Can integrated 18F-FDG PET/MR replace sentinel lymph node resection in malignant melanoma?

PURPOSE: To compare the sensitivity and specificity of 18F-fluordesoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), 18F-FDG PET/magnetic resonance (18F-FDG PET/MR) and 18F-FDG PET/MR including diffusion weighted imaging (DWI) in the detection of sentinel lymph node metastases in patients suffering from malignant melanoma. MATERIAL & METHODS: Fifty-two patients with malignant melanoma (female: n = 30, male: n = 22, mean age 50.5 ± 16.0 years, mean tumor thickness 2.28 ± 1.97 mm) who underwent 18F-FDG PET/CT and subsequent PET/MR & DWI for distant metastasis staging were included in this retrospective study. After hybrid imaging, lymphoscintigraphy including single photon emission computed tomography/CT (SPECT/CT) was performed to identify the sentinel lymph node prior to sentinel lymph node biopsy (SLNB). In a total of 87 sentinel lymph nodes in 64 lymph node basins visible on SPECT/CT, 17 lymph node metastases were detected by histopathology. In separate sessions PET/CT, PET/MR, and PET/MR & DWI were assessed for sentinel lymph node metastases by two independent readers. Discrepant results were resolved in a consensus reading. Sensitivities, specificities, positive predictive values and negative predictive values were calculated with histopathology following SPECT/CT guided SLNB as a reference standard. RESULTS: Compared with histopathology, lymph nodes were true positive in three cases, true negative in 65 cases, false positive in three cases and false negative in 14 cases in PET/CT. PET/MR was true positive in four cases, true negative in 63 cases, false positive in two cases and false negative in 13 cases. Hence, we observed a sensitivity, specificity, positive predictive value and negative predictive value of 17.7, 95.6, 50.0 and 82.3% for PET/CT and 23.5, 96.9, 66.7 and 82.3% for PET/MR. In DWI, 56 sentinel lymph node basins could be analyzed. Here, the additional analysis of DWI led to two additional false positive findings, while the number of true positive findings could not be increased. CONCLUSION: In conclusion, integrated 18F-FDG PET/MR does not reliably differentiate N-positive from N-negative melanoma patients. Additional DWI does not increase the sensitivity of 18F-FDG PET/MR. Hence, sentinel lymph node biopsy cannot be replaced by 18F-FDG-PE/MR or 18F-FDG-PET/CT.

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.

Evaluation of a radioactive and fluorescent hybrid tracer for sentinel lymph node biopsy in head and neck malignancies: prospective randomized clinical trial to compare ICG-(99m)Tc-nanocolloid hybrid tracer versus (99m)Tc-nanocolloid.

PURPOSE: There is some controversy about the value of sentinel lymph node excision (SLNE) in patients with head and neck malignancies. The gold standard for detection and targeted extirpation of the SLN is lymphoscintigraphy with (99m)Tc-nanocolloid. The purpose of this prospective randomized study was to analyse the feasibility and clinical benefit of a hybrid tracer comprising the near-infrared (NIR) fluorescent indocyanine green (ICG) and (99m)Tc-nanocolloid (ICG-(99m)Tc-nanocolloid) in direct comparison with standard (99m)Tc-nanocolloid for guiding SLNE in patients with head and neck cutaneous malignancies. METHODS: We analysed the data from 40 clinically lymph node-negative patients with melanoma, high-risk cutaneous squamous cell carcinoma, Merkel cell carcinoma or sweat gland carcinoma who underwent SLNE with ICG-(99m)Tc-nanocolloid (cohort A) or with the standard (99m)Tc-nanocolloid (cohort B). RESULTS: Overall SLNs were identified preoperatively in all 20 patients (100%) in cohort A and in 18 of 20 patients (90%) in cohort B. The SLN basin was detected preoperatively in 18 patients (90%) in cohort A and also in 18 patients (90%) in cohort B. SLNs were identified intraoperatively in all 20 patients (100%) in cohort A and in 19 patients (95%) in cohort B (p = 0.487). Metastatic SLNs were detected in 9 patients (22.5%), 3 (15.0%) in cohort A and 6 (30.0%) in cohort B (p = 0.228). CONCLUSION: The hybrid tracer ICG-(99m)Tc-nanocolloid is an innovative imaging tracer, reliably and readily providing additional information for the detection and excision of SLN in the head and neck region. Therefore, SLNE with combined radioactive and NIR fluorescence guidance is an attractive option for improving the SLN detection rate in patients with cutaneous head and neck malignancies.

