Consanguineous couple with SDHD gene mutations: Diagnosis, treatment, and implications of family genetic testing.

The newly published clinical consensus guideline on the management of PGL/PCC is helpful for decision-making for diagnostics and treatment. Still, the treatment of patients with SDHD gene mutations requires an individual approach and those patients belong to multiprofessional teams. It is often assumed that spouses are genetically unrelated. However, the genetic relationships between spouses should always be examined empathetically and impartially.

Combined Lanreotide Autogel and Temozolomide Treatment of Progressive Pancreatic and Intestinal Neuroendocrine Tumors: The Phase II SONNET Study.

BACKGROUND: In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. MATERIALS AND METHODS: SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. RESULTS: Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. CONCLUSIONS: LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.

NET-Induced Carcinoid Heart Disease Affecting Both Tricuspid and Aortic Valves Due to Patent Foramen Ovale and Right/Left Shunt: A Multi-imaging Challenge to Nuclear Medicine.

ABSTRACT: Carcinoid heart disease (Hedinger syndrome) is a long-term consequence in hormone-active neuroendocrine tumors with hepatic metastases and carcinoid syndrome. Because of serotonin, excess multiple cardiac and pulmonary symptoms evolve, which are further complicated by a patent foramen ovale due to right-left shunting. We present a 53-year-old man with an ileum-neuroendocrine tumor including gross liver metastases and long-term stable disease who subsequently developed Hedinger syndrome. Initially experiencing progressive dyspnea, he eventually experienced severe hypoxemia due to patent foramen ovale. 99mTc-MAA lung perfusion scintigraphy quantitatively identified the right-left shunting, whereas 68Ga-FAPI-46 PET/CT characterized the typical fibrous heart valve thickening due to serotonin-induced fibroblast proliferative properties.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT.

BACKGROUND: Historically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment. METHODS: The institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test. RESULTS: Patients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54-5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03-2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS. CONCLUSIONS: Baseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Hedinger Syndrome-Lessons Learnt: A Single-Center Experience.

BACKGROUND: Hedinger syndrome (HS) or carcinoid heart disease (CD) is a rare and challenging manifestation of malignant neuroendocrine tumours (NETs) involving the heart. We aimed to report our experience with surgical strategies and midterm results in HS patients. METHODS: Eleven patients (58 ± 11 (range 41 to 79 years); 5 females) with HS who underwent cardiac surgery in our department between 07/2005 and 05/2023 were analysed. RESULTS: All patients showed a New York Heart Association (NYHA) class III-IV and in all the tricuspid valve (TV) was involved. Four patients received a TV replacement, and three TV reconstruction. Recently, to preserve the geometry and function of the compromised right ventricle (RV), we have applied the TV "bio-prosthesis in native-valve" implantation technique with the preservation of the valve apparatus (tricuspid valve implantation: TVI) in four cases. Concomitant procedures included pulmonary valve replacement in four, pulmonary implantation in one, and aortic valve replacement in three cases. To treat RV failure, we adapted a combined TandemHeart®-CytoSorb® haemoperfusion strategy in Patient #10 and venoarterial extracorporeal membrane oxygenation (V-A ECMO) support avoidance, after experiencing an ECMO-induced carcinoid-storm-related death in Patient #8. Mortality at 30 days was 18% (2/11). The median follow up was 2 ± 2.1 years (range 1 month to 6 years) with an overall mortality during the follow-up period of 72.7% (8/11). CONCLUSIONS: HS surgery, despite being a high-risk procedure, can efficiently prolong survival, and represents a safe and feasible procedure. However, patient selection seems to be crucial. Further follow up and larger cohorts are needed.

Bone Metastases in Patients with Pancreatic NETs: Prevalence and Prognosis.

