Krenning Score Research Articles

Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

Assessing Krenning's score on 68 Ga-DOTATATE PET-CT and miPSMA score on 68 Ga-PSMA-11 PET-CT in TENIS: a comparison with FDG PET/CT and examining the feasibility of targeted radionuclide therapy.

The objective of this study was to assess receptor expression in metastatic differentiated thyroid carcinoma patients with progressive elevated thyroglobulin and negative iodine scintigraphy, we used 68 Ga-DOTATATE [Gallium-68 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)] (Krenning's score) and 68 Ga-PSMA-11 (Gallium-68 prostate-specific membrane antigen-11) PET-computed tomography (CT) [molecular imaging prostate-specific membrane antigen (miPSMA) score]. Patients with Krenning's score 3 and above and miPSMA score 2 and above were considered to determine the incidence of patients, who would qualify for treatment with 177 Lu-DOTATATE/PSMA [Lutetium-177 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)/prostate-specific membrane antigen]-based therapy. In addition, we compared 68 Ga-DOTATATE and 68 Ga-PSMA-11 PET-CT with 2-deoxy-2-[F-18]fluoroglucose ( 18 F-FDG) PET-CT (using maximum standardized uptake value). A total of 74 patients with histopathologically proven metastatic differentiated thyroid carcinoma with thyroglobulin elevation and negative iodine scintigraphy syndrome were studied retrospectively. They all had 18 F-FDG, 68 Ga-DOTATATE, and 68 Ga-PSMA-11 PET-CT scans available for undertaking this analysis. The lesions detected by 68 Ga-DOTATATE and 68 Ga-PSMA-11 were evaluated using Krenning's and miPSMA scores. In addition, quantitative comparisons of maximum standardized uptake values for 68 Ga-DOTATATE and 68 Ga-PSMA-11, as well as with 18 F-FDG, were conducted. Patient-wise analysis revealed positivity rates of 40.5% for 68 Ga-DOTATATE, 41.89% for 68 Ga-PSMA-11, and 75.67% for 18 F-FDG. Among the 74 patients, 14 (18.91%) were deemed eligible for 177 Lu-DOTATATE/PSMA-617 therapy based on Krenning's score of 3 and above both/either miPSMA score of 2 and above on 68 Ga-DOTATATE or 68 Ga-PSMA-11 PET-CT. Within this subgroup, seven out of 74 patients (9.45%) were eligible for 177 Lu-DOTATATE therapy, and nine out of 74 patients (12.16%) were eligible for 177 Lu-PSMA-targeted therapy. Four patients were eligible for both therapies. Among thyroglobulin elevation and negative iodine scintigraphy patient's subgroup, 9.45% could qualify for 177 Lu-DOTATATE and 12.16% for 177 Lu-PSMA-617. Four were eligible for both therapies. Given the lack of effective therapies, this subset of patients warrants consideration for radionuclide therapy exploration.

Survival and Response Outcomes for Gastrointestinal Neuroendocrine Tumor (GEP-NETs) Patients Treated with Lutetium-177-DOTATATE in a Brazilian Reference Center: A Six-Year Follow-Up Experience.

PRRT can be an option for all-grade GEP-NETs, but selecting patients is challenging. In this scenario, clinical-pathological and radiological characteristics, such as pre-treatment Ga-68 DOTA PET/CT, might have the potential to help. A retrospective chart review was conducted on advanced GEP-NETs treated with at least one PRRT dose. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Krenning Score (KS), and the maximum standardized uptake value (SUVmax) were derived from the pre-treatment scans. A maximally selected rank statistics test was used for SUVmax simple cut point estimate. Among 36 patients, 19 had primary pancreatic tumors. The numbers of G1, G2, and G3 tumors were 10, 18, and 7, respectively. During a median follow-up of 90.5 months, 4 patients died. Median OS was not reached for G1 and G2 tumors, and it was 30 months for G3 (p = 0.001). Median PFS was 23 months, with G3 showing lower PFS compared to G1 [7 versus 30 months; HR 8.41 (95%CI 2.2-31.0; p = 0.001)]. PRRT provides long-term PFS in patients with G1/G2 GEP-NETs independent of clinical characteristics and primary site. G3 has worse survival, but selected patients may experience long OS after PRRT treatment.

Clinical utility of somatostatin receptor positron emission tomography imaging biomarkers for characterization of meningioma among incidental central nervous system lesions.

