[en] Neuroendocrine tumors (NET) of the pancreas are rare entities. Functioning tumors tend to present early with specific symptoms and typical abnormalities in laboratory values. In contrast, non-functioning NET are often diagnosed with delay and become evident by tumor-related symptoms like pain, weight-loss or jaundice. The role of imaging is to localize and delineate the primary tumor and to detect metastases. In the diagnosis of NET radiologic techniques like computed tomography (CT) and magnetic resonance imaging (MRI) are applied. In certain cases nuclear medicine techniques like somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) using radioactively labelled somatostatin analogues are used. The present article reviews characteristic imaging findings of both functioning and non-functioning NET of the pancreas. (orig.)

[en] Neuroendocrine tumors (neuroendokrine Tumoren) are rare entities. They can be found in all organs and show substantial biologic heterogeneity depending on involved organ, clinical symptoms and histopathologic morphology. Involvement of organs like larynx, cervix uteri, ovary, gallbladder, liver or kidney is extensively rare. The majority of neuroendokrine Tumoren are found in gastrointestinal tract and lung and are classified as neuroendokrine Tumoren of foregut (stomach, duodenum, pancreas, lung), midgut (jejunum, ileum, appendix, right side of the colon) and hindgut (left side of the colon, rectum). The role of imaging is to localize and delineate the primary tumor and to detect metastases. In the diagnosis of neuroendokrine Tumoren radiologic techniques like computed tomography (CT) and magnetic resonance imaging (MRI) are applied. In certain cases nuclear medicine techniques like somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) using radioactively labelled somatostatin analogues are used. The present article reviews characteristic imaging findings of neuroendokrine Tumoren of the gastrointestinal tract. (orig.)

[en] Data are sparse regarding the feasibility of radioligand therapy (RLT) with [${}^{177}$Lu]Lu-PSMA-617 as a retreatment. We aimed to assess the outcome and safety of rechallenge PSMA-RLT in patients with progressive prostatic cancer who previously benefited from this therapy. Patients who received rechallenge therapy at our department from January 2015 to March 2018 were assessed. Non-haematological and haematological adverse events were evaluated from laboratory data and clinical reports and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Time to prostate-specific-antigen (PSA) progression and the overall survival (OS) rate of the study patients were calculated from the date of the first rechallenge cycle. Furthermore, the OS calculated from the first cycle baseline PSMA-RLT was compared with the survival of patients who received only baseline PSMA-RLT. The response data were determined using [${}^{68}$Ga]Ga-PSMA-PET/CT and measurements of the tumour marker PSA. Included in this retrospective study were 30 patients who were initially treated with a median of 3 cycles (range 1–5) of PSMA-RLT and were eventually retreated after a median of 6 months (range 2–26). Each patient received a median of 3 (range 1–6) rechallenge cycles. None of the patients experienced a disabling or life-threatening grade 4 adverse event according to the Common Toxicity Criteria (CTC). Grade 3 toxicity occurred in 8 patients (27%). Serious adverse events included leucopoenia (n = 2), neutropoenia (n = 1), anaemia (n = 4), thrombopenia (n = 4) and elevated renal parameters (n = 1). Irreversible adverse events occurred in 21 patients (70%). The permanent adverse events were mild/moderate (CTC grade 1/2) in 19 patients and serious (CTC grade 3) in two patients, respectively. According to PSA measurements, 75–90% of patients showed a benefit (response/stable) from the first 4 rechallenge cycles. The median OS was 12 months calculated from the first rechallenge cycle and 25 months calculated from the first cycle baseline PSMA-RLT. For comparison, the median OS in patients who received only baseline PSMA-RLT was 9 months. The difference according to the logrank test was significant: p value <0.001. Patients with a PSA decrease after the first cycle of rechallenge PSMA-RLT survived a median of 19 months, while patients with a PSA increase survived only 6 months. Rechallenge prostate-specific membrane antigen (PSMA) therapy has an acceptable safety profile. The majority of the retreated patients benefited from the rechallenge therapy. Patients who showed a biochemical response achieved a longer OS compared to patients who did not respond. The median OS was significantly longer in patients after rechallenge PSMA-RLT than in patients who received only baseline PSMA-RLT.

