Publications by authors named "Richard P Baum"

150 Publications

A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms.

Int J Med Sci 2021 19;18(10):2166-2175. Epub 2021 Mar 19.

CURANOSTICUM Wiesbaden-Frankfurt at DKD Helios Klinik, Wiesbaden, Germany.

Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on Ga somatostatin analogue PET/CT, eligible for surgery, and Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Surgery combined with Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
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http://dx.doi.org/10.7150/ijms.51740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040427PMC
March 2021

Symptom Diaries of Patients with Midgut Neuroendocrine Tumors Treated with Lu-DOTATATE.

J Nucl Med 2021 Mar 26. Epub 2021 Mar 26.

Cyclotron Rotterdam BV, Erasmus University Medical Center, Netherlands.

We report the impact of Lu DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors (NETs) often find burdensome. All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial (Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], = 117; high-dose octreotide LAR, = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Patients (intent-to-treat) who received Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 days per 4 weeks, respectively, compared with 0.99, 1.44, and 2.54 days for high-dose octreotide LAR. The mean differences were 3.11 days (95% confidence interval, 1.35-4.88; = 0.0007) for abdominal pain, 3.11 days (1.18-5.04; = 0.0017) for diarrhea, and 1.98 days (0.08-3.88; = 0.0413) for flushing, favoring Lu-DOTATATE. A positive repeated measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. In addition to efficacy and quality of life benefits, symptom diaries from NETTER-1 demonstrated that treatment with Lu DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut NETs, compared with high-dose octreotide LAR, supporting a beneficial effect of Lu DOTATATE on HRQoL.
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http://dx.doi.org/10.2967/jnumed.120.258897DOI Listing
March 2021

First-in-human study of novel SSTR antagonist Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: dosimetry, safety and efficacy.

J Nucl Med 2021 Mar 5. Epub 2021 Mar 5.

Department of Nuclear Medicine, Medical Center, University Hospital of Freiburg, Germany.

The objective of this study was to assess the safety, dosimetry, and efficacy of the Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo (D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Fifty-one patients (age 27-76, mean 51.6±13.9 years) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1±0.88 GBq (range 2.8-7.4 GBq). Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed in 11 patients and compared with the SSTR agonist Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Higher uptake and a longer effective half-life of Lu-DOTA-LM3 was found for whole-body as well as kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses as compared to the agonist Lu-DOTA-TOC. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was CTC-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of 47 patients monitored after Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 (14.9%) patients had progressive disease, and by EORTC criteria, complete remission in 2 (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%) patients. "Antagonist PRRT" with Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by the majority of patients, with thrombocytopenia occurring only in a few patients. No other severe adverse effects were observed, particularly no nephrotoxicity. The SSTR antagonist Lu-DOTA-LM3 appears to be very promising for PRRT, provides favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was very effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.
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http://dx.doi.org/10.2967/jnumed.120.258889DOI Listing
March 2021

First-in-Human Application of Terbium-161: A Feasibility Study Using Tb-DOTATOC.

J Nucl Med 2021 Feb 5. Epub 2021 Feb 5.

Center for Radiopharmaceutical Science PSI/ETHZ/USZ Paul Scherrer Institute, Switzerland.

Tb has similar decay properties as Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply Tb in a clinical setting and to investigate the feasibility to visualize the physiological and tumor biodistribution of Tb-DOTATOC. Tb was shipped from Paul Scherrer Institute, Switzerland, to Zentralklinik Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In two separate studies, 596 MBq and 1300 MBq Tb-DOTATOC were administered to a 35-year-old male patient with metastatic, well differentiated, non-functional malignant paraganglioma and a 70-year-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphies were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed, using a recently-established protocol and visually analyzed. Patients were checked for adverse events after application of Tb-DOTATOC. The radiolabeling of DOTATOC with Tb was readily achieved with high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of Tb-DOTATOC in liver, kidneys, spleen and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in the liver and bones. Application of Tb-DOTATOC was well tolerated and no related adverse events were reported. This study demonstrated the feasibility to image even small metastases after injection of relatively low activities of Tb-DOTATOC using γ-scintigraphy and SPECT. Based on this essential first step to translate Tb to clinics, further efforts will be directed towards the application of Tb for therapeutic purposes.
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http://dx.doi.org/10.2967/jnumed.120.258376DOI Listing
February 2021

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo.

