Name: treatment of liver metastases using an internal target volume method for stereotactic body radiotherapy
Uploaded: 2018-05-08T13:30:00
Description: Watch this Scientific Journal Video about Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy at JoVE.com

This research was supported by Taipei Medical University Hospital (106TMUH-NE-02).

Taipei Medical University Joint Institutional Review Board approval was obtained for this study.
1. SBRT Consultation
<ol>
	<li>Assess patient eligibility for SBRT for the treatment of liver metastases by consulting a multidisciplinary tumor board. 
	NOTE: The need for local ablation as well as operation and other treatment options must be evaluated by the tumor board. Our selection criteria were as follows: 1) adult patients with a good performance status (Eastern Cooperative Oncology ...

<ol>
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Rev Clin Oncol. 8 (6), 378-382 (2011).</li><li>Comito, T., Clerici, E., Tozzi, A., D'Agostino, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Liver+metastases+and+SBRT:+A+new+paradigm?.">Liver metastases and SBRT: A new paradigm?.</a> Rep Pract Oncol Radiother. 20 (6), 464-471 (2015).</li><li>Scorsetti, M., Clerici, E., Comito, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotactic+body+radiation+therapy+for+liver+metastases.">Stereotactic body radiation therapy for liver metastases.</a> J Gastrointest Oncol. 5 (3), 190-197 (2014).</li><li>Shady, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Percutaneous+Radiofrequency+Ablation+of+Colorectal+Cancer+Liver+Metastases:+Factors+Affecting+Outcomes--A+10-year+Experience+at+a+Single+Center.">Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes--A 10-year Experience at a Single Center.</a> Radiology. 278 (2), 601-611 (2016).</li><li>van Hazel, G. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=SIRFLOX:+Randomized+Phase+III+Trial+Comparing+First-Line+mFOLFOX6+(Plus+or+Minus+Bevacizumab)+Versus+mFOLFOX6+(Plus+or+Minus+Bevacizumab)+Plus+Selective+Internal+Radiation+Therapy+in+Patients+With+Metastatic+Colorectal+Cancer.">SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer.</a> J Clin Oncol. 34 (15), 1723-1731 (2016).</li><li>Salama, J. K., Milano, M. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Radical+irradiation+of+extracranial+oligometastases.">Radical irradiation of extracranial oligometastases.</a> J Clin Oncol. 32 (26), 2902-2912 (2014).</li><li>Rusthoven, K. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multi-institutional+phase+I/II+trial+of+stereotactic+body+radiation+therapy+for+liver+metastases.">Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases.</a> J Clin Oncol. 27 (10), 1572-1578 (2009).</li><li>Ricardi, U., Badellino, S., Filippi, A. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+applications+of+stereotactic+radiation+therapy+for+oligometastatic+cancer+patients:+a+disease-oriented+approach.">Clinical applications of stereotactic radiation therapy for oligometastatic cancer patients: a disease-oriented approach.</a> J Radiat Res. 57 (Suppl 1), i58-i68 (2016).</li><li>Wild, A. T., Yamada, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+Options+in+Oligometastatic+Disease:+Stereotactic+Body+Radiation+Therapy+-+Focus+on+Colorectal+Cancer.">Treatment Options in Oligometastatic Disease: Stereotactic Body Radiation Therapy - Focus on Colorectal Cancer.</a> Visc Med. 33 (1), 54-61 (2017).</li><li>Gill, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-reported+complications+from+fiducial+marker+implantation+for+prostate+image-guided+radiotherapy.">Patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy.</a> Br J Radiol. 85 (1015), 1011-1017 (2012).</li><li>Eldredge-Hindy, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Active+Breathing+Coordinator+Reduces+Radiation+Dose+to+the+Heart+and+Preserves+Local+Control+in+Patients+with+Left+Breast+Cancer:+Report+of+a+Prospective+Trial.">Active Breathing Coordinator Reduces Radiation Dose to the Heart and Preserves Local Control in Patients with Left Breast Cancer: Report of a Prospective Trial.