Somatostatin receptor (SSTR) PET imaging is utilized with increasing frequency in the clinical management of neuroendocrine tumors. Incidental PET-avid CNS lesions are commonly noted and presumed to be meningiomas. However, SSTR PET lacks specificity for meningioma identification. This study aimed to clarify the role of SSTR-based imaging in the classification of incidental CNS lesions based on current clinical practice. Patients who underwent both Ga-68-DOTATATE PET and brain MRI and had an incidental CNS lesion identified with a radiographic prediction of meningioma via one (discordant prediction) or both (concordant prediction) imaging modalities were retrospectively analyzed. Imaging indication, semiquantitative measures, and clinical history were recorded. Among 48 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (64.6%). Cases with concordant lesion-type prediction of meningioma between imaging modalities ( N = 24) displayed a significantly higher SUV max (median 7.9 vs. 4.0; P = 0.008) and Krenning score (median 3.0 vs. 2.0; P = 0.005) on Ga-68-DOTATATE PET compared with cases with a discordant prediction of meningioma ( N = 24). In cases with lower SUV max values, Ga-68-DOTATATE was more likely to discordantly predict meningioma without agreement by the corresponding MRI. Prior cranial radiation or use of somatostatin mimetics did not affect quantitative radiographic measures, and MRI-based tumor size was similar across groups. Lesions with increased avidity may be more confidently predicted as meningioma in Ga-68-DOTATATE PET scans, whereas there is more discrepancy in prediction among low SUV cases.

Survival outcomes for patients (pts) with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with lutetium-177-dotatate (Lu-177) in a Brazilian reference center: A six-year follow-up experience.

642 Background: GEP-NETs are the most common NETs primary site. Lu-177 is the standard treatment for patients with grade 1 (G1) or grade 2 (G2) midgut NETs who had disease progression during first-line somatostatin analog therapy. Methods: We performed a retrospective chart review including advanced GEP-NETs treated with at least one Lu-177 dose from our institution. Overall survival (OS) and progression-free survival (PFS) were calculated from the first Lu-177 dose using the Kaplan–Meier method. Cox regression analysis was performed for PFS adjusted by grade, primary tumor site, metastasis sites (1 vs.≥ 2), presence of liver metastasis, and previous local or other systemic treatments. Krenning Score (KS) and the maximum standardized uptake value (SUVmax) were calculated from the pre-treatment Ga-68 PET/CT. Maximally Selected Rank Statistics (MSRS) test was used for SUVmax simple cutpoint estimate and PFS was calculated using the Kaplan–Meier method. Results: 36 pts were included; the median age was 51 (range: 33-80). 19 (52.8%) pts had primary pancreatic NET and 17 (47.2%) had non-pancreatic primary NETs. Tumor grading was classified based on Ki67%. 10 pts were G1 (28.6%), 18 pts were G2 (51.4%), 7 pts were G3 (20%). 7 pts (19.4%) and 28 pts (77.7%) had KS 3 and 4, respectively. 125 cycles of Lu-177 were applied with 3.5 cycles per pts (mean; range: 1-6). 12 (33.3%) pts experienced grade 1 and 2 toxicity, mainly fatigue (n=4). No grade 3 or 4 toxicities were reported. 4 (11.1%) patients died (n=3 G3; n=1 G2) with median follow-up of 90.5 months (range: 16-122). 11 pts (30.6%) lost follow-up after Lu-177 treatment. 29 pts (80.5%) were eligible for OS. 24-month and 36-month survival rates were 92,7% (95% CI 73.7 - 98.1) and 86,9% (95% CI 63.5 - 95.7) respectively. The median OS was not reached for G1 and G2 tumors, and it was 30 months for G3 tumors (p=0.001). 34 (94%) pts were eligible for PFS. The median PFS was 23 months (95% CI 30.5-64.9) for the entire cohort. The median PFS was 30 months for G1, 27 months for G2 pts, and 7 months for G3 pts. G1/G2 vs. G3 median PFS was statistically different in the uni- and multivariate analysis [HR 8.41 (95%CI 2.2-31.0; p=0.001)]. The primary site, metastasis sites, number of previous systemic treatments, previous local treatment, and presence of liver metastasis did not correlate with PFS in the multivariate analyses. Pts with SUVmax &gt; 34.53 exhibited a statistical trend toward a longer PFS (median 52.0 vs 18.7 months; p=0.06). Conclusions: This real-life study supports that Lu-177 provides long-term PFS in pts KS 3/4 with G1/G2 GEP-NETs independent of clinical characteristics and primary site. Although G3 pts have worse survival, selected G3 GEP-NETs may experience long OS after Lu-177 treatment. SUVmax values from the pre-treatment Ga-68 PET/CT study may select ideal pts for Lu-177.

