[Differentiated Strategies for the Therapy of Liver Metastases in Gastro-entero-pancreatic Neuroendocrine Neoplasia]. / Differenzierte Therapiestrategie bei Lebermetastasen gastro-entero-pankreatischer Neuroendokriner Neoplasien.

Neuroendocrine neoplasias comprise a heterogenous group of malignant tumours, mostly arising from the gastro-entero-pancreatic system (GEP). Most of these tumours develop from the small intestine and pancreas and the liver is the predominant site for distant metastases. Patients may be asymptomatic for a long time and liver metastases are frequently diagnosed by chance or during operations for bowel obstruction, for example, during emergency surgery. The only curative therapy consists in complete removal of primary and metastases. In case of metastatic disease, various treatment modalities need to be discussed in interdisciplinary tumour boards comprised of specialists from gastroenterology, (liver-)surgery, radiology, nuclear medicine, radiotherapy, pathology and endocrinology. By combining different therapies, even patients with progressive disease may reach long-term overall survival with good quality of life. The most important factors for decisions on therapy are individual factors like tumour grading, hormonal functionality, type of metastases and evolution of the disease. Adequate treatment of liver metastases comprises various surgical strategies as well as locally ablative radiological interventions and nuclear medical therapies, in complement to systemic treatments.

An optimized imaging protocol for [99mTc]Tc-DPD scintigraphy and SPECT/CT quantification in cardiac transthyretin (ATTR) amyloidosis.

BACKGROUND: In [99mTc]Tc-DPD scintigraphy for myocardial ATTR amyloidosis, planar images 3 hour p.i. and SPECT/CT acquisition in L-mode are recommended. This study investigated if earlier planar images (1 hour p.i.) are beneficial and if SPECT/CT acquisition should be preferred in H-mode (180° detector angle) or L-mode (90°). METHODS: In SPECT/CT phantom measurements (NaI cameras, N = 2; CZT, N = 1), peak contrast recovery (CRpeak) was derived from sphere inserts or myocardial insert (cardiac phantom; signal-to-background ratio [SBR], 10:1 or 5:1). In 25 positive and 38 negative patients (reference: endomyocardial biopsy or clinical diagnosis), Perugini scores and heart-to-contralateral (H/CL) count ratios were derived from planar images 1 hour and 3 hour p.i. RESULTS: In phantom measurements, accuracy of myocardial CRpeak at SBR 10:1 (H-mode, 0.95-0.99) and reproducibility at 5:1 (H-mode, 1.02-1.14) was comparable for H-mode and L-mode. However, L-mode showed higher variability of background counts and sphere CRpeak throughout the field of view than H-mode. In patients, sensitivity/specificity were ≥ 95% for H/CL ratios at both time points and visual scoring 3 hour. At 1 hour, visual scores showed specificity of 89% and reduced reader's confidence. CONCLUSIONS: Early DPD images provided no additional value for visual scoring or H/CL ratios. In SPECT/CT, H-mode is preferred over L-mode, especially if quantification is applied apart from the myocardium.

Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.

To Perform, or Not to Perform Interim PET: Questioning the Impact of Midtherapy Evaluation During PRRT in GEP-NET Patients.

PURPOSE: This study aimed to analyze the impact of interim evaluation on the continuation of 177Lu-based peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to survey its usage across German university hospitals. PATIENTS AND METHODS: In 119 GEP-NET patients who underwent PRRT, we retrospectively assessed the results and therapeutic impact of restaging performed after 2 cycles using MRI/CT/somatostatin receptor imaging. Therapeutic decisions based on interim PET results were made in multidisciplinary tumor board meetings. Additionally, an online survey was conducted among 37 German university hospitals regarding their interim evaluation practices, focusing on the change in management. RESULTS: Of 119 patients, 83 completed 4 PRRT cycles; 36 stopped after 2: 27 showed PD, 3 had PR leading to surgery, 5 experienced toxicity, and 1 died. Those completing 4 cycles showed a median PFS of 38.0 months (95% confidence interval, 32.2-43.8). Seventeen of 37 surveyed hospitals routinely used interim evaluation. In a survey among 37 German university hospitals, 62% reported offering PRRT for GEP-NET patients, with 74% of these performing a routinely interim evaluation after 2 cycles of PRRT, primarily using PET/CT imaging techniques. CONCLUSIONS: Interim PET after 2 PRRT cycles helps to identify early progression in GEP-NET patients. Standardizing interim evaluation practices could enhance the comparability of clinical outcomes and optimize patient management.