The clinical relevance of bone metastases (BM) in advanced pancreatic neuroendocrine tumors (PanNETs) is poorly described. We analyzed 314 consecutive PanNET patients treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2021 in terms of the occurrence and clinical and prognostic impact of BM using hybrid imaging with 68Ga-DOTATOC PET/CT. According to UICC staging, 171/314 (54.5%) patients had stage IV PanNETs. BM was diagnosed in 62/171 (36.3%) patients. Initially, 35% of BMs were visible by pathological tracer uptake only. Skeletal-related events (SREs) were detected in 11 of the 62 patients (17.7%). Patients with antiresorptive therapy had a significantly lower rate of SRE (2/36, 5.6%) than individuals without bone-specific therapy (9/26, 34.6%) (odds ratio 9.0, p=0.0054, Fisher's exact test). The median overall survival (OS) was 82 months (53.6-110.4, 95% CI) in the stage IV PanNET cohort. The median OS was significantly lower for patients with BM (63 months; 49.9-76.0, 95% CI) than for patients with distant metastases other than BM (116 months; 87.6-144.3, 95% CI) (p=0.016, log-rank test). BM occurs in more than one-third of advanced PanNETs and is associated with an unfavorable prognosis. One in five patients experiences a persistent quality-of-life-lowering SRE. Antiresorptive therapy is associated with a more favorable risk of SREs and should be offered to all patients with BM in PanNETs.

Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study.

OBJECTIVE: Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. DESIGN: Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022. METHODS: Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed. RESULTS: In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P < 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. CONCLUSIONS: In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.

Identification of a new prognostic score for patients with high-grade metastatic GEP-NEN treated with palliative chemotherapy.

PURPOSE: High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies. METHODS: This retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed. RESULTS: Median OS of the study cohort was 9.0 months (95% CI 7.0-11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4-6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes. CONCLUSION: Outcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design.

[Oncological theranostics in nuclear medicine]. / Onkologische Theranostik in der Nuklearmedizin.

The theranostic principle describes the diagnostic and therapeutic use of radioactive nuclides linked to biochemically active ligands. The oldest and most prominent field of application of theranostics in oncology is differentiated thyroid cancer treated by radioiodine therapy, which allows imaging of the iodine uptake and thus tumor manifestations by gamma (γ) radiation of radioiodine. Other areas of application include neuroendocrine tumors, castration-resistant prostate cancer and, in the context of individual therapeutic approaches, fibroblastic tumors. Imaging with beta-plus (ß+) emitters is mainly performed using so-called hybrid imaging: positron emission tomography (PET) in combination with computed tomography or magnetic resonance imaging (PET/CT or PET/MRI). Beta-minus (ß-) emitters are predominantly used in therapy, but the use of alpha (α) emitters is also increasing, thus, enabling targeted cancer treatment with mostly low-grade side effects.

CT-derived body composition analysis could possibly replace DXA and BIA to monitor NET-patients.

Patients with neuroendocrine tumors of gastro-entero-pancreatic origin (GEP-NET) experience changes in fat and muscle composition. Dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) are currently used to analyze body composition. Changes thereof could indicate cancer progression or response to treatment. This study examines the correlation between CT-based (computed tomography) body composition analysis (BCA) and DXA or BIA measurement. 74 GEP-NET-patients received whole-body [68Ga]-DOTATOC-PET/CT, BIA, and DXA-scans. BCA was performed based on the non-contrast-enhanced, 5 mm, whole-body-CT images. BCA from CT shows a strong correlation between body fat ratio with DXA (r = 0.95, ρC = 0.83) and BIA (r = 0.92, ρC = 0.76) and between skeletal muscle ratio with BIA: r = 0.81, ρC = 0.49. The deep learning-network achieves highly accurate results (mean Sørensen-Dice-score 0.93). Using BCA on routine Positron emission tomography/CT-scans to monitor patients' body composition in the diagnostic workflow can reduce additional exams whilst substantially amplifying measurement in slower progressing cancers such as GEP-NET.

Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice.

BACKGROUND: Neuroendocrine neoplasia grade 3 (NEN G3) represents a rare and heterogeneous cancer type with a poor prognosis. The aim of our study was to analyze real-world data from the German NET Registry with a focus on therapeutic and prognostic aspects. METHODS: NEN G3 patients were identified within the German NET Registry. Demographic data and data on treatments and outcomes were retrieved. Univariate analyses were performed using the Kaplan-Meier-method. Multivariate analysis was performed using a Cox proportional hazard model. RESULTS: Of 445 included patients, 318 (71.5%) were diagnosed at stage IV. Well-differentiated morphology (NET G3) was described in 31.7%, 60% of cases were classified as neuroendocrine carcinoma (NEC), and the median Ki67 value was 50%. First-line treatment comprised chemotherapy in 43.8%, with differences in the choice of regimen with regard to NET or NEC, and surgery in 41.6% of patients. Median overall survival for the entire cohort was 31 months. Stage, performance status and Ki67 were significant prognostic factors in multivariate analysis. CONCLUSIONS: The survival data of our national registry compare favorably to population-based data, probably mainly because of a relatively low median Ki67 of 50%. Nevertheless, the best first- and second-line approaches for specific subgroups remain unclear, and an international effort to fill these gaps is needed.