[en] The uptake of ⁶⁸Ga PSMA in neo vasculature of breast cancer highest in triple negative tumor encourages therapeutic use of (¹⁷⁷Lu)Lu PSMA analogues. In this study, we evaluated the biodistribution and tumor lesion radiation absorbed doses in a breast carcinoma patient with therapeutic dose of (¹⁷⁷Lu)Lu PSMA-617. Female breast carcinoma patient 38 years and 68 kg weight was treated with 6,520 MBq of (¹⁷⁷Lu)Lu PSMA-617. Biodistribution was assessed with serial planar whole-body scintigraphy at 20 minutes, 1, 4, 24, and 48 hours and postinjection (p.i.) on day 8. Time activity curve for percentage injected activity in local breast lesion was determined. OLINDA/EXM software was used to determine residence times by applying biexponential curve fitting and using unit sphere model for radiation absorbed dose calculation in breast lesion. Immediate accumulation of (¹⁷⁷Lu)Lu PSMA-617 was seen in kidneys, urinary bladder, liver, and breast tumor lesion along with blood pool activity in heart and major blood vessels. Later activity increased in salivary, lacrimal glands, kidneys, urinary bladder, liver, small intestine, and breast tumor till 48 hours followed by clearance from breast lesion and other organs except small intestine till p.i. on day 8. Tumor absorbed dose to tumor tissue was found to be 0.333 mSv/MBq and a total of 2.08 Gy from 6.25 GBq of (¹⁷⁷Lu)Lu PSMA-617. Biodistribution of (¹⁷⁷Lu)Lu PSMA-617 was similar to mCRPC patients. However, tumor absorbed doses are found to be very low and does not support use of (¹⁷⁷Lu)Lu PSMA-617 for therapy in breast carcinoma patients. (author)

[en] Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with ²²⁵Ac and ²¹³Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of ²²⁵Ac-DOTA-F3 in comparison with that of ²¹³Bi-DTPA-F3. ID₅₀ values of ²¹³Bi-DTPA-F3 and ²²⁵Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. ID₅₀ values of ²¹³Bi-DTPA-F3 and ²²⁵Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 x 10⁷ MDA-MB-435 cells. Therapy with 6 x 1.85 kBq of ²²⁵Ac-DOTA-F3 or 6 x 1.85 MBq of ²¹³Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived ²¹³Bi (t_1/2 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of ²²⁵Ac-DOTA-F3 (t_1/2 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with ²²⁵Ac-DOTA-F3 (43%) and with ²¹³Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with ²²⁵Ac-DOTA-F3 or ²¹³Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both ²²⁵Ac-DOTA-F3 and ²¹³Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application. (orig.)

[en] 

Objective

Pre-clinical studies with gallium-68 zoledronate ([⁶⁸Ga]Ga-DOTA^ZOL) have proposed it to be a potent bisphosphonate for PET/CT diagnosis of bone diseases and diagnostic counterpart to [¹⁷⁷Lu]Lu-DOTA^ZOL and [²²⁵Ac]Ac-DOTA^ZOL. This study aims to be the first human biodistribution and dosimetric analysis of [⁶⁸Ga]Ga-DOTA^ZOL.

Methods

Five metastatic skeletal disease patients (mean age: 72 years, M: F; 4:1) were injected with 150–190 MBq (4.05–5.14 mCi) of [⁶⁸Ga]Ga-DOTA^ZOL i.v. Biodistribution of [⁶⁸Ga]Ga-DOTA^ZOL was studied with PET/CT initial dynamic imaging for 30 min; list mode over abdomen (reconstructed as six images of 300 s) followed by static (skull to mid-thigh) imaging at 45 min and 2.5 h with Siemens Biograph 2 PET/CT camera. Also, blood samples (8 time points) and urine samples (2 time points) were collected over a period of 2.5 h. Total activity (MBq) in source organs was determined using interview fusion software (MEDISO Medical Imaging Systems, Budapest, Hungary). A blood-based method for bone marrow self-dose determination and a trapezoidal method for urinary bladder contents residence time calculation were used. OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden) was used to generate residence times for source organs, organ absorbed doses and effective doses.