Keeping Up With ChatGPT: Evaluating Its Recognition and Interpretation of Nuclear Medicine Images.

PURPOSE: The latest iteration of GPT4 (generative pretrained transformer) is a large multimodal model that can integrate both text and image input, but its performance with medical images has not been systematically evaluated. We studied whether ChatGPT with GPT-4V(ision) can recognize images from common nuclear medicine examinations and interpret them. PATIENTS AND METHODS: Fifteen representative images (scintigraphy, 11; PET, 4) were submitted to ChatGPT with GPT-4V(ision), both in its Default and "Advanced Data Analysis (beta)" version. ChatGPT was asked to name the type of examination and tracer, explain the findings and whether there are abnormalities. ChatGPT should also mark anatomical structures or pathological findings. The appropriateness of the responses was rated by 3 nuclear medicine physicians. RESULTS: The Default version identified the examination and the tracer correctly in the majority of the 15 cases (60% or 53%) and gave an "appropriate" description of the findings or abnormalities in 47% or 33% of cases, respectively. The Default version cannot manipulate images. "Advanced Data Analysis (beta)" failed in all tasks in >90% of cases. A "major" or "incompatible" inconsistency between 3 trials of the same prompt was observed in 73% (Default version) or 87% of cases ("Advanced Data Analysis (beta)" version). CONCLUSIONS: Although GPT-4V(ision) demonstrates preliminary capabilities in analyzing nuclear medicine images, it exhibits significant limitations, particularly in its reliability (ie, correctness, predictability, and consistency).

Neurological affection and serum neurofilament light chain in wild type transthyretin amyloidosis.

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

68Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT for locally advanced or recurrent pancreatic cancer staging and restaging after chemoradiotherapy.

Purpose: 68Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer. Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT). The aim of this study was to evaluate [68Ga]Ga-FAPI-46 PET/CT staging in this setting. Methods: Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression. Quantitative PET parameters SUVmax, SUVmean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans. Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification. Results: FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons). Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis. Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake. During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUVmax p = 0.047, SUVmean p = 0.0092) compared to local failure. Conclusion: Compared to ceCT, FAPI PET/CT led to major therapeutic alterations in patients with LRPAC and LAPAC prior to and after radiotherapy, which might help identify patients benefiting from adjustments in every treatment stage. FAPI PET/CT should be considered a useful diagnostic tool in LRPAC or LAPAC before and after CRT.

Same same but different: dopamine transporter SPECT on scanners with CZT vs. NaI detectors.

BACKGROUND: The aims of this study were to establish a normal database (NDB) for semiquantification of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) with [123I]FP-CIT on a cadmium zinc telluride (CZT) camera, test the preexisting NaI-derived NDB for use in CZT scans, and compare the diagnostic findings in subjects imaged with a CZT scanner with either the preexisting NaI-based NDB or our newly defined CZT NDB. METHODS: The sample comprised 73 subjects with clinically uncertain parkinsonian syndrome (PS) who prospectively underwent [123I]FP-CIT SPECT on a CZT camera according to standard guidelines with identical acquisition and reconstruction protocols (DaTQUANT). Two experienced readers visually assessed the images and binarized the subjects into "non-neurodegenerative PS" and "neurodegenerative PS". Twenty-five subjects from the "non-neurodegenerative PS" subgroup were randomly selected to establish a CZT NDB. The remaining 48 subjects were defined as "test group". DaTQUANT was used to determine the specific binding ratio (SBR). For the test group, SBR values were transformed to z-scores for the putamen utilizing both the CZT NDB and the manufacturer-provided NaI-based NDB (GE NDB). A predefined fixed cut-off of -2 was used for dichotomization of z-scores to classify neurodegenerative and non-neurodegenerative PS. Performance of semiquantification using the two NDB to identify subjects with neurodegenerative PS was assessed in comparison with the visual rating. Furthermore, a randomized head-to-head comparison of both detector systems was performed semiquantitatively in a subset of 32 out of all 73 subjects. RESULTS: Compared to the visual rating as reference, semiquantification based on the dedicated CZT NDB led to fewer discordant ratings than the GE NDB in CZT scans (3 vs. 8 out of 48 subjects). This can be attributed to the putaminal z-scores being consistently higher with the GE NDB on a CZT camera (median absolute difference of 1.68), suggesting an optimal cut-off of -0.5 for the GE NDB instead of -2.0. Average binding ratios and z-scores were significantly lower in CZT compared to NaI data. CONCLUSIONS: Use of a dedicated, CZT-derived NDB is recommended in [123I]FP-CIT SPECT with a CZT camera since it improves agreement between semiquantification and visual assessment.

