ARX, PDX1, ISL1 and CDX2 expression distinguishes five subgroups of PanNETs with correlations to histology, hormone expression and outcome.

Many pancreatic neuroendocrine tumors (PanNETs) fall into two major prognostic subtypes based on DAXX/ATRX induced ALT phenotype and alpha and beta cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well characterized in terms of their histological and hormonal phenotype. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and to investigate their correlation with histological, hormonal molecular and prognostic findings. 185 PanNETs (non-functioning 165, functioning 20) resected between 1996 and 2023 were classified into five subgroups (A1, A2, B, C, D) by cluster analysis based on ARX, PDX1, ISL1 and CDX2 expression and correlated with trabecular vs. solid histology, expression of insulin, glucagon, PP, somatostatin, serotonin, gastrin, calcitonin, ACTH, DAXX/ATRX, MEN1 and ALT status by FISH, and disease-free survival (DFS). A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/ PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin and somatostatin expression (p<0.001). It included all insulinomas and had the best outcome (p<0.01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin und ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin and was an independent poor prognosticator (p<0.01). Differential expression of ARX, PDX1, ISL1 and CDX2 stratified PanNETs into five subgroups with different histology, hormone expression and outcome. Subgroups A1 and A2 resembled the alpha cell-like type, subgroup B the beta cell-like type. Subgroup C with almost a no transcription factor signature was unclear in cell lineage, while the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help to establish the diagnosis, predict the outcome, and guide the treatment.

Impact of a dedicated cardiac protocol on diagnosis of infective endocarditis in patients undergoing [18F]-FDG-thoracic digital-PET/CT - Effects of expertise level.

BACKGROUND: This study aimed to assess the impact of dedicated cardiac protocol (DCP) on diagnostic accuracy of state-of-the-art digital [18F]-FDG-PET/CT in infective endocarditis (IE) and the intra-individual comparison of the performance with that of conventional whole-body approach (WBA) and to analyze the effects of the expertise level of the investigators. METHODS: 44 patients suspected for IE underwent digital-FDG-PET/CT after overnight fasting. Each three consultants and trainees reread PET images blinded to the examination approach and clinical information. Visual and semiquantitative analyses were performed. RESULTS: Digital-FDG-PET/CT with DCP revealed sensitivity, specificity, and accuracy of 89%, 93%, and 91% for native valve endocarditis (NVE) and 93%, 86%, and 91% for prosthetic valve endocarditis. Compared to WBA, substantial improvement of the diagnostic performance for NVE in DCP was evident, especially in trainees, but not as high compared to consultants. Digital-FDG-PET/CT enabled 79.5% reclassification of modified-Duke-Clinical-Criteria (mDC) with 34.1% upgrading and 45.4% downgrading. CONCLUSIONS: This study provides new data using state-of-the-art digital-FDG-PET/CT with DCP improving the diagnostic accuracy in challenging cases of possible IE, particularly in NVE, provided that the investigators involved have the necessary expertise. These findings may have a significant impact on IE-related morbidity, mortality, and patient's management and might be meaningful for updates on the prevailing opinion regarding the value of FDG PET/CT in NVE.

Diagnostic significance of MRI versus CT using identical PET data in patients with recurrent differentiated thyroid cancer: A PET/MRI study.

In this retrospective study we compared magnet resonance imaging (MRI) and computed tomography (CT) each combined with identical 2-deoxy-2-[18F] fluoro-D-glucose or 2-[18F] F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) data in patients with recurrent differentiated thyroid cancer (DTC). In total 42 patients with DTC were examined. All patients underwent FDG PET/MRI and CT, the latter originating from one of the following examinations: I-131 single photon emission computed tomography/CT (32/42), low dose FDG PET/CT (5/42) or diagnostic FDG PET/CT (5/42). Two readers assessed FDG PET/MRI as well as FDG PET/CT, with the latter CT coming from one of the above examinations performed at a maximum temporal interval of 5 days from PET/MRI. Local recurrence, cervical lymph node - and pulmonary metastases were assessed in a consensus read. Lesions rated with a high malignancy score (score 4 or 5) were further analyzed. Every malignant lesion was verified if it was identified by one of both or by both modalities. In 20 of 42 patients altogether 100 malignant lesions were present. In 11/20 patients in total 15 local recurrences (15 in MRI/ 9 in CT: 9 CT/MRI, 6 MRI only, 0 CT only; P = .04) were found with a statistically significant better performance of MRI. Regarding lymph node metastases, in total 13 lesions (12 in MRI/ 8 in CT: 7 CT/MRI, 5 MRI only, 1 CT only; P = .22) in 8/20 patients were found with no significant difference between both modalities. Furthermore, in 9/20 patients in total 72 lung lesions (40 in MRI/ 63 in CT: 31 CT/MRI, 9 MRI only, 32 CT only; P = .001) were found with a statistically significant better performance of CT. In 33/42 patients follow up was available and supported the observations. In patients with recurrent DTC, PET/MRI showed superiority compared to PET/CT in evaluation of the neck region. PET/MRI was inferior to PET/CT in evaluation of the lung. PET/MRI in combination with a low dose CT of the lung may thus represent the ideal staging tool in patients with recurrent DTC.