</a> Pract Radiat Oncol. 5 (1), 4-10 (2015).</li><li>Swanson, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Six-year+experience+routinely+using+moderate+deep+inspiration+breath-hold+for+the+reduction+of+cardiac+dose+in+left-sided+breast+irradiation+for+patients+with+early-stage+or+locally+advanced+breast+cancer.">Six-year experience routinely using moderate deep inspiration breath-hold for the reduction of cardiac dose in left-sided breast irradiation for patients with early-stage or locally advanced breast cancer.</a> Am J Clin Oncol. 36 (1), 24-30 (2013).</li><li>Sweeney, R. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accuracy+and+inter-observer+variability+of+3D+versus+4D+cone-beam+CT+based+image-guidance+in+SBRT+for+lung+tumors.">Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors.</a> Radiat Oncol. 7, 81 (2012).</li><li>Takahashi, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Verification+of+Planning+Target+Volume+Settings+in+Volumetric+Modulated+Arc+Therapy+for+Stereotactic+Body+Radiation+Therapy+by+Using+In-Treatment+4-Dimensional+Cone+Beam+Computed+Tomography.">Verification of Planning Target Volume Settings in Volumetric Modulated Arc Therapy for Stereotactic Body Radiation Therapy by Using In-Treatment 4-Dimensional Cone Beam Computed Tomography.</a> Int J Radiat Oncol Biol Phys. 86 (3), 426-431 (2013).</li><li>Yeo, U. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+dosimetric+misrepresentations+from+3D+conventional+planning+of+liver+SBRT+using+4D+deformable+dose+integration.">Evaluation of dosimetric misrepresentations from 3D conventional planning of liver SBRT using 4D deformable dose integration.</a> J Appl Clin Med Phys. 15 (6), 4978 (2014).</li><li>Shinmohigashi, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tumor+motion+changes+in+stereotactic+body+radiotherapy+for+liver+tumors:+an+evaluation+based+on+four-dimensional+cone-beam+computed+tomography+and+fiducial+markers.">Tumor motion changes in stereotactic body radiotherapy for liver tumors: an evaluation based on four-dimensional cone-beam computed tomography and fiducial markers.</a> Radiat Oncol. 12, 61 (2017).</li><li>Goodman, B. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-term+safety+and+efficacy+of+stereotactic+body+radiation+therapy+for+hepatic+oligometastases.">Long-term safety and efficacy of stereotactic body radiation therapy for hepatic oligometastases.</a> Pract Radiat Oncol. 6 (2), 86-95 (2016).</li><li>Scorsetti, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Is+stereotactic+body+radiation+therapy+an+attractive+option+for+unresectable+liver+metastases?+A+preliminary+report+from+a+phase+2+trial.">Is stereotactic body radiation therapy an attractive option for unresectable liver metastases? A preliminary report from a phase 2 trial.</a> Int J Radiat Oncol Biol Phys. 86 (2), 336-342 (2013).</li><li>Andratschke, N. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotactic+radiation+therapy+for+liver+metastases:+factors+affecting+local+control+and+survival.">Stereotactic radiation therapy for liver metastases: factors affecting local control and survival.</a> Radiat Oncol. 10, 69 (2015).</li><li>Huang, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+parameters+for+predicting+radiation-induced+liver+disease+after+intrahepatic+reirradiation+for+hepatocellular+carcinoma.">Clinical parameters for predicting radiation-induced liver disease after intrahepatic reirradiation for hepatocellular carcinoma.</a> Radiat Oncol. 11 (89), (2016).</li><li>Huang, F., Wu, G., Yang, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oligometastasis+and+oligo-recurrence:+more+than+a+mirage.">Oligometastasis and oligo-recurrence: more than a mirage.</a> Radiat Oncol. 31 (9), 230 (2014).</li></ol>