Results

High uptake in skeleton as target organ, kidneys and urinary bladder as organs of excretion and faint uptake in liver, spleen and salivary glands were seen. Qualitative and quantitative analysis supported fast blood clearance, high bone to soft tissue and lesion to normal bone uptake with [⁶⁸Ga]Ga-DOTA^ZOL. Urinary bladder with the highest absorbed dose of 0.368 mSv/MBq presented the critical organ, followed by osteogenic cells, kidneys and red marrow receiving doses of 0.040, 0.031 and 0.027 mSv/MBq, respectively. The mean effective dose was found to be 0.0174 mSv/MBq which results in an effective dose of 2.61 mSv from 150 MBq.

Conclusions

Biodistribution of [⁶⁸Ga]Ga-DOTA^ZOL was comparable to [¹⁸F]NaF, [^99mTc]Tc-MDP and [⁶⁸Ga]Ga-PSMA-617. With proper hydration and diuresis to reduce urinary bladder and kidney absorbed doses, it has clear advantages over [¹⁸F]NaF owing to its onsite, low-cost production and theranostic potential of personalized dosimetry for treatment with [¹⁷⁷Lu]Lu-DOTA^ZOL and [²²⁵Ac]Ac-DOTA^ZOL.

[en] Targeted therapy with α-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the α-emitter ²¹³Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined ²¹³Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either ²¹³Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. Cytotoxicity of treatment with ²¹³Bi-DTPA-F3 and paclitaxel, alone or in combination, was assayed towards OVCAR-3 cells using the alamarBlue assay, the clonogenic assay and flow cytometric analyses of the mode of cell death and cell cycle arrest. Therapeutic efficacy of the different treatment options was assayed after repeated treatment of mice bearing intraperitoneal OVCAR-3 xenograft tumours. Therapy monitoring was performed by bioluminescence imaging and histopathologic analysis. Treatment of OVCAR-3 cells in vitro with combined ²¹³Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either ²¹³Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with ²¹³Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 μg) as demonstrated by bioluminescence imaging and histopathologic investigation of tumour spread on the mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined therapy with ²¹³Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either ²¹³Bi-DTPA-F3 or paclitaxel alone. Combined treatment with ²¹³Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application. (orig.)

[en] The purpose of our study was to show the feasibility and potential benefits of using ⁶⁸Ga-PSMA-PET/CT imaging for radiation therapy treatment planning of patients with primary prostate cancer using either integrated boost on the PET-positive volume or localized treatment of the PET-positive volume. The potential gain of such an approach, the improvement of tumor control, and reduction of the dose to organs-at-risk at the same time was analyzed using the QUANTEC biological model. Twenty-one prostate cancer patients (70 years average) without previous local therapy received ⁶⁸Ga-PSMA-PET/CT imaging. Organs-at-risk and standard prostate target volumes were manually defined on the obtained datasets. A PET active volume (PTV_PET) was segmented with a 40% of the maximum activity uptake in the lesion as threshold followed by manual adaption. Five different treatment plan variations were calculated for each patient. Analysis of derived treatment plans was done according to QUANTEC with in-house developed software. Tumor control probability (TCP) and normal tissue complication probability (NTCP) was calculated for all plan variations. Comparing the conventional plans to the plans with integrated boost and plans just treating the PET-positive tumor volume, we found that TCP increased to (95.2 ± 0.5%) for an integrated boost with 75.6 Gy, (98.1 ± 0.3%) for an integrated boost with 80 Gy, (94.7 ± 0.8%) for treatment of PET-positive volume with 75 Gy, and to (99.4 ± 0.1%) for treating PET-positive volume with 95 Gy (all p < 0.0001). For the integrated boost with 80 Gy, a significant increase of the median NTCP of the rectum was found, for all other plans no statistical significant increase in the NTCP neither of the rectum nor the bladder was found. Our study demonstrates that the use of ⁶⁸Ga-PSMA-PET/CT image information allows for more individualized prostate treatment planning. TCP values of identified active tumor volumes were increased, while rectum and bladder NTCP values either remained the same or were even lower. However, further studies need to clarify the clinical benefit for the patients applying these techniques. (orig.)