Neoplasia 2021 01 25;23(1):80-98. Epub 2020 Nov 25.

Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Department of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib.

Methods And Results: In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone.

Conclusions: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
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http://dx.doi.org/10.1016/j.neo.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701025PMC
January 2021

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany.

Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.
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http://dx.doi.org/10.3390/cancers12113448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699546PMC
November 2020

Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy.

Lancet Oncol 2020 09;21(9):e431-e443

Department of Surgery, Yale University School of Medicine, Yale University, New Haven, CT, USA.

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.
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http://dx.doi.org/10.1016/S1470-2045(20)30323-5DOI Listing
September 2020

Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

Eur J Nucl Med Mol Imaging 2021 Jan 8;48(1):113-122. Epub 2020 May 8.

Department of Nuclear Medicine, Medical University Innsbruck, Innsbruck, Austria.

Introduction: The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with Lu-PSMA-617.

Materials And Methods: The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated.

Results: The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS.

Conclusion: In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.
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http://dx.doi.org/10.1007/s00259-020-04797-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835179PMC
January 2021

Metastatic extent predicts survival as patients with metastatic castration-resistant prostate cancer are treated with Lu-PSMA radioligand therapy.

Theranostics 2020 30;10(11):4900-4902. Epub 2020 Mar 30.

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Bad Berka, Germany.

PSMA based radioligand is a new investigational drug for treatment of metastatic multidrug-resistant and castration-resistant prostate cancer. Prognostic factors point to above and below average overall survival (OS) after the treatment. Kessel et al. [Theranostics 2019;9:4841-8] reported for the first time that two sites of visceral metastases, lungs and liver, differed in impact on OS after treatment with Lu PSMA 617. Treatment with established drugs showed the same trend. The difference in OS between the sites is independent of the type of treatment and can reflect changes in tumor biology during the progression of metastatic prostate cancer.
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http://dx.doi.org/10.7150/thno.44568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163457PMC
April 2021

177Lu-DOTATOC Peptide Receptor Radionuclide Therapy in a Patient With Neuroendocrine Breast Carcinoma and Breast Invasive Ductal Carcinoma.

Clin Nucl Med 2020 May;45(5):e232-e235

Theranostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

Radiolabeled somatostatin analogs for somatostatin receptor (SSTR)-targeted imaging and peptide receptor radionuclide therapy (PRRT) have demonstrated remarkable success in the management of SSTR-expressing neuroendocrine neoplasms. Primary neuroendocrine breast carcinoma is rare. Heterogeneous SSTR overexpression has also been documented in breast cancer, in both human breast cancer specimens and clinical studies. We report here a case of a 69-year-old woman who had both breast invasive ductal carcinoma and primary large-cell neuroendocrine breast carcinoma (Ki-67 proliferation index of 20%), with disseminated bone and lymph node metastases, demonstrating exceptional tracer uptake on Ga-DOTATOC PET/CT, and remarkably partial remission after Lu-DOTATOC PRRT.
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http://dx.doi.org/10.1097/RLU.0000000000003005DOI Listing
May 2020

Prognostic Value of F-FDG PET/CT in a Large Cohort of Patients with Advanced Metastatic Neuroendocrine Neoplasms Treated with Peptide Receptor Radionuclide Therapy.

J Nucl Med 2020 11 13;61(11):1560-1569. Epub 2020 Mar 13.

Theranostics Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany.

