Novel CYP11B-ligand [123/131I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience.

PURPOSE: Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [123/131I]iodometomidate ([123/131I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. METHODS: Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [123I]IMTO and the most promising compound (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([123I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [131I]IMAZA in one of these patients was performed. RESULTS: We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [131I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. CONCLUSION: We developed the new radiopharmaceutical [123/131I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.

Predicitve Value of FDG Uptake in the Remaining Adrenal Gland Following Adrenalectomy for Adrenocortical Cancer.

Following initial surgery, patients with adrenocortical carcinoma (ACC) are commonly treated with the adrenolytic substance mitotane in an adjuvant or therapeutic setting. Treatment responses, however, are variable. The objective of the study was to investigate a possible correlation between FDG-PET activity of the remaining adrenal gland and therapeutic response of mitotane treatment. This is a retrospective study enrolling patients from two German centers with operated ACC and minimal information on PET-CT scanning. Eighty-two ACC patients after adrenalectomy were included (66 treated with mitotane and 16 without medical therapy). FDG uptake of the contralateral adrenal gland, liver and mediastinum was analyzed from a total of 291 PET/CT scans (median 4 scans per patient) and correlated with clinical annotations including overall and recurrence free survival. The majority of patients (81%) displayed a temporary increase in adrenal FDG uptake within the first 18 months following surgery, which was not associated with a morphological correlate for potential malignancy. This increase was mainly present in patients treated with mitotane (51/61, 84%) but less frequent in the control group (4/7, 57%). No direct correlation with mitotane plasma levels were evident. Patients following R0 resection with high adrenal uptake showed a tendency towards better clinical outcome without reaching a significance value (HR 1.41; CI 0.42-4.75; p=0.059). FDG update of the contralateral adrenal gland may not be misinterpreted as sign of malignancy but might be rather associated with a trend towards better clinical outcome.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.

PSMA Ligands for PET Imaging of Prostate Cancer.

Targeting the prostate-specific membrane antigen (PSMA) with 68Ga-labeled and 18F-labeled PET agents has become increasingly important in recent years. Imaging of biochemically recurrent prostate cancer has been established as a widely accepted clinical indication for PSMA ligand PET/CT in many parts of the world because of the results of multiple, primarily retrospective, studies that indicate superior detection efficacy compared with standard-of-care imaging. For high-risk primary prostate cancer, evidence is growing that this modality significantly aids in the detection of otherwise occult nodal and bone metastases. For both clinical indications in recurrent as well as in primary prostate cancer, preliminary data demonstrate a substantial impact on clinical management. Emerging data imply that intraprostatic tumor localization, therapy stratification, and treatment monitoring of advanced disease in specific clinical situations might become future indications. Current criteria for image reporting of PSMA ligand PET are evolving given the expanding body of literature on physiologic and pathologic uptake patterns and pitfalls. This article intends to give an educational overview on the current status of PSMA ligand PET imaging, including imaging procedure and interpretation, clinical indications, diagnostic potential, and impact on treatment planning.

68Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study.

