Diese Arbeit wurde von der Case Comprehensive Cancer Center (P30 CA43703) unterstützt.

1. Stereotaktische CyberKnife Radiochirurgie Beratung <ol><li> Beschreiben Cyberknife Behandlung. Cyberknife beinhaltet die Verwendung eines Linearbeschleunigers im industriellen Roboterarm Ähnliche Maschinen eingesetzt, um zu autos montiert. Der Roboterarm bewegt den Linearbeschleuniger im dreidimensionalen Raum um einen Patienten, wenn es durch mehrfache Behandlung Zwischenstationen für Strahlenzufuhrsystem fortschreitet. Cross-Flugzeug X-Strahlen während der Behandlung, den Patienten zu überprüfen, erhalten werden, ist in einer Position die richtige Behandlung. Da die Behandlung Strahlenzufuhrsystem ist nicht auf eine zweidimensionale Ebene beschränkt, dieses System weiter erhöht die Möglichkeit, konzentrierte Strahlendosen von Krebs Ziele erreicht werden bei gleichzeitiger Minimierung der Strahlendosis an kritischen Haut und viszeralen Organstrukturen. </li><li> Diskutieren Cyberknife Risiken. Cyberknife kann möglich Bräunung und Rötung der Haut, Müdigkeit, Übelkeit oder selten diarrh führenea, selten viszeralen Organ Verletzungen, Muskel-, Nerven, Knochen und Verletzungen, und sehr kleine Gefahr des zweiten Krebses. </li></ol> 2. Stereotaktische CyberKnife Radiochirurgie Fiducial Placement <ol><li> Beschreiben Fiducial Platzierung. Frauen, die gegen persistierenden oder rezidivierenden gynäkologischen Krebserkrankungen behandelt unterziehen operative oder CT-gesteuerte Platzierung von mindestens drei einzigen 1,6 x 3 mm Gold Weichgewebe Fiducials (etwa so groß wie ein Reiskorn) innerhalb oder nahe der Krebs-Target. Chirurgische Clips zum Zeitpunkt der vorherigen Operation gespeichert werden nicht die von ausreichender Dichte, um als radiochirurgische Bezugsmarkierungen verwendet werden. Chirurgische Clips nicht mit radiochirurgische Ausrichtung aufgrund der Dichte Diskrepanz stören. </li><li> Geben Fiducial Positionierung relativ zu radiochirurgischen Ziel. Fiducials werden in unterschiedlichen Tiefen des Gewebes rund um die radiochirurgischen Ziel gesetzt und muss von zwei Zentimetern oder mehr voneinander getrennt werden. Referenzmarken innerhalb von 4 bis 6 cm von der t positioniertArget. </li></ol> 3. Stereotaktische Cyberknife Behandlungsplanung <ol><li> Diskutieren radiochirurgischen Behandlungsplanung. Mindestens eine Woche nach Fiducial Platzierung (dh so, dass die Heilung eingetreten ist und Fiducial Bewegung wird minimiert) unterziehen sich Patienten CT-gesteuerte Behandlung SBRT Simulation. In unserem Programm wird zwei-poligen lokalisierte evakuierten Vakuum-Beutel Becken-Immobilisierung eingesetzt. </li><li> Geben Positionierung des Patienten auf dem Behandlungstisch. Frauen in Rückenlage Behandlung Stellung auf dem Cyberknife Radiochirurgie flachen Tischplatte behandelt werden. </li><li> Diskutieren Ziel und Patienten Immobilisierung. Patient kann evakuiert Vakuum-Beutel Immobilisierung auf intrafraction Bewegung während Strahlendosis Lieferung reduzieren unterziehen. Sobald immobilisiert, unterziehen Frauen nicht-zusammenhängenden kontrastiert axialen CT hochauflösende Bildgebung (1 bis 1 Stellplatz, 1,0 mm Schichtdicke, Spannung 120 kV, 450 mAs). </li><li> Besprechen Sie den Einsatz von fortschrittlichenBildgebung für Zielortung. Nach CT-Bildgebung, Frauen bevorzugt herkömmliche 18 F-FDG PET / CT-Bildgebung unterzogen werden in der gleichen Position SBRT Behandlung. Alternativ können Frauen unterziehen konventionellen kontrastiert Becken Kernspintomographie. </li><li> Beschreiben Bild Co-Registrierung für radiochirurgischen Behandlungsplanung. Bilder aus hochauflösenden CT-und 18 F-FDG PET / CT sind für die inverse Bestrahlungsplanung auf der MultiPlan 3.5.2 Treatment Planning System (Accuray) importiert. </li><li> Beschreiben Team-Ansatz zu radiochirurgischen Behandlungsplanung. Für die Bestrahlungsplanung, sowohl als Radio-Onkologe und gynäkologischen Onkologen Kontur Krebs-Target klinische Zielvolumen (CTV). Andere Krankheiten at-Risk-Gewebe ist konturiert und wird in FTV enthalten. In der Nähe normalen Gewebestrukturen wie den Dünndarm, Rektum, Blase, Leber, Nieren, Lungen, bilateralen proximalen Oberschenkelknochen, Vagina und sakralen Nervenwurzeln werden durch konturierteder Radio-Onkologe. </li><li> Beschreiben Strahlung Dosisvorschrift. Strahlungsempfindliche