Cost-effectiveness of preoperative SPECT/CT combined with lymphoscintigraphy vs. lymphoscintigraphy for sentinel lymph node excision in patients with cutaneous malignant melanoma.

PURPOSE: Malignant melanoma has become a major growing interdisciplinary problem in public health worldwide. Sentinel lymph node excision (SLNE) in conjunction with preoperative SPECT/CT is considered the most sensitive and specific staging test for the detection of micrometastatic melanoma in regional lymph nodes. Among patients with clinically lymph node-negative melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone has been found to be associated with a higher frequency of metastatic involvement and a higher rate of disease-free survival. The aim of this study was to analyse the cost-effectiveness of SLNE with preoperative SPECT/CT for detecting sentinel lymph nodes versus that of standard SLNE with preoperative lymphoscintigraphy from a single-institution database. METHODS: Cost-effectiveness analysis of two surgical approaches for SLNE for malignant melanoma at the University Hospital Essen, Skin Cancer Center in Essen, Germany. Between March 2003 and April 2011 464 patients eligible for SLNE were identified . Of these patients, 403 with clinically negative lymph nodes who underwent SLNE with or without preoperative SPECT/CT qualified for subsequent analysis. RESULTS: Between March 2003 and October 2008, 254 patients were operated upon with the standard technique. From November 2008, 149 patients underwent the SPECT/CT technique. Cost analysis showed a mean cost saving of 710.50 when SPECT/CT was added to preoperative imaging. This was achieved by a reduction in operative time (median, Q1;Q3, 40 min, 40;50 min, vs. 45 min, 35;60 min; p = 0.002), hospital stay duration (5 days, 3;8 days, vs. 8 days, 4.5;14.5 days; p < 0.001) and more frequent use of local anaesthesia (90.6 % vs. 70.5 %; p < 0.001). The median cost of SLNE using SPECT/CT was 1,619.7 (Q1;Q3 1,317.0;2,603.4) and of SLNE without SPECT/CT was 2,330.2 ( 1,468.3;4,058.1; p < 0.001), a cost saving of 30.5 %. CONCLUSION: In patients with cutaneous melanoma, the use of preoperative SPECT/CT-aided SLNE compared with standard SLNE was associated not only with higher detection of metastatic involvement but also with a significant cost reduction.

Evaluation of the PET component of simultaneous [(18)F]choline PET/MRI in prostate cancer: comparison with [(18)F]choline PET/CT.

PURPOSE: The aim of this study was to evaluate the positron emission tomography (PET) component of [(18)F]choline PET/MRI and compare it with the PET component of [(18)F]choline PET/CT in patients with histologically proven prostate cancer and suspected recurrent prostate cancer. METHODS: Thirty-six patients were examined with simultaneous [(18)F]choline PET/MRI following combined [(18)F]choline PET/CT. Fifty-eight PET-positive lesions in PET/CT and PET/MRI were evaluated by measuring the maximum and mean standardized uptake values (SUVmax and SUVmean) using volume of interest (VOI) analysis. A scoring system was applied to determine the quality of the PET images of both PET/CT and PET/MRI. Agreement between PET/CT and PET/MRI regarding SUVmax and SUVmean was tested using Pearson's product-moment correlation and Bland-Altman analysis. RESULTS: All PET-positive lesions that were visible on PET/CT were also detectable on PET/MRI. The quality of the PET images was comparable in both groups. Median SUVmax and SUVmean of all lesions were significantly lower in PET/MRI than in PET/CT (5.2 vs 6.1, p<0.05 and 2.0 vs 2.6, p<0.001, respectively). Pearson's product-moment correlation indicated highly significant correlations between SUVmax of PET/CT and PET/MRI (R=0.86, p<0.001) as well as between SUVmean of PET/CT and PET/MRI (R=0.81, p<0.001). Bland-Altman analysis revealed lower and upper limits of agreement of -2.77 to 3.64 between SUVmax of PET/CT vs PET/MRI and -1.12 to +2.23 between SUVmean of PET/CT vs PET/MRI. CONCLUSION: PET image quality of PET/MRI was comparable to that of PET/CT. A highly significant correlation between SUVmax and SUVmean was found. Both SUVmax and SUVmean were significantly lower in [(18)F]choline PET/MRI than in [(18)F]choline PET/CT. Differences of SUVmax and SUVmean might be caused by different techniques of attenuation correction. Furthermore, differences in biodistribution and biokinetics of [(18)F]choline between the subsequent examinations and in the respective organ systems have to be taken into account.