The interobserver agreement for 68Ga-PSMA-11 PET/CT study interpretations in patients with prostate cancer is unknown. Methods:68Ga-PSMA-11 PET/CT was performed in 50 patients with prostate cancer for biochemical recurrence (n = 25), primary diagnosis (n = 10), biochemical persistence after primary therapy (n = 5), or staging of known metastatic disease (n = 10). Images were reviewed by 16 observers who used a standardized approach for interpretation of local (T), nodal (N), bone (Mb), or visceral (Mc) involvement. Observers were classified as having a low (<30 prior 68Ga-PSMA-11 PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 6). Histopathology (n = 25, 50%), post-external-beam radiation therapy prostate-specific antigen response (n = 15, 30%), or follow-up PET/CT (n = 10, 20%) served as a standard of reference. Observer groups were compared by overall agreement (% patients matching the standard of reference) and Fleiss' κ with mean and corresponding 95% confidence interval (CI). Results: Agreement among all observers was substantial for T (κ = 0.62; 95% CI, 0.59-0.64) and N (κ = 0.74; 95% CI, 0.71-0.76) staging and almost perfect for Mb (κ = 0.88; 95% CI, 0.86-0.91) staging. Level of experience positively correlated with agreement for T (κ = 0.73/0.66/0.50 for high/intermediate/low experience, respectively), N (κ = 0.80/0.76/0.64, respectively), and Mc staging (κ = 0.61/0.46/0.36, respectively). Interobserver agreement for Mb was almost perfect irrespective of prior experience (κ = 0.87/0.91/0.88, respectively). Observers with low experience, when compared with intermediate and high experience, demonstrated significantly lower median overall agreement (54% vs. 66% and 76%, P = 0.041) and specificity for T staging (73% vs. 88% and 93%, P = 0.032). Conclusion: The interpretation of 68Ga-PSMA-11 PET/CT for prostate cancer staging is highly consistent among observers with high levels of experience, especially for nodal and bone assessments. Initial training on at least 30 patient cases is recommended to ensure acceptable performance.

Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor with limited treatment options. Preclinical studies confirmed overexpression of the chemokine receptor 4 (CXCR4) in this cancer type. This study aimed to analyze the role of CXCR4 imaging using Ga-pentixafor for ACC staging and selection of patients for CXCR4-directed endoradiotherapy. METHODS: Thirty patients with histologically proven advanced, metastasized ACC underwent F-FDG PET/CT and Ga-pentixafor PET/CT within a time interval of 3 ± 4 days to evaluate suitability for CXCR4-directed endoradiotherapy. Scans were analyzed retrospectively for visual extent of ACC and SUVmax/mean of the tumor lesions. Ga-pentixafor PET was compared with F-FDG PET, the reference imaging standard. All patients were rated for suitability of CXCR4-directed endoradiotherapy considering patient's history, previous treatment, and CXCR4 expression of FDG-positive lesions compared with background activity within the same organ. RESULTS: All patients had lesions that were positive for both F-FDG and Ga-pentixafor PET and were rated as positive for disease. In 2 patients (7%), Ga-pentixafor PET identified more lesions compared with F-FDG PET. In 5 patients (17%) and 10 patients (33%), complementary and comparable information, respectively, was provided by dual-tracer imaging. In 13 patients (43%), more tumor lesions were identified by F-FDG PET compared with Ga-pentixafor PET. The F-FDG uptake of the malignant lesions was significantly higher (P < 0.01) than the SUVmax/mean for Ga-pentixafor. Overall, 70% of the patients were rated as suitable or potentially suitable for CXCR4-directed treatment. CONCLUSIONS: Ga-pentixafor allows in vivo imaging of CXCR4 expression in patients with advanced ACC and may serve as companion diagnostic tool in selecting patients for potential CXCR4-directed endoradiotherapy. Seventy percent of the patients with advanced, metastasized ACC may be suitable for a CXCR4-directed treatment after failure of standard treatment options.

68Ga-DOTATATE PET/CT Interobserver Agreement for Neuroendocrine Tumor Assessment: Results of a Prospective Study on 50 Patients.