The objective of this retrospective study was to determine the role of F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. The 495 patients were treated with Lu- or Y-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-DOTATOC/TATE/NOC and F-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. F-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive F-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; = 0.0015) and OS (53.2 mo vs. 83.1 mo; < 0.001) than negative F-FDG results. Among the cases of pancreatic NENs, the median OS was 52.8 mo in F-FDG-positive subjects and 114.3 mo in F-FDG-negative subjects ( = 0.0006). For all patients positive for F-FDG uptake, and a ratio of more than 2 for the highest SUV on Ga-somatostatin receptor (SSTR) PET to the most F-FDG-avid tumor lesions, the median OS was 53.0 mo, compared with 43.4 mo in those patients with a ratio of less than 2 ( = 0.030). For patients with no F-FDG uptake (complete mismatch imaging pattern), the median OS was 108.3 mo versus 76.9 mo for an SUV of more than 15.0 and an SUV of 15.0 or less on Ga-SSTR PET/CT, respectively. The presence of positive lesions on F-FDG PET is an independent prognostic factor in patients with NENs treated with PRRT. Metabolic imaging with F-FDG PET/CT complements the molecular imaging aspect of Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative F-FDG PET/CT results is associated with the most favorable long-term prognosis.
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http://dx.doi.org/10.2967/jnumed.119.241414DOI Listing
November 2020

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with Lu-Dotatate: an analysis of the NETTER-1 study.

Eur J Nucl Med Mol Imaging 2020 09 2;47(10):2372-2382. Epub 2020 Mar 2.

Department of Nuclear Medicine, Hôpital de la Timone, Marseille, France.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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http://dx.doi.org/10.1007/s00259-020-04709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396396PMC
September 2020

Peptide Receptor Radionuclide Therapy Using 225Ac-DOTATOC Achieves Partial Remission in a Patient With Progressive Neuroendocrine Liver Metastases After Repeated β-Emitter Peptide Receptor Radionuclide Therapy.

Clin Nucl Med 2020 Mar;45(3):241-243

From the THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

We present here a case with β-radiation-refractory metastatic neuroendocrine tumors, who demonstrated an excellent therapy response after 1 cycle of Ac-DOTATOC, without any significant adverse effects even after 10 cycles of β-emitter peptide receptor radionuclide therapy followed by α-peptide receptor radionuclide therapy.
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http://dx.doi.org/10.1097/RLU.0000000000002915DOI Listing
March 2020

Successful Intra-arterial Peptide Receptor Radionuclide Therapy of DOTATOC-Negative High-Grade Liver Metastases of a Pancreatic Neuroendocrine Neoplasm Using 177Lu-DOTA-LM3: A Somatostatin Receptor Antagonist.

Clin Nucl Med 2020 Mar;45(3):e165-e168

From the THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

Radiolabeled somatostatin receptor (SSTR) antagonists have shown promise for imaging neuroendocrine neoplasms and the superiority to SSTR agonists, with lower liver background especially for the sensitive detection of liver metastases, higher tumor-to-background ratio, and favorable pharmacokinetics. The clinical data of radiolabeled SSTR antagonists for therapy are still limited. We report our experience treating a young patient with DOTATOC-negative high-grade liver metastases of a pancreatic neuroendocrine neoplasm who underwent intra-arterial peptide receptor radionuclide therapy using SSTR antagonist Lu-DOTA-LM3, demonstrating an excellent response, nearly complete remission according to molecular imaging criteria and morphological partial remission, without any significant toxicity.
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http://dx.doi.org/10.1097/RLU.0000000000002906DOI Listing
March 2020

Twelve-Year Survival of a Patient With Lymph Node, Pulmonary, Bone, Cardiac and Intraspinal Metastases of a Rectal Neuroendocrine Neoplasm Treated With Peptide Receptor Radionuclide Therapy-The Value of Salvage Peptide Receptor Radionuclide Therapy.