Respiration-induced liver deformity and organ motion contribute to the difficulties associated with radiation delivery, as well as contouring (target delineation) problems. Improvements in the techniques used for organ motion management have led to improvements in treatment accuracy and precision, which is fundamental to SBRT. Several image-guided techniques and respiratory motion management systems are currently available. Fiducial marker implantation is a common technique for target localization. A fiducial marker is u...

Conventionally, metastasis is considered the terminal stage of cancer and is associated with poor prognosis and survival. However, Mountain et al. in 1984 reported that according to their 20-year experience, complete surgical removal of pulmonary metastasis results in a relatively higher survival rate if the primary tumor site is under systemic control at the time of surgery1. Hellman and Weichselbaum in 1995 first proposed oligometastases, an intermediate stage between localized lesions and systemic disease with polymetastases, which can be cured using additional local treatment2,3. Over the past decades, early detection of metastasis, novel surgical methods for treating oligometastases (metastasectomy), and effective chemotherapy have improved the prognosis in patients with metastasis. The liver is one of the most common metastatic organs for solid tumors, and surgical resection of hepatic oligometastases can improve survival. Local ablation methods, including radiofrequency ablation, radioembolization, and radiotherapy, for treating liver metastases have been recommended for some inoperable patients to achieve the necessary local tumor control3,4,5,6,7. In past years, several prospective and retrospective studies have reported effective local tumor control of hepatic metastases through stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, with tolerable toxicity4,5,8,9.
Improvements have been made in patient positioning and immobilization methods; image acquisition, integration, and transfer to radiotherapy systems; respiratory motion management; high-dose output and fast radiation delivery; and steep dose gradients from target lesions to surrounding normal tissues. Because of these advances, SBRT achieves highly precise and accurate radiotherapy with minimal serious toxicity10,11. Respiratory motion management is fundamental to SBRT, particularly for hepatic and pulmonary lesions. A respiratory management technique that is noninvasive and clinically convenient would substantially increase the popularity of SBRT as a treatment option. This article details an SBRT protocol for liver metastases that uses four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) for image-guided assistance and liver motion management.

<table border="0" cellpadding="0" cellspacing="0" width="875">
	<tbody>
		<tr height="51">
			<td height="51" style="height:51px;width:195px;">CT scan</td>
			<td style="width:188px;">Philips</td>
			<td style="width:265px;">Brilliance&#160;Big Bore&#160;16 Slice&#160;CT, 7387</td>
			<td style="width:228px;">Acquire CT images for contouring and planning</td>
		</tr>
		<tr height="51">
			<td height="51" style="height:51px;width:195px;">CT contrast</td>
			<td style="width:188px;">GE Healthcare</td>
			<td style="width:265px;">Omnipaque 350 mg L/mL</td>
			<td style="width:228px;">Enhence lesion in CT images</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Linear accelerator</td>
			<td>Elekta</td>
			<td>Synergy</td>
			<td>Deliver radiotherapy</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Palnning system</td>
			<td>Pinnacle</td>
			<td>Pinnacle 9.8</td>
			<td>Implement radiotherapy planning</td>
		</tr>
		<tr height="65">
			<td height="65" style="height:65px;width:195px;">Immobilization: BlueBag BodyFix</td>
			<td>Elekta</td>
			<td>900 mm x 2325 mm, P10104840</td>
			<td>Immobilize the patient</td>
		</tr>
		<tr height="66">
			<td height="66" style="height:66px;width:195px;">Immobilization: BodyFix Cover sheet</td>
			<td>Elekta</td>
			<td>2700 mm x 1400 mm, P10102-304</td>
			<td>Immobilize the patient</td>
		</tr>
		<tr height="73">
			<td height="73" style="height:73px;width:195px;">Immobilization: BodyFix abdominal compressor</td>
			<td>Elekta</td>
			<td>diaphragm control, P10102-149</td>
			<td style="width:228px;">Restrict breath motion and organ/lesion motion</td>
		</tr>
		<tr height="57">
			<td height="57" style="height:57px;width:195px;">Immobilization: vacuum pump</td>
			<td>Elekta</td>
			<td>vacuum pump, p2 120V, P10102-110</td>
			<td style="width:228px;">Shape body bag and cover sheet according to the patient</td>
		</tr>
	</tbody>
</table>

treatment of liver metastases using an internal target volume method for stereotactic body radiotherapy

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For inoperable patients, local ablation therapies, such as stereotactic body radiotherapy (SBRT), can provide effective local tumor control with minimal toxicity. Because of its high precision and accuracy, SBRT delivers a higher radiation dose per fraction, is more effective, and targets smaller irradiation volumes than does conventional radiotherapy. In addition, steep dose gradients from target lesions to surrounding normal tissues are achieved using SBRT; thus, SBRT provides more effective tumor control and exhibits fewer side effects than conventional radiotherapy. The use of SBRT is prevalent for treating intracranial lesions (known as stereotactic radiosurgery); however, it is now also used for treating spinal and adrenal metastases. Because of advancements in image-guided assistance and respiratory motion management, several studies have investigated the use of SBRT for treating lung or liver tumors, which move as a patient breathes. The results of these studies have suggested that SBRT favorably controls tumors in the case of moving lesions.
Four-dimensional computed tomography (4D-CT) with an abdominal compressor (AC) is clinically convenient for effective respiratory motion management. Because this method is noninvasive and allows free breathing, its use reduces complications. Furthermore, patients consider this method convenient. Moreover, it is considered more efficient than other methods of respiratory motion management by physicians and therapists. The use of 4D-CT with an AC for treating pulmonary lesions has also been widely investigated, and the technique is gaining acceptance for treating hepatic lesions. However, the protocols for using 4D-CT with an AC for treating hepatic lesions are different from those used for treating pulmonary lesions. In this article, we describe a new protocol for SBRT with 4D-CT and an AC for treating liver metastases.

