p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors

The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response

Dystrophin Is a Tumor Suppressor in Human Cancers with Myogenic Programs

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation1–3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions inactivate larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer

Interventional Radiology in Oncology - Update 2021

Was ist neu? Transarterielle Tumorembolisationen Transarterielle Tumorembolisationen wie die transarterielle Chemoembolisation (TACE) und die selektive interne Radiotherapie (SIRT) haben sich als Therapieoption bei primaren und sekundaren Lebertumoren etabliert und werden in onkologischen Zentren i.d.R. routinema ss ig durchgefuhrt. Transkutane Thermoablationen Transkutane Thermoablationen wie Radiofrequenzablation (RFA) und Mikrowellenablation (MWA) haben sich als i.d.R. kurative Therapieoptionen bei primaren und sekundaren Lebertumoren etabliert. Daruber hinaus werden die Verfahren zunehmend auch bei Nieren- und Lungentumoren eingesetzt. Neue Verfahren Mit hochintensivem fokussiertem Ultraschall (HIFU) ist eine nichtinvasive Thermoablation moglich, bisher zugelassene Indikationen sind die Behandlung von Uterusmyomen, Prostatakarzinomen und Knochentumoren. Die irreversible Elektroporation (IRE) ist ein nichtthermisches Ablationsverfahren, das sich insbesondere in der Therapie von fortgeschrittenen, inoperablen Pankreaskarzinomen etabliert hat. Abstract Interventional radiology plays a crucial role in oncology. The most common interventional treatments are transarterial embolisation as well as percutaneous thermal ablations. Transarterial embolisation, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) are well established, usually palliatively intended treatment options for primary and secondary hepatic malignancies. Embolisation is usually well tolerated under conscious sedation and can be repeated several times. Percutaneous thermoablation is a local ablative, usually curatively intended treatment for hepatic, renal and pulmonary tumors. As a minimally invasive technique, it competes against surgery and radiation therapy. There are different types of thermoablation, most commonly used are radiofrequency ablation (RFA), microwave ablation (MWA) and cryo-ablation. Ablation is usually performed in general anesthesia, less common in conscious sedation. New interventional treatments are high intensity focused ultrasound (HIFU) and irreversible electroporation (IRE). HIFU allows a non-invasive, imaging-guided thermoablation that is currently certified for uterine myoma, prostate cancer and bone tumors. IRE is a minimal invasive non-thermal ablation that is especially established for locally advanced tumors that show a close relationship to large vessels, for example pancreatic cancer

Value of spectral detector computed tomography to differentiate infected from noninfected thoracoabominal fluid collections

Purpose: To investigate the diagnostic value of spectral detector CT (SDCT)-derived virtual non-contrast (VNC), virtual monoenergetic images (VMI) and iodine overlays (IO) for distinguishing infected from noninfected fluid collections (FC) in the chest or abdomen. Method: This retrospective study included 58 patients with venous phase SDCT with 77 FC. For all included FC, microbiological analysis of aspirated fluid served as reference. For quantitative analysis, wall thickness was measured, and (ROI)-based analysis performed within the fluid, the FC's wall (if any) and the aorta. Two radiologists qualitatively evaluated visibility of wall enhancement, diagnostic confidence regarding infection of fluid collection, confidence of CT-guided drainage catheter placement and visibility of anatomical landmarks in conventional images (CI) and VNC, VMI40keV, IO. Results: Wall thickness significantly differed between infected (n = 46) and noninfected (n = 31) FC (3.5 +/- 1.8 mm vs. 1.4 +/- 1.8 mm, AUC = 0.81; p < 0.05). Fluid attenuation and wall enhancement was significantly higher in infected as compared to noninfected FC in all reconstructions (p < 0.05, respectively). Highest AUC regarding A) attenuation in fluid was yielded in CI and VMI70,80keV (0.75); B) wall enhancement in CI (0.88) followed by iodine concentration (0.86). Contrast-to-noise ratio of wall vs. fluid was highest in VMI40keV (p < 0.05). All assessed qualitative parameters received significantly higher ratings when using spectral reconstructions vs. CI (p for all <0.05), except for visibility of wall enhancement. Conclusion: Spectral reconstructions improve the assessment of infected from noninfected thoracoabdominal fluid collections and depiction of wall enhancement. Diagnostic performance of the quantitative measurements in spectral reconstructions were comparable with measurements in conventional images

p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors

The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response.status: publishe

Evaluation of viscosities of typical drainage fluids to promote more evidence-based catheter size selection

Abstract Percutaneous drainage is a first-line therapy for abscesses and other fluid collections. However, experimental data on the viscosity of body fluids are scarce. This study analyses the apparent viscosity of serous, purulent and biliary fluids to provide reference data for the evaluation of drainage catheters. Serous, purulent and biliary fluid samples were collected during routine drainage procedures. In a first setup, the apparent kinematic viscosity of 50 fluid samples was measured using an Ubbelohde viscometer. In a second setup, the apparent dynamic viscosity of 20 fluid samples obtained during CT-guided percutaneous drainage was measured using an in-house designed capillary extrusion experiment. The median apparent kinematic viscosity was 0.96 mm2/s (IQR 0.90–1.15 mm2/s) for serous samples, 0.98 mm2/s (IQR 0.97–0.99 mm2/s) for purulent samples and 2.77 mm2/s (IQR 1.75–3.70 mm2/s) for biliary samples. The median apparent dynamic viscosity was 1.63 mPa*s (IQR 1.27–2.09 mPa*s) for serous samples, 2.45 mPa*s (IQR 1.69–3.22 mPa*s) for purulent samples and 3.50 mPa*s (IQR 2.81–3.90 mPa*s) for biliary samples (all differences p < 0.01). Relative to water, dynamic viscosities were increased by a factor of 1.36 for serous fluids, 2.26 for purulent fluids, and 4.03 for biliary fluids. Serous fluids have apparent viscosities similar to water, but biliary and purulent fluids are more viscous. These data can be used as a reference when selecting the drainage catheter size, with 8F catheters being appropriate for most percutaneous drainage cases

<i>TP53</i> sequencing results of 62 patients with primary localized (n = 40) or metastastic (n = 22) GIST.

<p><i>TP53</i> sequencing results of 62 patients with primary localized (n = 40) or metastastic (n = 22) GIST.</p

Primers used for the <i>TP53</i> Sequencing.

<p>Primers used for the <i>TP53</i> Sequencing.</p

Induction of apoptosis represented by amount of activated caspases 3 and 7 (graphs on the left side) and annexin V/7-AAD based FACS assay (graphs on the right side) in GIST48B (A), GIST-T1 (B), GIST48 (C) and GIST430 (D).

<p>Indicated concentrations of the inhibitors were assayed after 24 h and 48 h of incubation. DMSO was vehicle control. Bars, mean of quadruplicate cultures with SD represent multitudes of DMSO-only values. N = nutlin-3.</p

Analysis of nutlin-3 in combinational treatment.

<p>A: Induction of apoptosis represented by amount of activated caspases 3 and 7 in GIST430 and GIST48. Indicated concentrations of nutlin-3 were assayed alone and in combination with different KIT-inhibitors after 24 h and 48 h of incubation. DMSO was vehicle control. Bars, mean of quadruplicate cultures with SD represent multitudes of DMSO-only values. B: Western Blot analyses after 24 h of incubation with doses of nutlin-3 (5 µM) alone and in combination with different KIT-inhibitors in GIST430 and GIST48. N = nutin-3, IM = imatinib mesylate, SU = sunitinib.</p