ChatGPT: Can You Prepare My Patients for [18F]FDG PET/CT and Explain My Reports?

We evaluated whether the artificial intelligence chatbot ChatGPT can adequately answer patient questions related to [18F]FDG PET/CT in common clinical indications before and after scanning. Methods: Thirteen questions regarding [18F]FDG PET/CT were submitted to ChatGPT. ChatGPT was also asked to explain 6 PET/CT reports (lung cancer, Hodgkin lymphoma) and answer 6 follow-up questions (e.g., on tumor stage or recommended treatment). To be rated "useful" or "appropriate," a response had to be adequate by the standards of the nuclear medicine staff. Inconsistency was assessed by regenerating responses. Results: Responses were rated "appropriate" for 92% of 25 tasks and "useful" for 96%. Considerable inconsistencies were found between regenerated responses for 16% of tasks. Responses to 83% of sensitive questions (e.g., staging/treatment options) were rated "empathetic." Conclusion: ChatGPT might adequately substitute for advice given to patients by nuclear medicine staff in the investigated settings. Improving the consistency of ChatGPT would further increase reliability.

Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy.

BACKGROUND: Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. METHODS: A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. RESULTS: Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). CONCLUSIONS: Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.

Prognostic Value of the Largest Lesion Size for Progression-Free Survival in Patients with NET Undergoing Salvage PRRT with [177Lu]Lu-DOTATOC.

(1) Background: retreatment with radionuclide-labeled somatostatin analogues following disease progression after initial treatment cycles is often referred to as salvage peptide receptor radionuclide therapy (salvage PRRT). Salvage PRRT is shown to have a favorable safety profile in patients with metastatic neuroendocrine tumors (NETs), but numerous questions about the efficacy and prognostic or predictive factors remain to be answered. The purpose of this study was to evaluate two parameters that have shown prognostic significance in progression-free survival (PFS) in initial PRRT treatment, namely the size of the largest lesion (LLS) and the De Ritis ratio (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)), as prognostic factors in the context of salvage PRRT. In addition, the PFS after initial PRRT was evaluated as a predictor of the PFS following salvage PRRT. (2) Methods: retrospective, monocentric analysis in 32 patients with NETs (gastroenteropancreatic, 23; unknown primary, 7; kidney, 1; lung, 1) and progression after initial PRRT undergoing retreatment with [177Lu]Lu-DOTATOC. The prognostic values of LLS, the De Ritis ratio, and PFS after initial treatment cycles regarding PFS following salvage PRRT were evaluated with univariable and multivariable Cox regression. PFS was defined as the time from treatment start until tumor progression according to RECIST 1.1 criteria, death from any cause or start of a new treatment due to progression of cancer-related symptoms (namely carcinoid syndrome). (3) Results: progression after salvage PRRT was observed in 29 of 32 patients with median PFS of 10.8 months (95% confidence interval (CI), 8.0-15.9 months). A higher LLS (hazard ratio (HR): 1.03; p = 0.002) and a higher De Ritis ratio (HR: 2.64; p = 0.047) were associated with shorter PFS after salvage PRRT in univariable Cox regression. PFS after initial PRRT was not associated with PFS following salvage PRRT. In multivariable Cox regression, only LLS remained a significant predictor. (4) Conclusions: the size of the largest lesion is easy to obtain and might help identify patients at risk of early disease progression after salvage PRRT. Validation is required.

Same same, but different? The neurological presentation of wildtype transthyretin (ATTRwt) amyloidosis.