verschreibungspflichtige Dosis von 3 × 800 = 2400 cGy cGy (gemeinsam mit dem 70% Isodosislinie) ausgewählt wurde. In einem 200 cGy biologische Äquivalentdosis Berechnung werden fast 6170 cGy mit diesem Rezept Annahme einer &quot;α / β&quot;-Verhältnis von 10 für Tumor geliefert. Die Strahlung aus einem Linearbeschleuniger SBRT emittiert wird entweder durch die Verwendung einer von 12 festen Wolfram kreisförmigen Kollimatoren (5 bis 60 mm) oder mit einem Wolfram-Kupfer-Legierung segmentiert Sechseck IRIS Kollimator kollimiert. Normale 14 Organe haben eine Toleranz von Strahlung und die Verwendung von Dosis-Volumen-Histogramm Parameter für normales Gewebe Einschränkung bei ablativen stereotaktische Radiochirurgie sind in Tabelle 1 aufgeführt. </li></ol> 4. Stereotaktische Cyberknife Behandlung Lieferung <ol><li> Führen Sie Cross-Plane Bild Verifikation. Während Cyberknife SBRT, Weichteil-Fiducials(Oder in einigen Fällen starre anatomische Orientierungspunkte wie der Schädel für intrakranielle Läsionen und der Wirbelsäule für die Wirbelsäulen-Läsionen) werden durch Cross-Plane Röntgenaufnahmen verfolgt und bestätigt, dass in dem erwarteten Zielort durch das Ziel zu lokalisieren System (TLS)-Subsystem sein. </li><li> Überprüfen Sie, Ziel-Positionierung. Fiducials werden in drei und bis zu sechs Freiheitsgraden (dh x, y, z, Stampfen, Rollen und Gieren) verfolgt. Bilder von den TLS generiert werden automatisch registriert und verglichen mit digital rekonstruierte Röntgenbilder (DRR) von der ersten Behandlung planen CT-Scan erzeugt. </li><li> Überprüfen Sie, Ziel-Positionierung. Wenn die Ergebnisse der automatischen Registrierung, die Fiducials haben jenseits vorgegebener Toleranzen in einem der sechs Freiheitsgrade (x, y, z, Stampfen, Rollen und Gieren) verschoben zeigen, die Behandlung wird automatisch angehalten. Umlagerung des Patienten erfolgt dann. </li><li> Betrachten Zielbewegung. Ziele, die sich bewegen mit Atembewegung sind treated Ausnutzung des Synchrony Respiratory Tracking-Subsystem (Synchrony). Mit der Verwendung einer Kamera, der in dem Behandlungsraum, das System kontinuierlich die Atemmuster des Patienten (dh, zu erhalten externen Positionsdaten) unter Verwendung von Licht-emittierenden Dioden (LEDs), die an einer Weste um den Thorax des Patienten. 10 Zusammen mit der Fiducial Ortsinformationen (interne Positionsdaten) aus Cross-Plane X-Strahlen erhalten, baut der Synchrony System eine Korrelation Modell mit den externen Daten und den internen Daten. Diese Korrelation Modell ermöglicht es dem Roboterarm, jede respiratorische-induzierte Bewegung des Ziels, während bei der Anlieferung von jeglichen Behandlung Balken folgen. </li><li> Die Behandlung kann zur Folge 100-150 lieferbar Behandlung Positionen des Roboterarms. Die Behandlungen dauern 30 bis 90 Minuten. </li></ol> 5. Repräsentative Ergebnisse Stereotaktische Strahlentherapie Körper (SBRT) kann es sich um viele einzelne Strahlen (<html> blaue Vektoren) alle konvergierenden auf einzelnen oder mehreren eng verbundenen klinischen Strahlung Ziele, wie in Abbildung 1A dargestellt. Ein repräsentatives Ergebnis guter Planung radiochirurgischen gibt einen lieferbar SBRT Behandlung mit hohen Strahlendosis Krebs Zielvolumen Abdeckung und Krebs-Target Konformität. 1B-D-Show 131 Strahlen verwendet wurden, um auf einer Becken-Rezidiv eines Ovarialkarzinoms chemorefractory Ziel über 42 Minuten zu behandeln. SBRT verschrieben, um die 80% Isodosislinie gerendert 100% klinische Zielvolumen Abdeckung mit einem Index von 1,94 Konformität für eine Gesamtdosis von 2400 cGy in drei täglich 800 cGy Fraktionen. Die Dosis-Volumen-Histogramme für das klinische Ziel (rot) und für die kritischen Strukturen der Mastdarm (braun), Blase (gelb), Dünndarm (hellblau) Sakralnerven (TAN) und Hüfte (orange) sind in Abbildung 2 dargestellt. <img alt="1" src="/files/ftp_upload/3793/3793fig1.jpg" /> Abbildung 1.tp :/ / www.jove.com/files/ftp_upload/3793/3793fig1large.jpg &quot;target =&quot; _blank &quot;&gt; Klicken Sie hier für eine größere Abbildung zu sehen. <img alt="2" src="/files/ftp_upload/3793/3793fig2.jpg" /> Abbildung 2. Dosis-Volumen-Histogramme für das klinische Ziel (rot) und für die kritischen Strukturen der Mastdarm (braun), Blase (gelb), Dünndarm (hellblau) Sakralnerven (TAN) und Hüfte (orange).