Clin Nucl Med 2020 Apr;45(4):e198-e200

From the THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

We report here the 12-year survival after the first peptide receptor radionuclide therapy (PRRT) of a patient with metastatic rectal neuroendocrine neoplasms, who received 7 cycles of PRRT with Lu/Y-DOTATATE/DOTATOC in 4 treatment phases. The patient demonstrated excellent response to each cycle of treatment, without any adverse effect even after repeated PRRT cycles. Most recently, immunohistochemistry revealed a G3 neuroendocrine neoplasm and intraspinal metastasis were successfully resected by neurosurgical intervention. This case nicely demonstrates that several "salvage" PRRTs can be given over many years leading to repetitive benefit for the patient and saving patients of possible toxicity of alternative treatments.
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http://dx.doi.org/10.1097/RLU.0000000000002905DOI Listing
April 2020

PRRT neuroendocrine tumor response monitored using circulating transcript analysis: the NETest.

Eur J Nucl Med Mol Imaging 2020 04 14;47(4):895-906. Epub 2019 Dec 14.

LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka, 54 Portland Place, London, W1B1DY, UK.

Purpose: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction.

Methods: Three independent Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics.

Results: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS).

Conclusions: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.
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http://dx.doi.org/10.1007/s00259-019-04601-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515632PMC
April 2020

Ectopic Corticotropin-Releasing Hormone-Secreting Pancreatic Neuroendocrine Tumor: Excellent Response of Liver Metastases to Peptide Receptor Radionuclide Therapy as Demonstrated by 68Ga-DOTATOC and 18F-FDG PET/CT Imaging.

Clin Nucl Med 2020 Feb;45(2):e125-e127

From the Theranostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

Ectopic Cushing syndrome secondary to corticotropin releasing hormone (CRH)-secreting tumors or CRH and adrenocorticotropin hormone cosecreting tumors is extremely rare. We report here the case of a 54-year-old man who experienced CRH-secreting pancreatic neuroendocrine tumor causing Cushing syndrome, initially detected by SSTR (somatostatin receptor) scintigraphy, then significantly progressed with multiple liver metastases, demonstrating significantly increased SSTR expression on Ga-DOTATOC PET/CT and a "mismatch" imaging pattern on F-FDG PET/CT. The patient underwent peptide receptor radionuclide therapy with Lu/Y-DOTATOC and demonstrated excellent response to the treatment.
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http://dx.doi.org/10.1097/RLU.0000000000002834DOI Listing
February 2020

Metastatic Nasopharyngeal Carcinoma Treated With Intraarterial Combined With Intravenous Peptide Receptor Radionuclide Therapy.

Clin Nucl Med 2019 Dec;44(12):989-990

From the Theranostics Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Germany.

Nasopharyngeal carcinoma may express somatostatin receptors (SSTR). We present a case with metastatic nasopharyngeal carcinoma in the liver, bone, and lymph nodes. The patient was in progression after chemotherapy, external beam radiation therapy (ERBT), atezolizumab, and cetuximab. Due to strong SSTR expression of the metastases, PRRT was applied. After 3 cycles of intravenous Lu-DOTATOC and 1 cycle of intraarterial Y-DOTATOC therapy, the hepatic and bone metastases showed excellent response after PRRT. No nephrotoxicity or myelotoxicity was observed.
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http://dx.doi.org/10.1097/RLU.0000000000002788DOI Listing
December 2019

Excellent Response to 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in a Patient With Progressive Metastatic Castration-Resistant Prostate Cancer With Neuroendocrine Differentiation After 177Lu-PSMA Therapy.

Clin Nucl Med 2019 Nov;44(11):876-878

From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China.