Bilateral mydriasis as first manifestation of Hodgkin's lymphoma: a case report.

BACKGROUND: Bilateral mydriasis is usually associated with severe brain stem damage or drug-induced sympathomimetic stimulation. Herein we report it as a unique neurologic complication of Hodgkin's lymphoma. CASE PRESENTATION: A 23-year-old woman presented at our emergency department with dilated pupils unresponsive to light stimuli. MRI and CT scans showed bilaterally enlarged lymph nodes in the mediastinum and supraclavicular compressing the carotid artery on both sides. The histologic examination of lymph node biopsy specimens confirmed the diagnosis of Hodgkin's lymphoma. CONCLUSION: Pathologies around the carotid artery causing oculosympathetic spasm should be considered among the possible causes of a mydriasis, especially when other common causes like brain stem impairment are excluded.

Predictive value of clinical and 18F-FDG-PET/CT derived imaging parameters in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma.

Aim of this study was to validate the prognostic impact of clinical parameters and baseline 18F-FDG-PET/CT derived textural features to predict histopathologic response and survival in patients with esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiation (nCRT) and surgery. Between 2005 and 2014, 38 ESCC were treated with nCRT and surgery. For all patients, the 18F-FDG-PET-derived parameters metabolic tumor volume (MTV), SUVmax, contrast and busyness were calculated for the primary tumor using a SUV-threshold of 3. The parameter uniformity was calculated using contrast-enhanced computed tomography. Based on histopathological response to nCRT, patients were classified as good responders (< 10% residual tumor) (R) or non-responders (≥ 10% residual tumor) (NR). Regression analyses were used to analyse the association of clinical parameters and imaging parameters with treatment response and overall survival (OS). Good response to nCRT was seen in 27 patients (71.1%) and non-response was seen in 11 patients (28.9%). Grading was the only parameter predicting response to nCRT (Odds Ratio (OR) = 0.188, 95% CI: 0.040-0.883; p = 0.034). No association with histopathologic treatment response was seen for any of the evaluated imaging parameters including SUVmax, MTV, busyness, contrast and uniformity. Using multivariate Cox-regression analysis, the heterogeneity parameters busyness (Hazard Ratio (HR) = 1.424, 95% CI: 1.044-1.943; p = 0.026) and contrast (HR = 6.678, 95% CI: 1.969-22.643; p = 0.002) were independently associated with OS, while no independent association with OS was seen for SUVmax and MTV. In patients with ESCC undergoing nCRT and surgery, baseline 18F-FDG-PET/CT derived parameters could not predict histopathologic response to nCRT. However, the PET/CT derived features busyness and contrast were independently associated with OS and should be further investigated.

[Interdisciplinary expert consensus on innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer]. / Interdisziplinärer Expertenkonsensus zu Innovationen der bildgebenden Diagnostik und radionuklidbasierten Therapien des fortgeschrittenen Prostatakarzinoms.

BACKGROUND: Numerous diagnostic and therapeutic innovations in the treatment of advanced prostate cancer, both in the hormone-sensitive and in the castration-resistant situation, recently led to a new orientation in the management of this tumor. However, there are potential indications beyond the ones covered by the S3 guideline on early detection, diagnosis and therapy of prostate cancer in clinical care that might be helpful for patients. OBJECTIVES: Since July 2018, an interdisciplinary group of experts from nuclear medicine, radiologists, radio-oncologists and urologists developed a consensus paper on state-of-the-art innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer. CONCLUSIONS: Provided by the working group are suggestions and strategies to improve the implementation of new imaging techniques such as multiparametric magnetic resonance imaging (mpMRI), PSMA-PET/CT (prostate-specific membrane antigen-positron emission tomography/computed tomography) and innovative therapeutic options (radium-223 dichloride, lutetium-177-PSMA) in the complex treatment of metastatic castration-resistant prostate cancer (mCRPC).