<ol>
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Wir (CAK, JMB, RD) haben nichts zu offenbaren.

Ermutigende erste Ergebnisse SBRT haben klinische Untersuchung der Radiochirurgie zur Behandlung von persistierendem oder rezidivierendem gynäkologischen Krebserkrankungen. 7, 8 angeheizt, in Frage zu 15 Daten strahlenbiologischen Effekte und Modus des Zelltodes, die sich aus SBRT. Kleine klinische Studien haben gezeigt, dass ablative Strahlendosen durch SBRT vorausgesetzt gezielte Krankheitsbekämpfung Wachstumsraten von über 90% zu produzieren. Anders als bei der konventionellen Strahlentherapie ist es schwierig war, die mit SBRT radiosensitivierende und zytotoxische / zytostatische Chemotherapie zu kombinieren. Bessere Krebs Targeting durch verstärkte Planung der Behandlung Volumenausdehnungen und durch Einbeziehung von 18 F-FDG PET / CT-Bildern hat die klinischen Ergebnisse verbessert. Während es zwingend notwendig, um in andere Methoden der Bereitstellung von Dosis-eskalierte Strahlung mit hoher Präzision zu betrachten ist, bleibt es unentschieden, ob SBRT können vergleichbarer therapeutischer Wirkung als Low-und High dose-rate Brachytherapie liefern. In der Tat ist die Brachytherapie häufiger und Valivom Technik, um Strahlendosis Eskalation in der gynäkologischen Krebs Ziele zu erreichen. Als solche sind sowohl Enthusiasmus und Vorsicht angebracht bei der Lektüre zur Verfügung SBRT Daten für die Behandlung von gynäkologischen Krebserkrankungen.