Prostate cancer with neuroendocrine differentiation is associated with a poor prognosis, rapid disease progression, and treatment resistance, and constitutes a diagnostic and therapeutic dilemma. We present images of Lu-DOTATATE scan and Ga-DOTATATE PET/CT scan conducted on a 65-year-old man with prostate cancer with neuroendocrine differentiation, whose disease progressed despite conventional treatment and Lu-PSMA radioligand therapy; however, an extraordinary radiographic tumor remission, biochemical response, and improvement of clinical symptoms were observed after the patient underwent Lu-DOTATATE peptide receptor radionuclide therapy.
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http://dx.doi.org/10.1097/RLU.0000000000002780DOI Listing
November 2019

Neuroendocrine Neoplasms of the Small Bowel and Pancreas.

Neuroendocrinology 2020 27;110(6):444-476. Epub 2019 Sep 27.

Department of Surgery and Cancer, Imperial College London, London, United Kingdom,

The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.
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http://dx.doi.org/10.1159/000503721DOI Listing
September 2019

From Bench to Bedside-The Bad Berka Experience With First-in-Human Studies.

Semin Nucl Med 2019 09 6;49(5):422-437. Epub 2019 Jul 6.

THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany. Electronic address:

Precision oncology is being driven by rapid advances in novel diagnostics and therapeutic interventions, with treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in the theranostics paradigm is the assumption that diagnostic test results can precisely determine whether an individual is likely to benefit from a specific treatment. As part and integral in the current era of precision oncology, theranostics in the context of nuclear medicine aims to identify the appropriate molecular targets in neoplasms (diagnostic tool), so that the optimal ligands and radionuclides (therapeutic tool) with favorable labeling chemistry can be selected for personalized management of a specific disease, taking into consideration the specific patient, and subsequently monitor treatment response. Over the past two decades, the use of gallium-68 labeled peptides for somatostatin receptor (SSTR)-targeted PET/CT (or PET/MRI) imaging followed by lutetium-177 and yttrium-90 labeled SSTR-agonist for peptide receptor radionuclide therapy has demonstrated remarkable success in the management of neuroendocrine neoplasms, and paved the way to other indications of theranostics. Rapid advances are being made in the development of other peptide-based radiopharmaceuticals, small molecular-weight ligands and with newer radioisotopes with more favorable kinetics, potentially useful for theranostics strategies for the clinical application. The present review features the Bad Berka experience with first-in-human studies of new radiopharmaceuticals, for example, prostate-specific membrane antigen ligand, gastrin-releasing peptide receptor, neurotensin receptor 1 ligand, novel SSTR-targeting peptides and nonpeptide, and bone-seeking radiopharmaceuticals. Also new radioisotopes, for example, actinium (Ac), copper (Cu), scandium (Sc), and terbium (Tb/Tb) will be discussed briefly demonstrating the development from basic science to precision oncology in the clinical setting.
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http://dx.doi.org/10.1053/j.semnuclmed.2019.06.002DOI Listing
September 2019

Preclinical investigations and first-in-human application of Tb-PSMA-617 for PET/CT imaging of prostate cancer.

EJNMMI Res 2019 Jul 25;9(1):68. Epub 2019 Jul 25.

Theranostics Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Robert-Koch-Allee 9, 99437, Bad Berka, Germany.

Background: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: Tb and Tb are the radioisotopes identified for PET or SPECT imaging, while Tb and Tb have suitable decay characteristics for α- and combined β/Auger-e-therapy, respectively. In the present study, the application of Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC).

Results: Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by Ga-PSMA-11 PET/CT acquired 45 min p.i.

Conclusions: The results of this study demonstrate the successful preparation and preclinical testing of Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly Tb, which has promising decay characteristics for an effective treatment of mCRPC patients.
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http://dx.doi.org/10.1186/s13550-019-0538-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658632PMC
July 2019

Complete Regression of Lung Metastases in a Patient With Metastatic Castration-Resistant Prostate Cancer Using 177Lu-PSMA Radioligand Therapy.

Clin Nucl Med 2020 Jan;45(1):e48-e50

From the Theranostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany.

Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral (liver or lung) metastases have a poor prognosis and worse outcomes than those with bone disease with or without lymph nodes involvement. The high prostate-specific membrane antigen expression in prostate cancer metastases makes it a promising approach for targeted radionuclide therapy of prostate cancer. Lutetium-177 (Lu)-labeled prostate-specific membrane antigen radioligand therapy (Lu-PRLT) has demonstrated encouraging efficacy in mCRPC. We report here an mCRPC patient with lung, lymph nodes, and extensive bone metastases, who underwent Lu-PRLT and had excellent response to the treatment and complete regression of lung metastases after Lu-PRLT.
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http://dx.doi.org/10.1097/RLU.0000000000002655DOI Listing
January 2020

Instant kit preparation of Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [Ga]Ga-DATA-TOC.

EJNMMI Res 2019 May 23;9(1):48. Epub 2019 May 23.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany.

Purpose: The widespread use of Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr]octreotide (TOC), a somatostatin subtype 2 receptor (SST)-targeting vector for imaging and functional characterisation of SSTR expressing tumours.

Methods: The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex Ga(III) and Ga(III). Competition binding assays of [Ga]Ga-DATA-TOC or [Ga]Ga-DOTA-TOC against [I-Tyr]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST receptor subtypes (HEK293-hSST cells). First in vivo studies were performed in female NMRI-nude mice bearing SST-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST-specific tumour-targeting of [Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [Ga]Ga-DOTA-TOC reference. A direct comparison of [Ga]Ga-DATA-TOC with the well-established PET radiotracer [Ga]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [Ga]Ga-DATA-TOC.

Results: DATA-TOC was labelled with Ga with a radiolabelling efficiency of > 95% in less than 10 min at ambient temperature. A molar activity up to 35 MBq/nmol was achieved. The hSST-affinities of [Ga]Ga-DATA-TOC and [Ga]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC values. In mice, [Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two Ga-radiotracers, but with a higher tumour-to-liver contrast for [Ga]Ga-DATA-TOC.

Conclusion: [Ga]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [Ga]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of Ga-radiotracers in a routine clinical radiopharmacy setting.
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http://dx.doi.org/10.1186/s13550-019-0516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533321PMC
May 2019

Semiquantitative Parameters in PSMA-Targeted PET Imaging with [F]DCFPyL: Intrapatient and Interpatient Variability of Normal Organ Uptake.

Mol Imaging Biol 2020 02;22(1):181-189

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has impacted the management of patients with prostate cancer (PCa) in many parts of the world. PSMA-targeted endoradiotherapies are also being increasingly utilized and for these applications, the radiopharmaceutical distribution in normal organs is particularly important because it may limit the dose that can be delivered to tumors. In this study, we measured both interpatient and intrapatient variability of [F]DCFPyL uptake in the most relevant normal organs.

Procedures: Baseline and 6-month follow-up PSMA-targeted [F]DCFPyL PET/computed tomography (CT) scans from 39 patients with PCa were reviewed. Volumes of interest were manually drawn using the best visual approximation of the organ edge for both lacrimal glands, all four major salivary glands, the liver, the spleen, and both kidneys for all patients. The average SUV, the COVs, and intraclass correlation coefficients (ICCs) across scans were calculated. Bland-Altman analyses were performed for all organs to derive repeatability coefficients (RCs).

Results: The liver demonstrated the lowest interpatient variability (13.0 and 16.6 % at baseline and follow-up, respectively), while the spleen demonstrated the largest interpatient variability (44.6 and 51.0 % at baseline and follow-up, respectively). The lowest intrapatient variability was found in the spleen (ICC 0.86) while the highest intrapatient variability was in the kidneys (ICCs 0.40-0.50). Bland-Altman analyses showed 95 % repeatability coefficients for mean uptake > 40 % for multiple organs and were highest for the lacrimal glands, kidneys, and spleen.