SBRT can be implemented by intense-modulated radiotherapy (IMRT) (with <img alt="image" src="/files/ftp_upload/57050/57050imgv2.jpg" /> 6 radiation beams) or volumetric arc radiotherapy (VMAT) (with continuous dose delivery and gantry rotation) to cover all targets in a single treatment because a single surgery may not achieve removal of all the tumors. A representative SBRT treatment plan demonstrated successful radiotherapy planning for two hepatic metastatic tumors when surgery was inf...

Watch this Scientific Journal Video about Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy at JoVE.com

Treatment of Liver Metastases Using an Internal Target Volume Method for Stereotactic Body Radiotherapy

Stereotactic body radiotherapy (SBRT) requires rigorous accuracy and precision for delivering high radiation doses per fraction to small treatment volumes to improve tumor control and simultaneously reduce toxicity. Herein, we present a noninvasive and clinically convenient respiratory motion management protocol for SBRT for liver metastases.

The prognosis of patients with metastatic cancers has improved in the past decades due to effective chemotherapy and oligometastatic surgery. For ...

The overall goal of this motion management and image guided technique is to use stereotactic body radiotherapy or SBRT to treat liver metastases. This measure can help make SBRT a significantly more feasible and accessible option for treating liver metastases. The main advantages of this technique are that it is non-invasive, does not require extensive training, and has more manageable treatment and it work for us for both patients and the staff.We first had the idea when we compare fiducial marker, air breath control and full-dimensional computed tomography or CT with abdominal compressor use in the irradiation of hepatocellular carcinomas. Demonstrating the procedure will be Yang-Bin Lin, a technician from our department. To begin place the patient in the supine position, head first with the arms over the head, and secure the patient onto the couch.Make a personalized evacuated vacuum bag according to the patient's position and body shape, and cover the patient with the cover sheet. Apply an abdominal compressor, and mark the depth of the compressor. Then, place a breath tracking sensor on the chest wall, and monitor the respiratory wave form.To acquire CT images for radiotherapy treatment planning, first select the 4D-CT mode with a three millimeter slice thickness. Click go on both the screen and the control panel to conduct a SERV-U scan for obtaining both anterior, posterior, and lateral views of the patient. On the helical scan page, set the CT scanning coverage area to extend from the apex of both lungs to five centimeters from the caudal border of the liver.On the pulmonary gating scan page, set the 4D-CT scanning field to cover the liver, extending three to five centimeters from both the cranial and caudal liver borders. When the respiratory wave form has been stable for three minutes, inject 100 milliliters of an appropriate contrast agent through an 18 gauge IV catheter into the antecubital vein At a rate of four to five milliliters per second. 15 seconds after all of the agent has been injected, conduct a contrasted contiguous helical CT scan.Then, click next series to conduct a 4D-CT scan. For radiotherapy treatment planning, first import the images from the CT simulation and diagnostic scans into the planning system. To contour the metastatic tumors into gross tumor volume and adjacent organs at risk, first select an organ of interest, and a contour tool to select the organ in each slice of the CT slice.The gross tumor volume can be determined using the diagnostic images from the CT scan, MRI, and opaque scans. As well as the contrast images from the CT simulation. Next, contour the internal target volume of the tumors according to the organ motion observed on the dynamic tracking images adding a five millimeter margin to the internal target volume to obtain the planning target volume.Observe all of the dynamic images of the entire liver area to ascertain the tumor and liver movement during respiration. Then contour the internal target volume in all of the dynamic slices to encompass the entire tumor motion. On the day of the treatment, first identify the patient by name, birth date, and ID card.Position the patient in the vacuum bag. Place the cover sheet, and fix the abdominal compressor as just demonstrated. When the patient is ready, acquire a 4D cone beam CT image, and adjust the couch to corelate the target location obtained on the 4D cone beam CT image to that obtained on the simulation CT images.At the end of the scan, load the image into the image guided radiotherapy system. The upper left and lower right images are from the CT simulation for the contouring and treatment planning. The upper right and lower left images are from the 4D cone beam CT.Compare the difference of patient position according to images from CT simulation, and confirm treatment location daily.Then, manually adjust the couch position to eliminate set-up error of patient position. Record and print out the parameters for daily adjustment. Then, confirm the treatment plan and the system configuration, and click go to start the treatment, monitoring the patient during the entire treatment using real-time cameras to ensure patient safety.In this study, an SBRT treatment plan demonstrated successful radiotherapy planning for two hepatic metastatic tumors for which surgery or another local ablation therapy was not feasible. The two metastatic tumors were three centimeters and 4.3 centimeters in length with 13 cubic centimeter and 22 cubic centimeter volumes respectively. The prescribed dose was 50 grays in five fractions, and the four partial beam arcs were directed to avoid the organs at risk.These dose volume histograms illustrate the coverage over both of the tumors with 100%of the volume of the planning target volume covered by greater than 95%of the prescribed dose, and with the radiation doses to the organs at risk, within an appropriately restricted range. Once mastered, the CT simulation and image guidance before each fraction steps, can be completed in 10 minutes each if they are performed properly. While attempting this procedure, it's important to remember to monitor the patient's condition to confirm that they can tolerate and breathe normally under the abdominal compression.After its implementation, this technique has paved the way for radiation oncologists in the inspiration of exerting local control of all local metastases in the liver without invasive motion management or inconvenient image guidance techniques in SBRT. After watching this video, you should have a good understanding of how to adapt a 4D-CT scan with abdominal compressor in image guided radiotherapy and the internal target volume in SBRT for liver metastasis. As not every patient is eligible for or willing to have an invasive procedure, this technique provides a non-invasive convenient option that requires minimal training for local operation for a oligometastasis in the liver.

