-nitro-L-arginine methyl ester, a nonselective NOS inhibitor, had a marginal effect on the activity of C5aAP. Indomethacin, a nonselective cyclooxygenase inhibitor, suppressed C5aAP-induced increases in VP, whereas N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide, a selective cyclooxygenase-2 inhibitor, was active only at high doses. While C5aAP given i.p. did not alter tumor uptake of (125)I-B72.3, the i.v. administration resulted in approximately 40% increase, confirming the prerequisite interaction of C5aAP with PMNs. The sequence leading to the increased VP appears to be initiated by the interaction of C5aAP with C5a receptor expressed on PMNs followed by binding to endothelial cells of blood vessels. The interaction with P-selectin is responsible for the initiation of the nitric oxide cascade as evidenced by inducible NOS activation. Additionally, prostaglandins are required for expression of the full magnitude of the C5aAP activities.

Animals↗
PubMed2003

Dose linearity and uniformity of a linear accelerator designed for implementation of multileaf collimation system-based intensity modulated radiation therapy.

The dose linearity and uniformity of a linear accelerator designed for multileaf collimation system-(MLC) based IMRT was studied as a part of commissioning and also in response to recently published data. The linear accelerator is equipped with a PRIMEVIEW, a graphical interface and a SIMTEC IM-MAXX, which is an enhanced autofield sequencer. The SIMTEC IM-MAXX sequencer permits the radiation beam to be " ON" continuously while delivering intensity modulated radiation therapy subfields at a defined gantry angle. The dose delivery is inhibited when the electron beam in the linear accelerator is forced out of phase with the microwave power while the MLC configures the field shape of a subfield. This beam switching mechanism reduces the overhead time and hence shortens the patient treatment time. The dose linearity, reproducibility, and uniformity were assessed for this type of dose delivery mechanism. The subfields with monitor units ranged from 1 MU to 100 MU were delivered using 6 MV and 23 MV photon beams. The doses were computed and converted to dose per monitor unit. The dose linearity was found to vary within 2% for both 6 MV and 23 MV photon beam using high dose rate setting (300 MU/min) except below 2 MU. The dose uniformity was assessed by delivering 4 subfields to a Kodak X-OMAT TL film using identical low monitor units. The optical density was converted to dose and found to show small variation within 3%. Our results indicate that this linear accelerator with SIMTEC IM-MAXX sequencer has better dose linearity, reproducibility, and uniformity than had been reported.

Particle Accelerators↗
PubMed2002

Intensity-modulated radiation therapy (IMRT): the radiation oncologist's perspective.

Intensity-modulated radiation therapy (IMRT) is a new and evolving technological advance in high-precision radiation therapy. It is an extension of 3-dimensional conformal radiotherapy (3D-CRT) that allows the delivery of highly complex isodose profiles to the target while minimizing radiation exposure to surrounding normal tissues. Clinical data on IMRT are emerging and being collected, as more institutions are implementing or expanding the use of IMRT. However, the currently available IMRT and its applications are far from being well understood and established. In some circumstances, it remains impractical and too costly. This article discusses some practical issues from the radiation oncologist's perspective.

Attitude of Health Personnel↗
PubMed2002

Clinical implementation of intensity-modulated radiation therapy.

The clinical implementation of intensity-modulated radiation therapy (IMRT) is a complex process because of the introduction of new treatment planning algorithms and beam delivery systems compared to conventional 3-dimensional conformal radiation therapy (3D-CRT) and the lack of established national performance protocols. IMRT uses an inverse-planning algorithm to create nonuniform fields that are only deliverable through a newly designed beam-modulating delivery system. The intent of this paper is to describe our experience and to elucidate the new clinical procedures that must be executed to have a successful IMRT program. Patients who undergo IMRT at our institution are immobilized and simulated before proceeding to computed tomography scan for patient data acquisition. Treatment planning involves the use of different prescription dose formats and different planning techniques compared to 3D-CRT. The desired dose goals for the target and sensitive structures must be specified before initiating the planning process, which is computer intensive. After the plan is completed, the delivery instructions are transferred to the delivery system via either a floppy disk for MIMiC-based IMRT or through the network for MLC-based IMRT. Target localizations are carried out using orthogonal radiographs. Ultrasound imaging system (BAT) is used to localize the prostate. Dose validation is performed using films, ion chambers or dose-calculation-based techniques.