<table border="1"><tbody><tr><td> Name des Gerätes </td><td> Firma </td><td> Katalog-Nummer </td><td> Kommentare </td></tr><tr><td> Cyberknife-System </td><td> Accuray (Sunnyvale, CA) </td><td></td><td></td></tr></tbody></table>

stereotactic radiosurgery for gynecologic cancer

Stereotaktische Strahlentherapie Körper (SBRT) zeichnet sich durch mehr erforderlich starren Patientenfixierung Anteil von Atembewegung, komplizierte Planung der Behandlung, On-Board-Imaging und reduzierte Anzahl von ablativen Strahlendosen zu Krebs in der Regel richtet sich refraktär gegenüber einer Chemotherapie und einer konventionellen Bestrahlung. Steile SBRT Strahlendosis Drop-Off-Genehmigungen schmal &#39;pencil beam&#39; Behandlung Felder für ablativen Bestrahlung in 1 bis 3 Behandlungen kondensiert verwendet werden. Behandelnden Ärzte müssen erkennen, dass SBRT kommt zu einer größeren Gefahr von Verletzungen und normalem Gewebe Chance geographischen Tumor Fräulein. Beide müssen durch die Immobilisierung von Krebs Ziele und durch hochpräzise Behandlung Lieferung in Angriff genommen werden. Krebs-Target Immobilisierung wurde durch die Verwendung von indizierten angepasste Styropor Abgüsse, evakuiert Sitzsäcken oder Körper-fix Formen mit Patienten-unabhängige Bauchpresse erreicht worden. 3.1 Intrafraction Bewegung von Krebs targets durch die Atmung kann nun durch Patienten-responsive Atemanhaltezeit Techniken, 4 Patienten Mundstück atmungsaktiv Koordination, Atmung 5-korrelierte Computertomographie, 6 oder image-guided Verfolgung von Passermarken in und an einem beweglichen Tumor implantiert reduziert werden. 9.7 Der Cyberknife System (Accuray [Sunnyvale, CA]) verwendet eine Strahlung Linearbeschleuniger auf einem industriellen Roboterarm, der genau folgt Patientenbeatmungskreislauf Bewegung von einer Kamera-verfolgt von lichtemittierenden Dioden (LED) an einer Weste angebracht an einen Patienten angebracht ist, welches imprägniert. 10 wesentliche Senkung der Strahlentherapie Margen können von Motion-Tracking erreicht werden, letztlich erscheint mir aber ein kleiner Planung Zielvolumen, die mit Submillimeter-Genauigkeit bestrahlt werden. 11-13 Krebs-Targets durch SBRT behandelt werden, durch den konvergenten, eng gebündelte Strahlen bestrahlt. Resultierende Strahlendosis an Krebs Zielvolumen Histogramme haben eine mehr PronomenCED-Strahlung &quot;Schulter&quot; zeigt hohen Anteil Ziel-Abdeckung und eine kleine, hochdosierte Bestrahlung &quot;Schwanz&quot;. Somit kommt erhöhten Soll-Konformität auf Kosten einer verringerten Dosis Gleichförmigkeit in der Krebs-Target SBRT. Dies könnte Auswirkungen sowohl für die anschließende Tumorkontrolle in der SBRT Ziel-und normalem Gewebe von Organen Toleranz at-Risk. Aufgrund des starken Dosis Abnahme in SBRT, tritt die Möglichkeit einer okkulten Krankheit entkommen ablative Strahlendosis bei Krebs Ziele nicht in vollem Umfang anerkannt werden und unzureichende Margen SBRT Dosis angewendet werden. Klinische Zielvolumen (CTV) Expansion von 0,5 cm, was zu einem größeren Planungszielvolumen (PTV), mit einer erhöhten Zielsteuerung ohne unnötige normalen Gewebeverletzung verbunden ist. 7,8 weitere Verringerung der Wahrscheinlichkeit von geographischen Miss durch Einbau erreicht werden kann von 2 - [18 F] Fluor-2-desoxy-D-Glucose (18 F-FDG) Positronen-Emissions-Tomographie (PET) 8 Verwendung von 18 F-FDG PET / CT in SBRT treatme.NT-Planung ist erst der Anfang der Versuche, neue bildgebende Ziel molekulare Signaturen für gynäkologischen Krebserkrankungen zu entdecken.