Same-day comparative protocol PET/CT-PET/MRI [68 Ga]Ga-DOTA-TOC in paragangliomas and pheochromocytomas: an approach to personalized medicine

BackgroundPET/MRI is an emerging imaging modality which enables the evaluation and quantification of biochemical processes in tissues, complemented with accurate anatomical information and low radiation exposure. In the framework of theragnosis, PET/MRI is of special interest due to its ability to delineate small lesions, adequately quantify them, and therefore to plan targeted therapies. The aim of this study was to validate the diagnostic performance of [68 Ga]Ga-DOTA-TOC PET/MRI compared to PET/CT in advanced disease paragangliomas and pheochromocytomas (PGGLs) to assess in which clinical settings, PET/MRI may have a greater diagnostic yield.MethodsWe performed a same-day protocol with consecutive acquisition of a PET/CT and a PET/MRI after a single [68 Ga]Ga-DOTA-TOC injection in 25 patients. Intermodality agreement, Krenning Score (KS), SUVmax (Standard Uptake Value), target-to-liver-ratio (TLR), clinical setting, location, and size were assessed.ResultsThe diagnostic accuracy with PET/MRI increased by 14.6% compared to PET/CT especially in bone and liver locations (mean size of new lesions was 3.73 mm). PET/MRI revealed a higher overall lesion uptake than PET/CT (TLR 4.12 vs 2.44) and implied an upward elevation of the KS in up to 60% of patients. The KS changed in 30.4% of the evaluated lesions (mean size 11.89 mm), in 18.4% of the lesions it increased from KS 2 on PET/CT to a KS ≥ 3 on PET/MRI and 24.96% of the lesions per patient with multifocal disease displayed a KS ≥ 3 on PET/MR, that were not detected or showed lower KS on PET/CT. In 12% of patients, PET/MRI modified clinical management.ConclusionsPET/MRI showed minor advantages over conventional PET/CT in the detection of new lesions but increased the intensity of SSRs expression in a significant number of them, opening the door to select which patients and clinical settings can benefit from performing PET/MRI.

Quantitative analysis of 68Ga-DOTA(0)-Tyr(3)-octreotate positron emission tomography/computed tomography imaging for the differential diagnosis of primary pheochromocytoma and paraganglioma.

Pheochromocytomas/paragangliomas (PPGLs) predominantly express somatostatin receptors (SSTRs) 2 and 3. 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTA-TATE) is an imaging radiopharmaceutical that selectively targets SSTR 2 with high affinity. The purpose of this study was to evaluate the utility of 68Ga-DOTA-TATE in the differential diagnosis of suspected PPGLs, and determine the optimal threshold for differential diagnoses. This retrospective study reviewed consecutive patients referred to the Chinese PLA General Hospital, Beijing between April 2018 and December 2020 who underwent both biochemical testing for catecholamine and 68Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) for suspected PPGLs, without prior history. Patients with pathologic confirmation were selected for analysis. The following values were obtained for a quantitative analysis of 68Ga-DOTA-TATE imaging: maximal standardized uptake value (SUVmax), the ratio between the SUVmax of the lesion and the mean SUV (SUVmean) of the liver (SUVR), and the Krenning score (KS) of the lesion. According to their location, tumors were grouped as adrenal or extra-adrenal. Receiver operating characteristic (ROC) curves of the SUVR and KS were determined, and their diagnostic performance was calculated using general and subgroup-specific optimal thresholds. Concordance between the SUVR and KS was analyzed using a McNemar test. A total of 38 patients with PPGLs and 21 with non-PPGLs tumors were included in the final analysis. When a general optimal threshold for adrenal tumors was applied in pheochromocytoma (PCC) diagnosis, the sensitivity, specificity, and accuracy of the SUVR and KS were 86.4% (19/22) and 90.9% (20/22), 92.9% (13/14) and 78.6% (11/14), and 88.9% (32/36) and 86.1% (31/36), respectively. The SUVR and KS diagnostic results showed no differences in paraganglioma (PGL) diagnosis, with a sensitivity, specificity, and accuracy of 43.8% (7/16), 100.0% (7/7), and 60.9% (14/23), respectively. Using PPGL-specific optimal thresholds improved the diagnostic accuracy for extra-adrenal tumors. The diagnostic results of the SUVR and KS showed high concordance in both general and subgroup analyses. When PPGL-specific optimal thresholds were used, 68Ga-DOTA-TATE PET/CT correctly diagnosed 1 PCC with negative biochemical test results, and 5 PCCs and 1 PGL with borderline biochemical test results. Applying PPGL-specific thresholds of 68Ga-DOTA-TATE in diagnosing adrenal and extra-adrenal tumors is recommended for the differential diagnosis of PPGLs. When biochemical tests are negative or borderline, 68Ga-DOTA-TATE PET/CT should be included in the diagnostic procedure. The visual KS method has almost the same diagnostic efficiency as the quantitative SUVR method and has potential for recommendation in 68Ga-DOTA-TATE image analysis.