Biodistribution and radiation dosimetry of 124I-mIBG in adult patients with neural crest tumours and extrapolation to paediatric models.

AIM: Positron emission tomography (PET) using 124I-mIBG has been established for imaging and pretherapeutic dosimetry. Here, we report the first systematic analysis of the biodistribution and radiation dosimetry of 124I-mIBG in patients with neural crest tumours and project the results to paediatric patient models. METHODS: Adult patients with neural crest tumours who underwent sequential 124I-mIBG PET were included in this retrospective single-center analysis. PET data were acquired 4, 24, 48, and/or 120 h after administration of a mean of 43 MBq 124I-mIBG. Whole-body counting and blood sampling were performed at 2, 4, 24, 48 and 120 h after administration. Absorbed organ dose and effective dose coefficients were estimated in OLINDA/EXM 2.2 according to the MIRD formalism. Extrapolation to paediatric models was performed based on mass-fraction scaling of the organ-specific residence times. Biodistribution data for adults were also projected to 123I-mIBG and 131I-mIBG. RESULTS: Twenty-one patients (11 females, 10 males) were evaluated. For adults, the organs exposed to the highest dose per unit administered activity were urinary bladder (1.54 ± 0.40 mGy/MBq), salivary glands (0.77 ± 0.28 mGy/MBq) and liver (0.65 ± 0.22 mGy/MBq). Mean effective dose coefficient for adults was 0.25 ± 0.04 mSv/MBq (male: 0.24 ± 0.03 mSv/MBq, female: 0.26 ± 0.06 mSv/MBq), and increased gradually to 0.29, 0.44, 0.69, 1.21, and 2.94 mSv/MBq for the 15-, 10-, 5-, 1-years-old, and newborn paediatric reference patients. Projected mean effective dose coefficients for 123I-mIBG and 131I-mIBG for adults were 0.014 ± 0.002 mSv/MBq and 0.18 ± 0.04 mSv/MBq, respectively. CONCLUSION: PET-based derived radiation dosimetry data for 124I-mIBG from this study agreed well with historical projected data from ICRP 53. The effective dose coefficients presented here may aid in guidance for establishing weight-based activity administration protocols.

Safety and Efficacy of Selective Internal Radionuclide Therapy with 90Y Glass Microspheres in Patients with Progressive Hepatocellular Carcinoma after the Failure of Repeated Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2-14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110-120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan-Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9-13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4-8) vs. 12 months (95% CI, 10-14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

Diagnostic accuracy of dual-time-point 18F-FDG PET/CT for the detection of axillary lymph node metastases in breast cancer patients.