Streptozocin/5-fluorouracil chemotherapy of pancreatic neuroendocrine tumours in the era of targeted therapy.

PURPOSE: The role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines. METHODS: Data from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: STZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5-15.5) and 38 months (95% CI, 20.4-55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9-143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3-24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression). CONCLUSIONS: In patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.

90Y Radioembolization in the Treatment of Neuroendocrine Neoplasms: Results of an International Multicenter Retrospective Study.

In neuroendocrine neoplasms (NENs), the presence of distant metastases has a severe impact on survival leading to a relevant decrease in the 5-y survival rate. Here, 90Y radioembolization (90Y RE) might be an important treatment option; however, data to support clinical benefits for 90Y RE are scarce. Therefore, the purpose of this study was to analyze the use of 90Y RE in NEN patients with hepatic metastases in an international, multicenter retrospective analysis and assess the potential role of 90Y RE in a multimodal treatment concept. Methods: In total, 297 angiographic evaluations in NEN patients before 90Y RE were analyzed. Baseline characteristics and parameters derived from imaging evaluation and 90Y RE were analyzed. Tumor response was assessed using RECIST 1.1, and survival data were collected. Mean overall survival (OS) between different groups was compared using Kaplan-Meier curves and the log rank test. A P value of less than 0.05 indicated statistical significance. Results: After 90Y RE, the disease control rate according to RECIST 1.1 was 83.5% after 3 mo and 50.9% after 12 mo. OS in the entire population was 38.9 ± 33.0 mo. High tumor grade (P < 0.006) and high tumor burden (P = 0.001) were both associated with a significant decrease in OS. The presence of extrahepatic metastases (P = 0.335) and the type of metastatic vascularization pattern (P = 0.460) had no influence on OS. Patients who received 90Y RE as second-line therapy had a slightly longer but not statistically significant OS than patients who had 90Y RE in a salvage setting (44.8 vs. 30.6 mo, P = 0.078). Hepatic and global progression-free survival after 90Y RE was significantly decreased in heavily pretreated patients, compared with patients with second-line therapy (P = 0.011 and P = 0.010, respectively). Conclusion:90Y RE could be an important alternative to peptide receptor radionuclide therapy as second-line treatment in patients with progressive liver-dominant disease pretreated with somatostatin analogs.

Sunitinib-Induced Hypothyroidism and Survival in Pancreatic Neuroendocrine Tumors.

Sunitinib has been approved for the treatment of pancreatic neuroendocrine tumors, renal-cell carcinoma, and gastrointestinal stromal tumors. The elevation of thyroid-stimulating hormone serum levels is a common side effect. Studies suggest a correlation between sunitinib-induced hypothyroidism and treatment outcome in patients with renal-cell carcinoma and gastrointestinal stromal tumors. This study assessed whether sunitinib-induced hypothyroidism is a predictive marker of the objective response rate, progression-free survival, and overall survival in pancreatic neuroendocrine tumor patients. Twenty-nine patients treated with sunitinib for advanced pancreatic neuroendocrine tumors were included. The incidence of sunitinib-induced hypothyroidism was 33%. The median progression-free survival of patients who developed hypothyroidism was 16 months (95% confidence interval: 6.2-25.8 months) as compared with six months among euthyroid patients (95% confidence interval: 0.1-12.2 months) (p=0.02). The median overall survival was 77 months (95% confidence interval: 31.4-122.6 months) in hypothyroid patients but 12 months (95% confidence interval: 5.9-18.1 months) in subjects with euthyroidism (p=0.001). The median overall survival from the time of initial diagnosis ranged from 247 months in patients with hypothyroidism to 65 months in euthyroid subjects (p=0.015). Elevated thyroid-stimulating hormone levels are a prognostic biomarker of improved outcomes of sunitinib therapy in pancreatic neuroendocrine tumor patients.

Multicenter Analysis of Presacral Neuroendocrine Neoplasms-Clinicopathological Characterization and Treatment Outcomes of a Rare Disease.