Correlation of Somatostatin Receptor 2 Expression, 68Ga-DOTATATE PET Scan and Octreotide Treatment in Thymic Epithelial Tumors.

Somatostatin receptor 2 (SSTR2) has been shown to be expressed in a subset of neuroendocrine tumors and carcinomas and plays a role in imaging studies and guiding therapy. Patients with tumors expressing SSTR2 may be successfully treated with somatostatin inhibitors or radiolabeled somatostatin analogues. We studied SSTR2 expression in TET and correlated it with 68Ga-DOTATATE PET/CT or 68Ga-DOTATATE PET/MR results and treatment outcome. An institutional database of TET was searched for thymoma, thymic carcinoma, and thymic neuroendocrine tumor (TNET) with available resection specimens. Cases were subtyped (2021 WHO classification) and staged (8th AJCC/UICC staging). A section was stained with anti-SSTR2 antibody (clone UMB1). Percent tumor cells with membranous staining was recorded if present in ≥1% of tumor cells. Medical records were searched for 68Ga-DOTATATE PET scans and treatment. Statistical analysis was performed. Eighty patients (1969-2021) with a median age of 61.3 years (range, 19.1-87.3) (37 males, 46.3%) had thymic carcinoma (N=33), TNET (N=7), or thymoma (N=40). SSTR2 expression was identified in 29 (of 80, 36.3%) TET including 2/2 (100%) small cell carcinomas, 2/5 (40.0%) atypical carcinoid tumors, 16/23 (69.6%) squamous cell carcinomas, 2/2 (100%) lymphoepithelial carcinomas, 1/1 (100%) adenosquamous carcinoma, and 6/40 (15.0%) thymomas. SSTR2 expression in ≥50% of tumor cells (vs 1-49%) was associated with younger age (p=0.023) and shorter recurrence/metastasis-free survival (p=0.007). 68Ga-DOTATATE PET scans (N=9) revealed a Krenning score of 3 in patients with atypical carcinoid tumor, small cell carcinoma, and squamous cell carcinoma (N=1 each) with SSTR2 expression in 95, 100, and 5% of tumor cells, respectively. Scans with Krenning scores of ≤2 (N=5) were seen in tumors with no SSTR2 expression in 80% of cases and a single atypical carcinoid tumor with SSTR2 expression in 10% of tumor cells. One scan resulted as “increased uptake” was in a patient with no SSTR2 expression. In conclusion, 68Ga-DOTATATE PET scans correlated with SSTR2 expression in TET in most patients and appeared to be useful to identify patients with TET who may be amenable to treatment with somatostatin analogues. Larger studies including more patients with 68Ga-DOTATATE PET scans are necessary to independently and prospectively validate our findings.

Development of a new quantification method using partial volume effect correction for individual energy peaks in 111In-pentetreotide SPECT/CT

Objective(s):Somatostatin receptor scintigraphy (SRS) using 111In-pentetreotide has no established quantification method. The purpose of this study was to develop a new quantitative method to correct the partial volume effect (PVE) for individual energy peaks in 111In-pentetreotide single-photon emission computed tomography (SPECT).Methods:Phantom experiments were performed to construct a new quantitative method. In the phantom experiments, a NEMA IEC body phantom was used. Acquisition was performed using two energy peaks (171 keV and 245 keV) on the SPECT/CT system. The volume of interest was set at each hot sphere and lung insert in the SPECT images of each energy peak, and the recovery coefficient (RC) was calculated to understand the PVE. A new quantitative index, the indium uptake index (IUI), was calculated using the RC to correct the PVE. The quantitative accuracy of the IUI in the hot sphere was confirmed. Case studies were performed to clarify the quantitative accuracy. In a case study, the relationship between the IUI and the Krenning score, which is used as a visual assessment, was evaluated for each lesion.Results:The obtained RCs showed that the energy peak at 171 keV was faster in recovering the effect of PVE than that at 245 keV. The IUI in the 17-mm-diameter hot sphere was overestimated by 4.8% and 8.3% at 171 keV and 245 keV, respectively, compared to the actual IUIs. The relationship between IUI and Krenning score was rs=0.773 (p<0.005) at sum, rs=0.739 (p<0.005) at 171 keV, and rs=0.773 (p<0.005) at 245 keV.Conclusion: We have developed a new quantification method for 111In-pentetreotide SPECT/CT using RC-based PVE correction for an individual energy peak of 171 keV. The quantitative accuracy of this method was high even for accumulations of less than 20 mm, and it showed a good relationship with the Krenning score; therefore, the clinical usefulness of IUI was demonstrated.

Clinical usefulness of Somatostatin Receptor Scintigraphy in the Diagnosis of Neuroendocrine Neoplasms.