BACKGROUND: The diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph node metastases in breast cancer patients acquired 60 min after FDG administration is reported to be only moderate, especially due to low sensitivity. PURPOSE: To test whether a delayed scan 90 min after FDG administration could enhance the diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph node metastases. MATERIAL AND METHODS: Thirty-eight women suffering from primary breast cancer (mean age 52 years; range 25-78 years; standard deviation 14 years) underwent a pre-therapeutic dual-time-point FDG-PET/CT scan. The maximum standardized uptake value (SUVmax) of axillary lymph nodes was measured at two different time points (time point T1: 60 min after FDG injection, time point T2: 90 min after FDG injection). SUVmax of axillary lymph nodes at T1 and T2 were assessed for statistical significance using a paired Wilcoxon-Test (P < 0.05). At T1 a qualitative analysis of the FDG-PET/CT scan was performed to define physiologic and metastatic lymph nodes. At T2 an increase of the SUVmax of at least 3.75% over time was rated as indicating malignancy. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the accuracy of FDG-PET/CT for the detection of axillary lymph node metastases was calculated at time points T1 and T2. Statistically significant differences were determined using Fisher's exact test (P < 0.05). Histopathology served as the standard of reference. A compartment based analysis was done. RESULTS: Axillary lymph nodes had a mean SUVmax of 1.6 (range 0.6-10.8; SD 1.9) at T1 and a mean SUVmax of 1.8 (range 0.5-17.9; SD 3.5) at T2. This difference was statistically significant (P = 0.047). The sensitivity, specificity, PPV, NPV, and accuracy of FDG-PET/CT for the detection of axillary lymph node metastases was 81%, 100%, 100%, 88%, and 92% at T1, and 88%, 50%, 56%, 85%, and 66% at T2, respectively. This difference was not statistically significant (P = 0.27). CONCLUSION: There is a slight increase of the FDG accumulation of axillary lymph nodes between 60 and 90 min after FDG administration. This increase did not translate into a statistical significant enhancement of the diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph nodes. Especially due to false-positive results a delayed FDG-PET/CT scan 90 min after FDG administration is not able to enhance the diagnostic accuracy for the detection of lymph node metastases.

Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease-free survival in melanoma.

CONTEXT: Malignant melanoma has become an increasing interdisciplinary public health challenge worldwide. Sentinel lymph node excision (SLNE) is considered the most sensitive and specific staging test for the detection of micrometastatic melanoma in regional lymph nodes. OBJECTIVE: To compare metastatic node detection and disease-free survival using single-photon emission computed tomography/computed tomography (SPECT/CT)-aided SLNE vs standard SLNE in patients with melanoma. DESIGN, SETTING, AND PATIENTS: A prospective, computerized melanoma patient database at the University Hospital Essen, Skin Cancer Center, Essen, Germany, was used to identify a cohort of 464 patients eligible for SLNE between March 2003 and April 2011. A total of 403 patients with clinically negative lymph nodes, who underwent SLNE with or without preoperative SPECT/CT, qualified for subsequent analysis. MAIN OUTCOME MEASURES: Metastatic node detection and disease-free survival. RESULTS: Between March 2003 and October 2008, 254 patients underwent the standard SLNE technique. After November 2008, 149 patients underwent the SPECT/CT technique. Patients who did not receive SNLE in both intervals (46/300 [15.34%] for standard cohort vs 15/164 [9.15%] for SPECT/CT cohort; P = .06) did not differ in either age (difference, 69.20 years; 95% CI, 62.84-72.07 years; P = .38), tumor depth (difference, 2.90 mm; 95% CI, 2.87-4.54 mm; P = .54), or ulceration of the primary tumor (difference, -8.00%; 95% CI, -35.74% to 19.81%; P = .59). However, using SPECT/CT allowed SLNE in the head and neck area more frequently (2.0% for standard vs 23.5% for SPECT/CT; difference, 21.1%; 95% CI, 14.1%-28.2%; P < .001). In the SPECT/CT cohort, more sentinel lymph nodes per patient were detected than in the standard cohort (2.40 vs 1.87; 95% CI, 1.93-2.18; P < .001). The number of positive sentinel lymph nodes per patient was significantly higher in the SPECT/CT cohort than in the standard cohort (0.34 vs 0.21; 95% CI, 0.21-0.31; P = .04). The local relapse rate in the SPECT/CT cohort was lower than in the standard cohort (6.8% vs 23.8%, P = .03), which prolonged 4-year disease-free survival (93.9% vs 79.2%; P = .02). CONCLUSION: Among patients with clinically lymph node-negative melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone was associated with a higher frequency of metastatic involvement and a higher rate of disease-free survival.

Indocyanine green fluorescence-guided sentinel lymph node biopsy in dermato-oncology.