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Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 &mu;l every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

The purpose of this article is to describe the use of an orthotopic glioblastoma model for chemoradiation studies. This article will go though cell processing, implanting, and radiotherapy of the mouse using an intracranial model.

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the ...

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

Established cancer cell lines and xenografts have been the mainstay of cancer research for the past several decades. However, recent evidence suggests that therapeutic response is greatly influenced by the tumor cell microenvironment. Therefore, we have developed an ex vivo analysis of primary tumor specimens for drug development purposes.

The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both ...

Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable risks for normal tissue injury and the hazards of physical tumor miss. A first-of-its-kind SBRT platform achieves high-precision ablative radiation treatment through a combination of versatile real-time imaging solutions and sophisticated tumor tracking capabilities. It uses dual-diagnostic kV x-ray units for stereoscopic open-loop feedback of cancer target intrafraction movement occurring as a consequence of respiratory motions and heartbeat. Image-guided feedback drives a gimbaled radiation accelerator (maximum 15 x 15 cm field size) capable of real-time &#177;4 cm pan-and-tilt action. Robot-driven &#177;60&#176; pivots of an integrated &#177;185&#176; rotational gantry allow for coplanar and non-coplanar accelerator beam set-up angles, ultimately permitting unique treatment degrees of freedom. State-of-the-art software aids real-time six dimensional positioning, ensuring irradiation of cancer targets with sub-millimeter accuracy (0.4 mm at isocenter). Use of these features enables treating physicians to steer radiation dose to cancer tumor targets while simultaneously reducing radiation dose to normal tissues. By adding respiration correlated computed tomography (CT) and 2-[18F] fluoro-2-deoxy-&#7429;-glucose (18F-FDG) positron emission tomography (PET) images into the planning system for enhanced tumor target contouring, the likelihood of physical tumor miss becomes substantially less1. In this article, we describe new radiation plans for the treatment of moving lung tumors.

Stereotactic ablative body radiation therapy (SBRT) involves the precise delivery of high-dose radiation to cancer tumor targets. A novel SBRT platform offers a first-of-its-kind gimbaled radiation accelerator mounted within a pivoting O-ring gantry capable of dynamic image-guided tumor tracking. Here, we describe dynamic tumor tracking for lung targets.

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable ...