BACKGROUND: Both hereditary transthyretin (ATTRv) amyloidosis and wildtype transthyretin (ATTRwt) amyloidosis can be associated with neurological diseases such as carpal tunnel syndrome and polyneuropathy. While ATTRv amyloidosis has been extensively studied, to date little is known about neurological complications of ATTRwt amyloidosis. In particular, the prevalence, pattern and extent of polyneuropathy and autonomic dysfunction has not been adequately investigated in the context of ATTRwt amyloidosis. To tackle this issue, we aimed to characterise the neurological presentation of ATTRwt amyloidosis and to compare between the presentations of ATTRv and ATTRwt amyloidoses. PATIENTS AND METHODS: Between November 2019 and September 2020, we included 50 patients with ATTRwt amyloidosis in this cohort study. All patients presented to the amyloidosis centre in Berlin, Germany and underwent neurological, cardiological and radiological work-up including neurological examination, laboratory testing, nerve conduction studies (NCS), echocardiography and scintigraphy. Patients were screened for symptoms of autonomic dysregulation and a subgroup of patients underwent tilt-table testing for orthostatic dysregulation. RESULTS: The cohort included 46 men and 4 women; the mean age of the study participants was 80.6 (standard deviation [SD] ± 5.0) years. All patients showed signs of cardiomyopathy on echocardiography. Neurological examination revealed peripheral, symmetric and length-depended predominately sensory polyneuropathy in 74% (n = 37) of patients. Neuropathy impairment scores (NIS) ranged from 0 to 50 with an average score of 8.4 (SD ± 10.1) indicating mild to moderate impairment. 90% and 92% of patients were classified as FAP stage I and PND stage I, respectively. Unilateral or bilateral carpal tunnel syndrome (CTS) was present in 70% (n = 35) and spinal stenosis was seen in 11% (n = 5) of patients. We detected a low rate of autonomic symptoms with a median COMPASS-31 total score of 18.4 points (IQR 32.4 points). Additional tilt-table testing of a subgroup of 8 patients yielded negative results for orthostatic intolerance. CONCLUSION: Distal-symmetric, predominantly sensory polyneuropathy is a common neurological complication in ATTRwt amyloidosis besides carpal tunnel syndrome and spinal stenosis, further substantiating the systemic character of the disease. Compared to ATTRv amyloidosis, the severity of polyneuropathy in ATTRwt amyloidosis is milder and without relevant motor involvement. Symptoms of autonomic dysfunction were not common in this cohort. Nevertheless, ATTRwt amyloidosis is a treatable disease and should be included in the differential diagnosis of sensory polyneuropathy in the elderly.

Added Value of Tomoelastography for Characterization of Pancreatic Neuroendocrine Tumor Aggressiveness Based on Stiffness.

PURPOSE: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. METHODS: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson's r. RESULTS: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). CONCLUSIONS: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness.

The Prognostic Value of the De Ritis Ratio for Progression-Free Survival in Patients with NET Undergoing [177Lu]Lu-DOTATOC-PRRT: A Retrospective Analysis.

BACKGROUND: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). METHODS: Unicentric, retrospective analysis of 125 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC (female: 37%; median age: 66 years; G1+G2 NET: 95%). The prognostic value regarding progression-free survival (PFS) was analyzed with univariable and multivariable Cox regression. Prognostic accuracy was determined with Harrell's C index and a likelihood ratio test. RESULTS: Progression, relapse, or death after PRRT was observed in 102/125 patients. Median progression-free survival (PFS) was 15.8 months. Pancreatic or pulmonary origin, high De Ritis ratio, and high Chromogranin A (CgA) significantly predicted shorter PFS in univariable Cox. In multivariable Cox regression, only high De Ritis ratio >0.927 (HR: 1.7; p = 0.047) and high CgA >twice the upper normal limit (HR: 2.1; p = 0.005) remained independent predictors of shorter PFS. Adding the De Ritis ratio to the multivariable Cox model (age, Eastern Cooperative Oncology Group (ECOG) performance status, primary origin, CgA) significantly improved prognostic accuracy (p < 0.001). CONCLUSIONS: The De Ritis ratio is simple to obtain in clinical routine and can provide independent prognostic value for PFS in patients with NET undergoing PRRT.

Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment?

BACKGROUND: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. METHODS: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48-81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. RESULTS: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1-11.4 months) versus 14.4 (12.5-16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). CONCLUSION: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

Influence of Gender on Therapy and Outcome of Neuroendocrine Tumors of Gastroenteropancreatic Origin: A Single-Center Analysis.

INTRODUCTION: Gender-specific treatment is gaining growing attention in various fields of medicine. In gastrointestinal cancer, influence of sex on outcome has been discussed, while this has not been the case in neuroendocrine tumors. Overall, the incidence of neuroendocrine neoplasms is rising, especially for appendiceal neuroendocrine neoplasms in women. Also, women seem to have a slight advantage in response to therapy, especially for liver metastases. OBJECTIVES: This single-center analysis aimed to investigate gender-specific differences in our cohort related to distribution, therapy, and outcome. METHODS: Patients from the NET registry as well as the clinic database were evaluated retrospectively concerning overall survival and response to therapy with respect to gender. A subgroup analysis was carried out for patients with low grading and response to chemotherapy, as well as for patients with good and moderate grading receiving peptide receptor radionuclide therapy and for a group of patients with liver surgery. RESULTS: No specific differences could be detected for overall survival or response to therapy between male and female patients. Mean survival was estimated with 242.2 months (±10.39 SD) altogether and 221.7 months (± 13.02 SD) for male patients and 253.5 months (±15.24 SD) for female patients from the NET registry from initial diagnosis. There was no significant difference between female and male patients (p = 0.136). For patients receiving chemotherapy, overall survival from initial diagnosis was calculated with 26 months (±2.59) and did not show any significant differences between female and male patients 24.8 months (±2.81 SD) vs. 27.8 months (±3.86 SD, p = 0.87). Patients undergoing peptide receptor radionuclide therapy showed a median progression-free survival of 26.9 months (±2.82 SD), with 16.9 (±5.595 SD) and 26.9 months (±3.019 SD) for male and female patients, respectively (p = 0.2). In the group of patients with liver surgery, female patients reached an estimated overall survival of 64.7 months (±4.16 SD), male patients 65.1 months (±2.79 SD, p = 0.562). CONCLUSION: Our cohort did not reveal significant differences in outcome and response to therapy with regards to gender.

Shortened Tracer Uptake Time in GA-68-DOTATOC-PET of Meningiomas Does Not Impair Diagnostic Accuracy and PET Volume Definition.

Ga-68-DOTATOC-PET/MRI can affect the planning target volume (PTV) definition of meningiomas before radiosurgery. A shorter tracer uptake time before image acquisition could allow the examination of more patients. The aim of this study was to investigate if shortening uptake time is possible without compromising diagnostic accuracy and PET volume. Fifteen patients (f = 12; mean age 52 years (34-80 years)) with meningiomas were prospectively examined with dynamic [68Ga]Ga-68-labeled [DOTA0-Phe1-Tyr3] octreotide (Ga-68-DOTATOC)-PET/MRI over 70 min before radiosurgery planning. Meningiomas were delineated manually in the PET dataset. PET volumes at each time point were compared to the reference standard 60 min post tracer injection (p.i.) using the Friedman test followed by a Wilcoxon signed-rank test and Bonferroni correction. In all patients, the earliest time point with 100% lesion detection compared to 60 min p.i. was identified. PET volumes did not change significantly from 15 min p.i. (p = 1.0) compared to 60 min p.i. The earliest time point with 100% lesion detection in all patients was 10 min p.i. In patients with meningiomas undergoing Ga-68-DOTATOC-PET, the tracer uptake time can safely be reduced to 15 min p.i. with comparable PET volume and 100% lesion detection compared to 60 min p.i.

The association of intra-therapeutic heterogeneity of somatostatin receptor expression with morphological treatment response in patients undergoing PRRT with [177Lu]-DOTATATE.

AIM: Purpose of this study was to evaluate the association of the spatial heterogeneity (asphericity, ASP) in intra-therapeutic SPECT/ CT imaging of somatostatin receptor (SSR) positive metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) for morphological treatment response to peptide receptor radionuclide therapy (PRRT). Secondly, we correlated ASP derived form a pre-therapeutic OctreoScan (ASP[In]) and an intra-therapeutic [177Lu]-SPECT/CT (ASP[Lu]). MATERIALS AND METHODS: Data from first therapy cycle [177Lu-DOTA0-Tyr3]octreotate ([177Lu]-DOTATATE)-PRRT was retrospectively analyzed in 33 patients (m = 20; w = 13; median age, 72 [46-88] years). The evaluation of response to PRRT was performed according to RECIST 1.1 in responding lesions [RL (SD, PR, CR), n = 104] and non-responding lesions [NRL (PD), n = 27]. The association of SSR tumor heterogeneity with morphological response was evaluated by Kruskal-Wallis test and receiver operating characteristic curve (ROC). The optimal threshold for separation (RL vs. NRL) was calculated using the Youden-index. Relationship between pre- and intra-therapeutic ASP was determined with Spearman's rank correlation coefficient (ρ) and Bland-Altman plots. RESULTS: A total of 131 lesions (liver: n = 59, lymph nodes: n = 48, bone: n = 19, pancreas: n = 5) were analyzed. Lesions with higher ASP values showed a significantly poorer response to PRRT (PD, median: 11.3, IQR: 8.5-15.5; SD, median: 3.4, IQR: 2.1-4.5; PR, median 1.7, IQR: 0.9-2.8; CR, median: 0.5, IQR: 0.0-1.3); Kruskal-Wallis, p<0.001). ROC analyses revealed a significant separation between RL and NRL for ASP after 4 months (AUC 0.85, p<0.001) and after 12 months (AUC 0.94, p<0.001). The optimal threshold for ASP was >5.45% (sensitivity 96% and specificity 82%). The correlation coefficient of pre- and intra-therapeutic ASP revealed ρ = 0.72 (p <0.01). The mean absolute difference between ASP[In] and ASP[Lu] was -0.04 (95% Limits of Agreement, -6.1-6.0). CONCLUSION: Pre- and intra-therapeutic ASP shows a strong correlation and might be an useful tool for therapy monitoring.

Pre-operative quantification of pulmonary function using hybrid-SPECT/low-dose-CT: A pilot study.

RATIONALE: Pre-operative lobar function is estimated by scintigraphy in patients with pulmonary malignancies and compromised function. This study compared the lobar perfusion determined by scintigraphy (PS) with data from SPECT/low-dose-CT (SPECT/ldCT) analyzed manually and semi-automatic. METHODS: Retrospective analysis on 39 patients (m/f = 25/14; age: 72.5 [22-89] years) with indication for pulmonary perfusion scintigraphy. Imaging was performed using SPECT/ldCT. Data was analyzed manually and by semi-automatic software. Readers' confidence in 3D-segmentation was scored by two independent readers. Interrater agreement was calculated. In addition, Spearman's rank correlation and Wilcoxon's test were used. RESULTS: Results from PS differed significantly from SPECT/ldCT processed manually or semi-automatically in 4/5 lobes (total difference ≤21.6%; rho ≥0.44) and in 3/5 (total difference 21.6%; rho ≥0.37), respectively. Readers' confidence in 3D-segmentation showed a perfect interrater agreement (κ = 0.98). CONCLUSION: Quantification of lobar perfusion by SPECT/ldCT differs significantly from planar scintigraphy (e.g., with potential influence on therapy). The semi-automatic software analysis provides an applicable methodology.

Predictive Value of Asphericity in Pretherapeutic [111In]DTPA-Octreotide SPECT/CT for Response to Peptide Receptor Radionuclide Therapy with [177Lu]DOTATATE.

PURPOSE: The purpose of this study was to assess the value of the spatial heterogeneity of somatostatin receptor (SSR) volume, quantified as asphericity (ASP), and to predict response to peptide receptor radionuclide therapy (PRRT) in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). PROCEDURES: From June 2011 to May 2013, patients suffering from GEP-NEN who underwent pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®) prior to [177Lu-DOTA0-Tyr3]octreotate ([177Lu]DOTATATE)-PRRT were enrolled in this retrospective evaluation. SSR expression in 20 NEN patients was qualitatively and quantitatively assessed using the Krenning score, the metastasis to liver uptake ratio (M/L ratio), and ASP at baseline. Response to PRRT was evaluated based on lesions, which were classified as responding lesions (RL) and non-responding lesions (NRL) after 4- and 12-month follow-ups. The values of the Krenning score, M/L ratio, and ASP for response prediction were compared by using the Mann-Whitney U test, Kruskal-Wallis test, and receiver operating characteristic (ROC) curves. RESULTS: Seventy-seven metastases (liver, n = 40; lymph node, n = 24; bone, n = 11; pancreas, n = 2) showed SSR expression. A higher ASP level was significantly associated with poorer response at both time points. ROC analyses revealed the highest area under the curve (AUC) for discrimination between RL and NRL for ASP after 4 months (AUC 0.97; p = 0.019) and after 12 months (AUC 0.96; p < 0.001), followed by the Krenning score (AUC 0.74; p = 0.082 and AUC 0.85; p < 0.001, respectively) and M/L ratio (AUC 0.77; p = 0.107 and AUC 0.82; p < 0.001). The optimal cutoff value for ASP was 5.12 % (sensitivity, 90 %; specificity, 93 %). CONCLUSION: Asphericity of SSR-expressing lesions in pretherapeutic single-photon emission computed tomography with integrated computed tomography (SPECT/CT) is a promising parameter for predicting response to PRRT in gastroenteropancreatic neuroendocrine neoplasms.