Microsurgical Lymph Node Dissection for Metastatic Asymptomatic C-Cell Carcinoma

In persistent, clinically inapparent medullary thyroid carcinoma, microsurgical dissection of all lymph node compartments of the neck was performed. Between August 1988 and September 1991, 28 cases (mean age 43.3 years) were treated with 38 surgical interventions. Twenty patients had the sporadic form and eight patients the familial form. Unilateral neck dissection resulted in normalization of serum calcitonin (CT) levels even after pentagastrin stimulation in two patients whereas 16 patients exhibited abnormal CT stimulation tests. Eight of ten patients who had bilateral neck dissections had positive pentagastrin test results after surgery. The main postoperative complications included loss of local cutaneous sensation, generally temporary, and unilateral recurrent laryngeal nerve paralysis

Hepatic platelet and leukocyte adherence during endotoxemia

INTRODUCTION: Liver microcirculation disturbances are a cause of hepatic failure in sepsis. Increased leukocyte-endothelial interaction, platelet adherence and impaired microperfusion cause hepatocellular damage. The time course and reciprocal influences of ongoing microcirculatory events during endotoxemia have not been clarified. METHODS: Male Wistar rats (232 ± 17 g) underwent cecal ligation and puncture (CLP). Intravital microscopy (IVM) was performed 0, 1, 3, 5, 10 and 20 hours after CLP. Mean erythrocyte velocity, leukocyte and platelet rolling in postsinusoidal venules and sticking of leukocytes and platelets in postsinusoidal venules and hepatic sinusoids were determined. Heart rate (HR), mean arterial pressure (MAP) and portal venous blood flow (PBF) were measured. Blood count and investigation of hepatic enzyme release was performed after each IVM time point. RESULTS: Hepatic platelet-endothelial adherence in liver sinusoids and postsinusoidal venules occurred one hour after the induction of endotoxemia. Leukocyte-endothelial interaction started three to five hours after CLP. A decrease of hepatic microperfusion could be observed at three hours in sinusoids and ten hours in postsinusoidal venules after CLP, although PBF was reduced one hour after CLP. HR remained stable and MAP decreased ten hours after CLP. Hepatic enzymes in blood were significantly elevated ten hours after CLP. CONCLUSION: Hepatic platelet-endothelial interaction is an early event during endotoxemia. Leukocyte adherence occurs later, which underlines the probable involvement of platelets in leukocyte recruitment. Although PBF is reduced immediately after CLP, the later onset of hepatic microperfusion decrease makes the existence of autoregulatory liver mechanisms likely

Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility

It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10−/− mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10−/− mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10−/− mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10−/− mice. Germ-free AOM-treated Il10−/− mice showed normal colon histology and were devoid of tumors. Il10−/−; Myd88−/− mice treated with AOM displayed reduced expression of Il12p40 and Tnfα mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

Background: Patients with Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) positive lung cancer are sensitive to ALK-kinase inhibitors. TAE684 is a potent second generation ALK inhibitor that overcomes Crizotinib resistance. Radiotherapy is an integral therapeutic component of locally advanced lung cancer. Therefore, we sought to investigate the effects of combined radiotherapy and ALK-inhibition via TAE684 in ALK-positive vs. wild type lung cancer cells. Methods: Human non-small cell lung cancer (NSCLC) cell lines harboring wild-type ALK (A549), EML4-ALK translocation (H3122) and murine Lewis Lung Cancer (LLC) cells were investigated. Cells were irradiated with 1–4 Gy X-Rays (320 keV) and carbon ions (Spread-out Bragg Peak, SOBP (245.4–257.0 MeV/u)) at Heidelberg Ion Therapy center. TAE684 was administered at the dose range 0–100 nM. Clonogenic survival, proliferation and apoptosis via caspase 3/7 expression level were assessed in all three cell lines using time-lapse live microscopy. Results: TAE684 inhibited the proliferation of H3122 cells in a dose-dependent manner with a half maximal inhibitory concentration (IC50) of ~ 8.2 nM. However, A549 and LLC cells were relatively resistant to TAE684 and IC50 was not reached at concentrations tested (up to 100 nM) in proliferation assay. The antiproliferative effect of TAE684 was augmented by radiotherapy in H3122 cells. TAE684 significantly sensitized H3122 cells to particle therapy with carbon ions (sensitizer enhancement ratio ~1.61, p < 0.05). Caspase 3/7 activity was evidently enhanced after combination therapy in H3122 cells. Conclusions: This is the first report demonstrating synergistic effects of combined TAE684 and radiotherapy in EML4-ALK positive lung cancer cells. In addition to conventional photon radiotherapy, ALK-inhibition also enhanced the effects of particle irradiation using carbon ions. Our data indicate beneficial effects of combined ALK-inhibition and radiotherapy in treatment of this distinct subpopulation of NSCLC that warrant further evaluation

Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility

It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10−/− mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10−/− mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10−/− mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10−/− mice. Germ-free AOM-treated Il10−/− mice showed normal colon histology and were devoid of tumors. Il10−/−; Myd88−/− mice treated with AOM displayed reduced expression of Il12p40 and Tnfα mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma

Quantitative in vivo assessment of radiation injury of the liver using Gd-EOB-DTPA enhanced MRI: tolerance dose of small liver volumes

<p>Abstract</p> <p>Backround</p> <p>Hepatic radiation toxicity restricts irradiation of liver malignancies. Better knowledge of hepatic tolerance dose is favourable to gain higher safety and to optimize radiation regimes in radiotherapy of the liver. In this study we sought to determine the hepatic tolerance dose to small volume single fraction high dose rate irradiation.</p> <p>Materials and methods</p> <p>23 liver metastases were treated by CT-guided interstitial brachytherapy. MRI was performed 3 days, 6, 12 and 24 weeks after therapy. MR-sequences were conducted with T1-w GRE enhanced by hepatocyte-targeted Gd-EOB-DTPA. All MRI data sets were merged with 3D-dosimetry data. The reviewer indicated the border of hypointensity on T1-w images (loss of hepatocyte function) or hyperintensity on T2-w images (edema). Based on the volume data, a dose-volume-histogram was calculated. We estimated the threshold dose for edema or function loss as the D₉₀, i.e. the dose achieved in at least 90% of the pseudolesion volume.</p> <p>Results</p> <p>At six weeks post brachytherapy, the hepatocyte function loss reached its maximum extending to the former 9.4Gy isosurface in median (i.e., ≥9.4Gy dose exposure led to hepatocyte dysfunction). After 12 and 24 weeks, the dysfunctional volume had decreased significantly to a median of 11.4Gy and 14Gy isosurface, respectively, as a result of repair mechanisms. Development of edema was maximal at six weeks post brachytherapy (9.2Gy isosurface in median), and regeneration led to a decrease of the isosurface to a median of 11.3Gy between 6 and 12 weeks. The dose exposure leading to hepatocyte dysfunction was not significantly different from the dose provoking edema.</p> <p>Conclusion</p> <p>Hepatic injury peaked 6 weeks after small volume irradiation. Ongoing repair was observed up to 6 months. Individual dose sensitivity may differ as demonstrated by a relatively high standard deviation of threshold values in our own as well as all other published data.</p

Biological in-vivo measurement of dose distribution in patients' lymphocytes by gamma-H2AX immunofluorescence staining: 3D conformal- vs. step-and-shoot IMRT of the prostate gland