We evaluated observer agreement for 68Ga-DOTATATE PET/CT interpretations in patients with neuroendocrine tumor (NET). METHODS: 68Ga-DOTATATE PET/CT was performed on 50 patients with known or suspected NET of the small bowel (n = 19), pancreas (n = 14), lung (n = 4), or other location (n = 13). The images were reviewed by 7 observers, who used a standardized interpretation approach. The observers were classified as having a low level of experience (<500 scans or <5 y experience with 68Ga-DOTATATE PET/CT; n = 4) or a high level of experience (≥500 scans or ≥5 y experience with 68Ga-DOTATATE PET/CT; n = 3). Interpretation by the primary nuclear medicine physician, who had access to all clinical and imaging data, served as the reference standard. Interobserver agreement was determined by the Cohen κ statistic and intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95%CI). RESULTS: Interobserver agreement was substantial, and the median number of false findings was low for the overall scan result: that is, positive versus negative scan result (κ = 0.80; 95%CI, 0.74-0.86; false findings, 3), organ involvement (κ = 0.70; 95%CI, 0.64-0.76; false findings, 5), and lymph node involvement (κ = 0.71; 95%CI, 0.65-0.78; false findings, 6). Interobserver agreement was substantial to almost perfect, and the average absolute difference (Δ) from the reference observer was low for number of organ and lymph node metastases (organ: ICC, 0.84; 95%CI, 0.77-0.89; Δ = 0.45; lymph node: ICC, 0.77; 95%CI, 0.69-0.84; Δ = 0.45), tumor SUVmax (ICC, 0.99; 95%CI, 0.97-0.99; Δ = 0.44), and reference SUV (spleen: ICC, 0.81; Δ = 1.10; liver: ICC, 0.79; Δ = 0.62). Interpretations of appropriateness for peptide-receptor radionuclide therapy varied more significantly among observers (κ = 0.64; 95%CI, 0.57-0.70), and a higher frequency of false-positive recommendations for peptide-receptor radionuclide therapy occurred in observers with low experience than in those with high experience (range, 7-12 vs. 4-8). CONCLUSION: The interpretation of 68Ga-DOTATATE PET/CT images for NET staging is consistent among observers with low and high levels of experience. However, image-based recommendations for or against peptide-receptor radionuclide therapy require experience and training.

Impact of 68Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy.

BACKGROUND: Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced 68Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent 68Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of 68Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. RESULTS: Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months. CONCLUSIONS: 68Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.

The impact of 177Lu-octreotide therapy on 99mTc-MAG3 clearance is not predictive for late nephropathy.

Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of 99mTc-mercaptoacetyltriglycine (99mTc--MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq 177Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by 99mTc-MAG3-clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.

Fusion of freehand SPECT and ultrasound: First experience in preoperative localization of sentinel lymph nodes.

PURPOSE: Radioguided sentinel lymph node biopsy (SLNB) is the standard of care in breast cancer and melanoma. Additional preoperative Single-photon emission computed tomography (SPECT/CT) for improved anatomical co-registration of the SLNs causes additional radiation exposure and is time-consuming and expensive. The aim of this prospective study was to evaluate a novel approach involving real-time fusion of freehand SPECT (fhSPECT) and ultrasound (US) for anatomical co-registration of SLNs. METHODS: From February 2015 to February 2016, 153 patients were included in this prospective study. All patients underwent lymphoscintigraphy according to practical guidelines and 151 (118 cases of breast cancer, 30 cutaneous malignancies, and three cases of vulvar cancer) of the 153 patients were additionally investigated with fhSPECT-US. FhSPECT connected to a hand-held gamma detector generates three-dimensional images of the radioactivity distribution in the scanned area. For co-registration and real-time fusion of fhSPECT and subsequently performed US, an infrared stereo tracking system was used. RESULTS: In all patients an SLN was found on lymphoscintigraphy, and the fhSPECT detected corresponding hotspots in all but one patient. In 72 % of patients and 73 % of lymph node basins, real-time anatomical co-registration with US was feasible. The rate of success in achieving good co-registration increased from 60 to 75 % after training by a radiologist specialized in breast imaging. A higher co-registration rate (78 %) was observed in patients with only one SLN than in those with two SLNs (68 %) or three or more SLNs (0 %). CONCLUSIONS: Real-time fusion of fhSPECT and US for preoperative anatomical co-registration of SLNs is feasible. However, before this approach can completely replace preoperative lymphatic imaging, further technical developments are needed.

Epididymal Metastasis of Prostate Cancer Detected With 68Ga-PSMA-PET/CT.