Objective(s):We investigated the detectability of somatostatin receptor scintigraphy (SRS) for neuroendocrine neoplasms (NEN).Methods:From January 2016 to October 2020, 125 SRS examinations using indium-111 pentetreotide performed for patients with NEN lesions were retrospectively evaluated. The detection rate of NEN lesions was determined according to histopathological classification by primary site and by organ.Results:At least one NEN lesion was detected in 73% (91/125) with a positive Krenning score of ≥2 in SRS. The detection of abdominal NENs (gastrointestinal tract, 38; pancreas, 62; and others, 14) was 89% (49/55) for neuroendocrine tumor (NET)-grade (G) 1, 78% (32/41) for NET-G2, 66% (2/3) for NET-G3, 31% (4/13) for neuroendocrine carcinoma (NEC), 100% (1/1) for mixed neuroendocrine–non-neuroendocrine neoplasm, and 0% (0/1) for non-classified NEN. That of thoracic NENs was 33% (2/6) for typical carcinoid tumor and 40% (2/5) for atypical carcinoid tumor. For a total of 226 organ lesions, hepatic lesions were 76% (58/76); pancreatic lesions, 61% (31/51); lymph node lesions, 77% (27/35); bone lesions, 83% (20/24); duodenal lesions, 82% (9/11); and other lesions, 41% (11/27).Conclusion:The detectability of SRS for NEN in Japan was verified at a center, and its usefulness was confirmed.

NIMG-61. CLINICAL UTILITY OF SOMATOSTATIN RECEPTOR PET IMAGING BIOMARKERS FOR CHARACTERIZATION OF MENINGIOMA AMONG INCIDENTAL CNS LESIONS

Abstract BACKGROUND Somatostatin receptor (SSTR) PET/CT is utilized with increasing frequency in the clinical treatment of neuroendocrine tumors. Incidental CNS lesions are commonly noted and presumed to be meningiomas, however 68Gallium (Ga-68)-DOTATATE radionuclide use lacks specificity for meningioma identification. Currently there is no established SSTR-based imaging criteria for classification of incidental CNS lesions. METHODS We retrospectively analyzed patients across clinical and radiological databases at Mayo Clinic who had undergone both Ga-68-DOTATATE PET/CT and brain MR imaging who had an incidental CNS lesion identified with clinical or radiographic prediction of meningioma. Known meningioma diagnoses prior to imaging were excluded. Imaging indication, semi-quantitative measures, and corresponding clinical history were analyzed to identify metrics impacting both the predictive and descriptive utility of SSTR-based imaging as compared to corresponding MRI prediction in incidental CNS lesions. RESULTS Among 59 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (71%). Cases with concordant lesion type prediction of meningioma between imaging modalities (N = 25) displayed a higher median SUV max and Krenning score on Ga-68-DOTATATE PET compared to cases with concordant prediction of other lesions (N=10) or discordant prediction of meningioma (N=24). Ga-68-DOTATATE was more likely to discordantly predict meningioma as compared to the corresponding patient MRI in cases with lower SUV max values. The addition of Qclear technology was significantly associated with diagnostic clarification in cases of imaging discordant tumor type prediction. Prior cranial radiation or use of a somatostatin mimetic did not affect quantitative radiographic measures in lesion characterization, and MRI-based tumor size was similar across groups. CONCLUSION The continued development of SSTR-based imaging biomarker signatures across incidental CNS lesion subtypes will further define the role of this imaging modality in the clinical diagnosis and management of presumed meningiomas.

The association between lesion tracer uptake on 68Ga-DOTATATE PET with morphological response to 177Lu-DOTATATE therapy in patients with progressive metastatic neuroendocrine tumors.

To determine in a group of patients with progressive metastatic neuroendocrine tumors (PM-NETs) treated with 177Lu-DOTATATE whether a correlation exists between somatostatin receptor (SSTR)-2 expression in various tumors on baseline 68Ga-DOTATATE PET and their response to therapy. A secondary aim was to determine whether an association exists between tumor product of diameter (POD) and PET-derived Krenning score. Patients treated PM-NETs who had SSTR-2 overexpression (SSTR-RADS 5) on screening 68Ga-DOTATATE PET and CT at baseline and 3 months after therapy completion were included. Marker lesions on baseline CT were reassessed on CT after therapy using adapted Southwest Oncology Group solid tumor evaluation criteria. For each lesion, bidimensional diameter on CT and SSTR expression on PET (SSTR-RADS uptake score & PET-derived Krenning score) were recorded. Logistic regression models fitted through generalized estimating equations were used to assess for an association between SSTR expression and response to therapy, or lesion's POD. Forty-one patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE were included. There were 135 marker lesions (mean 3.2 lesions/patient) with Krenning score of 4 (n = 74), 3 (n = 44) or 2 (n = 17). There was no association found between SSTR-2 expression, as determined by SSTR-RADS uptake score or PET-derived Krenning score, and POD or response to therapy. In patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE, there was similar response to therapy for all lesions with PET-generated Krenning score ≥2. No correlation was found between lesion's POD and level of tracer uptake.