An Improved Method for Rapid Intubation of the Trachea in Mice

Despite some anatomical and physiological differences, mouse models continue to be an essential tool for studying human lung disease. Bleomycin toxicity is a commonly used model to study both acute lung injury and fibrosis, and multiple methods have been developed for administering bleomycin (and other toxic agents) into the lungs. However, many of these approaches, such as transtracheal instillation, have inherent drawbacks, including the need for strong anesthetics and survival surgery. This paper reports a quick, reproducible method of intratracheal intubation that involves mild inhaled anesthesia, visualization of the trachea, and the use of a surrogate spirometer to confirm exposure. As a proof of concept, 8-12 week old C57BL/6 mice were administered either 2.0 U/kg of bleomycin or an equivalent volume of PBS, and both damage and fibrotic endpoints were measured post-exposure. This procedure allows researchers to treat a large cohort of mice in a relatively short period with little expense and minimal post-procedure care.

This article presents a rapid and simple method for administering bleomycin directly into the mouse trachea via intubation. Key advantages of this method are that it is highly reproducible, easy to master, and does not require specialized equipment or lengthy recovery times.

Despite some anatomical and physiological differences, mouse models continue to be an essential tool for studying human lung disease. Bleomycin toxicity ...

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

In this manuscript, we describe percutaneous isolated hepatic perfusion with simultaneous chemofiltration as treatment for unresectable liver metastases. This procedure is performed under general anaesthesia in the angiosuite by an experienced team, consisting of an interventional radiologist, a clinical perfusionist and anaesthesiologist.

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn ...

Method of Direct Segmental Intra-hepatic Delivery Using a Rat Liver Hilar Clamp Model

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ischemia/reperfusion (I/R) injury with myriad negative consequences. Potential I/R injury in marginal organs destined for liver transplantation contributes to the current donor shortage secondary to a decreased organ utilization rate. A significant need exists to explore hepatic I/R injury in order to mediate its impact on graft function in transplantation. Rat liver hilar clamp models are used to investigate the impact of different molecules on hepatic I/R injury. Depending on the model, these molecules have been delivered using inhalation, epidural infusion, intraperitoneal injection, intravenous administration or injection into the peripheral superior mesenteric vein. A rat liver hilar clamp model has been developed for use in studying the impact of pharmacologic molecules in ameliorating I/R injury. The described model for rat liver hilar clamp includes direct cannulation of the portal supply to the ischemic hepatic segment via a side branch of the portal vein, allowing for direct segmental hepatic delivery. Our approach is to induce ischemia in the left lateral and median lobes for 60 min, during which time the substance under study is infused. In this case, pegylated-superoxide dismutase (PEG-SOD), a free radical scavenger, is infused directly into the ischemic segment. This series of experiments demonstrates that infusion of PEG-SOD is protective against hepatic I/R injury. Advantages of this approach include direct injection of the molecule into the ischemic segment with consequent decrease in volume of distribution and reduction in systemic side effects.

A unique rat liver hilar clamp model was developed for studying the impact of pharmacologic molecules in ameliorating ischemia-reperfusion injury. This model includes direct cannulation of the portal supply to the ischemic liver segment via a branch of the portal vein, allowing for direct hepatic delivery.

Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ...

Radiation Planning Assistant - A Streamlined, Fully Automated Radiotherapy Treatment Planning System

The Radiation Planning Assistant (RPA) is a system developed for the fully automated creation of radiotherapy treatment plans, including volume-modulated arc therapy (VMAT) plans for patients with head/neck cancer and 4-field box plans for patients with cervical cancer. It is a combination of specially developed in-house software that uses an application programming interface to communicate with a commercial radiotherapy treatment planning system. It also interfaces with a commercial secondary dose verification software. The necessary inputs to the system are a Treatment Plan Order, approved by the radiation oncologist, and a simulation computed tomography (CT) image, approved by the radiographer. The RPA then generates a complete radiotherapy treatment plan. For the cervical cancer treatment plans, no additional user intervention is necessary until the plan is complete. For head/neck treatment plans, after the normal tissue and some of the target structures are automatically delineated on the CT image, the radiation oncologist must review the contours, making edits if necessary. They also delineate the gross tumor volume. The RPA then completes the treatment planning process, creating a VMAT plan. Finally, the completed plan must be reviewed by qualified clinical staff.