Here, we report on a 73-year-old man with a biochemical relapse (PSA level, 1.1 ng/mL) 8 years after radical prostatectomy and radiotherapy. Four years after primary diagnosis, a bilateral subcapsular orchiectomy was performed for endogen androgen deprivation. Physical examination and transrectal ultrasound did not show any suspicious finding. Subsequently, a Ga-PSMA-PET/CT was performed and revealed a very rare epididymal metastasis. After surgery, the PSA level decreased to less than 0.07 ng/mL, and 4 months later, the patient is still tumor free.

Assessment of tumor heterogeneity in treatment-naïve adrenocortical cancer patients using (18)F-FDG positron emission tomography.

As an orphan malignancy, only limited treatment options are available in adrenocortical carcinoma (ACC). Non-invasive risk assessment has not been described but may be of value to stratify patients for treatment. We aimed to evaluate the potential value of intra-individual tumor heterogeneity as assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for outcome prediction in treatment-naïve ACC patients. Ten patients with primary diagnosis of ACC were included in this study. Prior to any treatment initiation, baseline (18)F-FDG PET scans were performed. Tumor staging was performed using the European Network for the Study of Adrenal Tumors (ENS@T). Intratumoral heterogeneity of the primary tumor was assessed by manual segmentation using conventional PET parameters (standardized uptake values and tumor-to-liver ratios) and textural features. The impact of tumoral heterogeneity based on pre-therapeutic (18)F-FDG PET to predict progression-free (PFS) and overall survival (OS) was evaluated by receiver operating characteristic analysis. On average, tumor recurrence or progression was detected after median of 561 days (range 71-1434 days) after the pre-therapeutic baseline PET scan. 50 % of the patients died of ACC within the follow-up period (mean 983 ± 404 days). Pre-therapeutic tumor volume was associated with PFS (r = -0.67, p = 0.05) and Ki67 index with OS (r = -0.66, p = 0.04). ENS@T tumor stage was the only parameter to correlate with both PFS and OS (r = -0.82, p = 0.001, and r = -0.72, p = 0.01, respectively). In the subgroup of patients without distant metastases (ENS@T stages II and III), age and pre-therapeutic tumor volume correlated significantly with PFS (r = 0.96, p = 0.01 and r = -0.93, p = 0.02, respectively) and OS (r = 0.95, p = 0.02 and r = -0.90, p = 0.04, respectively). None of the investigated classic or textural PET parameters predicted PFS or OS. In this pilot study in treatment-naïve ACC patients, conventional (18)F-FDG PET-derived parameters and textural tumor heterogeneity features were not suitable to identify high-risk patients.

68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT.

PURPOSE: Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. PATIENTS AND METHODS: One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). RESULTS: The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. CONCLUSIONS: The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.

3D scintigraphic imaging and navigation in radioguided surgery: freehand SPECT technology and its clinical applications.

Freehand SPECT (fhSPECT) is a technology platform for providing 3-dimensional (3D) navigation for radioguided surgical procedures, such as sentinel lymph node (SLN) biopsy (SLNB). In addition to the information provided by conventional handheld gamma detection probes, fhSPECT allows for direct visualization of the distribution of radioactivity in any given region of interest, allowing for improved navigation to radioactive target lesions and providing accurate lesion depth measurements. Herein, we will review the currently available clinical data on the use of fhSPECT: (i) for SLNB of various malignancies, including difficult-to-detect SLNs, and (ii) for radioguided localization of solid tumors. Moreover, the combination of fhSPECT with other technologies (e.g., small field-of-view gamma cameras, and diagnostic ultrasound) is discussed. These technical advances have the potential to greatly expand the clinical application of radioguided surgery in the future.

DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy.