Watch this Scientific Journal Video about Stereotactic Radiosurgery for Gynecologic Cancer at JoVE.com

Stereotactic Radiosurgery for Gynecologic Cancer

Stereotaktische Strahlentherapie Körper (SBRT) umfasst bildgestützte, ablative Strahlung geliefert, um Krebs gezielt refraktär auf Chemotherapie oder zur konventionellen Bestrahlung. Die Roboter-bewaffneten Cyberknife SBRT System, mit anspruchsvollen Ziel-Lokalisierung, liefert hypofraktionierter Strahlendosen in der Lage Sterilisieren Krebs Ziele. Dieser Artikel wird prüfen, neue therapeutische Rollen von SBRT für gynäkologische Krebserkrankungen.

Stereotaktische Radiochirurgie für Gynäkologische Krebs

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, ...

stereotactic-radiosurgery-for-gynecologic-cancer

Research

JoVE Journal

Medicine

17.5K Aufrufe.  University Hospitals Case Medical Center and Case Western Reserve University School of Medicine. Stereotaktische Strahlentherapie Körper (SBRT) umfasst bildgestützte, ablative Strahlung geliefert, um Krebs gezielt refraktär auf Chemotherapie oder zur konventionellen Bestrahlung. Die Roboter-bewaffneten Cyberknife SBRT System, mit anspruchsvollen Ziel-Lokalisierung, liefert hypofraktionierter Strahlendosen in der Lage Sterilisieren Krebs Ziele. Dieser Artikel wird prüfen, neue therapeutische Rollen von SBRT für gynäkologische Krebserkrankungen.

Serie: Stereotactic Radiosurgery for Gynecologic Cancer

Multispectral Real-time Fluorescence Imaging for Intraoperative Detection of the Sentinel Lymph Node in Gynecologic Oncology

The prognosis in virtually all solid tumors depends on the presence or absence of lymph node metastases.1-3 Surgical treatment most often combines radical excision of the tumor with a full lymphadenectomy in the drainage area of the tumor. However, removal of lymph nodes is associated with increased morbidity due to infection, wound breakdown and lymphedema.4,5 As an alternative, the sentinel lymph node procedure (SLN) was developed several decades ago to detect the first draining lymph node from the tumor.6 In case of lymphogenic dissemination, the SLN is the first lymph node that is affected (Figure 1). Hence, if the SLN does not contain metastases, downstream lymph nodes will also be free from tumor metastases and need not to be removed. The SLN procedure is part of the treatment for many tumor types, like breast cancer and melanoma, but also for cancer of the vulva and cervix.7 The current standard methodology for SLN-detection is by peritumoral injection of radiocolloid one day prior to surgery, and a colored dye intraoperatively. Disadvantages of the procedure in cervical and vulvar cancer are multiple injections in the genital area, leading to increased psychological distress for the patient, and the use of radioactive colloid.
Multispectral fluorescence imaging is an emerging imaging modality that can be applied intraoperatively without the need for injection of radiocolloid. For intraoperative fluorescence imaging, two components are needed: a fluorescent agent and a quantitative optical system for intraoperative imaging. As a fluorophore we have used indocyanine green (ICG). ICG has been used for many decades to assess cardiac function, cerebral perfusion and liver perfusion.8 It is an inert drug with a safe pharmaco-biological profile. When excited at around 750 nm, it emits light in the near-infrared spectrum around 800 nm. A custom-made multispectral fluorescence imaging camera system was used.9.
The aim of this video article is to demonstrate the detection of the SLN using intraoperative fluorescence imaging in patients with cervical and vulvar cancer. Fluorescence imaging is used in conjunction with the standard procedure, consisting of radiocolloid and a blue dye. In the future, intraoperative fluorescence imaging might replace the current method and is also easily transferable to other indications like breast cancer and melanoma.