Background and Aims: Neuroendocrine neoplasms (NENs) of the presacral space are an extremely rare disease entity with largely unknown outcome and no established standard of care treatment. Therefore, we wanted to analyze clinical presentation, histopathological findings, treatment outcomes, and prognosis in a multicentric patient cohort. Methods: We searched local databases of six German NEN centers for patients with presacral NEN. Retrospective descriptive analyses of age, sex, stage at diagnosis, symptoms, grade, immunohistochemical investigations, biomarkers, treatment, and treatment outcome were performed. Kaplan-Meier analysis was used to determine median overall survival. Results: We identified 17 patients (11 female, 6 male) with a median age of 50 years (range, 35-66) at diagnosis. Twelve cases presented initially with distant metastases including bone metastases in nine cases. On pathological review the majority of patients had well-differentiated G2 tumors. Immunohistochemical profile resembled rectal NENs. All but one patient had non-functioning tumors. Somatostatin receptor imaging was positive in 14 of 15 investigated cases. Eight patients were treated surgically including palliative resections; 14 patients received somatostatin analogs with limited efficacy. With 14 PRRTs completed, 79% showed clinical benefit, whereas only one patient with neuroendocrine carcinoma (NEC) responded to chemotherapy. Treatment with everolimus in three patients was not successful, whereas cabozantinib resulted in a disease stabilization in a heavily pretreated patient. During a median observation period of 44.5 months, 6 patients died. Median overall survival was not reached. Conclusion: Presacral NEN are histopathologically similar to rectal NENs. Presacral NEN should be considered as possible primary in NEN of unknown primary. The majority of tumors is non-functioning and somatostatin receptor positive. PRRT demonstrated promising activity; tyrosine kinase inhibitors warrant further investigations. Further molecular characterization and prospective evaluation of this rare tumor entity are needed.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria.

BACKGROUND: The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors. OBJECTIVE: To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice. METHODS: Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449). RESULTS: Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had previous surgery, 18.7% had received octreotide. The primary endpoint, defined by a <50% chromogranin A increase at month 12 compared with the lowest value between baseline and month 3 was achieved by 89.5% patients. Stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 was observed in 76.9 and 75.0% patients at months 12 and 24 of lanreotide treatment, respectively. Mean change of chromogranin A levels from baseline to month 24 was -0.12 × upper limit of normal (95% CI, -0.22; -0.45). In a post hoc analysis, 38.5% of the subgroup of patients with carcinoid syndrome had daily diarrhea at baseline vs. 21.4% at month 24. At baseline, 27.8% of patients received lanreotide 120 mg every 4 weeks vs. 56.7% at month 24. Quality of life data were heterogeneous. No new safety issues arose and/or required further investigation. CONCLUSIONS: Our study reflects routine lanreotide autogel use in patients with advanced/metastatic neuroendocrine tumors. This analysis shows effectiveness with stabilization of disease-related symptoms and good tolerability of lanreotide autogel in clinical practice.

Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study.

BACKGROUND AND PURPOSE: Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction. PATIENTS AND METHODS: Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]-naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2- ABC. RESULTS: During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE. CONCLUSION: The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other.

Correlation between contrast enhancement, standardized uptake value (SUV), and diffusion restriction (ADC) with tumor grading in patients with therapy-naive neuroendocrine neoplasms using hybrid 68Ga-DOTATOC PET/MRI.

OBJECTIVES: To investigate a correlation between 68Ga-DOTATOC PET/MR imaging parameters such as arterial and venous contrast enhancement, diffusion restriction, and maximum standardized uptake value (SUVmax) with histopathological tumor grading in patients with neuroendocrine neoplasms (NEN). MATERIAL AND METHODS: A total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwent 68Ga-DOTATOC PET/MRI. Images were evaluated regarding NEN lesion number and location, predominant tumor signal intensity on precontrast T1w and T2w images and on postcontrast arterial and portal venous phase T1w images, apparent diffusion coefficient (ADC) and SUVmax. Histopathological tumor grading was assessed and related to PET/MRI features using Pearson's correlation coefficient and Fisher's exact t-test. A binary logistic regression analysis was performed to evaluate a potential relation with an aggressive tumor biology and odds ratios (OR) were calculated. RESULTS: There was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001). CONCLUSION: The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness.