Thorsten Pöppel

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.

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

PurposeThe aim of this study was to evaluate the positron emission tomography (PET) component of [18F]choline PET/MRI and compare it with the PET component of [18F]choline PET/CT in patients with histologically proven prostate cancer and suspected recurrent prostate cancer.MethodsThirty-six patients were examined with simultaneous [18F]choline PET/MRI following combined [18F]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.ResultsAll 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.ConclusionPET 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 [18F]choline PET/MRI than in [18F]choline PET/CT. Differences of SUVmax and SUVmean might be caused by different techniques of attenuation correction. Furthermore, differences in biodistribution and biokinetics of [18F]choline between the subsequent examinations and in the respective organ systems have to be taken into account.

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.

Prognostic Stratification of Metastatic Gastroenteropancreatic Neuroendocrine Neoplasms by 18F-FDG PET: Feasibility of a Metabolic Grading System

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 18F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18F-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 18F-FDG PET.

Malignant Pheochromocytoma Imaging with [124I]mIBG PET/MR

Pheochromocytoma localized in the adrenal medulla (in 85%) or in the thoracic/abdominal sympathetic trunk (paraganglioma) has malignant potential in about 10% of cases. Metaiodobenzylguanidine (mIBG) can be labeled with 123-iodine (for scintigraphy), 131-iodine (basically for therapy), or 124-iodine [excellent positron emission tomography (PET) imaging and tumor dosimetry based on high spatial resolution] and has high sensitivity for the diagnosis of primary/metastatic pheochromocytoma (1–3). Thiscasereportsontheworldwidefirst [I]-mIBG-PET/ magnetic resonance imaging (MRI) performed with an integrated PET/MR (Biograph mMR; Siemens Healthcare, Erlangen, Germany) in a malignant pheochromocytoma. The addition of MRI to mIBG-PET is promising as it improves tumor delineation because of the high soft tissue contrast in MRI that is especially relevant in pretherapeutic dosimetry. Compared with conventional [I]mIBG scintigraphy, [I]mIBG-PET provides high-resolution images. A 24-yr-old woman suffering from progressive malignant pheochromocytoma (primary right adrenal) underwent dosimetry with [I]mIBG PET/computed tomography (CT) (50 MBq) for treatment planning before therapy with [I]mIBG. An additional whole-body PET/ MRI (48 h after [I]mIBG administration) was performed with the following examination parameters (entire acquisition time, 40 min): four bed positions (head to upper thigh); PET, 8-min list mode per bed position; MRI, DIXON (T1-weighted sequences in-/opposed phases) for acquiring the -map for attenuation correction, simultaneous with PET non-contrast-enhanced coronal T1, transversal fat-saturated T2, and diffusionweighted imaging non-simultaneous followed by coronal and axial fat-saturated T1 after administration of gadolinium-based contrast agent. The PET/MRI (Fig. 1A, PET maximum intensity projection (MIP); B, fused PET/MRI coronal T1; C, fused PET/CT coronal) revealed local tumor recurrence (right adrenal bed) and multiple metastases (liver, lymph nodes, abdominal muscles, peritoneal) with intense tracer uptake, hyperintense signal on T2, hypointense on nonen-

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).

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.

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.

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 Fishers 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.

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 Burkitts 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.