Conclusions: Normal organs demonstrate significant variability in uptake of the PSMA-targeted radiotracer [F]DCFPyL. Depending on the organ, different contributions of interpatient and intrapatient factors affect the intrinsic variability. The RCs also vary significantly among the different organs were highest for the lacrimal glands, kidneys, and spleen. These findings may have important implications for the design of clinical protocols and personalized dosimetry for PSMA-targeted endoradiotherapies.
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http://dx.doi.org/10.1007/s11307-019-01376-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955793PMC
February 2020

Efficacy of Detoxsan powder on diarrhea caused by gastrointestinal neuroendocrine tumors.

World J Gastroenterol 2019 May;25(17):2133-2143

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Bad Berka D-99437, Germany.

Background: Patients with neuroendocrine tumors (NETs) of the gastrointestinal tract suffer frequently from chronic diarrhea. A well characterized medical advice containing zeolite (Detoxsan powder) was applied to patients suffered from therapy-refractory diarrhea either by its frequency or by watery stool, despite receiving standard pharmacotherapy according to the guidelines for carcinoid syndrome and comorbidities. Detoxsan powder acts as an adsorbent and might reduce significantly symptoms of diarrhea in patients suffering from NETs.

Aim: To overcome the therapy-refractory diarrhea of patients with NETs by the zeolite containing medical advice Detoxsan powder.

Methods: A total of 20 patients (12 female and 8 male) suffering from diarrhea either by its frequency or from watery stool caused by NETs were included. In each patient, the diagnosis had been confirmed by histology and somatostatin receptors expression proven by positron emission tomography/computed tomography using Ga-68-labeled somatostatin analogs. All patients received standard-of-care pharmacotherapy and were additionally given Detoxsan powder as an extemporaneous drug containing 90% natural Cuban zeolite and 10% magnesium aspartate. Recommended daily dosage ranges between 3 g once to three times per day. Each day dose and bowel movements were documented by the patients themselves in a pre-defined table. Additionally to the bowel movements quantitative determinations of serotonin, urea, creatinine and single ions were performed within the serum of the patients by commercially available equipment used as a matter of routine in the clinic.

Results: All patients enrolled in this pilot study did not only suffer from NETs, but also from comorbidities and treatment-resistant diarrhea. There was insufficient control of diarrhea, most probably due to the secretion of hormones like serotonin produced by the slowly growing and highly differentiated NETs. All patients only took Detoxsan powder as an antidiarrheal drug. In general, response effects need several days to become perceptible and require an intake of Detoxsan powder for an extended time period or intermittently, if persisting stabilization of bowel movements could not be achieved. A correlation between NET grade, part and size of bowel resection and functionality of the tumor could not be demonstrated. Therefore, diarrhea seemed to be based on the metabolic activity of the well-differentiated NETs, which eventually led to treatment resistance. In summary, 14 out of the 20 patients (70%) declared to be very content with using Detoxsan powder and observed a significant reduction of diarrhea, while the effective dose and intake period that resulted in a symptom relief varied individually.

Conclusion: Detoxsan powder is able to reduce significantly symptoms of NET-related diarrhea in the majority of patients. The duration of taking Detoxsan powder and its dosage vary individually.
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http://dx.doi.org/10.3748/wjg.v25.i17.2133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506581PMC
May 2019

Prostate-Specific Membrane Antigen Accumulation in Lower Extremity Lymphedema.

Clin Nucl Med 2019 Jun;44(6):501-503

From the THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Bad Berka, Germany.

Prostate-specific membrane antigen (PSMA) is overexpressed in a majority of prostate cancer cells, which has led to the development of radiolabeled small-molecule inhibitors of PSMA for molecular imaging and targeted radioligand therapy. Lu-labeled PSMA, with therapeutic β-emission and concomitant γ radiation, permits posttherapy imaging for the assessment of biodistribution and uptake in tumors and normal organs, as well as dosimetry. We report a patient with prostate cancer and metastatic lymph nodes-related lower extremity lymphedema, who presented with dermal backflow and soft-tissue uptake in the lower extremity on posttherapeutic whole body scan after intravenous Lu-PSMA treatment.
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http://dx.doi.org/10.1097/RLU.0000000000002552DOI Listing
June 2019

Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin.

