Rescue of Historical Materials in Awaji atHanshin-Awaji Earthquake

Purpose: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from 131I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. Methods: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. Results: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 109/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq 177Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. Conclusion: The incidence of subacute haematological toxicity after PRRT with 177Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from 131I, seems not to be valid for PRRT with 177Lu-DOTATATE

Peptide Receptor Radionuclide Therapy & Oncology

Neuroendocrine tumors (NETs) are rare neoplasms with differences in clinical presentation, course and prognosis. Most of the NETs express the somatostatine receptor, which can be utilized for imaging and therapy. Radiolabeled somatostatin analogs can be used for peptide receptor radionuclide therapy (PRRT) in NET patients. 177Lu- DOTATATE is one of the most used radiopeptides for PRRT with tumor response rates of 15–35%. However PRRT elicits side effects. The first (and main) part of this thesis will cover the short- and long-term side effect in NET patients treated with 177Lu-DOTATATE. Particular, toxicity profiles for the kidneys, bone marrow and spleen will be discussed. Prostate and breast cancer also have receptors that can be used for imaging and therapy. In the second part of this thesis we explore a novel Gastrin-releasing Peptide Receptor (GRPR) antagonist 68Ga-SB3 for imaging of prostate and breast cancer

Exploring QA methods for realtime MRI guided radiotherapy

Purpose:The MR-linac is a novel hybrid system that is used in radiotherapy (RT) and combines irradiation with MR imaging. Novel adaptive image-guided radiotherapy techniques are developed for this machine. However, new qualityassurance (QA) techniques are required that check if the (adapted) planned radiation dose is the same as the dose given to the patient. Dose reconstruction, based on the MR-LINACs logfile, can be a new powerful QA tool. Here, we verify logfile based dose reconstruction with the treatment planning system (TPS) dose and Delta4 phantom MR+ on various timescale and discuss its potential as a new QA tool for the MR-LINAC.Method:Software was developed and validated for comparison of the different dose distributions. A patient RT-plan was selected with the intensity modulated RT step-and-shoot technique. The first experiment TPS dose – Logfile was performed at timescales: 1. Total RT-plan 2. Per beam. The second experiment Delta4 – Logfile was performed at timescales: 1. Total RT-plan 2. Per beam 3. Per segment 4. Per 200ms.For analysis, visual comparison, dose profiles, dose difference (DD) and gamma-index (90% of the data) were used.Results:The patient RT-plan had 7 fields and 57 segments. Outcomes of the first experiment were: 1. Total RT-plan: DD = -1.5 to 1.5% and gamma-index (DD=1% &amp; DTA=1mm) of 0.89. 2. Per beam: DD = -3.3 to 2.4% and gamma-index (DD=2% &amp; DTA=2mm) of 0.87.Outcomes of the second experiment were: 1. Total RT-plan: DD of -2.7 to 2.4% and a gamma-index (DD=2% and DTA=2mm) of 0.69. 2. Per beam: maximum DD of -4.7 to 2.5% and gamma-index (DD=2% and DTA=2mm) of 0.99considering all beams. 3. Per segment: maximum DD of -5.9 to 6.0% and gamma-index (DD=3% and DTA=3mm) of 1.0 considering all segments. 4. Per 200ms: the cumulative DD in a high irradiated area was -4.0 to 7.1%, after the2nd segment and -5.2 to 5.3%,. after the 7th segment.Conclusion:Logfile based dose reconstruction might be newest QA tool for the MR-LINAC. Accuracies meet current accepted criteria for IMRT treatment plans considering the total RT-plan and per beam timescale. Smaller timescales have a slightly higher error and require further optimization

Two functionally distinct Axin-like proteins regulate canonical Wnt signaling in C. elegans

Axin is a central component of the canonical Wnt signaling pathway that interacts with the adenomatous polyposis coli protein APC and the kinase GSK3β to downregulate the effector β-catenin. In the nematode Caenorhabditis elegans, canonical Wnt signaling is negatively regulated by the highly divergent Axin ortholog PRY-1. Mutation of pry-1 leads to constitutive activation of BAR-1/β-catenin-dependent Wnt signaling and results in a range of developmental defects. The pry-1 null phenotype is however not fully penetrant, indicating that additional factors may partially compensate for PRY-1 function. Here, we report the cloning and functional analysis of a second Axin-like protein, which we named AXL-1. We show that despite considerable sequence divergence with PRY-1 and other Axin family members, AXL-1 is a functional Axin ortholog. AXL-1 functions redundantly with PRY-1 in negatively regulating BAR-1/β-catenin signaling in the developing vulva and the Q neuroblast lineage. In addition, AXL-1 functions independently of PRY-1 in negatively regulating canonical Wnt signaling during excretory cell development. In contrast to vertebrate Axin and the related protein Conductin, AXL-1 and PRY-1 are not functionally equivalent. We conclude that Axin function in C. elegans is divided over two different Axin orthologs that have specific functions in negatively regulating canonical Wnt signaling