BACKGROUND: Sentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc-99m). The SLNE is controversially discussed internationally. This is especially given to the high false-negative rate up to 44 %. An alternative could be the fluorescent dye indocyanine green (ICG). MATERIAL AND METHODS: We investigated the advantage of intraoperative fluorescence detection of lymphatic vessels and SLN with a Near-Infrared (NIR) camera in comparison to conventional methods using preoperative lymphoscintigraphy and SPECT/CT in 22 patients with malignant melanoma. RESULTS: A total of 61 SLNs were removed in 22 operative procedures. In 7 SLN (10.3 %; 7/68) the histopathological assessment could demonstrate a metasta-tic involvement. 11 additional SLN (19.1 %) in 8 patients were only identified using the fluorescent labeling. Two of these additional SLN (9.1 %; 2/22) showed metastatic involvement. CONCLUSION: The ICG fluorescence-guided SLNB is an innovative imaging technique for dermato-oncology, reliable and providing additional information in the detection of SLN. Therefore SLNB with fluorescence-dye is an attractive option with intraoperative real-time lymphoscintigraphy to improve the detection of SLN in cutaneous malignancies and potential reduction of the false negative rate in SLN.

[Joint DGN, OGNMB and SGNM S1 guideline for radiosynoviorthesis]. / Gemeinsame Handlungsempfehlung (S1-Leitlinie) von DGN, OGNMB und SGNM ­ Radiosynoviorthese ­ Stand: 9/2019 ­ AWMF-Registernummer: 031-023.

This recommendation is intended to provide a guideline for radiosynoviorthesis (RSO) in the effective local treatment of chronic inflammatory (non-infectious) joint diseases. It was developed in an interdisciplinary manner and describes the general objectives, definitions, clinical background information, indication and contraindications of this radionuclide therapy. The requirements to be met by a treatment center, the results of pretherapeutic examinations as well as recommendations on how the treatment should be carried out. Here, organizational and technical issues have been considered. Furthermore, information on the surveillance and follow-up of the treated patients can be found. In general, treatment and follow-up should be done in in close cooperation of the participating disciplines.

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Integrated 68Ga-HBED-CC-PSMA-PET/MRI in patients with suspected recurrent prostate cancer.

AIM: Evaluate the diagnostic accuracy of 68Ga-labeled HBED-CC-PSMA-PET/MRI for detection of recurrent PCa in comparison to PET/CT. METHODS: 48 patients with suspected recurrent PCa underwent PET/CT after injection of the 68Ga-HBED-CC-PSMA ligand followed by integrated PET/MRI. Image analysis was performed by nuclear medicine physicians and radiologists with respect to the detection of lymph node metastases, bone metastases and local recurrence of the tumour. Image quality was evaluated visually based on a three-point ordinal scale. RESULTS: From 48 patients initially examined, 25 were finally eligible for qualitative and quantitative image evaluation. In 14 patients, neither PET/CT nor PET/MRI found tumour lesions, and 9 patients were excluded from image analysis due to a pronounced extinction artifact around the urinary bladder (halo). In comparison to 68Ga-HBED-CC-PSMA-PET/CT, 68Ga-HBED-CC-PSMA-PET/MRI identified 14 vs. 9 local recurrences in the prostate bed and 23 vs. 20 PET-positive lymph nodes, and 4 vs. 4 PET-positive bone lesions, respectively. While the improved detection of suspicious lymph nodes was primarily attributable to the PET component, the advantageous detection of tumour recurrences in the prostate bed was chiefly referable to the superior soft-tissue contrast of the MR component of integrated PET/MRI. Analysis of SUVmax revealed that 68Ga-HBED-CC-PSMA-PET/MRI provided significantly higher SUVmax compared to 68Ga-HBED-CC-PSMA-PET/CT (17.6, range 2.0-49.6, and 15.1, range 3.5-36.8, respectively, p = 0.0019). CONCLUSION: 68Ga-HBED-CC-PSMA-PET/MRI was found to be superior as compared to 68Ga-HBED-CC-PSMA-PET/CT in the detection of PSMA-expressing prostate bed recurrences.

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.

[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.

Intraoperative Fluorescence Imaging for Sentinel Lymph Node Detection: Prospective Clinical Trial to Compare the Usefulness of Indocyanine Green vs Technetium Tc 99m for Identification of Sentinel Lymph Nodes.

IMPORTANCE: The metastatic status of regional lymph nodes is the most relevant prognostic factor in breast cancer, melanoma, and other solid organ tumors with a lymphatic spread. The current gold standard for detection and targeted excision of the sentinel lymph node is preoperative lymphoscintigraphy with technetium Tc 99m. Because of the worldwide shortage of technetium Tc 99m, physicians are looking for nonradioactive dyes for sentinel lymph node labeling. Based on several retrospective studies, the fluorescent dye indocyanine green is considered a possible alternative to technetium Tc 99m. OBJECTIVE: To analyze the feasibility and clinical benefit of intraoperative near infrared fluorescence sentinel lymph node excision (SLNE) compared with standard technetium Tc 99m-guided SLNE using malignant melanoma in which SLNE is firmly established. DESIGN, SETTING, AND PARTICIPANTS: Analysis of a prospective clinical trial at the Skin Cancer Center, University Hospital Essen. Eighty patients with malignant melanoma on the trunk or extremities (upper and lower) who were scheduled to undergo SLNE were included in this study from January 1, 2013, to June 27, 2014. MAIN OUTCOMES AND MEASURES: Concordance of preoperative and intraoperative sentinel lymph node detection rates. RESULTS: During the study period, 80 patients were operated on with an additional intraoperative application of a near infrared fluorescent dye. In these 80 surgical procedures, 147 SLNs were excised. Detection of a technetium Tc 99m-marked SLN before surgery was possible in all cases. Intraoperative visualization of the SLN by indocyanine green before skin incision was successful in only 17 of 80 patients (21%). The number of SLNs identified using the near infrared fluorescence technique in the operative site after skin incision and initial tissue preparation was 141 of 147 (96%). CONCLUSIONS AND RELEVANCE: Among patients in whom the lymph node basin cannot be predicted correctly (eg, in cutaneous melanoma on the trunk), the use of indocyanine green for SLN detection is severely limited compared with SLNE using standard technique guided by technetium Tc 99m. Therefore, SLNE with the use of radiocolloid, followed if possible by single-photon emission computed tomography, remains the gold standard. TRIAL REGISTRATION: German Clinical Trials Register identifier DRKS00004619.

Quantitative evaluation of bone metastases from prostate cancer with simultaneous [18F] choline PET/MRI: combined SUV and ADC analysis.

OBJECTIVE: To quantitatively analyze bone metastases from prostate cancer and correlate the apparent diffusion coefficients (ADCs) and standardized uptake values (SUVs). METHODS: Fifty-five patients with biopsy-proven prostate cancer or suspected recurrent prostate cancer were examined with simultaneous [18F] choline Positron emission tomography (PET)/MRI at 3 T. In 11 patients, thirty-two PET-positive bone lesions could be identified that were located in the field-of-view of the Diffusion weighted imaging-sequence. Region-of-interest and volume-of-interest analyses were performed to measure the mean and minimal ADCs and to assess maximum and mean SUVs of every bone lesion. Correlations between maximum and mean SUVs and mean and minimal ADCs were calculated. RESULTS: The SUVmax of all lesions was 5.5±3.1 (mean±SD). The SUVmean was 1.8±0.9. The mean ADC (ADCmean) of all lesions was 0.67±0.13×10(-3) mm2/s. The minimal ADC (ADCmin) of all lesions was 0.56±0.14×10(-3) mm2/s. There was a moderate but significant inverse correlation of SUVmax vs. ADCmean with a correlation coefficient of -0.4 (p=0.02). There was also a significant inverse correlation of SUVmax vs. ADCmin with r=-0.41 (p=0.02). CONCLUSION: Our initial results demonstrate a moderate but significant inverse correlation between increased choline metabolism and ADC values of bone metastases from prostate cancer. Further research on a multimodality approach using simultaneous PET/MRI in bone metastasis of prostate cancer seems to be justified.

Combined PET imaging and diffusion-weighted imaging of intermediate and high-risk primary prostate carcinomas with simultaneous [18F] choline PET/MRI.