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Textural features in FDG-PET/CT can predict outcome in melanoma patients to treatment with Vemurafenib and Ipililumab.

AIM: Recently, textural parameters assessed in FDG-PET/CT as surrogate marker for tumor heterogeneity have been shown to provide prognostic power. Therefore, we investigated the use of such parameters in FDG-PET/CT examinations before the start of immunotherapy with vemurafenib or ipilimumab in patients with malignant melanoma. METHODS: In this retrospective analysis 26 patients with histologically proven advanced melanoma were included. FGD-PET/CT was performed before the start of treatment either with vemurafenib (n = 9) or ipilimumab (n = 17) and tumors were analyzed for textural parameters as well as conventional PET features. Lesions were classified as responding or not responding following PERCIST criteria. ROC analysis was performed to analyze the predictive power and cut-off values. In addition, the change of maximum SUV of the lesions between pretherapeutic PET/CT and another PET/CT performed about 12 weeks after start of treatment was evaluated and correlated with the pretreatment parameters. RESULTS: In both groups, six textural parameters showed statistically significant predictive power as well as the metabolic tumor volume. In the group treated with vemurafenib eight additional textural parameters as well as the maximum and mean SUV and the TLG showed significance. A statistically significant correlation between the change of maximum SUV in the course of treatment and the pretherapeutic parameters was found in both treatment groups for three textural features. CONCLUSION: In patients with malignant melanoma textural parameters in pretherapeutic FDG-PET/CT examinations seem to have prognostic power for treatment response of immunotherapy with vemurafenib and ipilimumab. This can be an important step towards personalized tumor therapy.

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). METHODS: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. RESULTS: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. CONCLUSION: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. TRIAL REGISTRATION: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

PURPOSE: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure. METHODS: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter. RESULTS: The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment. CONCLUSION: Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis.

BACKGROUND: Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis. RESULTS: Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h. No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO3- were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = - 0.21) as well as MAG-3-derived GFR (r = - 0.32) and the rise in potassium after 4 h. CONCLUSION: Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

Radiation Dosimetry for 177Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: Absorbed Dose in Normal Organs and Tumor Lesions.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is increasingly used in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed doses for normal organs and tumor lesions using 177Lu-PSMA I&T (I&T is imaging and therapy) in patients undergoing up to 4 cycles of radioligand therapy. Results were compared with pretherapeutic Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBEDCC)] (68Ga-PSMA-HBED-CC) PET. Methods: A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third, and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30-120 min, 24 h, and 6-8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pretherapeutic 68Ga-PSMA-HBED-CC PET/CT. Absorbed doses for individual cycles were calculated using OLINDA/EXM. SUVs from pretherapeutic PET were compared with absorbed doses and with change of SUV. Results: The mean whole-body effective dose for all cycles was 0.06 ± 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 ± 0.21 Gy/GBq for the kidneys; 0.12 ± 0.06 Gy/GBq for the liver; and 0.55 ± 0.14 Gy/GBq for the parotid, 0.64 ± 0.40 Gy/GBq for the submandibular, and 3.8 ± 1.4 Gy/GBq for the lacrimal glands. Absorbed organ doses were relatively constant among the 4 different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2 ± 2.6 Gy/GBq (range, 0.22-12 Gy/GBq). Doses to tumor lesions gradually decreased, with 3.5 ± 2.9 Gy/GBq for the first, 3.3 ± 2.5 Gy/GBq for the second, 2.7 ± 2.3 Gy/GBq for the third, and 2.4 ± 2.2 Gy/GBq for the fourth cycle. SUVs of pretherapeutic PET moderately correlated with absorbed dose (r = 0.44, P < 0.001 for SUVmax; r = 0.43, P < 0.001 for SUVmean) and moderately correlated with the change of SUV (r = 0.478, P < 0.001 for SUVmax, and r = 0.50, P < 0.001 for SUVmean). Conclusion: Organ- and tumor-absorbed doses for 177Lu-PSMA I&T are comparable to recent reports and complement these with information on an excellent correlation between the 4 therapy cycles. With the kidneys representing the critical organ, a cumulative activity of 40 GBq of 177Lu-PSMA I&T appears to be safe and justifiable. The correlation between pretherapeutic SUV and absorbed tumor dose emphasizes the need for PSMA-ligand PET imaging for patient selection.