1096O Lanreotide autogel/depot (LAN) in patients with advanced bronchopulmonary (BP) neuroendocrine tumors (NETs): Results from the phase III SPINET study

Well-differentiated BP-NETs (typical and atypical carcinoid; TC and AC) account for ∼25% of all NETs. However, there is a lack of prospective data with somatostatin analogs (SSAs) in BP-NETs. SPINET evaluated LAN in advanced somatostatin receptor (SSTR)-positive TC and AC BP-NETs. SPINET (EudraCT 2015-004992-62; NCT02683941) was a phase 3, randomized (2 LAN: 1 PBO, stratified by TC vs AC), double-blind (DB) study of LAN (120 mg/28 days), with optional open-label LAN treatment phase (OL-LAN). Enrollment was stopped due to slow accrual and ongoing patients in the DB phase could transition to open-label LAN. The primary endpoint was adapted: centrally assessed (RECIST 1.1) PFS during the DB/OL-LAN phases in patients randomized to LAN. Secondary endpoints included PFS and objective response rate (ORR) [central] and time to treatment failure (TTF) [local/central] in each treatment arm during DB phase, and safety. Overall, 77 patients were randomized and treated (intention-to-treat set: LAN, n=51; PBO, n=26; [OL-LAN, n=40]). Mean (SD) age was 66.2 (12.5) years and 42 (54.5%) were male; 45 (58.4%) and 32 (41.6%) patients had TC and AC respectively, all (Octreoscan) patients had a Krenning score ≥2, 6 (7.8%) had received prior cytotoxic chemotherapy, 71 (92.2%) had hepatic tumor load ≤25%, and 28 (57.1%) and 19 (38.8%) patients had liver and bone metastases, respectively. Median (95% CI) PFS in the LAN randomized group was 16.6 (12.8–21.9) months (TC 21.9 [12.8–not calculable (NC)] months; AC 14.1 [5.6–16.6] months). Key secondary endpoints are shown in the table. In the DB phase, PFS for LAN and PBO, respectively, was 21.9 (13.8–NC) vs 13.9 (13.4–NC) months in TC and 13.8 (5.6–16.6) vs 11.0 (2.8–16.9) months in AC.Table: 1096ODBLAN (n=51)PBO (n=26)HR [95% CI]aPFS (TC & AC), median (95% CI), mths16.6 (11.3–21.9)13.6 (8.3–NC)0.90 [0.46–1.88]ORR, % (95% CI)14.0 (5.8–26.7)0 (0.0–13.7)–TTF, median (95% CI), mths13.3 (5.6–14.1)9.8 (5.4–13.6)0.86 [0.50–1.50]DBOL-LANTEAEs, n (%)bLAN (n=51)PBO (n=26)All pts (n=40)Any49 (96.1)25 (96.2)26 (65.0)Related38 (74.5)14 (53.8)13 (32.5)Grade1234544 (86.3)37 (72.5)13 (25.5)1 (2.0)1 (2.0)23 (88.5)19 (73.1)8 (30.8)0025 (62.5)14 (35.0)3 (7.5)00Leading to study treatment withdrawal2 (3.9)3 (11.5)0Serious AEs10 (19.6)7 (26.9)1 (2.5)Related2 (3.9)1 (3.8)0aLAN vs PBO; bExcludes death/progression (part of PFS assessment) TEAE, treatment-emergent adverse event. Open table in a new tab aLAN vs PBO; bExcludes death/progression (part of PFS assessment) TEAE, treatment-emergent adverse event. SPINET, the largest prospective study to date with a SSA in SSTR-positive BP-NETs, suggests that LAN 120 mg could be an appropriate treatment option, especially for TC.

Somatostatin Receptor Imaging and Theranostics: Current Practice and Future Prospects.

A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals for PET imaging followed by peptide receptor radionuclide therapy (PRRT). With the transition from SSTR-based γ-scintigraphy to PET, the higher sensitivity of the latter raised questions regarding the direct application of the planar scintigraphy-based Krenning score for PRRT eligibility. Also, to date, the role of SSTR PET in response assessment and predicting outcome remains under evaluation. In this comprehensive review article, we discuss the current role of SSTR PET in all aspects of neuroendocrine neoplasms, including its relation to conventional imaging, selection of patients for PRRT, and the current understanding of SSTR PET-based response assessment. We also provide a standardized reporting template for SSTR PET with a brief discussion.

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study.