UNLABELLED: The aim of the study was to investigate DNA double-strand break (DSB) formation and its correlation to the absorbed dose to the blood in patients with surgically treated differentiated thyroid cancer undergoing their first radioiodine therapy for remnant ablation. METHODS: Twenty patients were included in this study. At least 7 peripheral blood samples were obtained before and between 0.5 and 120 h after administration of radioiodine. From the time-activity curves of the blood and the whole body, residence times for the blood self-irradiation and the irradiation from the whole body were determined. Peripheral blood lymphocytes were isolated, ethanol-fixed, and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was analyzed as a function of the absorbed dose to the blood and compared with an in vitro calibration curve for (131)I and (177)Lu established previously in our institution. RESULTS: The average number of radiation-induced foci (RIF) per cell increased over the first 3 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 2 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time points, RIF numbers diminished, along with dropping dose rates, indicating progression of DNA repair. Individual patient data were characterized by a linear dose-dependent increase and a biexponential response function describing a fast and a slow repair component. CONCLUSION: With the experimental results and model calculations presented in this work, a dose-response relationship is demonstrated, and an analytic function describing the time course of the in vivo damage response after internal irradiation of patients with (131)I is established.

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.

UNLABELLED: Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand ((68)Ga-pentixafor) for diagnostic receptor targeting, (177)Lu- and (90)Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. METHODS: CXCR4 target expression was demonstrated by baseline (68)Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic (177)Lu-pentixather dosimetry was performed before (177)Lu-pentixather or (90)Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue. RESULTS: A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in (18)F-FDG uptake. CONCLUSION: CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma.

Localization of Parathyroid Adenoma With Real-Time Ultrasound: Freehand SPECT Fusion.

Preoperative localization of parathyroid adenoma in primary hyperparathyroidism gains in importance as there is a trend toward minimally invasive parathyroid surgery. Besides MRI, 4-dimensional CT, PET/CT, invasive-selective venous sampling, or angiography, both ultrasound and scintigraphy are standard of care for lesion localization. Here we report on a 53-year-old woman with suspicion of primary hyperparathyroidism using real-time fusion of scintigraphic (freehand SPECT) and ultrasound imaging for adenoma localization. Real-time fusion of ultrasound and freehand SPECT allowed noninvasive dedicated metabolic and anatomic adenoma localization and treatment planning.

A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma.

BACKGROUND: Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin. CASE PRESENTATION: Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred. CONCLUSION: Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer.

iROLL: does 3-D radioguided occult lesion localization improve surgical management in early-stage breast cancer?

PURPOSE: To prospectively evaluate the feasibility of 3-D radioguided occult lesion localization (iROLL) and to compare iROLL with wire-guided localization (WGL) in patients with early-stage breast cancer undergoing breast-conserving surgery and sentinel lymph node biopsy (SLNB). METHODS: WGL (standard procedure) and iROLL in combination with SLNB were performed in 31 women (mean age 65.1 ± 11.2 years) with early-stage breast cancer and clinically negative axillae. Patient comfort in respect of both methods was assessed using a ten point scale. SLNB and iROLL were guided by freehand SPECT (fhSPECT). The results of the novel 3-D image-based method were compared with those of WGL, ultrasound-based lesion localization, and histopathology. RESULTS: iROLL successfully detected the malignant primary and at least one sentinel lymph node in 97% of patients. In a single patient (3%), only iROLL, and not WGL, enabled lesion localization. The variability between fhSPECT and ultrasound-based depth localization of breast lesions was low (1.2 ± 1.4 mm). Clear margins were achieved in 81% of the patients; however, precise prediction of clear histopathological surgical margins was not feasible using iROLL. Patients rated iROLL as less painful than WGL with a pain score 0.8 ± 1.2 points (p < 0.01) lower than the score for iROLL. CONCLUSION: iROLL is a well-tolerated and feasible technique for localizing early-stage breast cancer in the course of breast-conserving surgery, and is a suitable replacement for WGL. As a single image-based procedure for localization of breast lesions and sentinel nodes, iROLL may improve the entire surgical procedure. However, no advantages of the image-guided procedure were found with regard to prediction of complete tumour resection.