Sci Rep 2019 03 13;9(1):4339. Epub 2019 Mar 13.

Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.

Somatostatin receptors (SST), especially SST2A, are known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. However, comprehensive data are still lacking on potential differences in SST or CXCR4 expression pattern in GEP-NEN in dependence on the place of origin. Overall, 412 samples from 165 GEP-NEN patients, comprising both primary tumors (PT) and metastases (MTS), originating from different parts of the gastrointestinal tract or the pancreas were evaluated for SST and CXCR4 expression by means of immunohistochemistry using monoclonal antibodies. SST2A was present in 85% of PT with a high intensity of expression, followed by SST5 (23%), CXCR4 (21%), SST3 (10%), SST1 (9%), and SST4 (4%). PT displayed higher SST2A and chromogranin A (CgA) expression levels than MTS. In both PT and MTS lower SST2A and CgA expression levels were found in tumors originating from the appendix or colon, compared to tumors from other origins. Tumors derived from appendix or colon were associated with significantly worse patient outcomes. Positive correlations were noted between SST2A and CgA as well as between CXCR4 and Ki-67 expression levels. SST2A and CgA negativity of the tumors was significantly associated with poor patient outcomes. All in all, SST2A was the most prominent receptor expressed in the GEP-NEN samples investigated. However, expression levels varied considerably depending on the location of the primary tumor.
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http://dx.doi.org/10.1038/s41598-019-39607-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416272PMC
March 2019

Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients with a Single Functioning Kidney.

J Nucl Med 2019 11 8;60(11):1579-1586. Epub 2019 Mar 8.

Theranostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany; and

The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) using Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Sixteen patients (aged 53-78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using Tc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment ( > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). In patients with a single functioning kidney, Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.
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http://dx.doi.org/10.2967/jnumed.118.223149DOI Listing
November 2019

Parameters to Predict Progression-Free and Overall Survival After Peptide Receptor Radionuclide Therapy: A Multivariate Analysis in 782 Patients.

J Nucl Med 2019 09 8;60(9):1259-1265. Epub 2019 Mar 8.

Theranostics Centre for Molecular Radiotherapy and Precision Oncology, ENETS Centre of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany; and.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for patients with neuroendocrine neoplasms. The aim of this study was to identify clinical and treatment parameters associated with progression-free survival (PFS) and overall survival (OS). All patients treated from October 2002 until March 2016 at the Zentralklinik Bad Berka with at least 3 administrations of PRRT (maximal interval of 6 mo between consecutive administrations) were included. Data were collected in 5 categories: general patient characteristics, tumor characteristics, prior treatments, radioisotope used for PRRT, and blood chemistry. Survival was analyzed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. In total, 782 patients were included, with a median follow-up of 36 mo. The median PFS and OS were 22 and 53 mo, respectively. Parameters associated with lower PFS in the multivariate analysis were a Ki-67 of more than 5%, previous treatment with interferon-α and chemotherapy, presence of diabetes, and chromogranin-A (CgA) levels higher than 336 μg/L. Parameters associated with lower OS were a Ki-67 of more than 10%, performance status of at least 1, previous chemotherapy and ablation, and CgA levels higher than 112 μg/L. Higher Ki-67 values, as well as higher CgA levels and previous chemotherapy, had a negative outcome on both PFS and OS. Furthermore, PFS was negatively associated with previous interferon-α treatment and diabetes, whereas lower OS was related to prior ablation and higher performance status.
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http://dx.doi.org/10.2967/jnumed.118.224386DOI Listing
September 2019