Fluorescence imaging is a promising innovative modality for image-guided surgery in surgical oncology. In this video we describe the technical procedure for detection of the sentinel lymph node using fluorescence imaging as showcased in gynecologic oncologicy. A multispectral fluorescence camera system, together with the fluorescent agent indocyanine green, is applied.

Multispectral Real-time Fluoreszenz-Imaging für die intraoperative Detektion des Sentinel Lymph Node in Gynäkologische Onkologie

The prognosis in virtually all solid tumors depends on the presence or absence of lymph node metastases.1-3 Surgical treatment most often combines radical ...

Forschung

Medizin

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy 1. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM 2. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments 3-5. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

We describe an integrated method for the precise, stereotactic implantation of human glioblastoma multiforme cells into the brains of nude mice and subsequent serial in vivo imaging to monitor growth and response to treatment of the resultant xenografts.

Stereotaktische Intrakranielle Implantation und<em&gt; In vivo</em&gt; Bioluminescent Imaging der Tumorxenotransplantaten in einem Maus-Modell-System des Glioblastoma multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality ...

Cerenkov Luminescence Imaging (CLI) for Cancer Therapy Monitoring

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities1-3. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues.
 Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI)4-6. CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium7,8. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one 18F decay was estimated to produce an average of 3 photons in water5. 
 Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others4,5,9,10,11. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET.
 Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study12. We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor13,14. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments.

Cerenkov Luminescence Imaging CLI for Cancer Therapy Monitoring

Use of Cerenkov Luminescence Imaging (CLI) for monitoring preclinical cancer treatment is described here. This method takes advantage of Cerenkov Radiation (CR) and optical imaging (OI) to visualize radiolabeled probes and thus provides an alternative to PET in preclinical therapeutic monitoring and drug screening.

Cerenkov Lumineszenz Imaging (CLI) for Cancer Therapy Überwachung

In  molecular imaging, positron emission tomography (PET) and optical imaging (OI)  are two of the most important and thus most widely used modalities1-3. ...

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

Improved understanding of pancreatic cancer biology is critically needed to enable the development of better therapeutic options to treat pancreatic cancer. To address this need, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression using in vivo bioluminescence imaging.

Bioluminescent orthotopen Modell von Bauchspeicheldrüsenkrebs Progression

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%.  New therapeutic options are critically needed and depend on improved ...

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Estrogen plays vital roles in mammary gland development and breast cancer progression. It mediates its function by binding to and activating the estrogen receptors (ERs), ER&#945;, and ER&#946;. ER&#945; is frequently upregulated in breast cancer and drives the proliferation of breast cancer cells. The ERs function as transcription factors and regulate gene expression. Whereas ER&#945;&#39;s regulation of protein-coding genes is well established, its regulation of noncoding microRNA (miRNA) is less explored. miRNAs play a major role in the post-transcriptional regulation of genes, inhibiting their translation or degrading their mRNA. miRNAs can function as oncogenes or tumor suppressors&#160;and are also promising biomarkers. Among the miRNA assays available, microarray and quantitative real-time polymerase chain reaction (qPCR) have been extensively used to detect and quantify miRNA levels. To identify miRNAs regulated by estrogen signaling in breast cancer, their expression in ER&#945;-positive breast cancer cell lines were compared before and after estrogen-activation using both the &#181;Paraflo-microfluidic microarrays and Dual Labeled Probes-low density arrays. Results were validated using specific qPCR assays, applying both Cyanine dye-based and Dual Labeled Probes-based chemistry. Furthermore, a time-point assay was used to identify regulations over time. Advantages of the miRNA assay approach used in this study is that it enables a fast screening of mature miRNA regulations in numerous samples, even with limited sample amounts. The layout, including the specific conditions for cell culture and estrogen treatment, biological and technical replicates, and large-scale screening followed by in-depth confirmations using separate techniques, ensures a robust detection of miRNA regulations,&#160;and eliminates false positives and other artifacts. However, mutated or unknown miRNAs, or regulations at the primary and precursor transcript level, will not be detected. The method presented here represents a thorough investigation of estrogen-mediated miRNA regulation.