[Therapy of bone metastases with radium-223. German guidelines]. / Radionuklidtherapie von Knochenmetastasen mittels Radium-223. DGN-Handlungsempfehlung.

This document describes the guideline for therapy of bone metastases with radium-223 ((223)Ra) published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften in Germany (AWMF) under the auspices of the Deutsche Gesellschaft für Nuklearmedizin (DGN), Östereichische Gesellschaft für Nuklearmedizin (OGN), and Schweizerische Gesellschaft für Nuklearmedizin (SGNM). This guidance is based on an interdisciplinary consensus. These recommendations are a prerequisite for the quality management in the treatment of patients with bone metastases from prostate cancer using (223)Ra. They are aimed at guiding nuclear medicine specialists in selecting candidates to receive therapy and to deliver the treatment in a safe and effective manner. The document contains background information and definitions. It covers the rationale, indications and contraindications for therapy with (223)Ra. Essential topics are the requirements for institutions performing the therapy, which patient data have to be available prior to performance of therapy, and how treatment has to be carried out technically and organisationally. Moreover, essential elements of follow-up and aftercare are specified. As a matter of principle, the treatment inclusive aftercare has to be realised in close cooperation with the involved medical disciplines.

Biodistribution and radiation dosimetry of (68)Ga-PSMA HBED CC-a PSMA specific probe for PET imaging of prostate cancer.

PURPOSE: Positron emission tomography (PET) agents targeting the prostate-specific membrane antigen (PSMA) are currently under broad clinical and scientific investigation. (68)Ga-PSMA HBED-CC constitutes the first (68)Ga-labelled PSMA-inhibitor and has evolved as a promising agent for imaging PSMA expression in vivo. The aim of this study was to evaluate the whole-body distribution and radiation dosimetry of this new probe. METHODS: Five patients with a history or high suspicion of prostate cancer were injected intravenously with a mean of 139.8 ± 13.7 MBq of (68)Ga-PSMA HBED-CC (range 120-158 MBq). Four static skull to mid-thigh scans using a whole-body fully integrated PET/MR-system were performed 10 min, 60 min, 130 min, and 175 min after the tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses (ED) were calculated using OLINDA/EXM. RESULTS: Injection of a standard activity of 150 MBq (68)Ga-PSMA HBED-CC resulted in a median effective dose of 2.37 mSv (Range 1.08E-02 - 2.46E-02 mSv/MBq). The urinary bladder wall (median absorbed dose 1.64E-01 mGv/MBq; range 8.76E-02 - 2.91E-01 mGv/MBq) was the critical organ, followed by the kidneys (median absorbed dose 1.21E-01 mGv/MBq; range 7.16E-02 - 1.75E-01), spleen (median absorbed dose 4.13E-02 mGv/MBq; range 1.57E-02 - 7.32E-02 mGv/MBq) and liver (median absorbed dose 2.07E-02 mGv/MBq; range 1.80E-02 - 2.57E-02 mGv/MBq). No drug-related pharmacological effects occurred. CONCLUSION: The use of (68)Ga-PSMA HBED-CC results in a relatively low radiation exposure, delivering organ doses that are comparable to those of other (68)Ga-labelled PSMA-inhibitors used for PET-imaging. Total effective dose is lower than for other PET-agents used for prostate cancer imaging (e.g. (11)C- and (18)F-Choline).

Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer.

PURPOSE: We report our initial clinical experience with ß -emitting (177)Lu-PSMA-I&T ((177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy) for systemic treatment of metastatic castration resistant prostate cancer. MATERIALS AND METHODS: Patients with metastatic castration resistant prostate cancer who experienced treatment failure with chemotherapy and novel androgen receptor targeted therapy were treated for 8 weeks with up to 4 cycles of (177)Lu-PSMA-I&T. We report safety data, the antitumor response with prostate specific antigen decreases and the radiographic tumor response as well as the clinical outcome with changes in ECOG (Eastern Cooperative Oncology Group) performance status and pain severity. RESULTS: The first 3 patients were treated with a lower activity of 3.7 GBq in cycle 1. Due to a favorable safety profile the activity was increased to 7.4 GBq in 19 subsequent patients who completed a total of 40 cycles. With the higher activity no grade 3/4 toxicities were observed. The main nonhematological and hematological grade 1/2 toxicities were dry mouth in 7 patients (37%), anemia in 6 (32%) and thrombopenia in 5 (25%). The proportion of patients who achieved a maximum prostate specific antigen decrease of 30% or greater, 50% or greater and 90% or greater was 56%, 33% and 11%, respectively. Combined assessment of bone and soft tissue metastases showed complete remission in 5% of patients, stable disease in 63% and progressive disease in 32%. ECOG performance status improved or was stable in 74% of patients. Of men with bone pain 58% achieved complete resolution or reduced pain. CONCLUSIONS: Radioligand therapy with (177)Lu-PSMA-I&T appears to be safe and active in heavily pretreated patients with metastatic castration resistant prostate cancer.