PURPOSE: To characterize intermediate and high-risk prostate carcinomas with measurements of standardized uptake values (SUVs) and apparent diffusion coefficient (ADC) values by means of simultaneous [18F] choline PET/MRI. MATERIALS AND METHODS: 35 patients with primary prostate cancer underwent simultaneous [18F] choline PET/MRI. From these, 21 patients with an intermediate and high risk constellation who were not under ongoing hormonal therapy were included. Altogether 32 tumor lesions with a focal uptake of [18F] choline could be identified. Average ADC values (ADCaver) minimum ADC values (ADCmin) as well as maximum and mean SUVs (SUVmax, SUVmean) of tumor lesions were assessed with volume-of-interest (VOI) and Region-of-interest (ROI) measurements. As a reference, also ADCaver, ADCmin and SUVmax and SUVmean of non-tumorous prostate tissue were measured. Statistical analysis comprised calculation of descriptive parameters and calculation of Pearson's product moment correlations between ADC values and SUVs of tumor lesions. RESULTS: Mean ADCaver and ADCmin of tumor lesions were 0.94±0.22×10(-3) mm2/s and 0.65±0.21×10(-3) mm2/s, respectively. Mean SUVmax and SUVmean of tumor lesions were 6.3±2.3 and 2.6±0.8, respectively. These values were in each case significantly different from the reference values (p<0.001). There was no significant correlation between the measured SUVs and ADC values (SUVmax vs. ADCaver: R = -0.24, p = 0.179; SUVmax vs. ADCmin: R = -0.03, p = 0.877; SUVmean vs. ADCaver: R = -0.27, p = 0.136; SUVmean vs. ADCmin: R = -0.08, p = 0.679). CONCLUSION: Both SUVs and ADC values differ significantly between tumor lesions and healthy tissue. However, there is no significant correlation between these two parameters. This might be explained by the fact that SUVs and ADC values characterize different parts of tumor biology.

Prognostic stratification of metastatic gastroenteropancreatic neuroendocrine neoplasms by 18F-FDG PET: feasibility of a metabolic grading system.

UNLABELLED: The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of (18)F-FDG PET in inoperable multifocal disease. METHODS: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing (18)F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent (18)F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0-2.3; mG3, >2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 µg/L), neuron-specific enolase (≥25 µg/L), and classic grading (Ki-67-based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. RESULTS: The median follow-up period was 38 mo (95% confidence interval [CI], 27-49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21-37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On multivariate analysis, markedly elevated plasma neuron-specific enolase (P = 0.016; hazard ratio, 2.9; 95% CI, 1.2-7.0) and high metabolic grade (P = 0.015; hazard ratio, 4.7; 95% CI, 1.2-7.0) were independent predictors of survival. CONCLUSION: This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using (18)F-FDG PET.

Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate.

UNLABELLED: Myelosuppression may be the dose-limiting toxicity in peptide receptor radionuclide therapy (PRRT). The aim of this study was to investigate the incidence, severity, and reversibility of long-term hematotoxicity in a large cohort of patient undergoing PRRT with (177)Lu-octreotate for metastatic neuroendocrine tumors. The impact of potential risk factors, including initial cytopenia, advanced bone metastatic disease, previous chemotherapy, and cumulative administered activity, and the protective effects of splenectomy were of particular interest. METHODS: A total of 632 PRRT courses were performed in 203 patients with metastatic neuroendocrine tumors. A mean activity of 7.9 GBq of (177)Lu-octreotate was administered per treatment cycle, with a goal of 4 courses at standard intervals of 3 mo. Hematologic parameters were determined before each treatment course, at 2- to 4-wk intervals between the courses, 8-12 wk after the last course of PRRT, and at 3-month intervals for further follow-up. Toxicity was recorded with Common Terminology Criteria for Adverse Events (version 3.0). RESULTS: Myelodysplastic syndrome as a delayed adverse event was documented in 3 patients (1.4%). Relevant but reversible hematotoxicity (grade 3 or 4) occurred in 23 patients (11.3%) and 29 administrations (4.6%), with leukopenia in 2.7% and thrombocytopenia in 1.7%. The mean time to blood count recovery was 12 mo after the termination of PRRT (range, 3-22 mo). The only preexisting factor that contributed to hematotoxicity was initial cytopenia (P < 0.001). A high level of cumulative administered activity (>29.6 GBq) was associated with relevant leukopenia (P < 0.001). None of the patients with a history of splenectomy developed grade 3 or 4 hematotoxicity, and splenectomy was inversely associated with the incidence and degree of leukopenia (P = 0.02) and thrombocytopenia (P = 0.03). CONCLUSION: PRRT-induced myelosuppression is almost invariably reversible and rarely requires clinical measures. Administered activity and initial cytopenia are the only factors contributing to myelosuppression, whereas splenectomy may exert a protective effect.