Molecular signaling through both estrogen and microRNAs are critical in breast cancer development and growth. Estrogen activates the estrogen receptors, which are transcription factors. Many transcription factors can regulate the expression of microRNAs, and estrogen-regulated microRNAs can be profiled using different large-scale techniques.

Profiling von Östrogen-regulierte MicroRNAs in Brustkrebszellen

Estrogen plays vital roles in mammary gland development and breast cancer progression. It mediates its function by binding to and activating the estrogen ...

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer

Telomere dysfunction-induced loss of genome integrity and its associated DNA damage signaling and checkpoint responses are well-established drivers that cause tissue degeneration during ageing. Cancer, with incidence rates greatly increasing with age, is characterized by short telomere lengths and high telomerase activity. To study the roles of telomere dysfunction and telomerase reactivation in ageing and cancer, the protocol shows how to generate two murine inducible telomerase knock-in alleles 4-Hydroxytamoxifen (4-OHT)-inducible TERT-Estrogen Receptor (mTERT-ER) and Lox-Stopper-LoxTERT (LSL-mTERT). The protocol describes the procedures to induce telomere dysfunction and reactivate telomerase activity in mTERT-ER and LSL-mTERT mice in vivo. The representative data show that reactivation of telomerase activity can ameliorate the tissue degenerative phenotypes induced by telomere dysfunction. In order to determine the impact of telomerase reactivation on tumorigenesis, we generated prostate tumor model G4 PB-Cre4 PtenL/L p53L/L LSL-mTERTL/L and thymic T-cell lymphoma model G4 Atm-/- mTERTER/ER. The representative data show that telomerase reactivation in the backdrop of genomic instability induced by telomere dysfunction can greatly enhance tumorigenesis. The protocol also describes the procedures used to isolate neural stem cells (NSCs) from mTERT-ER and LSL-mTERT mice and reactivate telomerase activity in NSCs in vitro. The representative data show that reactivation of telomerase can enhance the self-renewal capability and neurogenesis in vitro. Finally, the protocol describes the procedures for performing telomere FISH (Fluorescence In Situ Hybridization) on both mouse FFPE (Formalin Fixed and Paraffin Embedded) brain tissues and metaphase chromosomes of cultured cells.

Telomere and telomerase play essential roles in ageing and tumorigenesis. The goal of this protocol is to show how to generate two murine inducible telomerase knock-in alleles and how to utilize them in the studies of tissue degeneration/regeneration and cancer.

Verwendung Murine induzierbare Telomerase Allele in den Studien von Tissue Degeneration / Regeneration und Krebs

Telomere dysfunction-induced loss of genome integrity and its associated DNA damage signaling and checkpoint responses are well-established drivers that ...

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) contains a subset of exclusively tumorigenic cancer stem cells (CSCs) which have been shown to drive tumor initiation, metastasis and resistance to radio- and chemotherapy. Here we describe a specific methodology for culturing primary human pancreatic CSCs as tumor spheres in anchorage-independent conditions. Cells are grown in serum-free, non-adherent conditions in order to enrich for CSCs while their more differentiated progenies do not survive and proliferate during the initial phase following seeding of single cells. This assay can be used to estimate the percentage of CSCs present in a population of tumor cells. Both size (which can range from 35 to 250 micrometers) and number of tumor spheres formed represents CSC activity harbored in either bulk populations of cultured cancer cells or freshly harvested and digested tumors 1,2. Using this assay, we recently found that metformin selectively ablates pancreatic CSCs; a finding that was subsequently further corroborated by demonstrating diminished expression of pluripotency-associated genes/surface markers and reduced in vivo tumorigenicity of metformin-treated cells. As the final step for preclinical development we treated mice bearing established tumors with metformin and found significantly prolonged survival. Clinical studies testing the use of metformin in patients with PDAC are currently underway (e.g., NCT01210911, NCT01167738, and NCT01488552). Mechanistically, we found that metformin induces a fatal energy crisis in CSCs by enhancing reactive oxygen species (ROS) production and reducing mitochondrial transmembrane potential. In contrast, non-CSCs were not eliminated by metformin treatment, but rather underwent reversible cell cycle arrest. Therefore, our study serves as a successful example for the potential of in vitro sphere formation as a screening tool to identify compounds that potentially target CSCs, but this technique will require further in vitro and in vivo validation to eliminate false discoveries.