Antineoplastic Protocols↗
PubMed2002

Potentiation of radioimmunotherapy with response-selective peptide agonist of human C5a.

UNLABELLED: Physiologic barriers to the delivery of macromolecules to solid tumors are a major obstacle to the clinical success of radioimmunotherapy (RIT). Only a small fraction of the injected dose of the radiolabeled monoclonal antibody (mAb) localizes at the tumor site. This situation worsens as the tumor burden increases. It is hypothesized that improvements to RIT of adenocarcinoma can be realized by inclusion of vasoactive agents, in particular agents able to increase the vascular permeability of tumor capillaries. In these studies, a response-selective peptide agonist of human C5a, GCGYSFKPMPLaR (AP), was used to transiently increase tumor vascular permeability in an effort to improve RIT of solid tumors. METHODS: Athymic mice xenografted with human colorectal adenocarcinoma LS174T were treated intravenously with low doses (9.25 MBq) of 131I-labeled mAb B72.3 in combination with various intravenous doses of AP. The progression of the disease or the loss of >20% body weight was taken as the endpoint. Biodistribution and tumor uptake kinetics were studied in the same tumor-antibody system. RESULTS: The uptake of 125I-B72.3 in LS174T xenografts increased in a dose-dependent manner with an apparent maximal effect between 3 and 6 h after intravenous administration of AP. Augmenting the dose of 9.25 MBq 131I-B72.3 with a single administration of 0.1 mg AP delayed tumor growth nearly 2-fold; the tumor quadrupling time (T(q)) was 14.2 +/- 3.3 d for 131I-B72.3 alone versus 26.0 +/- 3.6 d for 131I-B72.3 plus 0.1 mg AP (P < 0.001). An additional dose of 0.1 mg AP 24 h after 131I-B72.3 further improved the therapeutic outcome (T(q) = 48.5 +/- 7.9 d; P < 0.001) and resulted in several cases of tumor regression. CONCLUSION: The inclusion of agonist peptides of human C5a in the RIT scheme results in improved tumor responses without any manifest side effects.

Adenocarcinoma↗
PubMedDate not supplied

Radiolabeled constructs for evaluation of the asialoglycoprotein receptor status and hepatic functional reserves.

Transplantation of isolated hepatocytes may eventually replace a whole liver transplantation for the treatment of selected liver metabolic disorders and acute hepatic failure. To understand the behavior of transplanted hepatocytes, methods for longitudinal assessment of functional activity and survival of hepatocyte transplants must be developed. Targeting of asialoglycoprotein receptor (ASGPr) with various radiolabeled or Gd-labeled constructs of asialofetuin (AF) is expected to allow noninvasive and quantitative assessments of the ASGPr status in functioning hepatocytes before and after the transplant. Six new constructs of (125)I-, (99m)Tc-, (153)Gd-, and (111)In-radiolabeled AF with distinct stabilities and clearance rates were prepared and evaluated in vitro in mice, rat, porcine, and human hepatocytes, and in vivo in mice and rats. The blood and organ clearance rates, as well as liver and spleen uptake, were measured. Even extensive chemical modifications of AF with poly-l-lysine and various chelating agents do not appear to diminish AF's binding to ASGPr. Binding to isolated hepatocytes and the in vivo liver uptake studies indicate unimpaired functional activity of AF as evidenced by the rapid (<10 min) and nearly complete hepatic extraction of AF constructs from the systemic circulation. The catabolic processing and elimination of AF constructs from liver depend on the chemical modification used in the preparation of a given reagent. Radioiodinated AF has by far the shortest postabsorption (5.1 min +/- 0.05 min) and elimination half-lives (2.8 +/- 0.06 h) in liver. In comparison, the AF construct prepared by conjugation of DTPA- and 2-iminothiolane-substituted p-Lys with N-sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (SMPB)-modified AF (AF-SMPB-Traut-p-Lys-((111)In-DTPA)(20)(-)(30)) has a hepatic postabsorption time of 9.1 +/- 0.1 min and an elimination half-life of 44.3 +/- 3.08 h, whereas [(99m)Tc]technetium-labeled AF appears to be permanently retained in liver. These differences in rates of liver uptake and clearance of catabolized radiolabeled AF can be used to determine functional activity of liver and transplanted hepatocytes.

Animals↗