The purpose of this study was to assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Diagnostic and prognostic value of 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT in a single-center cohort of neuroendocrine tumors.

The aim was to assess the diagnostic value of 99mTc-Tektrotyd scintigraphy (TCT) and positron emission tomography/computed tomography using F-18 fluorodeoxyglucose (18F-FDG PET/CT) in the detection and follow-up of neuroendocrine tumors (NETs), and their predictive value for disease progression. In this retrospective cohort, TCT and 18F-FDG PET/CT were performed in 90 patients (37 men, 53 women, mean age 52.7 ±15.1), with NET. Correlation of Ki67 and tumor grade versus Krenning score and SUVmax was assessed, Kaplan-Meier analysis was used for progression-free survival (PFS), and Cox regression analysis was performed to identify the association between progression-related factors and PFS. Out of 90, true positive TCT was detected in 56 (62.2%) patients, true negative in 19 (21.1%), false positive in 4 (4.4%), false negative in 11 (12.2%), while 18F-FDG PET/CT was true positive in 69 (76.7%) patients, true negative in 10 (11.1%), false positive in 5 (5.5%), false negative in 6 (6.7%). Mean 18F-FDG PET/CT SUVmax was 6.8 ±6.2. Diagnostic sensitivity of TCT was 83.6%, specificity 82.6%, accuracy 83.3% vs. 18F-FDG PET/CT sensitivity was 92.0%, specificity 66.7%, accuracy 87.8%. A significant correlation between Ki67 and SUVmax was found in positive 18F-FDG PET/CT findings, unlike the correlation between Ki67 and Krenning score. Median PFS was 25 months (95% CI: 18.2-31.8), in 18F-FDG PET/CT positive patients 23 months (95% CI: 16.3-29.7) and 18F-FDG PET/CT negative 26 months (p = 0.279). Progression-free survival predictors were SUVmax and Krenning score. In our study, TCT and 18F-FDG PET/CT have high diagnostic accuracy in detection of NET. Higher Krenning score on TCT and SUVmax in positive 18F-FDG PET/CT findings are predictors of disease progression. 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT can be useful complementary tools in management of patients with NETs and in predicting patients' outcome.

Radiologic and clinicopathologic characteristics of thyroid nodules with focal 68Ga-DOTATATE PET activity.

Our aim was to determine the radiologic and clinicopathologic characteristics of thyroid nodules with focal 68Ga-DOTATATE activity. In this retrospective study of 1927 consecutive 68Ga-DOTATATE PET scans, 85 patients with incidental and nonincidental focal 68Ga-DOTATATE avid thyroid nodules were identified, of which 31 patients with 33 thyroid nodules underwent fine-needle aspiration (FNA) or surgery. These 33 nodules were reviewed for Krenning score and SUVmax of the thyroid nodule, contralateral thyroid lobe and left atrium. Cytology/histopathology included 58% (19/33) with benign findings, 18% (6/33) medullary thyroid carcinoma (MTC), 9% (3/33) atypia or follicular lesion of undetermined significance (AUS/FLUS), 9% (3/33) suspicious for follicular neoplasm and Hurthle cell adenoma (SFN/HCA) and 6% (2/33) nondiagnostic cytology. Median serum calcitonin was 1156 pg/mL (range, 460-1828) in MTC and was <5.0 pg/mL (<5.0-12.5) in patients with benign nodules. Nodules had Krenning score of 1, 2 and 3 in 46% (15/33), 27% (9/33) and 27% (9/33). The majority of MTC and AUS/FLUS nodules had a Krenning score of 3, and there was substantial intragroup variation in Krenning score among the benign nodules. The mean SUVmax for the entire cohort was 5.5 ± 2.9 (mean ± SD), and the range was 2.0-13.0. There was overlap in the nodule/contralateral thyroid SUVmax ratios between groups. The MTC and AUS/FLUS nodules tended to have a higher nodule/blood pool SUVmax ratio than the other pathologic groups. There was considerable variation in radiologic characteristics among benign thyroid nodules. The ratio of thyroid nodule SUVmax/blood pool SUVmax may be useful to differentiate pathologic groups, but larger studies are needed to investigate this further. Given the potential for malignancy in thyroid nodules with focal 68Ga-DOTATATE activity, further evaluation with serum calcitonin and FNA may be considered.Video Abstract: http://links.lww.com/NMC/A186.

Standardized uptake values and ratios on 68Ga-DOTATATE PET-computed tomography for normal organs and malignant lesions and their correlation with Krenning score in patients with metastatic neuroendocrine tumors.