Radiation therapy is a highly complex cancer treatment that requires multiple specialists to create a treatment plan and provide quality assurance (QA) prior to delivery to a patient. This protocol describes the use of a fully automated system, the Radiation Planning Assistant (RPA), to create high-quality radiation treatment plans.

The Radiation Planning Assistant (RPA) is a system developed for the fully automated creation of radiotherapy treatment plans, including volume-modulated ...

Measurement of the Hepatic Venous Pressure Gradient and Transjugular Liver Biopsy

Here we provide a detailed protocol describing the clinical procedure of hepatic venous pressure gradient (HVPG) measurement in patients with advanced chronic liver disease followed by an instruction for transjugular biopsy. Under local anesthesia and ultrasound guidance, a catheter introducer sheath is placed in the right internal jugular vein. Using&#160;fluoroscopic guidance, a balloon catheter is advanced into the inferior vena cava (IVC) and inserted into a large hepatic vein. Correct and sufficient wedge position of the catheter is ensured by injecting contrast media while the balloon is blocking the outflow of the cannulated hepatic vein. After calibrating the external pressure transducer, continuous pressure recordings are obtained with triplicate recordings of the wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP). The difference between FHVP and WHVP is referred to as HVPG, with values &#8805;10 mm Hg indicating clinically significant portal hypertension (CSPH). Before removing the catheter, pressure readings obtained in the IVC at the same level, as well as the right atrial pressure are recorded.
Finally, a transjugular liver biopsy can be obtained via the same vascular route. Different systems are available; however, core biopsy needles are preferred over aspiration needles, especially for cirrhotic livers. Again, under fluoroscopic guidance a biopsy needle introducer sheath is advanced into an hepatic vein. Next, the transjugular biopsy needle is gently advanced through the introducer sheath: (i) in case of aspiration biopsy, the needle is advanced into the liver parenchyma under aspiration and then removed quickly, or (ii) in case of a core biopsy, the cutting-mechanism is triggered inside the parenchyma. Several separate passages can be safely performed to obtain sufficient liver specimens via transjugular biopsy. In experienced hands, the combination of these procedures takes about 30-45 min.

Here, we present a protocol for measurement of hepatic venous pressure gradient (HVPG),the gold standard to diagnose clinically significant portal hypertension. Moreover, we describe how to perform a transjugular liver biopsy within the same session.

Here we provide a detailed protocol describing the clinical procedure of hepatic venous pressure gradient (HVPG) measurement in patients with advanced ...

3D Reconstruction for the Diagnosis and Treatment of Pulmonary Nodules

A 3D Digital Model for the Diagnosis and Treatment of Pulmonary Nodules

The three-dimensional (3D) reconstruction of pulmonary nodules using medical images has introduced new technical approaches for diagnosing and treating pulmonary nodules, and these approaches are progressively being acknowledged and adopted by physicians and patients. Nonetheless, constructing a relatively universal 3D digital model of pulmonary nodules for diagnosis and treatment is challenging due to device differences, shooting times, and nodule types. The objective of this study is to propose a new 3D digital model of pulmonary nodules that serves as a bridge between physicians and patients and is also a cutting-edge tool for pre-diagnosis and prognostic evaluation. Many AI-driven pulmonary nodule detection and recognition methods employ deep learning techniques to capture the radiological features of pulmonary nodules, and these methods can achieve a good area under-the-curve (AUC) performance. However, false positives and false negatives remain a challenge for radiologists and clinicians. The interpretation and expression of features from the perspective of pulmonary nodule classification and examination are still unsatisfactory. In this study, a method of continuous 3D reconstruction of the whole lung in horizontal and coronal positions is proposed by combining existing medical image processing technologies. Compared with other applicable methods, this method allows users to rapidly locate pulmonary nodules and identify their fundamental properties while also observing pulmonary nodules from multiple perspectives, thereby providing a more effective clinical tool for diagnosing and treating pulmonary nodules.

Author Spotlight: A 3D Digital Model for the Diagnosis and Treatment of Pulmonary Nodules  

The objective of this study is to develop a novel 3D digital model of pulmonary nodules that serves as a communication bridge between physicians and patients and is also a cutting-edge tool for pre-diagnosis and prognostic evaluation.

The three-dimensional (3D) reconstruction of pulmonary nodules using medical images has introduced new technical approaches for diagnosing and treating ...