Pancreatic cancer stem cells (CSCs) can be expanded in vitro using the anchorage-independent sphere culture technique, which represents a powerful tool to study CSC biology and can serve as the first step to develop novel CSC-targeting therapies. Here the methodology for expanding, analyzing and targeting of pancreatic CSCs is provided.

Studieren Bauchspeicheldrüsenkrebs Stammzelleigenschaften für die Entwicklung neuer Behandlungsstrategien

Pancreatic ductal adenocarcinoma (PDAC) contains a subset of exclusively tumorigenic cancer stem cells (CSCs) which have been shown to drive tumor ...

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.

Dynamische Lungentumor Tracking für stereotaktische Strahlentherapie Körper Ablative

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

Working with Human Tissues for Translational Cancer Research

Medical research for human benefit is greatly impeded by the necessity for human tissues and subjects. However, upon obtaining consent for human specimens, precious samples must be handled with the greatest care in order to ensure integrity of organs, tissues, and cells to the highest degree. Unfortunately, tissue processing by definition requires extraction of tissues from the host, a change which can cause great cellular stress and have major repercussions on subsequent analyses. These stresses could result in the specimen being no longer representative of the site from which it was retrieved. Therefore, a strict protocol must be adhered to while processing these specimens to ensure representativeness. The desired assay(s) must also be taken into consideration in order to ensure that an optimal technique is used for sample processing. Outlined here is a protocol for tissue retrieval, processing and various analyses which may be performed on processed tissue in order to maximize downstream production from limited tissue samples.

Translational cancer research is dependent on extraction of human tissues. Much work has gone into optimizing extraction methods for ex vivo analysis. Here, we describe tissue processing methods allowing for maximal data output from limited samples.

Arbeiten mit menschlichen Geweben für Translationale Krebsforschung

Medical research for human benefit is greatly impeded by the necessity for human tissues and subjects. However, upon obtaining consent for human ...

Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

The pattern of ovarian cancer metastasis is markedly different from that of most other epithelial tumors, because it rarely spreads hematogenously. Instead, ovarian cancer cells exfoliated from the primary tumor are carried by peritoneal fluid to metastatic sites within the peritoneal cavity. These sites, most notably the abdominal peritoneum and omentum, are organs covered by a mesothelium-lined surface. To investigate the processes of ovarian cancer dissemination, we assembled a complex three-dimensional culture system that reconstructs the lining of the peritoneal cavity in vitro. Primary human fibroblasts and mesothelial cells were isolated from human omentum. The fibroblasts were then mixed with extracellular matrix and covered with a layer of the primary human mesothelial cells to mimic the peritoneal and omental surfaces encountered by metastasizing ovarian cancer cells. The resulting organotypic model is, as shown, used to examine the early steps of ovarian cancer dissemination, including cancer cell adhesion, invasion, and proliferation. This model has been used in a number of studies to investigate the role of the microenvironment (cellular and acellular) in early ovarian cancer dissemination. It has also been successfully adapted to high throughput screening and used to identify and test inhibitors of ovarian cancer metastasis.

Here, we present a protocol to construct a three-dimensional in vitro model of the lining of the peritoneal cavity, composed of primary human mesothelial cells and fibroblasts layered with extracellular matrix, as a tool to investigate ovarian cancer cell adhesion, invasion, and proliferation.

Modellierung der frühen Schritte der Eierstockkrebs Verbreitung in einer organotypischen Kultur der Menschen Peritonealhöhle

The pattern of ovarian cancer metastasis is markedly different from that of most other epithelial tumors, because it rarely spreads hematogenously. ...