The aim was to estimate the physiological standardized uptake values (SUVs) on Ga-DOTATATE PET-computed tomography (CT) in normal organs and metastatic tumor lesions (both standard and delayed), and correlating the uptake values and ratios with Krenning Scores (K-score) in patients with metastatic/advanced neuroendocrine tumors (NETs) undergoing PET-CT studies for their management work-up. A total of 32 patients of metastatic NET with 95 discrete tumor lesions were included in this analysis. These patients underwent standard whole-body PET-CT following injection of 2-3 mCi (74-111 MBq) of Ga-DOTATATE at 1-1.5 h. The normal physiological SUVmean of the liver and spleen and SUVmax and SUVmean of tumor lesions were estimated by an in-built automated procedure. These patients also underwent a delayed scan (2.5-3 h) and the same parameters were obtained for the delayed study. The tumorous lesions were further classified on the basis of K-score, and this was correlated with the mean SUVmax on both early and delayed scans. SUVmean ratios (tumor-to-liver and tumor-to-spleen) were also calculated for both time-points and correlated with individual K-scores. In lesions with K-score 4, the mean SUVmax was 32.5 in early and 30.5 in delayed scan, for lesions with K-score of 3 and 2, the mean SUVmax were 17.3, 20, and 9.3, 9.2, respectively, while in K-score 1 (n = 1), the delayed mean SUVmax was found to be more than early mean SUVmax (3.2 to 2.3). Statistical significance was evaluated by paired t test, and the changes in SUVmax was found to be statistically insignificant (P > 0.05) in all 3 K-scores. The paired t test was also performed between early and delayed tumor/liver and tumor/spleen mean SUVmean ratios, and no significant changes were observed across all K scores. The mean SUVmean values of the liver in the standard 1-h scan and delayed scans were 8.05 (range: 3-15) and 8.17 (range: 3.2-16), while for spleen, the values were 18 (range: 8.4-36.7) and 20 (range: 10-38.6), respectively. Statistically significant changes were observed in delayed spleen SUVmean values compared to the early scan (P < 0.05), while for liver SUVmean, the difference was not significant. Thus, in the present study, the SUVmax and SUVmean (range and mean values) for normal liver and spleen, and malignant NET lesions, and tumor-to-liver and tumor-to-spleen SUVmean ratios of different K-scores were generated. As could be theoretically expected in receptor-based PET-CT, there was no significant change in the delayed scan compared to the standard 1-1.5 h values.

Does 68Ga-DOTA-NOC-PET/CT impact staging and therapeutic decision making in pulmonary carcinoid tumors?

Purpose of this study was to assess the utility of Ga-DOTA-NOC-PET/computed tomography (CT) (Ga-NOC-PET) in tumor detection, pathological differentiation and baseline staging of pulmonary carcinoids as well as to study its impact on therapeutic decision making. Patients who underwent a Ga-NOC-PET for initial evaluation of bronchopulmonary carcinoid tumors from August 2014 to December 2019 were included. Detection rate of Ga-NOC-PET for the primary lesion was calculated by visual estimation of tracer uptake as per Krenning score. SUVmax of typical and atypical carcinoid tumors was measured and difference compared using nonparametric statistical tests. Proportion of patients with distant metastases was also calculated and its impact on intended treatment was assessed. Imaging, histopathology and treatment details of 119 patients were available for analysis. Majority of tumors had an endobronchial location (74.7%) and showed histopathologic features of typical carcinoid (82.3%). Ga-NOC-PET showed a detection rate/sensitivity of 92.4%. Oncocytic variant on histopathology and smaller tumor size accounted for majority of negative results. Typical carcinoids showed significantly higher SUVmax than atypical tumors (median SUVmax 38.4 vs. 15.7, P = 0.002). Metastases to distant sites outside the thorax were seen in 14 patients (11.7%), primarily in liver and bones changing the intent of treatment from surgery to systemic therapy. Ga-NOC-PET detects asymptomatic distant metastatic disease in a sizeable number of patients (11.7%) with pulmonary carcinoid and thus contribute to clinical management by precluding futile surgeries. It shows a high sensitivity for tumor detection and can help differentiate between typical and atypical carcinoid variants by virtue of their variable tracer uptake. PET/CT using Ga-labeled DOTA peptides should be an integral part of diagnostic workup of patients with lung carcinoid.

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

BackgroundPredicting the aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs.MethodsThirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n = 20), an endoscopic ultrasonography and fine-needle biopsy (n = 2) or follow-up (n = 9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to histopathology. The mean follow-up time was 31.3 months.ResultsThirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and 10 patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P = 0.021). Further, the Krenning score correlated with tumor Ki-67 (P = 0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P = 0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3, or LN + PNETs); the negative predictive value was 69%.Conclusions18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade.Trial registrationThe study has been registered at ClinicalTrials.gov; Non-functional Pancreatic NET and PET imaging, NCT02621541.