<p>Abstract</p> <p>Background</p> <p>Different radiation-techniques in treating local staged prostate cancer differ in their dose- distribution. Physical phantom measurements indicate that for 3D, less healthy tissue is exposed to a relatively higher dose compared to SSIMRT. The purpose is to substantiate a dose distribution in lymphocytes <it>in-vivo </it>and to discuss the possibility of comparing it to the physical model of total body dose distribution.</p> <p>Methods</p> <p>For each technique (3D and SSIMRT), blood was taken from 20 patients before and 10 min after their first fraction of radiotherapy. The isolated leukocytes were fixed 2 hours after radiation. DNA double-strand breaks (DSB) in lymphocytes' nuclei were stained immunocytochemically using the gamma-H2AX protein. Gamma-H2AX foci inside each nucleus were counted in 300 irradiated as well as 50 non-irradiated lymphocytes per patient. In addition, lymphocytes of 5 volunteer subjects were irradiated externally at different doses and processed under same conditions as the patients' lymphocytes in order to generate a calibration-line. This calibration-line assigns dose-value to mean number of gamma-H2AX foci/ nucleus. So the dose distributions in patients' lymphocytes were determined regarding to the gamma-H2AX foci distribution. With this information a cumulative dose-lymphocyte-histogram (DLH) was generated. Visualized distribution of gamma-H2AX foci, correspondingly dose per nucleus, was compared to the technical dose-volume-histogram (DVH), related to the whole body-volume.</p> <p>Results</p> <p>Measured <it>in-vivo </it>(DLH) and according to the physical treatment-planning (DVH), more lymphocytes resulted with low-dose exposure (< 20% of the applied dose) and significantly fewer lymphocytes with middle-dose exposure (30%-60%) during Step-and-Shoot-IMRT, compared to conventional 3D conformal radiotherapy. The high-dose exposure (> 80%) was equal in both radiation techniques. The mean number of gamma-H2AX foci per lymphocyte was 0.49 (3D) and 0.47 (SSIMRT) without significant difference.</p> <p>Conclusions</p> <p><it>In-vivo </it>measurement of the dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci. In case of 3D and SSIMRT, the results of this method correlate with the physical calculated total body dose-distribution, but cannot be interpreted unrestrictedly due to the blood circulation. One possible application of the present method could be in radiation-protection for <it>in-vivo </it>dose estimation after accidental exposure to radiation.</p

In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver tolerance dose after single-fraction 192Ir high-dose-rate brachytherapy

<p>Abstract</p> <p>Background</p> <p>To assess brachytherapy catheter positioning accuracy and to evaluate the effects of prolonged irradiation time on the tolerance dose of normal liver parenchyma following single-fraction irradiation with ¹⁹²Ir.</p> <p>Materials and methods</p> <p>Fifty patients with 76 malignant liver tumors treated by computed tomography (CT)-guided high-dose-rate brachytherapy (HDR-BT) were included in the study. The prescribed radiation dose was delivered by 1 - 11 catheters with exposure times in the range of 844 - 4432 seconds. Magnetic resonance imaging (MRI) datasets for assessing irradiation effects on normal liver tissue, edema, and hepatocyte dysfunction, obtained 6 and 12 weeks after HDR-BT, were merged with 3D dosimetry data. The isodose of the treatment plan covering the same volume as the irradiation effect was taken as a surrogate for the liver tissue tolerance dose. Catheter positioning accuracy was assessed by calculating the shift between the 3D center coordinates of the irradiation effect volume and the tolerance dose volume for 38 irradiation effects in 30 patients induced by catheters implanted in nearly parallel arrangement. Effects of prolonged irradiation were assessed in areas where the irradiation effect volume and tolerance dose volume did not overlap (mismatch areas) by using a catheter contribution index. This index was calculated for 48 irradiation effects induced by at least two catheters in 44 patients.</p> <p>Results</p> <p>Positioning accuracy of the brachytherapy catheters was 5-6 mm. The orthogonal and axial shifts between the center coordinates of the irradiation effect volume and the tolerance dose volume in relation to the direction vector of catheter implantation were highly correlated and in first approximation identically in the T1-w and T2-w MRI sequences (<it>p </it>= 0.003 and <it>p </it>< 0.001, respectively), as were the shifts between 6 and 12 weeks examinations (<it>p </it>= 0.001 and <it>p </it>= 0.004, respectively). There was a significant shift of the irradiation effect towards the catheter entry site compared with the planned dose distribution (<it>p </it>< 0.005). Prolonged treatment time increases the normal tissue tolerance dose. Here, the catheter contribution indices indicated a lower tolerance dose of the liver parenchyma in areas with prolonged irradiation (<it>p </it>< 0.005).</p> <p>Conclusions</p> <p>Positioning accuracy of brachytherapy catheters is sufficient for clinical practice. Reduced tolerance dose in areas exposed to prolonged irradiation is contradictory to results published in the current literature. Effects of prolonged dose administration on the liver tolerance dose for treatment times of up to 60 minutes per HDR-BT session are not pronounced compared to effects of positioning accuracy of the brachytherapy catheters and are therefore of minor importance in treatment planning.</p