Changing the intraoperative nodal status of a breast cancer patient using freehand SPECT for sentinel lymph node biopsy.

Radio-guided sentinel lymph node biopsy in early-stage breast cancer is standard of care. Freehand SPECT is a system for intraoperative visualization of radioactivity in the body. It generates a 3-dimensional image of the radioactivity distribution complementing the acoustic information of the gamma probe by providing depth and radioactive uptake information. In the reported case, freehand SPECT was used in a breast cancer patient as a control method after conventional sentinel lymph node biopsy. Freehand SPECT identified an additional lymph node, changing the original stage from pN1(mic) (micrometastasis) to pN1a (nodal positive), resulting in an axillary lymph node dissection.

Freehand SPECT for image-guided sentinel lymph node biopsy in breast cancer.

PURPOSE: Sentinel lymph node biopsy (SLNB) is standard of care in early-stage breast cancer. Freehand SPECT (FhSPECT) is a system generating 3-D images for intraoperative visual detection of radioactivity in the body. The aim of our study was to evaluate the sensitivity of this technology for sentinel lymph node (SLN) detection and SLNB guidance. METHODS: In 40 patients, FhSPECT was additionally used after planar imaging and probe localization for SLNB. The number of SLNs detected was compared with the number detected by planar scintigraphy (reference method) and the conventional acoustic gamma probe (standard alternative). The sensitivity of FhSPECT was compared with that of the conventional gamma probe (McNemar's test). RESULTS: FhSPECT mapped the SLNs in 92.3 % of the basins (36/39) intraoperatively in identical positions to those seen on planar scintigrams. The conventional gamma probe correctly detected the SLNs in 35 of 39 basins (89.7 %). After SLNB, remaining radioactivity was detected by FhSPECT in nine patients, resulting in additional resection of SLNs in four patients. CONCLUSION: FhSPECT is a highly sensitive modality for intraoperative detection of SLNs, resulting in the identification of a higher number of SLNs than conventional gamma probe detection.

Myeloablative anti-CD20 radioimmunotherapy +/- high-dose chemotherapy followed by autologous stem cell support for relapsed/refractory B-cell lymphoma results in excellent long-term survival.

BACKGROUND: Radioimmunotherapy (RIT) has been used to treat relapsed/refractory CD20+ Non-Hodgkin lymphoma (NHL). Myeloablative anti-CD20 RIT followed by autologous stem cell infusion (ASCT) enables high radiation doses to lymphoma sites. We performed a phase I/II trial to assess feasibility and survival. METHODS: Twenty-three patients with relapsed/refractory NHL without complete remission (CR) to salvage chemotherapy were enrolled to evaluate RIT with Iodine-131 labelled rituximab (131I-rituximab) in a myeloablative setting. Biodistribution and dosimetric studies were performed to determine 131I activity required to induce a total body dose of 21-27Gy to critical organs. In 6/23 patients RIT was combined with high-dose chemotherapy. 8/23 patients received a sequential high-dose chemotherapy with a second ASCT. The median follow-up is 9.5 years. RESULTS: 6.956-19.425GBq of 131I was delivered to achieve the limiting organ dose to lungs or kidneys. No grade III/IV non-hematologic toxicity was seen with RIT alone. Significant grade III/IV toxicity (mucositis, fever, infection, one therapy related death) was observed in patients treated with RIT combined with high-dose chemotherapy. The overall response rate was 87% (64% CR). The median progression-free (PFS) and overall survival (OS) is 47.5 and 101.5 months. An international prognostic index score >1 was predictive for OS. CONCLUSION: Myeloablative RIT with 131I-rituximab followed by ASCT is feasible, well-tolerated and effective in high risk CD20+ NHL. Combination of RIT and high-dose chemotherapy increased toxicity significantly. Long-term results for PFS and OS are encouraging.